@article {pmid39621968, year = {2024}, author = {Pusztai, L and Hoag, JR and Albain, KS and Barlow, WE and Stemmer, SM and Meisner, A and Hortobagyi, GN and Shak, S and Rae, JM and Baehner, R and Sharma, P and Kalinsky, KM}, title = {Development and Validation of the RSClinN+ Tool to Predict Prognosis and Chemotherapy Benefit for Hormone Receptor-Positive, Node-Positive Breast Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401507}, doi = {10.1200/JCO-24-01507}, pmid = {39621968}, issn = {1527-7755}, abstract = {PURPOSE: Clinicopathological factors and the 21-gene Oncotype DX Breast Recurrence Score (RS) test both influence prognosis. Our goal was to develop a new tool, RSClinN+, to individualize recurrence risk and chemotherapy benefit predictions by menopausal status for patients with HR+/human epidermal growth factor receptor 2-negative, lymph node-positive breast cancer by integrating the RS result with clinicopathological factors (grade, tumor size, age).
METHODS: We used patient-level data from 5,283 patients treated with chemoendocrine therapy (CET) versus endocrine therapy alone (ET) in the S1007 (N = 4,916) and S8814 (N = 367) trials to develop the tool. Cox proportional hazards regression models stratified by trial were used to estimate 5-year invasive disease-free survival for pre- and postmenopausal woman, respectively. The integrated RSClinN+ model was compared with RS alone and clinicopathological models using likelihood ratio tests. Absolute CET benefit was estimated as the difference between ET and CET risk estimates. Validation of RSClinN+ was performed in 592 patients with node-positive disease in the Clalit Health Services registry.
RESULTS: RSClinN+ provides better prognostic information than RS model alone (premenopausal P = .034; postmenopausal P < .001) or clinicopathological model alone (premenopausal P = .002; postmenopausal, P < .001). In postmenopausal women, RS showed interaction with CET benefit (P = .016), with RSClinN+ absolute CET benefit ranging from <0.1% to 21.5% over RS ranges 0-50. In premenopausal patients with RS ≤25, there was no significant interaction between RS and CET benefit. In external validation, RSClinN+ risk estimates were prognostic (hazard ratio, 1.75 [95% CI, 1.38 to 2.20]) and concordant with observed risk (Lin's concordance, 0.92).
CONCLUSION: RSClinN+ provides improved estimates of prognosis and absolute CET benefit for individual patients compared with RS or with clinical data alone and could be used in patient counseling.}, }
@article {pmid39621930, year = {2024}, author = {Zanders, SE and Smith, GR}, title = {Killer meiotic drive executed by two alternative conformations of a single protein.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {50}, pages = {e2420620121}, doi = {10.1073/pnas.2420620121}, pmid = {39621930}, issn = {1091-6490}, support = {R35 GM151982/GM/NIGMS NIH HHS/United States ; GM118120//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, }
@article {pmid39621322, year = {2024}, author = {Terry, KL and Harris, HR and Missmer, SA}, title = {Endometriosis and Ovarian Cancer.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.21905}, pmid = {39621322}, issn = {1538-3598}, }
@article {pmid39619675, year = {2024}, author = {Little, A and Deek, RA and Zhang, A and Zhao, N and Ling, W and Wu, MC}, title = {Enhanced visualization of microbiome data in repeated measures designs.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1480972}, pmid = {39619675}, issn = {1664-8021}, abstract = {INTRODUCTION: Repeated measures microbiome studies, including longitudinal and clustered designs, offer valuable insights into the dynamics of microbial communities and their associations with various health outcomes. However, visualizing such multivariate data poses significant challenges, particularly in distinguishing meaningful biological patterns from noise introduced by covariates and the complexities of repeated measures.
METHODS: In this study, we propose a framework to enhance the visualization of repeated measures microbiome data using Principal Coordinates Analysis (PCoA) adjusted for covariates through linear mixed models (LMM). Our method adjusts for confounding variables and accounts for the repeated measures structure of the data, enabling clearer identification of microbial community variations across time points or clusters.
RESULTS: We demonstrate the utility of our approach through simulated scenarios and real datasets, showing that it effectively mitigates the influence of nuisance covariates and highlights key axes of microbiome variation.
DISCUSSION: This refined visualization technique provides a robust tool for researchers to explore and understand microbial community dynamics in repeated measures microbiome studies.}, }
@article {pmid39619274, year = {2024}, author = {Tsao, AS and Hsieh, MH and Koczywas, M and Tu, J and Riess, J and Tanvetyanon, T and Ma, BT and Zhao, YQ and Redman, MW and Edelman, MJ and Gandara, DR and Gray, JE and Kelly, KL}, title = {S1701, A Randomized Phase 2 Trial of Carboplatin-Paclitaxel With and Without Ramucirumab in Patients With Locally Advanced, Recurrent, or Metastatic Thymic Carcinoma.}, journal = {JTO clinical and research reports}, volume = {5}, number = {12}, pages = {100738}, pmid = {39619274}, issn = {2666-3643}, abstract = {INTRODUCTION: Thymic carcinoma is a rare and aggressive malignancy with few treatment options. Preclinical studies suggested that targeting the angiogenic pathway may be beneficial in this disease.
METHODS: This randomized phase 2 trial enrolled patients with unresectable, locally advanced, recurrent, or metastatic thymic carcinoma. Patients were randomized to receive carboplatin-paclitaxel with or without ramucirumab. The primary end point was progression-free survival (PFS) and secondary end points included response by Response Evaluation Criteria in Solid Tumors, disease control, toxicity, and overall survival. The primary analysis was done using a one-sided 10%-level log-rank test. Target sample size was 66 patients.
RESULTS: Between 2018 and 2022, 21 patients enrolled to ramucirumab plus carboplatin-paclitaxel (RCP, n = 8) and to the control arm (carboplatin-paclitaxel [CP], n = 13) with one patient on CP not meeting eligibility criteria. Owing to slow accrual, the study was terminated early by the Data and Safety Monitoring Board. Of the 20 eligible patients, eight on RCP and nine on CP received protocol treatment. PFS was not statistically different (hazard ratio = 0.51, 80% confidence interval [CI]: 0.24-1.09, p = 0.13). There were no grade 4 or higher treatment-related adverse events with RCP, although 50% experienced grade 3 adverse events, in which one patient had a grade 3 thromboembolic event. Among nine assessable patients for toxicity on CP, one patient (11%) encountered grade 4 neutropenia and one patient (11%) reported grade 3 thromboembolic events. Response rates favored the RCP arm, with an 88% (seven of eight, 80% CI: 59%-99%) response rate compared with 40% (four of 10, 80% CI: 19%-65%) on CP arm (p = 0.04). Disease control rate was higher in the RCP arm (100% versus 70%, p = 0.09). At the time of analysis, as only one death has been reported, overall survival remains immature.
CONCLUSIONS: Accrual to this population is challenging, and the study was closed early because of feasibility. Although PFS was not statistically better with RCP, the hazard ratio was 0.51 and the lack of significance was likely due to small sample sizes. Notably, addition of ramucirumab to CP led to higher response rates than CP alone. Future research should consider exploring larger multicenter trials and other combinations to improve outcomes. Challenges in enrollment emphasize the need for innovative strategies and larger collaborations in rare malignancies such as thymic carcinoma.}, }
@article {pmid39617269, year = {2024}, author = {Franić, D and Pravica, M and Zubčić, K and Miles, S and Bedalov, A and Boban, M}, title = {Quiescent cells maintain active degradation-mediated protein quality control requiring proteasome, autophagy and nucleus-vacuole junctions.}, journal = {The Journal of biological chemistry}, volume = {}, number = {}, pages = {108045}, doi = {10.1016/j.jbc.2024.108045}, pmid = {39617269}, issn = {1083-351X}, abstract = {Many cells spend a major part of their life in quiescence, a reversible state characterized by a distinct cellular organization and metabolism. In glucose-depleted quiescent yeast cells, there is a metabolic shift from glycolysis to mitochondrial respiration, and a large fraction of proteasomes are reorganized into cytoplasmic granules containing disassembled particles. Given these changes, the operation of protein quality control (PQC) in quiescent cells, in particular the reliance on degradation-mediated PQC and the specific pathways involved, remains unclear. By examining model misfolded proteins expressed in glucose-depleted quiescent yeast cells, we found that misfolded proteins are targeted for selective degradation requiring functional 26S proteasomes. This indicates that a significant pool of proteasomes remains active in degrading quality control substrates. Misfolded proteins were degraded in a manner dependent on the E3 ubiquitin ligases Ubr1 and San1, with Ubr1 playing a dominant role. In contrast to exponentially growing cells, the efficient clearance of certain misfolded proteins additionally required intact nucleus-vacuole junctions (NVJ) and Cue5-independent selective autophagy. Our findings suggest that proteasome activity, autophagy, and NVJ-dependent degradation operate in parallel. Together the data demonstrate that quiescent cells maintain active PQC that relies primarily on selective protein degradation. The necessity of multiple degradation pathways for the removal of misfolded proteins during quiescence underscores the importance of misfolded protein clearance in this cellular state.}, }
@article {pmid39617028, year = {2024}, author = {Bender Ignacio, RA and Shapiro, AE and Montaño, MA and Titanji, BK}, title = {An urgent call to address the intersection of mpox and HIV in Africa.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(24)02542-X}, pmid = {39617028}, issn = {1474-547X}, }
@article {pmid39616600, year = {2024}, author = {Hatlen, TJ and Bender Ignacio, R and Daar, ES}, title = {Advances in Treatment and Prevention of HIV.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.24027}, pmid = {39616600}, issn = {1538-3598}, }
@article {pmid39616467, year = {2024}, author = {Bryce, AH and Agarwal, N and Beltran, H and Hussain, MH and Sartor, O and Shore, N and Antonarakis, ES and Armstrong, AJ and Calais, J and Carducci, MA and Dorff, TB and Efstathiou, JA and Gleave, M and Gomella, LG and Higano, C and Hope, TA and Iagaru, A and Morgans, AK and Morris, DS and Morris, MJ and Petrylak, DP and Reiter, RE and Rettig, MB and Ryan, CJ and Sellinger, SB and Spratt, DE and Srinivas, S and Tagawa, ST and Taplin, ME and Yu, EY and Zhang, T and McKay, RR and Koo, PJ and Crawford, ED}, title = {Implementing evidence-based strategies for men with biochemically recurrent and advanced prostate cancer: Consensus recommendations from the US Prostate Cancer Conference 2024.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35612}, pmid = {39616467}, issn = {1097-0142}, abstract = {Current US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high-level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day-to-day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US-focused expert clinical decision-making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration-resistant prostate cancer; poly [ADP-ribose] polymerase inhibitors; prostate-specific membrane antigen radioligand therapy; and metastatic, castration-resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.}, }
@article {pmid39574839, year = {2024}, author = {Chang, YH and Head, ST and Harrison, T and Yu, Y and Huff, CD and Pasaniuc, B and Lindström, S and Bhattacharya, A}, title = {Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39574839}, support = {R01 CA194393/CA/NCI NIH HHS/United States ; R21 CA293419/CA/NCI NIH HHS/United States ; U01 CA194393/CA/NCI NIH HHS/United States ; }, abstract = {Integrating genome-wide association study (GWAS) and transcriptomic datasets can help identify potential mediators for germline genetic risk of cancer. However, traditional methods have been largely unsuccessful because of an overreliance on total gene expression. These approaches overlook alternative splicing, which can produce multiple isoforms from the same gene, each with potentially different effects on cancer risk. Here, we integrate genetic and multi-tissue isoform-level gene expression data from the Genotype Tissue-Expression Project (GTEx, N = 108-574) with publicly available European-ancestry GWAS summary statistics (all N > 20,000 cases) to identify both isoform- and gene-level risk associations with six cancers (breast, endometrial, colorectal, lung, ovarian, prostate) and six related cancer subtype classifications (N = 12 total). Compared to traditional methods leveraging total gene expression, directly modeling isoform expression through transcriptome-wide association studies (isoTWAS) substantially increases discovery of transcriptomic mechanisms underlying genetic associations. Using the same RNA-seq datasets, isoTWAS identified 164% more significant unique gene associations compared to TWAS (6,163 and 2,336, respectively), with isoTWAS-prioritized genes enriched 4-fold for evolutionarily-constrained genes (P = 6.1 × 10[-13]). isoTWAS tags transcriptomic associations at 52% more independent GWAS loci compared to TWAS across the six cancers. Additionally, isoform expression mediates an estimated 63% greater proportion of cancer risk SNP heritability compared to gene expression when evaluating cis-genetic influence on isoform expression. We highlight several notable isoTWAS associations that demonstrate GWAS colocalization at the isoform level but not at the gene level, including, CLPTM1L (lung cancer), LAMC1 (colorectal), and BABAM1 (breast). These results underscore the critical importance of modeling isoform-level expression to maximize discovery of genetic risk mechanisms for cancers.}, }
@article {pmid39574748, year = {2024}, author = {Gupta, S and Martinov, T and Thelen, A and Sunahara, M and Mureli, S and Vazquez, A and Gerdts, J and Dandekar, R and Cortese, I and Fouassier, C and Schanzer, E and Urnov, FD and Marson, A and Shy, BR and Greenberg, PD and Wilson, MR}, title = {Antigen-Specific T Cell Receptor Discovery for Treating Progressive Multifocal Leukoencephalopathy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574748}, issn = {2692-8205}, support = {K08 AI174061/AI/NIAID NIH HHS/United States ; K08 CA273529/CA/NCI NIH HHS/United States ; L30 TR002983/TR/NCATS NIH HHS/United States ; T32 GM007232/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease of the central nervous system caused by JC virus (JCV). Survival is dependent on early diagnosis and ability to re-establish anti-viral T cell immunity. Adoptive transfer of polyomavirus-specific T cells has shown promise; however, there are no readily available HLA-matched anti-viral T cells to facilitate rapid treatment.
OBJECTIVE: Identify epitopes of the JCV major capsid protein VP1 that elicit an immune response in the context of human leukocyte antigen allele A*02:01 (HLA-A2) and isolate cognate T cell receptors (TCRs) from healthy donors. Evaluate individual VP1-specific TCRs for their capacity to be expressed in T cells and clear JCV in vitro.
METHODS: PBMCs from HLA-A2+ healthy donors were stimulated with peptide libraries tiled across the JCV VP1 protein. Multiple rounds of stimulation were performed to identify the antigens that induced the largest expansion and CD8[+] T cell response (measured as INFγ, TNFα, CD137, and CD69 expression). High-affinity, antigen-specific CD8[+] T cells were isolated based on intensity of tetramer binding for downstream single-cell TCR sequencing. Candidate TCRs were selected based on tetramer binding affinity and activation assays. Promising TCRs were introduced into the T cell genome via viral transduction for in vitro validation including peptide-pulsed K562 cells and astrocyte cells, and JCV-infected astrocytes.
RESULTS: Four conserved JCV VP1 epitopes (amino acids 100-108, 251-259, 253-262, and 274-283) presented by HLA-A2 were identified. VP1(100-108) consistently elicited the highest level of IFN-γ production from multiple donors and this peptide is in a highly conserved region of VP1. We next identified fourteen high avidity TCRs specific for VP1(100-108). When virally transduced into primary human T cells, seven of these TCRs demonstrated specific binding to VP1(100-108):HLA-A2 tetramers, and four showed increased IFN-γ response when incubated with peptide. Primary CD8[+] T cells expressing two of these TCRs cleared both HLA-A2 positive K562 cells and HLA-A2 positive SVG astrocyte cell line presenting exogenously added VP1 peptide at a range of E:T ratios. In addition, both TCR-transduced T cell populations effectively lysed JCV-infected astrocytes.
CONCLUSIONS: We identified JCV VP1 epitopes that are immunogenic in the context of HLA-A2 MHC-I, including epitopes that have not been previously described. The VP1(100-108) epitope was used to isolate HLA-A2-restricted TCRs. When cloned into primary human CD8[+] T cells, these TCRs recognized VP1 (100-108)-presenting targets, and the transduced T cells conferred cytotoxic activity and eliminated K562 and astrocyte cells displaying the VP1(100-108) peptide and not sham peptide, as well as JCV-infected astrocytes. Taken together, these data suggest that JCV VP1-specific TCRs could be appealing therapeutics for HLA-A2+ individuals with PML in whom intrinsic T cell immunity cannot be rescued.}, }
@article {pmid39616411, year = {2024}, author = {Newton, H and Colla, CH and Busch, SH and Tomaino, M and Hardy, B and Brunette, MF and Agravat, D and Meara, E}, title = {Medicare Accountable Care Organization Treatment of Serious Mental Illness: Associations Between Behavioral Health Integration Activities and Outcomes.}, journal = {Medical care}, volume = {}, number = {}, pages = {}, pmid = {39616411}, issn = {1537-1948}, abstract = {OBJECTIVE: Characterize the association between Medicare Accountable Care Organizations' (ACOs) behavioral health integration capability and quality and utilization among adults with serious mental illness (SMI).
BACKGROUND: Controlled research supports the efficacy of integrating physical and mental health care for adults with SMI, yet little is known about the organizations integrating care and associations between integration capability and quality.
METHODS: We surveyed Medicare ACOs (2017-2018 National Survey of ACOs, response rate 69%) and linked responses to 2016-2017 fee-for-service Medicare claims for beneficiaries with SMI. We examined the cross-sectional association between ACO-reported integration capability (tertiles of a 14-item index) and 7 patient-level quality and utilization outcomes. We fit generalized linear models for each outcome as a function of ACO integration capability, adjusting for ACO and beneficiary characteristics.
RESULTS: Study sample included 274,928 beneficiary years (199,910 unique beneficiaries) attributed to 265 Medicare ACOs. ACOs with high behavioral health integration capability (top-tertile) served more dual-eligible beneficiaries (67.8%) than bottom-tertile (63.7%) and middle-tertile ACOs (63.3%). Most beneficiaries received follow-up 30 days after mental health hospitalization and chronic disease monitoring-exceeding national quality benchmarks-but beneficiaries receiving care from top-tertile (vs bottom-tertile) ACOs were modestly less likely to receive follow-up [-2.17 percentage points (pp), P < 0.05], diabetes monitoring (-2.19 pp, P < 0.05), and cardiovascular disease monitoring (-6.07 pp, P < 0.05). Integration capability was not correlated with utilization.
CONCLUSIONS: ACOs serving adults with substantial physical and mental health needs were more likely to report comprehensive integration capability but were not yet meeting the primary care needs of many adults with SMI.}, }
@article {pmid39616199, year = {2024}, author = {Vadathya, AK and Garza, T and Alam, U and Ho, A and Musaad, SMA and Beltran, A and Moreno, JP and Baranowski, T and Haidar, N and Hughes, SO and Mendoza, JA and Veeraraghavan, A and Young, J and Sano, A and O'Connor, TM}, title = {Validation studies of the FLASH-TV system to passively measure children's TV viewing.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {29805}, pmid = {39616199}, issn = {2045-2322}, support = {R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, mesh = {Humans ; *Television ; Female ; Male ; Child ; Screen Time ; Machine Learning ; Child, Preschool ; }, abstract = {TV viewing is associated with health risks, but existing measures of TV viewing are imprecise due to relying on self-report. We developed the Family Level Assessment of Screen use in the Home (FLASH)-TV, a machine learning pipeline with state-of-the-art computer vision methods to measure children's TV viewing. In three studies, lab pilot (n = 10), lab validation (n = 30), and home validation (n = 20), we tested the validity of FLASH-TV 3.0 in task-based protocols which included video observations of children for 60 min. To establish a gold-standard to compare FLASH-TV output, the videos were labeled by trained staff at 5-second epochs for whenever the child watched TV. For the combined sample with valid data (n = 59), FLASH-TV 3.0 provided a mean 85% (SD 8%) accuracy, 80% (SD 17%) sensitivity, 86% (SD 8%) specificity, and 0.71 (SD 0.15) kappa, compared to gold-standard. The mean intra-class correlation (ICC) of child's TV viewing durations of FLASH-TV 3.0 to gold-standard was 0.86. Overall, FLASH-TV 3.0 correlated well with the gold standard across a diverse sample of children, but with higher variability among Black children than others. FLASH-TV provides a tool to estimate children's TV viewing and increase the precision of research on TV viewing's impact on children's health.}, }
@article {pmid39612623, year = {2024}, author = {Lee, MJ and Litchford, ML and Vendrame, E and Vergara, R and Ranganath, T and Fish, CS and Chebet, D and Langat, A and Mburu, C and Neary, J and Benki, S and Wamalwa, D and John-Stewart, G and Lehman, DA and Blish, CA}, title = {Distinct immune profiles in children living with HIV based on timing and duration of suppressive antiretroviral treatment.}, journal = {Virology}, volume = {602}, number = {}, pages = {110318}, doi = {10.1016/j.virol.2024.110318}, pmid = {39612623}, issn = {1096-0341}, abstract = {Timely initiation of antiretroviral therapy (ART) remains a major challenge in the effort to treat children living with HIV ("CLH") and little is known regarding the dynamics of immune normalization following ART in CLH with varying times to and durations of ART. Here, we leveraged two cohorts of virally-suppressed CLH from Nairobi, Kenya to examine differences in the peripheral immune systems between two cohorts of age-matched children (to control for immune changes with age): one group which initiated ART during early HIV infection and had been on ART for 5-6 years at evaluation (early, long-term treated; "ELT" cohort), and one group which initiated ART later and had been on ART for approximately 9 months at evaluation (delayed, short-term treated; "DST" cohort). We profiled PBMC and purified NK cells from these two cohorts by mass cytometry time-of-flight (CyTOF). Although both groups of CLH had undetectable viral RNA load at evaluation, there were marked differences in both immune composition and immune phenotype between the ELT cohort and the DST cohort. DST donors had reduced CD4 T cell percentages, decreased naive to effector memory T cell ratios, and markedly higher expression of stress-induced markers. Conversely, ELT donors had higher naive to effector memory T cell ratios, low expression of stress-induced markers, and increased expression of markers associated with an effective antiviral response and resolution of inflammation. Collectively, our results demonstrate key differences in the immune systems of virally-suppressed CLH with different ages at ART initiation and durations of treatment and provide further rationale for emphasizing early onset of ART.}, }
@article {pmid39612163, year = {2024}, author = {Swensen, SN and Figuracion, KCF and Venur, VA and Emerson, S and Tseng, YD and Lo, SS and Ermoian, RP and Halasz, LM}, title = {Treatment Options for IDH-Mutant Malignant Gliomas.}, journal = {Current treatment options in oncology}, volume = {}, number = {}, pages = {}, pmid = {39612163}, issn = {1534-6277}, abstract = {As the peak incidence of isocitrate dehydrogenase (IDH)-mutant gliomas is amongst young adults, there is a need to balance tumor control with long term side effects of therapy. Following initial clinical presentation and acquisition of contrasted diagnostic imaging, tissue diagnosis is essential in suspected diffuse glioma. Depending on the location and extent of disease, maximal surgical resection is preferred both for histologic diagnosis and initial therapy. Partial resection or biopsy alone is considered when the tumor cannot be completely resected or if there are clinical reservations regarding a more significant operation. The classification of diffuse glioma has evolved over time, with histopathology and molecular marker status guiding discussions of prognosis and postoperative management. In patients with IDH-mutant grade 2 glioma and low-risk features, observation with active surveillance is generally recommended following a gross total resection. For those with high-risk features, which historically included age > 40 years or subtotal resection, adjuvant chemotherapy and radiation therapy are generally recommended, however decisions for adjuvant therapy pose challenges as many of the landmark historical trials guiding adjuvant therapy were performed prior to the molecularly defined era. This is an area where multiple clinical trials are ongoing and hold promise to inform treatment paradigms, including recent data on the use of IDH-mutant inhibitors in grade 2 tumors with recurrent or residual disease. For IDH-mutant grade 3 and 4 glioma, adjuvant chemotherapy and radiation are recommended for all patients after initial resection.}, }
@article {pmid39610699, year = {2024}, author = {Wu, P and Barros-Becker, F and Ogelman, R and Camci, ED and Linbo, TH and Simon, JA and Rubel, EW and Raible, DW}, title = {Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1480435}, pmid = {39610699}, issn = {1664-2295}, abstract = {Mechanosensory hair cells of the inner ears and lateral line of vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing and balance disorders. An important example is hair cell loss due to exposure to toxic agents including therapeutic drugs such as the aminoglycoside antibiotics neomycin and gentamicin and antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced hair cell death in zebrafish lateral line hair cells. Neomycin exposure results in death from acute exposure with most cells dying within 1 h of exposure. By contrast, exposure to gentamicin results primarily in delayed hair cell death, taking up to 24 h for maximal effect. Washout experiments demonstrate that delayed death does not require continuous exposure, demonstrating two mechanisms where downstream responses differ in their timing. Acute damage is associated with mitochondrial calcium fluxes and can be alleviated by the mitochondrially-targeted antioxidant mitoTEMPO, while delayed death is independent of these factors. Conversely delayed death is associated with lysosomal accumulation and is reduced by altering endolysosomal function, while acute death is not sensitive to lysosomal manipulations. These experiments reveal the complexity of responses of hair cells to closely related compounds, suggesting that intervention focusing on early events rather than specific death pathways may be a successful therapeutic strategy.}, }
@article {pmid39581232, year = {2024}, author = {Setia, M and Suvas, PK and Rana, M and Chakraborty, A and Suvas, S}, title = {Herpes stromal keratitis erodes the establishment of tissue-resident memory T cell pool in HSV-1 infected corneas.}, journal = {Mucosal immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mucimm.2024.11.003}, pmid = {39581232}, issn = {1935-3456}, abstract = {The recurrent herpes simplex virus-1 (HSV-1) infection of the cornea can cause the development of herpes stromal keratitis (HSK). This chronic immunoinflammatory condition is a major cause of infection-induced vision loss. The previous episodes of HSK increase the risk of future recurrences in the same cornea. However, not all HSV-1 infected corneas that shed infectious virus at the ocular surface develop HSK, suggesting that corneal HSV-1 infection may cause an establishment of protective immunity in HSV-1 infected corneas. However, upon recurrent corneal HSV-1 infection, the established protective immunity can get compromised, resulting in the development of HSK. In this study, we compared the quantity and quality of tissue-resident memory T (TRM) cells in HSV-1 infected corneas that did or did not develop HSK. Our results showed the predominance of TRM cell in the epithelium than in stroma of HSV-1 infected corneas. Furthermore, HSV-1 infected non-HSK corneas exhibited more CD4 and CD8 TRM cells than HSK corneas. The TRM cells in non-HSK than in HSK corneas were more effective in clearing the infectious virus upon secondary corneal HSV-1 infection. Our results demonstrate the differential quantity and quality of TRM cells in HSV-1 infected corneas that did or did not develop HSK.}, }
@article {pmid39610652, year = {2024}, author = {Nanduri, S and Black, A and Bedford, T and Huddleston, J}, title = {Dimensionality reduction distills complex evolutionary relationships in seasonal influenza and SARS-CoV-2.}, journal = {Virus evolution}, volume = {10}, number = {1}, pages = {veae087}, pmid = {39610652}, issn = {2057-1577}, abstract = {Public health researchers and practitioners commonly infer phylogenies from viral genome sequences to understand transmission dynamics and identify clusters of genetically-related samples. However, viruses that reassort or recombine violate phylogenetic assumptions and require more sophisticated methods. Even when phylogenies are appropriate, they can be unnecessary or difficult to interpret without specialty knowledge. For example, pairwise distances between sequences can be enough to identify clusters of related samples or assign new samples to existing phylogenetic clusters. In this work, we tested whether dimensionality reduction methods could capture known genetic groups within two human pathogenic viruses that cause substantial human morbidity and mortality and frequently reassort or recombine, respectively: seasonal influenza A/H3N2 and SARS-CoV-2. We applied principal component analysis, multidimensional scaling (MDS), t-distributed stochastic neighbor embedding (t-SNE), and uniform manifold approximation and projection to sequences with well-defined phylogenetic clades and either reassortment (H3N2) or recombination (SARS-CoV-2). For each low-dimensional embedding of sequences, we calculated the correlation between pairwise genetic and Euclidean distances in the embedding and applied a hierarchical clustering method to identify clusters in the embedding. We measured the accuracy of clusters compared to previously defined phylogenetic clades, reassortment clusters, or recombinant lineages. We found that MDS embeddings accurately represented pairwise genetic distances including the intermediate placement of recombinant SARS-CoV-2 lineages between parental lineages. Clusters from t-SNE embeddings accurately recapitulated known phylogenetic clades, H3N2 reassortment groups, and SARS-CoV-2 recombinant lineages. We show that simple statistical methods without a biological model can accurately represent known genetic relationships for relevant human pathogenic viruses. Our open source implementation of these methods for analysis of viral genome sequences can be easily applied when phylogenetic methods are either unnecessary or inappropriate.}, }
@article {pmid39609636, year = {2024}, author = {Thomas, CE and Peters, U}, title = {Genomic landscape of cancer in racially and ethnically diverse populations.}, journal = {Nature reviews. Genetics}, volume = {}, number = {}, pages = {}, pmid = {39609636}, issn = {1471-0064}, abstract = {Cancer incidence and mortality rates can vary widely among different racial and ethnic groups, attributed to a complex interplay of genetic, environmental and social factors. Recently, substantial progress has been made in investigating hereditary genetic risk factors and in characterizing tumour genomes. However, most research has been conducted in individuals of European ancestries and, increasingly, in individuals of Asian ancestries. The study of germline and somatic genetics in cancer across racial and ethnic groups using omics technologies offers opportunities to identify similarities and differences in both heritable traits and the molecular features of cancer genomes. An improved understanding of population-specific cancer genomics, as well as translation of those findings across populations, will help reduce cancer disparities and ensure that personalized medicine and public health approaches are equitable across racial and ethnic groups.}, }
@article {pmid39609400, year = {2024}, author = {Lemos, MP and Astronomo, RD and Huang, Y and Narpala, S and Prabhakaran, M and Mann, P and Paez, CA and Lu, Y and Mize, GJ and Glantz, H and Westerberg, K and Colegrove, H and Smythe, KS and Lin, M and Pierce, RH and Hutter, J and Frank, I and Mascola, JR and McDermott, AB and Bekker, LG and McElrath, MJ}, title = {Enhanced and sustained biodistribution of HIV-1 neutralizing antibody VRC01LS in human genital and rectal mucosa.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10332}, pmid = {39609400}, issn = {2041-1723}, support = {UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; UM1 AI069501/AI/NIAID NIH HHS/United States ; UM1 AI069534/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *HIV-1/immunology ; *Rectum/virology ; *HIV Antibodies/immunology ; Adult ; Male ; *HIV Infections/immunology/prevention & control/virology ; *Broadly Neutralizing Antibodies/immunology ; *Antibodies, Monoclonal/pharmacokinetics/immunology/administration & dosage ; Tissue Distribution ; Mucous Membrane/immunology/virology/metabolism ; Antibodies, Neutralizing/immunology ; Middle Aged ; Vagina/virology/immunology ; Young Adult ; Half-Life ; Intestinal Mucosa/metabolism/immunology ; }, abstract = {To prevent sexually-acquired HIV-1 infection by immunoprophylaxis, effective concentrations of broadly neutralizing antibodies are likely needed at mucosal sites of exposure. Here, we examine the biodistribution of monoclonal antibody VRC01 and its extended half-life variant, VRC01LS, in colorectal and genitourinary tracts of healthy adults 1-52 weeks after intravenous infusion. At 1-2 weeks, VRC01LS levels are ~3-4 times higher than VRC01 in serum (p = 0.048), rectal (p = 0.067), vaginal (p = 0.003) and cervical tissues (p = 0.003); these differences increase over time. Both antibodies primarily localize within rectal lamina propria and cervicovaginal stroma, with limited and variable epithelial distribution. Although 8-28% of serum mAb levels reach mucosal tissues, <3% are in seminal and rectal secretions. Elimination half-lives in mucosal tissues are 20-28 days for VRC01 and 51-68 days for VRC01LS. Thus, VRC01LS infusion achieves higher, sustained concentrations in human mucosal tissues than VRC01, supporting the future investigation of potent, long-acting LS-modified antibodies to prevent HIV-1.}, }
@article {pmid39607987, year = {2024}, author = {Weiss, NS}, title = {Gauging the efficacy of multicancer screening: the road ahead may be long and bumpy.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae267}, pmid = {39607987}, issn = {1460-2105}, support = {/CA/NCI NIH HHS/United States ; }, }
@article {pmid39607599, year = {2024}, author = {Ondeng'e, K and Guo, X and Mbeda, C and Schnabel, D and Panchia, R and Dominguez, K and Dadabhai, S and Hamilton, EL and Sandfort, TGM}, title = {Bisexuality among Men who have Sex with Men in Sub-Saharan Africa: Findings from the HPTN 075 Study.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {39607599}, issn = {1573-3254}, support = {UM1-AI068619//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1-AI068617//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1-AI068613//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; P30-MH43520/MH/NIMH NIH HHS/United States ; R21-MH130217//National Institute of Mental Health and Neurosciences/ ; }, abstract = {Studies among men who have sex with men (MSM) in sub-Saharan Africa (SSA) focus mainly on HIV epidemiology, revealing little about the diversity within this population. We utilized data from the HIV Prevention Trials Network (HPTN) 075 study, to explore demographic and psychosexual characteristics of MSM in SSA who also have sex with women. Persons included in the analyses were aged 18-44 years and assigned male sex at birth and identified as male, reported anal sex with a man in the past 3 months, and had enrolled at one of four study sites (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Nearly a quarter of the participants had recently engaged in sex with both men and women (MSMW). These men differed in terms of demographic and psychosexual characteristics, and sexual behavior from men who only had had sex with men (MSME). Compared to the latter, MSMW were more likely to prefer the insertive sexual role, reported more sexual partners in the past three months, and had more instances of condomless insertive anal intercourse with a man. These findings suggest that men who have sex with both men and women have specific characteristics and need tailored interventions that take their specific needs into account.}, }
@article {pmid39605281, year = {2024}, author = {Zheng, C and Furukawa, C and Liu, J and Sankaran, S and Lin, H and Munugeti, N and Wang, M and Smith, GR}, title = {Debunking the dogma that RecBCD nuclease destroys phage.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyae199}, pmid = {39605281}, issn = {1943-2631}, abstract = {For decades, it has been repeatedly claimed that the potent bacterial helicase-nuclease RecBCD (exonuclease V) destroys foreign (non-self) DNA, such as that of phages, but repairs and recombines cellular (self) DNA. While this would constitute a strong host-survival mechanism, no phage destroyed by RecBCD is ever specified in those claims. To determine which phages are destroyed by RecBCD, we searched for phage isolates that grow on Escherichia coli ΔrecBCD but not on recBCD+. In contrast to the prevailing claim, we found none among >80 new isolates from nature and >80 from previous collections. Based on these and previous observations, we conclude that RecBCD repairs broken DNA that can recombine but destroys DNA that cannot recombine and recycles the nucleotides.}, }
@article {pmid39604409, year = {2024}, author = {Holmes, S and Li, H and Shen, X and Martin, M and Tuck, R and Chen, Y and Giorgi, EE and Kirshner, HF and Berry, M and Van Italie, E and Venkatayogi, S and Martin Beem, JS and Edwards, RJ and Mansouri, K and Singh, A and Kuykendall, C and Gurley, T and Anthony Moody, M and DeNayer, N and Demarco, T and Denny, TN and Wang, Y and Evangelous, TD and Clinton, JT and Hora, B and Wagh, K and Seaman, MS and Saunders, KO and Solomotis, N and Misamore, J and Lewis, MG and Wiehe, K and Montefiori, DC and Shaw, GM and Williams, WB}, title = {Neonatal immunity associated with heterologous HIV-1 neutralizing antibody induction in SHIV-infected Rhesus Macaques.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10302}, pmid = {39604409}, issn = {2041-1723}, support = {AI140897//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI160607//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; HHSN272201800004C/AI/NIAID NIH HHS/United States ; HHSN272201800004C/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Macaca mulatta/immunology ; *HIV-1/immunology ; *Simian Acquired Immunodeficiency Syndrome/immunology/virology ; *Simian Immunodeficiency Virus/immunology ; *Antibodies, Neutralizing/immunology ; *HIV Antibodies/immunology/blood ; *Animals, Newborn ; Female ; Humans ; Male ; B-Lymphocytes/immunology ; HIV Infections/immunology/virology ; T-Lymphocytes, Regulatory/immunology ; Germinal Center/immunology ; Disease Models, Animal ; Epitopes/immunology ; }, abstract = {The details of the pediatric immune system that supports induction of antibodies capable of neutralizing geographically-diverse or heterologous HIV-1 is currently unclear. Here we explore the pediatric immune environment in neonatal macaque undergoing Simian-HIV infection. Simian-HIV infection of 11 pairs of therapy-naive dams and infant rhesus macaques for 24 months results in heterologous HIV-1 neutralizing antibodies in 64% of young macaques compared to 18% of adult macaques. Heterologous HIV-1 neutralizing antibodies emerge by 12 months post-infection in young macaques, in association with lower expression of immunosuppressive genes, fewer germinal center CD4 + T regulatory cells, and a lower ratio of CD4 + T follicular regulatory to helper cells. Antibodies from peripheral blood B cells in two young macaques following SHIV infection neutralize 13% of 119 heterologous HIV-1 strains and map to regions of canonical broadly neutralizing antibody epitopes on the envelope surface protein. Here we show that pediatric immunity to SHIV infection in a macaque model may inform vaccine strategies to induce effective HIV-1 neutralizing antibodies in infants and children prior to viral exposure.}, }
@article {pmid39604364, year = {2024}, author = {Gem, H and Ebadi, M and Sebastian, G and Abasaeed, R and Lloid, M and Minot, SS and Dean, DR and Rashidi, A}, title = {A sex-dependent salivary bacterium influences oral mucositis severity after allogeneic hematopoietic cell transplantation.}, journal = {NPJ biofilms and microbiomes}, volume = {10}, number = {1}, pages = {140}, pmid = {39604364}, issn = {2055-5008}, support = {P30 CA015704/NH/NIH HHS/United States ; Dr. Douglass L. Morell Dentistry Research Fund//Research Advisory Committee of the University of Washington School of Dentistry/ ; resident research award//American Academy of Oral Medicine Research Advancement Committee/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Male ; Female ; *Stomatitis/etiology/microbiology ; *Saliva/microbiology ; Middle Aged ; Adult ; *Transplantation, Homologous/adverse effects ; Sex Factors ; Microbiota ; Severity of Illness Index ; Uric Acid/analysis ; Aged ; }, abstract = {The success of allogeneic hematopoietic cell transplantation (alloHCT) in curing hematologic disorders is limited by its short- and long-term toxicities. One such toxicity is oral mucositis (OM), causing pain, speech/swallowing difficulty, and prolonged hospitalization. Although conditioning chemoradiotherapy is the direct cause of OM, potential host-intrinsic mediators of mucosal injury remain elusive. We hypothesized that the oral microbiota may influence OM severity. We used a validated comprehensive scoring system based on specialized Oral Medicine examinations to longitudinally quantify OM severity in alloHCT recipients. High-throughput multi-site profiling of the oral microbiota was performed in parallel. We identify a sex-dependent commensal bacterium, Oribacterium asaccharolyticum, whose presence in saliva before transplantation is associated with more severe OM 14 days after transplantation. The sex predilection of this species correlated with higher uric acid levels in men. Our findings represent the first sex-dependent microbiota-mediated pathway in OM pathogenesis and introduce novel targets for preventative interventions.}, }
@article {pmid39603592, year = {2024}, author = {Thomson, CA and Arnold, KB and Anderson, G and Sun, V and Secord, AA and Yung, A and Al-Kasspooles, M and Nfonsam, VN and Grant, M and Deutsch, GB and Deneve, JL and Krouse, RS}, title = {Intake and Nutritional Adequacy in Patients with Cancer Diagnosed with Malignant Bowel Obstruction: A secondary analysis of a randomized trial.}, journal = {Journal of the Academy of Nutrition and Dietetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jand.2024.11.011}, pmid = {39603592}, issn = {2212-2672}, abstract = {BACKGROUND: Malignant bowel obstruction (MBO) is experienced by many with advanced cancer. Patients with MBO cannot eat and may have reduced ability to eat once the acute process has resolved. Sparse data exist to describe oral intake capacity and adequacy of nutrition in MBO patients. These data are critical to developing effective supportive care nutrition therapy for patients with MBO.
OBJECTIVE: To describe the ability to consume food/liquids orally estimating nutritional adequacy of diet in a sample of patients who received surgical or non-surgical treatment for MBO.
DESIGN: A descriptive secondary data analysis of repeated dietary intake measures from S1316, a pragmatic comparative effectiveness trial of surgical and non-surgical treatment for MBO. Participant enrollment occurred between 2015 and 2020. Ability to eat was assessed through self-reported telephone survey and intake was estimated using telephone-based 24-hour recalls, applying USDA multi-pass methodology.
PARTICIPANTS/SETTING: The primary trial was conducted within the SWOG Cancer Research Network and included recruitment sites across the U.S. and Latin America. Eligible participants were diagnosed with, and hospitalized for, MBO.
MAIN OUTCOME MEASURES: The main outcomes measures were self- or caregiver reported ability to eat, as well as overall nutrient intake.
STATISTICAL ANALYSIS: Descriptive statistics were used to report patient characteristics, intake, and nutrient adequacy. Nutrient intake was presented by tertiles of gastrointestinal symptom severity and assessed.
RESULTS: 221 participants were registered; 199 were eligible and included. At Week 1, 51% of patients with MBO reported consuming some solid food orally; 34% reported no oral intake; 13% were on enteral feeding only. For patients alive and responsive to recalls at 13 weeks (n=57), 82% (n=47) reported consuming solid food. Compared to recommendations, mean reported intake was inadequate for most nutrients.
CONCLUSIONS: Oral intake is reported in more than half of patients diagnosed with MBO. Medical nutrition therapy should be tailored to patients' tolerance for eating and with consideration or patient's desire to address nutritional inadequacies.}, }
@article {pmid39574678, year = {2024}, author = {Zhu, L and Beichman, A and Harris, K}, title = {Population size interacts with reproductive longevity to shape the germline mutation rate.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39574678}, issn = {2692-8205}, support = {R35 GM133428/GM/NIGMS NIH HHS/United States ; T32 AG066574/AG/NIA NIH HHS/United States ; }, abstract = {Mutation rates vary across the tree of life by many orders of magnitude, with lower mutation rates in species that reproduce quickly and maintain large effective population sizes. A compelling explanation for this trend is that large effective population sizes facilitate selection against weakly deleterious "mutator alleles" such as variants that interfere with the molecular efficacy of DNA repair. However, in multicellular organisms, the relationship of the mutation rate to DNA repair efficacy is complicated by variation in reproductive age. Long generation times leave more time for mutations to accrue each generation, and late reproduction likely amplifies the fitness consequences of any DNA repair defect that creates extra mutations in the sperm or eggs. Here, we present theoretical and empirical evidence that a long generation time amplifies the strength of selection for low mutation rates in the spermatocytes and oocytes. This leads to the counterintuitive prediction that the species with the highest germline mutation rates per generation are also the species with most effective mechanisms for DNA proofreading and repair in their germ cells. In contrast, species with different generation times accumulate similar mutation loads during embryonic development. Our results parallel recent findings that the longest-lived species have the lowest mutation rates in adult somatic tissues, potentially due to selection to keep the lifetime mutation load below a harmful threshold.}, }
@article {pmid39600206, year = {2024}, author = {Antin, T and Cartujano-Barrera, F and De Genna, NM and Hinds, JT and Kaner, E and Lee, J and Patterson, JG and Ruiz, RA and Stimatze, T and Tan, ASL and Heffner, JL}, title = {Structural stigma and inequities in tobacco use among sexual and gender minoritized people: Accounting for context and intersectionality.}, journal = {Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntae280}, pmid = {39600206}, issn = {1469-994X}, }
@article {pmid39599646, year = {2024}, author = {Smith, KS and Gudenkauf, LM and Hoogland, AI and Li, X and Hoobler, R and Playdon, MC and Gigic, B and Small, BJ and Gonzalez, BD and Oswald, LB and Byrd, DA and Greathouse, KL and Ulrich, CM and Li, CI and Shibata, D and Toriola, AT and Peoples, AR and Siegel, EM and Figueiredo, JC and Jim, HSL and Crowder, SL}, title = {Associations Between Dietary Patterns and Quality of Life in a Longitudinal Cohort of Colorectal Cancer Survivors.}, journal = {Nutrients}, volume = {16}, number = {22}, pages = {}, doi = {10.3390/nu16223860}, pmid = {39599646}, issn = {2072-6643}, support = {R01NR018762/NR/NINR NIH HHS/United States ; T32CA009168, R2 U01CA206110, 1A1 R01CA189184, R01CA207371, and T32CA090314/CA/NCI NIH HHS/United States ; P30-CA076292//Cancer Center Support Grant/ ; }, mesh = {Humans ; *Quality of Life ; Female ; Male ; Middle Aged ; *Colorectal Neoplasms/psychology ; *Cancer Survivors/psychology/statistics & numerical data ; Aged ; Longitudinal Studies ; Prospective Studies ; *Diet ; Adult ; Cross-Sectional Studies ; Feeding Behavior/psychology ; United States/epidemiology ; Dietary Patterns ; }, abstract = {PURPOSE: To characterize dietary patterns and examine associations with cross-sectional and longitudinal changes in quality of life (QOL) over approximately one year after colorectal cancer (CRC) diagnosis.
METHODS: The ColoCare Study is an international, multi-center, prospective cohort study of newly diagnosed CRC survivors of any stage. A subset of participants with CRC in the United States completed patient-reported outcome measures at 6- and 12-months post-enrollment, including the Food Frequency Questionnaire (FFQ) and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Dietary patterns at 6 months (around the time of treatment completion) were identified using Principal Component Analysis (PCA) with varimax rotation. Adherence scores were calculated for participants within each dietary pattern, with higher scores indicating higher adherence. Mixed models were used to examine the effect of each dietary pattern on changes in QOL at 6- and 12-month follow-ups, controlling for cancer stage, biological sex, body mass index (BMI), smoking status, and age.
RESULTS: Participants (N = 174) were, on average, 56 ± 14 years old and were mostly female (51.5%), stage III or IV (51.7%), never smokers (60.2%), non-Hispanic (97.1%), and White (83.3%) with a BMI of 27.9 ± 6.1 kg/m[2]. PCA revealed two emerging dietary patterns: "Western diet", characterized by processed meats, refined grains, and sugars, and "Prudent diet" characterized by lean proteins, fruits, and vegetables. Higher adherence to a Western diet was associated with worse social functioning at 6-month follow-up (FE = -12.6, p = 0.010). Loss of appetite from 6 to 12 months was associated with higher adherence to both the Western and Prudent dietary patterns (FE = 1.5, p = 0.044; FE = 1.3, p = 0.046, respectively). Neither dietary pattern was associated with global QOL score at 6- or 12-month follow-up (p's > 0.05).
CONCLUSIONS: Among CRC survivors in the United States, the Western diet was concurrently associated with worse social functioning. Loss of appetite was reported by CRC survivors following both dietary patterns, suggesting that loss of appetite may be a global experience for CRC survivors during this timeframe. Further research is needed to understand specific social challenges experienced by CRC survivors and develop supportive care interventions to address appetite and nutritional concerns.}, }
@article {pmid39596582, year = {2024}, author = {Ha, ET and Haessler, J and Taylor, KD and Tuftin, B and Briggs, M and Parikh, MA and Peterson, SJ and Gerszten, RE and Wilson, JG and Kelsey, K and Tahir, UA and Seeman, T and Rich, SS and Carson, AP and Post, WS and Kooperberg, C and Rotter, JI and Raffield, LM and Auer, P and Reiner, AP}, title = {The Relationship of Duffy Gene Polymorphism with High-Sensitivity C-Reactive Protein, Mortality, and Cardiovascular Outcomes in Black Individuals.}, journal = {Genes}, volume = {15}, number = {11}, pages = {}, doi = {10.3390/genes15111382}, pmid = {39596582}, issn = {2073-4425}, mesh = {Humans ; *Duffy Blood-Group System/genetics ; Female ; *C-Reactive Protein/genetics/metabolism ; Male ; *Polymorphism, Single Nucleotide ; *Cardiovascular Diseases/genetics/mortality ; Aged ; Middle Aged ; Receptors, Cell Surface/genetics ; Black or African American/genetics ; White ; }, abstract = {Background: Black adults have higher incidence of all-cause mortality and worse cardiovascular disease (CVD) outcomes when compared to other U.S. populations. The Duffy chemokine receptor is not expressed on erythrocytes in a large majority of Black adults, but the clinical implications of this are unclear. Methods: Here, we investigated the relationship of Duffy receptor status, high-sensitivity C-reactive protein (hs-CRP), and mortality and incident CVD events (coronary heart disease, stroke, and heart failure) in self-identified Black members of three contemporary, longitudinal cohort studies (the Women's Health Initiative, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis). Data on 14,358 Black participants (9023 Duffy-null and 5335 Duffy-receptor-positive, as defined using single-nucleotide polymorphism (SNP) rs2814778) were included in this analysis. Results: Duffy null was strongly associated with higher hs-CRP (meta-analysis p = 2.62 × 10[-9]), but the association was largely attenuated, though still marginally significant (p = 0.005), after conditioning on known CRP locus alleles in linkage disequilibrium with the Duffy gene. In our discovery cohorts, Duffy-null status appeared to be associated with a higher risk of all-cause mortality and incident stroke, though these associations were attenuated and non-significant following adjustment for traditional risk factors including hs-CRP. Moreover, the association of Duffy-null status with mortality could not be replicated in an independent sample of Black adults from the UK Biobank. Conclusions: These findings suggest that the higher levels of hs-CRP found in Duffy-null individuals may be in part independent of CRP alleles known to influence circulating levels of hs-CRP. During the follow-up of this community-based sample of Black participants, Duffy-null status was not associated with mortality or incident CVD events independently of traditional risk factors including hs-CRP.}, }
@article {pmid39596404, year = {2024}, author = {Wang, Z and Kaplan, RC and Burk, RD and Qi, Q}, title = {The Oral Microbiota, Microbial Metabolites, and Immuno-Inflammatory Mechanisms in Cardiovascular Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, doi = {10.3390/ijms252212337}, pmid = {39596404}, issn = {1422-0067}, support = {K01 HL169019/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Cardiovascular Diseases/microbiology/immunology/metabolism ; *Mouth/microbiology ; Inflammation/microbiology/metabolism/immunology ; Gastrointestinal Microbiome ; Microbiota ; Animals ; }, abstract = {Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality. Recent advancements in high-throughput omics techniques have enhanced our understanding of the human microbiome's role in the development of CVDs. Although the relationship between the gut microbiome and CVDs has attracted considerable research attention and has been rapidly evolving in recent years, the role of the oral microbiome remains less understood, with most prior studies focusing on periodontitis-related pathogens. In this review, we summarized previously reported associations between the oral microbiome and CVD, highlighting known CVD-associated taxa such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. We also discussed the interactions between the oral and gut microbes. The potential mechanisms by which the oral microbiota can influence CVD development include oral and systemic inflammation, immune responses, cytokine release, translocation of oral bacteria into the bloodstream, and the impact of microbial-related products such as microbial metabolites (e.g., short-chain fatty acids [SCFAs], trimethylamine oxide [TMAO], hydrogen sulfide [H2S], nitric oxide [NO]) and specific toxins (e.g., lipopolysaccharide [LPS], leukotoxin [LtxA]). The processes driven by these mechanisms may contribute to atherosclerosis, endothelial dysfunction, and other cardiovascular pathologies. Integrated multi-omics methodologies, along with large-scale longitudinal population studies and intervention studies, will facilitate a deeper understanding of the metabolic and functional roles of the oral microbiome in cardiovascular health. This fundamental knowledge will support the development of targeted interventions and effective therapies to prevent or reduce the progression from cardiovascular risk to clinical CVD events.}, }
@article {pmid39594840, year = {2024}, author = {Dekker, SE and Deng, L}, title = {Clinical Advances and Challenges in Targeting KRAS Mutations in Non-Small Cell Lung Cancer.}, journal = {Cancers}, volume = {16}, number = {22}, pages = {}, doi = {10.3390/cancers16223885}, pmid = {39594840}, issn = {2072-6694}, abstract = {KRAS mutation is one of the most common oncogenic drivers in non-small cell lung cancer. Since its discovery about four decades ago, drug development targeting KRAS has been met with countless failures. Recently, KRAS G12C, a subvariant of KRAS, became the first druggable KRAS mutation. The efficacy of the first-generation KRAS inhibitor is modest, but with scientific advancement, KRAS G12C inhibitors with higher potency are on the horizon. Additionally, novel therapeutic approaches targeting other KRAS subvariants are also being explored in clinical trials with encouraging early data. We will review the clinical advances and challenges for patients with KRAS-mutated non-small cell lung cancer, with a focus on small molecule inhibitors.}, }
@article {pmid39594810, year = {2024}, author = {Ally, F and Chen, X}, title = {Acute Myeloid Leukemia: Diagnosis and Evaluation by Flow Cytometry.}, journal = {Cancers}, volume = {16}, number = {22}, pages = {}, doi = {10.3390/cancers16223855}, pmid = {39594810}, issn = {2072-6694}, abstract = {With recent technological advances and significant progress in understanding the pathogenesis of acute myeloid leukemia (AML), the updated fifth edition WHO Classification (WHO-HAEM5) and the newly introduced International Consensus Classification (ICC), as well as the European LeukemiaNet (ELN) recommendations in 2022, require the integration of immunophenotypic, cytogenetic, and molecular data, alongside clinical and morphologic findings, for accurate diagnosis, prognostication, and guiding therapeutic strategies in AML. Flow cytometry offers rapid and sensitive immunophenotyping through a multiparametric approach and is a pivotal laboratory tool for the classification of AML, identification of therapeutic targets, and monitoring of measurable residual disease (MRD) post therapy. The association of immunophenotypic features and recurrent genetic abnormalities has been recognized and applied in informing further diagnostic evaluation and immediate therapeutic decision-making. Recently, the evolving role of machine learning models in assisting flow cytometric data analysis for the automated diagnosis and prediction of underlying genetic alterations has been illustrated.}, }
@article {pmid39591433, year = {2024}, author = {Peebles, K and Matrajt, L and Baeten, JM and Palanee-Phillips, T and Brown, ER and , }, title = {Understanding the sources of efficacy dilution in a trial of a monthly dapivirine vaginal ring for HIV-1 prevention.}, journal = {International journal of STD & AIDS}, volume = {}, number = {}, pages = {9564624241300199}, doi = {10.1177/09564624241300199}, pmid = {39591433}, issn = {1758-1052}, abstract = {INTRODUCTION: Women-initiated HIV - 1 prevention products are key to reducing women's HIV-1 risk. Clinical trials of vaginal microbicides have shown limited to no efficacy in intention-to-treat (ITT) analyses. It is hypothesized that these negative results are partly due to efficacy dilution.
METHODS: We developed a microsimulation model of MTN-020/ASPIRE, a phase 3 trial that evaluated monthly use of a dapivirine vaginal ring for HIV-1 prevention. We evaluated four sources of efficacy dilution: trial-level factors: (i) an imbalance in the number of monthly sex acts between study arms and (ii) heterogeneity in risk emergent over time; and individual-level factors: (iii) product non-adherence and (iv) receptive anal intercourse.
RESULTS: Assuming 70% per-vaginal exposure efficacy (consistent with the ITT estimate of 27%), heterogeneity in risk accounted for the largest proportion of efficacy dilution, at 42% (90% CrI: 38, 45), followed by non-adherence (33%; 90% CrI: 27, 39), an imbalance in arms (18%; 90% CrI: 16, 21) and lastly, anal intercourse with less than 10% of efficacy dilution.
CONCLUSION: Our results suggest that heterogeneity in risk was the most important source of efficacy dilution in the ASPIRE trial. Future trials of HIV-1 prevention products for women should consider alternative trial designs and analytic approaches that minimize bias introduced by heterogeneity in risk.}, }
@article {pmid39589879, year = {2024}, author = {Varuzhanyan, G and Chen, CC and Freeland, J and He, T and Tran, W and Song, K and Wang, L and Cheng, D and Xu, S and Dibernardo, GA and Esedebe, FN and Bhatia, V and Han, M and Abt, ER and Park, JW and Memarzadeh, S and Shackelford, DB and Lee, JK and Graeber, TG and Shirihai, OS and Witte, ON}, title = {PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {49}, pages = {e2416882121}, doi = {10.1073/pnas.2416882121}, pmid = {39589879}, issn = {1091-6490}, support = {01//G. Harold and Leila Y. Mathers Foundation (Mathers Foundation)/ ; P50CA092131Â//NIH UCLA SPORE in Prostate Cancer/ ; R01CA222877Â//NIH R01 Grant/ ; 01//UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Hal Gaba Director's Fund for Cancer Stem Cell Research/ ; 01//Parker Institute for Cancer Immunotherapy (PICI)/ ; NIH T32 CA-009056//UCLA Tumor Cell Biology Training Program (USHHS) Ruth L. Kirschstein Institutional national Research Service Award/ ; 01//UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research predoctoral fellowship/ ; 01//UCLA Dissertation Year Fellowship/ ; I01BX006019//Veteran Affairs funds/ ; I01BX006019//Veteran Affairs funds/ ; 01//UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award/ ; 01//University of California-Historically Black Colleges and Universities (UC-HBCU) Initiative Fellowship provided by University of California Office of the President (UCOP)./ ; DP2 CA271301/CA/NCI NIH HHS/United States ; 2 P30 CA016042-44//NIH (NIH)/ ; 1 S10 OD026917-01A1//NIH (NIH)/ ; }, mesh = {Humans ; *Basic Helix-Loop-Helix Transcription Factors/metabolism/genetics ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Mitochondria/metabolism ; Male ; *Oxidative Phosphorylation ; Animals ; Cell Line, Tumor ; *Disease Progression ; Mice ; Prostatic Neoplasms/metabolism/pathology/genetics ; Gene Expression Regulation, Neoplastic ; Neuroendocrine Tumors/metabolism/pathology/genetics ; Cell Proliferation ; }, abstract = {Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.}, }
@article {pmid39589470, year = {2024}, author = {Udovicich, C and Lo, SS and Guckenberger, M and Sahgal, A}, title = {Shifting the Landscape of Spine and Non-Spine Bone Metastases: A Review of Stereotactic Body Radiotherapy.}, journal = {Cancer journal (Sudbury, Mass.)}, volume = {30}, number = {6}, pages = {385-392}, pmid = {39589470}, issn = {1540-336X}, mesh = {Humans ; *Radiosurgery/methods ; *Spinal Neoplasms/secondary/radiotherapy ; *Bone Neoplasms/secondary/radiotherapy ; Palliative Care/methods ; Treatment Outcome ; }, abstract = {Both spine and nonspine bone metastases are frequent sites of spread from solid organ malignancies. As bone metastases frequently cause significant morbidity for patients, it is critical to offer a treatment that can achieve rapid and durable symptomatic relief and local control, without being associated with serious risks of toxicity. Conventional palliative radiation therapy has a key treatment component in the multidisciplinary management of these patients; however, over the past decade, it has evolved to routinely deliver high biologically effective doses with precision in the form of stereotactic body radiation therapy. This change in paradigm is a result of the shifting landscape in cancer care, such that short-term pain relief is no longer the sole therapeutic aim for selected patients, and durable symptom relief and local tumor control are the goals. This review discusses the randomized prospective evidence, ongoing trials, approach to surveillance imaging, and treatment delivery for stereotactic body radiation therapy, to both spine and nonspine bone metastases, with a specific section on sacral metastases.}, }
@article {pmid39589370, year = {2024}, author = {Lerner, SP and Tangen, C and Svatek, RS and Daneshmand, S and Pohar, KS and Skinner, E and Schuckman, A and Sagalowsky, AI and Smith, ND and Kamat, AM and Kassouf, W and Plets, M and Bangs, R and Koppie, TM and Alva, A and La Rosa, FG and Pal, SK and Kibel, AS and Canter, DJ and Thompson, IM and , }, title = {Standard or Extended Lymphadenectomy for Muscle-Invasive Bladder Cancer.}, journal = {The New England journal of medicine}, volume = {391}, number = {13}, pages = {1206-1216}, doi = {10.1056/NEJMoa2401497}, pmid = {39589370}, issn = {1533-4406}, support = {U10CA180888 U10CA180819, U10CA180820, U10CA180821,/CA/NCI NIH HHS/United States ; 707213//Canadian Cancer Society/ ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/surgery/pathology/mortality ; *Lymph Node Excision ; Male ; Female ; Aged ; Middle Aged ; *Cystectomy/methods ; *Neoplasm Invasiveness ; Disease-Free Survival ; *Neoplasm Staging ; Lymphatic Metastasis ; Neoadjuvant Therapy ; Kaplan-Meier Estimate ; Chemotherapy, Adjuvant ; }, abstract = {BACKGROUND: Whether extended lymphadenectomy is associated with improved disease-free and overall survival, as compared with standard lymphadenectomy, among patients with localized muscle-invasive bladder cancer undergoing radical cystectomy is unclear.
METHODS: We randomly assigned, in a 1:1 ratio, patients with localized muscle-invasive bladder cancer of clinical stage T2 (confined to muscle) to T4a (invading adjacent organs) with two or fewer positive nodes (N0, N1, or N2) to undergo bilateral standard lymphadenectomy (dissection of lymph nodes on both sides of the pelvis) or extended lymphadenectomy involving removal of common iliac, presciatic, and presacral nodes. Randomization was performed during surgery and stratified according to the receipt and type of neoadjuvant chemotherapy, tumor stage (T2 vs. T3 or T4a), and a Zubrod's performance-status score (0 or 1 vs. 2; assessed on a 5-point scale, with higher scores indicating greater disability). The primary outcome was disease-free survival. Overall survival and safety were also assessed.
RESULTS: Of 658 patients who were enrolled, 592 eligible patients were randomly assigned to undergo extended lymphadenectomy (292 patients) or standard lymphadenectomy (300). Surgery was performed by 36 surgeons at 27 sites in the United States and Canada. Neoadjuvant chemotherapy had been received by 57% of the patients. At a median follow-up of 6.1 years, recurrence or death had occurred in 130 patients (45%) in the extended-lymphadenectomy group and in 127 (42%) in the standard-lymphadenectomy group, and the estimated 5-year disease-free survival was 56% and 60%, respectively (hazard ratio for recurrence or death, 1.10; 95% confidence interval [CI], 0.86 to 1.40; P = 0.45). Overall survival at 5 years was 59% in the extended-lymphadenectomy group and 63% in the standard-lymphadenectomy group (hazard ratio for death, 1.13; 95% CI, 0.88 to 1.45). Adverse events of grade 3 to 5 occurred in 157 patients (54%) in the extended-lymphadenectomy group and in 132 (44%) in the standard-lymphadenectomy group; death within 90 days after surgery occurred in 19 patients (7%) and 7 patients (2%), respectively.
CONCLUSIONS: As compared with standard lymphadenectomy, extended lymphadenectomy did not result in improved disease-free or overall survival among patients with muscle-invasive bladder cancer undergoing radical cystectomy and was associated with higher perioperative morbidity and mortality. (Funded by the National Cancer Institute and the Canadian Cancer Society; SWOG S1011 ClinicalTrials.gov number, NCT01224665.).}, }
@article {pmid39589343, year = {2024}, author = {Haffner, MC and Morris, MJ and Ding, CC and Sayar, E and Mehra, R and Robinson, B and True, LD and Gleave, M and Lotan, TL and Aggarwal, R and Huang, J and Loda, M and Nelson, PS and Rubin, MA and Beltran, H}, title = {Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-2061}, pmid = {39589343}, issn = {1557-3265}, abstract = {Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC) occurs in up to 15-20% of patients with castration-resistant prostate cancer (CRPC) as mechanism of treatment resistance and is associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of neuroendocrine (NE) lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions making clinical trial design challenging. Here we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and immunohistochemical markers with a priority for AR, NKX3.1, INSM1, synaptophysin and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.}, }
@article {pmid39587707, year = {2024}, author = {Ilozumba, MN and Lin, T and Hardikar, S and Byrd, DA and Round, JL and Stephens, WZ and Holowatyj, AN and Warby, CA and Damerell, V and Li, CI and Figueiredo, JC and Toriola, AT and Shibata, D and Fillmore, GC and Pickron, B and Siegel, EM and Kahlert, C and Florou, V and Gigic, B and Ose, J and Ulrich, CM}, title = {Fusobacterium nucleatum Abundance is Associated with Cachexia in Colorectal Cancer Patients: The ColoCare Study.}, journal = {Cancer medicine}, volume = {13}, number = {22}, pages = {e70431}, doi = {10.1002/cam4.70431}, pmid = {39587707}, issn = {2045-7634}, support = {//the German Ministry of Education and Research project PerMiCCion (01KD2101D)/ ; //German Cancer Research Center/ ; //the German Consortium of Translational Cancer Research, (DKTK)/ ; R01 CA189184/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R01 CA211705/CA/NCI NIH HHS/United States ; R01 CA254108/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; //University of Utah Immunology, Inflammation, and Infectious Disease Initiative/ ; //Huntsman Cancer Foundation/ ; //Stiftung LebensBlicke, Matthias Lackas Stiftung, Claussen-Simon Stiftung/ ; //the Rahel-Goitein-Straus-Program, Medical Faculty Heidelberg University/ ; //ERA-NET (European Research Area Network) on Translational Cancer Research (TRANSCAN) project/ ; //Cancer Control and Population Health Sciences (CCPS) at the University of Utah/ ; }, mesh = {Humans ; *Colorectal Neoplasms/complications/microbiology ; Male ; *Cachexia/etiology/microbiology ; *Fusobacterium nucleatum/isolation & purification ; Female ; Aged ; Middle Aged ; *Feces/microbiology ; Fusobacterium Infections/complications/microbiology ; Neoplasm Staging ; Risk Factors ; }, abstract = {BACKGROUND: Cachexia accounts for about 20% of all cancer-related deaths and indicates poor prognosis. The impact of Fusobacterium nucleatum (Fn), a microbial risk factor for colorectal cancer (CRC), on the development of cachexia in CRC has not been established.
METHODS: We evaluated the association between Fn abundance in pre-surgical stool samples and onset of cachexia at 6 months post-surgery in n = 87 patients with stages I-III CRC in the ColoCare Study.
RESULTS: High fecal Fn abundance compared to negative/low fecal Fn abundance was associated with 4-fold increased risk of cachexia onset at 6 months post-surgery (OR = 4.82, 95% CI = 1.15, 20.10, p = 0.03).
CONCLUSION: Our findings suggest that high fecal Fn abundance was associated with an increased risk of cachexia at 6 months post-surgery in CRC patients. This is the first study to link Fn abundance with cachexia in CRC patients, offering novel insights into biological mechanisms and potential management of cancer cachexia. Due to the small sample size, our results should be interpreted with caution. Future studies with larger sample sizes are needed to validate these findings.}, }
@article {pmid39587448, year = {2024}, author = {Papadimitriou, N and Murphy, N and Jenab, M and Chen, Z and Brenner, H and Kweon, SS and Le Marchand, L and Moreno, V and Platz, EA and van Duijnhoven, FJB and Cheng, I and Pai, RK and Phipps, AI and Peters, U and Zheng, W and Hughes, DJ}, title = {Body mass index at birth and early life and colorectal cancer: A two-sample Mendelian randomization analysis in European and East Asian genetic similarity populations.}, journal = {Pediatric obesity}, volume = {}, number = {}, pages = {e13186}, doi = {10.1111/ijpo.13186}, pmid = {39587448}, issn = {2047-6310}, support = {31312020//International Health Cohorts Consortium/Global Genomic Medicine Collaborative/ ; R01CA188214/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Varying obesogenic inherited predisposition in early to later life may differentially impact colorectal cancer (CRC) development. Previous Mendelian randomization (MR) studies, conducted in populations of European genetic similarity, have not observed any significant associations between early life body weight with CRC risk. However, it remains unclear whether body mass index (BMI) at different early lifetime points is causally related with CRC risk in both Europeans and East Asian populations.
OBJECTIVES: We conducted a two-sample MR study to investigate potential causal relationships between genetically predicted BMI during early life (birth to 8 years old) and at specific periods (birth, transient, early rise and late rise) and CRC risk.
METHODS: Summary data were obtained from genome-wide association study (GWAS) of BMI in 28 681 children from the Norwegian Mother, Father and Child Cohort Study (MoBa) study and applied to CRC GWAS data from European and East Asian descent populations (102 893 cases and 485 083 non-cases).
RESULTS: There were no significant associations observed between early life BMI and CRC risk in European or East Asian populations. The effect estimates were similar in European studies (odds ratio [OR] per a 1-standard deviation [SD] increase: 1.01, 95% confidence interval [CI]: 0.95, 1.07) and in East Asians (OR per a 1-SD increase: 1.02, 95% CI: 0.91, 1.14). Similar nonsignificant associations were found between time of BMI measurement during childhood and cancer-site-specific analyses.
CONCLUSIONS: We found little evidence of any associations between early life adiposity on later life CRC risk.}, }
@article {pmid39586191, year = {2024}, author = {Dean, NE and Halloran, ME and Zarnitsyna, VI}, title = {Poor vaccine responders mask the true trend in vaccine effectiveness against progression to severe disease.}, journal = {Vaccine}, volume = {43}, number = {Pt 2}, pages = {126516}, doi = {10.1016/j.vaccine.2024.126516}, pmid = {39586191}, issn = {1873-2518}, abstract = {Vaccines can reduce an individual's risk of infection and their risk of progression to severe disease given infection. The latter effect is less commonly estimated but is relevant for vaccine impact modeling and cost-effectiveness calculations. Using a motivating example from the COVID-19 literature, we note how vaccine effectiveness against progression to severe disease can appear to increase from below 0 % to over 70 % within 8 months. With true biological strengthening of this magnitude being unlikely, we use a mathematical modeling framework to identify parameter combinations where this phenomenon can occur. Fundamental features are an immunocompetent population with high initial protection against infection, contrasted with a vulnerable subpopulation with poor vaccine response against infection and progression. As a result, the earliest infections are among those with the weakest protection against severe disease. This work highlights methodological challenges in isolating a vaccine's effect on progression to severe disease after infection, and it signals the need for refined analytical methods to adjust for differences between the vaccinated infected and the unvaccinated infected populations.}, }
@article {pmid39586040, year = {2024}, author = {LeBlanc, ML}, title = {Using Cure Models for Trial Analysis and Design.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2401918}, doi = {10.1200/JCO-24-01918}, pmid = {39586040}, issn = {1527-7755}, }
@article {pmid39584453, year = {2024}, author = {Colasurdo, M and Ferrer-Font, L and Middlebrook, A and Konecny, AJ and Prlic, M and Spidlen, J}, title = {SingletSeeker: an unsupervised clustering approach for automated singlet discrimination in cytometry.}, journal = {Cytometry. Part B, Clinical cytometry}, volume = {}, number = {}, pages = {}, doi = {10.1002/cyto.b.22216}, pmid = {39584453}, issn = {1552-4957}, support = {R01 AI123323/NH/NIH HHS/United States ; R56 DE032009/NH/NIH HHS/United States ; //Emerson Collective/ ; }, abstract = {Flow cytometry is a high-throughput, high-dimensional technique that generates large sets of single-cell data. Prior to analyzing this data, it is common to exclude any events that contain two or more cells, multiplets, to ensure downstream analysis and quantification is of single-cell events, singlets, only. The process of singlet discrimination is critical yet fundamentally subjective and time-consuming; it is performed manually by the user, where the proper exclusion of multiplets depends on the user's expertise and often varies from experiment to experiment. To address this problem, we have developed an algorithm to automatically discriminate singlets from other unwanted events such as multiplets and debris. Using parameters derived from imaging, the algorithm first identifies high-density clusters of events using a density-based clustering algorithm, and then classifies the clusters based on their properties. Multiplets are discarded in the first step, while singlets are distinguished from debris in the second step. The algorithm can use different strategies on imaging feature selection-based user's preferences and imaging features available. In addition, the relative importance of singlets precision vs. sensitivity can be further tweaked via a density coefficient adjustment. Twenty-two datasets from various sites and of various cell types acquired on the BD FACSDiscover™ S8 Cell Sorter with CellView™ Image Technology were used to develop and validate the algorithm across multiple imaging feature sets. A consistent singlets precision >97% with a solid >88% sensitivity has been demonstrated with a LightLoss feature set and the default density coefficient. This work yields a high-precision, high-sensitivity algorithm capable of objective and automated singlet discrimination across multiple cell types using various imaging-derived parameters. A free FlowJo™ Software plugin implementation is available for simple and reproducible singlet discrimination for use at the beginning of any user's workflow.}, }
@article {pmid39582620, year = {2024}, author = {Isacchini, G and Quiniou, V and Barennes, P and Mhanna, V and Vantomme, H and Stys, P and Mariotti-Ferrandiz, E and Klatzmann, D and Walczak, AM and Mora, T and Nourmohammad, A}, title = {Local and Global Variability in Developing Human T-Cell Repertoires.}, journal = {PRX life}, volume = {2}, number = {1}, pages = {}, pmid = {39582620}, issn = {2835-8279}, abstract = {The adaptive immune response relies on T cells that combine phenotypic specialization with diversity of T-cell receptors (TCRs) to recognize a wide range of pathogens. TCRs are acquired and selected during T-cell maturation in the thymus. Characterizing TCR repertoires across individuals and T-cell maturation stages is important for better understanding adaptive immune responses and for developing new diagnostics and therapies. Analyzing a dataset of human TCR repertoires from thymocyte subsets, we find that the variability between individuals generated during the TCR V(D)J recombination is maintained through all stages of T-cell maturation and differentiation. The interindividual variability of repertoires of the same cell type is of comparable magnitude to the variability across cell types within the same individual. To zoom in on smaller scales than whole repertoires, we defined a distance measuring the relative overlap of locally similar sequences in repertoires. We find that the whole repertoire models correctly predict local similarity networks, suggesting a lack of forbidden T-cell receptor sequences. The local measure correlates well with distances calculated using whole repertoire traits and carries information about cell types.}, }
@article {pmid39581347, year = {2024}, author = {Wittenauer, R and Bacci, JL and Shah, PD and Stergachis, A}, title = {Vaccination payments in states with provider status for pharmacists: a claims analysis.}, journal = {Journal of the American Pharmacists Association : JAPhA}, volume = {}, number = {}, pages = {102301}, doi = {10.1016/j.japh.2024.102301}, pmid = {39581347}, issn = {1544-3450}, abstract = {BACKGROUND: Federal-level legislation to recognize pharmacists as providers and thus allow insurance reimbursement for health services claims, not just prescription drug claims (known as provider status), has been advocated by the profession but is yet to be passed into federal law. Several state governments have enacted this recognition for commercial insurance and/or Medicaid plans. However, the impact of these laws on reimbursement and access to health services has yet to be explored empirically.
OBJECTIVE: Compare commercial reimbursements for influenza and herpes zoster vaccinations for adults in provider status vs non-provider status states to determine whether these laws have had an intended effect of increasing reimbursement to pharmacists for provided services.
METHODS: We used pharmaceutical and outpatient services claims from a national claims database, Marketscan, to examine payments made to pharmacies for all codes billed during vaccination visits. We then used a multivariable logistic regression model to compare the net revenue of vaccination visits in commercial provider status states versus non-provider-status states.
RESULTS: Our dataset contained 2.3 million vaccination visits for influenza and herpes zoster during 2021-2022. We found that the odds of a vaccination visit having positive net revenue were slightly higher in provider status states (shingles OR: 1.03, p<0.001; influenza OR 1.01:, p<0.001). These findings are limited by the stark lack of health services claims by pharmacies in our dataset; only 0.4% of visits included any outpatient services claims, even among provider status states.
CONCLUSION: This indicates that pharmacists are not submitting claims for reimbursement to payors for health services they are providing. This absence could be due to several reasons and limits the ability to generate evidence about the effect of these laws on health and economic outcomes for patients and health systems. Further research is needed to identify and address barriers to implementation of provider status laws.}, }
@article {pmid39580580, year = {2024}, author = {Chan, WC and Liu, L and Bouras, E and Zuber, V and Wen, W and Long, J and Gill, D and Murphy, N and Gunter, MJ and Assimes, TL and Bujanda, L and Gruber, SB and Küry, S and Lynch, BM and Qu, C and Thomas, M and White, E and Woods, MO and Peters, U and Li, CI and Chan, AT and Brenner, H and Tsilidis, KK and Zheng, W}, title = {Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, pmid = {39580580}, issn = {1532-1827}, abstract = {BACKGROUND: Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear.
METHODS: Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium (n = 1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium (n = 58,221 cases and 67,694 controls). Our main analysis was a multivariable MR (MVMR) with mutual adjustments for LDL-C, HDL-C, and triglycerides. Secondary analyses, including MVMR additionally-adjusting for BMI or diabetes, were also performed.
RESULTS: Genetically-predicted LDL-C was positively associated with CRC risk in the MVMR adjusted for HDL-C and triglycerides (OR = 1.09; 95%CI 1.02-1.16 per SD increase) and additionally-adjusted for BMI (OR = 1.12; 95%CI 1.05-1.21) or diabetes (OR = 1.09; 95%CI 1.02-1.17). Associations were generally consistent across anatomical subsites. No clear evidence of association was found for other lipids, lipoproteins, or LDL-lowering drug-targets.
CONCLUSIONS: We found evidence of a weak positive association between LDL-C and CRC that did not appear to be explained by potential pleiotropic pathways such as via HDL-C, triglycerides, BMI, or diabetes.}, }
@article {pmid39579334, year = {2024}, author = {Clement, ME and Hanscom, B and Haines, D and Bazan, JA and Chotirosniramit, N and Kofron, R and Mannheimer, S and Mayer, KH and Torres Silva, MS and Soto-Torres, L and Rinehart, AR and Rooney, JF and Jennings, A and Gomez-Feliciano, K and McCauley, M and Grinsztejn, B and Landovitz, RJ and , }, title = {Cabotegravir Maintains Protective Efficacy in the Setting of Bacterial STIs: A Secondary Analysis of HPTN 083.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae572}, pmid = {39579334}, issn = {1537-6591}, abstract = {BACKGROUND: Sexually transmitted infections (STIs) have been shown to facilitate HIV transmission and acquisition. HPTN 083, a global clinical trial, demonstrated superiority of long-acting cabotegravir (CAB-LA) versus daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV prevention among transgender women and cisgender men who have sex with men. This analysis assessed whether CAB-LA maintained protective efficacy when bacterial STIs (syphilis, rectal/urethral gonorrhea and chlamydia) were present.
METHODS: STI events per 100 person-years (PY) were calculated, including by subgroups (age, race/ethnicity, gender, education, treatment arm, drug use, alcohol use, region/country, condom usage, partner number, marital status, baseline STI). Association between baseline factors and STI incidence was modeled using Poisson regression. Cox proportional hazards modeling with STI status as a time-varying covariate was used to evaluate potential interactions between STI status and the relative efficacy of CAB-LA vs. TDF/FTC.
FINDINGS: Among 3,859 participants, overall STI incidence rate was 50.7 infections/100PY. STIs were diagnosed in 1,562 (40.5%) participants; 79% of STIs occurred in 25% of the participants. STI incidence was not different by PrEP arm. In the final multivariable model, age, region, race, education level, marital status, and baseline STI were associated with incident STI (p<0.05). HIV incidence was lower with CAB-LA vs. TDF/FTC with or without STIs (hazard ratios 0.37 and 0.31, respectively), with no significant interaction between STIs and the HR for HIV incidence (p = 0.75).
CONCLUSION: In a large PrEP trial with high STI incidence, CAB-LA maintained robust protective efficacy relative to TDF/FTC in the setting of bacterial STIs.}, }
@article {pmid39577421, year = {2024}, author = {Hamidi, H and Senbabaoglu, Y and Beig, N and Roels, J and Manuel, C and Guan, X and Koeppen, H and Assaf, ZJ and Nabet, BY and Waddell, A and Yuen, K and Maund, S and Sokol, E and Giltnane, JM and Schedlbauer, A and Fuentes, E and Cowan, JD and Kadel, EE and Degaonkar, V and Andreev-Drakhlin, A and Williams, P and Carter, C and Gupta, S and Steinberg, E and Loriot, Y and Bellmunt, J and Grivas, P and Rosenberg, J and van der Heijden, MS and Galsky, MD and Powles, T and Mariathasan, S and Banchereau, R}, title = {Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2024.10.016}, pmid = {39577421}, issn = {1878-3686}, abstract = {Checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have revolutionized cancer therapy across many indications including urothelial carcinoma (UC). Because many patients do not benefit, a better understanding of the molecular mechanisms underlying response and resistance is needed to improve outcomes. We profiled tumors from 2,803 UC patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab by RNA sequencing (RNA-seq), a targeted DNA panel, immunohistochemistry, and digital pathology. Machine learning identifies four transcriptional subtypes, representing luminal desert, stromal, immune, and basal tumors. Overall survival benefit from atezolizumab over standard-of-care is observed in immune and basal tumors, through different response mechanisms. A self-supervised digital pathology approach can classify molecular subtypes from H&E slides with high accuracy, which could accelerate tumor molecular profiling. This study represents a large integration of UC molecular and clinical data in randomized trials, paving the way for clinical studies tailoring treatment to specific molecular subtypes in UC and other indications.}, }
@article {pmid39576958, year = {2024}, author = {Adams, RC and MacDonald, KP and Hill, GR}, title = {The Contribution of the Monocyte-Macrophage Lineage to Immunotherapy Outcomes.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025680}, pmid = {39576958}, issn = {1528-0020}, abstract = {Macrophages execute core functions in maintaining tissue homeostasis, where their extensive plasticity permits a spectrum of functions from tissue remodelling to immune defence. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic haematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)-dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1R to induce macrophage depletion showed remarkable capacity to prevent fibrosis in pre-clinical models and has subsequently demonstrated impressive efficacy for improving fibrotic cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with CAR T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualise this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signalling axis, for therapeutic benefit in the context of both cellular and immunotherapy.}, }
@article {pmid39576815, year = {2024}, author = {Weissman, JL and Chappell, CR and Francesco Rodrigues de Oliveira, B and Evans, N and Fagre, AC and Forsythe, D and Frese, SA and Gregor, R and Ishaq, SL and Johnston, J and K R, B and Matsuda, SB and McCarren, S and Ortiz Alvarez de la Campa, M and Roepke, TA and Sinnott-Armstrong, N and Stobie, CS and Talluto, L and Vargas-Muñiz, JM and , }, title = {Queer- and trans-inclusive faculty hiring-A call for change.}, journal = {PLoS biology}, volume = {22}, number = {11}, pages = {e3002919}, doi = {10.1371/journal.pbio.3002919}, pmid = {39576815}, issn = {1545-7885}, abstract = {As queer and trans scientists, we face varied and systemic barriers to our professional success, resulting in our relative absence from faculty ranks at many institutions. In this Perspective, we call for a change in faculty hiring practices and present concrete guidance to make it a more inclusive process.}, }
@article {pmid39576760, year = {2024}, author = {Correa-Medero, RL and Pai, R and Ebare, K and Buchanan, DD and Jenkins, MA and Phipps, AI and Newcomb, PA and Gallinger, S and Grant, R and Le Marchand, L and Banerjee, I}, title = {Causal debiasing for unknown bias in histopathology-A colon cancer use case.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0303415}, doi = {10.1371/journal.pone.0303415}, pmid = {39576760}, issn = {1932-6203}, mesh = {Humans ; *Colonic Neoplasms/pathology ; Proportional Hazards Models ; Bias ; Prognosis ; Female ; Male ; Disease-Free Survival ; }, abstract = {Advancement of AI has opened new possibility for accurate diagnosis and prognosis using digital histopathology slides which not only saves hours of expert effort but also makes the estimation more standardized and accurate. However, preserving the AI model performance on the external sites is an extremely challenging problem in the histopathology domain which is primarily due to the difference in data acquisition and/or sampling bias. Although, AI models can also learn spurious correlation, they provide unequal performance across validation population. While it is crucial to detect and remove the bias from the AI model before the clinical application, the cause of the bias is often unknown. We proposed a Causal Survival model that can reduce the effect of unknown bias by leveraging the causal reasoning framework. We use the model to predict recurrence-free survival for the colorectal cancer patients using quantitative histopathology features from seven geographically distributed sites and achieve equalized performance compared to the baseline traditional Cox Proportional Hazards and DeepSurvival model. Through ablation study, we demonstrated benefit of novel addition of latent probability adjustment and auxiliary losses. Although detection of cause of unknown bias is unsolved, we proposed a causal debiasing solution to reduce the bias and improve the AI model generalizibility on the histopathology domain across sites. Open-source codebase for the model training can be accessed from https://github.com/ramon349/fair_survival.git.}, }
@article {pmid39576210, year = {2024}, author = {Sweis, RF and Chatta, GS and Jain, RK and Moon, H and Delacroix, SE and Fang, A and D'Amico, L and Kask, AS and Cheever, MA and Fling, S and Sharon, E and Lacroix, A and Kaiser, JC and Pachynski, RK and Yu, EY}, title = {A phase II open label, randomized clinical trial of atezolizumab with or without human recombinant IL-7 (CYT107) in advanced urothelial cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1728}, pmid = {39576210}, issn = {1557-3265}, abstract = {PURPOSE: Advanced urothelial cancer generally has high mortality despite modern anti-PD-1/L1 antibody-based combinations. Augmenting checkpoint inhibitor-mediated immune responses with lymphocyte growth factors may improve outcomes. We conducted a randomized phase II study (CITN-14) in 47 patients to explore whether human recombinant IL-7 (CYT107) could be safely combined with PD-L1 inhibition to enhance responses.
PATIENTS AND METHODS: Patients with urothelial cancer following platinum chemotherapy were randomized to atezolizumab alone or with CYT107 weekly for four doses. The primary objective was clinical efficacy by objective response rate (ORR). Secondary objectives included safety, toxicity, and other clinical outcomes. Correlative endpoints included peripheral immunophenotyping and quantification of cytokines.
RESULTS: CYT107 plus atezolizumab was well-tolerated, without dose-limiting toxicities (DLTs), and lower grade 3-4 treatment-related adverse events (TRAEs) compared to atezolizumab. The ORR was 26.3% for the combination versus 23.8% for atezolizumab alone (p = 0.428). The complete response (CR) rate was 10.5% for the combination versus 4.8% for monotherapy. Three patients on the combination had responses >21 months versus one with monotherapy. CD4+ and CD8+ T lymphocyte expansion occurred in patients with response to combination therapy, with the greatest effect in T memory stem cell (Tscm) cells. Responding patients had elevated baseline CCL4 and decreased VEGF-A and TNF.
CONCLUSIONS: Combining CYT107 with atezolizumab was safe and resulted in lymphocyte expansion, a doubling of the CR rate, and durable responses exceeding 2 years, however, the ORR was similar to atezolizumab alone. Increased and sustained doses of CYT107 coupled with patient selection strategies should be further investigated.}, }
@article {pmid39575237, year = {2024}, author = {Byrne, C and Schiffer, JT}, title = {Ensemble modeling of SARS-CoV-2 immune dynamics in immunologically naïve rhesus macaques predicts that potent, early innate immune responses drive viral elimination.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1426016}, pmid = {39575237}, issn = {1664-3224}, mesh = {Animals ; *Macaca mulatta ; *SARS-CoV-2/immunology ; *COVID-19/immunology/virology ; *Immunity, Innate ; *Viral Load ; Antibodies, Viral/immunology/blood ; Lung/immunology/virology ; }, abstract = {INTRODUCTION: An unprecedented breadth of longitudinal viral and multi-scale immunological data has been gathered during SARS-CoV-2 infection. However, due to the high complexity, non-linearity, multi-dimensionality, mixed anatomic sampling, and possible autocorrelation of available immune data, it is challenging to identify the components of the innate and adaptive immune response that drive viral elimination. Novel mathematical models and analytical approaches are required to synthesize contemporaneously gathered cytokine, transcriptomic, flow cytometry, antibody response, and viral load data into a coherent story of viral control, and ultimately to discriminate drivers of mild versus severe infection.
METHODS: We investigated a dataset describing innate, SARS-CoV-2 specific T cell, and antibody responses in the lung during early and late stages of infection in immunologically naïve rhesus macaques. We used multi-model inference and ensemble modeling approaches from ecology and weather forecasting to compare and combine various competing models.
RESULTS AND DISCUSSION: Model outputs suggest that the innate immune response plays a crucial role in controlling early infection, while SARS-CoV-2 specific CD4+ T cells correspond to later viral elimination, and anti-spike IgG antibodies do not impact viral dynamics. Among the numerous genes potentially contributing to the innate response, we identified IFI27 as most closely linked to viral load decline. A 90% knockdown of the innate response from our validated model resulted in a ~10-fold increase in peak viral load during infection. Our approach provides a novel methodological framework for future analyses of similar complex, non-linear multi-component immunologic data sets.}, }
@article {pmid39554199, year = {2024}, author = {Yu, Z and Vromman, A and Nguyen, NQH and Schuermans, A and Rentz, T and Vellarikkal, SK and Uddin, MM and Niroula, A and Griffin, G and Honigberg, MC and Lin, AE and Gibson, CJ and Katz, DH and Tahir, U and Fang, S and Haidermota, S and Ganesh, S and Antoine, T and Weinstock, J and Austin, TR and Ramachandran, VS and Peloso, GM and Hornsby, W and Ganz, P and Manson, JE and Haring, B and Kooperberg, CL and Reiner, AP and Bis, JC and Psaty, BM and Min, YI and Correa, A and Lange, LA and Post, WS and Rotter, JI and Rich, SS and Wilson, JG and Ebert, BL and Yu, B and Ballantyne, CM and Coresh, J and Sankaran, VG and Bick, AG and Jaiswal, S and Gerszten, RE and , and Libby, P and Gupta, RM and Natarajan, P}, title = {Human Plasma Proteomic Profile of Clonal Hematopoiesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39554199}, issn = {2692-8205}, support = {RC2 HL102419/HL/NHLBI NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; R01 HL134892/HL/NHLBI NIH HHS/United States ; R01 HL127564/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01HC95160/HL/NHLBI NIH HHS/United States ; DP5 OD029586/OD/NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; U01 DK108809/DK/NIDDK NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; R01 MH104964/MH/NIMH NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; R01 HL153499/HL/NHLBI NIH HHS/United States ; R01 HL151283/HL/NHLBI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; R01 HL163099/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; R01 DK125782/DK/NIDDK NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01HC95169/HL/NHLBI NIH HHS/United States ; U01 HG004402/HG/NHGRI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; N01HC95168/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; R01 HL142711/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 HL159081/HL/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95159/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; N01HC95161/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; DP2 HL157540/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; R01 MH123451/MH/NIMH NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; N01HC95166/HL/NHLBI NIH HHS/United States ; R01 HL135242/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; R01 HL134320/HL/NHLBI NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; R01 HL148050/HL/NHLBI NIH HHS/United States ; T32 HL007604/HL/NHLBI NIH HHS/United States ; }, abstract = {Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.}, }
@article {pmid38826243, year = {2024}, author = {Tran-Kiem, C and Paredes, MI and Perofsky, AC and Frisbie, LA and Xie, H and Kong, K and Weixler, A and Greninger, AL and Roychoudhury, P and Peterson, JM and Delgado, A and Halstead, H and MacKellar, D and Dykema, P and Gamboa, L and Frazar, CD and Ryke, E and Stone, J and Reinhart, D and Starita, L and Thibodeau, A and Yun, C and Aragona, F and Black, A and Viboud, C and Bedford, T}, title = {Fine-scale spatial and social patterns of SARS-CoV-2 transmission from identical pathogen sequences.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {38826243}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 CK000630/CK/NCEZID CDC HHS/United States ; }, abstract = {Pathogen genomics can provide insights into underlying infectious disease transmission patterns, but new methods are needed to handle modern large-scale pathogen genome datasets and realize this full potential. In particular, genetically proximal viruses should be highly informative about transmission events as genetic proximity indicates epidemiological linkage. Here, we leverage pairs of identical sequences to characterise fine-scale transmission patterns using 114,298 SARS-CoV-2 genomes collected through Washington State (USA) genomic sentinel surveillance with associated age and residence location information between March 2021 and December 2022. This corresponds to 59,660 sequences with another identical sequence in the dataset. We find that the location of pairs of identical sequences is highly consistent with expectations from mobility and social contact data. Outliers in the relationship between genetic and mobility data can be explained by SARS-CoV-2 transmission between postal codes with male prisons, consistent with transmission between prison facilities. We find that transmission patterns between age groups vary across spatial scales. Finally, we use the timing of sequence collection to understand the age groups driving transmission. Overall, this work improves our ability to leverage large pathogen genome datasets to understand the determinants of infectious disease spread.}, }
@article {pmid38677728, year = {2024}, author = {Amery, T and Tabatabaei, S and Sonpatki, M and Yu, EY and Beer, TM}, title = {MAOA Inhibitor Plus Docetaxel in Patients Receiving and Progressing on Docetaxel Therapy.}, journal = {Anticancer research}, volume = {44}, number = {5}, pages = {2247-2248}, doi = {10.21873/anticanres.17033}, pmid = {38677728}, issn = {1791-7530}, mesh = {Humans ; Male ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Disease Progression ; *Docetaxel/therapeutic use/administration & dosage ; }, }
@article {pmid39575442, year = {2019}, author = {Wang, Y and Chen, YQ}, title = {Estimating Attributable Life Expectancy Under the Proportional Mean Residual Life Model.}, journal = {Statistics in biosciences}, volume = {11}, number = {3}, pages = {659-676}, pmid = {39575442}, issn = {1867-1764}, abstract = {In population-based health research, the so-called population attributable fraction is an important quantity that calculates the percentage of excess risk of morbidity and mortality associated with modifiable risk factors for a given population. While the concept of "risk" is usually measured by event probabilities, in practice it may be of a more direct interest to know the excess life expectancy associated with the modifiable risk factors instead, particularly when mortality is of the ultimate concern. In this paper, we thus propose to study a novel quantity, termed "attributable life expectancy," to measure the population attributable fraction of life expectancy. We further develop a model-based approach for the attributable life expectancy under the Oakes-Dasu proportional mean residual life model, and establish its asymptotic properties for inferences. Numerical studies that includes Monte-Carlo simulations and an actual analysis of the mortality associated with smoking cessation in an Asia Cohort Consortium, are conducted to evaluate the performance of our proposed method.}, }
@article {pmid39572695, year = {2024}, author = {Schuermans, A and Pournamdari, AB and Lee, J and Bhukar, R and Ganesh, S and Darosa, N and Small, AM and Yu, Z and Hornsby, W and Koyama, S and Kooperberg, C and Reiner, AP and Januzzi, JL and Honigberg, MC and Natarajan, P}, title = {Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction.}, journal = {Nature cardiovascular research}, volume = {}, number = {}, pages = {}, pmid = {39572695}, issn = {2731-0590}, support = {Paul & Phyllis Fireman Endowed Chair in Vascular Medicine//Massachusetts General Hospital (MGH)/ ; R01HL127564//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; K08HL166687//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 940166//American Heart Association (American Heart Association, Inc.)/ ; 979465//American Heart Association (American Heart Association, Inc.)/ ; }, abstract = {Cardiac diseases represent common highly morbid conditions for which molecular mechanisms remain incompletely understood. Here we report the analysis of 1,459 protein measurements in 44,313 UK Biobank participants to characterize the circulating proteome associated with incident coronary artery disease, heart failure, atrial fibrillation and aortic stenosis. Multivariable-adjusted Cox regression identified 820 protein-disease associations-including 441 proteins-at Bonferroni-adjusted P < 8.6 × 10[-6]. Cis-Mendelian randomization suggested causal roles aligning with epidemiological findings for 4% of proteins identified in primary analyses, prioritizing therapeutic targets across cardiac diseases (for example, spondin-1 for atrial fibrillation and the Kunitz-type protease inhibitor 1 for coronary artery disease). Interaction analyses identified seven protein-disease associations that differed Bonferroni-significantly by sex. Models incorporating proteomic data (versus clinical risk factors alone) improved prediction for coronary artery disease, heart failure and atrial fibrillation. These results lay a foundation for future investigations to uncover disease mechanisms and assess the utility of protein-based prevention strategies for cardiac diseases.}, }
@article {pmid39571171, year = {2024}, author = {Chong, EA and Penuel, E and Napier, EB and Lundberg, RK and Budde, LE and Shadman, M and Matasar, MJ and Bartlett, NL and Flinn, IW and Bosch, F and Fay, K and Goy, A and Kumar, A and Nastoupil, LJ and Wei, MC and Wu, M and Yin, S and Fraietta, JA and Chong, ER and Schuster, SJ}, title = {Impact of prior CAR-T cell therapy on mosunetuzumab efficacy in patients with relapsed or refractory B-cell lymphomas.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024013640}, pmid = {39571171}, issn = {2473-9537}, abstract = {Mosunetuzumab and other CD20/CD3 bispecific antibodies (BsAbs) have efficacy in B-cell lymphomas relapsing after or refractory to CD19-directed chimeric antigen receptor-modified T cells (CAR-T). The optimal timing of BsAbs and biomarkers of BsAb response after CAR-T are unknown. We addressed these questions using clinical data and blood samples from patients previously treated with CAR-T treated on a phase I/II study of mosunetuzumab (clinicaltrials.gov; NCT02500407). Thirty patients had paired samples at baseline and after 1 cycle of mosunetuzumab. Median time from CAR-T to mosunetuzumab was significantly longer for responding than for nonresponding patients (p=0.006, unadjusted for multiple comparisons). Most patients (20/30) did not receive intervening therapy between CAR-T administration and mosunetuzumab. The remainder of patients received one intervening therapy after a protocol-mandated drug washout. After mosunetuzumab, responding patients had higher lymphocytes (995 vs 400 cells/µL, p = 0.02) and greater increases in CD4 and CD8 cells (median change, 73 vs -90 cells/µL, p=0.005; 243 vs -103 cells/µL, p=0.004, respectively). Additionally, responding patients had an increase in activated CD8 cells (median 1.7-fold-change, p=0.02). Non-responders had a relative decrease in CAR transgene levels (N=16; p=0.04). This is the first study to assess changes in lymphocytes, T cells, and CAR transgene levels in patients treated with BsAb after CAR-T. These findings suggest an interaction between prior CAR-T and BsAb outcomes, and have implications for optimal timing of BsAb after CAR-T.}, }
@article {pmid39570997, year = {2024}, author = {Courret, C and Hemmer, LW and Wei, X and Patel, PD and Chabot, BJ and Fuda, NJ and Geng, X and Chang, CH and Mellone, BG and Larracuente, AM}, title = {Turnover of retroelements and satellite DNA drives centromere reorganization over short evolutionary timescales in Drosophila.}, journal = {PLoS biology}, volume = {22}, number = {11}, pages = {e3002911}, doi = {10.1371/journal.pbio.3002911}, pmid = {39570997}, issn = {1545-7885}, abstract = {Centromeres reside in rapidly evolving, repeat-rich genomic regions, despite their essential function in chromosome segregation. Across organisms, centromeres are rich in selfish genetic elements such as transposable elements and satellite DNAs that can bias their transmission through meiosis. However, these elements still need to cooperate at some level and contribute to, or avoid interfering with, centromere function. To gain insight into the balance between conflict and cooperation at centromeric DNA, we take advantage of the close evolutionary relationships within the Drosophila simulans clade-D. simulans, D. sechellia, and D. mauritiana-and their relative, D. melanogaster. Using chromatin profiling combined with high-resolution fluorescence in situ hybridization on stretched chromatin fibers, we characterize all centromeres across these species. We discovered dramatic centromere reorganization involving recurrent shifts between retroelements and satellite DNAs over short evolutionary timescales. We also reveal the recent origin (<240 Kya) of telocentric chromosomes in D. sechellia, where the X and fourth centromeres now sit on telomere-specific retroelements. Finally, the Y chromosome centromeres, which are the only chromosomes that do not experience female meiosis, do not show dynamic cycling between satDNA and TEs. The patterns of rapid centromere turnover in these species are consistent with genetic conflicts in the female germline and have implications for centromeric DNA function and karyotype evolution. Regardless of the evolutionary forces driving this turnover, the rapid reorganization of centromeric sequences over short evolutionary timescales highlights their potential as hotspots for evolutionary innovation.}, }
@article {pmid39570620, year = {2024}, author = {Jabbour, E and Oehler, VG and Koller, PB and Jamy, O and Lomaia, E and Hunter, AM and Uspenskaya, O and Samarina, S and Mukherjee, S and Cortes, JE and Baer, MR and Zherebtsova, V and Shuvaev, V and Turkina, A and Davydkin, I and Guo, H and Chen, Z and Fu, T and Jiang, L and Wang, C and Wang, H and Yang, D and Zhai, Y and Kantarjian, H}, title = {Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2024.5157}, pmid = {39570620}, issn = {2374-2445}, abstract = {IMPORTANCE: Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients.
OBJECTIVE: To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome-positive ALL resistant or intolerant to at least 2 TKIs.
This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome-positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib.
INTERVENTIONS: Patients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles.
MAIN OUTCOMES AND MEASURES: Pharmacokinetic profile of olverembatinib.
RESULTS: Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators' assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants.
CONCLUSIONS AND RELEVANCE: In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04260022.}, }
@article {pmid39570045, year = {2024}, author = {Valint, DJ and Fiedler, TL and Liu, C and Srinivasan, S and Fredricks, DN}, title = {Effect of metronidazole on concentrations of vaginal bacteria associated with risk of HIV acquisition.}, journal = {mBio}, volume = {}, number = {}, pages = {e0111024}, doi = {10.1128/mbio.01110-24}, pmid = {39570045}, issn = {2150-7511}, abstract = {Several bacterial vaginosis (BV)-associated bacteria have been associated with elevated risk of human immunodeficiency virus (HIV) acquisition; however, susceptibility of these bacteria to antibiotics is poorly understood. Vaginal samples were collected from 22 persons daily for 2 weeks following BV diagnosis. Metronidazole treatment was prescribed for 5-7 days. Changes in bacterial concentrations were measured with taxon-specific 16S rRNA gene quantitative PCR (qPCR) assays. A culture-based antimicrobial assay confirmed presence of antibiotics in vaginal swab samples. Bacterial DNA concentrations decreased during antibiotic administration for all 13 bacterial taxa tested. Comparison of bacterial DNA concentrations in samples before administration of antibiotics to samples taken on the last day of antimicrobial assay-confirmed antibiotic presence showed a 2.25-4.78 log10-fold decrease across all taxa. Concentrations were frequently reduced to the qPCR assay's limit of detection, suggesting eradication of bacteria. Mean clearance time varied across taxa (1.2-7.9 days), with several bacteria (e.g., Sneathia spp., Vaginal TM7, and Eggerthella-like sp.) taking >7 days to suppress. Metronidazole reduces quantities of bacterial taxa associated with increased HIV acquisition risk.IMPORTANCEHuman immunodeficiency virus (HIV) transmission through sex remains a major public health challenge despite efforts at risk reduction and use of anti-retroviral pre-exposure prophylaxis. Many bacterial vaginosis (BV)-associated vaginal bacteria have been associated with increased HIV infection risk among women. If these bacteria help mediate HIV infection risk, then eradication of these bacteria is one potential strategy to reduce this risk. However, the best approach to eradicate HIV-high risk bacteria from the vagina is not known. We analyzed vaginal swabs collected daily from women with BV to determine the impact of metronidazole treatment on 13 vaginal bacterial taxa linked to elevated risk of HIV infection through use of taxon-directed quantitative PCR assays. We conclude that eradication of high-risk vaginal bacteria using metronidazole is one promising avenue for reducing HIV acquisition risk, and we provide evidence that a 5-7-day treatment course may not be sufficient to suppress all bacteria.}, }
@article {pmid39569838, year = {2024}, author = {Triplette, M and Snidarich, M and Heffner, JL and Omernik, B and Ahmed, A and Brooks, E and Telew, B and Crothers, K and Brown, M}, title = {A Community-Engaged Research Study to Inform Tailored Programming for Smoking Cessation and Lung Cancer Screening Among At-Risk LGBTQ+ Elders.}, journal = {Health promotion practice}, volume = {}, number = {}, pages = {15248399241296101}, doi = {10.1177/15248399241296101}, pmid = {39569838}, issn = {1524-8399}, abstract = {Purpose. Lung cancer is the leading cause of cancer death, with most cases attributable to cigarette smoking. Many communities within the lesbian, gay, bisexual, transgender and queer/questioning (LGBTQ+) umbrella have high rates of smoking, but focused lung cancer prevention is limited. Our objective was to utilize a community-based participatory research (CBPR) approach to guide the development of a program focused on lung cancer prevention in LGBTQ+ elders. Methods. Through community partnerships, we recruited participants who self-identified as LGBTQ+ and were eligible for lung cancer screening (LCS) to participate in semi-structured qualitative discussions with complementary surveys. Qualitative guides were developed to collect data on determinants of smoking cessation and LCS and to elicit feedback on interventions to support lung cancer prevention through a tailored approach to patient navigation. Qualitative data were analyzed using rapid templated analysis to elucidate themes. Results. The 21 enrolled participants had diverse sexual and gender identities and 57% were of minoritized race/ethnicity. Most (81%) had experience with smoking cessation but few (10%) had undergone LCS. Overall themes suggest interest in personalized (to individuals), tailored (to the LGBTQ+ community) and integrated longitudinal programs to support lung cancer prevention. Themes suggest strong endorsement of focused messaging to LGBTQ+ persons and reducing stigma related to LGBTQ+ identity and smoking. Conclusions. Themes highlight the need for integrated tobacco and LCS programming which can provide longitudinal support, and ideally, center community settings and peer support. This formative work will be utilized to adapt a patient navigation program to assist screen-eligible LGBTQ+ elders.}, }
@article {pmid39567685, year = {2024}, author = {Reyes, RA and Raghavan, SSR and Hurlburt, NK and Introini, V and Bol, S and Kana, IH and Jensen, RW and Martinez-Scholze, E and Gestal-Mato, M and López-Gutiérrez, B and Sanz, S and Bancells, C and Fernández-Quintero, ML and Loeffler, JR and Ferguson, JA and Lee, WH and Martin, GM and Theander, TG and Lusingu, JPA and Minja, DTR and Ssewanyana, I and Feeney, ME and Greenhouse, B and Ward, AB and Bernabeu, M and Pancera, M and Turner, L and Bunnik, EM and Lavstsen, T}, title = {Broadly inhibitory antibodies to severe malaria virulence proteins.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {39567685}, issn = {1476-4687}, abstract = {Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels[1]. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis[2]. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here we describe two broadly reactive and inhibitory human monoclonal antibodies to CIDRα1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins, as well as parasite sequestration in bioengineered 3D human brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with three different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies are likely to represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.}, }
@article {pmid39567681, year = {2024}, author = {Leyderman, M and Chandrasekar, T and Grivas, P and Li, R and Bhat, S and Basnet, A and Shapiro, O and Jacob, J and Daneshvar, MA and Kord, E and Bratslavsky, G and Goldberg, H}, title = {Metastasis development in non-muscle-invasive bladder cancer.}, journal = {Nature reviews. Urology}, volume = {}, number = {}, pages = {}, pmid = {39567681}, issn = {1759-4820}, abstract = {Non-muscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer presentation and is characterized by a varying probability of recurrence and progression. Sporadically, patients with NMIBC might also develop tumour metastases without any pathological evidence of muscle-invasive disease within the bladder, a condition known as metastatic NMIBC. In the published literature, this phenomenon is limited to several case reports and small reviews, with few data regarding the possible aetiologies. Several possible factors can be potentially associated with metastatic NMIBC, including tumour understaging, the number of transurethral resection procedures received by the patient, the presence of circulating tumour cells, the modality used for diagnostic cystoscopy and possible gender-associated differences. In this Perspective, our aim was to integrate and report currently available data on this relatively rare entity and provide some potential aetiological explanations.}, }
@article {pmid39567499, year = {2024}, author = {Chatterjee, SS and Linares, JF and Cid-Diaz, T and Duran, A and Khan, MIK and Osrodek, M and Brady, NJ and Reina-Campos, M and Marzio, A and Venkadakrishnan, VB and Bakht, MK and Khani, F and Mosquera, JM and Robinson, BD and Moyer, J and Elemento, O and Hsieh, AC and Goodrich, DW and Rickman, DS and Beltran, H and Moscat, J and Diaz-Meco, MT}, title = {Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9755}, pmid = {39567499}, issn = {2041-1723}, support = {R01CA246765//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R01CA277857//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R50CA283476//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R50CA265332//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; }, mesh = {*Enhancer of Zeste Homolog 2 Protein/metabolism/genetics ; Male ; *Phenylthiohydantoin/pharmacology ; *Benzamides ; Humans ; *Nitriles/pharmacology ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/metabolism/pathology ; *Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor ; Animals ; Phosphorylation ; Protein Biosynthesis/drug effects ; Mice ; Transforming Growth Factor beta/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Protein Kinase C/metabolism/genetics ; }, abstract = {Overcoming resistance to therapy is a major challenge in castration-resistant prostate cancer (CRPC). Lineage plasticity towards a neuroendocrine phenotype enables CRPC to adapt and survive targeted therapies. However, the molecular mechanisms of epigenetic reprogramming during this process are still poorly understood. Here we show that the protein kinase PKCλ/ι-mediated phosphorylation of enhancer of zeste homolog 2 (EZH2) regulates its proteasomal degradation and maintains EZH2 as part of the canonical polycomb repressive complex (PRC2). Loss of PKCλ/ι promotes a switch during enzalutamide treatment to a non-canonical EZH2 cistrome that triggers the transcriptional activation of the translational machinery to induce a transforming growth factor β (TGFβ) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCλ/ι-deficient CRPC.}, }
@article {pmid39565920, year = {2024}, author = {Hammarlund, N and Holt, SK and Etzioni, R and Morehead, D and Lee, JR and Wolff, EM and Burrola-Mendez, Y and Sage, L and Gore, JL and Nyame, YA}, title = {The Association of Where Patients with Prostate Cancer Live and Receive Care on Racial Treatment Inequities.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae302}, pmid = {39565920}, issn = {1460-2105}, abstract = {Black individuals are less likely to be treated for prostate cancer even though they are more than twice as likely to die compared to White individuals. The complex causes of these inequities are influenced by social and structural factors, including racism, which contribute to the differential delivery of care. This study investigates how factors related to the location of where individuals live and receive care affect treatment inequities for prostate cancer between Black and White individuals. We hypothesize that both location and race independently influence treatment inequities. We used data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry linked to Medicare claims to estimate the treatment inequity, as defined by differences in radiation or radical prostatectomy. Fixed effects at the physician, hospital, and patient ZIP code levels were incorporated to adjust for all time-invariant factors at these levels. The results indicate that residential location-related factors explain only half of the treatment inequity, while provider- and hospital-level factors do not significantly account for disparities. Even after accounting for all time-invariant factors, significant differences in treatment rates persist. The study highlights the importance of understanding race as a social construct and racism as a systemic and structural phenomenon in addressing treatment inequities. These findings provide a necessary step toward understanding equitable care and designing interventions to solve this inequity.}, }
@article {pmid39565908, year = {2024}, author = {Othus, M and Patel, SP and Chae, YK and Dietrich, E and Streicher, H and Sharon, E and Kurzrock, R}, title = {First Cycle Toxicity and Survival in Patients with Rare Cancers Treated with Checkpoint Inhibitors.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae297}, pmid = {39565908}, issn = {1460-2105}, abstract = {BACKGROUND: Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally-funded basket trial ((NCT02834013) for patients with rare cancers (N = 684) to evaluate associations between irAEs and overall survival and progression-free survival.
METHODS: Patients were treated with nivolumab and ipilimumab; the trial was opened at > 1000 sites. Landmark Cox regression models were used to assess first cycle irAE associations with progression-free and overall survival.
RESULTS: We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer overall survival (OS) (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p < .001) compared to no treatment-related irAE, while grade 3-4 irAEs were associated with shorter OS (HR = 1.41, 95% CI = 1.04-1.90, p = .025). Similar, but weaker, associations were observed with progression-free survival (PFS) and grade 1-2 treatment-related irAEs: HR = 0.83, 95% CI = 0.67-1.01, p = .067 and grade 3-4: HR = 1.35, 95% CI = 1.02-1.78, p = .037 compared to no treatment-related irAEs. Grade 1-2 dermatologic toxicity was associated with improved OS compared to other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52-0.85, p = .002). There was no significant OS difference between patients with Grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other Grade 1-2 toxicities.
CONCLUSIONS: In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of irAE in the first cycle was predictive for survival.}, }
@article {pmid39565901, year = {2024}, author = {Zhao, Y and Gulati, R and Yang, Z and Newcomb, L and Zheng, Y and Zhu, K and Liu, M and Heijnsdijk, EAM and Haffner, MC and Cooperberg, M and Eggener, SE and De Marzo, AM and Kibel, AS and Rizopoulos, D and Hall, IJ and Etzioni, R}, title = {Projected Outcomes of Reduced-Biopsy Management of Grade Group 1 Prostate Cancer: Implications for Relabeling.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae296}, pmid = {39565901}, issn = {1460-2105}, abstract = {BACKGROUND: Implications of relabeling grade group (GG) 1 prostate cancer as non-cancer will depend on the recommended active surveillance (AS) strategy. Whether relabeling should prompt de-intensifying, PSA-based active monitoring approaches is unclear. We investigated outcomes of biopsy-based AS strategies vs PSA-based active monitoring for GG1 diagnoses under different patient adherence rates.
METHODS: We analyzed longitudinal PSA levels and time to GG ≥ 2 reclassification among 850 patients diagnosed with GG1 disease from the Canary Prostate Active Surveillance Study (2008-2013). We then simulated 20,000 patients over 12 years, comparing GG ≥ 2 detection under biennial biopsy against three PSA-based strategies:(1) PSA: biopsy for PSA change ≥20%/year, (2) PSA+MRI: MRI for PSA change ≥20%/year and biopsy for PI-RADS ≥3, and (3) Predicted risk: biopsy for predicted upgrading risk ≥10%.
RESULTS: Under biennial biopsies and 20% dropout to active treatment, 17% of patients had a > 2-year delay in GG ≥ 2 detection. The PSA strategy reduced biopsies by 39% but delayed detection in 32% of patients. The PSA+MRI strategy cut biopsies by 52%, with a 34% delay. The predicted risk strategy reduced biopsies by 31%, with only an 8% delay. These findings are robust to biopsy sensitivity and confirmatory biopsy.
CONCLUSIONS: PSA-based active monitoring could substantially reduce biopsy frequency; however, a precision strategy based on an individual upgrading risk is most likely to minimize delays in disease progression detection. This strategy may be preferred if AS is deintensified under relabeling, provided patient adherence remains unaffected.}, }
@article {pmid39565830, year = {2024}, author = {Hannon, PA and Harris, JR and Doody, DR}, title = {Opportunities to Improve Health Equity for Employees in Low-Wage Industries in the United States.}, journal = {Annual review of public health}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-publhealth-071723-120104}, pmid = {39565830}, issn = {1545-2093}, abstract = {This review describes employees working in low-wage industries in the United States, their health risks, and their access to health promotion and other health-related resources through their employers. We use publicly available datasets to illustrate how low-wage jobs affect employees' social determinants of health, health risk behaviors, and chronic conditions. We also discuss how the COVID-19 pandemic has shifted these employees' and employers' health-related priorities and work settings. We describe employees' access to health supports through federal programs and their employers and the potential ways in which low-wage employers could support employee health and well-being. We close with a brief research and practice agenda to improve health equity for employees in low-wage industries. The goal of this review is to help practitioners and researchers in workplace health promotion, occupational health, and public health reach employees and employers in low-wage industries with interventions that address employees' health risks and employees' and employers' health priorities.}, }
@article {pmid39565459, year = {2024}, author = {Ziu, M and Halasz, LM and Kumthekar, PU and McGranahan, TM and Lo, SS and Olson, JJ}, title = {Congress of Neurological Surgeons systematic review and evidence-based guidelines for the role of chemotherapy in newly diagnosed WHO Grade II diffuse glioma in adults: update.}, journal = {Journal of neuro-oncology}, volume = {}, number = {}, pages = {}, pmid = {39565459}, issn = {1573-7373}, abstract = {UNLABELLED: Questions and recommendations from the prior version of these guidelines without changeTarget populationAdult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed oligoastrocytoma).QuestionIs there a role for chemotherapy as adjuvant therapy of choice in treatment of patients with newly diagnosed low-grade gliomas?RecommendationLevel III: Chemotherapy is recommended as a treatment option to postpone the use of radiotherapy, to slow tumor growth and to improve progression free survival (PFS), overall survival (OS) and clinical symptoms in adult patients with newly diagnosed LGG.QuestionWho are the patients with newly diagnosed LGG that would benefit the most from chemotherapy?RecommendationLevel III: Chemotherapy is recommended as an optional component alone or in combination with radiation as the initial adjuvant therapy for all patients who cannot undergo gross total resection (GTR) of a newly diagnosed LGG. Patients with residual tumor >1 cm on post-operative MRI, presenting diameter of 4 cm or older than 40 years of age should be considered for adjuvant therapy as well.QuestionAre there tumor markers that can predict which patients can benefit the most from initial treatment with chemotherapy?RecommendationLevel III: The addition of chemotherapy to standard RT is recommended in LGG patients that carry IDH mutation. In addition, temozolomide (TMZ) is recommended as a treatment option to slow tumor growth in patients who harbor the 1p/19q co-deletion.QuestionHow soon should the chemotherapy be started once the diagnosis of LGG is confirmed?RecommendationThere is insufficient evidence to make a definitive recommendation on the timing of starting chemotherapy after surgical/pathological diagnosis of LGG has been made. However, using the 12 weeks mark as the latest timeframe to start adjuvant chemotherapy is suggested. It is recommended that patients be enrolled in properly designed clinical trials to assess the timing of chemotherapy initiation once diagnosis is confirmed for this target population.QuestionWhat chemotherapeutic agents should be used for treatment of newly diagnosed LGG?RecommendationThere is insufficient evidence to make a recommendation of one particular regimen. Enrollment of subjects in properly designed trials comparing the efficacy of these or other agents is recommended so as to determine which of these regimens is superior.QuestionWhat is the optimal duration and dosing of chemotherapy as initial treatment for LGG?RecommendationInsufficient evidence exists regarding the duration of any specific cytotoxic drug regimen for treatment of newly diagnosed LGG. Enrollment of subjects in properly designed clinical investigations assessing the optimal duration of this therapy is recommended.QuestionShould chemotherapy be given alone or in conjunction with RT as initial therapy for LGG?RecommendationInsufficient evidence exists to make recommendations in this regard. Hence, enrollment of patients in properly designed clinical trials assessing the difference between chemotherapy alone, RT alone or a combination of them is recommended.QuestionShould chemotherapy be given in addition to other type of adjuvant therapy to patients with newly diagnosed LGG?RecommendationLevel II: It is recommended that chemotherapy be added to the RT in patients with unfavorable LGG to improve their progression free survival.Updated Question and Recommendations from the Prior Version of These GuidelinesQuestionIn adult patients with pathologically confirmed WHO Grade II diffuse glioma does chemotherapy alone, combined with radiation therapy or after radiation therapy compared to radiotherapy alone result in better overall survival, progression free survival, local control, fewer complications, neurocognitive preservation, and quality of life?RecommendationLevel I: It is recommended that chemotherapy (PCV) be added to radiation therapy (RT) in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma (Patients younger than 40 unable to get gross total resection and older than 40 regardless of the degree of resection) to improve their overall survival.
LEVEL II: It is recommended that chemotherapy be added to radiation therapy in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma to improve overall survival without a decline in neurocognitive function.
LEVEL III: It is suggested that chemotherapy (temozolomide) be added to RT in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma to improve progression free survival and overall survival.
LEVEL III: It is suggested that chemotherapy alone should be considered in patients with newly diagnosed WHO Grade II diffuse glioma in cases with 1p/19q co-deletion.New questions and recommendationsTarget populationThese recommendations apply to adult patients diagnosed with WHO Grade II diffuse glioma.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of chemotherapy prior to surgical resection improve extent of resection, provide longer progression free survival and overall survival when compared to chemotherapy alone?RecommendationLevel III: Neo-adjuvant temozolomide may be used in patients with WHO Grade II diffuse gliomas deemed unsafe for resection due to infiltration of eloquent areas or with large contralateral extension as an initial step to improve the extent of resection.There is insufficient evidence to support a recommendation regarding the ability of chemotherapy provided prior to surgical resection to improve progression free survival (PFS) and overall survival (OS).QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does the administration of temozolomide increase the rate of malignant transformation when compared to no chemotherapy or other chemotherapy regimens?RecommendationThere is insufficient evidence to support a recommendation against the use of temozolomide for WHO Grade II diffuse gliomas due to concern over increasing the rate of malignant transformation.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of multi-agent chemotherapy improve progression free survival and overall survival when compared to administration of single-agent chemotherapy?RecommendationThere is insufficient evidence to support a recommendation for or against the use of multi-agent chemotherapy to improve progression free survival and overall survival when compared to administration of single-agent chemotherapy in patients with newly diagnosed WHO Grade II diffuse glioma.}, }
@article {pmid39563927, year = {2024}, author = {Kassamali-Escobar, Z and Hartlage, W and Chan, JD and Castillo, A and Martinez-Paz, N and Bajenov, M and Jain, R and Lynch, JB and Bryson-Cahn, C}, title = {Antimicrobial stewardship and quality improvement strategies in critical access hospitals: a process evaluation of an intensive quality improvement cohort.}, journal = {Antimicrobial stewardship & healthcare epidemiology : ASHE}, volume = {4}, number = {1}, pages = {e201}, pmid = {39563927}, issn = {2732-494X}, abstract = {We describe our experience implementing an intensive quality improvement cohort pilot focused on managing asymptomatic bacteriuria in 19 critical access hospitals. Participation in the pilot was high, and almost all sites identified an improvement goal and collected clinical data. Barriers to implementation included staffing shortages, turnover, and lack of bandwidth.}, }
@article {pmid39562313, year = {2024}, author = {Bollinger, BJ and Chrisman, SP and Sahlberg, J and Mendoza, JA and Palermo, TM and Zhou, C and Brooks, MA and Rivara, FP and Pedersen, P and Prentice, E and Hansen, C}, title = {Understanding factors influencing exercise program adherence for youth with persistent post-concussive symptoms (PPCS).}, journal = {Brain injury}, volume = {}, number = {}, pages = {1-14}, doi = {10.1080/02699052.2024.2428404}, pmid = {39562313}, issn = {1362-301X}, abstract = {BACKGROUND: A significant portion of youth sustain a concussion every year, with around 30% experiencing persistent post-concussion symptoms (PPCS). Research has shown exercising just below the exertion level that provokes symptoms can lead to more rapid recovery. However, youth often struggle to adhere to exercise recommendations following concussion.
METHODS: We conducted structured qualitative interviews (n = 32) with concussed youth and their parents to examine factors influencing motivation to engage in exercise post-concussion. Questions were framed through the lens of Self-Determination Theory (SDT) and Thematic Analysis was used to code and analyze transcripts.
RESULTS: Four primary factors appeared to motivate youth to exercise after receiving a concussion: 1) social support, 2) accountability, 3) goal setting, and 4) structure. Utilizing the lens of SDT, one could theorize that including social support and accountability helped fulfill the need of relatedness, setting goals helped fulfill the need of autonomy, and providing program structure helped fulfill the need for competence.
CONCLUSIONS: Our results suggest that Self-Determination Theory may be a useful frame for examining exercise adherence post-concussion. Incorporating social support, accountability, goal setting and structure could increase the effectiveness of exercise prescription post-concussion and should be the focus of further study.}, }
@article {pmid39561920, year = {2024}, author = {Yi, JC and Ballard, S and Walsh, C and Friedman, DN and Ganz, PA and Jacobs, LA and Partridge, AH and Mitchell, SA and Leisenring, WM and Syrjala, KL and Baker, KS}, title = {INteractive survivorship program to improve health care REsources [INSPIRE]: A study protocol testing a digital intervention with stepped care telehealth to improve outcomes for adolescent and young adult survivors.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {107745}, doi = {10.1016/j.cct.2024.107745}, pmid = {39561920}, issn = {1559-2030}, abstract = {BACKGROUND: Adolescents and young adults with cancer (AYAs, ages 15-39 at the time of diagnosis) experience significant adverse health and psychosocial outcomes. AYAs live with emotional distress and health care demands that exceed those of their healthy peers but can have difficulty accessing care. Digitally delivered interventions are an attractive option for AYA survivors, a population that routinely utilizes online resources when seeking health information and support.
AIM: By improving access to survivorship resources and support and strengthening health literacy and self-management skills, the INteractive Survivorship Program to Improve Health care REsources [INSPIRE] is designed to improve adherence to AYA health care guidelines and reduce cancer-related distress. We describe the protocol for a two-arm randomized controlled trial (RCT) testing the AYA-adapted INSPIRE program.
METHODS/DESIGN: The intervention includes an interactive mobile app, study website, and social media platforms, adding telehealth for those with continued distress, lower survivorship health care literacy, or poor engagement with the digital program at 6 weeks. Participants are randomized to INSPIRE or an active control. In the active control arm, survivors receive access to a study website with links to existing AYA survivor resources followed by delayed access to the INSPIRE program. Participants are not blinded; study staff not providing telehealth are blinded. The primary outcomes are cancer-related distress and health care adherence specific to second cancer and cardiometabolic screenings.
DISCUSSION: If effective, the program is positioned for accelerated implementation to improve care for AYA survivors by using a scalable informatics-based administration and largely digital intervention program.}, }
@article {pmid39561770, year = {2024}, author = {Kullo, IJ and Conomos, MP and Nelson, SC and Adebamowo, SN and Choudhury, A and Conti, D and Fullerton, SM and Gogarten, SM and Heavner, B and Hornsby, WE and Kenny, EE and Khan, A and Khera, AV and Li, Y and Martin, I and Mercader, JM and Ng, M and Raffield, LM and Reiner, A and Rowley, R and Schaid, D and Stilp, A and Wiley, K and Wilson, R and Witte, JS and Natarajan, P and , }, title = {The PRIMED Consortium: Reducing disparities in polygenic risk assessment.}, journal = {American journal of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2024.10.010}, pmid = {39561770}, issn = {1537-6605}, abstract = {By improving disease risk prediction, polygenic risk scores (PRSs) could have a significant impact on health promotion and disease prevention. Due to the historical oversampling of populations with European ancestry for genome-wide association studies, PRSs perform less well in other, understudied populations, leading to concerns that clinical use in their current forms could widen health care disparities. The PRIMED Consortium was established to develop methods to improve the performance of PRSs in global populations and individuals of diverse genetic ancestry. To this end, PRIMED is aggregating and harmonizing multiple phenotype and genotype datasets on AnVIL, an interoperable secure cloud-based platform, to perform individual- and summary-level analyses using population and statistical genetics approaches. Study sites, the coordinating center, and representatives from the NIH work alongside other NHGRI and global consortia to achieve these goals. PRIMED is also evaluating ethical and social implications of PRS implementation and investigating the joint modeling of social determinants of health and PRS in computing disease risk. The phenotypes of interest are primarily cardiometabolic diseases and cancer, the leading causes of death and disability worldwide. Early deliverables of the consortium include methods for data sharing on AnVIL, development of a common data model to harmonize phenotype and genotype data from cohort studies as well as electronic health records, adaptation of recent guidelines for population descriptors to global cohorts, and sharing of PRS methods/tools. As a multisite collaboration, PRIMED aims to foster equity in the development and use of polygenic risk assessment.}, }
@article {pmid39561372, year = {2024}, author = {Luque Paz, D and Gagelmann, N and Benajiba, L and Riou, J and Salit, RB and Orvain, C and Schroeder, T and Bories, C and Gurnari, C and Badbaran, A and Boyer-Perrard, F and Pagliuca, S and Rautenberg, C and Tavitian, S and Panagiota, V and Ianotto, JC and Thol, FR and Cayssials, E and Heuser, M and Rubio, MT and Cassinat, B and Daltro de Oliveira, R and Sauter, CS and Maciejewski, JP and Reinhardt, HC and Scott, BL and Ugo, V and Kröger, N and Kiladjian, JJ and Robin, M}, title = {Role of molecular alterations in transplantation decisions for patients with primary myelofibrosis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014368}, pmid = {39561372}, issn = {2473-9537}, abstract = {The aim of our study was to analyze the potential survival benefit associated with HSCT according to clinico-biological scores which incorporate molecular data (MIPSS70 and MIPSS70+V2) to facilitate decision-making in this context. One transplant (n=241) and one non-transplant cohorts (n=239) were used to test the hypothesis that PMF patients with higher risk molecular score benefit from HSCT. A weighted propensity score was applied to balance confounding factors with the transplanted cohort as reference. Weighted Cox proportional hazard models and logistic regression analyses were performed. 105 non-transplanted patients could be matched to the 239 transplanted patients. Mean age in transplanted and non-transplanted matched patients was 55.5 and 57.9 years. Blood cell count and DIPSS score distribution were similar in both groups. HSCT was associated with a higher 6-year OS rate in intermediate-2 (60.1% versus 41.5%) and high-risk DIPSS patients (44.4% versus 6.55%), high-risk MIPSS70 (46.5 versus 23.9%), high-risk (73.2% versus 39.7%) or very high-risk MIPSS70V2 (51.8% versus 24%). Intermediate MIPSS70 patients have an advantage of survival with HSCT only when their MTSS were low or intermediate. Transplanted patients had an increased mortality risk the first year but a significant benefit with HSCT after the one-year landmark was observed in higher risk patients. This study confirms that similar to DIPSS, MIPSS70 and MIPSS70+V2 risk score in addition to MTSS can be used to determine which patients with primary myelofibrosis have survival benefit from HSCT over non-HSCT strategies.}, }
@article {pmid39561273, year = {2024}, author = {Chae, YK and Corthell, L and Patel, SP and Edwards, R and Scalici, JM and Kim, HS and Chung, LI and Othus, M and McLeod, CM and Chen, HX and Sharon, E and Streicher, H and Ryan, CW and Blanke, CD and Kurzrock, R}, title = {A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: Vulvar Cancers.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1957}, pmid = {39561273}, issn = {1557-3265}, abstract = {BACKGROUND: Dual PD-1/CTLA-4 inhibition shows promise in various malignancies. The SWOG S1609 DART trial presents initial results of ipilimumab/nivolumab in vulvar cancers.
METHODS: DART is a prospective/open-label/multicenter (1,016 US sites)/multi-cohort phase II clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate [ORR, confirmed complete and partial responses (CR and PR, respectively)] per RECISTv1.1; progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; overall response plus stable disease (SD) ≥6 months], and toxicity are secondary endpoints.
RESULTS: Sixteen evaluable patients (median age, 55.5 years; 0-6 prior therapies; no prior immunotherapy) were analyzed, all of whom had squamous cell carcinoma histology. ORR was 18.8% (3/16), CBR was 25% (4/16), and CBR plus unconfirmed PR rate was 31% (5/16); PFS was 34.1, 16.7. 15.5, 7.2 and 7.0 months for these five patients. The median PFS and OS were 2.2 and 7.6 months. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n=4 each). Grade 3-4 adverse events occurred in 25% of patients (n=4). There was 1 grade 1-2 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event.
CONCLUSION: Ipilimumab plus nivolumab in vulvar cancers resulted in an objective response in three out of 16 patients, all of whom had durable responses lasting over one year. Notably, two additional patients experienced durable SD and unconfirmed PR. Correlative studies to determine response and resistance markers are ongoing.}, }
@article {pmid39561007, year = {2024}, author = {Schoenfeld, DA and Djureinovic, D and Su, DG and Zhang, L and Lu, BY and Kamga, L and Mann, JE and Huck, JD and Hurwitz, M and Braun, DA and Jilaveanu, L and Ring, AM and Kluger, HM}, title = {Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma.}, journal = {JCI insight}, volume = {}, number = {}, pages = {}, doi = {10.1172/jci.insight.184545}, pmid = {39561007}, issn = {2379-3708}, abstract = {The cytokine interleukin-18 (IL-18) has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18's anti-cancer efficacy. A "decoy-resistant" form of IL-18 (DR-18), that avoids sequestration by IL-18BP while maintaining its immunostimulatory potential, has recently been developed. Here, we investigated the therapeutic potential of DR-18 in renal cell carcinoma (RCC). Using pan-tumor transcriptomic data, we found that clear cell RCC had among the highest expression of IL-18 receptor subunits and IL18BP of tumor types in the database. In samples from RCC patients treated with immune checkpoint inhibitors, IL-18BP protein expression increased in the tumor microenvironment and circulating in plasma in non-responding patients and decreased in the majority of responding patients. We used immunocompetent RCC murine models to assess the efficacy of DR-18 in combination with single- and dual-agent anti-PD-1 and anti-CTLA-4. In contrast to preclinical models of other tumor types, in RCC models DR-18 enhanced the activity of anti-CTLA-4 but not anti-PD-1 treatment. This activity correlated with intra-tumoral enrichment and clonal expansion of effector CD8+ T cells, decreased regulatory T cell levels, and enrichment of pro-inflammatory, anti-tumor myeloid cell populations. Our findings support further clinical investigation of the combination of DR-18 and anti-CTLA-4 in RCC.}, }
@article {pmid39560823, year = {2024}, author = {Vaidya, R and Till, C and Henry, NL and Fisch, MJ and Hershman, DL and Unger, JM}, title = {Neighborhood socioeconomic deprivation and patient-reported outcomes in symptom management trials for women with breast cancer.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {39560823}, issn = {1573-7217}, support = {CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; CA189974//National Cancer Institute at the National Institutes of Health/ ; }, abstract = {PURPOSE: Neighborhood socioeconomic deprivation (NSD) is associated with worse outcomes among patients with cancer, but little is known about NSD-related disparities in patient-reported outcomes (PRO) in clinical trials. We examined the relationship between PROs and NSD in symptom management trials among women with breast cancer.
METHODS: We pooled data from three SWOG randomized trials to examine four outcomes: physical and functional wellbeing (PWB, FWB), average pain, and pain interference. NSD was measured using participants' zip code linked to the area deprivation index (ADI) score, categorized into tertiles. Multivariable linear regression adjusted for sociodemographic and clinical characteristics was used to analyze baseline PROs. Linear mixed models were used to examine if trajectory of PROs from baseline through 24 weeks varied by ADI.
RESULTS: We examined 761 participants, of whom 51% were from least deprived neighborhoods. Participants in the most deprived neighborhoods had worse average pain at baseline (β = .38, 95% CI = .03 to .72, p = .03) while participants in somewhat deprived areas also had worse FWB (β = -1.07, 95% CI = -1.95 to -.20, p = .02) and pain interference (β = 0.42, 95% CI = .09 to .75, p = .01) compared to those from least deprived areas. Hispanic ethnicity and having Medicaid/no insurance were associated with worse outcomes. After adjusting for baseline score, ADI was not associated with any outcome over time.
CONCLUSIONS: Breast cancer patients living in areas with NSD had worse FWB, joint pain, and pain interference at baseline. Clinical trial participants should be screened for community-level needs. Implementing interventions to address those needs could help mitigate disparities.}, }
@article {pmid39560645, year = {2024}, author = {Kohrt, SE and Novak, EJ and Tapadar, S and Wu, B and Strope, J and Asante, Y and Kim, H and Chang, MS and Gurdak, D and Khalil, A and Rood, M and Raftery, E and Stavreva, D and Nguyen, HM and Brown, LG and Ramser, M and Peer, C and Meyers, WM and Aboreden, N and Chakravortee, M and Sallari, R and Nelson, PS and Kelly, KK and Graham, TGW and Darzacq, X and Figg, WD and Oyelere, AK and Corey, E and Adelaiye-Ogala, R and Gryder, BE}, title = {Small-molecule disruption of androgen receptor-dependent chromatin clusters.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {48}, pages = {e2406239121}, doi = {10.1073/pnas.2406239121}, pmid = {39560645}, issn = {1091-6490}, support = {CA097186//Prostate Cancer Foundation (PCF)/ ; RO1 CA266013//HHS | National Institutes of Health (NIH)/ ; W81XWH-19-1-0715//U.S. Department of Defense (DOD)/ ; 1K22CA255594//HHS | National Institutes of Health (NIH)/ ; P50CA97186//HHS | National Institutes of Health (NIH)/ ; 5R01CA291963-02//HHS | National Institutes of Health (NIH)/ ; }, mesh = {*Receptors, Androgen/metabolism/genetics ; Humans ; *Chromatin/metabolism ; Male ; Cell Line, Tumor ; Animals ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/metabolism/genetics/pathology ; *Androgen Receptor Antagonists/pharmacology/metabolism ; Mice ; Gene Expression Regulation, Neoplastic/drug effects ; Promoter Regions, Genetic ; Xenograft Model Antitumor Assays ; Signal Transduction/drug effects ; }, abstract = {Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.}, }
@article {pmid39560376, year = {2024}, author = {Stafford, E and Dimitrov, D and Trinidad, SB and Matrajt, L}, title = {Closing the gap in race-based inequities for seasonal influenza hospitalizations: a modeling study.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae564}, pmid = {39560376}, issn = {1537-6591}, abstract = {BACKGROUND: BIPOC (Black, Indigenous, and other People of Color) communities bear a disproportional burden of seasonal influenza hospitalizations in the United States.
METHODS: We developed a race-stratified (5 racial-ethnic groups) agent-based model of seasonal influenza transmission and quantify the effects of 5 idealized interventions aimed at reducing inequities in symptomatic infections and hospitalizations. The interventions assumed (i) equalized vaccination rates, (ii) equalized comorbidities, (iii) work-risk distribution proportional to the distribution of the population, (iv) reduced work contacts for all, or (v) a combination of equalizing vaccination rates and comorbidities and reducing work contacts.
RESULTS: Our analysis suggests that symptomatic infections could be greatly reduced (by up to 17% in BIPOC adults aged 18-49) by strategies reducing work contacts or equalizing vaccination rates. All tested interventions reduced the inequity in influenza hospitalizations in all racial-ethnic groups, but interventions equalizing comorbidities were the most effective, with over 40% less hospitalizations in BIPOC groups. Inequities in hospitalizations in different racial-ethnic groups responded differently to interventions, pointing to the need of tailored interventions for different populations. Notably, these interventions resulted in better outcomes across all racial-ethnic groups, not only those prioritized by the interventions.
CONCLUSIONS: In this simulation modeling study, equalizing vaccination rates and reducing number of work contacts (e.g., improving air filtration systems, tailored vaccination campaigns) reduced both inequity and the total number of symptomatic infections and hospitalizations in all age and racial-ethnic groups. Reducing inequity in influenza hospitalizations requires different interventions for different groups.}, }
@article {pmid39559248, year = {2024}, author = {Kopmar, NE and Cassaday, RD}, title = {Clinical Insights on Brexucabtagene Autoleucel for the Treatment of Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia.}, journal = {Cancer management and research}, volume = {16}, number = {}, pages = {1587-1596}, pmid = {39559248}, issn = {1179-1322}, abstract = {Autologous chimeric antigen receptor-modified T-cell therapy (CAR-T) has revolutionized treatment paradigms across multiple lymphoid malignancies, including relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). The introduction of the CD19-directed CAR-T product brexucabtagene autoleucel (brexu-cel; Tecartus) in October 2021 made this treatment approach available for the first time for adults with R/R B-ALL, a historically challenging clinical entity to treat. In this review, we will discuss the pivotal clinical trial data from the ZUMA-3 study that led to the US Food and Drug Administration (FDA) approval of brexu-cel, including clinical outcomes and key toxicity data (most importantly, the incidence and severity of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome). Additionally, we will compare and contrast these data from the ZUMA-3 study with "real-world" data from examinations of patient outcomes with brexu-cel as an FDA-approved therapy in R/R B-ALL, and discuss practical considerations with brexu-cel use in the clinic, including the role of consolidative allografting for patients post-brexu-cel. We finish by discussing future directions for CAR-T use in R/R B-ALL with the anticipated introduction of a new CD19-directed CAR-T product - obecabtagene autoleucel - in the near future.}, }
@article {pmid39556786, year = {2024}, author = {Huang, IJ and Baek, GT and Cohen, J and Khajaviyan, S and Louie, S and Samples, L and Smith, SD and Till, BG and Warren, EH and Gopal, AK and Poh, C and Lynch, RC and Ujjani, CS and Shadman, M}, title = {Clinical Relevance of Intensive Laboratory Monitoring With Standard Venetoclax Ramp-Up for Chronic Lymphocytic Leukemia: A Real-World Experience.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400416}, doi = {10.1200/OP.24.00416}, pmid = {39556786}, issn = {2688-1535}, abstract = {PURPOSE: Venetoclax is the standard of care for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) but requires intensive monitoring for optimal safety. Clinical relevance of intensive monitoring in practice is unknown, especially for patients with low or intermediate risk for tumor lysis syndrome (TLS).
PATIENTS AND METHODS: A retrospective review was conducted to determine clinical significance of monitoring for TLS during standard ramp-up for patients with CLL/SLL. Patients receiving abbreviated ramp-up, clinical trials, or concurrent Bruton tyrosine kinase inhibitors were excluded. The primary end point was TLS incidence, with secondary end points describing associated clinical interventions.
RESULTS: Fifty-five patients met study criteria. The majority of patients received venetoclax as first-line therapy (58%), with anti-CD20 antibody therapy (82%), and were at low risk of TLS (75%). No clinical TLS events occurred, whereas laboratory TLS occurred in only 1.8% of patients. No patients required antihyperuricemic therapy, and few interventions for hyperphosphatemia or hypocalcemia (3.6% of patients) were required. Additional intravenous fluids were uncommonly required (1.8% of patients), and no unplanned hospitalizations were required.
CONCLUSION: These findings support efforts to reduce intensive monitoring requirements during venetoclax ramp-up for patients with CLL, potentially increasing accessibility of venetoclax.}, }
@article {pmid39555026, year = {2024}, author = {Huang, Y and Feng, Z}, title = {ASSESSING SCREENING EFFICACY IN THE PRESENCE OF CANCER OVERDIAGNOSIS.}, journal = {The annals of applied statistics}, volume = {18}, number = {2}, pages = {1543-1564}, pmid = {39555026}, issn = {1932-6157}, abstract = {Cancer screening facilitates the early detection of cancer, at a stage when treatment is often most effective. However, it also brings the risk of over-diagnosis, where a diagnosis made through screening would not have led to symptoms or death during the patient's lifetime. In this paper, we tackle a significant unresolved issue in the evaluation of screening efficacy: selecting primary endpoints and inferential procedures that efficiently consider potential overdiagnosis in screening trials. This is motivated by the necessity to design and analyze a phase IV Early Detection Initiative (EDI) trial for evaluating a pancreatic cancer screening strategy. We introduce two novel approaches for assessing screening efficacy, grounded on cancer stage-shift. These methods address potential overdiagnosis by: i) borrowing information about clinical diagnosis from the control arm that hasn't undergone screening (the BR approach), and ii) performing sensitivity analysis, contingent upon a conservative bound of the overdiagnosis magnitude (the SEN-T approach). Analytical methods and extensive simulation studies underscore the superiority of our proposed methods, demonstrating enhanced efficiency in estimating and testing screening efficacy compared to existing methods. The latter either overlook overdiagnosis or adhere to a valid, yet conservative, cumulative incidence endpoint. We illustrate the practical application of these approaches using ovarian cancer data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The results affirm that our methods bolster an efficient and robust study design for cancer screening trials.}, }
@article {pmid39553428, year = {2024}, author = {Nealy, ES and Reed, SJ and Adelmund, SM and Badeau, BA and Shadish, JA and Girard, EJ and Brasel, K and Pakiam, FJ and Mhyre, AJ and Price, JP and Sarkar, S and Kalia, V and DeForest, CA and Olson, JM}, title = {Versatile tissue-injectable hydrogels capable of the extended hydrolytic release of bioactive protein therapeutics.}, journal = {Bioengineering & translational medicine}, volume = {9}, number = {5}, pages = {e10668}, pmid = {39553428}, issn = {2380-6761}, abstract = {Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA-approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature-sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti-CD47 monoclonal antibodies, when incorporated into subsurface-injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high-grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site-specific modification with hydrolysable "azidoester" adapters, allowing for user-defined release profiles from the hydrogel. Hydrogel-generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8[+] T-cells and the attenuation of tumor growth in a "cold" syngeneic melanoma model. This study highlights a highly customizable, hydrogel-based delivery system for local protein therapeutic administration to meet diverse clinical needs.}, }
@article {pmid39551677, year = {2024}, author = {Simunic, M and McGraw, K and Pavletic, SZ and Rashidi, A}, title = {Intestinal microbiome and myelodysplastic syndromes: Current state of knowledge and perspectives for future.}, journal = {Seminars in hematology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.seminhematol.2024.10.006}, pmid = {39551677}, issn = {1532-8686}, abstract = {The intestinal microbiome has been mechanistically linked with health and many disease processes. Cancer is no exception. Both in solid tumors and hematologic malignancies, there is increasing evidence supporting the involvement of the intestinal microbiome in tumor development, disease progression, response to treatment, and treatment toxicity. Consistent with microbiome mediation of the immune system and the potent effect of the immune system on cancer, the most compelling evidence has been obtained in the setting of cancer immunotherapy. Here, we review the current state of knowledge about microbiome effects in myelodysplastic syndromes, identify gaps and challenges in related research, and provide insights for future work.}, }
@article {pmid39550102, year = {2025}, author = {Waghmare, A and Hijano, DR}, title = {SARS-CoV-2 Infection and COVID-19 in Children.}, journal = {Rheumatic diseases clinics of North America}, volume = {51}, number = {1}, pages = {139-156}, doi = {10.1016/j.rdc.2024.09.003}, pmid = {39550102}, issn = {1558-3163}, mesh = {Humans ; *COVID-19/complications ; Child ; *Systemic Inflammatory Response Syndrome/therapy/physiopathology ; SARS-CoV-2 ; }, abstract = {Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is common in children, and clinical manifestations can vary depending on age, underlying disease, and vaccination status. Most children will have asymptomatic or mild infection, but certain baseline characteristics can increase the risk of moderate to severe disease. The following article will provide an overview of the clinical manifestations of coronavirus disease 2019 in children, including the post-infectious phenomenon called multisystem inflammatory syndrome in children. Currently available treatment and prophylaxis strategies will be outlined, with the caveat that new therapeutics and clinical efficacy data are constantly on the horizon.}, }
@article {pmid39549763, year = {2024}, author = {Tseng, YD and Stevenson, P and Nguyen, B and Li, DC and Lee, D and Paydar, I and Nakashima, J and Balogh, A and Ravella, R and Barbour, AB and Post, C and Ababneh, H and Pinnix, CC and Ballas, LK and Binkley, MS and Dedeckova, K and Hoppe, RT and Patel, C and Nabavizadeh, N and Kelsey, CR and Kumar, KA and Landsburg, D and Figura, N and Lo, AC and Plastaras, JP}, title = {Impact of Myc-Altered Pathology on Radiotherapy Efficacy Among Patients with Relapsed/Refractory Large-B Cell Lymphoma: A Collaborative Study by XXX: Impact of double hit pathology on RT efficacy.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2024.11.072}, pmid = {39549763}, issn = {1879-355X}, abstract = {PURPOSE: Presence of MYC and BCL2 translocations (i.e. double-hit lymphoma, DHL) in large B-cell lymphoma (LBCL) is associated with reduced chemosensitivity, but less is known on its impact on radiotherapy (RT) efficacy.
METHODS/MATERIALS: Patients with LBCL that received their first course of RT for relapsed/refractory (r/r) disease between 2008-2020 were eligible if there was adequate pathologic evaluation to be categorized as DHL versus non-DHL as per WHO (5[th] edition). Separate analyses were conducted by treatment intent. Predictors for response (complete and partial) and local recurrence (LR) were evaluated using Cox regression analysis. LR analysis was restricted to curative-intent patients to ensure adequate follow-up.
RESULTS: 383 patients (102 DHL, 281 non-DHL, 44% curative) were treated to 447 sites. Median time from diagnosis to RT was 11.6 months, with 38.7% patients having primary chemorefractory disease, 37.4% having received >2 lines of systemic therapy, and 24% status post stem cell transplant. Median biological equivalent dose (alpha/beta 10) was 28 Gy (range 3.2-60.0) for palliative and 46.9 Gy (range 6.4-84.0) for curative-intent patients. With a median follow-up of 41.1 and 41.5 months among curative and palliative patients, respectively, response was high (81.1% curative, 60.1% palliative). On univariate analysis, DHL pathology was not associated with RT response in either curative or palliative patients. Among curative patients, 2-year LR rate was 38.8%. On multivariable analysis, DHL pathology was associated with a 2 times higher risk of LR (95% CI 1.05-3.67,p=.03), with a crude LR rate of 42.9% (DHL) versus 28.9% (non-DHL). RT was well tolerated with low rates of grade 3 or higher acute toxicity (1.8% curative, 2.9% palliative).
CONCLUSIONS: Relapsed/refractory LBCL remains radioresponsive with 60-80% response rate to RT. While DHL pathology does not appear to influence RT response, its presence is associated with higher rates of local recurrence, suggesting it may be more radioresistant.}, }
@article {pmid39546840, year = {2024}, author = {Bellows, AL and Palmer, AC and Curriero, F and Thorne-Lyman, AL and Shamim, AA and Shaikh, S and Haque, R and Ali, H and Sugimoto, JD and Christian, P and West, KP and Labrique, AB}, title = {Changes in urbanicity and household availability of and proximity to food vendors from 2004 to 2020 in a rural district of northwestern Bangladesh.}, journal = {Health & place}, volume = {90}, number = {}, pages = {103374}, doi = {10.1016/j.healthplace.2024.103374}, pmid = {39546840}, issn = {1873-2054}, abstract = {BACKGROUND: The nutrition transition underway in South Asia is likely mediated by changes to the food environment. Yet, few studies have been conducted in rural areas of South Asia to describe how the food environment has changed.
OBJECTIVE: This analysis assessed changes in household availability of and proximity to markets, grocery shops, and tea shops over a 16-year time period in Gaibandha, Bangladesh.
METHODS: We analyzed household demographic and geospatial data collected at 3 time points from 2004 to 2020 in a contiguous rural area (435 km[2]). We defined availability as number of food vendors within 400- and 1600-m radius of households and proximity as distance to nearest vendor. We used linear and Poisson models to estimate associations between household socioeconomic status (SES) and food vendor availability and proximity. We used multi-level models to conduct similar analyses for community-level urbanicity.
RESULTS: From 2004 to 2020, the numbers of markets, grocery shops and tea shops increased by 21%, 66% and 270%, respectively. Food vendor proximity did not change by household SES, but less urban households witnessed larger increases in proximity to markets (p for interaction<0.001) and tea shops (p for interaction<0.001) over time. Grocery shop and tea shop availability was initially higher and increased more over time for households in higher urbanicity areas (p for interaction<0.001).
CONCLUSION: Over a 16-year period, this rural area of Bangladesh became more urbanized, increasing the availability of and proximity to markets, grocery shops, and tea shops. Further research is needed to see how these changes impact rural residents' intake and nutritional status.}, }
@article {pmid39543541, year = {2024}, author = {Pan, C and Ng, K and Voutsinas, J and Barber, B and Rizvi, ZH and Marchiano, E and Ferrandino, RM and Futran, N and Laramore, GE and Liao, JJ and Parvathaneni, U and Panjwani, N and Martins, RG and Rodriguez, CP and Wu, QV}, title = {Development of a prognostic signature for overall survival using peripheral blood biomarkers in head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.}, journal = {BMC cancer}, volume = {24}, number = {1}, pages = {1406}, pmid = {39543541}, issn = {1471-2407}, support = {T32 DC000018/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: We previously reported in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs), pretreatment higher lactate dehydrogenase (LDH) and absolute (abx) neutrophils as well as lower percent (%) lymphocytes correlated with worse overall survival (OS). In this study we aimed to develop a prognostic signature for HNSCC treated with ICIs using these peripheral blood biomarkers (PBBMs).
METHODS: Adults with R/M HNSCC treated with ICIs at our institution from 08/2012 to 03/2021 with pretreatment PBBMs were included. Follow-up continued until 02/15/2022. The cohort (n = 151) was randomly split into training (n = 100) and testing (n = 51) datasets. A prognostic score incorporating LDH, % lymphocytes, and abx neutrophils was developed from the training dataset using Cox proportional hazards regression. In the training dataset, a grid search identified the optimal cutpoints classifying patients into high, medium, and low-risk groups (trichotomized signature) as well as high vs. low-risk groups (dichotomized signature). The prognostic score, dichotomized and trichotomized signatures were then validated in the testing dataset.
RESULTS: Training and testing datasets showed no clinically meaningful differences in clinicodemographic characteristics or PBBMs. An OS prognostic model was developed from the training dataset: Risk score = 1.24*log10(LDH) - 1.95*log10(% lymphocytes) + 0.47*log10(abx neutrophils). Optimal risk score cutpoints for the dichotomized and trichotomized signatures were defined in the training dataset, and Kaplan-Meier curves for both dichotomized and trichotomized signatures showed good separation between risk groups. Risk scores were calculated in the testing dataset, where the trichotomized signature demonstrated overlap between low and medium-risk groups but good separation from the high-risk group while the dichotomized signature showed clear separation between low and high-risk groups. Higher risk score correlated with worse OS (HR 2.08, [95%CI 1.17-3.68], p = 0.012). Progression-free survival Kaplan-Meier curves likewise showed excellent separation between dichotomized risk groups in the training and testing datasets.
CONCLUSIONS: We developed a prognostic signature for OS based on 3 previously identified PBBMs for HNSCC treated with ICIs and identified a high-risk group of patients least likely to have survival benefit from ICIs. This signature may improve ICI patient selection and warrants validation in an independent cohort as well as correlation with CPS.}, }
@article {pmid39542703, year = {2024}, author = {Demirci, RA and Ghodsi, A and Gulati, R and Behnia, S and Nelson, PS and Cheng, HH and Yezefski, TA and Haffner, MC and Hawley, JE and Montgomery, RB and Yu, EY and Schweizer, MT and Chen, DL and Iravani, A}, title = {PET-Based TheraP Eligibility and Outcomes of VISION-Eligible Patients with Metastatic Castration-Resistant Prostate Cancer Who Received [177]Lu-PSMA-617: Importance of [18]F-FDG-Avid Discordant Findings.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.124.268167}, pmid = {39542703}, issn = {1535-5667}, abstract = {The VISION and TheraP trials introduced different PET-based criteria for patient selection for treatment with [177]Lu-PSMA-617 (LuPSMA). TheraP used a higher prostate-specific membrane antigen (PSMA) uptake threshold than VISION and required [18]F-FDG PET to exclude patients with discordant findings. Although the screen-failed patients had shorter overall survival (OS) than those treated with LuPSMA, it remains unclear whether their outcomes might have been modified if they had been exposed to LuPSMA. In this study, we evaluated associations between the TheraP eligibility criteria and subgroups and the treatment outcomes of patients who were deemed suitable and treated on the basis of VISION criteria. Methods: Consecutive patients who were treated with LuPSMA and who underwent pretreatment PSMA and [18]F-FDG PET were classified as TheraP-eligible (TheraP-E) and TheraP-ineligible (TheraP-I), the latter of which were subclassified as low PSMA or discordant. Odds ratios for an at least 50% decline in prostate-specific antigen (PSA50) were computed using logistic regression, and hazard ratios (HRs) for PSA progression-free survival (PSA-PFS) and OS were computed using Cox regressions. Multivariable analyses were adjusted for baseline imaging and clinical parameters. Results: Of 75 patients, 31 (41%) were deemed TheraP-I; of those, 24 were subclassified as having discordant disease. TheraP-I patients had a lower PSA50 rate than that of TheraP-E patients (28% vs. 67%; odds ratio, 0.19; 95% CI, 0.06-0.52; P = 0.002) and a higher risk of PSA progression (HR, 2.0; 95% CI, 1.2-3.3; P = 0.007). OS in the TheraP-I group was numerically shorter than in the TheraP-E group, but the comparison was only marginally significant (10.4 mo vs. not reached; HR, 1.9; 95% CI, 1.0-3.7; P = 0.054). TheraP-I patients with low PSMA had no significantly different risk of death (P = 0.9) from that of TheraP-E patients, but those with discordant findings had higher risk of death (HR, 2.3; 95% CI, 1.1-4.6; P = 0.02). Discordant disease remained prognostic for OS after adjusting for baseline imaging and clinical parameters (HR, 3.0; 95% CI, 1.3-6.8; P = 0.01). Conclusion: In VISION-eligible patients who were treated with LuPSMA, TheraP-I patients with discordant findings had lower PSA50, PSA-PFS, and OS. Our study suggests that the shorter OS of TheraP-I patients is mainly driven by the presence of discordant disease.}, }
@article {pmid39542654, year = {2024}, author = {Shatila, M and Zhang, HC and Shirwaikar Thomas, A and Machado, AP and Naz, S and Mittal, N and Catinis, C and Varatharajalu, K and Colli Cruz, C and Lu, E and Wu, D and Brahmer, JR and Carbonnel, F and Hanauer, SB and Lashner, B and Schneider, B and Thompson, JA and Obeid, M and Farris, DP and Wang, Y}, title = {Systematic review of immune checkpoint inhibitor-related gastrointestinal, hepatobiliary, and pancreatic adverse events.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {11}, pages = {}, doi = {10.1136/jitc-2024-009742}, pmid = {39542654}, issn = {2051-1426}, mesh = {Humans ; *Immune Checkpoint Inhibitors/adverse effects ; *Gastrointestinal Diseases/chemically induced ; Immunotherapy/adverse effects/methods ; Pancreatic Diseases/chemically induced ; Neoplasms/drug therapy ; }, abstract = {Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management.}, }
@article {pmid39542408, year = {2024}, author = {Wechkin, HA and Menzel, PT and Loggers, ET and Macauley, RC and Pope, TM and Reagan, PL and Quill, TE}, title = {"Mr. Smith Has No Mealtimes": Minimal Comfort Feeding for Patients with Advanced Dementia.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2024.11.001}, pmid = {39542408}, issn = {1873-6513}, abstract = {While Comfort Feeding Only is appropriate for patients with advanced dementia, its emphasis on assiduous hand-feeding that may prolong life for years fails to accommodate the preferences of those who do not want to continue living with this illness. Some have proposed advance directives to completely halt the provision of oral nutrition and hydration once a person has reached an advanced stage of dementia. However, these directives may fail to address patients' discomfort, caregivers' obligations, or current care and regulatory standards when patients reside in facilities. In response to these dilemmas, we introduce Minimal Comfort Feeding (MCF). Rather than offering food and liquids proactively as with Comfort Feeding Only, caregivers provide nutrition and hydration only in response to signs of hunger and thirst. While further study is required to define and negotiate challenges in operationalizing this approach, MCF provides a framework that resolves competing ethical and clinical considerations in caring for those with advanced dementia.}, }
@article {pmid39542140, year = {2024}, author = {Welch, SR and Bilello, JP and Carter, K and Delang, L and Dirr, L and Durantel, D and Feng, JY and Gowen, BB and Herrero, LJ and Janeba, Z and Kleymann, G and Lee, AA and Meier, C and Moffat, J and Schang, LM and Schiffer, JT and Seley-Radtke, KL and Sheahan, TP and Spengler, JR}, title = {Meeting Report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20-24, 2024, organized by the International Society for Antiviral Research.}, journal = {Antiviral research}, volume = {}, number = {}, pages = {106037}, doi = {10.1016/j.antiviral.2024.106037}, pmid = {39542140}, issn = {1872-9096}, abstract = {The 37[th] International Conference on Antiviral Research (ICAR) was held in Gold Coast, Australia, May 20-24, 2024. ICAR 2024 featured over 75 presentations along with two poster sessions and special events, including those specifically tailored for trainees and early-career scientists. The meeting served as a platform for the exchange of cutting-edge research, with presentations and discussions covering novel antiviral compounds, vaccine development, clinical trials, and therapeutic advancements. A comprehensive array of topics in antiviral science was covered, from the latest breakthroughs in antiviral drug development to innovative strategies for combating emerging viral threats. The keynote presentations provided fascinating insight into two diverse areas fundamental to medical countermeasure development and use, including virus emergence at the human-animal interface and practical considerations for bringing antivirals to the clinic. Additional sessions addressed a variety of timely post-pandemic topics, such as the hunt for broad spectrum antivirals, combination therapy, pandemic preparedness, application of in silico tools and AI in drug discovery, the virosphere, and more. Here, we summarize all the presentations and special sessions of ICAR 2024 and introduce the 38[th] ICAR, which will be held in Las Vegas, USA, March 17-21, 2025.}, }
@article {pmid39541580, year = {2024}, author = {Nagarajan, R and Kondo, M and Salas, F and Sezgin, E and Yao, Y and Klotzman, V and Godambe, SA and Khan, N and Limon, A and Stephenson, G and Taraman, S and Walton, N and Ehwerhemuepha, L and Pandit, J and Pandita, D and Weiss, M and Golden, C and Gold, A and Henderson, J and Shippy, A and Celi, LA and Hogan, WR and Oermann, EK and Sanger, T and Martel, S}, title = {Economics and Equity of Large Language Models: Health Care Perspective.}, journal = {Journal of medical Internet research}, volume = {26}, number = {}, pages = {e64226}, doi = {10.2196/64226}, pmid = {39541580}, issn = {1438-8871}, mesh = {Humans ; *Delivery of Health Care ; Language ; }, abstract = {Large language models (LLMs) continue to exhibit noteworthy capabilities across a spectrum of areas, including emerging proficiencies across the health care continuum. Successful LLM implementation and adoption depend on digital readiness, modern infrastructure, a trained workforce, privacy, and an ethical regulatory landscape. These factors can vary significantly across health care ecosystems, dictating the choice of a particular LLM implementation pathway. This perspective discusses 3 LLM implementation pathways-training from scratch pathway (TSP), fine-tuned pathway (FTP), and out-of-the-box pathway (OBP)-as potential onboarding points for health systems while facilitating equitable adoption. The choice of a particular pathway is governed by needs as well as affordability. Therefore, the risks, benefits, and economics of these pathways across 4 major cloud service providers (Amazon, Microsoft, Google, and Oracle) are presented. While cost comparisons, such as on-demand and spot pricing across the cloud service providers for the 3 pathways, are presented for completeness, the usefulness of managed services and cloud enterprise tools is elucidated. Managed services can complement the traditional workforce and expertise, while enterprise tools, such as federated learning, can overcome sample size challenges when implementing LLMs using health care data. Of the 3 pathways, TSP is expected to be the most resource-intensive regarding infrastructure and workforce while providing maximum customization, enhanced transparency, and performance. Because TSP trains the LLM using enterprise health care data, it is expected to harness the digital signatures of the population served by the health care system with the potential to impact outcomes. The use of pretrained models in FTP is a limitation. It may impact its performance because the training data used in the pretrained model may have hidden bias and may not necessarily be health care-related. However, FTP provides a balance between customization, cost, and performance. While OBP can be rapidly deployed, it provides minimal customization and transparency without guaranteeing long-term availability. OBP may also present challenges in interfacing seamlessly with downstream applications in health care settings with variations in pricing and use over time. Lack of customization in OBP can significantly limit its ability to impact outcomes. Finally, potential applications of LLMs in health care, including conversational artificial intelligence, chatbots, summarization, and machine translation, are highlighted. While the 3 implementation pathways discussed in this perspective have the potential to facilitate equitable adoption and democratization of LLMs, transitions between them may be necessary as the needs of health systems evolve. Understanding the economics and trade-offs of these onboarding pathways can guide their strategic adoption and demonstrate value while impacting health care outcomes favorably.}, }
@article {pmid39541411, year = {2024}, author = {Lin, L and Spreng, RL and Seaton, KE and Dennison, SM and Dahora, LC and Schuster, DJ and Sawant, S and Gilbert, PB and Fong, Y and Kisalu, N and Pollard, AJ and Tomaras, GD and Li, J}, title = {GeM-LR: Discovering predictive biomarkers for small datasets in vaccine studies.}, journal = {PLoS computational biology}, volume = {20}, number = {11}, pages = {e1012581}, doi = {10.1371/journal.pcbi.1012581}, pmid = {39541411}, issn = {1553-7358}, abstract = {Despite significant progress in vaccine research, the level of protection provided by vaccination can vary significantly across individuals. As a result, understanding immunologic variation across individuals in response to vaccination is important for developing next-generation efficacious vaccines. Accurate outcome prediction and identification of predictive biomarkers would represent a significant step towards this goal. Moreover, in early phase vaccine clinical trials, small datasets are prevalent, raising the need and challenge of building a robust and explainable prediction model that can reveal heterogeneity in small datasets. We propose a new model named Generative Mixture of Logistic Regression (GeM-LR), which combines characteristics of both a generative and a discriminative model. In addition, we propose a set of model selection strategies to enhance the robustness and interpretability of the model. GeM-LR extends a linear classifier to a non-linear classifier without losing interpretability and empowers the notion of predictive clustering for characterizing data heterogeneity in connection with the outcome variable. We demonstrate the strengths and utility of GeM-LR by applying it to data from several studies. GeM-LR achieves better prediction results than other popular methods while providing interpretations at different levels.}, }
@article {pmid39540294, year = {2024}, author = {Karra, P and Hardikar, S and Winn, M and Anderson, GL and Haaland, B and Shadyab, AH and Neuhouser, ML and Seguin-Fowler, RA and Thomson, CA and Coday, M and Wactawski-Wende, J and Stefanick, ML and Zhang, X and Cheng, TD and Karanth, S and Sun, Y and Saquib, N and Pichardo, MS and Jung, SY and Tabung, FK and Summers, SA and Holland, WL and Jalili, T and Gunter, MJ and Playdon, MC}, title = {Metabolic phenotype and risk of obesity-related cancers in the Women's Health Initiative.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {}, number = {}, pages = {}, doi = {10.1158/1940-6207.CAPR-24-0082}, pmid = {39540294}, issn = {1940-6215}, abstract = {Body mass index (BMI) may misclassify obesity-related cancer (ORC) risk, as metabolic dysfunction can occur across BMI levels. We hypothesized that metabolic dysfunction at any BMI increases ORC risk compared to normal BMI without metabolic dysfunction. Postmenopausal women (n=20,593) in the Women's Health Initiative with baseline metabolic dysfunction biomarkers (blood pressure, fasting triglycerides, high-density lipoprotein-cholesterol, fasting glucose, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and high sensitive C-reactive protein (hs-CRP)) were included. Metabolic phenotype (metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obese (MHO), metabolically unhealthy overweight/obese (MUO)) was classified using four definitions of metabolic dysfunction: (1) Wildman criteria, (2) National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), (3) HOMA-IR, and (4) hs-CRP. Multivariable Cox proportional hazards regression, with death as a competing risk, was used to assess the association between metabolic phenotype and ORC risk. After a median (IQR) follow-up duration of 21 (IQR 15-22) years, 2,367 women developed an ORC. The risk of any ORC was elevated among MUNW (HR 1.12, 95% CI: 0.90-1.39), MHO (HR 1.15, 95% CI: 1.00-1.32), and MUO (HR 1.35, 95% CI: 1.18-1.54) compared with MHNW using Wildman criteria. Results were similar using ATP III criteria, hs-CRP alone, or HOMA-IR alone to define metabolic phenotype. Individuals with overweight or obesity with or without metabolic dysfunction were at higher risk of ORCs compared with metabolically healthy normal weight individuals. The magnitude of risk was greater among those with metabolic dysfunction, although the confidence intervals of each category overlapped.}, }
@article {pmid39540227, year = {2024}, author = {Zelikson, V and Gurumurthi, A and Sawalha, Y and Annunzio, K and Saha, A and Dong, N and Qualls, D and Amoozgar, B and Kahl, B and Baird, J and Challa, P and Huntington, SF and Santos, J and Bair, S and Narkhede, M and Li, S and Frosch, Z and Ho, C and Smith, SD and Winter, A and Landsburg, D and Furqan, F and Hamadani, M and Baird, K and Romancik, J and Alharthy, H and Law, J and Bojanini, L and Advani, R and Hu, B and Johnson, PC and Grover, NS and Merril, M and Crombie, JL and Shafagati, N and Sterling, C and Nastoupil, LJ and Epperla, N and Ayers, EC}, title = {Loncastuximab in high-risk and heavily pretreated relapsed / refractory diffuse large B-cell lymphoma: a real-world analysis from 21 US centers.}, journal = {Haematologica}, volume = {}, number = {}, pages = {0}, doi = {10.3324/haematol.2024.285977}, pmid = {39540227}, issn = {1592-8721}, abstract = {Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab-teserine (Lonca) is an antibody drug conjugate (ADC) which was FDA approved for R/R DLBCL patients who have received at least 2 prior lines of therapy based on the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting (RWS). This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis includes 187 patients with notably higher risk baseline features compared to LOTIS-2 including a higher proportion of patients with bulky disease (17% vs 0%), high-grade B-cell histology (HGBL) (22% vs 8%), and increased number of prior lines of therapy (median 4 vs 3). The complete response (CR) rate was 14% and overall response rate (ORR) was 32%. Median event free (EFS) and overall survival (OS) were 2.1 and 4.6 months, respectively. Those with bulky disease and HGBL had significantly worse outcomes, and those with non-germinal center cell of origin and CR to most recent line of therapy demonstrated superior outcomes. In summary, in this largest retrospective cohort study of Lonca in the RWS, the response rates, EFS, and OS were lower than those reported in LOTIS-2, which is likely reflective of its use in higher risk and more heavily pre-treated patients within the real world compared to those enrolled on clinical study.}, }
@article {pmid39538264, year = {2024}, author = {Carnegie, L and McCrone, JT and du Plessis, L and Hasan, M and Ali, MZ and Begum, R and Hassan, MZ and Islam, S and Rahman, MH and Uddin, ASM and Sarker, MS and Das, T and Hossain, M and Khan, M and Razu, MH and Akram, A and Arina, S and Hoque, E and Molla, MMA and Nafisaa, T and Angra, P and Rambaut, A and Pullan, ST and Osman, KL and Hoque, MA and Biswas, P and Flora, MS and Raghwani, J and Fournié, G and Samad, MA and Hill, SC}, title = {Genomic epidemiology of early SARS-CoV-2 transmission dynamics in Bangladesh.}, journal = {Virology journal}, volume = {21}, number = {1}, pages = {291}, pmid = {39538264}, issn = {1743-422X}, support = {BB/T008709/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; NU2GGH002077//Combating the threats of antimicrobial resistance and zoonotic diseases to achieve the GHSA in Bangladesh/ ; NU2GGH002077//Combating the threats of antimicrobial resistance and zoonotic diseases to achieve the GHSA in Bangladesh/ ; NU2GGH002077//Combating the threats of antimicrobial resistance and zoonotic diseases to achieve the GHSA in Bangladesh/ ; BB/S011269/1//UK Research and Innovation/ ; BB/S011269/1//UK Research and Innovation/ ; 223038200//Zoonosis and Transboundary Animal Diseases Prevention and Control project/ ; 220414/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Bangladesh/epidemiology ; *COVID-19/transmission/epidemiology/virology ; Humans ; *SARS-CoV-2/genetics/classification ; *Genome, Viral ; *Phylogeography ; Phylogeny ; Whole Genome Sequencing ; Genomics ; Molecular Epidemiology ; Male ; Adult ; Female ; Middle Aged ; Young Adult ; Adolescent ; Child ; }, abstract = {BACKGROUND: Genomic epidemiology has helped reconstruct the global and regional movement of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is still a lack of understanding of SARS-CoV-2 spread in some of the world's least developed countries (LDCs).
METHODS: To begin to address this disparity, we studied the transmission dynamics of the virus in Bangladesh during the country's first COVID-19 wave by analysing case reports and whole-genome sequences from all eight divisions of the country.
RESULTS: We detected > 50 virus introductions to the country during the period, including during a period of national lockdown. Additionally, through discrete phylogeographic analyses, we identified that geographical distance and population -density and/or -size influenced virus spatial dispersal in Bangladesh.
CONCLUSIONS: Overall, this study expands our knowledge of SARS-CoV-2 genomic epidemiology in Bangladesh, shedding light on crucial transmission characteristics within the country, while also acknowledging resemblances and differences to patterns observed in other nations.}, }
@article {pmid39538107, year = {2024}, author = {Timperanza, C and Gustafsson-Lutz, A and Bäck, T and Green, DJ and Lindegren, S and Aneheim, E}, title = {Modified poly-L-lysine for use as a clearing agent in pretargeted radioimmunotherapy.}, journal = {EJNMMI radiopharmacy and chemistry}, volume = {9}, number = {1}, pages = {76}, pmid = {39538107}, issn = {2365-421X}, support = {2021:354//Stiftelsen Jubileumsklinikens Forskningsfond mot Cancer/ ; 21 1842 Pj 01 H//Cancerfonden/ ; }, abstract = {BACKGROUND: Pretargeted radioimmunotherapy of cancer has the potential to increase tumor specific uptake of activity when compared with conventional radioimmunotherapy. This is especially true in radioimmunotherapy with nuclides that exhibit a relatively short half-life. When administering antibody-based pretargeting molecules systemically, the antibodies often show a relatively slow clearance from the blood. Therefore, the use of a clearing agent is advantageous to remove unbound pretargeting molecules from the circulation, facilitating a reduction in the nonspecific radiation exposure to normal tissue while maximizing the dose delivered to the tumors.
RESULTS: In the current study, two types of poly-L-lysine based clearing agents were produced for two different pretargeting systems: (strept)avidin/biotin and Tetrazine/Transcyclooctene. Poly-L-lysine was used as scaffold for production of clearing agents. The polymer is available in multiple sizes and can readily be modified with several functional groups, allowing different pretargeting strategies to be used. In vivo evaluation of the biotin-functionalized poly-L-lysine clearing agent, 110 repeating units, resulted in a decrease in blood concentration of the Iodine-125 labeled pretargeting agent of 50%, circa 23 h after injection, compared to controls. Two sizes, 68 and 143 repeating units, of the tetrazine-functionalized poly-L-lysine clearing agent were also evaluated, which at 23 h after injection decreased the blood concentration of the Iodine-125 labeled pretargeting agent to 58 and 38% respectively.
CONCLUSION: The straightforward synthesis of poly-L-lysine based clearing agents makes kit preparation possible and these agents show good potential for further evaluation, especially within the Tetrazine/Transcyclooctene pretargeting system where no liver or kidney accumulation was observed.}, }
@article {pmid39537980, year = {2024}, author = {Sheridan, L and Pocobelli, G and Anderson, M and Li, CI and Kruse, GR and Tiro, JA and Kamineni, A}, title = {Cervical cancer screening rates in females living with HIV at three healthcare settings in the United States, 2010-2019.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {39537980}, issn = {1573-7225}, support = {UM1CA221940//National Cancer Institute of the National Institutes of Health/ ; }, abstract = {PURPOSE: Females living with human immunodeficiency virus (FLWHIV) are at increased risk of cervical cancer and U.S. guidelines, first published in 2009 and updated since then, recommend more frequent screening in this population. We examined screening rates among FLWHIV in the U.S. during 2010-2019.
METHODS: This cohort study included 18-89-year-old FLWHIV during 2010-2019 at three U.S. healthcare settings. Sociodemographics, comorbidities, and cervical cancer screening tests were ascertained from administrative and clinical databases. We reported cervical cancer screening rates overall and by modality. Generalized estimating equations with Poisson distribution were used to estimate screening rate ratios (SRRs) and 95% confidence intervals (CIs) for the associations between screening rates and calendar year, age, race and ethnicity, and comorbidity.
RESULTS: Among 3,556 FLWHIV, a total of 7,704 cervical cancer screening tests were received over 18,605 person-years during 2010-2019 (screening rate = 41.4 per 100 person-years). Relatively lower screening rates were associated with later calendar years (SRR = 0.71 [95% CI 0.68-0.75] for 2017-2019 versus 2010-2013), older age (SRR = 0.82 [95% CI 0.74-0.89] for 50-65-year-olds versus 18-29-year-olds), non-Hispanic white race versus non-Hispanic Black race (SRR = 0.89 [95% CI 0.81-0.98]) and greater comorbidity burden (SRR = 0.89 [95% CI 0.82-0.98] for ≥ 9 versus 0-6 comorbidity score).
CONCLUSION: The decrease in cervical cancer screening rates during 2010-2019 in this large cohort of FLWHIV may be explained at least partly by guideline changes during the study period recommending longer screening intervals. Our findings of relatively lower screening rates in FLWHIV who were non-Hispanic white, older, and with greater comorbidity burden should be confirmed in other U.S.}, }
@article {pmid39536820, year = {2024}, author = {Nilius, H and Naas, S and Studt, JD and Tsakiris, DA and Greinacher, A and Mendez, A and Schmidt, A and Wuillemin, WA and Gerber, B and Vishnu, P and Graf, L and Kremer Hovinga, JA and Bakchoul, T and Nakas, C and Nagler, M}, title = {The dynamic range of immunoassays for heparin-induced thrombocytopenia.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtha.2024.10.026}, pmid = {39536820}, issn = {1538-7836}, abstract = {BACKGROUND: Following the current guidelines, immunoassays for the diagnosis of heparin-induced thrombocytopenia (HIT) are interpreted dichotomously, with test results categorized as either positive or negative. However, the extent to which test results hold diagnostic significance across the entire dynamic range remains unclear.
OBJECTIVES: We utilized data from the prospective TORADI-HIT study, comprising 1,393 consecutive patients with suspected HIT, to assess the diagnostic significance of two H/PF4 immunoassay test results across their respective dynamic ranges: HemoSil Acustar HIT IgG [CLIA] and Lifecodes PF4 IgG [ELISA].
METHODS: HIT diagnosis was determined by a washed-platelet heparin-induced platelet activation assay (HIPA). For each measurement point in the dataset, we computed likelihood ratios (LR), sensitivities, and specificities. To provide post-test probabilities for individual test results, we calculated interval-specific likelihood ratios and integrated it into a web-based calculator.
RESULTS: The prevalence of HIT was 8.5% (n = 119). A likelihood ratio of ≥ 10 was first achieved at 0.3% of the dynamic range (0.4 U/ml; CLIA) and 16% (0.64 OD; ELISA), respectively. A likelihood ratio of ≥ 100 was present at 9.4% (12 U/ml; CLIA) and 75.0% (3.0 OD; ELISA). The slope of the linear regression line (LR ∼ dynamic range) was 9.5 (CLIA) and 0.9 (ELISA).
CONCLUSION: Despite both immunoassays showing an association between results and diagnostic significance, the strength of that association varies by assay. CLIA has a larger increase per measurement unit. Post-test probabilities for individual patients can be estimated using a web-based calculator: https://pcd-research.shinyapps.io/BayesianCalculator/.}, }
@article {pmid39536447, year = {2024}, author = {Oehler, VG and Huang, IJ and Siu, C and Kim, M and Signorelli, J and Bell, CS and Hobbs, GS}, title = {Dose Modifications in the Management of Chronic Phase Chronic Myeloid Leukemia: Who, What, and When.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {}, doi = {10.6004/jnccn.2024.7044}, pmid = {39536447}, issn = {1540-1413}, mesh = {Humans ; *Protein Kinase Inhibitors/therapeutic use/adverse effects/administration & dosage ; Leukemia, Myeloid, Chronic-Phase/drug therapy ; Antineoplastic Agents/therapeutic use/administration & dosage/adverse effects ; Fusion Proteins, bcr-abl/antagonists & inhibitors/genetics ; Treatment Outcome ; Quality of Life ; Disease Management ; }, abstract = {With the availability of BCR::ABL1 targeted tyrosine kinase inhibitors (TKIs), outcomes for most individuals with chronic phase chronic myeloid leukemia (CP-CML) are outstanding, with life expectancy similar to age-matched peers. Treatment-emergent adverse events (TEAEs) impair quality of life and many patients struggle with low-level chronic AEs, which for some individuals impact emotional well-being as well as social and work functioning. An emerging body of data supports that many TEAEs are related to therapy dose and can improve with dose reduction. However, it is critical that dose reductions do not alter current outcomes, especially in the rare patients who are at greater risk of losing response or transforming to acute leukemia. Organizations including the National Comprehensive Cancer Network have begun to address when dose reductions may be considered in patients with CP-CML. In this manuscript, we review retrospective and prospective data reporting outcomes in patients after dose reduction and review data supporting lower dose preemptive dosing in first-line and later-line therapy. Switching therapy for intolerance can result in improvements in symptoms and limit toxicity, but other TEAEs may occur. Additionally, emerging therapeutics such as the new class of BCR::ABL1 allosteric inhibitors are under evaluation with a goal of improving tolerability. However, with many TKIs on the cusp of becoming generic, dose reduction becomes an appealing and important cost-effective strategy to minimize TEAEs and improve quality of life while preserving outstanding outcomes in CP-CML.}, }
@article {pmid39536442, year = {2024}, author = {Xu, YG and Lim, Y and Bordeaux, JS and Aasi, SZ and Alam, M and Chen, PL and Contreras, CM and DiMaio, D and Donigan, JM and Farma, JM and Grekin, RC and Mark, L and Nehal, KS and Nghiem, P and Olino, K and Patel, T and Scott, J and Shaha, AR and Srivastava, D and Schmults, CD}, title = {Achieving Adherence With NCCN Guidelines for Nonmelanoma Skin Cancer Regarding Peripheral and Deep En Face Margin Assessment (PDEMA).}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {9}, pages = {}, doi = {10.6004/jnccn.2024.7037}, pmid = {39536442}, issn = {1540-1413}, mesh = {Humans ; *Skin Neoplasms/pathology/surgery/therapy/diagnosis ; *Margins of Excision ; *Mohs Surgery/methods/standards ; Guideline Adherence/statistics & numerical data ; Practice Guidelines as Topic ; Carcinoma, Squamous Cell/pathology/surgery/therapy/diagnosis ; }, abstract = {Peripheral and deep en face margin assessment (PDEMA), formerly termed by NCCN as complete circumferential peripheral and deep margin assessment (CCPDMA), has the advantages of histologic visualization of the entire marginal surface, highly accurate resection of involved tissue, and sparing of uninvolved tissue. Owing to its highest reported cure rates, PDEMA is the NCCN-preferred treatment for dermatofibrosarcoma protuberans, high-risk basal cell carcinoma, and very-high-risk cutaneous squamous cell carcinoma. In the United States, Mohs micrographic surgery (Mohs) is the most common method of PDEMA. In Germany and some other countries, non-Mohs methods of PDEMA referred to as the Tubingen torte and muffin techniques are more widely used. The Tubingen methods of PDEMA require close communication between surgeon and pathologist. This article describes the background of both Mohs and Tubingen PDEMA, reviews what constitutes PDEMA, and provides a protocol for Tubingen PDEMA detailing critical components in a stepwise fashion using illustrative photos and diagrams. We hope to broaden understanding of the NCCN Guidelines and their rationale, align practice, and optimize patient outcomes.}, }
@article {pmid39534377, year = {2024}, author = {Brusselmans, M and Carvalho, LM and L Hong, S and Gao, J and Matsen Iv, FA and Rambaut, A and Lemey, P and Suchard, MA and Dudas, G and Baele, G}, title = {On the importance of assessing topological convergence in Bayesian phylogenetic inference.}, journal = {Virus evolution}, volume = {10}, number = {1}, pages = {veae081}, pmid = {39534377}, issn = {2057-1577}, abstract = {Modern phylogenetics research is often performed within a Bayesian framework, using sampling algorithms such as Markov chain Monte Carlo (MCMC) to approximate the posterior distribution. These algorithms require careful evaluation of the quality of the generated samples. Within the field of phylogenetics, one frequently adopted diagnostic approach is to evaluate the effective sample size and to investigate trace graphs of the sampled parameters. A major limitation of these approaches is that they are developed for continuous parameters and therefore incompatible with a crucial parameter in these inferences: the tree topology. Several recent advancements have aimed at extending these diagnostics to topological space. In this reflection paper, we present two case studies-one on Ebola virus and one on HIV-illustrating how these topological diagnostics can contain information not found in standard diagnostics, and how decisions regarding which of these diagnostics to compute can impact inferences regarding MCMC convergence and mixing. Our results show the importance of running multiple replicate analyses and of carefully assessing topological convergence using the output of these replicate analyses. To this end, we illustrate different ways of assessing and visualizing the topological convergence of these replicates. Given the major importance of detecting convergence and mixing issues in Bayesian phylogenetic analyses, the lack of a unified approach to this problem warrants further action, especially now that additional tools are becoming available to researchers.}, }
@article {pmid39529638, year = {2024}, author = {Treekitkarnmongkol, W and Dai, J and Liu, S and Sankaran, D and Nguyen, T and Balasenthil, S and Hurd, MW and Chen, M and Katayama, H and Roy-Chowdhuri, S and Calin, GA and Brand, RE and Lampe, PD and Hu, TY and Maitra, A and Koay, EJ and Killary, AM and Sen, S}, title = {Blood-Based microRNA Biomarker Signature of Early-Stage Pancreatic Ductal Adenocarcinoma With Lead-Time Trajectory in Prediagnostic Samples.}, journal = {Gastro hep advances}, volume = {3}, number = {8}, pages = {1098-1115}, pmid = {39529638}, issn = {2772-5723}, abstract = {BACKGROUND AND AIMS: Clinically validated biomarker of pancreatic ductal adenocarcinoma (PDAC), carbohydrate antigen 19-9 (CA19-9), has limited sensitivity and specificity for early-stage disease. Circulating miRNAs in plasma associated with cancer relevant pathways were developed as early detection biomarkers.
METHODS: 2083 miRNAs in 15 μl of plasma from multicenter age-matched cohorts (N = 203: healthy controls, n = 46; pancreatitis controls, n = 36; diagnosed cases: n = 121) and a prediagnostic Prostate, Lung, Colorectal, and Ovarian age- and gender-matched cohort (N = 96; controls, n = 48; prediagnosed cases, n = 48) were interrogated. A three-miRNA biomarker signature was developed for early-stage PDAC.
RESULTS: The three-miRNA signature (let-7i-5p, miR-130a-3p and miR-221-3p) detected PDAC from healthy controls independently (area under the curve [AUC] of stage I, II, I-IV = 0.970, 0.975, 0.974) and in combination with CA19-9 (AUC of stage I, II, I-IV = 1.000, 0.992, 0.995). It also discriminated chronic pancreatitis (AUC of stage I, II, I-IV = 0.932, 0.931, 0.929), improving performance of CA19-9 alone (AUC of stage I, II, I-IV = 0.763, 0.701, 0.735) in combination (AUC of stage I, II, I-IV = 0.971, 0.943, 0.951). Blinded validation in prediagnostic Prostate, Lung, Colorectal, and Ovarian cohort revealed lead-time trajectory increase in AUC from 0.702 to 0.729 to 0.757 at twelve-, six-, and three-months before PDAC diagnosis, respectively. The signature also helped stratification of patients with different circulating tumor DNA and imaging subtypes.
CONCLUSION: Plasma miRNAs associated with oncogenic pathways may serve as PDAC early detection biomarkers.}, }
@article {pmid39533017, year = {2024}, author = {Liang, EC and Rejeski, K and Fei, T and Albittar, A and Huang, JJ and Portuguese, AJ and Wu, Q and Raj, S and Subklewe, M and Shouval, R and Gauthier, J}, title = {Correction: Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-024-02453-6}, pmid = {39533017}, issn = {1476-5365}, }
@article {pmid39532861, year = {2024}, author = {Carpp, LN and Hyrien, O and Fong, Y and Benkeser, D and Roels, S and Stieh, DJ and Van Dromme, I and Van Roey, GA and Kenny, A and Huang, Y and Carone, M and McDermott, AB and Houchens, CR and Martins, K and Jayashankar, L and Castellino, F and Amoa-Awua, O and Basappa, M and Flach, B and Lin, BC and Moore, C and Naisan, M and Naqvi, M and Narpala, S and O'Connell, S and Mueller, A and Serebryannyy, L and Castro, M and Wang, J and Petropoulos, CJ and Luedtke, A and Lu, Y and Yu, C and Juraska, M and Hejazi, NS and Wolfe, DN and Sadoff, J and Gray, GE and Grinsztejn, B and Goepfert, PA and Bekker, LG and Gaur, AH and Veloso, VG and Randhawa, AK and Andrasik, MP and Hendriks, J and Truyers, C and Vandebosch, A and Struyf, F and Schuitemaker, H and Douoguih, M and Kublin, JG and Corey, L and Neuzil, KM and Follmann, D and Koup, RA and Donis, RO and Gilbert, PB and , and , and , }, title = {Neutralizing antibody correlate of protection against severe-critical COVID-19 in the ENSEMBLE single-dose Ad26.COV2.S vaccine efficacy trial.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9785}, pmid = {39532861}, issn = {2041-1723}, mesh = {Humans ; *Antibodies, Neutralizing/immunology/blood ; *COVID-19/immunology/prevention & control/virology ; *SARS-CoV-2/immunology ; *Antibodies, Viral/immunology/blood ; *COVID-19 Vaccines/immunology/administration & dosage ; Female ; Male ; Middle Aged ; Adult ; Vaccine Efficacy ; Spike Glycoprotein, Coronavirus/immunology ; Ad26COVS1/immunology ; Vaccination ; Aged ; }, abstract = {Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.S vaccination as correlates of risk and of protection against severe-critical COVID-19 through 220 days post-vaccination in the ENSEMBLE trial (NCT04505722), constituting ~4.5 months longer follow-up than our previous correlates analysis and enabling inclusion of 42 severe-critical vaccine-breakthrough cases. Neutralizing antibody titer is a strong inverse correlate of severe-critical COVID-19, with estimated hazard ratio (HR) per 10-fold increase 0.35 (95% CI: 0.13, 0.90). In a multivariable model, HRs are 0.31 (0.11, 0.89) for neutralizing antibody titer and 1.22 (0.49, 3.02) for anti-Spike binding antibody concentration. VE against severe-critical COVID-19 rises with neutralizing antibody titer: 63.1% (95% CI: 40.0%, 77.3%) at unquantifiable [<4.8975 International Units (IU)50/ml], 85.2% (47.2%, 95.3%) at just-quantifiable (5.2 IU50/ml), and 95.1% (81.1%, 96.9%) at 90[th] percentile (30.2 IU50/ml). At the same titers, VE against moderate COVID-19 is 32.5% (11.8%, 48.4%), 33.9% (19.1%, 59.3%), and 60.7% (40.4%, 76.4%). Protection against moderate vs. severe disease may require higher antibody levels, and very low antibody levels and/or other immune responses may associate with protection against severe disease.}, }
@article {pmid39532048, year = {2024}, author = {Grivas, P and Barata, P and Moon, H and Gupta, S and Hutson, T and Sternberg, CN and Brown, JR and Dave, V and Downey, C and Shillington, AC and Katzenstein, HM and Kirker, M and Hanson, S and Liu, FX and Morris, V and Bhanegaonkar, A and Sonpavde, GP}, title = {Avelumab First-Line Maintenance for Locally Advanced or Metastatic Urothelial Carcinoma: Results From the Real-World US PATRIOT-II Study.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {6}, pages = {102238}, doi = {10.1016/j.clgc.2024.102238}, pmid = {39532048}, issn = {1938-0682}, abstract = {INTRODUCTION: In JAVELIN Bladder 100, avelumab first-line maintenance (1LM) improved overall survival (OS) and progression-free survival (PFS) in patients with locally advanced/metastatic urothelial carcinoma (la/mUC) without progression following 1L platinum-based chemotherapy (PBC) versus best supportive care. PATRIOT-II describes real-world outcomes with avelumab 1LM.
PATIENTS AND METHODS: This observational, retrospective study of avelumab 1LM in US community/academic centers used medical record data collected from avelumab initiation for ≥12 months to assess survival, safety, and healthcare resource utilization; analyses are descriptive.
RESULTS: The study included 160 patients from 37 centers (median age, 70 years; 77% male). Avelumab 1LM was initiated at a median of 4 weeks (IQR 3-6) after PBC completion. Median follow-up from avelumab 1LM was 16 months (IQR 11-21). At study end, 19.4% of patients continued avelumab; 73.7% had discontinued due to progression, adverse events (AEs), or performance status deterioration. Median PFS and OS from avelumab initiation were 5.4 months (95% CI, 3.8-6.9) and 24.4 months (95% CI, 20.4-28.4), respectively. Grade ≥3 treatment-related AEs (TRAEs) occurred in 15 patients (9.4%); 35 (21.9%) had any-grade immune-related AEs, and 23 (14.3%) received high-dose systemic corticosteroids for AEs. Forty-four patients (27.5%) were hospitalized during the avelumab treatment period, of whom 13 (8.1%) were hospitalized due to TRAEs. Limitations of this study include a small sample size, potential selection bias, and missing/unknown data.
CONCLUSION: These results align with the JAVELIN Bladder 100 clinical trial and other real-world studies, supporting avelumab 1LM use in patients with la/mUC without progression following 1L PBC.}, }
@article {pmid39531474, year = {2024}, author = {Dadonaite, B and Ahn, JJ and Ort, JT and Yu, J and Furey, C and Dosey, A and Hannon, WW and Vincent Baker, AL and Webby, RJ and King, NP and Liu, Y and Hensley, SE and Peacock, TP and Moncla, LH and Bloom, JD}, title = {Deep mutational scanning of H5 hemagglutinin to inform influenza virus surveillance.}, journal = {PLoS biology}, volume = {22}, number = {11}, pages = {e3002916}, doi = {10.1371/journal.pbio.3002916}, pmid = {39531474}, issn = {1545-7885}, abstract = {H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple nonhuman mammalian species. Previous studies have identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute to pandemic potential in humans, including cell entry, receptor preference, HA stability, and reduced neutralization by polyclonal sera. However, prior experimental work has only measured how these phenotypes are affected by a handful of the >10,000 different possible amino-acid mutations to HA. Here, we use pseudovirus deep mutational scanning to measure how all mutations to a 2.3.4.4b H5 HA affect each phenotype. We identify mutations that allow HA to better bind α2-6-linked sialic acids and show that some viruses already carry mutations that stabilize HA. We also measure how all HA mutations affect neutralization by sera from mice and ferrets vaccinated against or infected with 2.3.4.4b H5 viruses. These antigenic maps enable rapid assessment of when new viral strains have acquired mutations that may create mismatches with candidate vaccine virus, and we show that a mutation present in some recent H5 HAs causes a large antigenic change. Overall, the systematic nature of deep mutational scanning combined with the safety of pseudoviruses enables comprehensive measurements of the phenotypic effects of mutations that can inform real-time interpretation of viral variation observed during surveillance of H5 influenza.}, }
@article {pmid39530736, year = {2024}, author = {Shearer, T and Comstock, M and Williams, RL and Johnson, MC and Cendrowicz, E and Leonowens, C and Smith, M and Baughman, TM and Breitbach, CJ and Cheng, S and Green, DJ}, title = {Kinetics of nirogacestat-mediated increases in B-cell maturation antigen on plasma cells inform therapeutic combinations in multiple myeloma.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-24-0075}, pmid = {39530736}, issn = {2767-9764}, abstract = {B-cell maturation antigen (BCMA) is the target of several investigational and approved drugs for multiple myeloma (MM). BCMA expressed on plasma cells (PCs) and MM cells is cleaved by the enzyme gamma secretase, reducing membrane-bound BCMA (mbBCMA) receptor density. Gamma secretase inhibitors (GSIs) have been shown to increase mbBCMA density and may enhance efficacy of BCMA-targeted therapies. The pharmacodynamic profile of the GSI nirogacestat was evaluated in MM cell lines and a phase 1 study in healthy volunteers. In MM cell lines, mbBCMA density and soluble BCMA (sBCMA) concentrations were measured before and after short-duration nirogacestat exposure and at serial timepoints following washout. In the phase 1 study, 23 participants were administered a single oral dose of nirogacestat 50, 150, or 300 mg or repeated doses of 100 mg every 12h for up to 48h; mbBCMA density on PCs (from whole blood and bone marrow) and nirogacestat plasma concentrations were measured at baseline and postdose. After single-dose administration, serum nirogacestat concentrations rapidly increased (Tmax ~1h), and a two-compartment model with linear absorption and clearance best described nirogacestat pharmacokinetics. In MM cells and healthy volunteers' PCs, nirogacestat resulted in rapid and robust increases in mbBCMA density, with increases up to 20-fold within 4-8h of exposure. Concomitant decreases in sBCMA were observed. Nirogacestat is currently being evaluated in combination with several BCMA-directed therapeutic agents in patients with MM. Elucidating the kinetics of BCMA in response to nirogacestat is key to guiding dosing and therapeutic strategies in MM.}, }
@article {pmid39528599, year = {2024}, author = {Paik, J and Kim, A and Fogassy, K and Snyder, JM and Brabb, T and Dill-McFarland, KA and He, Q and Amory, JK}, title = {Weight loss and metabolic effects of an ALDH1A1-specific inhibitor, FSI-TN42, in a diet induced mouse model of obesity.}, journal = {International journal of obesity (2005)}, volume = {}, number = {}, pages = {}, pmid = {39528599}, issn = {1476-5497}, abstract = {BACKGROUND: Retinoic acid (RA) participates in weight regulation and energy metabolism. Mice lacking ALDH1A1, one of the major enzymes responsible for RA biosynthesis, are resistant to diet-induced obesity. Previously, we identified FSI-TN42 (N42) as an ALDH1A1-specific inhibitor and reported its pharmacokinetics and pharmacodynamics as well as its efficacy in weight suppression.
METHODS: In the first study, C57BL/6 J male mice were fed a high fat diet for 8 weeks to induce obesity. Mice were then divided into three groups and fed (1) moderate fat diet (MFD), (2) MFD + WIN 18,446 (1 g/kg diet), or (3) MFD + N42 (1 g/kg diet) for 8 weeks. A control group of mice were fed a low-fat diet for the entire period. Mice were weighed weekly and fasting glucose was determined every 4 weeks. Tissues were examined for potential toxicity using histopathology and complete blood counts. In the second study, we examined influences of N42 on energy balance and/or appetite by determining food intake, activity and energy expenditure in mice with obesity treated with MFD or MFD + N42. Lastly, we tested fertility with a mating study.
RESULTS: N42 significantly accelerated weight loss compared to MFD alone in mice with obesity by reducing fat mass without decreasing lean mass. N42 did not alter food intake or activity levels. While mice treated with N42 lost significantly more weight, they maintained a similar level of energy expenditure compared to mice fed MFD only. Mice fed N42 preferentially used fat postprandially, especially under thermoneutral or mild cold challenge. N42 did not affect male fertility.
CONCLUSIONS: N42 promotes weight loss when used with MFD in mice with diet-induced obesity without causing significant organ toxicity or male infertility. Future studies will determine if N42 can be used to promote further weight loss if combined with current weight loss drugs.}, }
@article {pmid39528488, year = {2024}, author = {Giaccherini, M and Clay-Gilmour, AI and Liotti, R and Macauda, A and Gentiluomo, M and Brown, EE and Machiela, MJ and Chanock, SJ and Hildebrandt, MAT and Norman, AD and Manasanch, E and Rajkumar, SV and Hofmann, JN and Berndt, SI and Bhatti, P and Giles, GG and Ziv, E and Kumar, SK and Camp, NJ and Cozen, W and Slager, SL and Canzian, F and Gemignani, F and Vachon, CM and Campa, D}, title = {Genetically determined telomere length in monoclonal gammopathy of undetermined significance, multiple myeloma risk and outcome.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {200}, pmid = {39528488}, issn = {2044-5385}, }
@article {pmid39527587, year = {2024}, author = {Dankwa, S and Kosman, C and Dennis, M and Giorgi, EE and Vuong, K and Pahountis, I and Garza, A and Binuya, C and McCarthy, J and Mayer, BT and Ngo, JT and Enemuo, CA and Carnathan, DG and Stanfield-Oakley, S and Berendam, SJ and Weinbaum, C and Engelman, K and Magnani, DM and Chan, C and Ferrari, G and Silvestri, G and Amara, RR and Chahroudi, A and Permar, SR and Fouda, GG and Goswami, R}, title = {A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions.}, journal = {PloS one}, volume = {19}, number = {11}, pages = {e0312411}, pmid = {39527587}, issn = {1932-6203}, mesh = {Animals ; *Macaca mulatta ; *Immunization, Passive/methods ; *HIV Antibodies/immunology/blood ; *HIV Infections/immunology/drug therapy/prevention & control ; *Simian Immunodeficiency Virus/immunology ; *Antibodies, Neutralizing/immunology/blood ; Humans ; HIV-1/immunology ; Broadly Neutralizing Antibodies/immunology ; Simian Acquired Immunodeficiency Syndrome/prevention & control/immunology ; }, abstract = {To eliminate vertical HIV transmission and achieve therapy-free viral suppression among children living with HIV, novel strategies beyond antiretroviral therapy (ART) are necessary. Our group previously identified a triple broadly neutralizing antibody (bNAb) combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robust in vitro neutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). In this study, we evaluated the safety, pharmacokinetics, and antiviral potency of this bNAb combination in infant rhesus macaques (RMs). We demonstrate that subcutaneous infusion of the triple bNAb regimen was well tolerated in pediatric monkeys and resulted in durable systemic and mucosal distribution. Plasma obtained from passively-immunized RMs demonstrated potent HIV-neutralizing and Fc-mediated antiviral effector functions. Finally, using the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker threshold of >200, which was recently identified as a surrogate endpoint for evaluation of the preventative efficacy of bNAbs against mucosal viral acquisition in human clinical trials, we demonstrated that our regimen has PT80>200 against a large panel of plasma and breast milk-derived HIV strains and cross-clade SHIV variants. This data will guide the development of combination bNAbs for eliminating vertical HIV transmission and for achieving ART-free viral suppression among children living with HIV.}, }
@article {pmid39522103, year = {2024}, author = {Abbaspour, E and Mansoori, B and Karimzadhagh, S and Chalian, M and Pouramini, A and Sheida, F and Daskareh, M and Haseli, S}, title = {Machine learning and deep learning models for preoperative detection of lymph node metastasis in colorectal cancer: a systematic review and meta-analysis.}, journal = {Abdominal radiology (New York)}, volume = {}, number = {}, pages = {}, pmid = {39522103}, issn = {2366-0058}, abstract = {OBJECTIVE: To evaluate the diagnostic performance of Machine Learning (ML) and Deep Learning (DL) models for predicting preoperative Lymph Node Metastasis (LNM) in Colorectal Cancer (CRC) patients.
METHODS: A systematic review and meta-analysis were conducted following PRISMA-DTA and AMSTAR-2 guidelines. We searched PubMed, Web of Science, Embase, and Cochrane Library databases until February 16, 2024. Study quality and risk of bias were assessed using the QUADAS-2 tool. Data were analyzed using STATA v18, applying random-effects models to all analyses.
RESULTS: Twelve studies involving 8321 patients were included, with most published in 2021-2024 (9/12). The pooled AUC of ML models for predicting LNM in CRC patients was 0.87 (95% CI: 0.82-0.91, I[2]:86.17) with a sensitivity of 78% (95% CI: 69-87%) and a specificity of 77% (95% CI: 64%-90%). In addition, when assessing the AUC reported by radiologists, both junior and senior radiologists had similar performance, significantly lower than the ML models. (P < 0.001). Subgroup analysis revealed higher AUCs in prospective studies (0.95, 95% CI: 0.87-1) compared to retrospective studies (0.85, 95% CI: 0.81-0.89) (P = 0.03). Studies without external validation exhibited significantly higher AUCs than those with external validation (P < 0.01). While there was no significant difference in AUC and sensitivity between the T1-T2 and T2-T4 stages, specificity was significantly higher in the T2-T4 stages than the low stages of T1 and T2 (95%, 95% CI: 92-98% vs. 61%, 95% CI: 44-78%; P < 0.01).
CONCLUSION: ML models demonstrate strong potential for preoperative LNM staging and treatment planning in CRC, potentially reducing the need for additional surgeries and related health and financial burdens. Further prospective multicenter studies, with standardized reporting of algorithms, modality parameters, and LNM staging, are needed to validate these findings.}, }
@article {pmid39522029, year = {2024}, author = {Gregg, JR and Newcomb, L and Wu, R and Dennison, J and Davis, JW and Pettaway, C and Pisters, L and Ward, JF and Chapin, BF and Chéry, L and Urkmez, A and Fang, AM and Higgason, N and Troncoso, P and Daniel, CR and Logothetis, C and Thompson, TC and Hahn, AW and Liu, M and Zheng, Y and Lin, DW and Hanash, S and Irajizad, E and Fahrmann, J}, title = {Validation of a prognostic blood-based sphingolipid panel for men with localized prostate cancer followed on active surveillance.}, journal = {Biomarker research}, volume = {12}, number = {1}, pages = {134}, pmid = {39522029}, issn = {2050-7771}, support = {P50 CA140388/CA/NCI NIH HHS/United States ; P50 CA140388/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: We previously reported that increases in circulating sphingolipids are associated with elevated risk of biopsy Gleason grade group (GG) upgrading in men on Active Surveillance (AS) for prostate cancer. Here, we aimed to validate these findings and establish a blood-based sphingolipid biomarker panel for identifying men on AS who are at high-risk of biopsy GG upgrading.
METHODS: Men diagnosed with low- or intermediate-risk prostate cancer in one of two AS cohorts (CANARY PASS and MDACC) were followed for GG upgrading after diagnostic and confirmatory biopsy. The PASS cohort consisted of 544 patients whereas the MDACC Cohort consisted of 697 patients. The number of patients with GG upgrading during course of study follow-up in the PASS and MDACC cohorts were 98 (17.7%) and 133 (19.1%), respectively. Plasmas collected prior to confirmatory biopsy were used for mass spectrometry-based quantitation of 87 unique sphingolipid species. A neural network layer based on 21 sphingolipids was developed in the CANARY PASS cohort for predicting biopsy GG upgrading. Tertile-based thresholds for low-, intermediate-, and high-risk strata were subsequently developed for the sphingolipid panel as well as a model that combined the sphingolipid panel with PSA density and rate of core positivity on diagnostic biopsy. The resultant models and risk thresholds for GG upgrading were validated in the MDACC cohort. Performance was assessed using Cox proportional hazard models, C-index, AUC, and cumulative incidence curves.
RESULTS: The sphingolipid panel had a HR (per unit standard deviation increase) of 1.36 (95% CI: 1.07-1.70) and 1.35 (95% CI: 1.11-1.64) for predicting GG biopsy upgrading in the PASS and MDACC cohort, respectively. The model that combined the sphingolipid panel with PSA density and rate of core positivity achieved a HR of 1.63 (95% CI: 1.33-2.00) and 1.44 (1.25-1.66), respectively. Tertile-based thresholds, established in the PASS cohort, were applied to the independent MDACC cohort. Compared to the low-risk group, MDACC patients in the high-risk strata had a GG biopsy upgrade HR of 3.65 (95% CI: 2.21-6.02), capturing 50% of the patients that had biopsy upgrading during study follow-up.
CONCLUSIONS: The sphingolipid panel is independently associated with GG biopsy upgrading among men in two independent AS cohorts who have previously undergone diagnostic and confirmatory biopsy. The sphingolipid panel, together with clinical factors, provides a potential means for risk stratification to better guide clinical management of men on AS.}, }
@article {pmid39521703, year = {2024}, author = {Niraula, S and Gouli, S and Baran, AM and O'Regan, R and Tyburski, H and Zhang, H and Hardy, S and Mohile, N and Anders, CK and Dhakal, A}, title = {Effect of Breast Cancer Receptor Subtypes and CSF Cytology Status on Survival of Patients With Leptomeningeal Disease.}, journal = {Clinical breast cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clbc.2024.09.019}, pmid = {39521703}, issn = {1938-0666}, abstract = {BACKGROUND: It is unclear whether breast cancer (BC) subtypes or CSF cytology results are associated with overall survival (OS) among patients with BC leptomeningeal disease (LMD). This single-institution retrospective study compares OS among BC patients with LMD across various breast cancer subtypes and CSF cytology results.
METHODOLOGY: The study enrolled BC patients diagnosed with LMD between 2010 and 2023. Breast cancer subtypes were classified as A. ER+/HER2-, HER2+, or triple-negative BC (TNBC); B. HER2+, HER2-Low, HER2-Zero. CSF cytology subtypes included CSF+, CSF-, or CSF not tested (NT). OS was summarized via Kaplan-Meier analysis and compared using log-rank test. Cox models were used for multivariate analyses.
RESULTS: Out of 69 patients registered, median OS (95% CI) for ER+/HER2- (n = 33), HER2+ (n = 12) and TNBC (n = 24) subtypes were 8.0 (3.02, 24.8), 5.71 (1.61, not estimated) and 3.2 (1.11, 4.95) months (P = .17). In multivariate analysis, TNBC was associated with worse OS versus ER+/HER2- [Hazard Ratio (HR), 95% CI: 2.64, 1.23-5.80, P = .04]. HER2 subtypes (HER2-Zero, n = 21; HER2-Low, n = 32; HER2+, n = 12) showed no significant differences in OS. Median OS (95% CI) for CSF+ (n = 16), CSF- (n = 18), and CSF NT (n = 35) groups were 3.54 (1.61, 12.72), 13.41 (4.95, 61.93) and 3.28 (1.44, 6.92) months (P = .04). Multivariate analysis showed both CSF+ and CSF NT were associated with shorter OS compared to CSF- group [HR (95% CI) 4.50 (1.75, 12.11) for CSF+ vs. CSF-; 2.91 (1.45, 6.26) for CSF NT vs. CSF-; P = .002].
CONCLUSION: TNBC LMD group was associated with worse OS than ER+/HER2- BC LMD when adjusting for other prognostic factors. CSF- LMD patients had better OS than CSF+ or CSF NT LMD.}, }
@article {pmid39521614, year = {2024}, author = {Liao, JB and Dai, JY and Reichow, JL and Lim, JB and Hitchcock-Bernhardt, KM and Stanton, SE and Salazar, LG and Gooley, TA and Disis, ML}, title = {Magnitude of antigen-specific T-cell immunity the month after completing vaccination series predicts the development of long-term persistence of antitumor immune response.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {11}, pages = {}, pmid = {39521614}, issn = {2051-1426}, mesh = {Humans ; Female ; *Cancer Vaccines/immunology/therapeutic use ; *T-Lymphocytes/immunology ; Middle Aged ; Receptor, ErbB-2/immunology ; Male ; Aged ; Vaccination ; Adult ; Neoplasms/immunology ; }, abstract = {BACKGROUND: For best efficacy, vaccines must provide long-lasting immunity. To measure longevity, memory from B and T cells are surrogate endpoints for vaccine efficacy. When antibodies are insufficient for protection, the immune response must rely on T cells. The magnitude and differentiation of effective, durable immune responses depend on antigen-specific precursor frequencies. However, development of vaccines that induce durable T-cell responses for cancer treatment has remained elusive.
METHODS: To address long-lasting immunity, patients with HER2+ (human epidermal growth factor receptor 2) advanced stage cancer received HER2/neu targeted vaccines. Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot measuring HER2/neu IFN-γ T cells were analyzed from 86 patients from three time points: baseline, 1 month after vaccine series, and long-term follow-up at 1 year, following one in vitro stimulation. The baseline and 1-month post-vaccine series responses were correlated with immunity at long-term follow-up by logistic regression. Immunity was modeled by non-linear functions using generalized additive models.
RESULTS: Antigen-specific T-cell responses at baseline were associated with a 0.33-log increase in response at long-term follow-up, 95% CI (0.11, 0.54), p=0.003. 63% of patients that had HER2/neu specific T cells at baseline continued to have responses at long-term follow-up. Increased HER2/neu specific T-cell response 1 month after the vaccine series was associated with a 0.47-log increase in T-cell response at long-term follow-up, 95% CI (0.27, 0.67), p=2e-5. 74% of patients that had an increased IFN-γ HER2 response 1 month after vaccines retained immunity long-term. As the 1-month post-vaccination series precursor frequency of HER2+IFN-γ T-cell responses increased, the probability of retaining these responses long-term increased (OR=1.49 for every one natural log increase of precursor frequency, p=0.0002), reaching an OR of 20 for a precursor frequency of 1:3,000 CONCLUSIONS: Patients not destined to achieve long-term immunity can be identified immediately after completing the vaccine series. Log-fold increases in antigen-specific precursor frequencies after vaccinations correlate with increased odds of retaining long-term HER2 immune responses. Further vaccine boosting or immune checkpoint inhibitors or other immune stimulator therapy should be explored in patients that do not develop antigen-specific T-cell responses to improve overall response rates.}, }
@article {pmid39521255, year = {2024}, author = {Fujiwara, N and Lopez, C and Marsh, TL and Raman, I and Marquez, CA and Paul, S and Mishra, SK and Kubota, N and Katz, C and Kanzaki, H and Gonzalez, M and Quirk, L and Deodhar, S and Selvakumar, P and Raj, P and Parikh, ND and Roberts, LR and Schwartz, ME and Nguyen, MH and Befeler, AS and Page-Lester, S and Srivastava, S and Feng, Z and Reddy, KR and Khaderi, S and Asrani, SK and Kanwal, F and El-Serag, HB and Marrero, JA and Singal, AG and Hoshida, Y}, title = {Phase 3 validation of PAaM for hepatocellular carcinoma risk stratification in cirrhosis.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2024.10.035}, pmid = {39521255}, issn = {1528-0012}, abstract = {BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis.
METHODS: Molecular (Prognostic Liver Secretome signature with alpha-fetoprotein) and clinical (aMAP score) variable-based scores were integrated to develop PAaM, which was subsequently validated in two phase 3 biomarker validation studies: the statewide Texas HCC Consortium (THCCC) and nationwide HCC Early Detection Strategy (HEDS) prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation (PRoBE) design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events.
RESULTS: Of 2,156 cirrhosis patients in THCCC, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared to low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios (sHRs) for incident HCC of 7.51 (95% confidence interval [CI], 4.42-12.8) and 4.20 (95%CI, 2.52-7.01), respectively. Of 1,328 cirrhosis patients in HEDS, PAaM identified 201 (15%) high-risk, 540 (41%) intermediate-risk, and 587 (44%) low-risk patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate risk groups were associated with sHRs for incident HCC of 6.54 (95%CI, 3.85-11.1) and 1.77 (95%CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease (MASLD) and cured hepatitis C infection.
CONCLUSION: PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.}, }
@article {pmid39520444, year = {2024}, author = {Shetty, NS and Gaonkar, M and Pampana, A and Patel, N and Morrison, AC and Reiner, AP and Carson, AP and Yu, B and Psaty, BM and Kooperberg, C and Fatkin, D and Boerwinkle, E and Rotter, JI and Taylor, KD and Hou, L and Irvin, MR and Hall, ME and Maurer, M and Fornage, M and Armstrong, ND and Bart, N and Goyal, P and Rich, SS and Vasan, RS and Li, P and Arora, G and Arora, P}, title = {Cardiovascular Risk Factors and Genetic Risk in Transthyretin V142I Carriers.}, journal = {JACC. Heart failure}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jchf.2024.08.019}, pmid = {39520444}, issn = {2213-1787}, abstract = {BACKGROUND: Nearly 3% to 4% of Black individuals in the United States carry the transthyretin V142I variant, which increases their risk of heart failure. However, the role of cardiovascular (CV) risk factors (RFs) in influencing the risk of clinical outcomes among V142I variant carriers is unknown.
OBJECTIVES: This study aimed to assess the impact of CV RFs on the risk of heart failure in V142I carriers.
METHODS: This study included self-identified Black individuals without prevalent heart failure from 6 TOPMed (Trans-Omics for Precision Medicine) cohorts, the REGARDS (Reasons for Geographic And Racial Differences in Stroke) study, and the All of Us Research Program. The cohort was stratified based on the V142I genotype and the number of CV RFs (hypertension, diabetes, obesity, and hypercholesterolemia). Adjusted Cox models were used to assess the association of heart failure with the V142I genotype and CV RF profile, taking noncarriers with a favorable CV RF profile as reference.
RESULTS: The cross-sectional analysis, including 1,625 V142I carriers among 48,365 Black individuals, found that the prevalence of CV RFs did not vary by V142I carrier status. In the longitudinal analysis, there were 587 (3.2%) V142I carriers among 18,407 Black individuals (median age: 60 years [Q1-Q3: 52-68 years], 63.0% female). Among carriers, the heart failure risk was attenuated with a favorable (0 or 1 RF) CV RF profile (adjusted HR: 2.26; 95% CI: 1.58-3.23) compared with an unfavorable (3 or 4 RFs) CV RF profile (adjusted HR: 4.14; 95% CI: 2.79-6.14).
CONCLUSIONS: A favorable CV RF profile lowers but does not abrogate V142I variant-associated heart failure risk. This study highlights the importance of having a favorable CV RF profile among V142I carriers for risk reduction of heart failure.}, }
@article {pmid39516665, year = {2024}, author = {Xu, Y and Miller, CP and Xue, J and Zheng, Y and Warren, EH and Tykodi, SS and Akilesh, S}, title = {Single cell atlas of kidney cancer endothelial cells reveals distinct expression profiles and phenotypes.}, journal = {BJC reports}, volume = {2}, number = {1}, pages = {23}, pmid = {39516665}, issn = {2731-9377}, support = {KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; KC180135//U.S. Department of Defense/ ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; S10OD028685/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Tumor endothelial cells (TECs) represent the primary interface between the tumor microenvironment and circulating immune cells, however their phenotypes are incompletely understood in highly vascularized clear cell renal cell carcinoma (ccRCC).
METHODS: We purified tumor and matched normal endothelial cells (NECs) from ccRCC specimens and performed single-cell RNA-sequencing to create a reference-quality atlas available as a searchable web resource for gene expression patterns. We established paired primary TECs and NECs cultures for ex vivo functional testing.
RESULTS: TECs from multiple donors shared a common phenotype with increased expression of pathways related to extracellular matrix regulation, cell-cell communication, and insulin-like growth factor signaling. This phenotype was shared with hepatocellular carcinoma associated TECs, suggesting convergent TEC phenotypes between unrelated tumors. Cultured TECs stably maintained a core program of differentially regulated genes which promoted resistance to apoptosis after vascular endothelial growth factor removal and increased adhesiveness to subsets of immune cells including regulatory T-cells.
CONCLUSIONS: Our studies demonstrate that TECs have a distinct phenotype that is shared by TECs from different tumor types and stable in ex vivo culture. The distinct adhesive interaction of TECs with immune cells raises the possibility of their modulation to improve immune cell-based therapies for RCC.}, }
@article {pmid39516359, year = {2024}, author = {Stockem, CF and Einerhand, SMH and Rodríguez, IM and Salhi, Y and Pérez, E and Bakaloudi, DR and Talukder, R and Caramelo, B and Morales-Barrera, R and De Meulenaere, A and Rametta, A and Bottelli, A and Lefort, F and Giannatempo, P and Vulsteke, C and Carles, J and Duran, I and Grivas, P and de Liaño, AG and Robbrecht, DGJ and Valderrama, BP and van der Noort, V and van der Heijden, MS}, title = {Long-term survival following anti-PD-(L)1 monotherapy in advanced urothelial cancer and an assessment of potential prognostic clinical factors: a multicentre observational study.}, journal = {BJC reports}, volume = {2}, number = {1}, pages = {84}, pmid = {39516359}, issn = {2731-9377}, abstract = {BACKGROUND: Anti-PD-(L)1 agent are approved as first- and second-line treatment options in advanced urothelial cancer (UC), but information about long-term survival is scarce. There is a need for prognostic factors, as these may help in the decision-making concerning anti-PD-(L)1 in patients with UC. Here, we examined long-term survival following anti-PD-(L)1 in advanced UC and assessed clinical factors for their correlation with survival.
METHODS: We collected data from patients with advanced UC treated with anti-PD-(L)1 between 2013 and 2023. Overall- and progression-free survival (OS, PFS) were determined using the Kaplan-Meier method. Independent variables were analysed by uni- and multivariate Cox regression for their association with OS and PFS.
RESULTS: Survival analyses included 552 patients. Patient characteristics in our cohort were consistent with those of a typical advanced UC population. After median follow-up of 49 months, five-year OS and PFS rates were 16.0% and 6.9% respectively. The absence of visceral and/or bone metastases and elevated C-reactive protein level, gamma-glutamyltransferase level and neutrophil-to-lymphocyte ratio were identified as favourable prognostic factors for OS.
CONCLUSIONS: A selected subset of patients with advanced UC may experience long-term clinical benefit from anti-PD-(L)1 treatment. We identified prognostic factors that might be used for risk assessment and clinical trial stratification.}, }
@article {pmid39513720, year = {2024}, author = {Hansman, GS and Reese, T and Pancera, M and Rudd, PA and Masic, V and Haselhorst, T and von Itzstein, M}, title = {Structural analysis of a non-pathogenic hare calicivirus capsid bound to a histo-blood group antigen co-factor.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0167524}, doi = {10.1128/jvi.01675-24}, pmid = {39513720}, issn = {1098-5514}, }
@article {pmid39513224, year = {2024}, author = {Bazhenova, L and Kim, DW and Cho, BC and Goel, S and Heist, R and Werner, TL and Eaton, KD and Wang, JS and Pant, S and Adkins, DR and Blakely, CM and Yan, X and Neuteboom, S and Christensen, JG and Chao, R and Bauer, T}, title = {Sitravatinib in patients with solid tumors selected by molecular alterations: results from a Phase Ib study.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/14796694.2024.2418285}, pmid = {39513224}, issn = {1744-8301}, abstract = {Aim: We report clinical activity and safety of sitravatinib in patients with advanced cancer from basket cohorts with specific molecular alterations, in a Phase Ib study.Materials & methods: Patients with advanced solid tumors harboring amplification, mutation, or rearrangement of MET, AXL, RET, NTRK, DDR2, KDR, PDGFRA, KIT or CBL received sitravatinib once daily. Primary end point was confirmed objective response rate (ORR).Results: In total, 113 patients were enrolled following a median of 3 (range 1-18) prior systemic regimens. Altered RET (n = 31), CBL (n = 31) and MET (n = 17) were most frequent cohorts. Overall, 68.9% had reduced tumor volume and most (61.5%) had a best objective response of stable disease. ORR was highest in patients with RET-rearranged non-small cell lung cancer (21.1%) but did not differ significantly from the null hypothesis (ORR ≤15%; p = 0.316). Median progression-free survival and overall survival (5.7 and 24.2 months, respectively) were also longest in the RET-rearranged non-small cell lung cancer cohort. Diarrhea (61.1%), fatigue (50.4%) and hypertension (46.9%) were the most frequent treatment-emergent adverse events. Most treatment-emergent adverse events were mild-to-moderate in severity. The study closed before the planned number of patients were enrolled in all cohorts.Conclusion: Sitravatinib had a manageable safety profile with modest signals of clinical activity in patients with molecularly selected solid tumors.Clinical trial registration: www.clinicaltrials.gov identifier is NCT02219711.}, }
@article {pmid39512128, year = {2024}, author = {Baxter-Lowe, LA and Wang, T and Kuxhausen, M and Spellman, SR and Maiers, M and Lee, S and Saultz, J and Arrieta-Bolaños, E and Gadalla, SM and Bolon, YT and Betts, BC}, title = {Novel Scoring System for Ranking Hematopoietic Stem Cell Transplantation.}, journal = {Clinical transplantation}, volume = {38}, number = {11}, pages = {e15478}, doi = {10.1111/ctr.15478}, pmid = {39512128}, issn = {1399-0012}, support = {/CA/NCI NIH HHS/United States ; //the National Heart, Lung and Blood Institute/ ; //National Institute of Allergy and Infectious Diseases/ ; N00014-23-1-2057//Office of Naval Research/ ; N00014-24-1-2057//Office of Naval Research/ ; //Medical College of Wisconsin/ ; //NMDP/ ; //Gateway for Cancer Research/ ; //Pediatric Transplantation and Cellular Therapy Consortium/ ; //AbbVie/ ; //Actinium Pharmaceuticals, Inc./ ; //Adaptive Biotechnologies Corporation/ ; //ADC Therapeutics/ ; //Adienne SA/ ; //Alexion/ ; //AlloVir, Inc./ ; //Amgen, Inc./ ; //Astellas Pharma US/ ; //AstraZeneca/ ; //Atara Biotherapeutics/ ; //BeiGene/ ; //BioLineRX/ ; //Blue Spark Technologies/ ; //bluebird bio, inc./ ; //Blueprint Medicines/ ; //Bristol Myers Squibb Co./ ; //CareDx Inc./ ; //CSL Behring/ ; //CytoSen Therapeutics, Inc./ ; //DKMS/ ; //Editas Medicine/ ; //Elevance Health/ ; //Eurofins Viracor, DBA Eurofins Transplant Diagnostics/ ; //Gamida-Cell, Ltd./ ; //Gift of Life Biologics/ ; //Gift of Life Marrow Registry/ ; //GlaxoSmithKline/ ; //HistoGenetics/ ; //Incyte Corporation/ ; //Iovance/ ; //Janssen Research & Development, LLC/ ; //Janssen/Johnson & Johnson/ ; //Jasper Therapeutics/ ; //Jazz Pharmaceuticals, Inc./ ; //Karius/ ; //Kashi Clinical Laboratories/ ; //Kiadis Pharma/ ; //Kite, a Gilead Company/ ; //Kyowa Kirin/ ; //Labcorp/ ; //Legend Biotech/ ; //Mallinckrodt Pharmaceuticals/ ; //Med Learning Group/ ; //Medac GmbH/ ; //Merck & Co./ ; //Mesoblast/ ; //Millennium, the Takeda Oncology Co./ ; //Miller Pharmacal Group, Inc./ ; //Miltenyi Biomedicine/ ; //Miltenyi Biotec, Inc./ ; //MorphoSys/ ; //MSA-EDITLife/ ; //Neovii Pharmaceuticals AG/ ; //Novartis Pharmaceuticals Corporation/ ; //Omeros Corporation/ ; //OptumHealth/ ; //Orca Biosystems, Inc./ ; //OriGen BioMedical/ ; //Ossium Health, Inc./ ; //Pfizer, Inc./ ; //Pharmacyclics, LLC, An AbbVie Company/ ; //PPD Development, LP/ ; //REGiMMUNE/ ; //Registry Partners/ ; //Rigel Pharmaceuticals/ ; //Sanofi/ ; //Sarah Cannon/ ; //Seagen Inc./ ; //Sobi, Inc./ ; //Stemcell Technologies/ ; //Stemline Technologies/ ; //STEMSOFT/ ; //Takeda Pharmaceuticals/ ; //Talaris Therapeutics/ ; //Vertex Pharmaceuticals/ ; //Vor Biopharma Inc./ ; //Xenikos BV/ ; /HL/NHLBI NIH HHS/United States ; //U.S. Public Health Service/ ; 75R60222C00011/HRSA/HRSA HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; Female ; Male ; Middle Aged ; *Graft vs Host Disease ; Adult ; Prognosis ; *HLA Antigens/immunology ; Follow-Up Studies ; *Histocompatibility Testing ; *Myelodysplastic Syndromes/therapy ; Young Adult ; Adolescent ; Survival Rate ; Aged ; Leukemia/therapy/mortality ; Child ; Unrelated Donors ; Retrospective Studies ; Child, Preschool ; }, abstract = {BACKGROUND: When human leukocyte antigen (HLA)-matched donors are not available for hematopoietic stem cell transplants (HSCT), there are no well-accepted guidelines for ranking 7/8 HLA-matched unrelated donors to achieve optimal transplant outcomes. A novel scoring system for ranking HLA mismatches for these donors was investigated.
METHODS: High-resolution HLA types were used to determine amino acid mismatches located in the HLA antigen-recognition domain. The location and physicochemical properties of mismatched amino acids were used to assign scores for peptide binding, T-cell receptor docking, and HLA structure/function. The scores were tested using a cohort of 2319 patients with leukemia or myelodysplastic syndrome who received their first unrelated donor transplant using conventional graft-versus-host disease (GVHD) prophylaxis between 2000 and 2014. Donors were 7/8 HLA-matched with a single HLA Class I mismatch. Primary outcomes were overall survival and acute GVHD.
RESULTS: The scores did not significantly (p < 0.01) associate with transplant outcomes, although a Peptide Score = 0 (i.e., no differences in peptide binding; N = 146, 6.3%) appears to have lower transplant-related mortality (TRM) compared to higher scores (p = 0.019). HLA mismatches with Peptide Score = 0 were predominately HLA-C*03:03/03:04 (62%), previously reported to be a permissive mismatch, and a group of 28 other HLA mismatches (38%) that showed similar associations with TRM.
CONCLUSIONS: This study suggests that HLA mismatches that do not alter peptide binding or orientation (Peptide Score = 0) could expand the number of permissive HLA mismatches. Further investigation is needed to confirm this observation and to explore alternative scoring systems for ranking HLA mismatched donors.}, }
@article {pmid39510589, year = {2024}, author = {Demirci, RA and Gulati, R and Hawley, JE and Yezefski, T and Haffner, MC and Cheng, HH and Montgomery, RB and Schweizer, MT and Yu, EY and Nelson, PS and Chen, DL and Iravani, A}, title = {SPECT/CT in Early Response Assessment of Patients with Metastatic Castration-Resistant Prostate Cancer Receiving [177]Lu-PSMA-617.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.124.267665}, pmid = {39510589}, issn = {1535-5667}, abstract = {[177]Lu-PSMA-617 (LuPSMA) is a newly established treatment for patients with metastatic castration-resistant prostate cancer (mCRPC), but survival outcomes vary widely, and predictors of treatment responses are needed. This study investigated the role of total tumor volumes (TTVs) and new lesions (NLs) determined by LuPSMA SPECT/CT in early cycles to predict subsequent outcomes in a real-world practice setting. Methods: Between June and December 2022, consecutive patients with mCRPC who received at least 2 administrations of LuPSMA with SPECT/CT 24 h after treatment were retrospectively reviewed. We evaluated associations between TTVs and the appearance of NLs at cycles 2 and 3 with subsequent prostate-specific antigen (PSA) progression-free survival and overall survival (OS) using multivariate Cox regression. All analyses were adjusted for changes in PSA level relative to baseline. Results: Sixty-six mCRPC patients (median age, 74 y) received a median of 4 (interquartile range, 3-5) cycles of LuPSMA. Median follow-up starting at cycle 2 was 42 wk (interquartile range, 33-48 wk), with 24 of 66 patients deceased at the time of the analysis. Changes in TTV measured at the start of cycles 2 and 3 relative to baseline correlated significantly with corresponding changes in PSA level (r = 0.55 and 0.56), but absolute TTVs did not correlate significantly (r = 0.00 and 0.18). Patients with a higher absolute TTV at the start of cycle 2 had worse PSA progression-free survival and OS (hazard ratio [HR], 1.4 [95% CI, 1.1-1.8] and 2.1 [95% CI, 1.5-2.9]), with consistent results at the start of cycle 3 (HR, 2 [95% CI, 1.4-2.9] and 2 [95% CI, 1.2-3.2]). NLs were identified in 13 of 66 and 11 of 51 patients at the start of cycles 2 and 3. NLs at the start of cycle 2 were associated with worse OS (HR, 5.8 [95% CI, 1.9-17.5]), with consistent results at the start of cycle 3 (HR, 4.9 [95% CI, 1.3-18.6]). In multivariate analysis, a higher TTV and the appearance of NLs at the start of cycles 2 and 3 were independently associated with poorer OS. Conclusion: Higher TTVs and NLs on LuPSMA SPECT/CT at the start of cycles 2 and 3 were independently associated with higher risk of death. These measures provided prognostic information independent of changes in PSA. Development of prognostic and predictive models including TTV, NLs, and PSA changes is warranted.}, }
@article {pmid39509091, year = {2024}, author = {Unger, JM and Till, C and Tangen, CM and Hershman, DL and Goodman, PJ and LeBlanc, M and Barlow, WE and Vaidya, R and Minasian, LM and Parnes, HL and Thompson, IM}, title = {Long-Term Adverse Effects and Complications After Prostate Cancer Treatment.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {39509091}, issn = {2374-2445}, abstract = {IMPORTANCE: Due to the often indolent nature of prostate cancer (PCA), treatment decisions must weigh the risks and benefits of cancer control with those of treatment-associated morbidities.
OBJECTIVE: To characterize long-term treatment-related adverse effects and complications in patients treated for PCA compared to a general population of older males.
This cohort study used a novel approach linking data from 2 large PCA prevention clinical trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin-E Cancer Prevention Trial) with Medicare claims records. This analysis included patients with PCA who had been treated with prostatectomy or radiotherapy compared with an untreated control group. Multivariable Cox regression was used, with a time-varying covariate for the occurrence of PCA treatment, adjusted for age, race, and year of time-at-risk initiation, and stratified by study and intervention arm. Data analyses were performed from September 21, 2022, to March 18, 2024.
EXPOSURE: Prostatectomy and radiotherapy occurring after a PCA diagnosis, identified from trial data or Medicare claims records.
MAIN OUTCOMES AND MEASURES: Ten potential PCA treatment-related complications identified from Medicare claims data.
RESULTS: The study sample comprised 29 196 participants (mean [SD] age at time-at-risk initiation, 68.7 [4.8] years). Of these, 3946 participants had PCA, among whom 655 were treated with prostatectomy and 1056 with radiotherapy. The 12-year hazard risk of urinary or sexual complications was 7.23 times greater for those with prostatectomy (95% CI, 5.96-8.78; P < .001) and 2.76 times greater for radiotherapy (95% CI, 2.26-3.37; P < .001) compared to untreated participants. Moreover, among participants treated with radiotherapy, there was a nearly 3-fold greater hazard risk of bladder cancer than in the untreated (hazard ratio [HR], 2.78; 95% CI, 1.92-4.02; P < .001), as well as an approximately 100-fold increased hazard risk of radiation-specific outcomes including radiation cystitis (HR, 131.47; 95% CI, 52.48-329.35; P < .001) and radiation proctitis (HR, 87.91; 95% CI, 48.12-160.61; P < .001). The incidence per 1000 person-years of any 1 of the 10 treatment-related complications was 124.26 for prostatectomy, 62.15 for radiotherapy, and 23.61 for untreated participants.
CONCLUSIONS AND RELEVANCE: This cohort study found that, even after accounting for age-related symptoms and disease, PCA treatment was associated with higher rates of complications in the 12 years after treatment. Given the uncertain benefit of PCA treatment for most patients, these findings highlight the importance of patient counseling before PCA screening and treatment and provide a rationale for pursuing opportunities for cancer prevention.}, }
@article {pmid39508344, year = {2024}, author = {Chappidi, MR and Lin, DW and de la Calle, CM}, title = {Editorial Comment.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000004307}, doi = {10.1097/JU.0000000000004307}, pmid = {39508344}, issn = {1527-3792}, }
@article {pmid39507884, year = {2024}, author = {Childs-Kean, LM and Beieler, AM and Cortés-Penfield, N and Keller, SC and Rivera, CG and Ryan, KL and Yoke, LH and Mahoney, MV}, title = {A Bundle of the "Top 10" Outpatient Parenteral Antimicrobial Therapy Publications in 2023.}, journal = {Open forum infectious diseases}, volume = {11}, number = {11}, pages = {ofae635}, pmid = {39507884}, issn = {2328-8957}, abstract = {Outpatient parenteral antimicrobial therapy (OPAT) has become more common in infectious diseases practice settings. Similarly, OPAT-related publications have also increased. The objective of this article was to summarize clinically important OPAT-related publications from 2023. Eighty-one articles were found on initial search, with 52 meeting inclusion criteria. A survey containing the 19 articles that had at least 1 citation was sent to an email listserv of multidisciplinary clinicians with OPAT experience. This article summarizes the "top 10" 2023 OPAT articles from the survey results.}, }
@article {pmid39505858, year = {2024}, author = {Srinivasan, S and Kryza, T and Bock, N and Tse, BWC and Sokolowski, KA and Janaththani, P and Fernando, A and Moya, L and Stephens, C and Dong, Y and Röhl, J and Alinezhad, S and Vela, I and Perry-Keene, JL and Buzacott, K and Nica, R and , and Gago-Dominguez, M and , and Schleutker, J and Maier, C and Muir, K and Tangen, CM and Gronberg, H and Pashayan, N and Albanes, D and Wolk, A and Stanford, JL and Berndt, SI and Mucci, LA and Koutros, S and Cussenot, O and Sorensen, KD and Grindedal, EM and Travis, RC and Haiman, CA and MacInnis, RJ and Vega, A and Wiklund, F and Neal, DE and Kogevinas, M and Penney, KL and Nordestgaard, BG and Brenner, H and John, EM and Gamulin, M and Claessens, F and Melander, O and Dahlin, A and Stattin, P and Hallmans, G and Häggström, C and Johansson, R and Thysell, E and Rönn, AC and Li, W and Brown, N and Dimeski, G and Shepherd, B and Dadaev, T and Brook, MN and Spurdle, AB and Stenman, UH and Koistinen, H and Kote-Jarai, Z and Klein, RJ and Lilja, H and Ecker, RC and Eeles, R and , and , and Clements, J and Batra, J}, title = {A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9587}, pmid = {39505858}, issn = {2041-1723}, support = {AQIRF175-2019RD2//State of Queensland | Advance Queensland/ ; R01 CA244948/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA199338/CA/NCI NIH HHS/United States ; R01 CA175491/CA/NCI NIH HHS/United States ; W81XWH-19-1-0343//U.S. Department of Defense (United States Department of Defense)/ ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms/genetics/pathology/metabolism/mortality ; *Polymorphism, Single Nucleotide ; *Prostate-Specific Antigen/blood/metabolism ; *Kallikreins/genetics/metabolism ; Genetic Predisposition to Disease ; Aged ; Animals ; Chromosomes, Human, Pair 19/genetics ; Middle Aged ; Mice ; Alleles ; Cell Line, Tumor ; }, abstract = {Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.}, }
@article {pmid39505278, year = {2024}, author = {Sutherland, NM and Zhou, B and Zhang, L and Ong, MS and Hong, JS and Pak, A and Liu, KJ and Frigault, MJ and Maus, MV and Hill, JA and Reynolds, K and Walter, JE and Camargo, CA and Barmettler, S}, title = {Association of CD19+-Targeted Chimeric Antigen Receptor (CAR) T-cell Therapy with Hypogammaglobulinemia, Infection and Mortality.}, journal = {The Journal of allergy and clinical immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaci.2024.10.021}, pmid = {39505278}, issn = {1097-6825}, abstract = {BACKGROUND: CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19+ receptors on B-cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse.
OBJECTIVE: To evaluate hypogammaglobulinemia after CD19-targeted CAR-T therapy and risk factors for hypogammaglobulinemia, infections, and mortality.
METHODS: We performed a retrospective evaluation of 579 patients receiving CD19-directed CAR-T therapy and evaluated demographics, hypogammaglobulinemia (immunoglobulin G [IgG]≤600mg/dL), infections pre- and post-CAR-T therapy, and risk factors for hypogammaglobulinemia, infection, hospitalizations, and mortality.
RESULTS: Patients had a mean age of 64 years and 64% were male. Prior to CAR-T therapy, 60% of patients had hypogammaglobulinemia, which increased to 91% post-CAR-T therapy. Mean IgG levels decreased from pre- to post-CAR-T therapy (587 to 362 mg/dL; p<0.0001). 37% of patients developed a serious infection post-CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was associated with worsening hypogammaglobulinemia post-CAR-T therapy. Hypogammaglobulinemia post-CAR-T therapy was associated with an increased risk of serious infection post-CAR-T therapy (IRR=2.7; 95% CI=1.5-5.2; p=0.002). Risk factors for mortality included mild hypogammaglobulinemia (400mg/dL
CONCLUSIONS: We identified ∼90% of patients with hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was strongly predictive of worsening hypogammaglobulinemia post-CAR-T therapy, which was associated with an increased risk of serious infection and mortality post-CAR-T therapy. Increased immunological monitoring is needed to identify high-risk patients who may benefit from interventions to decrease morbidity and mortality.}, }
@article {pmid39505259, year = {2024}, author = {Karim, NA and Miao, J and Reckamp, KL and Gay, CM and Byers, LA and Zhao, YQ and Redman, MW and Carrizosa, DR and Wang, WL and Petty, WJ and Mehta, K and Faller, BA and Agamah, ES and Kasbari, SS and Malisetti, RK and Kumar, A and Schallenkamp, J and Alluri, KC and Gray, JE and Kelly, K}, title = {Phase II randomized study of maintenance atezolizumab (A) versus atezolizumab + talazoparib (AT) in patients with SLFN11 positive extensive stage small cell lung cancer. S1929.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtho.2024.10.021}, pmid = {39505259}, issn = {1556-1380}, abstract = {PURPOSE: To evaluate whether the addition of a poly (ADP-ribose) polymerase inhibitor (PARPi) talazoparib to maintenance immune checkpoint inhibitor (ICI) atezolizumab following frontline chemoimmunotherapy improved outcomes in patients with Schlafen 11 (SLFN11)-positive extensive stage small cell lung cancer (ES-SCLC).
METHODS: Patients with newly diagnosed SLFN11 expressing (H-score ≥ 1, evaluated centrally) ES-SCLC were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) following frontline chemotherapy plus atezolizumab. The primary objective was to compare progression-free survival (PFS) using a 1-sided 10% level stratified log-rank test. Secondary endpoints included objective response rate (ORR), overall survival (OS), and toxicity. Target sample size was 84 eligible patients.
RESULTS: From June 15, 2020 to December 15, 2022, 106 eligible patients were randomized (54 to AT and 52 to A). PFS was improved with AT versus A (hazard ratio [HR], 0.66; 80% confidence interval [CI]: 0.50-0.86; 1-sided P = 0.019) with a median PFS of 2.9 and 2.4 months; OS was not different between groups (HR, 0.98; 80% CI: 0.71-1.36; 1-sided P = 0.47). Grade ≥ 3 non-hematologic treatment-related adverse events (TRAEs) occurred in 17% of patients with AT and 14% of patients with A. Grade ≥ 3 hematological TRAEs were more common in AT (50%) than in A (4%) (P < 0.001).
CONCLUSION: Maintenance AT improved PFS in patients with SLFN11-positive ES-SCLC that did not progress following initial chemo-immunotherapy. Hematologic toxicity, primarily grade 3 anemia, was increased with AT, as expected. Prospective biomarker-selection was demonstrated, paving the way for future evaluation of novel therapies in molecularly defined SCLC populations.}, }
@article {pmid39503494, year = {2024}, author = {Greninger, AL and Larcena, A and Patel, A and Webster, B and Ulen, C and Green, DF and King, D and Patel, DR and McElvania, E and Harnett, G and Jandali, I and Gibson, J and Killion, J and Atwi, J and Bergmann, K and Slade, L and Allen Staat, M and Faron, M and Washington, M and Patel, R and Annamalai, R and Ackerman, R and Stewart, WP and Amador, YM and Rao, D and Liu, X and Raman, A}, title = {Prospective, multi-site evaluation of the Cepheid Xpert Xpress CoV-2 plus test on nasal and nasopharyngeal swabs.}, journal = {Journal of clinical microbiology}, volume = {}, number = {}, pages = {e0121924}, doi = {10.1128/jcm.01219-24}, pmid = {39503494}, issn = {1098-660X}, abstract = {UNLABELLED: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues its largely aseasonal spread with millions of cases per year. Highly sensitive, point-of-care testing is critical for rapid detection of coronavirus disease 2019 (COVID-19) cases and initiation of antiviral therapy to avert adverse health outcomes and reduce onward transmission of the virus. While hundreds of COVID-19 diagnostics received emergency use authorization from the FDA during the pandemic, significantly fewer have navigated the course to FDA clearance or approval. Here, we determined the clinical performance of the Cepheid Xpert Xpress CoV-2 plus for detection of SARS-CoV-2 in 3,750 anterior nasal swab (NS) specimens and nasopharyngeal swab (NPS) from 32 sites in comparison to the FDA-authorized BioFire Respiratory Panel 2.1. Three-quarters of specimens collected were tested on the Xpert Xpress CoV-2 plus in the point-of-care setting. Overall positive percent agreement (PPA) was 98.1% (95% CI: 96.7%-98.9%) and negative percent agreement (NPA) was 98.3% (97.7%-98.7%). Performance of the Xpert Xpress CoV-2 plus was slightly improved in NS compared to NPS specimens, with PPA of 99.3% versus 97.0% (Fisher's exact test, P = 0.06) and NPA of 98.3% versus 98.2% (P = 0.89), respectively. Assay PPA was similar between untrained and trained users (98.7% vs 97.3%, P = 0.75), while NPA was slightly improved for untrained users (99.0% vs 97.6%, P = 0.0003). This study showed that Cepheid Xpert Xpress COV-2 plus is highly sensitive and specific/has high PPA and NPA for detection of SARS-CoV-2 from both NS and NPS specimens.
IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause millions of infections and tens of thousands of deaths per year in the United States. While the FDA authorized hundreds of SARS-CoV-2 tests during the public health emergency, significantly fewer have made the transition to being cleared or approved. There continues to be a need for FDA-authorized point-of-care SARS-CoV-2 testing that can be performed by untrained users. We conducted a large prospective study of the Cepheid Xpert Xpress CoV-2 plus test for detection of SARS-CoV-2 in both nasal and nasopharyngeal swabs by trained and untrained users. The assay demonstrated excellent clinical performance characteristics and, as a result of this study, was cleared by the FDA.}, }
@article {pmid39499893, year = {2024}, author = {Iyer, G and Tangen, CM and Sarfaty, M and Regazzi, AM and Lee, IL and Fong, M and Choi, W and Dinney, CPN and Flaig, TW and Thompson, IM and Lerner, SP and McConkey, DJ and Rosenberg, JE}, title = {DNA Damage Response Alterations Predict for Neoadjuvant Chemotherapy Sensitivity in Muscle-Invasive Bladder Cancer: A Correlative Analysis of the SWOG S1314 Trial.}, journal = {JCO precision oncology}, volume = {8}, number = {}, pages = {e2400287}, doi = {10.1200/PO.24.00287}, pmid = {39499893}, issn = {2473-4284}, mesh = {Humans ; *Urinary Bladder Neoplasms/drug therapy/genetics/pathology ; Male ; Female ; *Neoadjuvant Therapy ; Middle Aged ; Aged ; *DNA Damage ; Xeroderma Pigmentosum Group D Protein/genetics ; Cisplatin/therapeutic use ; Neoplasm Invasiveness ; Adult ; }, abstract = {PURPOSE: Alterations in DNA damage response (DDR) genes, including ERCC2, have been correlated with response to neoadjuvant cisplatin-based chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). The SWOG 1314 (S1314) trial enrolled patients with MIBC who received one of two NAC regimens followed by radical cystectomy. We examined the prevalence of DDR alterations in NAC responders versus nonresponders and correlated DDR alteration status with response.
METHODS: Pretreatment tumor specimens from 179 evaluable patients underwent next-generation sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay). Associations were determined between any or only deleterious alterations within nine predefined DDR genes, or any alterations in ERCC2, and progression-free survival (PFS) and overall survival using Cox regression, and, in a subset of evaluable patients, pathologic response (complete response, pT0, or downstaging to
RESULTS: Deleterious DDR alterations were detected in 41 (23%) of 179 patients. Of the 151 patients evaluable for pathologic response, patients with deleterious DDR alterations (n = 39) demonstrated a higher pathologic response rate than those without (odds ratio [OR], 3.24 [95% CI, 1.51 to 6.94]; P = .003). In 24 ERCC2-mutant patients, the OR for pT0 was 3.33 (95% CI, 1.35 to 8.22; P = .009) and for
CONCLUSION: Deleterious DDR alterations were associated with pathologic response following NAC in S1314. Functional validation of ERCC2 and other DDR alterations is underway to help refine such alterations as biomarkers of NAC in patients with bladder cancer.}, }
@article {pmid39498208, year = {2024}, author = {Hyde, ET and Nguyen, S and LaMonte, MJ and Di, C and Bellettiere, J and Tinker, LF and Foraker, RE and Tindle, HA and Stefanick, ML and LaCroix, AZ}, title = {Influence of physical activity measurement on the association between Life's Essential 8 and incident cardiovascular disease in older women.}, journal = {Preventive medicine reports}, volume = {47}, number = {}, pages = {102904}, pmid = {39498208}, issn = {2211-3355}, abstract = {OBJECTIVE: The American Heart Association's Life's Essential 8 (LE8) metric includes self-reported physical activity as one of the metrics for assessing cardiovascular health. Self-reported physical activity is prone to misclassification, whereas accelerometer measures are less biased. We examined associations of LE8 and incident cardiovascular disease (CVD) using self-reported and accelerometer-measured physical activity.
METHODS: Participants in the Women's Health Initiative (WHI) Objective Physical Activity and Cardiovascular Health Study (n = 4,243; mean age = 79 ± 7 years) with no CVD history completed the WHI physical activity questionnaire and the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire prior to wearing a hip-worn accelerometer for up to seven days in 2012-2014. LE8 components (physical activity, diet, sleep, body mass index, smoking, blood pressure, non-HDL cholesterol, and glucose) were scored according to guidelines. Scores were created using five physical activity measures: WHI questionnaire (LE8WHI), CHAMPS (LE8CHAMPS), accelerometer-measured physical activity (LE8A), and sample quantiles of accelerometer-measured physical activity (LE8AQ) and daily steps (LE8STEPS). Hazard ratios (HR) for physician-adjudicated CVD were estimated using Cox regression.
RESULTS: 707 incident CVD events occurred over an average 7.5 years. Multivariable HRs (95 % CI) comparing women in the highest vs. lowest quartiles of LE8 scores were: LE8WHI = 0.53 (0.43-0.67), LE8CHAMPS = 0.47 (0.38-0.60), LE8A = 0.44 (0.36-0.56), LE8AQ = 0.44 (0.35-0.55), and LE8STEPS = 0.45 (0.35-0.57).
CONCLUSIONS: The LE8-incident CVD association varies by physical activity measurement, however all methods showed reduced risk. Device-measures of physical activity may be more accurate in the LE8, but when impractical to implement, also support use of self-reported measures.}, }
@article {pmid39495136, year = {2024}, author = {Singal, AG and Parikh, ND and Kanwal, F and Marrero, JA and Deodhar, S and Page-Lester, S and Lopez, C and Feng, Z and Tayob, N}, title = {National Liver Cancer Screening Trial (TRACER) study protocol.}, journal = {Hepatology communications}, volume = {8}, number = {11}, pages = {}, pmid = {39495136}, issn = {2471-254X}, support = {U01 CA271887/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Liver Neoplasms/diagnosis/blood/diagnostic imaging ; *Early Detection of Cancer/methods ; *alpha-Fetoproteins/analysis ; *Carcinoma, Hepatocellular/diagnosis/blood/diagnostic imaging ; Male ; Female ; *Biomarkers, Tumor/blood ; Prothrombin/analysis ; Ultrasonography ; Hepatitis B, Chronic/diagnosis/blood ; Middle Aged ; Protein Precursors/blood ; Adult ; Liver Cirrhosis/blood/diagnosis/diagnostic imaging ; Aged ; Pragmatic Clinical Trials as Topic ; Biomarkers ; }, abstract = {BACKGROUND: Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice.
METHODS: The National Liver Cancer Screening Trial is an adaptive pragmatic randomized phase IV trial, which began enrollment in January 2024, comparing ultrasound-based versus biomarker-based screening in 5500 patients with chronic hepatitis B infection or cirrhosis from any etiology. Eligible patients are randomly assigned in a 1:1 ratio to semi-annual screening with ultrasound ± alpha-fetoprotein (arm A) or semi-annual screening with GALAD (arm B). Randomization is stratified by enrollment site, liver disease severity (per Child-Pugh class), liver disease etiology (viral, nonviral, and noncirrhotic HBV), and sex. Patients are being recruited from 15 sites (a mix of tertiary care academic referral centers, safety-net health systems, and large community health systems) over a 3-year period, and the primary endpoint, reduction in late-stage HCC, will be assessed at the end of year 5.5.
DISCUSSION: The results of this trial will inform the best strategy for HCC screening and early-stage detection in patients with chronic liver diseases. If GALAD shows superiority, HCC screening would primarily shift from an ultrasound-based strategy to the adoption of the biomarker panel.
TRIAL REGISTRATION: NCT06084234.
TRIAL STATUS: The TRACER Study is actively enrolling.}, }
@article {pmid39493537, year = {2024}, author = {Colquhoun, R and O'Toole, Á and Hill, V and McCrone, JT and Yu, X and Nicholls, SM and Poplawski, R and Whalley, T and Groves, N and Ellaby, N and Loman, N and Connor, T and Rambaut, A}, title = {A phylogenetics and variant calling pipeline to support SARS-CoV-2 genomic epidemiology in the UK.}, journal = {Virus evolution}, volume = {10}, number = {1}, pages = {veae083}, pmid = {39493537}, issn = {2057-1577}, abstract = {In response to the escalating SARS-CoV-2 pandemic, in March 2020 the COVID-19 Genomics UK (COG-UK) consortium was established to enable national-scale genomic surveillance in the UK. By the end of 2020, 49% of all SARS-CoV-2 genome sequences globally had been generated as part of the COG-UK programme, and to date, this system has generated >3 million SARS-CoV-2 genomes. Rapidly and reliably analysing this unprecedented number of genomes was an enormous challenge. To fulfil this need and to inform public health decision-making, we developed a centralized pipeline that performs quality control, alignment, and variant calling and provides the global phylogenetic context of sequences. We present this pipeline and describe how we tailored it as the pandemic progressed to scale with the increasing amounts of data and to provide the most relevant analyses on a daily basis.}, }
@article {pmid39492698, year = {2024}, author = {Heldman, MR and Boeckh, MJ and Limaye, AP}, title = {Current and future strategies for the prevention and treatment of cytomegalovirus infections in transplantation.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae535}, pmid = {39492698}, issn = {1537-6591}, abstract = {Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ and allogeneic hematopoietic cell transplantation. Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. Observational studies and interventional trials of commercially-available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.}, }
@article {pmid39490766, year = {2024}, author = {Bricker, JB and Sullivan, BM and Mull, KE and Lavista-Ferres, J and Santiago-Torres, M}, title = {Efficacy of a conversational chatbot for cigarette smoking cessation: Protocol of the QuitBot full-scale randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {147}, number = {}, pages = {107727}, doi = {10.1016/j.cct.2024.107727}, pmid = {39490766}, issn = {1559-2030}, abstract = {Globally, cigarette smoking results in over 8 million premature annual deaths. Addressing this issue requires high-impact, cost-effective population-level interventions for smoking cessation. Conversational chatbots offer a potential solution given the recent advancements in machine learning and large language models. Chatbots can deliver supportive, empathetic behaviors, personalized responses, and timely advice tailored to users' needs that is engaging through therapeutic conversations aimed at creating lasting social-emotional connections. Despite their promise, little is known about the efficacy and underlying mechanisms of chatbots for cigarette smoking cessation. We developed QuitBot, a quit smoking program of two to three-minute conversations covering topics ranging from motivations to quit, setting a quit date, choosing cessation medications, coping with triggers, maintaining abstinence, and recovering from a relapse. QuitBot employs conversational interactions, powered by an expert-curated large language model, allowing users to ask questions and receive personalized guidance on quitting smoking. Here, we report the design and execution of a randomized clinical trial comparing QuitBot (n = 760) against Smokefree TXT (SFT) text messaging program (n = 760), with a 12-month follow-up period. Both interventions include 42-days of content on motivations to quit, skills to cope with triggers, and relapse prevention. The key distinction between QuitBot and SFT is that QuitBot has communication and engagement features. This study aims to determine: whether QuitBot yields higher quit rates than SFT; and whether therapeutic alliance processes and engagement are mechanisms underlying cessation outcomes. Additionally, we will explore whether baseline factors including trust, social support, and demographics, moderate the efficacy of QuitBot. Trial Registration numberClinicalTrials.govNCT04308759.}, }
@article {pmid39490125, year = {2024}, author = {Walia, R and Fertrin, KY and Sabath, DE}, title = {A Winding Road to Health Care Equity in Sickle Cell Disease.}, journal = {Clinics in laboratory medicine}, volume = {44}, number = {4}, pages = {693-704}, doi = {10.1016/j.cll.2024.07.005}, pmid = {39490125}, issn = {1557-9832}, mesh = {*Anemia, Sickle Cell/therapy ; Humans ; Health Equity ; Health Services Accessibility ; Healthcare Disparities ; }, abstract = {Sickle cell disease (SCD) is a genetic disorder where red blood cells sickle, causing anemia and pain. Historically linked to marginalized groups, SCD saw little progress in treatment strategies for decades. Addressing these requires holistic strategies including dedicated centers, education, patient inclusion, and tackling implicit bias. Efforts must ensure treatments are accessible and stigma-free. Progress depends on collaboration and advocacy, aiming for an equitable, patient-focused health care system responsive to the unique needs of those with SCD. This review illustrates the actionable steps that the medical community can take to improve care for patients with SCD.}, }
@article {pmid39490124, year = {2024}, author = {Walia, R and Fertrin, KY and Sabath, DE}, title = {History, Advances, and Challenges of Sickle Cell Disease Treatment.}, journal = {Clinics in laboratory medicine}, volume = {44}, number = {4}, pages = {679-691}, doi = {10.1016/j.cll.2024.07.004}, pmid = {39490124}, issn = {1557-9832}, mesh = {*Anemia, Sickle Cell/therapy ; Humans ; *Genetic Therapy ; Antisickling Agents/therapeutic use ; History, 20th Century ; History, 21st Century ; }, abstract = {Sickle cell disease (SCD) is marked by red blood cells that deform into a sickle shape, causing severe health complications. Historic neglect and slow therapeutic progress have left many, especially African descendants, vulnerable. Recent treatment strides include novel drugs and gene therapy, promising improved management. Nonetheless, challenges persist with treatment adoption because of cost, adverse effects, and accessibility. Advancements hold hope for enhanced life quality and longevity for SCD patients.}, }
@article {pmid39489920, year = {2024}, author = {Li, C and Georgakopoulou, A and Paschoudi, K and Anderson, AK and Huang, L and Gil, S and Giannaki, M and Vlachaki, E and Newby, GA and Liu, DR and Yannaki, E and Kiem, HP and Lieber, A}, title = {Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2024.10.018}, pmid = {39489920}, issn = {1525-0024}, abstract = {Precise repair of the pathogenic mutation in hematopoietic stem cells (HSCs) represents an ideal cure for patients with sickle cell disease (SCD). Here, we demonstrate correction of the SCD phenotype by converting the sickle mutation codon (GTG) into a benign G-Makassar variant (GCG) using in vivo base editing in HSCs. We show successful production of helper-dependent adenoviral vectors expressing an all-in-one base editor mapping to the sickle mutation site. In HSC-enriched cells from SCD patients, transduction with the base editing vector in vitro resulted in 35% GTG > GCG conversion and phenotypic improvements in the derived red blood cells. After ex vivo transduction of HSCs from an SCD mouse model and subsequent transplantation, we achieved an average of 88% editing at the target site in transplanted mice. Importantly, in vivo HSC base editing followed by selection generated 24.5% Makassar variant in long-term repopulating HSCs of SCD mice. The treated animals demonstrated correction of disease hallmarks without any noticeable side effects. Off-target analyses at top-scored genomic sites revealed no off-target editing. This in vivo approach requires a single non-integrating vector, only intravenous/subcutaneous injections, and minimal in vivo selection. This technically simple approach holds potential for scalable applications in resource-limiting regions where SCD is prevalent.}, }
@article {pmid39487536, year = {2024}, author = {Patty, BJ and Jordan, C and Lardo, SM and Troy, K and Hainer, SJ}, title = {H3.3K122A results in a neomorphic phenotype in mouse embryonic stem cells.}, journal = {Epigenetics & chromatin}, volume = {17}, number = {1}, pages = {32}, pmid = {39487536}, issn = {1756-8935}, support = {R35 GM133732/GM/NIGMS NIH HHS/United States ; S10 OD028483/OD/NIH HHS/United States ; R35GM133732/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Histones/metabolism ; Mice ; *Mouse Embryonic Stem Cells/metabolism/cytology ; *Phenotype ; Cell Differentiation ; Protein Processing, Post-Translational ; Acetylation ; }, abstract = {Canonical histone H3 and histone variant H3.3 are posttranslationally modified with the genomic distribution of these marks denoting different features and these modifications may influence transcription. While the majority of posttranslational modifications occur on histone tails, there are defined modifications within the globular domain, such as acetylation of H3K122/H3.3K122. To understand the function of the amino acid H3.3K122 in transcriptional regulation, we attempted to generate H3.3K122A mouse embryonic stem (mES) cells but were unsuccessful. Through multi-omic profiling of mutant cell lines harboring two or three of four H3.3 targeted alleles, we have uncovered that H3.3K122A is neomorphic and results in lethality. This is surprising as prior studies demonstrate H3.3-null mES cells are viable and pluripotent but exhibit a reduced differentiation capacity. Together, these studies have uncovered a novel dependence of a globular domain residue within H3.3 for viability and broadened our understanding of how histone variants contribute to transcription regulation and pluripotency in mES cells.}, }
@article {pmid39484623, year = {2024}, author = {Jagota, M and Hsu, C and Mazumder, T and Sung, K and DeWitt, WS and Listgarten, J and Matsen, FA and Ye, CJ and Song, YS}, title = {Learning antibody sequence constraints from allelic inclusion.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39484623}, issn = {2692-8205}, support = {R35 GM134922/GM/NIGMS NIH HHS/United States ; }, abstract = {Antibodies and B-cell receptors (BCRs) are produced by B cells, and are built of a heavy chain and a light chain. Although each B cell could express two different heavy chains and four different light chains, usually only a unique pair of heavy chain and light chain is expressed-a phenomenon known as allelic exclusion. However, a small fraction of naive-B cells violate allelic exclusion by expressing two productive light chains, one of which has impaired function; this has been called allelic inclusion. We demonstrate that these B cells can be used to learn constraints on antibody sequence. Using large-scale single-cell sequencing data from humans, we find examples of light chain allelic inclusion in thousands of naive-B cells, which is an order of magnitude larger than existing datasets. We train machine learning models to identify the abnormal sequences in these cells. The resulting models correlate with antibody properties that they were not trained on, including polyreactivity, surface expression, and mutation usage in affinity maturation. These correlations are larger than what is achieved by existing antibody modeling approaches, indicating that allelic inclusion data contains useful new information. We also investigate the impact of similar selection forces on the heavy chain in mouse, and observe that pairing with the surrogate light chain significantly restricts heavy chain diversity.}, }
@article {pmid39484476, year = {2024}, author = {Arora, S and Nuechterlein, N and Jensen, M and Glatzer, G and Sievers, P and Varadharajan, S and Korshunov, A and Sahm, F and Mack, SC and Taylor, MD and Holland, EC}, title = {Transcriptomic landscape identifies two unrecognized ependymoma subtypes and novel pathways in medulloblastoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39484476}, issn = {2692-8205}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; }, abstract = {Medulloblastoma and ependymoma are prevalent pediatric central nervous system tumors with significant molecular and clinical heterogeneity. We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. Following rigorous batch effect correction, normalization, and dimensionality reduction, we constructed a unified landscape to explore gene expression, signaling pathways, gene fusions, and copy number variations. Our analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with specific gene fusions and molecular signatures. In medulloblastoma, we achieved precise stratification of Group 3/4 tumors by subtype and in SHH tumors by patient age. Our landscape serves as a vital resource for identifying biomarkers, refining diagnoses, and enables the mapping of new patients' bulk RNA-seq data onto the reference framework to facilitate accurate disease subtype identification. The landscape is accessible via Oncoscape, an interactive platform, empowering global exploration and application.}, }
@article {pmid39484446, year = {2024}, author = {, and Dekker, J and Oksuz, BA and Zhang, Y and Wang, Y and Minsk, MK and Kuang, S and Yang, L and Gibcus, JH and Krietenstein, N and Rando, OJ and Xu, J and Janssens, DH and Henikoff, S and Kukalev, A and Willemin, A and Winick-Ng, W and Kempfer, R and Pombo, A and Yu, M and Kumar, P and Zhang, L and Belmont, AS and Sasaki, T and van Schaik, T and Brueckner, L and Peric-Hupkes, D and van Steensel, B and Wang, P and Chai, H and Kim, M and Ruan, Y and Zhang, R and Quinodoz, SA and Bhat, P and Guttman, M and Zhao, W and Chien, S and Liu, Y and Venev, SV and Plewczynski, D and Azcarate, II and Szabó, D and Thieme, CJ and Szczepińska, T and Chiliński, M and Sengupta, K and Conte, M and Esposito, A and Abraham, A and Zhang, R and Wang, Y and Wen, X and Wu, Q and Yang, Y and Liu, J and Boninsegna, L and Yildirim, A and Zhan, Y and Chiariello, AM and Bianco, S and Lee, L and Hu, M and Li, Y and Barnett, RJ and Cook, AL and Emerson, DJ and Marchal, C and Zhao, P and Park, P and Alver, BH and Schroeder, A and Navelkar, R and Bakker, C and Ronchetti, W and Ehmsen, S and Veit, A and Gehlenborg, N and Wang, T and Li, D and Wang, X and Nicodemi, M and Ren, B and Zhong, S and Phillips-Cremins, JE and Gilbert, DM and Pollard, KS and Alber, F and Ma, J and Noble, WS and Yue, F}, title = {An integrated view of the structure and function of the human 4D nucleome.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39484446}, issn = {2692-8205}, support = {U54 DK107981/DK/NIDDK NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; U54 DK107967/DK/NIDDK NIH HHS/United States ; U01 DA052715/DA/NIDA NIH HHS/United States ; U01 CA200060/CA/NCI NIH HHS/United States ; U54 DK107979/DK/NIDDK NIH HHS/United States ; U01 DK127405/DK/NIDDK NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; U01 CA200147/CA/NCI NIH HHS/United States ; UM1 HG011593/HG/NHGRI NIH HHS/United States ; U01 HL130007/HL/NHLBI NIH HHS/United States ; UM1 HG011536/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; U01 DA052769/DA/NIDA NIH HHS/United States ; U01 DA040612/DA/NIDA NIH HHS/United States ; U01 DK127420/DK/NIDDK NIH HHS/United States ; U54 DK107965/DK/NIDDK NIH HHS/United States ; UM1 HG011585/HG/NHGRI NIH HHS/United States ; U01 CA200059/CA/NCI NIH HHS/United States ; U01 HL157989/HL/NHLBI NIH HHS/United States ; }, abstract = {The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general.}, }
@article {pmid39484284, year = {2024}, author = {Violari, A and Otwombe, K and Hahn, W and Chen, S and Josipovic, D and Baba, V and Angelidou, A and Smolen, KK and Levy, O and Mkhize, NN and Woodward, AS and Martin, TM and Haynes, B and Williams, WB and Sagawa, ZK and Kublin, J and Polakowski, L and Isaacs, MB and Yen, C and Tomaras, G and Corey, L and Janes, H and Gray, G}, title = {Safety and implementation of a phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39484284}, support = {K08 AI168487/AI/NIAID NIH HHS/United States ; U19 AI168643/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; HHSN272201800047C/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV.
METHODS: HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants in South Africa aged ≤5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks.
RESULTS: 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, p = 0.25; 4, 40.0% systemic, p = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded.
CONCLUSIONS: This study illustrates the feasibility of conducting trials of novel adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04607408.
FUNDING: National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH).}, }
@article {pmid39486411, year = {2024}, author = {Davar, D and Morrison, RM and Dzutsev, AK and Karunamurthy, A and Chauvin, JM and Amatore, F and Deutsch, JS and Das Neves, RX and Rodrigues, RR and McCulloch, JA and Wang, H and Hartman, DJ and Badger, JH and Fernandes, MR and Bai, Y and Sun, J and Cole, AM and Aggarwal, P and Fang, JR and Deitrick, C and Bao, R and Duvvuri, U and Sridharan, SS and Kim, SW and A Choudry, H and Holtzman, MP and Pingpank, JF and O'Toole, JP and DeBlasio, R and Jin, Y and Ding, Q and Gao, W and Groetsch, C and Pagliano, O and Rose, A and Urban, C and Singh, J and Divarkar, P and Mauro, D and Bobilev, D and Wooldridge, J and Krieg, AM and Fury, MG and Whiteaker, JR and Zhao, L and Paulovich, AG and Najjar, YG and Luke, JJ and Kirkwood, JM and Taube, JM and Park, HJ and Trinchieri, G and Zarour, HM}, title = {Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial.}, journal = {Cancer cell}, volume = {42}, number = {11}, pages = {1898-1918.e12}, pmid = {39486411}, issn = {1878-3686}, support = {P50 CA254865/CA/NCI NIH HHS/United States ; R01 CA257265/CA/NCI NIH HHS/United States ; R01 CA222203/CA/NCI NIH HHS/United States ; U01 CA268806/CA/NCI NIH HHS/United States ; U01 CA271407/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/drug therapy/immunology/genetics ; *Nivolumab/administration & dosage/therapeutic use ; Male ; Female ; Middle Aged ; *Neoadjuvant Therapy/methods ; Prospective Studies ; Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology ; Adult ; Lymphocytes, Tumor-Infiltrating/immunology/drug effects ; Tumor Microenvironment/immunology/drug effects ; Gastrointestinal Microbiome/drug effects ; Immune Checkpoint Inhibitors/therapeutic use/pharmacology/administration & dosage ; }, abstract = {Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8[+] tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67[+]CD8[+] T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641.}, }
@article {pmid39486408, year = {2024}, author = {Borda, V and Loesch, DP and Guo, B and Laboulaye, R and Veliz-Otani, D and French, JN and Leal, TP and Gogarten, SM and Ikpe, S and Gouveia, MH and Mendes, M and Abecasis, GR and Alvim, I and Arboleda-Bustos, CE and Arboleda, G and Arboleda, H and Barreto, ML and Barwick, L and Bezzera, MA and Blangero, J and Borges, V and Caceres, O and Cai, J and Chana-Cuevas, P and Chen, Z and Custer, B and Dean, M and Dinardo, C and Domingos, I and Duggirala, R and Dieguez, E and Fernandez, W and Ferraz, HB and Gilliland, F and Guio, H and Horta, B and Curran, JE and Johnsen, JM and Kaplan, RC and Kelly, S and Kenny, EE and Konkle, BA and Kooperberg, C and Lescano, A and Lima-Costa, MF and Loos, RJF and Manichaikul, A and Meyers, DA and Naslavsky, MS and Nickerson, DA and North, KE and Padilla, C and Preuss, M and Raggio, V and Reiner, AP and Rich, SS and Rieder, CR and Rienstra, M and Rotter, JI and Rundek, T and Sacco, RL and Sanchez, C and Sankaran, VG and Santos-Lobato, BL and Schumacher-Schuh, AF and Scliar, MO and Silverman, EK and Sofer, T and Lasky-Su, J and Tumas, V and Weiss, ST and , and , and , and Mata, IF and Hernandez, RD and Tarazona-Santos, E and O'Connor, TD}, title = {Genetics of Latin American Diversity Project: Insights into population genetics and association studies in admixed groups in the Americas.}, journal = {Cell genomics}, volume = {4}, number = {11}, pages = {100692}, doi = {10.1016/j.xgen.2024.100692}, pmid = {39486408}, issn = {2666-979X}, mesh = {Humans ; Latin America ; *Genetics, Population ; Genome-Wide Association Study ; Haplotypes ; Algorithms ; Genetic Variation/genetics ; Software ; }, abstract = {Latin Americans are underrepresented in genetic studies, increasing disparities in personalized genomic medicine. Despite available genetic data from thousands of Latin Americans, accessing and navigating the bureaucratic hurdles for consent or access remains challenging. To address this, we introduce the Genetics of Latin American Diversity (GLAD) Project, compiling genome-wide information from 53,738 Latin Americans across 39 studies representing 46 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene flow across the Americas. Additionally, we developed GLAD-match, a simulated annealing-based algorithm, to match the genetic background of external samples to our database, sharing summary statistics (i.e., allele and haplotype frequencies) without transferring individual-level genotypes. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic software in the presence of admixture. By providing this resource, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people.}, }
@article {pmid39486012, year = {2024}, author = {Dubois, MM and Jao, J and Sun, S and Legbedze, J and Schenkel, S and Mmasa, N and Kgole, SW and Masasa, G and Happel, AU and Iwase, SC and Haghighat, R and Moyo, S and Sharma, TS and Edlefsen, PT and Shao, D and Jaspan, H and Powis, KM}, title = {Infectious Morbidity and All-cause Mortality of Infants HIV-exposed Uninfected Compared to Infants HIV-unexposed Uninfected in Botswana.}, journal = {The Pediatric infectious disease journal}, volume = {}, number = {}, pages = {}, doi = {10.1097/INF.0000000000004603}, pmid = {39486012}, issn = {1532-0987}, abstract = {Some studies have reported increased infectious morbidity and all-cause mortality risk among infants HIV-exposed uninfected compared with infants HIV-unexposed uninfected. In a retrospective analysis of infants enrolled in the Botswana-based Tshilo Dikotla study, we found no difference in the prevalence of infectious hospitalizations or deaths from any cause in the first year of life by perinatal HIV exposure.}, }
@article {pmid39485483, year = {2024}, author = {Roberti, S and van Leeuwen, FE and Diallo, I and de Vathaire, F and Schaapveld, M and Leisenring, WM and Howell, RM and Armstrong, GT and Moskowitz, CS and Smith, SA and Aleman, BMP and Krul, IM and Russell, NS and Pfeiffer, RM and Hauptmann, M}, title = {Prediction of breast cancer risk for adolescents and young adults with Hodgkin lymphoma.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djae274}, pmid = {39485483}, issn = {1460-2105}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: While female survivors of Hodgkin lymphoma (HL) have an increased risk of breast cancer (BC), no BC risk prediction model is available. We developed such models incorporating mean radiation dose to the breast or breast quadrant-specific radiation doses.
METHODS: Relative risks and age-specific incidence for BC and competing events (mortality or other subsequent cancer) were estimated from 1194 Dutch five-year HL survivors, treated at ages 11-40 during 1965-2000. Predictors were doses to ten breast segments or mean breast radiation dose, BC family history, year of and age at HL diagnosis, ages at menopause and first live birth. Models were independently validated using U.S. Childhood Cancer Survivor Study cohort participants.
RESULTS: Predicted absolute BC risks 25 years after HL diagnosis ranged from 1.0% for survivors diagnosed at ages 20-24, with <10 Gy mean breast radiation dose and menopausal 5 years after HL diagnosis, to 22.0% for survivors 25-29 years at diagnosis, ≥25 Gy mean breast dose, and no menopause within 5 years. In external validation, the observed/expected BC case ratio was 1.19 (95% confidence interval 0.97 to 1.47) for the breast segment-specific doses model, and 1.29 (1.05 to 1.60) for the mean breast dose model. The areas under the receiver operating characteristic curve were 0.68 (0.63 to 0.74) and 0.68 (0.62 to 0.73), respectively.
CONCLUSION: Breast segment-specific or mean breast radiation dose with personal and clinical characteristics predicted absolute BC risk in HL survivors with moderate discrimination but good calibration, rendering the models useful for clinical decision-making.}, }
@article {pmid39485274, year = {2025}, author = {Larson, JD and Heitkamp, NA and Murray, LE and Popchock, AR and Biggins, S and Asbury, CL}, title = {Kinetochores grip microtubules with directionally asymmetric strength.}, journal = {The Journal of cell biology}, volume = {224}, number = {1}, pages = {}, pmid = {39485274}, issn = {1540-8140}, support = {F32 GM136010/GM/NIGMS NIH HHS/United States ; T32HL007312/NH/NIH HHS/United States ; T32 HL007312/HL/NHLBI NIH HHS/United States ; R01 GM079373/GM/NIGMS NIH HHS/United States ; //University of Washington/ ; /HHMI/Howard Hughes Medical Institute/United States ; R01 GM064386/GM/NIGMS NIH HHS/United States ; //Washington Research Foundation/ ; R35 GM134842/GM/NIGMS NIH HHS/United States ; }, mesh = {*Kinetochores/metabolism ; *Microtubules/metabolism ; Humans ; *Mitosis ; Saccharomyces cerevisiae/metabolism/genetics ; Saccharomyces cerevisiae Proteins/metabolism/genetics ; Microtubule-Associated Proteins/metabolism/genetics ; Chromosome Segregation ; HeLa Cells ; }, abstract = {For accurate mitosis, all chromosomes must achieve "biorientation," with replicated sister chromatids coupled via kinetochores to the plus ends of opposing microtubules. However, kinetochores first bind the sides of microtubules and subsequently find plus ends through a trial-and-error process; accurate biorientation depends on the selective release of erroneous attachments. Proposed mechanisms for error-correction have focused mainly on plus-end attachments. Whether erroneous side attachments are distinguished from correct side attachments is unknown. Here, we show that side-attached kinetochores are very sensitive to microtubule polarity, gripping sixfold more strongly when pulled toward plus versus minus ends. This directionally asymmetric grip is conserved in human and yeast subcomplexes, and it correlates with changes in the axial arrangement of subcomplexes within the kinetochore, suggesting that internal architecture dictates attachment strength. We propose that the kinetochore's directional grip promotes accuracy during early mitosis by stabilizing correct attachments even before both sisters have found plus ends.}, }
@article {pmid39485107, year = {2024}, author = {Loroña, NC and Othus, M and Malone, KE and Linden, HM and Tang, MC and Li, CI}, title = {Metabolic syndrome and risks of breast cancer outcomes for luminal, triple-negative, and HER2-overexpressing subtypes.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-1167}, pmid = {39485107}, issn = {1538-7755}, abstract = {BACKGROUND: We evaluated the association between metabolic syndrome (obesity plus two metabolic risk factors) and breast cancer outcomes according to molecular subtype.
METHODS: This population-based prospective cohort consisted of 3,267 women aged 20-69 diagnosed with a first primary invasive breast cancer from 2004-2015 in the Seattle-Puget Sound region. Breast cancer was categorized into three subtypes based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression: luminal (ER+), triple-negative (ER-/PR-/HER2-), and HER2-overexpressing (H2E) (ER-/HER2+). We used time-varying Cox models to assess the association between prevalent and incident metabolic syndrome and risks of recurrence, breast cancer-specific mortality, and all-cause mortality.
RESULTS: Metabolic syndrome was associated with a greater risk of recurrence (HR:3.24; 95% CI:1.13-9.33) and breast cancer-specific mortality (HR:5.34; 95% CI:2.32-12.31) only for the H2E subtype, and greater risks of all-cause mortality for luminal (HR:1.92; 95% CI:1.37-2.68), H2E (HR:5.09; 95% CI:2.51-10.32), and all cases combined (HR:1.90; 95% CI:1.42,2.53). We also observed heterogeneity in recurrence and mortality outcomes across specific components of metabolic syndrome and molecular subtypes.
CONCLUSIONS: Metabolic syndrome is associated with all-cause mortality among women with breast cancer and with breast cancer-specific mortality among women with the H2E subtype.
IMPACT: These results highlight the importance of managing comorbidities to decrease the risk for adverse outcomes among breast cancer survivors.}, }
@article {pmid39479331, year = {2024}, author = {Armenian, SH and Hudson, MM and Lindenfeld, L and Chen, S and Chow, EJ and Colan, S and Echevarria, M and Wong, FL and Chen, MH and Bhatia, S}, title = {Carvedilol to Improve Cardiac Remodeling in Anthracycline-Exposed Childhood Cancer Survivors: Subgroup Analysis of COG ALTE1621.}, journal = {JACC. CardioOncology}, volume = {6}, number = {5}, pages = {791-793}, pmid = {39479331}, issn = {2666-0873}, support = {R01 CA196854/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; K12 CA001727/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; }, }
@article {pmid39478506, year = {2024}, author = {Lynch, MM and Al-Marayaty, R and Obeidin, F and Alexiev, BA and Chen, EY and Viveiros, P and Schroeder, BA and Hudkins, K and Fan, TM and Redman, MW and Baker, KK and Jour, G and Cranmer, LD and Pollack, SM}, title = {B7-H3 is widely expressed in soft tissue sarcomas.}, journal = {BMC cancer}, volume = {24}, number = {1}, pages = {1336}, pmid = {39478506}, issn = {1471-2407}, support = {R01CA244872/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *B7 Antigens/metabolism ; *Sarcoma/metabolism/pathology ; Female ; Male ; Middle Aged ; Retrospective Studies ; Adult ; Aged ; Biomarkers, Tumor/metabolism ; Immunohistochemistry ; Aged, 80 and over ; Young Adult ; Adolescent ; }, abstract = {PURPOSE: Targeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS.
PATIENTS AND METHODS: This retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature.
RESULTS: Specimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93-0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61-0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1.
CONCLUSION: These data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.}, }
@article {pmid39478321, year = {2024}, author = {Dombrowski, JC and Donnell, D and Grabow, C and Cohen, SE and Cannon, CA and Brown, CE and Buchbinder, SP and Celum, C and Luetkemeyer, AF}, title = {Evidence-Informed Provision of Doxycycline Post-Exposure Prophylaxis for Prevention of Bacterial Sexually Transmitted Infections.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae527}, pmid = {39478321}, issn = {1537-6591}, abstract = {Doxycycline post-exposure prophylaxis (doxy-PEP) reduces the risk of bacterial sexually transmitted infections (STIs) among men who have sex with men and transgender women. In the United States, doxy-PEP is in an early stage of integration into clinical practice, and national guidelines for its use were recently released. The goal of this manuscript is to provide practical guidance for clinicians who are considering or currently prescribing doxy-PEP. We address five clinical questions using post hoc analyses of data from the DoxyPEP randomized controlled trial and discuss the potential implications and limitations of each question with the goal of informing clinical practice and implementation of doxy-PEP programs. The questions address patient eligibility criteria for doxy-PEP, the expected benefit and associated doxy-PEP doses for the average patient, the initial number of doses prescribed, and laboratory monitoring of persons taking doxy-PEP.}, }
@article {pmid39477498, year = {2024}, author = {Huang, RR and Zuo, C and Mona, CE and Holzgreve, A and Morrissey, C and Nelson, PS and Brady, L and True, L and Sisk, A and Czernin, J and Calais, J and Ye, H}, title = {FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.124.268037}, pmid = {39477498}, issn = {1535-5667}, abstract = {Prostate-specific membrane antigen (PSMA) is a theranostic target for metastatic prostate cancer (PCa). However, castration-resistant PCa (CRPC) may lose PSMA expression after systemic therapy. Fibroblast activation protein (FAP), expressed by carcinoma-associated fibroblasts in various cancer types, including PCa, has the potential to be an alternative target. In this study, we evaluated FAP expression in CRPC to assess its potential, using PSMA as a comparison. Methods: FAP expression was assessed using immunohistochemistry in 116 CRPC tumors: 78 adenocarcinomas, 11 small cell carcinomas, and 27 anaplastic carcinomas. Correlation analysis between manual scoring and automated scoring was performed on 54 whole-slide sections of metastatic CRPC. Paired FAP and PSMA stains were assessed in tissue microarray cores of CRPC (n = 62), consisting of locally advanced CRPC (n = 9) and metastatic CRPC (n = 53). FAP and PSMA positivity was defined by an immunohistochemistry score of at least 10. To explore the correlation of PSMA and FAP inhibitor (FAPi) PET imaging and immunohistochemistry, a preliminary analysis of 4 patients included in a [[68]Ga]-FAPi-46 imaging trial (NCT04457232) was conducted. Results: Manual and automated scoring of FAP yielded results with strong correlations. Overall, FAP expression in CRPC was notably lower than PSMA expression (median immunoscores, 14 vs. 72; P < 0.001). Different histologic subtypes of CRPC demonstrated distinct levels of PSMA expression, whereas their FAP expression levels were comparable. Among the 19 PSMA-negative tumors, 11 (58%) exhibited FAP positivity. FAP expression levels in lymph node metastases were significantly lower than those in nonnodal metastases (P = 0.021). Liver metastases showed significant enrichment of tumors with strong FAP expression compared with nonliver lesions (P = 0.016). In the 4 clinical trial patients, the biopsied metastatic lesions showed lower uptake on FAPi PET than on PSMA PET (median SUVmax, 9.6 vs. 14.5), consistent with FAP expression that was lower than PSMA expression in the corresponding tumor biopsy samples (median immunoscores, 30 vs. 160). Conclusion: Because of the low FAP expression levels in CRPC, the utility of FAPi PET imaging may be limited. Although FAPi PET imaging may be further tested in PSMA-negative CRPC, such as small cell carcinoma, other molecular imaging modalities should be evaluated as alternative choices.}, }
@article {pmid39475359, year = {2024}, author = {Fléchon, A and Morales-Barrera, R and Powles, T and Alva, A and Özgüroğlu, M and Csöszi, T and Loriot, Y and Rodriguez-Vida, A and Géczi, L and Cheng, SY and Fradet, Y and Oudard, S and Vulsteke, C and Gunduz, S and Mamtani, R and Yu, EY and Montesa Pino, A and Anido, U and Sendur, MAN and Gravis, G and Révész, J and Kostorov, V and Huillard, O and Ma, J and Rajasagi, M and Vajdi, A and Lunceford, J and Cristescu, R and Imai, K and Homet Moreno, B and Matsubara, N}, title = {Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {OF1-OF12}, doi = {10.1158/1078-0432.CCR-23-3518}, pmid = {39475359}, issn = {1557-3265}, abstract = {PURPOSE: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes.
PATIENTS AND METHODS: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1).
RESULTS: Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥175 mutations/exome and PD-L1 CPS ≥10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone.
CONCLUSIONS: These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.}, }
@article {pmid39475323, year = {2024}, author = {Kessler, RC and Bossarte, RM and Hwang, I and Luedtke, A and Naifeh, JA and Nock, MK and Petukhova, M and Sadikova, E and Sampson, NA and Sverdrup, E and Zubizarreta, JR and Wager, S and Wagner, J and Stein, MB and Ursano, RJ}, title = {A prediction model for differential resilience to the effects of combat-related stressors in US army soldiers.}, journal = {International journal of methods in psychiatric research}, volume = {33}, number = {4}, pages = {e70006}, pmid = {39475323}, issn = {1557-0657}, support = {U01MH087981/MH/NIMH NIH HHS/United States ; HU0001-15-2-0004//U.S. Department of Defense/ ; U01MH087981//U.S. Army/ ; }, mesh = {Humans ; *Military Personnel/psychology ; *Resilience, Psychological ; Adult ; Male ; Female ; *Stress Disorders, Post-Traumatic/diagnosis ; United States ; Young Adult ; *Combat Disorders/diagnosis ; Follow-Up Studies ; Afghan Campaign 2001- ; Retrospective Studies ; Adolescent ; Stress, Psychological ; }, abstract = {OBJECTIVES: To develop a composite score for differential resilience to effects of combat-related stressors (CRS) on persistent DSM-IV post-traumatic stress disorder (PTSD) among US Army combat arms soldiers using survey data collected before deployment.
METHODS: A sample of n = 2542 US Army combat arms soldiers completed a survey shortly before deployment to Afghanistan and then again two to three and 8-9 months after redeployment. Retrospective self-reports were obtained about CRS. Precision treatment methods were used to determine whether differential resilience to persistent PTSD in the follow-up surveys could be developed from pre-deployment survey data in a 60% training sample and validated in a 40% test sample.
RESULTS: 40.8% of respondents experienced high CRS and 5.4% developed persistent PTSD. Significant test sample heterogeneity was found in resilience (t = 2.1, p = 0.032), with average treatment effect (ATE) of high CRS in the 20% least resilient soldiers of 17.1% (SE = 5.5%) compared to ATE = 3.8% (SE = 1.2%) in the remaining 80%. The most important predictors involved recent and lifetime pre-deployment distress disorders.
CONCLUSIONS: A reliable pre-deployment resilience score can be constructed to predict variation in the effects of high CRS on persistent PTSD among combat arms soldiers. Such a score could be used to target preventive interventions to reduce PTSD or other resilience-related outcomes.}, }
@article {pmid39474526, year = {2024}, author = {McCamy, W and Yousefiasl, M and Tretiakova, M and Jagtiani, M and Hall, E}, title = {Metastatic SMARCB1-Deficient Renal Medullary Carcinoma without Hemoglobinopathy with Durable and Dramatic Response to Pembrolizumab plus Lenvatinib: Case Report.}, journal = {Case reports in oncology}, volume = {17}, number = {1}, pages = {1025-1033}, pmid = {39474526}, issn = {1662-6575}, abstract = {INTRODUCTION: Renal medullary carcinoma (RMC) is a rare form of renal cell carcinoma (RCC) that is typically associated with a loss of function in SMARCB1 and diagnosis of sickle cell or other hemoglobinopathy. In rare cases, this disease can be seen in patients without hemoglobinopathy and is classified as "SMARCB1-deficient RMC without hemoglobinopathy" or referred to as "RCC unclassified with medullary phenotype" in some of the literature. Platinum-based cytotoxic chemotherapy is currently the recommended first-line treatment for this rare disease.
CASE PRESENTATION: Here we report a 53-year-old male who was diagnosed with metastatic SMARCB1-deficient RMC without hemoglobinopathy after presenting with left flank and abdominal pain. After initiating first-line pembrolizumab and lenvatinib systemic therapy, imaging showed regression at 6 weeks. To date, this patient continues to show a near complete response to this treatment regimen.
CONCLUSION: To our knowledge, this is the first documented case of SMARCB1-deficient RMC without hemoglobinopathy to receive this treatment regimen and show such a response.}, }
@article {pmid39473183, year = {2024}, author = {Rao, H and Weiss, MC and Moon, JY and Perreira, KM and Daviglus, ML and Kaplan, R and North, KE and Argos, M and Fernández-Rhodes, L and Sofer, T}, title = {Advancements in genetic research by the Hispanic Community Health Study/Study of Latinos (HCHS/SOL): A 10-year Retrospective Review.}, journal = {HGG advances}, volume = {}, number = {}, pages = {100376}, doi = {10.1016/j.xhgg.2024.100376}, pmid = {39473183}, issn = {2666-2477}, support = {R01 HL163262/HL/NHLBI NIH HHS/United States ; }, abstract = {The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, longitudinal cohort study designed to evaluate environmental, lifestyle, and genetic risk factors as they relate to cardiometabolic and other chronic diseases among Hispanic/Latino populations in the United States. Since the study's inception in 2008, as a result of the study's robust genetic measures, HCHS/SOL has facilitated major contributions to the field of genetic research. This 15-year retrospective review highlights the major findings for genotype phenotype relationships and advancements in statistical methods owing to the HCHS/SOL. Furthermore, we discuss the ethical and societal challenges of genetic research, especially among Hispanic/Latino adults in the U.S. Continued genetic research, ancillary study expansion, and consortia collaboration through HCHS/SOL will further drive knowledge and advancements in human genetics research.}, }
@article {pmid39472576, year = {2024}, author = {Janssens, DH and Duran, M and Otto, DJ and Wu, W and Xu, Y and Kirkey, D and Mullighan, CG and Yi, JS and Meshinchi, S and Sarthy, JF and Ahmad, K and Henikoff, S}, title = {MLL oncoprotein levels influence leukemia lineage identities.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {9341}, pmid = {39472576}, issn = {2041-1723}, support = {Henikoff//Howard Hughes Medical Institute (HHMI)/ ; R01 HG010492/HG/NHGRI NIH HHS/United States ; Derek Janssens//Hartwell Foundation (The Hartwell Foundation)/ ; NCI R35 CA297695//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Mullighan//American Lebanese Syrian Associated Charities (ALSAC)/ ; }, mesh = {*Myeloid-Lymphoid Leukemia Protein/metabolism/genetics ; Humans ; *Leukemia, Myeloid, Acute/genetics/metabolism ; *Oncogene Proteins, Fusion/metabolism/genetics ; *Cell Lineage/genetics ; *Histone-Lysine N-Methyltransferase/metabolism/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics/metabolism/pathology ; Gene Expression Regulation, Leukemic ; Proto-Oncogene Proteins/metabolism/genetics ; Mutation ; Translocation, Genetic ; Hematopoietic Stem Cells/metabolism ; Chromatin/metabolism ; }, abstract = {Chromosomal translocations involving the mixed-lineage leukemia (MLL) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representative MLL-rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose MLL oncoproteins promote lineage-switching events through dynamic chromatin binding at lineage-specific target genes, and may support resistance to menin inhibitors through similar changes in chromatin occupancy.}, }
@article {pmid39472320, year = {2024}, author = {Zhang, R and Bozic, I}, title = {Accumulation of Oncogenic Mutations During Progression from Healthy Tissue to Cancer.}, journal = {Bulletin of mathematical biology}, volume = {86}, number = {12}, pages = {142}, pmid = {39472320}, issn = {1522-9602}, support = {DMS-2045166//National Science Foundation/ ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/pathology ; *Disease Progression ; *Mutation ; *Mathematical Concepts ; *Oncogenes/genetics ; *Models, Genetic ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/pathology ; Neoplasms/genetics/pathology ; Carcinogenesis/genetics ; Mutation Accumulation ; Precancerous Conditions/genetics/pathology ; Computer Simulation ; }, abstract = {Cancers are typically fueled by sequential accumulation of driver mutations in a previously healthy cell. Some of these mutations, such as inactivation of the first copy of a tumor suppressor gene, can be neutral, and some, like those resulting in activation of oncogenes, may provide cells with a selective growth advantage. We study a multi-type branching process that starts with healthy tissue in homeostasis and models accumulation of neutral and advantageous mutations on the way to cancer. We provide results regarding the sizes of premalignant populations and the waiting times to the first cell with a particular combination of mutations, including the waiting time to malignancy. Finally, we apply our results to two specific biological settings: initiation of colorectal cancer and age incidence of chronic myeloid leukemia. Our model allows for any order of neutral and advantageous mutations and can be applied to other evolutionary settings.}, }
@article {pmid39472202, year = {2024}, author = {Oh, WK and Agarwal, N and Bryce, A and Barata, P and Bugler, C and Carlsson, SV and Cornell, B and Dahut, W and George, D and Loeb, S and Montgomery, B and Morris, D and Mucci, LA and Omlin, A and Palapattu, G and Riaz, IB and Ryan, C and Schoen, MW and Washington, SL and Gillessen, S}, title = {What's in a Name? Why Words Matter in Advanced Prostate Cancer.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.10.017}, pmid = {39472202}, issn = {1873-7560}, abstract = {Much of the disease nomenclature used for patients with advanced prostate cancer has negative connotations and can be confusing or intimidating. Experts in the field convened to recommend a clearer and more accurate approach to defining the nomenclature.}, }
@article {pmid39470729, year = {2024}, author = {Nelson, BH and Hamilton, PT and Phung, MT and Milne, K and Harris, B and Thornton, S and Stevens, DL and Kalaria, S and Singh, K and Laumont, CM and Moss, E and Alimujiang, A and Meagher, NS and Bolithon, A and Fereday, S and Kennedy, CJ and Hendley, J and Ariyaratne, D and Alsop, K and Traficante, N and Goode, EL and Karnezis, AN and Shen, H and Richardson, J and McKinnon Deurloo, C and Chase, A and Grout, B and Doherty, JA and Harris, HR and Cushing-Haugen, KL and Anglesio, MS and Heinze, K and Huntsman, D and Talhouk, A and Hanley, GE and Alsop, J and Jimenez-Linan, M and Pharoah, PD and Boros, J and Brand, AH and Harnett, PR and Sharma, R and Hecht, JL and Sasamoto, N and Terry, KL and Karlan, BY and Lester, J and Carney, ME and Goodman, MT and Hernandez, BY and Wilkens, LR and Behrens, S and Turzanski Fortner, R and Fasching, PA and Bisinotto, C and Candido Dos Reis, FJ and Ghatage, P and Köbel, M and Elishaev, E and Modugno, F and Cook, LS and Le, ND and Gentry-Maharaj, A and Menon, U and García, MJ and Rodriguez-Antona, C and Farrington, KM and Kelemen, LE and Kommoss, S and Staebler, A and Garsed, DW and Brenton, JD and Piskorz, AM and Bowtell, DD and DeFazio, A and Ramus, SJ and Pike, MC and Pearce, CL}, title = {Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI179501}, pmid = {39470729}, issn = {1558-8238}, abstract = {BACKGROUND: Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment.
METHODS: We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content.
RESULTS: Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype.
CONCLUSIONS: The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy.
FUNDING: Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.}, }
@article {pmid39470275, year = {2024}, author = {Piliper, EA and Reed, JC and Greninger, AL}, title = {Clinical validation of an RSV neutralization assay and analysis of cross-sectional sera associated with 2021-2023 RSV outbreaks to investigate the immunity debt hypothesis.}, journal = {Microbiology spectrum}, volume = {}, number = {}, pages = {e0211524}, doi = {10.1128/spectrum.02115-24}, pmid = {39470275}, issn = {2165-0497}, abstract = {UNLABELLED: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infections and hospitalization in infants and the elderly. Newly approved vaccines and the prophylactic antibody nirsevimab have heightened interest in RSV immunologic surveillance, necessitating the development of high-throughput assays assessing anti-RSV neutralizing activity. Quantitative viral neutralization remains the best correlate of protection for RSV infection and the gold standard for RSV immunological testing. Here, we developed a high-throughput RSV strain A2 focus-reduction neutralization test validated to Clinical Laboratory Improvement Amendments (CLIA)/ Good Clinical Laboratory Practices (GCLP) standards using both clinical specimens and commercially available reference sera. The assay is highly accurate, generating reference serum neutralizing titers within twofold of established assays, with an analytical measurement range between 8 and 1,798 international units per mL (IU/mL). Neutralizing activity measured by the assay strongly correlated with antibody titer determined via indirect enzyme-linked immunosorbent assay (ELISA) (ρ = 1.0, P = 0.0014). Individuals recently having tested positive via quantitative reverse transcription polymerase chain reaction (RT-qPCR) for RSV had a 9.1-fold higher geometric mean neutralizing titer relative to RSV PCR negatives (P-value = 0.09). The validated assay was then used to investigate the immunity debt hypothesis for resurgent RSV outbreaks in the 2022-2023 season, using adult clinical remnant sera sent for herpes simplex virus (HSV)-1/2 antibody testing. There was no difference in geometric mean anti-RSV neutralizing titers between sera sampled before and after the 2022-2023 RSV outbreak (P = 0.68). These data are consistent with limited changes in RSV-neutralizing antibody levels in adults across the 2022-23 RSV outbreak.
IMPORTANCE: Population surveillance studies of serum-neutralizing activity against RSV are crucial for evaluating RSV vaccine efficacy and vulnerabilities to new strains. Here, we designed and validated a high-throughput assay for assessing anti-RSV neutralizing activity, standardized its measurements for comparison with other methodologies, and demonstrated its applicability to real-world samples. Our assay is precise, linear, and yields measurements consistent with other standardized assays, offering a methodology useful for large-scale studies of RSV immunity. We also find no significant difference in neutralizing titers among adults between those taken before and after large RSV outbreaks associated with the latter stages of the coronavirus disease of 2019 (COVID-19) public health emergency, underlining the need for a greater understanding of the dynamics of serological responses to RSV infection.}, }
@article {pmid39468273, year = {2024}, author = {Kim, D and Cooper, JA and Helfman, DM}, title = {Loss of myosin light chain kinase induces the cellular senescence associated secretory phenotype to promote breast epithelial cell migration.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {25786}, pmid = {39468273}, issn = {2045-2322}, support = {NFR 2018R1A2A2A05021262//National Research Foundation of Korea/ ; NFR 2018R1A2A2A05021262//National Research Foundation of Korea/ ; }, mesh = {Female ; Humans ; Breast/metabolism/pathology ; Breast Neoplasms/pathology/metabolism/genetics ; *Cell Movement ; Cellular Senescence ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; *Epithelial Cells/metabolism ; Intercellular Adhesion Molecule-1/metabolism/genetics ; *Myosin-Light-Chain Kinase/metabolism/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Senescence-Associated Secretory Phenotype ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; Tumor Suppressor Protein p53/metabolism/genetics ; }, abstract = {Overexpression or activation of oncogenes or loss of tumor-suppressor genes can induce cellular senescence as a defense mechanism against tumor development, thereby maintaining cellular homeostasis. However, cancer cells can circumvent this senescent state and continue to spread. Myosin light chain kinase (MLCK) is downregulated in many breast cancers. Here we report that downregulation of MLCK in normal breast epithelial cells induces a senescence-associated secretory phenotype and stimulates migration. The reduction of MLCK results in increased p21[Cip1] expression, dependent on p53 and the AKT-mammalian target of rapamycin pathway. Subsequently, p21[Cip1] promotes the secretion of soluble ICAM-1, IL-1α, IL-6 and IL-8, thereby enhancing collective cell migration in a non-cell-autonomous manner. These findings provide new mechanistic insights into the role of MLCK in cellular senescence and cancer progression.}, }
@article {pmid39468212, year = {2024}, author = {Tsue, AF and Kania, EE and Lei, DQ and Fields, R and McGann, CD and Marciniak, DM and Hershberg, EA and Deng, X and Kihiu, M and Ong, SE and Disteche, CM and Kugel, S and Beliveau, BJ and Schweppe, DK and Shechner, DM}, title = {Multiomic characterization of RNA microenvironments by oligonucleotide-mediated proximity-interactome mapping.}, journal = {Nature methods}, volume = {21}, number = {11}, pages = {2058-2071}, pmid = {39468212}, issn = {1548-7105}, support = {902616//American Heart Association (American Heart Association, Inc.)/ ; R37CA241472//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; GM131745//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R01GM138799-01//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01GM129090//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; S10OD021502//U.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)/ ; T32HG000035//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; T32GM007750//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; UM1HG011586//U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; 1R35GM137916//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R35GM150919-01//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R01HL160825-01//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 GM138799/GM/NIGMS NIH HHS/United States ; DEB2016186//National Science Foundation (NSF)/ ; }, mesh = {Animals ; Mice ; *In Situ Hybridization, Fluorescence/methods ; Biotinylation ; Oligonucleotides/genetics/chemistry ; Humans ; RNA, Long Noncoding/genetics ; RNA/genetics/metabolism ; }, abstract = {RNA molecules form complex networks of molecular interactions that are central to their function and to cellular architecture. But these interaction networks are difficult to probe in situ. Here, we introduce Oligonucleotide-mediated proximity-interactome MAPping (O-MAP), a method for elucidating the biomolecules near an RNA of interest, within its native context. O-MAP uses RNA-fluorescence in situ hybridization-like oligonucleotide probes to deliver proximity-biotinylating enzymes to a target RNA in situ, enabling nearby molecules to be enriched by streptavidin pulldown. This induces exceptionally precise biotinylation that can be easily optimized and ported to new targets or sample types. Using the noncoding RNAs 47S, 7SK and Xist as models, we develop O-MAP workflows for discovering RNA-proximal proteins, transcripts and genomic loci, yielding a multiomic characterization of these RNAs' subcellular compartments and new regulatory interactions. O-MAP requires no genetic manipulation, uses exclusively off-the-shelf parts and requires orders of magnitude fewer cells than established methods, making it accessible to most laboratories.}, }
@article {pmid39466880, year = {2024}, author = {Ruiz, F and Foreman, WB and Lilly, M and Baharani, VA and Depierreux, DM and Chohan, V and Taylor, AL and Guenthoer, J and Ralph, D and Matsen Iv, FA and Chu, HY and Bieniasz, PD and Côté, M and Starr, TN and Overbaugh, J}, title = {Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses.}, journal = {PLoS pathogens}, volume = {20}, number = {10}, pages = {e1012650}, pmid = {39466880}, issn = {1553-7374}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; P01 AI165075/AI/NIAID NIH HHS/United States ; P01 AI167966/AI/NIAID NIH HHS/United States ; DP2 AI177890/AI/NIAID NIH HHS/United States ; S10 OD021644/OD/NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; }, mesh = {*SARS-CoV-2/immunology ; *Cross Reactions/immunology ; *Antibodies, Viral/immunology ; Humans ; Animals ; *Spike Glycoprotein, Coronavirus/immunology ; *Antibodies, Neutralizing/immunology ; *COVID-19/immunology/virology ; Epitopes/immunology ; Mice ; Severe acute respiratory syndrome-related coronavirus/immunology ; Betacoronavirus/immunology ; }, abstract = {The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we characterized the functional breadth and potency of antibodies targeting the receptor binding domain (RBD) of the spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 and sarbecoviruses from diverse clades and animal origins with spillover potential. One neutralizing antibody, C68.61, showed remarkable neutralization breadth against both SARS-CoV-2 variants and viruses from different sarbecovirus clades. C68.61, which targets a conserved RBD class 5 epitope, did not select for escape variants of SARS-CoV-2 or SARS-CoV-1 in culture nor have predicted escape variants among circulating SARS-CoV-2 strains, suggesting this epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive antibodies that target the more sequence conserved class 4 and class 5 epitopes within RBD that show activity against a subset of diverse sarbecoviruses with one antibody binding every single sarbecovirus RBD tested. A subset of these antibodies exhibited Fc-mediated effector functions as potent as antibodies that impact infection outcome in animal models. Thus, our study identified antibodies targeting conserved regions across SARS-CoV-2 variants and sarbecoviruses that may serve as therapeutics for pandemic preparedness as well as blueprints for the design of immunogens capable of eliciting cross-neutralizing responses.}, }
@article {pmid39466048, year = {2024}, author = {Fogel, JM and Persaud, D and Piwowar-Manning, E and Richardson, P and Szewczyk, J and Marzinke, MA and Wang, Z and Guo, X and McCauley, M and Farrior, J and Tran, HV and Ungsedhapand, C and Mathew, CA and Mpendo, J and Rinehart, AR and Rooney, JF and Cohen, MS and Hanscom, B and Grinsztejn, B and Hosseinipour, MC and Delany-Moretlwe, S and Landovitz, RJ and Eshleman, SH and , }, title = {HIV DNA Levels in Persons Who Acquired HIV in the Setting of Long-Acting Cabotegravir for HIV Prevention: Analysis of Cases from HPTN 083 and 084.}, journal = {AIDS research and human retroviruses}, volume = {}, number = {}, pages = {}, doi = {10.1089/aid.2024.0049}, pmid = {39466048}, issn = {1931-8405}, abstract = {We evaluated HIV DNA levels in individuals who received long-acting cabotegravir (CAB-LA) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis in the HPTN 083 and 084 trials and had HIV DNA testing performed to help determine HIV status. HIV DNA testing was performed using peripheral blood mononuclear cell (PBMC) samples collected after a reactive HIV test was obtained at a study site. DNA was quantified using droplet digital PCR (lower limit of detection [LLOD]: 4.09 copies/million PBMCs). Final HIV status and the timing of the first HIV-positive visit were determined by an independent adjudication committee based on HIV test results from real-time site testing and retrospective testing at a centralized laboratory. HIV DNA testing was performed for 133 participants [21 HIV-positive (7 CAB-LA arm, 14 TDF/FTC arm) and 112 HIV-negative; 1-6 tests/person]. For persons with HIV, the time between the first HIV-positive visit and collection of the first sample for DNA testing was a median of 81 days for those receiving CAB-LA (range 41-246) and 11 days for those receiving TDF/FTC (range 3-127). Four (57.1%) of the seven CAB-LA cases with infection had a low initial DNA result [three detected
PATIENTS & METHODS: Twenty-one patients with ROR1+ tumors received CAR T cells at one of four dose levels (DL): 3.3x105/1x106/3.3x106/1x107 cells/kg, administered after lymphodepletion with Cyclophosphamide/Fludarabine (Cy/Flu) or Oxaliplatin/Cyclophosphamide (Ox/Cy). Cohort A included patients with chronic lymphocytic leukemia (CLL, n=3); cohort B included patients with triple-negative breast cancer (TNBC, n=10) or non-small-cell lung cancer (NSCLC, n=8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion.
RESULTS: Treatment was well tolerated apart from one dose limiting toxicity at DL4 in a patient with advanced NSCLC. Two of the three (67%) CLL patients showed robust CAR T expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR T cells expanded to variable levels, infiltrated tumor poorly, and one of eighteen patients (5.5%) achieved partial response by RECIST 1.1.
CONCLUSION: ROR1 CAR T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations.}, }
@article {pmid39465550, year = {2024}, author = {O'Donnell, PH and Loriot, Y and Csoszi, T and Matsubara, N and Shin, SJ and Park, SH and Atduev, V and Gumus, M and Karaca, SB and Grivas, P and de Wit, R and Castellano, DE and Powles, T and Vuky, J and Zhao, Y and O'Hara, K and Okpara, CE and Franco, S and Homet Moreno, B and Żołnierek, J and Siefker-Radtke, AO}, title = {Efficacy and safety of pembrolizumab in patients with advanced urothelial carcinoma deemed potentially ineligible for platinum-containing chemotherapy: Post hoc analysis of KEYNOTE-052 and LEAP-011.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35601}, pmid = {39465550}, issn = {1097-0142}, support = {//Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. (Rahway, New Jersey, USA)/ ; }, abstract = {BACKGROUND: First-line pembrolizumab monotherapy is a standard of care for platinum-ineligible patients with advanced urothelial carcinoma (UC). No global standardized definition of platinum ineligibility exists. This study aimed to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with UC who met various criteria for platinum ineligibility.
METHODS: Patients from KEYNOTE-052 and LEAP-011 deemed potentially platinum ineligible were pooled for this post hoc exploratory analysis as follows: group 1: Eastern Cooperative Oncology Group performance status (ECOG PS) 2; group 2: ECOG PS 2 and age ≥80 years, renal dysfunction, or visceral disease; and group 3: any two other factors regardless of ECOG PS. Patients received pembrolizumab 200 mg intravenously every 3 weeks. End points included objective response rate (ORR), progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review, overall survival (OS), and safety.
RESULTS: A total of 612 patients treated with pembrolizumab from KEYNOTE-052 (n = 370) and LEAP-011 (n = 242) were included; the median (range) follow-up was 56.3 months (51.2-65.3 months) and 12.8 months (0.2-25.1 months), respectively. For group 1, ORR was 26.2%, median PFS was 2.7 months, and median OS was 10.1 months. For group 2, ORR ranged from 23.5% to 33.3%, median PFS ranged from 2.1 to 4.4 months, and median OS ranged from 9.1 to 10.1 months. For group 3, ORR ranged from 25.7% to 27.9%, median PFS ranged from 2.1 to 2.8 months, and median OS ranged from 9.0 to 10.6 months. Treatment-related adverse event rates were consistent across groups.
CONCLUSIONS: Frontline pembrolizumab has consistent antitumor activity and safety in patients with advanced UC categorized as potentially ineligible for platinum-based chemotherapy, regardless of the variable definitions of platinum ineligibility used.}, }
@article {pmid39464162, year = {2024}, author = {Russell, ML and Trofimov, A and Bradley, P and Matsen, FA}, title = {Statistical analysis of repertoire data demonstrates the influence of microhomology in V(D)J recombination.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464162}, issn = {2692-8205}, support = {S10 OD028685/OD/NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; }, abstract = {V(D)J recombination generates the diverse B and T cell receptors essential for recognizing a wide array of antigens. This diversity arises from the combinatorial assembly of V(D)J genes and the junctional deletion and insertion of nucleotides. While previous in vitro studies have shown that microhomology--short stretches of sequence homology between gene ends--can bias the recombination process, the extent of microhomology's impact in vivo, particularly in humans, remains unknown. In this paper, we assess how germline-encoded microhomology influences trimming and ligation during V(D)J recombination using statistical inference on previously-published high-throughput TCRα repertoire sequencing data. We find that microhomology increases both trimming and ligation probabilities, making it an important predictor of recombination outcomes. These effects are consistent across different receptor loci and sequence types. Further, we demonstrate that accounting for microhomology effects significantly alters sequence annotation probabilities and rankings, highlighting its practical importance for accurately inferring the V(D)J recombination events that generated an observed sequence. Together, these results enhance our understanding of how microhomologous nucleotides shape the human V(D)J recombination process.}, }
@article {pmid39464160, year = {2024}, author = {Hsieh, YP and O'Keefe, IP and Sun, W and Wang, Z and Yang, H and Vu, LM and Ernst, RK and Dandekar, AA and Malik, HS}, title = {A novel PhoPQ-potentiated mechanism of colistin resistance impairs membrane integrity in Pseudomonas aeruginosa.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464160}, issn = {2692-8205}, support = {R01 AI104895/AI/NIAID NIH HHS/United States ; R35 GM152107/GM/NIGMS NIH HHS/United States ; }, abstract = {Polymicrobial communities are often recalcitrant to antibiotic treatment because interactions between different microbes can dramatically alter their responses and susceptibility to antimicrobials. However, the mechanisms of evolving antimicrobial resistance in such polymicrobial environments are poorly understood. We previously reported that Mg[2+] depletion caused by the fungus Candida albicans can enable Pseudomonas aeruginosa to acquire significant resistance to colistin, a last-resort antibiotic targeting bacterial membrane. Here, we dissect the genetic and biochemical basis of this increased colistin resistance. We show that P. aeruginosa cells can acquire colistin resistance using three distinct evolutionary trajectories involving mutations in genes involved in lipid A biosynthesis, lipid A modifications that are dependent on low Mg[2+], and a putative Mg[2+] transporter, PA4824. These mutations confer colistin resistance by altering acyl chains, hydroxylation, and aminoarabinose modification of lipid A moieties on the bacterial outer membrane. In all cases, enhanced colistin resistance initially depends on the low Mg[2+]-responsive PhoPQ pathway, which potentiates the evolution of resistance mutations and lipid A modifications that do not occur without Mg[2+] depletion. However, the PhoPQ pathway is not required to maintain high colistin resistance in all cases. In most cases, the genetic and biochemical changes associated with these novel forms of colistin resistance also impair bacterial membrane integrity, leading to fitness costs. Our findings provide molecular insights into how nutritional competition drives a novel antibiotic resistance mechanism and its ensuing fitness tradeoffs.}, }
@article {pmid39464114, year = {2024}, author = {Bridge, J and Johnson, MJ and Kim, J and Wenthe, S and Krueger, J and Wick, B and Kluesner, M and Crane, AT and Bell, J and Skeate, JG and Moriarity, BS and Webber, BR}, title = {Efficient multiplex non-viral engineering and expansion of polyclonal γδ CAR-T cells for immunotherapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39464114}, issn = {2692-8205}, support = {R01 AI161017/AI/NIAID NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; U24 OD026641/OD/NIH HHS/United States ; R21 CA237789/CA/NCI NIH HHS/United States ; U54 CA232561/CA/NCI NIH HHS/United States ; R21 AI163731/AI/NIAID NIH HHS/United States ; P01 CA254849/CA/NCI NIH HHS/United States ; R01 AI146009/AI/NIAID NIH HHS/United States ; U54 CA268069/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, abstract = {Gamma delta (γδ) T cells are defined by their unique ability to recognize a limited repertoire of non-peptide, non-MHC-associated antigens on transformed and pathogen-infected cells. In addition to their lack of alloreactivity, γδ T cells exhibit properties distinct from other lymphocyte subsets, prompting significant interest in their development as an off-the-shelf cellular immunotherapeutic. However, their low abundance in circulation, heterogeneity, limited methods for ex vivo expansion, and under-developed methodologies for genetic modification have hindered basic study and clinical application of γδ T cells. Here, we implement a feeder-free, scalable approach for ex vivo manufacture of polyclonal, non-virally modified, gene edited chimeric antigen receptor (CAR)-γδ T cells in support of therapeutic application. Engineered CAR-γδ T cells demonstrate high function in vitro and and in vivo. Longitudinal in vivo pharmacokinetic profiling of adoptively transferred polyclonal CAR-γδ T cells uncover subset-specific responses to IL-15 cytokine armoring and multiplex base editing. Our results present a robust platform for genetic modification of polyclonal CAR-γδ T cells and present unique opportunities to further define synergy and the contribution of discrete, engineered CAR-γδ T cell subsets to therapeutic efficacy in vivo.}, }
@article {pmid39462857, year = {2024}, author = {Panch, SR and Vassallo, RR and Adams, S and Borge, DP and Gammon, R and Gandhi, MJ and Philogene, M and Sullivan, HC and Wu, Y and Kopko, P}, title = {Management of human leukocyte antigen-mediated platelet transfusion refractoriness: Brief synopsis and recent literature review.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.18036}, pmid = {39462857}, issn = {1537-2995}, }
@article {pmid39456570, year = {2024}, author = {Lim, SYT and Huo, J and Laszlo, GS and Cole, FM and Kehret, AR and Li, J and Lunn-Halbert, MC and Persicke, JL and Rupert, PB and Strong, RK and Walter, RB}, title = {Optimizing Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders.}, journal = {Cancers}, volume = {16}, number = {20}, pages = {}, pmid = {39456570}, issn = {2072-6694}, support = {R21-AI150566//National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Background/Objective: Current treatments for eosinophilic and mast cell disorders are often ineffective. One promising target to improve outcomes is sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8). As limitations, there are few Siglec-8 monoclonal antibodies (mAbs) available to date, and Siglec-8-directed treatments have so far primarily focused on unconjugated mAbs, which may be inadequate, especially against mast cells. Methods: Here, we used transgenic mice to raise a diverse panel of fully human mAbs that either recognize the V-set domain, membrane-distal C2-set domain, or membrane-proximal C2-set domain of full-length Siglec-8 as a basis for novel therapeutics. Results: All mAbs were efficiently internalized into Siglec-8-expressing cells, suggesting their potential to deliver cytotoxic payloads. Tool T cell-engaging bispecific antibodies (BiAbs) and chimeric antigen receptor (CAR)-modified natural killer (NK) cells using single-chain variable fragments from Siglec-8 mAbs showed highly potent cytolytic activity against Siglec-8-positive cells even in cases of very low target antigen abundance, whereas they elicited no cytolytic activity against Siglec-8-negative target cells. Siglec-8[V-set]-directed T cell-engaging BiAbs and Siglec-8[V-set]-directed CAR-modified NK cells induced substantially greater cytotoxicity against cells expressing an artificial smaller Siglec-8 variant containing only the V-set domain than cells expressing full-length Siglec-8, consistent with the notion that targeting membrane-proximal epitopes enhances effector functions of Siglec-8 antibody-based therapeutics. Indeed, unconjugated Siglec-8[C2-set] mAbs, Siglec-8[C2-set]-directed T cell-engaging BiAbs, and Siglec-8[C2-set]-directed CAR-modified NK cells showed high antigen-specific cytolytic activity against Siglec-8-positive human cell lines and primary patient eosinophils. Conclusions: Together, these data demonstrate Siglec-8-directed immunotherapies can be highly potent, supporting their further development for eosinophilic and mast cell disorders.}, }
@article {pmid39454280, year = {2024}, author = {Pidala, JA and Kim, J and Kalos, D and Cutler, CS and DeFilipp, Z and Flowers, ME and Hamilton, BK and Chin, KK and Rotta, M and El Jurdi, N and Hamadani, M and Ahmed, G and Kitko, CL and Ponce, DM and Sung, AD and Tang, H and Farhadfar, N and Nemecek, ER and Pusic, I and Qayed, M and Rangarajan, HG and Hogan, WJ and Etra, AM and Jaglowski, SM}, title = {Ibrutinib for therapy of steroid-refractory chronic graft vs. host disease: A multicenter real-world analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014374}, pmid = {39454280}, issn = {2473-9537}, abstract = {To examine activity of ibrutinib in steroid-refractory chronic GVHD (SR-cGVHD) after FDA approval, we conducted a multicenter retrospective study. Data were standardly collected (N=270 from 19 centers). Involved organs included skin (75%), eye (61%), mouth (54%), joint/fascia (47%), GI (26%), lung (27%), liver (19%), genital (7%), other (4.4%). NIH severity was mild in 5.7%, moderate 42%, severe 53%. 39% had overlap subtype. KPS was ≥ 80% in 72%. Median prednisone (mg/kg) was 0.21 (0-2.27). Ibrutinib was started at median of 18.2 months after cGVHD onset and in earlier lines of therapy (2nd line: 26%, 3rd: 30%, 4th: 21%, 5th: 9.6%, 6th: 10%, 7th or higher: 1.2%)). Among evaluable subjects, the 6 month NIH overall response rate (CR/PR) was 45% (PR 42%, CR 3%). Median duration of response was 15 months (range 1-46). Liver involvement had association with 6 month ORR (multivariate (MVA) OR 5.49 (95% CI 2.3-14.2, p <0.001). Best overall response was 56%, with most (86%) achieving by 1-3 months. With median follow up for survivors of 30.5 months, FFS was 59% (53-65%) at 6 months and 41% (36-48%) at 12 months. On MVA, increased age (HR 1.01, 95% CI 1.0-1.02, p=0.033), higher baseline prednisone (HR 1.92, 1.09-3.38, p=0.032), and lung involvement (HR 1.58, 1.1-2.28, p=0.016) had worse FFS. Ibrutinib discontinuation was most commonly due to progressive cGVHD (44%) or toxicity (42%). These data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with discontinuation.}, }
@article {pmid39454232, year = {2024}, author = {, }, title = {Global, regional, and national burden of injuries, and burden attributable to injuries risk factors, 1990 to 2019: results from the Global Burden of Disease study 2019.}, journal = {Public health}, volume = {237}, number = {}, pages = {212-231}, doi = {10.1016/j.puhe.2024.06.011}, pmid = {39454232}, issn = {1476-5616}, abstract = {OBJECTIVES: In this study, the trends and current situation of the injury burden as well as attributable burden to injury risk factors at global, regional, and national levels based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 are presented.
STUDY DESIGN: To assess the attributable burden of injury risk factors, the data of interest on data sources were retrieved from the Global Health Data Exchange (GHDx) and analyzed.
METHODS: Cause-specific death from injuries was estimated using the Cause of Death Ensemble model in the GBD 2019. The burden attributable to each injury risk factor was incorporated in the population attributable fraction to estimate the total attributable deaths and disability-adjusted life years. The Socio-demographic Index (SDI) was used to evaluate countries' developmental status.
RESULTS: Globally, there were 713.9 million (95% uncertainty interval [UI]: 663.8 to 766.9) injuries incidence and 4.3 million (UI: 3.9 to 4.6) deaths caused by injuries in 2019. There was an inverse relationship between age-standardized disability-adjusted life year rate and SDI quintiles in 2019. Overall, low bone mineral density was the leading risk factor of injury deaths in 2019, with a contribution of 10.5% (UI: 9.0 to 11.6) of total injuries and age-standardized deaths, followed by occupational risks (7.0% [UI: 6.3-7.9]) and alcohol use (6.8% [UI: 5.2 to 8.5]).
CONCLUSION: Various risks were responsible for the imposed burden of injuries. This study highlighted the small but persistent share of injuries in the global burden of diseases and injuries to provide beneficial data to produce proper policies to reach an effective global injury prevention plan.}, }
@article {pmid39454203, year = {2024}, author = {Farhadfar, N and Lee, SJ}, title = {Reply to Letter to Editor by Fingrut, et al.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014712}, pmid = {39454203}, issn = {2473-9537}, }
@article {pmid39454125, year = {2024}, author = {Mosher, CE and Lee, S and Addington, EL and Park, S and Lewson, AB and Snyder, S and Hirsh, AT and Bricker, JB and Miller, KD and Ballinger, TJ and Schneider, BP and Storniolo, AM and Newton, EV and Champion, VL and Johns, SA}, title = {Randomized Controlled Trial of Acceptance and Commitment Therapy for Fatigue Interference With Functioning in Metastatic Breast Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2400965}, doi = {10.1200/JCO.24.00965}, pmid = {39454125}, issn = {1527-7755}, abstract = {PURPOSE: Fatigue is a highly prevalent and disabling symptom for patients with metastatic breast cancer (MBC). Evidence-based interventions for managing fatigue in advanced cancer populations are lacking. This phase II randomized controlled trial tested the effect of acceptance and commitment therapy (ACT) on fatigue interference with functioning in patients with MBC.
METHODS: Eligible patients were women with stage IV breast cancer who had moderate to severe fatigue interference. Patients completed a baseline assessment that included self-report measures of fatigue interference with activities, mood, and cognition (primary outcome) and sleep interference with functioning, engagement in daily activities, and quality of life (QOL; secondary outcomes). Then patients were randomly assigned to six weekly telephone-delivered sessions of either ACT (n = 116) or education/support (n = 120). Follow-up assessments occurred at 2 weeks, 3 months, and 6 months postintervention (means, 9.69, 20.51, and 33.59 weeks postbaseline, respectively).
RESULTS: Linear mixed model analyses showed that compared with patients in the education/support condition, patients in the ACT condition reported significantly less fatigue interference (P = .018). These results were significant at 2 weeks and 6 months postintervention. ACT's effect on sleep interference was not statistically significant after the Sidak adjustment for multiple comparisons (P = .037). ACT patients showed a steady decline in sleep interference, a trend that was not found for education/support patients. Engagement in daily activities and QOL did not significantly differ between study groups, except for functional QOL (P = .006). Compared with education/support patients, ACT patients showed significantly better functional QOL at 2 weeks and 6 months postintervention.
CONCLUSION: Results suggest that a brief, telephone-delivered ACT intervention can reduce fatigue interference with functioning in patients with MBC.}, }
@article {pmid39453463, year = {2024}, author = {Collienne, L and Barker, M and Suchard, MA and Matsen Iv, FA}, title = {Phylogenetic tree instability after taxon addition: empirical frequency, predictability, and consequences for online inference.}, journal = {Systematic biology}, volume = {}, number = {}, pages = {}, doi = {10.1093/sysbio/syae059}, pmid = {39453463}, issn = {1076-836X}, abstract = {Online phylogenetic inference methods add sequentially arriving sequences to an inferred phylogeny without the need to recompute the entire tree from scratch. Some online method implementations exist already, but there remains concern that additional sequences may change the topological relationship among the original set of taxa. We call such a change in tree topology a lack of stability for the inferred tree. In this paper, we analyze the stability of single taxon addition in a Maximum Likelihood framework across 1, 000 empirical datasets. We find that instability occurs in almost 90% of our examples, although observed topological differences do not always reach significance under the AU-test. Changes in tree topology after addition of a taxon rarely occur close to its attachment location, and are more frequently observed in more distant tree locations carrying low bootstrap support. To investigate whether instability is predictable, we hypothesize sources of instability and design summary statistics addressing these hypotheses. Using these summary statistics as input features for machine learning under random forests, we are able to predict instability and can identify the most influential features. In summary, it does not appear that a strict insertion-only online inference method will deliver globally optimal trees, although relaxing insertion strictness by allowing for a small number of final tree rearrangements or accepting slightly suboptimal solutions appears feasible.}, }
@article {pmid39453271, year = {2024}, author = {Shaik, F and Uldrick, TS and Mazinu, M and Gwebushe, N and Mosam, A}, title = {Early Changes in Health-Related Quality of Life as a Biomarker of Survival in African Patients with HIV-Associated Kaposi Sarcoma.}, journal = {Tropical medicine and infectious disease}, volume = {9}, number = {10}, pages = {}, pmid = {39453271}, issn = {2414-6366}, support = {SELF-INITIATED RESEARCH (SIR) GRANT//South African Medical Research Council/ ; }, abstract = {Sub-Saharan Africa bears the largest public health burden of Kaposi sarcoma (KS), a leading cause of cancer mortality. Quality of life (QOL) assessments in cancer patients can provide information on prognosis beyond traditional biomarkers or biological measures. The prognostic value of QOL measures in patients with HIV-KS was evaluated. Prognostic associations of baseline QOL scores (by quartiles or thresholds for clinical importance) and changes in QOL scores (using minimum important difference) over the first 3 months of therapy were evaluated in 112 participants with HIV-KS randomised to receive ART, with or without chemotherapy. Cox's regression analysis assessed the prognostic contribution of QOL scores from the EORTC QLQ-C30 questionnaire. Survival curves were generated using the Kaplan-Meier method. Baseline QOL scores did not predict overall survival. The change in the 3-month QOL scores for the global health scale, fatigue, and pain domains was prognostic; the hazard ratios were 3.88 (95% CI 1.32-11.38, p = 0.01), 3.72 (95% CI 1.61-8.62, p = 0.00) and 5.96 (95% CI 2.46-14.43, p = 0.00), respectively. QOL assessments can provide useful prognostic information in patients with HIV-KS. Patients lacking meaningful improvement early into treatment represent a population at high risk of death.}, }
@article {pmid39450393, year = {2024}, author = {Sanchez, E and Krantz, EM and Escobar, ZK and Tverdek, F and Rosen, EA and Oshima, MU and Carpenter, PA and Pergam, SA and Liu, C}, title = {Epidemiology and Outcomes of Recurrent C Difficile Infection Among Hematopoietic Cell Transplant Recipients: A Single-center, Retrospective 10-year Study.}, journal = {Open forum infectious diseases}, volume = {11}, number = {10}, pages = {ofae570}, pmid = {39450393}, issn = {2328-8957}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: There are limited data on the contemporary epidemiology of recurrent Clostridioides difficile infection (CDI) among hematopoietic cell transplant (HCT) recipients. We aimed to determine the incidence, risk factors, and outcomes for recurrent CDI among HCT recipients.
METHODS: We conducted a retrospective study of adult HCT recipients between 2012 and 2021 diagnosed with index CDI between HCT day -7 and +100. Recurrent CDI was defined as new symptoms and a positive test within 12 weeks after treatment for index CDI. Cox proportional hazards models were used to investigate associations between prespecified variables (age, neutropenia, exposure to antibiotics with antianaerobic coverage, cytomegalovirus viremia/disease, and metronidazole monotherapy) and recurrent infection, presented as hazard ratios with 95% confidence intervals (CI).
RESULTS: Of 3479 HCT recipients, 416 (12%) had index CDI and were treated with oral vancomycin (31%), metronidazole (41%), oral vancomycin and metronidazole (29%). Of 381 patients eligible for recurrent CDI analysis, 35 had recurrent infection; cumulative incidence was 10% (95% CI, 7-13) at 12 weeks. In the 14 days after recurrence, 2/25 (8%) patients required hospital admission; none died within 30 days. Metronidazole monotherapy for treatment of index CDI was associated with an increased rate of recurrence (adjusted hazard ratio, 2.0; 95% CI, 1.0-4.0; P = .048).
CONCLUSIONS: Recurrent CDI occurred in 10% of HCT recipients in the early posttransplant period and was associated with use of metronidazole. Further study is needed to characterize risk factors for recurrent CDI among HCT recipients to guide use of agents aimed at preventing recurrence.}, }
@article {pmid39449055, year = {2024}, author = {Behera, S and Belyeu, JR and Chen, X and Paulin, LF and Nguyen, NQH and Newman, E and Mahmoud, M and Menon, VK and Qi, Q and Joshi, P and Marcovina, S and Rossi, M and Roller, E and Han, J and Onuchic, V and Avery, CL and Ballantyne, CM and Rodriguez, CJ and Kaplan, RC and Muzny, DM and Metcalf, GA and Gibbs, RA and Yu, B and Boerwinkle, E and Eberle, MA and Sedlazeck, FJ}, title = {Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk.}, journal = {BMC medical genomics}, volume = {17}, number = {1}, pages = {255}, pmid = {39449055}, issn = {1755-8794}, mesh = {Humans ; *Cardiovascular Diseases/genetics ; *Alleles ; *Lipoprotein(a)/genetics/blood ; DNA Copy Number Variations ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; }, abstract = {The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.}, }
@article {pmid39448999, year = {2024}, author = {Thuo, N and Bardon, AR and Mogere, P and Kiptinness, C and Casmir, E and Wairimu, N and Owidi, E and Okello, P and Mugo, NR and Baeten, JM and Ngure, K and Ortblad, KF}, title = {Acceptability of six-monthly PrEP dispensing supported with interim HIV self-testing to simplify PrEP delivery in Kenya: findings from qualitative research.}, journal = {BMC health services research}, volume = {24}, number = {1}, pages = {1281}, pmid = {39448999}, issn = {1472-6963}, support = {R00 MH121166/MH/NIMH NIH HHS/United States ; R01 MH113572/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Kenya ; *Pre-Exposure Prophylaxis/methods ; Female ; Male ; *HIV Infections/prevention & control ; Adult ; *Qualitative Research ; *Self-Testing ; *Patient Acceptance of Health Care/statistics & numerical data ; Anti-HIV Agents/therapeutic use/administration & dosage ; Young Adult ; HIV Testing/methods ; Interviews as Topic ; }, abstract = {BACKGROUND: In Africa, dispensing oral HIV pre-exposure prophylaxis (PrEP) within already strained public health facilities has led to prolonged waiting periods and suboptimal experiences for clients. We sought to explore the acceptability of dispensing PrEP semiannually with interim HIV self-testing (HIVST) versus quarterly PrEP dispensing with clinic-based HIV testing to optimize clinic-delivered PrEP services.
METHODS: We conducted a qualitative study within a non-inferiority individual-level randomized controlled trial testing the effect of six-monthly PrEP dispensing with HIVST compared to the standard-of-care three-monthly PrEP dispensing on PrEP clinical outcomes in Kenya (ClinicalTrials.gov: NCT03593629). Eligible participants were ≥ 18 years, refilling PrEP for the first time, and either in an HIV serodifferent relationship (men and women) or singly enrolled (women only). A subset of participants in the intervention group completed serial in-depth interviews (IDIs) at enrollment, six months, and 12 months. We utilized stratified purposive sampling to ensure representation across participant groups. We analyzed our qualitative data thematically using a combination of inductive and deductive approaches, the latter guided by the Theoretical Framework of Acceptability (TFA).
RESULTS: Between May 2018 and June 2021, we conducted 120 serial IDIs with 55 participants; 64% (35/55) were in a serodifferent relationship, 64% (35/55) were women, and the median age was 32 years (IQR 27-40). Overall, participants found this novel PrEP delivery model highly acceptable; it was well-liked, private (TFA construct: affective attitude), and less burdensome (TFA construct: burden) compared to standard PrEP delivery. Additionally, participants were confident in their ability to participate in the intervention (TFA construct: self-efficacy). Some participants, however, highlighted model disadvantages, including fewer opportunities for in-person counseling and potentially less accurate HIV testing (TFA construct: opportunity costs). Ultimately, most participants reported that the intervention allowed them to achieve their HIV prevention goals (TFA construct: perceived effectiveness) and that their confidence in at-home HIVST and PrEP continuation increased following each semiannual clinic visit.
CONCLUSIONS: Semiannual PrEP clinic visits supported with six-monthly drug dispensing and interim HIVST was acceptable among PrEP users who experienced the intervention in Kenya. More comprehensive pre-intervention counseling and training on HIVST may help alleviate the client concerns presented, which were often resolved over time with intervention experience.}, }
@article {pmid39447443, year = {2024}, author = {Ronsley, R and Cole, B and Ketterl, T and Wright, J and Ermoian, R and Hoffman, LM and Margol, AS and Leary, SES}, title = {Pediatric Central Nervous System Embryonal Tumors: Presentation, Diagnosis, Therapeutic Strategies, and Survivorship-A Review.}, journal = {Pediatric neurology}, volume = {161}, number = {}, pages = {237-246}, doi = {10.1016/j.pediatrneurol.2024.09.031}, pmid = {39447443}, issn = {1873-5150}, abstract = {Central nervous system (CNS) embryonal tumors represent a diverse group of neoplasms and have a peak incidence in early childhood. These tumors can be located anywhere within the CNS, and presenting symptoms typically represent tumor location. These tumors display distinctive findings on neuroimaging and are staged using magnetic resonance imaging of the brain and spine as well as evaluation of cerebrospinal fluid. Diagnosis is made based on an integrated analysis of histologic and molecular features via tissue sampling. Risk stratification is based on integration of clinical staging and extent of resection with histologic and molecular risk factors. The therapeutic approach for these tumors is multimodal and includes surgery, chemotherapy, and radiation, tailored to the individual patient factors (including age) and specific tumor type. Comprehensive supportive care including management of nausea, nutrition support, pain, fertility preservation, and mitigation of therapy-related morbidity (including hearing protection) is imperative through treatment of CNS embryonal tumors. Despite advances in therapy and supportive care, the long-term consequences of current treatment strategies are substantial. Integration of less toxic, molecularly targeted therapies and a comprehensive, multidisciplinary approach to survivorship care are essential to improving survival and the overall quality of life for survivors.}, }
@article {pmid39447094, year = {2024}, author = {Sehn, LH and Bartlett, NL and Matasar, MJ and Schuster, SJ and Assouline, SE and Giri, P and Kuruvilla, J and Shadman, M and Cheah, CY and Dietrich, S and Fay, K and Ku, M and Nastoupil, LJ and Wei, MC and Yin, S and To, I and Kaufman, D and Kwan, A and Penuel, E and Bolen, CR and Budde, LE}, title = {Long-term 3-year follow-up of mosunetuzumab in relapsed or refractory follicular lymphoma after ≥2 prior therapies.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025454}, pmid = {39447094}, issn = {1528-0020}, abstract = {Mosunetuzumab, a CD20xCD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate (ORR) were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7-not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of complete response was not reached (NR) (95% CI, 33.0-NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE-NE). Median progression-free survival was 24.0 months (95% CI, 12.0-NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) following 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or Grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe and effective treatment for patients with R/R FL, including those with high-risk disease. Trial registration: www.clinicaltrials.gov (NCT02500407).}, }
@article {pmid39447043, year = {2024}, author = {Mcdougall, JA and Adler Jaffe, S and Jacobson, K and Shaver, TL and Wilson, JLF and Baca, K and Boyce, T and Tawfik, B and Page-Reeves, J}, title = {Randomized pilot trial of an unconditional cash transfer intervention to address food insecurity in oncology.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkae107}, pmid = {39447043}, issn = {2515-5091}, abstract = {Screening for food insecurity and other social determinants of health is being integrated into oncology practice. We performed a pilot randomized trial to investigate whether an unconditional cash transfer (UCT) could be used to address food insecurity among female breast and gynecologic cancer survivors. Food insecure cancer survivors completed a baseline survey and were randomized to receive $100/month for three months (UCT) or usual care (UC). Participants (n = 14) completed a follow-up survey after 3-months and we compared changes in health-related quality of life, indicators of food insecurity, diet quality, and whether a participant had to forgo, delay, or make changes to medical care because of cost. The UCT was associated with higher physical health scores, fewer indicators of food insecurity, better diet quality, and a lower likelihood of forgoing medical care than those who received UC. Our results suggest that UCTs can improve outcomes for food insecure cancer survivors.}, }
@article {pmid39446892, year = {2024}, author = {Schaefer, R and Donaldson, L and Leus, M and Osakwe, CE and Chimukangara, B and Dalal, S and Duerr, A and Gao, F and Glidden, DV and Grinsztejn, B and Justman, J and Kumwenda, G and Laeyendecker, O and Lee, HY and Maldarelli, F and Mayer, KH and Murray, J and Parekh, BS and Rice, B and Robertson, MN and Saito, S and Vannappagari, V and Warren, M and Zeballos, D and Zinserling, J and Miller, V}, title = {Promising results of HIV prevention trials highlight the benefits of collaboration in global health: The perspective of the Forum HIV Recency Assay Working Group.}, journal = {PLOS global public health}, volume = {4}, number = {10}, pages = {e0003878}, pmid = {39446892}, issn = {2767-3375}, }
@article {pmid39446266, year = {2024}, author = {Gichane, MW and Velloza, J and Hosek, S and Beauchamp, G and Anderson, P and Delany-Moretlwe, S and Celum, C and , }, title = {Hoping to Adhere? Examining the Relationship Between Hope and Pre-exposure Prophylaxis Willingness, Adherence, and Persistence Among Young Women in South Africa and Zimbabwe (HPTN 082).}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {39446266}, issn = {1573-3254}, support = {UM1AI068619//National Institute of Allergy and Infectious Diseases/ ; UM1AI068617//National Institute of Allergy and Infectious Diseases/ ; UM1AI068613//National Institute of Allergy and Infectious Diseases/ ; K01MH134775/MH/NIMH NIH HHS/United States ; }, abstract = {Hope is a powerful psychological construct which is linked to positive health. Greater hope is associated with improved antiretroviral therapy adherence; however, less is known about the impact of hope on oral pre-exposure prophylaxis (PrEP) outcomes. HIV Prevention Trials Network 082, was an open-label PrEP study among young women (ages 16-25) in South Africa and Zimbabwe. Hope was measured at baseline and follow-up using a subset of the Hope for the Future Scale (score range 6-24) and PrEP willingness was measured using a subscale of the HIV Prevention Readiness Measure (score range 6-30). Intracellular tenofovir-diphosphate (TFV-DP) concentrations were obtained from dried blood spot samples at weeks 13, 26, and 52; high PrEP adherence was defined as TFV-DP concentrations ≥ 700 fmol/punch. Persistence was defined as TFV-DP > 16 fmol/punch at weeks 26 and 52. Linear regression and generalized estimating equations were used to assess the relationship between hope and PrEP willingness, adherence, and persistence. The median age of participants (n = 432) was 21 years (interquartile range [IQR]: 19-22). The mean hope score at baseline was 21.0 (SD = 3.4). Although hope was positively associated with PrEP willingness (β = 0.22, 95% CI 0.15, 0.37), it was not associated with high PrEP adherence (aRR = 1.00, 95% CI 0.96, 1.05), or persistence at follow-up (aRR = 1.02, 95% CI 0.99, 1.05). While cultivating hope may be an important strategy in building willingness to take oral PrEP, it may not be enough to sustain PrEP adherence or persistence.}, }
@article {pmid39445720, year = {2024}, author = {Compton, ZT and Mellon, W and Harris, VK and Rupp, S and Mallo, D and Kapsetaki, SE and Wilmot, M and Kennington, R and Noble, K and Baciu, C and Ramirez, LN and Peraza, A and Martins, B and Sudhakar, S and Aksoy, S and Furukawa, G and Vincze, O and Giraudeau, M and Duke, EG and Spiro, S and Flach, E and Davidson, H and Li, CI and Zehnder, A and Graham, TA and Troan, BV and Harrison, TM and Tollis, M and Schiffman, JD and Aktipis, CA and Abegglen, LM and Maley, CC and Boddy, AM}, title = {Cancer Prevalence across Vertebrates.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {OF1-OF18}, doi = {10.1158/2159-8290.CD-24-0573}, pmid = {39445720}, issn = {2159-8290}, support = {U54 CA217376/CA/NCI NIH HHS/United States ; T32 CA272303/CA/NCI NIH HHS/United States ; BC132057//Congressionally Directed Medical Research Programs (CDMRP)/ ; ADHS18-198847//Arizona Biomedical Research Commission (ABRC)/ ; //Hyundai Hope On Wheels (Hope On Wheels)/ ; COVER ANR-23-CE02-0019//Agence Nationale de la Recherche (ANR)/ ; OTKA K143421//Agence Nationale de la Recherche (ANR)/ ; }, abstract = {Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.}, }
@article {pmid39442617, year = {2024}, author = {Hortobagyi, GN and Lacko, A and Sohn, J and Cruz, F and Borrego, MR and Manikhas, A and Park, YH and Stroyakovskiy, D and Yardley, DA and Huang, CS and Fasching, PA and Crown, J and Bardia, A and Chia, S and Im, SA and Martin, M and Loi, S and Xu, B and Hurvitz, S and Barrios, C and Untch, M and Moroose, R and Visco, F and Parnizari, F and Zarate, JP and Li, Z and Waters, S and Chakravartty, A and Slamon, D}, title = {A phase III trial of adjuvant ribociclib plus endocrine therapy vs endocrine therapy alone in patients with HR+/HER2- early breast cancer: final invasive disease-free survival results from the NATALEE trial.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2024.10.015}, pmid = {39442617}, issn = {1569-8041}, abstract = {BACKGROUND: NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus NSAI compared with a nonsteroidal aromatase inhibitor (NSAI) alone in a broad population of patients with HR+/HER2- early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS).
PATIENTS AND METHODS: Premenopausal/postmenopausal women and men were randomized 1:1 to ribociclib (n=2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n=2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS (DDFS), and overall survival (OS). This final iDFS analysis was planned after ≈500 events.
RESULTS: At data cutoff (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI vs NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone (Hazard Ratio 0.749, 95% Confidence Interval [CI] 0.628-0.892; P=0.0012). The 3-year iDFS rates were 90.7% (95% CI 89.3%-91.8%) vs 87.6% (95% CI 86.1%-88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (+/-). DDFS and RFS favored ribociclib plus NSAI. OS data were immature. No new safety signals were observed.
CONCLUSIONS: With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.}, }
@article {pmid39442371, year = {2024}, author = {Yonemori, K and Boni, V and Min, KG and Meniawy, TM and Lombard, J and Kaufman, PA and Richardson, DL and Bender, L and Okera, M and Matsumoto, K and Giridhar, KV and García-Sáenz, JA and Prenen, H and de Speville Uribe, BD and Dizon, DS and Garcia-Corbacho, J and Van Nieuwenhuysen, E and Li, Y and Estrem, ST and Nguyen, B and Bacchion, F and Ismail-Khan, R and Jhaveri, K and Banda, K}, title = {Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, in recurrent/advanced ER-positive endometrioid endometrial cancer: Results from the phase 1a/1b EMBER study.}, journal = {Gynecologic oncology}, volume = {191}, number = {}, pages = {172-181}, doi = {10.1016/j.ygyno.2024.10.006}, pmid = {39442371}, issn = {1095-6859}, abstract = {OBJECTIVE: Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) target inhibition. EMBER is a phase 1a/b trial of imlunestrant, as monotherapy and combined with targeted therapy, in patients with ER+ advanced breast cancer or endometrioid endometrial cancer (EEC). This report focuses on patients with ER+ EEC.
METHODS: EMBER used an i3 + 3 dose-escalation design to determine the recommended phase 2 dose (RP2D) followed by dose-expansion cohorts (1:1 randomization): imlunestrant monotherapy and imlunestrant plus abemaciclib (150 mg twice daily). Eligible patients had measurable disease and progression or recurrence after platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor was not allowed. Secondary endpoints included safety, pharmacokinetics and antitumor activity.
RESULTS: In total, 72 patients with a median of 2 prior anticancer therapies were treated. Among the 39 patients who received imlunestrant (400 mg [RP2D], n = 33; 800 mg, n = 6), the most common treatment-emergent adverse events (TEAEs) were grade 1-2 nausea (35.9 %), diarrhea (25.6 %), urinary tract infection (25.6 %), and abdominal pain (20.5 %). Overall response rate (ORR) was 10.3 %, clinical benefit rate (CBR) was 33.3 %, and median progression-free survival (mPFS) was 3.8 months (95 % CI, 1.8-6.7). Among the 33 patients who received imlunestrant (400 mg [RP2D], n = 29; 800 mg, n = 4) plus abemaciclib, the most common TEAEs were diarrhea (87.9 %), nausea (66.7 %), fatigue (48.5 %), and anemia (45.5 %). ORR was 18.2 %, CBR was 42.4 %, and mPFS was 6.8 months (95 % CI, 2.1-12).
CONCLUSION: Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC.}, }
@article {pmid39441907, year = {2024}, author = {Oshima, MU and Higgins, J and Jenkins, I and Randolph, T and Smith, T and Valentine, C and Salk, J and Yeung, C and Beppu, L and Campbell, J and Carpenter, PA and Lee, SJ and Flowers, ME and Radich, JP and Storb, R}, title = {Characterization of clonal dynamics using duplex sequencing in donor-recipient pairs decades after hematopoietic cell transplantation.}, journal = {Science translational medicine}, volume = {16}, number = {770}, pages = {eado5108}, doi = {10.1126/scitranslmed.ado5108}, pmid = {39441907}, issn = {1946-6242}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *Tissue Donors ; Adult ; Middle Aged ; Male ; Mutation/genetics ; Female ; Young Adult ; Child ; Clonal Hematopoiesis/genetics ; Transplant Recipients ; Adolescent ; }, abstract = {After allogeneic hematopoietic cell transplantation (HCT), a very small number of donor stem cells reconstitute the recipient hematopoietic system, whereas the donor is left with a near-normal pool of stem cells. We hypothesized that the increased replicative stress on transplanted donor cells in the recipient could lead to the disproportionate proliferation of clonal hematopoiesis (CH) variants. We obtained blood samples from 16 related donor-recipient pairs at a median of 33.8 years (range: 6.6 to 45.7) after HCT, including the longest surviving HCT recipients in the world. For 11 of 16 pairs, a donor sample from the time of HCT was available for comparison. We performed ultrasensitive duplex sequencing of genes recurrently mutated in myeloid malignancies and CH, as well as a set of functionally neutral genomic regions representative of human genomic content at large. CH variants were observed in all donors, even those as young as 12 years old. Where donor pre-HCT sample was available, the average mutation rate in donors compared to recipients post-HCT was similar (2.0% versus 2.6% per year, respectively) within genes recurrently mutated in myeloid malignancies. Twenty-two (5.6%) of the 393 variants shared between paired donors and recipients post-HCT showed ≥10-fold higher variant allele frequency (VAF) in the recipient. A longer time since HCT was positively associated with the expansion of shared variant VAFs in the recipient. In conclusion, even decades after HCT, there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system.}, }
@article {pmid39441819, year = {2024}, author = {Owens, L and Brahme, O and Gulati, R and Etzioni, R}, title = {Trends in Age and Prostate-Specific Antigen at Prostate Cancer Diagnosis between 2010 and 2019.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkae106}, pmid = {39441819}, issn = {2515-5091}, abstract = {Recent studies have shown that de novo metastatic prostate cancer incidence in the U.S. increased from 2010 to 2019. Plausible explanations include delayed detection following recommendations against prostate cancer screening or upstaging associated with use of more sensitive imaging technologies. Using Surveillance, Epidemiology and End Results cases and controlling for aging of the population, we found the median age and prostate-specific antigen (PSA) level at prostate cancer diagnosis increased by 1.4 years of age (95% CI 1.3-1.5) and 1.4 ng/mL (95% CI 1.4-1.5) over this period, consistent with the delayed detection hypothesis. Racial differences were noted, with 75th percentiles of PSA at diagnosis increasing by 4.3 ng/mL (95% CI 3.7-4.8) over this time period for non-Hispanic Black men compared to 3.0 ng/mL (95% CI 2.8-3.2) for non-Hispanic White men. Overall, patient characteristics at diagnosis suggest that delayed detection contributed at least in part to increases in de novo metastatic disease.}, }
@article {pmid39439295, year = {2024}, author = {Colonne, CK and Kimble, EL and Turtle, CJ}, title = {Evolving strategies to overcome barriers in CAR-T cell therapy for acute myeloid leukemia.}, journal = {Expert review of hematology}, volume = {}, number = {}, pages = {1-22}, doi = {10.1080/17474086.2024.2420614}, pmid = {39439295}, issn = {1747-4094}, abstract = {INTRODUCTION: Acute myeloid leukemia (AML) is a complex and heterogeneous disease characterized by an aggressive clinical course and limited efficacious treatment options in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy is an investigational treatment strategy for R/R AML that has shown some promise. However, obstacles to successful CAR-T cell immunotherapy for AML remain.
AREAS COVERED: In analyses of clinical trials of CAR-T cell therapy for R/R AML, complete responses without measurable residual disease have been reported, but the durability of those responses remains unclear. Significant barriers to successful CAR-T cell therapy in AML include the scarcity of suitable tumor-target antigens (TTA), inherent T cell functional deficits, and the immunoinhibitory and hostile tumor microenvironment (TME). This review will focus on these barriers to successful CAR-T cell therapy in AML, and discuss scientific advancements and evolving strategies to overcome them.
EXPERT OPINION: Achieving durable remissions in R/R AML will likely require a multifaceted approach that integrates advancements in TTA selection, enhancement of the intrinsic quality of CAR-T cells, and development of strategies to overcome inhibitory mechanisms in the AML TME.}, }
@article {pmid39438074, year = {2024}, author = {McGillivray, E and Ashouri, K and Chatziioannou, E and Gallegos, JAO and Zarka, J and Kechter, J and Hwang, AS and Zhang, K and Barros, M and Yeh, J and Okazaki, I and Crocker, AB and Maeda, T and Park, SJ and Choi, J and Andreoli, M and Darwish, T and Savage, DJ and Kim, KB and Gupta, J and Shen, J and Shirai, K and Choi, A and Pai, L and de Lima Vazquez, V and Moser, J and Amaral, T and Hernandez Aya, LF and Lutzky, J and Najjar, YG and Costello, CM and Mangold, AR and Bhatia, S and Gibney, GT and Farma, JM and Daniels, GA and Sosman, J and Chandra, S and Mangla, A and Bollin, K and Abrão Possik, P and Robles Espinoza, CD and Ito, F and In, GK}, title = {Combined PD-1 and CTLA-4 Blockade in an International Cohort of Patients with Acral Lentiginous Melanoma.}, journal = {The British journal of dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1093/bjd/ljae401}, pmid = {39438074}, issn = {1365-2133}, abstract = {BACKGROUND: Combination immune checkpoint blockade targeting PD-1 and CTLA-4 leads to high response rates and improved survival in advanced cutaneous melanoma (CM). Less is known about the efficacy of this combination in acral lentiginous melanoma (ALM).
OBJECTIVES: To determine the efficacy of combination immune checkpoint blockade targeting PD-1 and CTLA-4 in a real-world, diverse population of ALM.
METHODS: This multi-institutional retrospective study analyzed patients with histologically confirmed ALM treated with the combination of PD-1 and CTLA-4 inhibitors between 2010-2022. The primary objective of the study was objective response rate (ORR) per RECIST criteria. The secondary objectives were progression-free survival (PFS) and overall survival (OS).
RESULTS: In total, 109 patients with advanced ALM treated with combined PD-1 and CTLA-4 blockade in any line of treatment were included. The majority of patients had stage IV disease (n=81, 74.2%). The ORR for the entire cohort was 18.3% (95% CI 11.6-26.9%), with 9 (8.3%) complete responses (CR) and 11 (10.1%) partial responses (PR). An additional 22 patients (20.2%) had stable disease (SD), and the disease control rate (DCR) was 38.5%. The median PFS was 4.2 months [95% CI 3.25-5.62], while the median OS was 17 months [95% CI 12.4%-23.1%]. A total of 95 patients (87.2%) had a treatment-related adverse event, with 40.4% (n=44/109) experiencing at least one grade 3 or 4 toxicity. Elevated LDH (p=.04), 2+ lines of prior therapy (p=.03), and Asian race/ethnicity (p=.04) were associated with worse OS, while Hispanic/Latino race/ethnicity was associated with better OS (p=.02).
CONCLUSIONS: Combination of PD-1 and CTLA-4 blockade is less effective for ALM, as compared to CM, despite similar toxicity. Asian patients, in particular, appear to derive lower benefit from this regimen. Novel treatment approaches are needed for this rare melanoma subtype.}, }
@article {pmid39437647, year = {2024}, author = {Wickline, MM and Carpenter, PA and Harris, JR and Iribarren, SJ and Reding, KW and Pike, KC and Lee, SJ and Salit, RB and Oshima, MU and Vo, PT and Berry, DL}, title = {Vaccine hesitancy and routine revaccination among adult HCT survivors in the United States: A convergent mixed methods analysis.}, journal = {Vaccine}, volume = {42}, number = {26}, pages = {126374}, doi = {10.1016/j.vaccine.2024.126374}, pmid = {39437647}, issn = {1873-2518}, abstract = {Revaccination to restore immunity to vaccine-preventable diseases (VPDs) is essential risk mitigation in the prevention of infectious morbidity and mortality after hematopoietic cell transplantation (HCT). However, revaccination rates have been shown to be insufficient and to what extent vaccine hesitancy contributes to survivors not becoming fully revaccinated is unknown. We performed a cross-sectional, mixed methods survey-based study to explore how vaccine hesitancy influences revaccination among US adult HCT survivors who were 2 to 8 years after transplant. Participants were asked to complete the Vaccination Confidence Scale (VCS) and open-ended survey items regarding vaccine confidence. The survey response rate was 30 %; among 332 respondents, vaccine confidence was high in 69 %, medium in 20 %, and low in 11 %. On multivariable analysis, four factors associated with high vaccine confidence were: predominantly Democrat zip codes (per 2020 election results), ability to pay for revaccination out of pocket, receipt of pre-HCT adult vaccines, and receipt of COVID-19 vaccines. From 189 participants who also answered open-ended items, 14 themes associated with vaccine confidence were identified and collapsed into 4 categories based on the VCS: Benefits, Harms, Trust, and Other. Merged analysis showed congruence between VCS scores and open-ended survey responses and created a narrative about the relative importance of the constructs when approaching revaccination by vaccine confidence level. These findings significantly expand our knowledge of how vaccine hesitancy influences revaccination uptake among US adult HCT survivors. Population-specific interventions to approach vaccine-hesitant survivors should be developed and tested.}, }
@article {pmid39436293, year = {2024}, author = {Partridge, SC and Xu, J}, title = {Cellular Characterization of Breast Cancer Using Microstructural Diffusion MRI.}, journal = {Radiology}, volume = {313}, number = {1}, pages = {e242268}, pmid = {39436293}, issn = {1527-1315}, support = {R01 CA190299/CA/NCI NIH HHS/United States ; R01 CA207290/CA/NCI NIH HHS/United States ; R01 CA269620/CA/NCI NIH HHS/United States ; R21 CA270731/CA/NCI NIH HHS/United States ; }, }
@article {pmid39433652, year = {2024}, author = {Adesina, OO and Jenkins, IC and Galvão, F and de Moura, AC and Fertrin, KY and Zemel, BS and Saad, STO}, title = {Alendronate preserves bone mineral density in adults with sickle cell disease and osteoporosis.}, journal = {Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA}, volume = {}, number = {}, pages = {}, pmid = {39433652}, issn = {1433-2965}, support = {5K23HL148310-02/HL/NHLBI NIH HHS/United States ; CSDA 2020095/DDCF/Doris Duke Charitable Foundation/United States ; }, abstract = {UNLABELLED: Low bone mineral density is highly prevalent in sickle cell disease (SCD); whether bisphosphonates can safely preserve or increase bone mass in SCD adults remains unknown. In this study, lumbar spine bone density remained stable with alendronate use, and treatment-related side effects were mostly mild and self-limited.
PURPOSE: To describe the effects of alendronate in adults with sickle cell disease (SCD) and osteoporosis.
METHODS: We reviewed retrospective clinical data from adults with SCD and osteoporosis treated with alendronate at a single center in Brazil (2009-2019). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck, and total hip. We analyzed BMD changes by alendronate treatment duration (months), stratified by sex, skeletal site, and SCD genotype.
RESULTS: Sixty-four SCD adults with osteoporosis (69% females, 73% HbSS, mean age ± standard deviation 42.4 ± 10.9 years) received alendronate for a median (interquartile range) of 48 (29, 73) months. Compared with males, females had significantly lower baseline BMD (g/cm[2]) at the femoral neck (0.72 vs 0.85, p = < 0.001) and total hip (0.79 vs 0.88, p = 0.009). The between-sex differences in BMD changes were insignificant. Mean lumbar spine BMD significantly changed by 0.0357 g/cm[2] (p = 0.028) in those on alendronate for > 5 years. Four adults (6.3%) reported mild therapy-related side effects. An atypical femoral diaphysis fracture, attributed to alendronate, was incidentally noted in a 37-year-old man on treatment for 4 years.
CONCLUSION: In this retrospective cohort of adults with SCD and osteoporosis on alendronate for a median of 48 months, we found no significant interactions between sex and changes in lumbar spine, femoral neck, or total hip BMD with alendronate. Lumbar spine BMD was stable in those on alendronate for < 5 years. Side effects of alendronate were mild, though one patient developed an atypical femoral fracture.}, }
@article {pmid39432443, year = {2024}, author = {Molstad, AJ and Cai, Y and Reiner, AP and Kooperberg, C and Sun, W and Hsu, L}, title = {Heterogeneity-aware integrative regression for ancestry-specific association studies.}, journal = {Biometrics}, volume = {80}, number = {4}, pages = {}, pmid = {39432443}, issn = {1541-0420}, support = {//WHI/ ; /HL/NHLBI NIH HHS/United States ; R01 HL145806/NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Polymorphism, Single Nucleotide ; *Quantitative Trait Loci ; Genome-Wide Association Study/statistics & numerical data ; Regression Analysis ; Likelihood Functions ; Black People/genetics/statistics & numerical data ; Proteome ; Computer Simulation ; Models, Statistical ; Biometry/methods ; }, abstract = {Ancestry-specific proteome-wide association studies (PWAS) based on genetically predicted protein expression can reveal complex disease etiology specific to certain ancestral groups. These studies require ancestry-specific models for protein expression as a function of SNP genotypes. In order to improve protein expression prediction in ancestral populations historically underrepresented in genomic studies, we propose a new penalized maximum likelihood estimator for fitting ancestry-specific joint protein quantitative trait loci models. Our estimator borrows information across ancestral groups, while simultaneously allowing for heterogeneous error variances and regression coefficients. We propose an alternative parameterization of our model that makes the objective function convex and the penalty scale invariant. To improve computational efficiency, we propose an approximate version of our method and study its theoretical properties. Our method provides a substantial improvement in protein expression prediction accuracy in individuals of African ancestry, and in a downstream PWAS analysis, leads to the discovery of multiple associations between protein expression and blood lipid traits in the African ancestry population.}, }
@article {pmid39431098, year = {2024}, author = {Rodarte, J and Baehr, C and Hicks, D and McGovern, M and Zhang, Y and Silva-Ortiz, P and Hannon, B and Duddu, S and Pancera, M and Pravetoni, M}, title = {Structure-Based Engineering of Monoclonal Antibodies for Improved Binding to Counteract the Effects of Fentanyl and Carfentanil.}, journal = {ACS omega}, volume = {9}, number = {41}, pages = {42506-42519}, pmid = {39431098}, issn = {2470-1343}, abstract = {The opioid overdose epidemic is a growing and evolving public health crisis fueled by the widespread presence of fentanyl and fentanyl analogues (F/FAs) in both street mixtures and counterfeit pills. To expand current treatment options, drug-targeting monoclonal antibodies (mAbs) offer a viable therapeutic for both pre- and postexposure clinical scenarios. This study reports the isolation, in vitro characterization, and in vivo efficacy of two murine mAb families targeting fentanyl, carfentanil, or both. Because humanization of the mAbs by CDR grafting negatively impacted affinity for both fentanyl and carfentanil, crystal structures of mAbs in complex with fentanyl or carfentanil were analyzed to identify key residues involved in ligand binding in murine versus humanized structures, and site-directed mutagenesis was used to verify their functional importance. The structural analysis identified a framework residue, Tyr36, present in the murine germline sequence of two mAbs, which was critical for binding to fentanyl and carfentanil. These studies emphasize the importance of structural considerations in mAb engineering to optimize mAbs targeting small molecules including opioids and other drugs of public health interest.}, }
@article {pmid39430319, year = {2024}, author = {Ye, L and Ryu, H and Granadier, D and Nguyen, LT and Simoni, Y and Dick, I and Firth, T and Rouse, E and Chiang, P and Lee, YCG and Robinson, BW and Creaney, J and Newell, EW and Redwood, AJ}, title = {Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma.}, journal = {Translational lung cancer research}, volume = {13}, number = {9}, pages = {2352-2372}, pmid = {39430319}, issn = {2218-6751}, abstract = {BACKGROUND: Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8[+] T cells include less differentiated stem-like exhausted T (Tex[stem]) cells and terminally exhausted T (Tex[term]) cells. Both subsets have been proposed as prognostic biomarkers in cancer patients. In this study, we retrospectively investigated their prognostic significance in patients with metastatic non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort.
METHODS: Pre-treatment malignant pleural effusions (PEs) from 43 NSCLC (41 non-squamous, 2 squamous) patients were analyzed by flow cytometry. The percentages of Tex[stem] and Tex[term] CD8 T cells were correlated with overall survival (OS) after adjusting for clinicopathological variables. Findings were validated using a mesothelioma cohort (n=49). Mass cytometry was performed on 16 pre-treatment PE samples from 5 mesothelioma and 3 NSCLC patients for T-cell phenotyping. Single-cell multi-omics analysis was performed on 4 pre-treatment PE samples from 2 NSCLC patients and 2 mesothelioma patients for analysis of the transcriptomic profiles, surface markers and T cell receptor (TCR) repertoire.
RESULTS: Higher frequency of Tex[stem] was associated with significantly increased OS [median 9.9 vs. 3.4 months, hazard ratio (HR) 0.36, 95% CI: 0.16-0.79, P=0.01]. The frequency of Tex[term] was not associated with OS. These findings were validated in the mesothelioma cohort (high vs. low Tex[stem], median OS 32.1 vs. 19.8 months, HR 0.31, 95% CI: 0.10-0.96, P=0.04). Detailed single-cell sequencing and mass cytometry profiling revealed that exhausted T cells from NSCLC expressed greater stem-likeness and less inhibitory markers than those from mesothelioma and that Tex[stem] cells also contained 'bystander' virus-specific T cells.
CONCLUSIONS: This study demonstrates that PE CD8 Tex[stem] cell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.}, }
@article {pmid39429723, year = {2024}, author = {Georgakopoulou, A and Li, C and Kiem, HP and Lieber, A}, title = {In vitro and in vivo expansion of CD33/HBG promoter-edited HSPCs with Mylotarg.}, journal = {Molecular therapy. Methods & clinical development}, volume = {32}, number = {4}, pages = {101343}, pmid = {39429723}, issn = {2329-0501}, abstract = {We developed an in vivo HSC gene therapy approach that consists of HSC mobilization and intravenous injection of HSC-tropic HDAd vectors. To achieve therapeutically relevant numbers of corrected cells, we incorporated in vivo expansion of transduced cells. We used an HDAd vector for a multiplex adenine base editing approach to (1) remove the region within CD33 that is recognized by gemtuzumab ozogamicin (GO) (Mylotarg), and (2) create therapeutic edits within the HBG1/2 promoters to reactivate γ-globin/HbF. In vitro studies with HDAd-transduced human CD34[+] cells showed editing of both targeted sites and a 2- to 3-fold GO-mediated expansion of edited erythroid/myeloid progenitors. After erythroid in vitro differentiation, up to 40% of erythrocytes were HbF positive. For in vivo studies, mice were transplanted with human CD34[+] cells. After engraftment, HSCs were mobilized with G-CSF/AMD3100 followed by an intravenous HDAd injection and GO-mediated in vivo selection. Two months later, editing in human cells within the bone marrow was significantly higher in GO-treated mice. The percentage of HbF[+] human erythroid cells was 2.5-fold greater compared with untreated mice. These data indicate that in vivo GO selection can increase edited erythroid cells.}, }
@article {pmid39428758, year = {2024}, author = {Minot, SS and Mayer-Blackwell, K and Fiore-Gartland, A and Johnson, A and Self, S and Bhatti, P and Yao, L and Liu, L and Sun, X and Jinfa, Y and Kublin, J}, title = {Species- and subspecies-level characterization of health-associated bacterial consortia that colonize the human gut during infancy.}, journal = {Gut microbes}, volume = {16}, number = {1}, pages = {2414975}, pmid = {39428758}, issn = {1949-0984}, support = {R01 AI127100/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; Infant ; *Feces/microbiology ; *Bacteria/classification/genetics/isolation & purification ; Male ; Female ; Metagenomics ; Microbial Consortia ; Metagenome ; Infant, Newborn ; Cohort Studies ; Cystic Fibrosis/microbiology ; }, abstract = {BACKGROUND: The human gut microbiome develops rapidly during infancy, a key window of development coinciding with the maturation of the adaptive immune system. However, little is known about the microbiome growth dynamics over the first few months of life and whether there are any generalizable patterns across human populations. We performed metagenomic sequencing on stool samples (n = 94) from a cohort of infants (n = 15) at monthly intervals in the first 6 months of life, augmenting our dataset with seven published studies for a total of 4,441 metagenomes from 1,162 infants.
RESULTS: Strain-level de novo analysis was used to identify 592 of the most abundant organisms in the infant gut microbiome. Previously unrecognized consortia were identified which exhibited highly correlated abundances across samples and were composed of diverse species spanning multiple genera. Analysis of a published cohort of infants with cystic fibrosis identified one such novel consortium of diverse Enterobacterales which was positively correlated with weight gain. While all studies showed an increased community stability during the first year of life, microbial dynamics varied widely in the first few months of life, both by study and by individual.
CONCLUSION: By augmenting published metagenomic datasets with data from a newly established cohort, we were able to identify novel groups of organisms that are correlated with measures of robust human development. We hypothesize that the presence of these groups may impact human health in aggregate in ways that individual species may not in isolation.}, }
@article {pmid39428129, year = {2024}, author = {Samorodnitsky, S and Wu, MC}, title = {Statistical analysis of multiple regions-of-interest in multiplexed spatial proteomics data.}, journal = {Briefings in bioinformatics}, volume = {25}, number = {6}, pages = {}, pmid = {39428129}, issn = {1477-4054}, support = {U10 CA180819/GF/NIH HHS/United States ; //Hope Foundation for Cancer Research/ ; }, mesh = {Humans ; *Proteomics/methods ; Neoplasms/metabolism/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism/pathology/genetics ; Triple Negative Breast Neoplasms/pathology/metabolism/genetics ; Colorectal Neoplasms/metabolism/pathology/genetics ; Lung Neoplasms/metabolism/pathology/genetics ; Data Interpretation, Statistical ; Algorithms ; }, abstract = {Multiplexed spatial proteomics reveals the spatial organization of cells in tumors, which is associated with important clinical outcomes such as survival and treatment response. This spatial organization is often summarized using spatial summary statistics, including Ripley's K and Besag's L. However, if multiple regions of the same tumor are imaged, it is unclear how to synthesize the relationship with a single patient-level endpoint. We evaluate extant approaches for accommodating multiple images within the context of associating summary statistics with outcomes. First, we consider averaging-based approaches wherein multiple summaries for a single sample are combined in a weighted mean. We then propose a novel class of ensemble testing approaches in which we simulate random weights used to aggregate summaries, test for an association with outcomes, and combine the $P$-values. We systematically evaluate the performance of these approaches via simulation and application to data from non-small cell lung cancer, colorectal cancer, and triple negative breast cancer. We find that the optimal strategy varies, but a simple weighted average of the summary statistics based on the number of cells in each image often offers the highest power and controls type I error effectively. When the size of the imaged regions varies, incorporating this variation into the weighted aggregation may yield additional power in cases where the varying size is informative. Ensemble testing (but not resampling) offered high power and type I error control across conditions in our simulated data sets.}, }
@article {pmid39424451, year = {2024}, author = {Li, T and Isautier, J and Lee, JM and Marinovich, ML and Houssami, N}, title = {Performance of Digital Breast Tomosynthesis Versus Digital Mammography in Women With a Family History of Breast Cancer: A Systematic Review.}, journal = {Clinical breast cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clbc.2024.09.013}, pmid = {39424451}, issn = {1938-0666}, abstract = {BACKGROUND: There is limited evidence on the performance of digital breast tomosynthesis (DBT) in populations at increased risk of breast cancer. Our objective was to systematically review evidence on the performance of DBT versus digital mammography (DM) in women with a family history of breast cancer (FHBC).
METHODS: We searched 5 databases (2011-January 2024) for studies comparing DBT and DM in women with a FHBC that reported any measure of cancer detection, recall, sensitivity and specificity. Findings were presented using a descriptive and narrative approach. Risk of bias was assessed using QUADAS-2/C.
RESULTS: Five (4 screening, 1 diagnostic) studies were included (total 3089 DBT, 3024 DM) with most (4/5) being prospective including 1 RCT. All studies were assessed as being at high risk of bias or applicability concern. Four screening studies reported recall rate (range: DBT: 2.7%-4.5%, DM: 2.8%-11.5%) with 3 reporting DBT had lower rates than DM. Cancer detection rates (CDR) were reported in the same studies (DBT: 5.1-11.6 per 1000, DM: 3.8-8.3); 3 reported higher CDR for DBT (vs. DM), and 1 reported same CDR for both. Compared with DM, higher values for sensitivity, specificity and PPV for DBT were reported in 2 studies.
CONCLUSION: This review provides early evidence that DBT may outperform DM for screening women with a FHBC. Our findings support further evaluation of DBT in this population. However, summarized findings were based on few studies and participants, and high-quality studies with improved methodology are needed to address biases identified in our review.}, }
@article {pmid39424273, year = {2024}, author = {Liese, AD and Julceus, EF and Brown, AD and Pihoker, C and Frongillo, EA and Sauder, KA and Malik, FS and Bellatorre, A and Reboussin, BA and Mendoza, JA}, title = {Reassessing the Burden of Food Insecurity in Youth and Young Adults With Youth-onset Diabetes: The Importance of Marginal Food Security.}, journal = {Canadian journal of diabetes}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jcjd.2024.10.006}, pmid = {39424273}, issn = {2352-3840}, abstract = {INTRODUCTION: Whereas marginal food insecurity has been recognized as important in Canadian food security policy, the category of marginal food security (MFS) is often ignored in US food security research.
METHODS: Prevalence of FI was estimated according to the conventional and an alternate classification of MFS with food insecurity among 938 youth and young adults (YYA) with youth-onset type 1 diabetes (T1D) and 156 with youth-onset of type 2 diabetes (T2D) from the SEARCH Food Security Cohort Study (2018-2021). Multivariable regression was used to estimate the association of MFS and conventionally defined food insecurity (FI) ascertained with diabetes-related outcomes, including acute diabetes complications, health care utilization, and diabetes self-management among YYA with T1D.
RESULTS: MFS affected 10% of participants with T1D diabetes and 20% of participants with T2D. Classifying MFS with FI increased FI prevalence from 18.0% to 27.8% in participants with T1D and 34.6% to 55.1% in participants with T2D. Compared to T1D with high food security, YYA with T1D who were FI had higher odds hypoglycemia (2.1, 95% CI 1.2 to 3.6) and ketoacidosis (1.6, 95% CI 1.0 to 2.6), but no association was seen in MFS. The FI group also had higher odds of emergency department use and hospitalization (2.3, 95% CI 1.5 to 3.4; 2.4, 95% CI 1.5 to 3.9) and lower odds of technology use and checking glucose (0.6, 95% CI 0.4 to 0.9; 0.3, 95% CI 0.1 to 0.6). The MFS group exhibited associations of similar directions.
DISCUSSION AND CONCLUSION: Health care providers should consider care of patients with T1D and MFS the same way they care for patients with FI.}, }
@article {pmid39422615, year = {2024}, author = {Lazarchuk, P and Nguyen, MM and Curca, CM and Pavlova, MN and Oshima, J and Sidorova, JM}, title = {Werner syndrome RECQ helicase participates in and directs maintenance of the protein complexes of constitutive heterochromatin in proliferating human cells.}, journal = {Aging}, volume = {16}, number = {20}, pages = {12977-13011}, pmid = {39422615}, issn = {1945-4589}, support = {R01 CA210916/CA/NCI NIH HHS/United States ; R01 GM115482/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Werner Syndrome Helicase/metabolism/genetics ; *Heterochromatin/metabolism ; *Werner Syndrome/genetics/metabolism ; *Fibroblasts/metabolism ; *Cell Proliferation ; Chromobox Protein Homolog 5/metabolism ; Histone Deacetylase 2/metabolism/genetics ; DNA Replication ; Cellular Senescence ; RecQ Helicases/metabolism/genetics ; }, abstract = {Werner syndrome of premature aging is caused by mutations in the WRN RECQ helicase/exonuclease, which functions in DNA replication, repair, transcription, and telomere maintenance. How the loss of WRN accelerates aging is not understood in full. Here we show that WRN is necessary for optimal constitutive heterochromatin levels in proliferating human fibroblasts. Locally, WRN deficiency derepresses SATII pericentromeric satellite repeats but does not reduce replication fork progression on SATII repeats. Globally, WRN loss reduces a subset of protein-protein interactions responsible for the organization of constitutive heterochromatin in the nucleus, namely, the interactions involving Lamin B1 and Lamin B receptor, LBR. Both the mRNA level and subcellular distribution of LBR are affected by WRN deficiency, and unlike the former, the latter phenotype does not require WRN catalytic activities. The phenotypes of heterochromatin disruption seen in WRN-deficient proliferating fibroblasts are also observed in WRN-proficient fibroblasts undergoing replicative or oncogene-induced senescence. WRN interacts with histone deacetylase 2, HDAC2; WRN/HDAC2 association is mediated by heterochromatin protein alpha, HP1α, and WRN complexes with HP1α and HDAC2 are downregulated in senescing cells. The data suggest that the effect of WRN loss on heterochromatin is separable from senescence program, but mimics at least some of the heterochromatin changes associated with it.}, }
@article {pmid39422601, year = {2024}, author = {Samorodnitsky, S and Othus, M and LeBlanc, M and Wu, MC}, title = {Reverse Selection Designs for Accommodating Multiple Control Arms.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1282}, pmid = {39422601}, issn = {1557-3265}, abstract = {Evaluating a novel treatment in a randomized controlled trial requires comparison against existing therapies. If several existing therapies of similar benefit exist, the identification of a single control regimen may be difficult. For this situation, we propose a reverse selection design which, in its simplest form, includes a single experimental treatment arm and two control arms. Rather than carrying both control arms through the entire trial, the control arms are compared at an early interim analysis, ideally while accrual is ongoing. At this time, the worst-performing control arm is dropped and randomization continues to the remaining arms. At the end of the study, we compare the treatment to the remaining control arm. When no head-to-head comparison of the extant therapies is available or feasible, this design requires a smaller sample size than a traditional three-arm design or two sequential trials in which the extant therapies are compared and the better treatment is used in a subsequent trial as the control arm. This is because the final comparison is only between two arms and because the early interim analysis occurs prior to the end of accrual - yet with enough information such that any substantially better control arm will be selected. We evaluate the operating characteristics of a reverse selection design via simulation and show that it reduces the required sample size needed to compare the treatment against the best control, controls type I error, and likely selects the right control arm to use in the final analysis.}, }
@article {pmid39420548, year = {2024}, author = {Kelly, JP and Runco, DV and Slaven, JE and Niehaus, JZ}, title = {Healthcare Utilization in Pediatric Cancer Patients Near the End-of-Life.}, journal = {The American journal of hospice & palliative care}, volume = {}, number = {}, pages = {10499091241294055}, doi = {10.1177/10499091241294055}, pmid = {39420548}, issn = {1938-2715}, abstract = {Objective: Describe the healthcare utilization in the last 60 days of life in pediatric patients with cancer who died at home under hospice care and those that died in the hospital. Methods: Retrospective chart review of the medical records of those children with cancer diagnosis with palliative care consult and died either under hospice care at home or in the hospital. Results: Patients dying under hospice care spent a median of 44 days at home. Patients dying in the hospital spent a median of 30.5 days in the hospital, 10.5 days in the intensive care unit, and underwent 3.5 procedures requiring anesthesia. 45% of those that died in the hospital were compassionately extubated. Conclusion: For those dying with a cancer diagnosis, hospice care can allow for significant time at home with minimal healthcare while those dying in the hospital do spend a significant time in the hospital. This provides more information to both providers and families about end-of-life healthcare utilization.}, }
@article {pmid39420192, year = {2024}, author = {Wallis, W and Gulbis, AM and Wang, T and Lee, CJ and Sharma, A and Williams, KM and Nishihori, T and Prestidge, T and Gowda, L and Byrne, M and Krem, MM and MacMillan, ML and Kitko, CL and Pidala, J and Spellman, SR and Lee, SJ and Alousi, AM}, title = {Incidence of bacterial blood stream infections in patients with acute GVHD.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {39420192}, issn = {1476-5365}, abstract = {Bacterial bloodstream infections (BSI) can be a substantial contributor to complications of GVHD treatment. The aim of this study was to determine the risk for BSI from neutrophil engraftment through day 100 post transplant in patients with acute GVHD (AGVHD) based on organ involvement and severity. Patients (n = 4064) who underwent an allogeneic hematopoietic stem cell transplant (HCT) reported to the CIBMTR registry were analyzed. Grade II-IV AGVHD occurred in 1607 (39.5%) patients and was associated with a greater day-100 incidence of post engraftment BSI than with grade 0/I (24.9 vs. 15.3%). Patients with grade III/IV AGVHD had the highest BSI risk (HR 2.45; 95% CI 1.99-3.0; p < 0.0001). Lower GI involvement increased BSI risk (HR 1.54; 95% CI 1.17-2.02; p = 0.0019). BSI post-engraftment through day 100 was associated with worse survival (HR 1.64, 95% CI 1.43-1.87; p < 0.001) and higher non-relapse mortality (NRM), (HR 2.22; 95% CI 1.91-2.59; p < 0.001). Those with stage III/IV GI involvement are at highest risk for BSI. Future studies evaluating novel methods for preventing BSI in these high risk populations are needed to reduce mortality associated with AGVHD.}, }
@article {pmid39419747, year = {2024}, author = {Lehrbach, N}, title = {Anything you can do, glycans do better: deglycosylation and noncanonical ubiquitination vie to rule the proteasome.}, journal = {Trends in biochemical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tibs.2024.10.001}, pmid = {39419747}, issn = {0968-0004}, abstract = {The Nrf1/Nfe2L1 transcription factor is a master regulator of proteasome biogenesis. New work by Yoshida and colleagues reveals a surprising mechanism by which ubiquitination of N-glycosylated Nrf1 controls its function.}, }
@article {pmid39418644, year = {2024}, author = {Uy, GL and Pullarkat, VA and Baratam, P and Stuart, RK and Walter, RB and Winer, ES and Wang, Q and Faderl, S and Chakravarthy, D and Menno, D and Cheung, RS and Lin, TL}, title = {Lower-intensity CPX-351 plus venetoclax induction for adults with newly diagnosed AML unfit for intensive chemotherapy.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024013687}, pmid = {39418644}, issn = {2473-9537}, abstract = {Preclinical data suggest a rationale for combining CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, with venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor. This phase 1b study evaluated lower-intensity CPX-351 combined with venetoclax in adults with acute myeloid leukemia (AML) considered unfit/ineligible for intensive chemotherapy. In a dose-exploration phase using a 3+3 design, patients received stepwise dosing of CPX‑351 intravenously on days 1 and 3 plus venetoclax 400 mg orally on days 2-21 per cycle to determine the recommended phase 2 dose (RP2D) for this combination. During the expansion phase, additional patients received CPX-351 plus venetoclax at the identified RP2D. The primary endpoints were the RP2D and safety of CPX‑351 combined with venetoclax. Secondary endpoints included preliminary efficacy and pharmacokinetics. Overall, 35 patients were enrolled in the study. A RP2D of CPX-351 30 units/m2 (daunorubicin 13.2 mg/m2 and cytarabine 30 mg/m2) plus venetoclax 400 mg was established. The safety profile of the combination was consistent with the known safety profiles of CPX-351 and venetoclax. Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved by 17/35 (49%) patients, all after cycle 1; of these, 14 were negative for measurable residual disease. CR was achieved by 1/8 (13%) patients with a mutation in TP53, and CR/CRi was achieved by 15/26 (58%) patients with wild-type TP53. This study highlights that lower-intensity therapy of CPX-351 plus venetoclax as induction therapy provides a well-tolerated treatment option in adults with AML deemed unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT04038437.}, }
@article {pmid39417692, year = {2024}, author = {Chae, YK and Othus, M and Patel, SP and Wilkinson, KJ and Whitman-Purves, EM and Lea, J and Schallenkamp, JM and Adra, N and Appleman, LJ and Alden, M and Thomes Pepin, J and Ellerton, JA and Poklepovic, A and Walter, A and Rampurwala, MM and Robinson, WR and Kim, HS and Chung, LI and McLeod, CM and Lopez, G and Chen, HX and Sharon, E and Streicher, H and Ryan, CW and Blanke, CD and Kurzrock, R}, title = {SWOG/NCI Phase II Dual Anti-CTLA-4/PD-1 Blockade in Rare Tumors (DART): Non-Epithelial Ovarian Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-0606}, pmid = {39417692}, issn = {1557-3265}, support = {U10 CA180868/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: The role of dual checkpoint inhibition in advanced rare/ultra-rare non-epithelial ovarian cancers (NEOCs) is yet to be explored.
METHODS: DART is a prospective, multicenter (1,016 US sites), multi-cohort, single-arm phase II trial conducted through the Early Therapeutics and Rare Cancer SWOG/NCI Committee, assessing ipilimumab (anti-CTLA-4) (1mg/kg every 6 weeks) and nivolumab (anti-PD-1) (240mg every 2 weeks) in adults with advanced NEOCs who lack beneficial standard therapy. Primary outcome was overall response rate [ORR; complete response (CR)/partial response (PR)]; secondary outcomes were progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; stable disease (SD) ≥6 months plus ORR], and toxicity.
RESULTS: Seventeen patients (median age: 64; number of prior therapies ranged from 0-8 with no immunotherapy exposure; 8 granulosa, 6 carcinosarcomas, 1 Sertoli-Leydig, 1 yolk sac, 1 Wolffian) were evaluated. In granulosa cell tumors, ORR was 25% (n=2/8; 1 CR, 1 PR) and CBR, 50% (n=4/8); PFS of 58.3 (CR), 50.7+ (PR), 30.4 (SD), and 8.7 (SD) months. Median PFS was 3.5 months (95% confidence intervals (CI) 1.7-11.2 months); median OS, 42.5 months (95% CI 10.1 months-not reached). One Sertoli-Leydig cell tumor showed a 22% regression (PFS 11.2 months). Carcinosarcomas had no response. Three participants (18%) discontinued treatment due to grade 3-4 adverse events.
CONCLUSIONS: Ipilimumab-nivolumab shows activity in treatment-refractory granulosa cell tumors, with 25% (n=2/8) of patients experiencing either CR or PR lasting over 4 years..}, }
@article {pmid39416221, year = {2024}, author = {Geiger, RA and Khera, D and Tenthorey, JL and Kochs, G and Graf, L and Emerman, M and Malik, HS}, title = {Heterozygous and generalist MxA super-restrictors overcome breadth-specificity tradeoffs in antiviral restriction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416221}, issn = {2692-8205}, support = {T32 HG000035/HG/NHGRI NIH HHS/United States ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, abstract = {Antiviral restriction factors such as MxA (myxovirus resistance protein A) inhibit a broad range of viruses. However, they face the challenge of maintaining this breadth as viruses evolve to escape their defense. Viral escape drives restriction factors to evolve rapidly, selecting for amino acid changes at their virus-binding interfaces to regain defense. How do restriction factors balance the breadth of antiviral functions against the need to evolve specificity against individual escaping viruses? We explored this question in human MxA, which uses its rapidly evolving loop L4 as the specificity determinant for orthomyxoviruses such as THOV and IAV. Previous combinatorial mutagenesis of rapidly evolving residues in human MxA loop L4 revealed variants with a ten-fold increase in potency against THOV. However, this strategy did not yield improved IAV restriction, suggesting a strong tradeoff between antiviral specificity and breadth. Here, using a modified combinatorial mutagenesis strategy, we find 'super-restrictor' MxA variants with over ten-fold enhanced restriction of the avian IAV strain H5N1 but reduced THOV restriction. Analysis of super-restrictor MxA variants reveals that the identity of residue 561 explains most of MxA's breadth-specificity tradeoff in H5N1 versus THOV restriction. However, rare 'generalist' super-restrictors with enhanced restriction of both viruses allow MxA to overcome the breadth-specificity tradeoff. Finally, we show that a heterozygous combination of two 'specialist' super-restrictors, one against THOV and the other against IAV, enhances restriction against both viruses. Thus, two strategies enable restriction factors such as MxA to increase their restriction of diverse viruses to overcome breadth-specificity tradeoffs that may be pervasive in host-virus conflicts.}, }
@article {pmid39416011, year = {2024}, author = {Haack, AJ and Brown, LG and Goldstein, AJ and Mulimani, P and Berthier, J and Viswanathan, AR and Kopyeva, I and Whitten, JM and Lin, A and Nguyen, SH and Leahy, TP and Bouker, EE and Padgett, RM and Mazzawi, NA and Tokihiro, JC and Bretherton, RC and Wu, A and Tapscott, SJ and DeForest, CA and Popowics, TE and Berthier, E and Sniadecki, NJ and Theberge, AB}, title = {Suspended Tissue Open Microfluidic Patterning (STOMP).}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39416011}, issn = {2692-8205}, support = {F30 HL158030/HL/NHLBI NIH HHS/United States ; R01 HL149734/HL/NHLBI NIH HHS/United States ; R90 DE023059/DE/NIDCR NIH HHS/United States ; R35 GM128648/GM/NIGMS NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; R03 DE029827/DE/NIDCR NIH HHS/United States ; R35 GM138036/GM/NIGMS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; P50 AR065139/AR/NIAMS NIH HHS/United States ; }, abstract = {Cell-laden hydrogel constructs suspended between pillars are powerful tools for modeling tissue structure and physiology, though current fabrication techniques often limit them to uniform compositions. In contrast, tissues are complex in nature with spatial arrangements of cell types and extracellular matrices. Thus, we present Suspended Tissue Open Microfluidic Patterning (STOMP), which utilizes a removable, open microfluidic patterning channel to pattern multiple spatial regions across a single suspended tissue. The STOMP platform contains capillary pinning features along the open channel that controls the fluid front, allowing multiple cell and extracellular matrix precursors to be pipetted into one tissue. We have used this technique to pattern suspended tissues with multiple regional components using a variety of native and synthetic extracellular matrices, including fibrin, collagen, and poly(ethylene glycol). Here, we demonstrate that STOMP models a region of fibrosis in a functional heart tissue and a bone-ligament junction in periodontal tissues. Additionally, the STOMP platform can be customized to allow patterning of suspended cores and more spatial configurations, enhancing its utility in complex tissue modeling. STOMP is a versatile technique for generating suspended tissue models with increased control over cell and hydrogel composition to model interfacial tissue regions in a suspended tissue.}, }
@article {pmid39415317, year = {2024}, author = {Purice, MD and Lago-Baldaia, I and Fernandes, VM and Singhvi, A}, title = {Molecular profiling of invertebrate glia.}, journal = {Glia}, volume = {}, number = {}, pages = {}, doi = {10.1002/glia.24623}, pmid = {39415317}, issn = {1098-1136}, support = {5T32CA080416-25/NH/NIH HHS/United States ; NS114222/NH/NIH HHS/United States ; 227823//Esther A. and Joseph Klingenstein Fund/ ; BRFSG-2023-10//Brain Research Foundation/ ; 225986/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; //Washington Research Foundation/ ; }, abstract = {Caenorhabditis elegans and Drosophila melanogaster are powerful experimental models for uncovering fundamental tenets of nervous system organization and function. Findings over the last two decades show that molecular and cellular features are broadly conserved between invertebrates and vertebrates, indicating that insights derived from invertebrate models can broadly inform our understanding of glial operating principles across diverse species. In recent years, these model systems have led to exciting discoveries in glial biology and mechanisms of glia-neuron interactions. Here, we summarize studies that have applied current state-of-the-art "-omics" techniques to C. elegans and D. melanogaster glia. Coupled with the remarkable acceleration in the pace of mechanistic studies of glia biology in recent years, these indicate that invertebrate glia also exhibit striking molecular complexity, specificity, and heterogeneity. We provide an overview of these studies and discuss their implications as well as emerging questions where C. elegans and D. melanogaster are well-poised to fill critical knowledge gaps in our understanding of glial biology.}, }
@article {pmid39414943, year = {2024}, author = {Wang, T and Roach, MJ and Harvey, K and Morlanes, JE and Kiedik, B and Al-Eryani, G and Greenwald, A and Kalavros, N and Dezem, FS and Ma, Y and Pita-Juarez, YH and Wise, K and Degletagne, C and Elz, A and Hadadianpour, A and Johanneson, J and Pakiam, F and Ryu, H and Newell, EW and Tonon, L and Kohlway, A and Drennon, T and Abousoud, J and Stott, R and Lund, P and Durruthy, J and Vallejo, AF and Li, W and Salomon, R and Kaczorowski, D and Warren, J and Butler, LM and O'Toole, S and Plummer, J and Vlachos, IS and Lundeberg, J and Swarbrick, A and Martelotto, LG}, title = {snPATHO-seq, a versatile FFPE single-nucleus RNA sequencing method to unlock pathology archives.}, journal = {Communications biology}, volume = {7}, number = {1}, pages = {1340}, pmid = {39414943}, issn = {2399-3642}, support = {APP2004774//Department of Health | National Health and Medical Research Council (NHMRC)/ ; }, mesh = {*Paraffin Embedding/methods ; Humans ; *Sequence Analysis, RNA/methods ; *Tissue Fixation/methods ; *Single-Cell Analysis/methods ; Formaldehyde/chemistry ; Transcriptome ; Gene Expression Profiling/methods ; Workflow ; }, abstract = {Formalin-fixed paraffin-embedded (FFPE) samples are valuable but underutilized in single-cell omics research due to their low RNA quality. In this study, leveraging a recent advance in single-cell genomic technology, we introduce snPATHO-seq, a versatile method to derive high-quality single-nucleus transcriptomic data from FFPE samples. We benchmarked the performance of the snPATHO-seq workflow against existing 10x 3' and Flex assays designed for frozen or fresh samples and highlighted the consistency in snRNA-seq data produced by all workflows. The snPATHO-seq workflow also demonstrated high robustness when tested across a wide range of healthy and diseased FFPE tissue samples. When combined with FFPE spatial transcriptomic technologies such as FFPE Visium, the snPATHO-seq provides a multi-modal sampling approach for FFPE samples, allowing more comprehensive transcriptomic characterization.}, }
@article {pmid39414769, year = {2024}, author = {Fortuna, GG and Banerjee, R and Savid-Frontera, C and Song, J and Morán-Segura, CM and Nguyen, JV and Lekakis, L and Fernandez-Pol, S and Samraj, AN and Naresh, KN and Vazquez-Martinez, M and Baz, RC and Spiegel, JY and Mikkilineni, L and Gubatan, JM and Sidana, S and de Menezes Silva Corraes, A and Kalariya, NM and Patel, KK and Shim, KG and Fonseca, R and Ferreri, C and Voorhees, PM and Richard, S and Valdes, CR and Sireesha Asoori, and Wolf, JL and Cowan, AJ and Sborov, DW and Locke, FL and Lin, Y and Wang, Y and Hansen, DK}, title = {Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma.}, journal = {Blood cancer journal}, volume = {14}, number = {1}, pages = {180}, pmid = {39414769}, issn = {2044-5385}, support = {P30 CA076292/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/therapy/immunology/drug therapy ; *Enterocolitis/etiology/therapy/immunology ; Male ; Middle Aged ; Female ; Aged ; *Immunotherapy, Adoptive/adverse effects ; Adult ; Receptors, Chimeric Antigen/therapeutic use/immunology ; }, abstract = {We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22-210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1-3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.}, }
@article {pmid39414027, year = {2024}, author = {Wong, WW and Speakman, JR and Ainslie, PN and Anderson, LJ and Arab, L and Baddou, I and Bedu-Addo, K and Blaak, EE and Blanc, S and Bonomi, AG and Bouten, CV and Bovet, P and Buchowski, MS and Butte, NF and Camps, SG and Casper, R and Close, GL and Colbert, LH and Cooper, JA and Das, SK and Davies, PS and Eaton, S and Ekelund, U and Hambly, C and El Hamdouchi, A and Entringer, S and Fudge, BW and Gillingham, M and Goris, AH and Gurven, M and Hoos, MB and Hu, S and Joosen, A and Katzmarzyk, PT and Kempen, KP and Kimura, M and Kraus, WE and Kushner, RF and Larsson, CL and Morehen, JC and Morton, JP and Neuhouser, ML and Nicklas, TA and Ojiambo, RM and Pietilainen, KH and Pitsiladis, YP and Plasqui, G and Prentice, RL and Rabinovich, R and Racette, SB and Raichen, DA and Redman, L and Ravussin, E and Reilly, JJ and Roberts, S and Scuitt, AJ and Sjödin, AM and Stice, E and Urlacher, SS and Valenti, G and van Etten, LM and Van Mil, EA and Verbunt, JA and Wells, JC and Wilson, G and Yoshida, T and Zhang, X and Loechl, CU and Luke, A and Murphy-Alford, AJ and Pontzer, H and Sagayama, H and Rood, JC and Schoeller, DA and Westerterp, KR and Yamada, Y and , }, title = {Decline in Isotope Dilution Space Ratio Above Age 60 Could Affect Energy Estimates Using the Doubly Labeled Water Method.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tjnut.2024.10.016}, pmid = {39414027}, issn = {1541-6100}, abstract = {BACKGROUND: Doubly labeled water is gold standard for measuring total energy expenditure (TEE). Measurements using the method are sensitive to the isotope dilution space ratio (DSR). Accuracy and precision of the method might be improved if we could identify factors influencing DSR.
OBJECTIVES: We evaluated the potential associations of age, sex, ethnicity, anthropometry, body composition, turnover rates of the isotopes, and geographical elevation with DSR.
METHODS: We used univariate regression analysis to explore the relationships between the continuous variables and analysis of variance to test the relationships between the categorical variables with DSR. Subsequently, we used general linear model (GLM) and 1-way analysis of variance to evaluate the simultaneous associations of age, sex, ethnicity, fat-free mass (FFM) and fat mass (FM) on DSR.
RESULTS: From 5678 measurements complied from studies around the world with diverse ethnicity and living at various elevations, the mean DSR was 1.0364 ± 0.0141. No meaningful physiologic effect of any of the continuous and categorical variable on DSR was detected. General linear model analysis revealed no effect of FFM and FM (P > 0.33) on DSR, but DSR decreased with age (P < 0.001) among those aged 60 y and older regardless of sex. Among the Whites who were younger than 60 y, DSR was not related to FFM and FM (P = 0.73) but was affected by both age and sex (P < 0.001).
CONCLUSIONS: Previous estimates of age-related decline in TEE may have overestimated TEE at age 90 y. Validation studies on older participants are required to confirm this finding.}, }
@article {pmid39413835, year = {2024}, author = {Liu, J and Berchuck, A and Backes, FJ and Cohen, J and Grisham, R and Leath, CA and Martin, L and Matei, D and Miller, DS and Robertson, S and Barroilhet, L and Uppal, S and Hendrickson, AW and Gershenson, DM and Gray, HJ and Hakam, A and Jain, A and Konecny, GE and Moroney, J and Ratner, E and Schorge, J and Thaker, PH and Werner, TL and Zsiros, E and Behbakht, K and Chen, LM and DeRosa, M and Eisenhauer, EL and Leiserowitz, G and Litkouhi, B and McHale, M and Percac-Lima, S and Rodabaugh, K and Vargas, R and Jones, F and Kovach, E and Hang, L and Ramakrishnan, S and Alvarez, RD and Armstrong, DK}, title = {NCCN Guidelines® Insights: Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer, Version 3.2024.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {8}, pages = {512-519}, doi = {10.6004/jnccn.2024.0052}, pmid = {39413835}, issn = {1540-1413}, mesh = {Humans ; Female ; *Ovarian Neoplasms/diagnosis/therapy/pathology ; *Peritoneal Neoplasms/therapy/diagnosis ; *Fallopian Tube Neoplasms/diagnosis/therapy/pathology ; Medical Oncology/standards/methods ; Neoplasm Staging ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; }, abstract = {The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.}, }
@article {pmid39413812, year = {2024}, author = {Shah, B and Mattison, RJ and Abboud, R and Abdelmessieh, P and Aldoss, I and Burke, PW and DeAngelo, DJ and Dinner, S and Fathi, AT and Gauthier, J and Haddadin, M and Jain, N and Jonas, B and Kirby, S and Liedtke, M and Litzow, M and Logan, A and Long, M and Luger, S and Mangan, JK and Massaro, S and May, W and Oluwole, O and Park, J and Przespolewski, A and Rangaraju, S and Saygin, C and Schwartz, M and Shami, P and Tomlinson, B and Webster, J and Awotiwon, A and Stehman, K}, title = {Acute Lymphoblastic Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {8}, pages = {563-576}, doi = {10.6004/jnccn.2024.0051}, pmid = {39413812}, issn = {1540-1413}, mesh = {Humans ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/diagnosis ; Medical Oncology/standards/methods ; Adult ; Philadelphia Chromosome ; Adolescent ; }, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.}, }
@article {pmid39413375, year = {2024}, author = {Herrera, AF and LeBlanc, M and Castellino, SM and Li, H and Rutherford, SC and Evens, AM and Davison, K and Punnett, A and Parsons, SK and Ahmed, S and Casulo, C and Bartlett, NL and Tuscano, JM and Mei, MG and Hess, BT and Jacobs, R and Saeed, H and Torka, P and Hu, B and Moskowitz, C and Kaur, S and Goyal, G and Forlenza, C and Doan, A and Lamble, A and Kumar, P and Chowdhury, S and Brinker, B and Sharma, N and Singh, A and Blum, KA and Perry, AM and Kovach, A and Hodgson, D and Constine, LS and Shields, LK and Prica, A and Dillon, H and Little, RF and Shipp, MA and Crump, M and Kahl, B and Leonard, JP and Smith, SM and Song, JY and Kelly, KM and Friedberg, JW}, title = {Nivolumab+AVD in Advanced-Stage Classic Hodgkin's Lymphoma.}, journal = {The New England journal of medicine}, volume = {391}, number = {15}, pages = {1379-1389}, pmid = {39413375}, issn = {1533-4406}, support = {UG1CA189955/NH/NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10CA180819/NH/NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10 CA180863/CA/NCI NIH HHS/United States ; U10CA180863/NH/NIH HHS/United States ; U10CA180888/NH/NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10CA180821/NH/NIH HHS/United States ; U10CA180820/NH/NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Child ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse effects ; *Brentuximab Vedotin/administration & dosage/adverse effects ; *Dacarbazine/administration & dosage/adverse effects ; *Doxorubicin/administration & dosage/adverse effects ; *Hodgkin Disease/drug therapy/mortality/radiotherapy/pathology ; Intention to Treat Analysis ; Kaplan-Meier Estimate ; Neoplasm Staging ; *Nivolumab/administration & dosage/adverse effects ; Progression-Free Survival ; *Vinblastine/administration & dosage/adverse effects ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients.
METHODS: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause.
RESULTS: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation.
CONCLUSIONS: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.).}, }
@article {pmid39412842, year = {2024}, author = {Fabens, I and Makhele, C and Igaba, NK and Hlongwane, S and Phohole, M and Waweru, E and Oni, F and Khwepeya, M and Sardini, M and Moyo, K and Tweya, H and Wafula, MB and Pienaar, J and Ndebele, F and Setswe, G and Dong, TQ and Feldacker, C}, title = {WhatsApp Versus SMS for 2-Way, Text-Based Follow-Up After Voluntary Medical Male Circumcision in South Africa: Exploration of Messaging Platform Choice.}, journal = {JMIR formative research}, volume = {8}, number = {}, pages = {e62762}, pmid = {39412842}, issn = {2561-326X}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 NR019229/NR/NINR NIH HHS/United States ; }, mesh = {Humans ; Male ; *Circumcision, Male/psychology ; *Text Messaging ; South Africa ; Adult ; Adolescent ; *Mobile Applications ; Telemedicine ; Young Adult ; Patient Satisfaction ; Middle Aged ; Aftercare/methods ; }, abstract = {BACKGROUND: Telehealth is growing, especially in areas where access to health facilities is difficult. We previously used 2-way texting (2wT) via SMS to improve the quality of postoperative care after voluntary medical male circumcision in South Africa. In this study, we offered males aged 15 years and older WhatsApp or SMS as their message delivery and interaction platform to explore user preferences and behaviors.
OBJECTIVE: The objectives of this process evaluation embedded within a larger 2wT expansion trial were to (1) explore 2wT client preferences, including client satisfaction, with WhatsApp or SMS; (2) examine response rates (participation) by SMS and WhatsApp; and (3) gather feedback from the 2wT implementation team on the WhatsApp approach.
METHODS: Males aged 15 years and older undergoing voluntary medical male circumcision in program sites could choose their follow-up approach, selecting 2wT via SMS or WhatsApp or routine care (in-person postoperative visits). The 2wT system provided 1-way educational messages and an open 2-way communication channel between providers and clients. We analyzed quantitative data from the 2wT database on message delivery platforms (WhatsApp vs SMS), response rates, and user behaviors using chi-square tests, z tests, and t tests. The team conducted short phone calls with WhatsApp and SMS clients about their perceptions of this 2wT platform using a short, structured interview guide. We consider informal reflections from the technical team members on the use of WhatsApp. We applied an implementation science lens using the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework to focus results on practice and policy improvement.
RESULTS: Over a 2-month period-from August to October, 2023-337 males enrolled in 2wT and were offered WhatsApp or SMS and were included in the analysis. For 2wT reach, 177 (53%) participants chose WhatsApp as their platform (P=.38). Mean client age was 30 years, and 253 (75%) participants chose English for automated messages. From quality assurance calls, almost all respondents (87/89, 98%) were happy with the way they were followed up. For effectiveness, on average for the days on which responses were requested, 58 (33%) WhatsApp clients and 44 (28%) SMS clients responded (P=.50). All 2wT team members believed WhatsApp limited the automated message content, language choices, and inclusivity as compared with the SMS-based 2wT approach.
CONCLUSIONS: When presented with a choice of 2wT communication platform, clients appear evenly split between SMS and WhatsApp. However, WhatsApp requires a smartphone and data plan, potentially reducing reach at scale. Clients using both platforms responded to 2wT interactive prompts, demonstrating similar effectiveness in engaging clients in follow-up. For telehealth interventions, digital health designers should maintain an SMS-based platform and carefully consider adding WhatsApp as an option for clients, using an implementation science approach to present evidence that guides the best implementation approach for their setting.}, }
@article {pmid39410956, year = {2024}, author = {Parker, SA and Weygand, J and Bernat, BG and Jackson, AM and Mawlawi, O and Barreto, I and Hao, Y and Khan, R and Yorke, AA and Swanson, W and Huq, MS and Lief, E and Biancia, CD and Njeh, CF and Al-Basheer, A and Chau, OW and Avery, S and Ngwa, W and Sandwall, PA}, title = {Assessing Radiology and Radiation Therapy Needs for Cancer Care in Low-and-Middle-Income Countries: Insight From a Global Survey of Departmental and Institutional Leaders.}, journal = {Advances in radiation oncology}, volume = {9}, number = {11}, pages = {101615}, pmid = {39410956}, issn = {2452-1094}, abstract = {PURPOSE: The global cancer burden and mortality rates are increasing, with significant disparities in access to care in low- and middle-income countries (LMICs). This study aimed to identify radiology and radiation therapy needs in LMICs from the perspective of departmental and institutional leaders.
METHODS AND MATERIALS: A survey was developed and conducted by the American Association of Physicists in Medicine Global Needs Assessment Committee and the American Association of Physicists in Medicine International Council. The survey, organized into 5 sections (Introduction, Infrastructure Needs, Education Needs, Research Needs, and General Information), was open to respondents from March 1, to August 16, 2022.
RESULTS: A total of 175 responses were received from 6 global regions: Africa (31.4%), the Americas (17.7%), the Eastern Mediterranean (14.3%), Europe (9.1%), Southeast Asia (23.4%), and the Western Pacific (4.0%). The greatest reported need was for new or updated equipment, particularly positron emission tomography/computed tomography imaging technology. There was also a high demand for clinical and equipment training. Approximately 25% of institutions reported a lack of radiology-based cancer screening programs because of high health care costs and a shortage of specialized equipment. Many institutions that expressed interest in research face funding and grant challenges.
CONCLUSIONS: The findings highlight critical areas where organizations can support LMICs in enhancing radiology and radiation therapy services to mitigate the growing cancer burden.}, }
@article {pmid39406835, year = {2024}, author = {Li, Z and Li, R and Ganan-Gomez, I and Abbas, HA and Garcia-Manero, G and Sun, W}, title = {Accurate identification of locally aneuploid cells by incorporating cytogenetic information in single cell data analysis.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {24152}, pmid = {39406835}, issn = {2045-2322}, support = {R01 GM105785/GM/NIGMS NIH HHS/United States ; U24 CA274212/CA/NCI NIH HHS/United States ; R03CA270725/NH/NIH HHS/United States ; R01GM105785/NH/NIH HHS/United States ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; *Aneuploidy ; *Algorithms ; Cytogenetic Analysis/methods ; Markov Chains ; Sequence Analysis, RNA/methods ; Leukemia, Myeloid, Acute/genetics/pathology ; Data Analysis ; }, abstract = {Single-cell RNA sequencing is a powerful tool to investigate the cellular makeup of tumor samples. However, due to the sparse data and the complex tumor microenvironment, it can be challenging to identify neoplastic cells that play important roles in tumor growth and disease progression. This is especially relevant for blood cancers, where neoplastic cells may be highly similar to normal cells. To address this challenge, we have developed partCNV and partCNVH, two methods for rapid and accurate detection of aneuploid cells with local copy number deletion or amplification. PartCNV uses an expectation-maximization (EM) algorithm with mixtures of Poisson distributions and incorporates cytogenetic information to guide the classification. PartCNVH further improves partCNV by integrating a hidden Markov model for feature selection. We have thoroughly evaluated the performance of partCNV and partCNVH through simulation studies and real data analysis using three scRNA-seq datasets from blood cancer patients. Our results show that partCNV and partCNVH have favorable accuracy and provide more interpretable results compared to existing methods. In the real data analysis, we have identified multiple biological processes involved in the oncogenesis of myelodysplastic syndromes and acute myeloid leukemia.}, }
@article {pmid39405343, year = {2024}, author = {Hamilton, E and Galsky, MD and Ochsenreither, S and Del Conte, G and Martín, M and de Miguel, MJ and Yu, EY and Williams, A and Gion, M and Tan, AR and Agrawal, L and Rutten, A and Machiels, JP and Cresta, S and Debruyne, PR and Hennequin, A and Moreno, V and Minchom, A and Valdes-Albini, F and Petrylak, D and Li, L and Tsuchihashi, Z and Suto, F and Cheng, FC and Kandil, M and Barrios, D and Hurvitz, S}, title = {Trastuzumab Deruxtecan With Nivolumab in HER2-Expressing Metastatic Breast or Urothelial Cancer: Analysis of the Phase Ib DS8201-A-U105 Study.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1513}, pmid = {39405343}, issn = {1557-3265}, abstract = {PURPOSE: This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC).
PATIENTS AND METHODS: Part 1 determined the recommended dose for expansion (RDE) of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate (cORR) by independent central review.
RESULTS: Seven patients with mBC were enrolled in part 1 and received T-DXd 3.2 mg/kg (4 patients) or 5.4 mg/kg (3 patients) plus nivolumab. The RDE for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously/3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of 3 administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and 4 with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the cORR (95% CI) for cohorts 1-4 was 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. Median treatment duration (range) with T-DXd in cohorts 1-4 was 8.9 (1-23), 6.9 (1-21), 3.9 (1-21) months, and not assessed; most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, 75.0%). Adjudicated drug-related ILD/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0% (1 grade 5 each, cohorts 1 and 3).
CONCLUSION: T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T‑DXd. ILD/pneumonitis is an important risk and requires careful monitoring and prompt intervention.}, }
@article {pmid39404767, year = {2024}, author = {Li, Y and Lee, T and Marin, K and Hua, X and Srinivasan, S and Fredricks, DN and Lee, JR and Ling, W}, title = {SurvBal: compositional microbiome balances for survival outcomes.}, journal = {Bioinformatics (Oxford, England)}, volume = {40}, number = {10}, pages = {}, doi = {10.1093/bioinformatics/btae612}, pmid = {39404767}, issn = {1367-4811}, support = {R01 GM129512/GM/NIGMS NIH HHS/United States ; }, mesh = {*Microbiota ; *Software ; Humans ; Proportional Hazards Models ; Survival Analysis ; Bacteria/classification ; }, abstract = {SUMMARY: Identification of balances of bacterial taxa in relation to continuous and dichotomous outcomes is an increasingly frequent analytic objective in microbiome profiling experiments. SurvBal enables the selection of balances in relation to censored survival or time-to-event outcomes which are of considerable interest in many biomedical studies. The most commonly used survival models-the Cox proportional hazards and parametric survival models are included in the package, which are used in combination with step-wise selection procedures to identify the optimal associated balance of microbiome, i.e. the ratio of the geometric means of two groups of taxa's relative abundances.
The SurvBal R package and Shiny app can be accessed at https://github.com/yinglia/SurvBal and https://yinglistats.shinyapps.io/shinyapp-survbal/.}, }
@article {pmid39403956, year = {2024}, author = {Young, CL and Beichman, AC and Mas-Ponte, D and Hemker, SL and Zhu, L and Kitzman, JO and Shirts, BH and Harris, K}, title = {A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyae166}, pmid = {39403956}, issn = {1943-2631}, abstract = {Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo.}, }
@article {pmid39403932, year = {2024}, author = {Zhang, P and Minnie, SA and Hill, GR}, title = {Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD. Reply.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {20}, pages = {}, pmid = {39403932}, issn = {1558-8238}, mesh = {Animals ; Humans ; Mice ; Calcineurin/metabolism/immunology/genetics ; *Calcineurin Inhibitors ; Chronic Disease ; *Graft vs Host Disease/immunology/pathology ; Immunologic Memory ; *Isoantigens/immunology ; Memory T Cells/immunology ; T-Lymphocyte Subsets/immunology/metabolism ; }, }
@article {pmid39402405, year = {2024}, author = {Bologna, E and Licari, LC and Badani, KK and Razdan, S and Psutka, SP and Ditonno, F and Ramos-Carpinteyro, R and Soputro, NA and Jackson, JC and Nelson, R and Rais-Bahrami, S and White, WM and Djaladat, H and Pierorazio, PM and Eun, DD and Kutikov, A and Margulis, V and Kovac, E and Kim, IY and Anele, UA and Mehrazin, R and Ben-David, R and Viers, BR and Su, LM and Rogers, CG and Abdollah, F and Ghazi, A and Cherullo, EE and Vourganti, S and Coogan, CL and Raman, JD and Sundaram, CP and Stifelman, M and Link, RE and Kaouk, J and Crivellaro, S and Autorino, R}, title = {The impact of single-port robotic surgery: a survey among urology residents and fellows in the United States.}, journal = {Journal of robotic surgery}, volume = {18}, number = {1}, pages = {369}, pmid = {39402405}, issn = {1863-2491}, mesh = {*Robotic Surgical Procedures/education/statistics & numerical data ; *Internship and Residency ; United States ; Humans ; Surveys and Questionnaires ; *Urology/education ; *Fellowships and Scholarships ; Urologic Surgical Procedures/education ; Male ; Female ; Clinical Competence ; }, abstract = {Our aim was to investigate the perception and future expectations of Single-Port (SP) surgery among urology trainees in the United States. A 34-item online survey was distributed to urological residency and fellowship programs across the US, covering demographic profiles, SP training opportunities, perceived educational impact, and future perspectives. Descriptive analysis and multivariable linear regression were used to assess predictors of SP adoption. 201 surveys were completed (28.6% completion rate). Among institutions with an SP platform, about 50% have used it regularly for over 2 years, though often in less than 50% of procedures. While robotic simulators are commonly available, only 17% offer both multi-port and SP simulators, and structured pre-clinical SP training is limited. Approximately 30% of respondents expressed concerns over limited hands-on experience and a steeper learning curve with SP. Around 40% felt that their robotic surgery exposure was negatively impacted by SP's introduction. SP surgery's benefits are seen mostly in the immediate post-operative period and a significant number of respondents foresee a major role for SP in urology. However, proficiency in SP surgery is not seen as crucial for career advancement or job opportunities. Academic job aspirations, SP platform availability, and SP surgery workload are predictors of future SP implementation. Trainees increasingly recognize the clinical benefits of SP procedures but express concerns about the potential negative impact on hands-on experience. Training programs should more systematically integrate SP technology into curricula. There is a correlation between training in high-volume SP centers and future SP adoption.}, }
@article {pmid39401968, year = {2024}, author = {Pulliam, T and Jani, S and Goff, PH and Bhakuni, R and Tabachnick-Cherny, S and Smythe, K and Seaton, BW and Tachiki, L and Kulikauskas, R and Church, C and Koelle, DM and Nghiem, P and Bhatia, S}, title = {Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {10}, pages = {}, pmid = {39401968}, issn = {2051-1426}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; F30 CA254168/CA/NCI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/drug therapy/immunology ; *Membrane Proteins/metabolism ; Skin Neoplasms/drug therapy/immunology/pathology ; Biomarkers, Tumor/metabolism ; Male ; B7-H1 Antigen/metabolism ; Aged ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Antibodies blocking programmed death (PD)-1 or its ligand (PD-L1) have revolutionized cancer care, but many patients do not experience durable benefits. Novel treatments to stimulate antitumor immunity are needed in the PD-(L)1 refractory setting. The stimulator of interferon genes (STING) protein, an innate sensor of cytoplasmic DNA, is a promising target with several agonists in development. However, response rates in most recent clinical trials have been low and mechanisms of response remain unclear. We report detailed biomarker analyses in a patient with anti-PD-L1 refractory, Merkel cell polyomavirus (MCPyV)-positive, metastatic Merkel cell carcinoma (MCC) who was treated with an intratumoral (IT) STING agonist (ADU-S100) plus intravenous anti-PD-1 antibody (spartalizumab) and experienced a durable objective response with regression of both injected and non-injected lesions.
METHODS: We analyzed pretreatment and post-treatment tumor and peripheral blood samples from our patient with single-cell RNA sequencing, 30-parameter flow cytometry, T cell receptor sequencing, and multiplexed immunohistochemistry. We analyzed cancer-specific CD8 T cells using human leukocyte antigen (HLA)-I tetramers loaded with MCPyV peptides. We also analyzed STING expression and signaling in the tumor microenvironment (TME) of 88 additional MCC tumor specimens and in MCC cell lines.
RESULTS: We observed high levels of MCPyV-specific T cells (12% of T cells) in our patient's tumor at baseline. These cancer-specific CD8 T cells exhibited characteristics of exhaustion including high TOX and low TCF1 proteins. Following treatment with STING-agonist plus anti-PD-1, IT CD8 T cells expanded threefold. We also observed evidence of likely improved antigen presentation in the MCC TME (greater than fourfold increase of HLA-I-positive cancer cells). STING expression was not detected in any cancer cells within our patient's tumor or in 88 other MCC tumors, however high STING expression was observed in immune and stromal cells within all 89 MCC tumors.
CONCLUSIONS: Our results suggest that STING agonists may be able to work indirectly in MCC via signaling through immune and stromal cells in the TME, and may not necessarily need STING expression in the cancer cells. This approach may be particularly effective in tumors that are already infiltrated by inflammatory cells in the TME but are evading immune detection via HLA-I downregulation.}, }
@article {pmid39398350, year = {2024}, author = {Chen, Z and Li, X and Zhang, B}, title = {The role of randomization inference in unraveling individual treatment effects in early phase vaccine trials.}, journal = {Statistical communications in infectious diseases}, volume = {16}, number = {1}, pages = {}, pmid = {39398350}, issn = {2194-6310}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {Randomization inference is a powerful tool in early phase vaccine trials when estimating the causal effect of a regimen against a placebo or another regimen. Randomization-based inference often focuses on testing either Fisher's sharp null hypothesis of no treatment effect for any participant or Neyman's weak null hypothesis of no sample average treatment effect. Many recent efforts have explored conducting exact randomization-based inference for other summaries of the treatment effect profile, for instance, quantiles of the treatment effect distribution function. In this article, we systematically review methods that conduct exact, randomization-based inference for quantiles of individual treatment effects (ITEs) and extend some results to a special case where naïve participants are expected not to exhibit responses to highly specific endpoints. These methods are suitable for completely randomized trials, stratified completely randomized trials, and a matched study comparing two non-randomized arms from possibly different trials. We evaluate the usefulness of these methods using synthetic data in simulation studies. Finally, we apply these methods to HIV Vaccine Trials Network Study 086 (HVTN 086) and HVTN 205 and showcase a wide range of application scenarios of the methods. R code that replicates all analyses in this article can be found in first author's GitHub page at https://github.com/Zhe-Chen-1999/ITE-Inference.}, }
@article {pmid39396254, year = {2024}, author = {Petersdorf, EW}, title = {HLA structure and function in hematopoietic-cell transplantation.}, journal = {Best practice & research. Clinical haematology}, volume = {37}, number = {3}, pages = {101564}, doi = {10.1016/j.beha.2024.101564}, pmid = {39396254}, issn = {1532-1924}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *HLA Antigens/immunology/genetics ; Killer Cells, Natural/immunology ; Polymorphism, Genetic ; Donor Selection ; Allografts ; Histocompatibility Testing ; Transplantation, Homologous ; }, abstract = {The degree of HLA compatibility between a patient and donor has formed the basis of donor selection since the development of allogeneic hematopoietic cell transplantation over 50 years ago and has advanced understanding of the basic immunobiology of HLA. New evidence supports a role for germline variation in the patient and the donor that do not require HLA matching for their effects to have clinical consequences. The discovery of novel non-coding polymorphisms, structural features of HLA molecules, and expression provide new models for donor selection and inspire the development of tools for clinical translation. Pairwise effects of HLA ligand/donor NK receptors may play an important role in transplant outcomes and showcase the value of understanding the role played by each constituent of the NK pathway in modulating donor responses to target antigens.}, }
@article {pmid39396092, year = {2024}, author = {Denos, M and Sun, YQ and Brumpton, BM and Li, Y and Albanes, D and Burnett-Hartman, A and Campbell, PT and Küry, S and Li, CI and White, E and Samadder, JN and Jenkins, MA and Mai, XM}, title = {Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23891}, pmid = {39396092}, issn = {2045-2322}, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; Female ; *Mendelian Randomization Analysis ; *Lung Neoplasms/genetics/epidemiology ; *Genome-Wide Association Study ; *Gonadal Steroid Hormones/metabolism ; Sex Hormone-Binding Globulin/genetics/metabolism ; Risk Factors ; Testosterone/blood ; Polymorphism, Single Nucleotide ; Middle Aged ; White People/genetics ; }, abstract = {The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.}, }
@article {pmid39396053, year = {2024}, author = {Marcink, TC and Zipursky, G and Sobolik, EB and Golub, K and Herman, E and Stearns, K and Greninger, AL and Porotto, M and Moscona, A}, title = {How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8831}, pmid = {39396053}, issn = {2041-1723}, support = {R01 AI160953/AI/NIAID NIH HHS/United States ; R01 AI114736/AI/NIAID NIH HHS/United States ; U19 AI181984/AI/NIAID NIH HHS/United States ; AI121349//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; R01 AI160961/AI/NIAID NIH HHS/United States ; AI160961//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI160953//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI152275//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; AI114736//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; F32 AI152275/AI/NIAID NIH HHS/United States ; R01 AI121349/AI/NIAID NIH HHS/United States ; }, mesh = {*Antibodies, Neutralizing/immunology ; *Viral Fusion Proteins/immunology/metabolism/chemistry ; Humans ; *Virus Internalization ; *Parainfluenza Virus 3, Human/immunology ; Antibodies, Viral/immunology ; Cryoelectron Microscopy ; HN Protein/metabolism/immunology/chemistry/genetics ; Antibodies, Monoclonal/immunology ; Animals ; Mutation ; Models, Molecular ; }, abstract = {Paramyxoviruses including measles, Nipah, and parainfluenza viruses are public health threats with pandemic potential. Human parainfluenza virus type 3 (HPIV3) is a leading cause of illness in pediatric, older, and immunocompromised populations. There are no approved vaccines or therapeutics for HPIV3. Neutralizing monoclonal antibodies (mAbs) that target viral fusion are a potential strategy for mitigating paramyxovirus infection, however their utility may be curtailed by viral evolution that leads to resistance. Paramyxoviruses enter cells by fusing with the cell membrane in a process mediated by a complex consisting of a receptor binding protein (HN) and a fusion protein (F). Existing atomic resolution structures fail to reveal physiologically relevant interactions during viral entry. We present cryo-ET structures of pre-fusion HN-F complexes in situ on surfaces of virions that evolved resistance to an anti-HPIV3 F neutralizing mAb. Single mutations in F abolish mAb binding and neutralization. In these complexes, the HN protein that normally restrains F triggering has shifted to uncap the F apex. These complexes are more readily triggered to fuse. These structures shed light on the adaptability of the pre-fusion HN-F complex and mechanisms of paramyxoviral resistance to mAbs, and help define potential barriers to resistance for the design of mAbs.}, }
@article {pmid39395534, year = {2024}, author = {Henry, NL and Unger, JM and Vaidya, R and Darke, AK and Skaar, TC and Fisch, MJ and Hershman, DL}, title = {Active symptom monitoring for premenopausal women with breast cancer initiating adjuvant endocrine therapy: Protocol for the SWOG S2010 randomized controlled efficacy trial.}, journal = {Contemporary clinical trials}, volume = {147}, number = {}, pages = {107712}, doi = {10.1016/j.cct.2024.107712}, pmid = {39395534}, issn = {1559-2030}, abstract = {BACKGROUND: Premenopausal women with early stage, high risk hormone receptor positive breast cancer are at risk of early discontinuation of adjuvant endocrine therapy (ET), primarily because of toxicity, which can increase the risk of disease recurrence and death. We hypothesize that identification of bothersome symptoms between clinic visits, and automated notification of clinicians about symptoms, will result in improved persistence with ET.
METHODS: Pre- and perimenopausal women planning to receive adjuvant treatment with tamoxifen or an aromatase inhibitor plus ovarian function suppression or ablation for treatment of breast cancer are eligible. A total of 540 participants will be enrolled and randomized 1:1 to patient education with or without Active Symptom Monitoring (ASM). The ASM intervention includes 6 symptom questions (hot flashes, sadness, anxiety, insomnia, vaginal dryness, joint pain) that will be completed via text, email, or telephone weekly for 24 weeks, then every 4 weeks for 48 weeks. All participants will complete a battery of questionnaires every 12 weeks to examine symptoms, beliefs about medicine, self-efficacy, and ET adherence. Optional blood draws will be collected at baseline and after 12, 48, and 72 weeks of therapy to examine estradiol and ET concentrations. The primary endpoint is time to nonpersistence with initially prescribed ET within the first 72 weeks, evaluated using Kaplan-Meier plots and multivariable Cox regression.
CONCLUSION: We expect early identification and management of ET-related toxicities to improve persistence with breast cancer therapy, breast cancer outcomes, and quality of life for premenopausal women at high risk of breast cancer recurrence.
CLINICALTRIALS: govNCT05568472.}, }
@article {pmid39395448, year = {2024}, author = {Zhu, A and Psutka, SP}, title = {Editorial Comment on "Comparing Frailty Indices for Risk Stratification in Urologic Oncology: Which Index to Choose?" How Should We Measure Frailty? More Importantly, Is That Enough?.}, journal = {Urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urology.2024.10.009}, pmid = {39395448}, issn = {1527-9995}, }
@article {pmid39387238, year = {2024}, author = {Khanijow, K and Rosendale, N and Wright, S and Lee, RS and Nass, S and Keniston, A and Dalal, M and Jager, LR and Anstett, T}, title = {Characterizing hospitalists' comfort and familiarity with LGBTQ clinical topics.}, journal = {Hospital practice (1995)}, volume = {}, number = {}, pages = {}, doi = {10.1080/21548331.2024.2414734}, pmid = {39387238}, issn = {2154-8331}, support = {UL1 TR003098/TR/NCATS NIH HHS/United States ; }, abstract = {OBJECTIVES: Evidence has shown that lesbian, gay, bisexual, queer (LGBQ) and transgender patients (LGBTQ) experience disparities in health care delivery and clinical outcomes. As the predominant U.S. inpatient provider workforce, this paper's objective was to understand hospitalists' comfort with LGBTQ health.
METHODS: A 58-question anonymous online survey was distributed in 2019 to practicing hospitalists through the Society of Hospital Medicine regarding their experiences in caring for hospitalized LGBTQ patients.
RESULTS: Two hundred and eighteen hospitalist providers completed the entire survey. While hospitalists reported high levels of comfort in caring for these populations (LGBQ: 90.6%, Transgender: 77.8%), they acknowledged feeling less confident in their clinical competence (LGBQ: 71.6%, Transgender: 51.2%). Hospitalist providers who were themselves LGBQ reported more comfort with most aspects of LGBQ patient clinical care than heterosexual respondents (p < 0.05 for 4 of 6 comfort variables). Seventy-four percent of hospitalists wanted training to advance their knowledge and skills in working with LGBTQ patients.
CONCLUSIONS: Hospitalist clinicians are regularly exposed to LGBTQ patients yet their comfort and expertise in caring for this vulnerable population is highly variable. Educational interventions that include reflective practice may serve to optimize hospitalists' ability to more confidently and competently serve LGBTQ patients.}, }
@article {pmid39394376, year = {2024}, author = {Ogimi, C and Xie, H and Waghmare, A and Jerome, KR and Leisenring, WM and Ueda Oshima, M and Carpenter, PA and Englund, JA and Boeckh, M}, title = {Correction: Novel factors to predict respiratory viral disease progression in allogeneic hematopoietic cell transplant recipients.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-024-02418-9}, pmid = {39394376}, issn = {1476-5365}, }
@article {pmid39394013, year = {2024}, author = {Gillessen, S and Turco, F and Davis, ID and Efstathiou, JA and Fizazi, K and James, ND and Shore, N and Small, E and Smith, M and Sweeney, CJ and Tombal, B and Zilli, T and Agarwal, N and Antonarakis, ES and Aparicio, A and Armstrong, AJ and Bastos, DA and Attard, G and Axcrona, K and Ayadi, M and Beltran, H and Bjartell, A and Blanchard, P and Bourlon, MT and Briganti, A and Bulbul, M and Buttigliero, C and Caffo, O and Castellano, D and Castro, E and Cheng, HH and Chi, KN and Clarke, CS and Clarke, N and de Bono, JS and De Santis, M and Duran, I and Efstathiou, E and Ekeke, ON and El Nahas, TIH and Emmett, L and Fanti, S and Fatiregun, OA and Feng, FY and Fong, PCC and Fonteyne, V and Fossati, N and George, DJ and Gleave, ME and Gravis, G and Halabi, S and Heinrich, D and Herrmann, K and Hofman, MS and Hope, TA and Horvath, LG and Hussain, MHA and Jereczek-Fossa, BA and Jones, RJ and Joshua, AM and Kanesvaran, R and Keizman, D and Khauli, RB and Kramer, G and Loeb, S and Mahal, BA and Maluf, FC and Mateo, J and Matheson, D and Matikainen, MP and McDermott, R and McKay, RR and Mehra, N and Merseburger, AS and Morgans, AK and Morris, MJ and Mrabti, H and Mukherji, D and Murphy, DG and Murthy, V and Mutambirwa, SBA and Nguyen, PL and Oh, WK and Ost, P and O'Sullivan, JM and Padhani, AR and Parker, C and Poon, DMC and Pritchard, CC and Rabah, DM and Rathkopf, D and Reiter, RE and Renard-Penna, R and Ryan, CJ and Saad, F and Sade, JP and Sandhu, S and Sartor, OA and Schaeffer, E and Scher, HI and Sharifi, N and Skoneczna, IA and Soule, HR and Spratt, DE and Srinivas, S and Sternberg, CN and Suzuki, H and Taplin, ME and Thellenberg-Karlsson, C and Tilki, D and Türkeri, LN and Uemura, H and Ürün, Y and Vale, CL and Vapiwala, N and Walz, J and Yamoah, K and Ye, D and Yu, EY and Zapatero, A and Omlin, A}, title = {Management of Patients with Advanced Prostate Cancer. Report from the 2024 Advanced Prostate Cancer Consensus Conference (APCCC).}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.09.017}, pmid = {39394013}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024.
METHODS: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists").
KEY FINDINGS AND LIMITATIONS: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis.
The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.}, }
@article {pmid39392812, year = {2024}, author = {Sharma, V and Fadel, A and Tollefson, MK and Psutka, SP and Blezek, DJ and Frank, I and Thapa, P and Tarrell, R and Viers, LD and Potretzke, AM and Hartman, RP and Boorjian, SA and Viers, BR}, title = {Artificial Intelligence-Based Assessment of Preoperative Body Composition is Associated With Early Complications After Radical Cystectomy.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000004292}, doi = {10.1097/JU.0000000000004292}, pmid = {39392812}, issn = {1527-3792}, abstract = {PURPOSE: We aimed to use a validated artificial intelligence (AI) algorithm to extract muscle and adipose areas from CT images before radical cystectomy (RCx) and then correlate these measures with 90-day post-RCx complications.
MATERIALS AND METHODS: A tertiary referral center's cystectomy registry was queried for patients who underwent RCx between 2009 and 2017 for bladder cancer. Eight hundred forty-three RCx patients with CT imaging within 90 days of preceding surgery were included, to allow for extraction of body composition parameters by AI. We assessed complications within 90 days of surgery including wound, infectious, and major complications; readmission; and death. Multivariable logistic regressions associated pre-RCx measures with post-RCx complications.
RESULTS: Increasing subcutaneous adipose tissue was associated with more wound complications, while patients with increasing visceral adipose tissue had greater odds of infectious-related complications. After adjusting for patient characteristics, every 10 cm[2] increases in fat mass index were associated with more infectious (OR, 1.04; P = .002) and wound (OR, 1.06; P < .001) complications. On multivariable analysis, a higher preoperative skeletal muscle index was associated with lower odds of major complications (OR, 0.75 for every 10 cm[2]; P = .008), while higher intramuscular adipose was associated with higher odds of major complications (OR, 1.93; P = .008).
CONCLUSIONS: Automated AI body composition measurements preoperatively are associated with post-RCx complications. These measurements, in addition to patient (ECOG performance status and smoking status) and surgical (robotic approach and continent diversion) characteristics, can then be used to individualize patient counseling and facilitate triage of nutritional and rehabilitation efforts.}, }
@article {pmid39391570, year = {2024}, author = {Brown, MC and Snidarich, M and Budak, JZ and Murphy, N and Giustini, N and Romine, PE and Weiner, BJ and Caverly, T and Crothers, K and Triplette, M}, title = {Adaptation of a Tailored Lung Cancer Screening Decision Aid for People With HIV.}, journal = {CHEST pulmonary}, volume = {2}, number = {3}, pages = {}, pmid = {39391570}, issn = {2949-7892}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: People with HIV are both at elevated risk of lung cancer and at high risk of multimorbidity, which makes shared decision-making (SDM) for lung cancer screening (LCS) in people with HIV complex. Currently no known tools have been adapted for SDM in people with HIV.
RESEARCH QUESTION: Can an SDM decision aid be adapted to include HIV-specific measures with input from both people with HIV and their providers?
STUDY DESIGN AND METHODS: This study used qualitative methods including focus groups of people with HIV and interviews with HIV care providers to adapt and iterate an SDM tool for people with HIV. Eligible participants were those with HIV enrolled in an HIV primary care clinic who met age and smoking eligibility criteria for LCS and HIV care providers at the clinic. Both the focus groups and interviews included semistructured discussions of SDM and decision aid elements for people with HIV. We used a framework-guided thematic analysis, mapping themes onto the Health Equity Implementation framework.
RESULTS: Forty-three people with HIV participated in eight focus groups; 10 providers were interviewed. Key themes from patients included broad interest in adapting LCS SDM specifically for people with HIV, a preference for clear LCS recommendations, and the need for positive framing emphasizing survival. Providers were enthusiastic about personalized LCS risk assessments and point-of-care tools. Both patients and providers gave mixed views on the usefulness of HIV-specific risk measures in patient-facing tools. Themes were used to adapt a personalized and flexible SDM tool for LCS in people with HIV.
INTERPRETATION: People with HIV and providers were enthusiastic about specific tools for SDM that are personalized and tailored for people with HIV, that make recommendations, and that inform LCS decision-making. Divergent views on presenting patient-facing quantitative risk assessments suggests that these elements could be optional but available for review. This tool may have usefulness in complex decision-making for LCS in this population and currently is being evaluated in a pilot prospective trial.}, }
@article {pmid39389851, year = {2024}, author = {Swank, Z and Borberg, E and Chen, Y and Senussi, Y and Chalise, S and Manickas-Hill, Z and Yu, XG and Li, JZ and Alter, G and Henrich, TJ and Kelly, JD and Hoh, R and Goldberg, SA and Deeks, SG and Martin, JN and Peluso, MJ and Talla, A and Li, X and Skene, P and Bumol, TF and Torgerson, TR and Czartoski, JL and McElrath, MJ and Karlson, EW and Walt, DR and , }, title = {Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study.}, journal = {Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cmi.2024.09.001}, pmid = {39389851}, issn = {1469-0691}, abstract = {OBJECTIVES: To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detection with postacute sequelae of COVID-19 (PASC) symptoms.
METHODS: Plasma and serum samples were collected from adults participating in four independent studies at different time points, ranging from several days up to 14 months post-SARS-CoV-2 infection. The primary outcome measure was to quantify SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid, in participant samples. The presence of 34 commonly reported PASC symptoms during the postacute period was determined from participant surveys or chart reviews of electronic health records.
RESULTS: Of the 1569 samples analysed from 706 individuals infected with SARS-CoV-2, 21% (95% CI, 18-24%) were positive for either S1, spike, or nucleocapsid. Spike was predominantly detected, and the highest proportion of samples was spike positive (20%; 95% CI, 18-22%) between 4 and 7 months postinfection. In total, 578 participants (82%) reported at least one of the 34 PASC symptoms included in our analysis ≥1 month postinfection. Cardiopulmonary, musculoskeletal, and neurologic symptoms had the highest reported prevalence in over half of all participants, and among those participants, 43% (95% CI, 40-45%) on average were antigen-positive. Among the participants who reported no ongoing symptoms (128, 18%), antigen was detected in 28 participants (21%). The presence of antigen was associated with the presence of one or more PASC symptoms, adjusting for sex, age, time postinfection, and cohort (OR, 1.8; 95% CI, 1.4-2.2).
DISCUSSION: The findings of this multicohort study indicate that SARS-CoV-2 antigens can be detected in the blood of a substantial proportion of individuals up to 14 months after infection. While approximately one in five asymptomatic individuals was antigen-positive, roughly half of all individuals reporting ongoing cardiopulmonary, musculoskeletal, and neurologic symptoms were antigen-positive.}, }
@article {pmid39388026, year = {2024}, author = {Chen, JG and Zhang, YH and Lu, JH and Kensler, TW}, title = {Liver Cancer Etiology: Old Issues and New Perspectives.}, journal = {Current oncology reports}, volume = {}, number = {}, pages = {}, pmid = {39388026}, issn = {1534-6269}, abstract = {PURPOSE OF REVIEW: This review aims to synthesize the old issues and current understandings of the etiology of liver cancer, focusing on the diverse causative factors influenced by geographical, socioeconomic, and lifestyle variations across different regions.
RECENT FINDINGS: We highlight significant geographic disparities in liver cancer risk factors. While hepatitis B and C viruses, aflatoxin exposure, and alcohol consumption remain globally established contributors; metabolic dysfunction-associated steatotic liver disease and metabolic syndromes are increasingly prominent in the West. Chronic HBV and aflatoxin continue to dominate as risk factors in Asia and Africa. Dietary factors, metabolic diseases like diabetes and obesity, genetic predispositions, environmental risk factors and lifestyle choices such as smoking and alcohol use play substantial roles in specific populations. Protective factors like coffee and tea consumption, along with aspirin use, vegetables and fruits have shown potential in reducing HCC risk, although findings vary by population and dietary habits. Liver cancer etiology is influenced by various factors that differ by region. Established risk factors include hepatitis B and C, aflatoxin, and alcohol. Emerging risks, such as metabolic dysfunction-associated steatotic liver disease, are more prevalent in Western countries, while aflatoxin and HBV remains significant in Asia and Africa. Diet, metabolic conditions like diabetes and obesity, genetic predispositions, and lifestyle choices also play crucial roles. Coffee, tea, aspirin, vegetables, and fruits may reduce HCC risk, but effectiveness varies. Future research should integrate epidemiology, genetics, and nutrition, with global cooperation and data sharing essential for effective cancer control strategies.}, }
@article {pmid39388304, year = {2024}, author = {Bryce, Y and Whitton, JA and Stratton, KL and Leisenring, WM and Chow, EJ and Armstrong, G and Weil, B and Dieffenbach, B and Howell, RM and Oeffinger, KC and Nathan, PC and Tonorezos, ES}, title = {Prevalence of carotid ultrasound screening in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35591}, pmid = {39388304}, issn = {1097-0142}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; U24 CA55727//Childhood Cancer Survivor Study/ ; P30 CA 008748//Vickers/ ; }, abstract = {INTRODUCTION: Many childhood cancer survivors are at risk for cardiovascular disease and stroke. The North American Children's Oncology Group long-term follow-up guidelines recommend carotid ultrasound in cancer survivors 10 years after neck radiation therapy (RT) ≥40 Gy. The use of carotid ultrasound in this population has not been described.
METHODS: Survivors of childhood cancer diagnosed 1970-1999 (N = 8693) and siblings (N = 1989) enrolled in the Childhood Cancer Survivor Study were asked if they had ever had a carotid ultrasound. Prevalence of carotid ultrasound was evaluated. Prevalence ratios (PR) and 95% confidence intervals (CIs) were evaluated in multivariate Poisson regression models.
RESULTS: Among participants with no reported cardiovascular condition, prevalence of carotid ultrasound among survivors with RT ≥40 Gy to the neck (N = 172) was 29.7% (95% CI, 22.5-36.8), significantly higher than those with <40 Gy (prevalence 10.7%; 95% CI, 9.9%-11.4%). Siblings without a cardiovascular condition (N = 1621) had the lowest prevalence of carotid ultrasound (4.7%; 95% CI, 3.6%-5.7%). In a multivariable models among survivors with no reported cardiovascular condition and RT ≥40 Gy to the neck, those who were over age 50 (vs. 18-49) at follow-up (PR = 1.82; 95% CI, 1.09-3.05), with a history of seeing a cancer specialist in the last 2 years (PR = 2.58; 95% CI, 1.53-4.33), or having a colonoscopy (PR = 2.02; 95% CI, 1.17-3.48) or echocardiogram (PR = 6.42; 95% CI, 1.54-26.85) were more likely to have had a carotid ultrasound.
CONCLUSION: Many survivors do not undergo carotid ultrasound despite meeting existing guidelines. Health care delivery features such as having seen a cancer specialist or having other testing are relevant.}, }
@article {pmid39386724, year = {2024}, author = {Alassaf, M and Rajan, A}, title = {Adipocyte metabolic state regulates glial phagocytic function.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386724}, issn = {2692-8205}, support = {P40 OD018537/OD/NIH HHS/United States ; R35 GM124593/GM/NIGMS NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; }, abstract = {Obesity and type 2 diabetes are well-established risk factors for neurodegenerative disorders[1-4], yet the underlying mechanisms remain poorly understood. The adipocyte-brain axis is crucial for brain function, as adipocytes secrete signaling molecules, including lipids and adipokines, that impinge on neural circuits to regulate feeding and energy expenditure[5]. Disruptions in the adipocyte-brain axis are associated with neurodegenerative conditions[6], but the causal links are not fully understood. Neural debris accumulates with age and injury, and glial phagocytic function is crucial for clearing this debris and maintaining a healthy brain microenvironment[7-9]. Using adult Drosophila, we investigate how adipocyte metabolism influences glial phagocytic activity in the brain. We demonstrate that a prolonged obesogenic diet increases adipocyte fatty acid oxidation and ketogenesis. Genetic manipulations that mimic obesogenic diet-induced changes in adipocyte lipid and mitochondrial metabolism unexpectedly reduce the expression of the phagocytic receptor Draper in Drosophila microglia-like cells in the brain. We identify Apolpp-the Drosophila equivalent of human apolipoprotein B (ApoB)-as a critical adipocyte-derived signal that regulates glial phagocytosis. Additionally, we show that Lipoprotein Receptor 1 (LpR1), the LDL receptor on phagocytic glia, is required for glial capacity to clear injury-induced neuronal debris. Our findings establish that adipocyte-brain lipoprotein signaling regulates glial phagocytic function, revealing a novel pathway that links adipocyte metabolic disorders with neurodegeneration.}, }
@article {pmid39386474, year = {2024}, author = {Freie, B and Ibrahim, AH and Carroll, PA and Bronson, RT and Augert, A and MacPherson, D and Eisenman, RN}, title = {MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386474}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA248762/CA/NCI NIH HHS/United States ; R35 CA231989/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Surprisingly, inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Delet-ing Max across multiple mouse neuroendocrine tissues, we find Max inactivation alone produces pituitary adenomas while Max loss cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C-cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a striking shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.}, }
@article {pmid39386462, year = {2024}, author = {Wellington, R and Cheng, X and Campbell, CA and Trapnell, C and Espin-Palazon, R and Hadland, B and Doulatov, S}, title = {Developmental regulation of endothelial-to-hematopoietic transition from induced pluripotent stem cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386462}, issn = {2692-8205}, support = {RC2 DK127989/DK/NIDDK NIH HHS/United States ; R01 HL169156/HL/NHLBI NIH HHS/United States ; R01 DK131162/DK/NIDDK NIH HHS/United States ; DP2 HL147126/HL/NHLBI NIH HHS/United States ; R01 HL168110/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; }, abstract = {Hematopoietic stem cells (HSCs) arise in embryogenesis from a specialized hemogenic endothelium (HE). In this process, HE cells undergo a unique fate change termed endothelial-to-hematopoietic transition, or EHT. While induced pluripotent stem cells (iPSCs) give rise to HE with robust hemogenic potential, the generation of bona fide HSCs from iPSCs remains a challenge. Here, we map single cell dynamics of EHT during embryoid body differentiation from iPSCs and integrate it with human embryo datasets to identify key transcriptional differences between in vitro and in vivo cell states. We further map ligand-receptor interactions associated with differential expression of developmental programs in the iPSC system. We found that the expression of endothelial genes was incompletely repressed during iPSC EHT. Elevated FGF signaling by FGF23, an endothelial pathway ligand, was associated with differential gene expression between in vitro and in vivo EHT. Chemical inhibition of FGF signaling during EHT increased HSPC generation in the zebrafish, while an FGF agonist had the opposite effect. Consistently, chemical inhibition of FGF signaling increased hematopoietic output from iPSCs. In summary, we map the dynamics of EHT from iPSCs at single cell resolution and identify ligand-receptor interactions that can be modulated to improve iPSC differentiation protocols. We show, as proof of principle, that chemical inhibition of FGF signaling during EHT improves hematopoietic output in zebrafish and the iPSC system.}, }
@article {pmid39386436, year = {2024}, author = {Nguyen, TNH and Horowitz, LF and Nguyen, B and Lockhart, E and Zhu, S and Gujral, TS and Folch, A}, title = {Microfluidic Modulation of Microvasculature in Microdissected Tumors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39386436}, issn = {2692-8205}, support = {R01 CA181445/CA/NCI NIH HHS/United States ; R01 CA272677/CA/NCI NIH HHS/United States ; }, abstract = {The microvasculature within the tumor microenvironment (TME) plays an essential role in cancer signaling beyond nutrient delivery. However, it has been challenging to control the generation and/or maintenance of microvasculature in ex vivo systems, a critical step for establishing cancer models of high clinical biomimicry. There have been great successes in engineering tissues incorporating microvasculature de novo (e.g., organoids and organs-on-chip), but these reconstituted tissues are formed with non-native cellular and molecular components that can skew certain outcomes such as drug efficacy. Microdissected tumors, on the other hand, show promise in preserving the TME, which is key for creating cancer models that can bridge the gap between bench and bedside. However, microdissected tumors are challenging to perfuse. Here, we developed a microfluidic platform that allows for perfusing the microvasculature of microdissected tumors. We demonstrate that, compared to diffusive transport, microfluidically perfused tissues feature larger and longer microvascular structures, with a better expression of CD31, a marker for endothelial cells, as analyzed by 3D imaging. This study also explores the effects of nitric oxide pathway-related drugs on endothelial cells, which are sensitive to shear stress and can activate endothelial nitric oxide synthase, producing nitric oxide. Our findings highlight the critical role of controlled perfusion and biochemical modulation in preserving tumor microvasculature, offering valuable insights for developing more effective cancer treatments.}, }
@article {pmid39385741, year = {2024}, author = {Mosna, F and Borlenghi, E and Litzow, M and Byrd, JC and Papayannidis, C and Tecchio, C and Ferrara, F and Marcucci, G and Cairoli, R and Morgan, EA and Gurrieri, C and Yeung, CCS and Deeg, HJ and Capelli, D and Candoni, A and Gotlib, JR and Lunghi, M and Pullarkat, S and Lanza, F and Galimberti, S and Forghieri, F and Venditti, A and Festuccia, M and Audisio, E and Marvalle, D and Rigolin, GM and Roti, G and DiBona, E and Visani, G and Albano, F and Eisfeld, AK and Valent, P and Huls, G and Borthakur, G and Krampera, M and Martinelli, G and Kröger, N and Sperotto, A and Gottardi, M}, title = {Long-term survival can be achieved in a significant fraction of older patients with core binding factor acute myeloid leukemia treated with intensive chemotherapy.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.285448}, pmid = {39385741}, issn = {1592-8721}, abstract = {Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event - free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of >70-year patients who completed intensive therapy (induction + >3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 - 15.2) and OS was 40.0% (95%CI, 36.4 - 44.1) at 5yr. In univariate analysis, age >70 (hazard ratio (HR) 1.78, [95%CI, 1.15 - 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 - 13.8], p=<.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 - 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 - 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.}, }
@article {pmid39385266, year = {2024}, author = {Saldarriaga, EM and Chen, Y and Montaño, MA and Thuo, N and Kiptinness, C and Terris-Prestholt, F and Stergachis, A and Mugambi, ML and Ngure, K and Ortblad, KF and Sharma, M}, title = {Preferences for pre-exposure prophylaxis delivery via online pharmacy among potential users in Kenya: a discrete choice experiment.}, journal = {Journal of the International AIDS Society}, volume = {27}, number = {10}, pages = {e26356}, pmid = {39385266}, issn = {1758-2652}, support = {INV-037646/GATES/Bill & Melinda Gates Foundation/United States ; INV 035424//Bill and Melinda Gates Foundation/ ; INV-035932/GATES/Bill & Melinda Gates Foundation/United States ; INV-038498/GATES/Bill & Melinda Gates Foundation/United States ; }, mesh = {Humans ; *Pre-Exposure Prophylaxis/methods ; Kenya ; Male ; Female ; *HIV Infections/prevention & control ; Adult ; Young Adult ; Adolescent ; Middle Aged ; Anti-HIV Agents/therapeutic use/administration & dosage ; Pharmaceutical Services, Online ; Patient Preference ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) is highly effective, but coverage remains low in high HIV prevalence settings. Initiating and continuing PrEP remotely via online pharmacies is a promising strategy to expand PrEP uptake, but little is known about potential users' preferences.
METHODS: We conducted a discrete choice experiment (DCE) to assess preferences for online pharmacy PrEP services. We partnered with MYDAWA, an online pharmacy in Nairobi, Kenya. Eligibility criteria were: ≥18 years, not known HIV positive, interested in PrEP. The DCE contained four attributes: PrEP eligibility assessment (online self-assessed, guided), HIV test type (provider administered, oral HIV self-test [HIVST], blood-based HIVST), clinical consultation (remote, in-person) and user support options (text messages, phone/video call, email). Additionally, participants indicated whether they were willing to uptake their selected service. The survey was advertised on MYDAWA's website; interested participants met staff in-person at a convenient location to complete the survey from 1 June to 20 November 2022. We used conditional logit modelling with an interaction by current PrEP use to estimate overall preferences and latent class analysis (LCA) to assess preference heterogeneity.
RESULTS: Overall, 772 participants completed the DCE; the mean age was 25 years and 54% were female. Most participants indicated a willingness to acquire online PrEP services, with particularly high demand among PrEP-naive individuals. Overall, participants preferred remote clinical consultation, HIV self-testing, online self-assessment and phone call user support. The LCA identified three subgroups: the "prefer online PrEP with remote components" group (60.3% of the sample) whose preferences aligned with the main analysis, the "prefer online PrEP with in-person components" group (20.7%), who preferred in-person consultation, provider-administered HIV testing, and guided assessment, and the "prefer remote PrEP (18.9%)" group who preferred online PrEP services only if they were remote.
CONCLUSIONS: Online pharmacy PrEP is highly acceptable and may expand PrEP coverage to those interested in PrEP but not accessing services. Most participants valued privacy and autonomy, preferring HIVST and remote provider interactions. However, when needing support for questions regarding PrEP, participants preferred phone/SMS contact with a provider. One-fifth of participants preferred online PrEP with in-person components, suggesting that providing multiple options can increase uptake.}, }
@article {pmid39385257, year = {2024}, author = {Edwards, LA and Yang, C and Sharma, S and Chen, ZH and Gorantla, L and Joshi, SA and Longhi, NJ and Worku, N and Yang, JS and Martinez Di Pietro, B and Armenian, S and Bhat, A and Border, W and Buddhe, S and Blythe, N and Stratton, K and Leger, KJ and Leisenring, WM and Meacham, LR and Nathan, PC and Narasimhan, S and Sachdeva, R and Sadak, K and Chow, EJ and Boyle, PM}, title = {Building a machine learning-assisted echocardiography prediction tool for children at risk for cancer therapy-related cardiomyopathy.}, journal = {Cardio-oncology (London, England)}, volume = {10}, number = {1}, pages = {66}, pmid = {39385257}, issn = {2057-3804}, support = {R21 CA277746/CA/NCI NIH HHS/United States ; CA277746//National Cancer Institute of the National Institutes of Health/ ; }, abstract = {BACKGROUND: Despite routine echocardiographic surveillance for childhood cancer survivors, the ability to predict cardiomyopathy risk in individual patients is limited. We explored the feasibility and optimal processes for machine learning-enhanced cardiomyopathy prediction in survivors using serial echocardiograms from five centers.
METHODS: We designed a series of deep convolutional neural networks (DCNNs) for prediction of cardiomyopathy (shortening fraction ≤ 28% or ejection fraction ≤ 50% on two occasions) for at-risk survivors ≥ 1-year post initial cancer therapy. We built DCNNs with four subsets of echocardiographic data differing in timing relative to case (survivor who developed cardiomyopathy) index diagnosis and two input formats (montages) with differing image selections. We used holdout subsets in a 10-fold cross-validation framework and standard metrics to assess model performance (e.g., F1-score, area under the precision-recall curve [AUPRC]). Performance of the input formats was compared using a combined 5 × 2 cross-validation F-test.
RESULTS: The dataset included 542 pairs of montages: 171 montage pairs from 45 cases at time of cardiomyopathy diagnosis or pre-diagnosis and 371 pairs from 70 at-risk survivors who didn't develop cardiomyopathy during follow-up (non-case). The DCNN trained to distinguish between non-case and time of cardiomyopathy diagnosis or pre-diagnosis case montages achieved an AUROC of 0.89 ± 0.02, AUPRC 0.83 ± 0.03, and F1-score: 0.76 ± 0.04. When limited to smaller subsets of case data (e.g., ≥ 1 or 2 years pre-diagnosis), performance worsened. Model input format did not impact performance accuracy across models.
CONCLUSIONS: This methodology is a promising first step toward development of a DCNN capable of accurately differentiating pre-diagnosis versus non-case echocardiograms to predict survivors more likely to develop cardiomyopathy.}, }
@article {pmid39384953, year = {2024}, author = {Appelbaum, FR}, title = {Offering patients a second chance: what is the minimum cure rate needed to justify allogeneic hematopoietic cell transplantation?.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {39384953}, issn = {1476-5551}, }
@article {pmid39384951, year = {2024}, author = {Anczukow, O and Allain, FH and Angarola, BL and Black, DL and Brooks, AN and Cheng, C and Conesa, A and Crosse, EI and Eyras, E and Guccione, E and Lu, SX and Neugebauer, KM and Sehgal, P and Song, X and Tothova, Z and Valcárcel, J and Weeks, KM and Yeo, GW and Thomas-Tikhonenko, A}, title = {Steering research on mRNA splicing in cancer towards clinical translation.}, journal = {Nature reviews. Cancer}, volume = {}, number = {}, pages = {}, pmid = {39384951}, issn = {1474-1768}, abstract = {Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also 'moonlight' in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. To start with, the general landscape of splicing aberrations in cancer is not well defined, due to limitations of short-read RNA sequencing not adept at resolving complete mRNA isoforms, as well as the shallow read depth inherent in long-read RNA-sequencing, especially at single-cell level. Although individual cancer-associated isoforms are known to contribute to cancer progression, widespread splicing alterations could be an equally important and, perhaps, more readily actionable feature of human cancers. This is to say that in addition to 'repairing' mis-spliced transcripts, possible therapeutic avenues include exacerbating splicing aberration with small-molecule spliceosome inhibitors, targeting recurrent splicing aberrations with synthetic lethal approaches, and training the immune system to recognize splicing-derived neoantigens.}, }
@article {pmid39384807, year = {2024}, author = {Minot, SS and Li, N and Srinivasan, H and Ayers, JL and Yu, M and Koester, ST and Stangis, MM and Dominitz, JA and Halberg, RB and Grady, WM and Dey, N}, title = {Colorectal cancer-associated bacteria are broadly distributed in global microbiomes and drivers of precancerous change.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {23646}, pmid = {39384807}, issn = {2045-2322}, support = {K08 DK111941/DK/NIDDK NIH HHS/United States ; R50 CA233042/CA/NCI NIH HHS/United States ; U54 CA274374/CA/NCI NIH HHS/United States ; R50CA233042//U.S. Department of Health and Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {*Colorectal Neoplasms/microbiology/genetics ; *Gastrointestinal Microbiome/genetics ; Animals ; Humans ; Mice ; *Bacteria/genetics/classification ; *Precancerous Conditions/microbiology ; Metagenomics/methods ; }, abstract = {The gut microbiome is implicated in the pathogenesis of colorectal cancer (CRC), but the full scope of this dialogue is unknown. Here we aimed to define the scale and membership of the body of CRC- and health-associated gut bacteria in global populations. We performed a microbiome-CRC correlation analysis of published ultra-deep shotgun metagenomic sequencing data from global microbiome surveys, utilizing a de novo (reference-agnostic) gene-level clustering approach to identify protein-coding co-abundant gene (CAGs) clusters. We link an unprecedented ~ 23-40% of gut bacteria to CRC or health, split nearly evenly as CRC- or health-associated. These microbes encode 2319 CAGs encompassing 427,261 bacterial genes significantly enriched or depleted in CRC. We identified many microbes that had not previously been linked to CRC, thus expanding the scope of "known unknowns" of CRC-associated microbes. We performed an agnostic CAG-based screen of bacterial isolates and validated predicted effects of previously unimplicated bacteria in preclinical models, in which we observed differential induction of precancerous adenomas and field effects. Single-cell RNA sequencing disclosed microbiome-induced senescence-associated gene expression signatures in discrete colonic populations including fibroblasts. In organoid co-cultures, primary colon fibroblasts from mice with microbiomes promoted significantly greater growth than fibroblasts from microbiome-depleted mice. These results offer proof-of-principle for gene-level metagenomic analysis enabling discovery of microbiome links to health and demonstrate that the microbiome can drive precancer states, thereby potentially revealing novel cancer prevention opportunities.}, }
@article {pmid39384761, year = {2024}, author = {Rocheleau, G and Clarke, SL and Auguste, G and Hasbani, NR and Morrison, AC and Heath, AS and Bielak, LF and Iyer, KR and Young, EP and Stitziel, NO and Jun, G and Laurie, C and Broome, JG and Khan, AT and Arnett, DK and Becker, LC and Bis, JC and Boerwinkle, E and Bowden, DW and Carson, AP and Ellinor, PT and Fornage, M and Franceschini, N and Freedman, BI and Heard-Costa, NL and Hou, L and Chen, YI and Kenny, EE and Kooperberg, C and Kral, BG and Loos, RJF and Lutz, SM and Manson, JE and Martin, LW and Mitchell, BD and Nassir, R and Palmer, ND and Post, WS and Preuss, MH and Psaty, BM and Raffield, LM and Regan, EA and Rich, SS and Smith, JA and Taylor, KD and Yanek, LR and Young, KA and , and Hilliard, AT and Tcheandjieu, C and Peyser, PA and Vasan, RS and Rotter, JI and Miller, CL and Assimes, TL and de Vries, PS and Do, R}, title = {Rare variant contribution to the heritability of coronary artery disease.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8741}, pmid = {39384761}, issn = {2041-1723}, support = {R01 HL139731/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R35 GM124836/GM/NIGMS NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; S10 OD026880/OD/NIH HHS/United States ; R35-GM124836//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 HL146860/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; R01 HL157635/HL/NHLBI NIH HHS/United States ; HHSN268201600033C/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; HHSN268201100037C/HL/NHLBI NIH HHS/United States ; R01 HL112064/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; R01 HL121007/HL/NHLBI NIH HHS/United States ; R01-HL139865, R01-HL155915//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL139865/HL/NHLBI NIH HHS/United States ; R01 HL089856/HL/NHLBI NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; UM1 HG008853/HG/NHGRI NIH HHS/United States ; HHSN268201500015C/HL/NHLBI NIH HHS/United States ; R01 HL164577/HL/NHLBI NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; R01 HL148239/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; R01 HL155915/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Coronary Artery Disease/genetics ; *Genetic Predisposition to Disease ; *Linkage Disequilibrium ; *Polymorphism, Single Nucleotide ; Male ; Female ; Gene Frequency ; Genome-Wide Association Study ; White People/genetics ; Case-Control Studies ; Whole Genome Sequencing ; Genetic Variation ; Middle Aged ; }, abstract = {Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.}, }
@article {pmid39384759, year = {2024}, author = {Crook, ZR and Sevilla, GP and Young, P and Girard, EJ and Phi, TD and Howard, ML and Price, J and Olson, JM and Nairn, NW}, title = {CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8731}, pmid = {39384759}, issn = {2041-1723}, support = {R01 CA223674/CA/NCI NIH HHS/United States ; R01-CA223674//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Proteolysis/drug effects ; *Receptors, Transferrin/metabolism ; Animals ; Cell Line, Tumor ; *ErbB Receptors/metabolism ; *Lysosomes/metabolism ; Mice ; Carcinoma, Non-Small-Cell Lung/metabolism/drug therapy/genetics/pathology ; Hydrogen-Ion Concentration ; B7-H1 Antigen/metabolism ; Female ; Lung Neoplasms/metabolism/drug therapy/genetics ; Catalysis ; Endosomes/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal delivery of surface and extracellular targets while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer.}, }
@article {pmid39383036, year = {2024}, author = {Scharffenberger, SC and Wan, YH and Homad, LJ and Kher, G and Haynes, AM and Poudel, B and Sinha, IR and Aldridge, N and Pai, A and Bibby, M and Chhan, CB and Davis, AR and Moodie, Z and Palacio, MB and Escolano, A and McElrath, MJ and Boonyaratanakornkit, J and Pancera, M and McGuire, AT}, title = {Targeting RSV-neutralizing B cell receptors with anti-idiotypic antibodies.}, journal = {Cell reports}, volume = {43}, number = {10}, pages = {114811}, pmid = {39383036}, issn = {2211-1247}, mesh = {*Antibodies, Neutralizing/immunology ; Animals ; *Receptors, Antigen, B-Cell/immunology/metabolism ; Humans ; *Antibodies, Anti-Idiotypic/immunology/pharmacology ; Mice ; B-Lymphocytes/immunology ; Respiratory Syncytial Virus Infections/immunology ; Respiratory Syncytial Viruses/immunology ; Antibodies, Monoclonal/immunology ; Antibodies, Viral/immunology ; Female ; Respiratory Syncytial Virus, Human/immunology ; Mice, Inbred BALB C ; }, abstract = {Respiratory syncytial virus (RSV) causes lower respiratory tract infections with significant morbidity and mortality at the extremes of age. Vaccines based on the viral fusion protein are approved for adults over 60, but infant protection relies on passive immunity via antibody transfer or maternal vaccination. An infant vaccine that rapidly elicits protective antibodies would fulfill a critical unmet need. Antibodies arising from the VH3-21/VL1-40 gene pairing can neutralize RSV without the need for affinity maturation, making them attractive to target through vaccination. Here, we develop an anti-idiotypic monoclonal antibody (ai-mAb) immunogen that is specific for unmutated VH3-21/VL1-40 B cell receptors (BCRs). The ai-mAb efficiently engages B cells with bona fide target BCRs and does not activate off-target non-neutralizing B cells, unlike recombinant pre-fusion (preF) protein used in current RSV vaccines. These results establish proof of concept for using an ai-mAb-derived vaccine to target B cells hardwired to produce RSV-neutralizing antibodies.}, }
@article {pmid39382296, year = {2024}, author = {Stearns, K and Lampe, G and Hanan, R and Marcink, T and Niewiesk, S and Sternberg, SH and Greninger, AL and Porotto, M and Moscona, A}, title = {Human parainfluenza virus 3 field strains undergo extracellular fusion protein cleavage to activate entry.}, journal = {mBio}, volume = {15}, number = {11}, pages = {e0232724}, pmid = {39382296}, issn = {2150-7511}, support = {R01 AI114736/AI/NIAID NIH HHS/United States ; R01AI031971, R01AI114736, R01AI175362//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; F31 AI176760/AI/NIAID NIH HHS/United States ; R01 AI175362/AI/NIAID NIH HHS/United States ; //Sharon Golub Fund at Columbia University Vagelos College of Physicians & Surgeons/ ; R01AI175362//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AI031971/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Virus Internalization ; *Viral Fusion Proteins/metabolism/genetics ; *Parainfluenza Virus 3, Human/genetics/physiology/metabolism ; HEK293 Cells ; Furin/metabolism/genetics ; HN Protein/metabolism/genetics ; Animals ; Cell Line ; Proteolysis ; }, abstract = {UNLABELLED: Human parainfluenza virus 3 (HPIV3) infection is driven by the coordinated action of viral surface glycoproteins hemagglutinin-neuraminidase (HN) and fusion protein (F). Receptor-engaged HN activates F to insert into the target cell membrane and drive virion-cell membrane fusion. For F to mediate entry, its precursor (F0) must first be cleaved by host proteases. F0 cleavage has been thought to be executed during viral glycoprotein transit through the trans-Golgi network by the ubiquitously expressed furin because F0 proteins of laboratory-adapted viruses contain a furin recognition dibasic cleavage motif RXKR around residue 108. Here, we show that the F proteins of field strains have a different cleavage motif from laboratory-adapted strains and are cleaved by unidentified proteases expressed in only a narrow subset of cell types. We demonstrate that extracellular serine protease inhibitors block HPIV3 F0 cleavage for field strains, suggesting F0 cleavage occurs at the cell surface facilitated by transmembrane proteases. Candidate proteases that may process HPIV3 F in vivo were identified by a genome-wide CRISPRa screen in HEK293/dCas9-VP64 + MPH cells. The lung-expressed extracellular serine proteases TMPRSS2 and TMPRSS13 are both sufficient to cleave HPIV3 F and enable infectious virus release by otherwise non-permissive cells. Our findings support an alternative mechanism of F activation in vivo, reliant on extracellular membrane-bound serine proteases expressed in a narrow subset of cells. The proportion of HPIV3 F proteins cleaved and infectious virus release is determined by host cell expression of requisite proteases, allowing just-in-time activation of F and positioning F cleavage as another key regulator of HPIV3 spread.
IMPORTANCE: Enveloped viruses cause a wide range of diseases in humans. At the first step of infection, these viruses must fuse their envelope with a cell membrane to initiate infection. This fusion is mediated by viral proteins that require a critical activating cleavage event. It was previously thought that for parainfluenza virus 3, an important cause of respiratory disease and a representative of a group of important pathogens, this cleavage event was mediated by furin in the cell secretory pathways prior to formation of the virions. We show that this is only true for laboratory strain viruses, and that clinical viruses that infect humans utilize extracellular proteases that are only made by a small subset of cells. These results highlight the importance of studying authentic clinical viruses that infect human tissues for understanding natural infection.}, }
@article {pmid39381003, year = {2024}, author = {Fiore-Gartland, A and Srivastava, H and Seese, A and Day, T and Penn-Nicholson, A and Luabeya, AKK and Du Plessis, N and Loxton, AG and Bekker, LG and Diacon, A and Walzl, G and Sagawa, ZK and Reed, SG and Scriba, TJ and Hatherill, M and Coler, R}, title = {Co-regulation of innate and adaptive immune responses induced by ID93+GLA-SE vaccination in humans.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1441944}, pmid = {39381003}, issn = {1664-3224}, mesh = {Humans ; *Immunity, Innate ; *Adaptive Immunity ; Female ; Male ; *Tuberculosis Vaccines/immunology/administration & dosage ; *Vaccination ; Adult ; Tuberculosis/prevention & control/immunology ; Mycobacterium tuberculosis/immunology ; CD4-Positive T-Lymphocytes/immunology ; Antibodies, Bacterial/blood/immunology ; Vaccines, Subunit/immunology/administration & dosage ; }, abstract = {INTRODUCTION: Development of an effective vaccine against tuberculosis is a critical step towards reducing the global burden of disease. A therapeutic vaccine might also reduce the high rate of TB recurrence and help address the challenges of drug-resistant strains. ID93+GLA-SE is a candidate subunit vaccine that will soon be evaluated in a phase 2b efficacy trial for prevention of recurrent TB among patients undergoing TB treatment. ID93+GLA-SE vaccination was shown to elicit robust CD4+ T cell and IgG antibody responses among recently treated TB patients in the TBVPX-203 Phase 2a study (NCT02465216), but the mechanisms underlying these responses are not well understood.
METHODS: In this study we used specimens from TBVPX-203 participants to describe the changes in peripheral blood gene expression that occur after ID93+GLA-SE vaccination.
RESULTS: Analyses revealed several distinct modules of co-varying genes that were either up- or down-regulated after vaccination, including genes associated with innate immune pathways at 3 days post-vaccination and genes associated with lymphocyte expansion and B cell activation at 7 days post-vaccination. Notably, the regulation of these gene modules was affected by the dose schedule and by participant sex, and early innate gene signatures were correlated with the ID93-specific CD4+ T cell response.
DISCUSSION: The results provide insight into the complex interplay of the innate and adaptive arms of the immune system in developing responses to vaccination with ID93+GLA-SE and demonstrate how dosing and schedule can affect vaccine responses.}, }
@article {pmid39380691, year = {2024}, author = {Parrish, AG and Arora, S and Thirimanne, HN and Rudoy, D and Schmid, S and Sievers, P and Sahm, F and Holland, EC and Szulzewsky, F}, title = {Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4.}, journal = {Neuro-oncology advances}, volume = {6}, number = {1}, pages = {vdae148}, pmid = {39380691}, issn = {2632-2498}, abstract = {BACKGROUND: Meningiomas are the most common primary central nervous system tumors in adults. Although generally benign, a subset is of higher grade and ultimately fatal. Around half of all meningiomas harbor inactivating mutations in NF2, leading to deregulation of oncogenic YAP1 activity. While benign NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. It is unclear if NF2 mutant meningiomas of different grades are equally reliant on YAP activity.
METHODS: We analyzed bulk and single-cell RNA-Seq data from a large cohort of human meningiomas for the expression of YAP1 target genes and Hippo effectors as well as in vitro cell line experiments.
RESULTS: Aggressive NF2 mutant meningiomas harbor decreased expression levels of YAP1 target genes and increased expression levels of the YAP1 antagonist VGLL4 and the upstream regulators FAT3/4 compared to their benign counterparts. Decreased expression of YAP1 target genes as well as high expression of VGLL4 and FAT3/4 is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas.
CONCLUSIONS: Our results shed new insight into the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.}, }
@article {pmid39379736, year = {2024}, author = {Bloom, A and Springer, R and Angier, H and Heintzman, J and Likumahuwa-Ackman, S and Huguet, N and Moreno, L and DeVoe, J}, title = {Association Between a Mother's Cervical Cancer Screening and Child's Human Papillomavirus (HPV) Vaccination Status.}, journal = {Maternal and child health journal}, volume = {28}, number = {12}, pages = {2137-2146}, pmid = {39379736}, issn = {1573-6628}, support = {R01HS025962//Agency for Healthcare Research and Quality/ ; }, mesh = {Humans ; Female ; *Uterine Cervical Neoplasms/prevention & control/diagnosis ; *Papillomavirus Vaccines/administration & dosage ; *Early Detection of Cancer/methods/statistics & numerical data ; *Papillomavirus Infections/prevention & control/diagnosis ; Child ; *Mothers/psychology/statistics & numerical data ; Adult ; Adolescent ; Vaccination/statistics & numerical data ; Male ; United States/epidemiology ; Mass Screening/methods/statistics & numerical data ; Cohort Studies ; Human Papillomavirus Viruses ; }, abstract = {OBJECTIVES: To investigate the association between maternal cervical cancer (CC) screening status and child human papillomavirus (HPV) vaccination uptake. To understand if child sex or social deprivation index (SDI) modify this association.
METHODS: We used a national cohort of children linked to at least one parent using electronic health record (EHR) data from a network of community health centers across the United States. We used SDI scores and child sex as moderating variables. We performed the analysis (1) for the whole sample (with SDI and child sex added as covariates), (2) stratified by SDI quartile (with child sex added as a covariate), and (3) stratified by SDI quartile and child sex, to examine whether associations vary by SDI quartile and by child sex.
RESULTS: N = 52,919 linked mother-child pairs. Mother's receipt of CC screening was positively associated with the linked child's odds of receiving HPV vaccination [adjusted odds ratio (AOR) 1.39, 95% confidence interval (CI) 1.32, 1.47]. Neither sex or SDI modified this association. There were no significant differences in odds of HPV vaccination in children between SDI quartiles or between male and female children.
CONCLUSIONS FOR PRACTICE: An effective way to improve rates of HPV vaccination among children and adolescents may be to target attention towards increasing CC screening rates among mothers. Further, focusing resources and efforts on CC screenings and care of both mothers and their children may be more worthwhile than isolated efforts targeting HPV vaccination for children and adolescents.}, }
@article {pmid39379678, year = {2024}, author = {Akhiwu, TO and Adewunmi, C and Bilalaga, M and Atarere, JO and Gaddipati, G and Chido-Amajuoyi, OG and Eziuche, DK and Onyeaka, H and Amonoo, HL}, title = {Clinical trial knowledge among cancer survivors in the United States: the role of health information technology.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {39379678}, issn = {1573-7225}, support = {K08CA251654/NH/NIH HHS/United States ; }, abstract = {PURPOSE: Clinical trials are essential to the advancement of cancer care. However, clinical trial knowledge and participation remain critically low among adult patients with cancer. Health information technology (HIT) could play an important role in improving clinical trial knowledge and engagement among cancer survivors.
METHODS: We used data from 3,794 adults who completed the 2020 Health Information National Trends Survey, 626 (16.2%) of whom were cancer survivors. We examined the prevalence of HIT use in the study population and by cancer history using chi-squared tests. We used multivariable logistic regression models to examine the impact of HIT use on clinical trial knowledge for cancer survivors and respondents with no cancer history, respectively.
RESULTS: Approximately 63.8% of cancer survivors reported having some knowledge of clinical trials. Almost half of the cancer survivors used HIT to communicate with doctors (47.1%) and make health appointments (49.4%), 68.0% used HIT to look up health information online and 42.2% used it to check test results. In the adjusted models, the use of HIT in communicating with doctors [OR 2.79; 95% CI (1.41, 5.54)], looking up health information online [OR 2.84; 95% CI (1.04, 7.77)], and checking test results [OR 2.47; 95% CI (1.12, 5.43)] was associated with having some knowledge of clinical trials.
CONCLUSION: HIT use for engaging with the healthcare team and health information gathering is associated with higher clinical trial knowledge in cancer survivors. Given the rapid increase in mobile technology access globally and the increased use of HIT, digital technology can be leveraged to improve clinical trial knowledge and engagement among cancer survivors.}, }
@article {pmid39377755, year = {2024}, author = {Montaño, M and Shapiro, AE and Whitney, BM and Bamford, L and Burkholder, G and Cachay, ER and Christopoulos, KA and Crane, HM and Delaney, JAC and Eron, JJ and Fredericksen, RJ and Hunt, PW and Jacobson, JM and Keruly, JC and Kim, HN and Mayer, KH and Moore, RD and Napravnik, S and Pettit, A and Saag, MS and Yendewa, GA and Kitahata, MM and Bender Ignacio, RA}, title = {Mpox in People With Human Immunodeficiency Virus: Predictors of Diagnosis, Outcomes, and Vaccine Effectiveness in a Multisite Cohort.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae464}, pmid = {39377755}, issn = {1537-6591}, support = {//National Institute of Allergy and Infectious Diseases/ ; R24 AI067039/AI/NIAID NIH HHS/United States ; //CFAR/ ; P30 AI027767/AI/NIAID NIH HHS/United States ; //University of Washington/ ; P30 AI036214/AI/NIAID NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; P30 AI094189/AI/NIAID NIH HHS/United States ; P30 AI50410//University of North Carolina Chapel Hill/ ; //Vanderbilt Univ/ ; P30 AI110527/AI/NIAID NIH HHS/United States ; P30 AI073961/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: Since its global reemergence in 2022, monkeypox (mpox) has demonstrated increased incidence and severity among people with human immunodeficiency virus (HIV [PWH]). Predictors of mpox diagnosis, vaccination, and outcomes among PWH are limited.
METHODS: We included PWH with primary care visits after 1 January 2022 at 9 US sites participating in the Centers for AIDS Research Network of Integrated Clinic Systems Network. We identified mpox diagnosed between 1 June 2022 and 31 May 2023, through a combination of polymerase chain reaction result, diagnosis code, and/or tecovirimat receipt. We examined validated clinical diagnoses, laboratory results, vaccine data, and patient reported outcomes. We evaluated relative risks (RR) of mpox diagnosis, hospitalization, tecovirimat treatment, and vaccine receipt.
FINDINGS: Among 19 777 PWH in care, 413 mpox cases (all male sex at birth) occurred (2.2 cases/100 person-years). Age <40 years, geographic region, Hispanic/Latine ethnicity, lack of antiretroviral therapy, detectable HIV viral load, and recent bacterial sexually transmitted infection predicted mpox diagnosis. PWH with CD4 200-349 cells/mm3 were most likely to be hospitalized (adjusted RR, 3.20; 95% confidence interval: 1.44-7.09) compared to CD4 ≥500, but half as likely as those with CD4 <200 to receive tecovirimat. Overall, smallpox/mpox vaccine effectiveness of ≥1 vaccine was 71% (adjusted RR, 0.29; 95% confidence interval: .14-.47) at preventing mpox, and 86% or better with CD4 ≥350 or HIV viral suppression. Non-Hispanic Black PWH were less likely to be vaccinated than other racial/ethnic identities.
INTERPRETATION: PWH not on antiretroviral therapy or with unsuppressed HIV were more likely to be diagnosed with, and hospitalized for, mpox. Mpox/smallpox vaccine effectiveness was high, inclusive of those with low CD4 count and HIV viremia.}, }
@article {pmid39377586, year = {2024}, author = {Belmont, L and Contreras, M and Cartwright-Acar, CH and Marceau, CD and Agrawal, A and Levoir, LM and Lubow, J and Goo, L}, title = {Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0158224}, doi = {10.1128/jvi.01582-24}, pmid = {39377586}, issn = {1098-5514}, abstract = {Under some conditions, dengue virus (DENV) can hijack IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR)-a process known as antibody-dependent enhancement (ADE) of infection. Beyond a requirement for FcgR, host dependency factors for this unusual IgG-mediated infection route remain unknown. To identify cellular factors exclusively required for ADE, here, we performed CRISPR knockout (KO) screens in an in vitro system poorly permissive to infection in the absence of IgG antibodies. Validating our approach, a top hit was FcgRIIa, which facilitates the binding and internalization of IgG-bound DENV but is not required for canonical infection. Additionally, we identified host factors with no previously described role in DENV infection, including TBC1D24 and SV2B, which have known functions in regulated secretion. Using genetic knockout and trans-complemented cells, we validated a functional requirement for these host factors in ADE assays performed with monoclonal antibodies and polyclonal sera in multiple cell lines and using all four DENV serotypes. We show that knockout of TBC1D24 or SV2B impaired the binding of IgG-DENV complexes to cells without affecting FcgRIIa expression levels. Thus, we identify cellular factors beyond FcgR that promote efficient ADE of DENV infection. Our findings represent a first step toward advancing fundamental knowledge behind the biology of a non-canonical infection route implicated in disease.IMPORTANCEAntibodies can paradoxically enhance rather than inhibit dengue virus (DENV) infection in some cases. To advance knowledge of the functional requirements of antibody-dependent enhancement (ADE) of infection beyond existing descriptive studies, we performed a genome-scale CRISPR knockout (KO) screen in an optimized in vitro system permissive to efficient DENV infection only in the presence of IgG. In addition to FcgRIIa, a known receptor that facilitates IgG-mediated uptake of IgG-bound, but not naked DENV particles, our screens identified TBC1D24 and SV2B, cellular factors with no known role in DENV infection. We validated a functional role for TBC1D24 and SV2B in mediating ADE of all four DENV serotypes in different cell lines and using various antibodies. Thus, we identify cellular factors beyond Fc gamma receptors that promote ADE mechanisms. This study represents a first step toward advancing fundamental knowledge beyond a poorly understood non-canonical viral entry mechanism.}, }
@article {pmid39375704, year = {2024}, author = {Gabel, AM and Belleville, AE and Thomas, JD and Pineda, JMB and Bradley, RK}, title = {APC mutations dysregulate alternative polyadenylation in cancer.}, journal = {Genome biology}, volume = {25}, number = {1}, pages = {255}, pmid = {39375704}, issn = {1474-760X}, mesh = {*Polyadenylation ; Humans ; *Adenomatous Polyposis Coli Protein/genetics/metabolism ; *3' Untranslated Regions ; Mutation ; Colorectal Neoplasms/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Neoplasms/genetics/metabolism ; Poly A/metabolism ; Adenocarcinoma/genetics/metabolism/pathology ; }, abstract = {BACKGROUND: Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in all studied cancers. However, the mechanistic origins of this dysregulation are incompletely understood.
RESULTS: We describe an unbiased analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identify that colorectal adenocarcinoma is an outlier relative to all other cancer subtypes. This distinction arises from the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which are strongly associated with long 3' UTR expression relative to tumors lacking APC mutations. APC knockout similarly dysregulates APA in human colon organoids. By mining previously published APC eCLIP data, we show that APC preferentially binds G- and C-rich motifs just upstream of proximal poly(A) sites. Lastly, we find that reduced APC expression is associated with APA dysregulation in tumor types lacking recurrent APC mutations.
CONCLUSIONS: As APC has been previously identified as an RNA-binding protein that preferentially binds 3' UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.}, }
@article {pmid39375464, year = {2024}, author = {Crespillo-Casado, A and Pothukuchi, P and Naydenova, K and Yip, MCJ and Young, JM and Boulanger, J and Dharamdasani, V and Harper, C and Hammoudi, PM and Otten, EG and Boyle, K and Gogoi, M and Malik, HS and Randow, F}, title = {Recognition of phylogenetically diverse pathogens through enzymatically amplified recruitment of RNF213.}, journal = {EMBO reports}, volume = {25}, number = {11}, pages = {4979-5005}, pmid = {39375464}, issn = {1469-3178}, support = {P400PB_191083//the Swiss National Science Foundation (SNSF)/ ; U54 AI170792 (PI: Nevan Krogan)//the National Institutes of Health/ ; BI31336//Diamond Light Source (Diamond)/ ; U105170648//UK Research and Innovation (UKRI)/ ; /WT_/Wellcome Trust/United Kingdom ; U54 AI170792/AI/NIAID NIH HHS/United States ; 222503/Z/21/Z//Wellcome Trust (WT)/ ; }, mesh = {*Ubiquitin-Protein Ligases/metabolism/genetics ; *Phylogeny ; Humans ; Toxoplasma/genetics/metabolism ; Listeria/genetics ; Cryoelectron Microscopy ; Salmonella/genetics/metabolism ; Protein Binding ; Immunity, Innate ; Adenosine Triphosphate/metabolism ; Host-Pathogen Interactions/genetics ; }, abstract = {Innate immunity senses microbial ligands known as pathogen-associated molecular patterns (PAMPs). Except for nucleic acids, PAMPs are exceedingly taxa-specific, thus enabling pattern recognition receptors to detect cognate pathogens while ignoring others. How the E3 ubiquitin ligase RNF213 can respond to phylogenetically distant pathogens, including Gram-negative Salmonella, Gram-positive Listeria, and eukaryotic Toxoplasma, remains unknown. Here we report that the evolutionary history of RNF213 is indicative of repeated adaptation to diverse pathogen target structures, especially in and around its newly identified CBM20 carbohydrate-binding domain, which we have resolved by cryo-EM. We find that RNF213 forms coats on phylogenetically distant pathogens. ATP hydrolysis by RNF213's dynein-like domain is essential for coat formation on all three pathogens studied as is RZ finger-mediated E3 ligase activity for bacteria. Coat formation is not diffusion-limited but instead relies on rate-limiting initiation events and subsequent cooperative incorporation of further RNF213 molecules. We conclude that RNF213 responds to evolutionarily distant pathogens through enzymatically amplified cooperative recruitment.}, }
@article {pmid39374582, year = {2024}, author = {Ali, N and Othus, M and Rodríguez-Arbolí, E and Orvain, C and Milano, F and Sandmaier, BM and Davis, C and Basom, R and Appelbaum, FR and Walter, RB}, title = {Measurable Residual Disease as Predictor of Post-Day +100 Relapses Following Allografting in Adult AML.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024013214}, pmid = {39374582}, issn = {2473-9537}, abstract = {Measurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing for the prediction of later relapses, we examined 935 adults with AML or myelodysplastic neoplasm (MDS)/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 post-HCT and were alive and without relapse by day +100. Of these 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70-100. In day +100 landmark analyses, pre-HCT and day +70-100 MFC MRD were both associated with relapse (both P<0.001), relapse-free survival (RFS; both P<0.001) overall survival (OS; both P<0.001), and, for post-HCT MRD, non-relapse mortality (P=0.001) after multivariable adjustment. Importantly, while 126 of the 136 patients (92%) with MRD before HCT tested negative for MRD at day +70-100, their outcomes were inferior to those without MRD before HCT and at day +70-100, with 3-year relapse risk of 40% vs. 15% (P<0.001), 3-year RFS of 50% vs. 72% (P<0.001), and 3-year OS of 56% vs. 76% (P<0.001), whereas 3-year NRM estimates were similar (P=0.53). Thus, despite high MRD conversion rates, outcomes for MRDpos/MRDneg patients are inferior to MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for pre-emptive therapeutic strategies after allografting.}, }
@article {pmid39374522, year = {2024}, author = {Coffey, DG and Atilla, PA and Atilla, E and Landgren, O and Cowan, AJ and Simon, S and Pont, M and Comstock, ML and Hill, GR and Riddell, SR and Green, DJ}, title = {Single-cell analysis of the multiple myeloma microenvironment after gamma-secretase inhibition and CAR T-cell therapy.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025231}, pmid = {39374522}, issn = {1528-0020}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; }, abstract = {Chimeric antigen receptor (CAR) T-cells and bispecific antibodies (BsAb) targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma (MM). Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by gamma-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase I clinical trial of the gamma-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T-cells (FCARH143), we utilized single-nuclei RNA sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which are known to promote tumor growth. In addition to observing a reduction in the frequency of non-classical monocytes, we also detected significant changes in gene expression, chromatin accessibility, and inferred cell-cell interactions following exposure to GSI. Although many genes with altered expression are associated with gamma-secretase-dependent signaling, such as Notch, other pathways were affected, indicating GSI has far-reaching effects. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (median PFS 57 days versus 861 days). GSIs are being explored in combination with the full spectrum of BCMA targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies.}, }
@article {pmid39374449, year = {2024}, author = {Dizman, N and Bakouny, Z and Haykal, T and Riano, I and Desai, A and Butt, A and Basu, A and Zhao, D and Saad, E and Saliby, RM and Gosain, R and Gosain, R and Ardeshir, F and Deng, L and Matt-Amaral, L and Arnaoutakis, K and Bekaii-Saab, T and Manochakian, R and Marshall, A and Forde, P and Murphy, M and Subbiah, V and Chavez-MacGregor, M and Owonikoko, TK and Lopes, G and Aggarwal, C and Lee, AI and Choueiri, TK}, title = {Guide to Understanding and Supporting International Medical Graduates in Hematology/Oncology by the ASCO International Medical Graduates Community of Practice.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400565}, doi = {10.1200/OP-24-00565}, pmid = {39374449}, issn = {2688-1535}, abstract = {PURPOSE: International medical graduates (IMGs) are an essential component of the oncology workforce in the United States, comprising a third of all practicing oncologists and almost half of hematology/oncology fellows. In this article, we discuss the contributions of IMGs in the US oncology workforce, review unique challenges faced by IMGs, and propose potential solutions to overcome these challenges.
METHODS: ASCO's IMG Community of Practice was established with the mission to connect, mentor, guide, raise awareness, and overcome the challenges unique to IMGs interested in pursuing medical oncology in the United States. The content of this article is based on discussions at the IMG Community of Practice meetings at ASCO's 2023 and 2024 Annual Meetings.
RESULTS: IMGs bring an inherent diversity of thought and experience to the oncology workforce. They provide high-quality, culture- and language-concordant care to a diverse population of patients with cancer. However, IMGs in oncology face significant hardships throughout their careers, including visa-related restrictions, psychosocial and cultural struggles, as well as differential treatment while applying for residency and fellowship training, and early career positions. Greater awareness of these challenges among the members of the hematology/oncology community, along with institutional and individual efforts to support IMGs, is warranted.
CONCLUSION: We encourage oncology professionals and institutions to join our efforts in recognizing the unique paths of IMGs and providing support and advocacy to maximize the potential of IMGs in the US oncology workforce.}, }
@article {pmid39374015, year = {2024}, author = {Goldkorn, A and Tangen, C and Plets, M and Bsteh, D and Xu, T and Pinski, JK and Ingles, S and Triche, TJ and MacVicar, GR and Vaena, DA and Crispino, AW and McConkey, DJ and Lara, PN and Hussain, MHA and Quinn, DI and Dorff, TB and Lerner, SP and Thompson, I and Agarwal, N}, title = {Circulating Tumor Cell Count and Overall Survival in Patients With Metastatic Hormone-Sensitive Prostate Cancer.}, journal = {JAMA network open}, volume = {7}, number = {10}, pages = {e2437871}, doi = {10.1001/jamanetworkopen.2024.37871}, pmid = {39374015}, issn = {2574-3805}, mesh = {Male ; Humans ; *Neoplastic Cells, Circulating ; Aged ; Prognosis ; Middle Aged ; Prospective Studies ; Prostatic Neoplasms/mortality/pathology/blood/drug therapy ; Prostatic Neoplasms, Castration-Resistant/blood/mortality/drug therapy/pathology ; Aged, 80 and over ; Biomarkers, Tumor/blood ; Neoplasm Metastasis ; Prostate-Specific Antigen/blood ; }, abstract = {IMPORTANCE: In metastatic hormone-sensitive prostate cancer (mHSPC), new first-line combination therapies have enhanced overall survival (OS), but clinical outcomes for individual patients vary greatly and are difficult to predict. Peripheral blood circulating tumor cell (CTC) count is the most extensively validated prognostic liquid biomarker in metastatic castration-resistant prostate cancer (mCRPC), and recent studies have suggested that it may also be informative in mHSPC.
OBJECTIVE: To examine the prognostic value of CTC count in men with mHSPC.
In this prognostic study, peripheral blood was drawn at registration (baseline) and at progression to mCRPC in the S1216 study (March 1, 2013, to July 15, 2017), a phase 3, prospective, randomized clinical trial in men with mHSPC. The CTCs were enumerated using a US Food and Drug Administration-cleared isolation platform. Counts were categorized as 0, 1 to 4, or 5 or more CTCs per 7.5 mL based on the prognostic value of these cut points in prior studies. The data analysis was performed between October 28, 2022, and June 15, 2023.
EXPOSURE: Metastatic hormone-sensitive prostate cancer.
MAIN OUTCOMES AND MEASURES: Circulating tumor cell count was evaluated for an association with 3 prespecified trial end points: OS, progression-free survival, and 7-month prostate-specific antigen, after adjusting for other baseline covariates using proportional hazards and logistic regression models.
RESULTS: Of 1313 S1216 participants (median [IQR] age, 68 [44-92] years), evaluable samples from 503 (median [IQR] age, 69 [46-90] years) with newly diagnosed mHSPC were collected at baseline, and 93 samples were collected at progression. Baseline counts were 5 or more CTCs per 7.5 mL in 60 samples (11.9%), 1 to 4 CTCs per 7.5 mL in 107 samples (21.3%), and 0 CTCs per 7.5 mL in 336 samples (66.8%). Median OS for men with 5 or more CTCs per 7.5 mL was 27.9 months (95% CI, 24.1-31.2 months) compared with 56.2 months (95% CI, 45.7-69.8 months) for men with 1 to 4 CTCs per 7.5 mL and not reached at 78.0 months follow-up for men with 0 CTCs per 7.5 mL. After adjusting for baseline clinical covariates, men with 5 or more CTCs per 7.5 mL at baseline had a significantly higher hazard of death (hazard ratio, 3.22; 95% CI, 2.22-4.68) and disease progression (hazard ratio, 2.46; 95% CI, 1.76-3.43) and a lower likelihood of prostate-specific antigen complete response (odds ratio, 0.26; 95% CI, 0.12-0.54) compared with men with 0 CTCs per 7.5 mL at baseline. Adding baseline CTC count to other known prognostic factors (covariates only: area under the curve, 0.73; 95% CI, 0.67-0.79) resulted in an increased prognostic value for 3-year survival (area under the curve, 0.79; 95% CI, 0.73-0.84).
CONCLUSIONS AND RELEVANCE: In this prognostic study, the findings validate CTC count as a prognostic biomarker that improved upon existing prognostic factors and estimated vastly divergent survival outcomes regardless of subsequent lines of therapy. As such, baseline CTC count in mHSPC may serve as a valuable noninvasive biomarker to identify men likely to have poor survival who may benefit from clinical trials of intensified or novel regimens.}, }
@article {pmid39373644, year = {2024}, author = {Wickline, M and Carpenter, PA and Harris, JR and Iribarren, SJ and Reding, KW and Pike, KC and Lee, SJ and Salit, RB and Oshima, MU and Vo, PT and Berry, DL}, title = {Barriers and facilitators to routine revaccination among adult Hematopoietic Cell Transplant survivors in the United States: A convergent mixed methods analysis.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e14388}, doi = {10.1111/tid.14388}, pmid = {39373644}, issn = {1399-3062}, support = {//Oncology Nursing Society Foundation/ ; //School of Nursing, University of Washington/ ; //Hester McLaws Nursing Scholarship/ ; }, abstract = {BACKGROUND: Hematopoietic cell transplant (HCT) survivorship care includes recommendations for post-HCT revaccination to restore immunity to vaccine-preventable diseases (VPDs). However, not all survivors agree to be vaccinated. No existing studies have comprehensively reported barriers and facilitators to adult HCT survivors completing revaccination.
METHODS: A cross-sectional survey of 194 adult HCT survivors was analyzed using convergent mixed methods. The analysis used various statistical methods to determine the prevalence of barriers and facilitators and the association between revaccination and the number and specific type of barriers and facilitators. Content analysis was applied to open-ended item responses. Integrated analysis merged quantitative and qualitative findings.
RESULTS: The most frequent barriers included the inability to receive live vaccines because of immunosuppression, identifying a suitable community location for administering childhood vaccines to adults, and delayed immune recovery. The most frequent facilitators were having healthcare insurance and a clear calendar of the revaccination schedule. Complete revaccination rates were lower with each additional reported barrier (OR = 0.58; 95% CI 0.459-0.722) and higher with each additional reported facilitator (OR = 1.31; 95% CI 1.05-1.63). Content analysis suggested that most barriers were practical issues. One significant facilitator highlighted by respondents was for the transplant center to coordinate and serve as the vaccination location for revaccination services. Merged analysis indicated convergence between quantitative and qualitative data.
CONCLUSION: Practical barriers and facilitators played a consequential role in revaccination uptake, and survivors would like to be revaccinated at the transplant center.}, }
@article {pmid39373623, year = {2024}, author = {Loroña, NC and Himbert, C and Ose, J and Cohen, SA and Strehli, I and Ulrich, CM and Cobos, S and Jean-Baptiste, E and Bloomer, AM and Figueiredo, JC and Gigic, B and Hardikar, S and Karchi, M and Mutch, M and Peoples, AR and Schneider, M and Shibata, D and Siegel, EM and Toriola, AT and Wood, EH and Li, CI}, title = {Alcohol consumption and smoking history at time of diagnosis, and risk of colorectal cancer recurrence and mortality: Results from the ColoCare Study.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-0834}, pmid = {39373623}, issn = {1538-7755}, abstract = {BACKGROUND: Findings from studies investigating the impacts of alcohol use and smoking on colorectal cancer (CRC) outcomes are inconclusive. This study aimed to investigate associations between alcohol use and smoking status at the time of diagnosis on recurrence and overall mortality among patients with CRC.
METHODS: The present study included 2,216 stage I-IV patients with CRC from the longitudinal multi-center ColoCare study, with available data on recurrence and CRC-specific mortality. Cox proportional hazards models adjusted for age, sex, race, ethnicity, stage, tumor site, treatment, comorbidities, body mass index, and study site were fit, with imputations for missing data.
RESULTS: We observed 235 recurrences and 308 CRC-specific deaths over an average of 3 years of follow-up. After adjusting for confounders, current alcohol consumption and ever smoking, relative to not current consumption and never smoking, respectively, were not statistically significantly associated with CRC recurrence (Alcohol - HR: 0.95. 95% CI: 0.71-1.29; Ever smoking - HR: 0.98, 95% CI: 0.75-1.29) or CRC-specific mortality (Alcohol - HR: 0.95. 95% CI: 0.74-1.22; Ever smoking - HR: 0.98, 95% CI: 0.77-1.24).
CONCLUSIONS: No associations were observed between alcohol and smoking at diagnosis and clinical outcomes in this well-annotated longitudinal cohort.
IMPACT: Our cohort study reports no significant associations; however, limiting alcohol use and avoiding smoking are health behaviors recommended for CRC survivors for prevention of other cancers and chronic conditions.}, }
@article {pmid39373353, year = {2024}, author = {Amonoo, HL and Daskalakis, E and Lam, JA and Wolfe, ED and Guo, M and Onyeaka, HK and Newcomb, RA and Barata, A and Ghanime, PM and Keane, EP and Boardman, AC and Cutler, C and Pirl, WF and Peteet, JR and Gudenkauf, LM and Lee, SJ and Huffman, JC and El-Jawahri, A}, title = {Association between positive affect, flourishing, quality of life, and psychological distress in allogeneic hematopoietic stem cell transplantation.}, journal = {Journal of psychosocial oncology}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/07347332.2024.2410929}, pmid = {39373353}, issn = {1540-7586}, abstract = {PURPOSE: To examine the associations between state positive psychological well-being (PPWB) constructs, mood, and quality of life (QOL) in hematopoietic stem cell transplantation (HSCT) survivors.
DESIGN: The study was a secondary analysis of cross-sectional data.
SAMPLE/METHODS: We analyzed self-report data assessing positive affect, flourishing, QOL, depression and anxiety, and PTSD symptoms from 158 allogeneic HSCT recipients at day-100 post-transplant enrolled in supportive care studies.
FINDINGS: Univariate analysis showed that factors associated with greater levels of various state PPWB constructs include older age, disability status, greater social support, and presence of graft-versus-host disease. Multivariate analysis showed that state PPWB constructs-greater levels of positive affect and flourishing-were significantly associated with better QOL and lower PTSD, anxiety, and depression symptomatology.
IMPLICATIONS: Our findings suggest that longitudinal studies are needed to examine the links between state PPWB constructs and HSCT outcomes, which may inform population specific interventions and opportunities to improve outcomes.}, }
@article {pmid39373106, year = {2024}, author = {Poston, JN and Brown, SP and Ginsburg, AS and Ilich, A and Herren, H and El Kassar, N and Triulzi, DJ and Key, NS and May, S and Gernsheimer, TB}, title = {Analysis of bleeding outcomes in patients with hypoproliferative thrombocytopenia in the A-TREAT clinical trial.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.18028}, pmid = {39373106}, issn = {1537-2995}, support = {HL122272/HL/NHLBI NIH HHS/United States ; HL122894/HL/NHLBI NIH HHS/United States ; HL143403/HL/NHLBI NIH HHS/United States ; HL146226/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Despite prophylactic platelet transfusions, hypoproliferative thrombocytopenia is associated with bleeding; historical risk factors include hematocrit (HCT) ≤ $$ \le $$ 25%, activated partial thromboplastin time ≥ $$ \ge $$ 30 s, international normalized ratio ≥ $$ \ge $$ 1.2, and platelets ≤ $$ \le $$ 5000/μL.
METHODS: We performed a post hoc analysis of bleeding outcomes and risk factors in participants with hematologic malignancy and hypoproliferative thrombocytopenia enrolled in the American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (A-TREAT) and randomized to receive either tranexamic acid (TXA) or placebo.
RESULTS: World Health Organization (WHO) grade 2+ bleeding occurred in 46% of 330 participants, with no difference between the TXA (44%) and placebo (47%) groups (p = 0.66). Overall, the most common sites of bleeding were oronasal (18%), skin (17%), gastrointestinal (11%), and genitourinary (11%). Among participants of childbearing potential, 28% experienced vaginal bleeding. Platelets ≤5000/μL and HCT < 21% (after adjusting for severe thrombocytopenia) were independently associated with increased bleeding risk (HR 3.78, 95% CI 2.16-6.61; HR 2.67, 95% CI 1.35-5.27, respectively). Allogeneic stem cell transplant was associated with nonsignificant increased risk of bleeding versus chemotherapy alone (HR 1.34, 95% CI 0.94-1.91).
DISCUSSION: The overall rate of WHO grade 2+ bleeding was similar to previous reports, albeit with lower rates of gastrointestinal bleeding. Vaginal bleeding was common in participants of childbearing potential. Platelets ≤5000/μL remained a risk factor for bleeding. Regardless of platelet count, bleeding risk increased with HCT < 21%, suggesting a red blood cell transfusion threshold above 21% should be considered to mitigate bleeding. More investigation is needed on strategies to reduce bleeding in this population.}, }
@article {pmid39371366, year = {2024}, author = {Krantz, EM and Mutyaba, I and Nankoma, J and Okuku, F and Casper, C and Orem, J and Swan, DA and Phipps, W and Schiffer, JT}, title = {Highly Heterogeneous Kaposi Sarcoma-Associated Herpesvirus Oral Shedding Kinetics Among People With and Without Kaposi Sarcoma and Human Immunodeficiency Virus Coinfection.}, journal = {Open forum infectious diseases}, volume = {11}, number = {10}, pages = {ofae548}, pmid = {39371366}, issn = {2328-8957}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: An improved understanding of oral Kaposi sarcoma-associated herpesvirus (KSHV) viral dynamics could provide insights into transmission risk and guide vaccine development.
METHODS: We evaluated KSHV oral shedding dynamics in Ugandan adults stratified by Kaposi sarcoma (KS) and human immunodeficiency virus (HIV) status. Participants were followed for ≥4 weeks, with daily home oral swab collection to quantify KSHV using polymerase chain reaction. Shedding rates were defined by number of days with KSHV DNA detected divided by total days with swabs and compared by group using hurdle models.
RESULTS: Two hundred ninety-five participants were enrolled; median age was 35 years (range, 18-71 years), and 134 (45%) were male. KSHV was detected more frequently among participants with KS (HIV positive [HIV[+]]/KS[+], 56/76 [74%]; HIV negative [HIV[-]]/KS[+], 9/18 [50%]) than those without KS (HIV[+]/KS[-], 36/125 [29%]; HIV[-]/KS[-], 16/76 [21%]); odds of shedding did not differ significantly by HIV status. Among participants with KSHV detected, shedding rates did not differ significantly by group. Median per-participant viral loads among positive samples were lowest in HIV[+]/KS[+] (3.1 log10 copies/mL) and HIV[-]/KS[+] (3.3 log10 copies/mL) participants relative to HIV[+]/KS[-] (3.8 log10 copies/mL) and HIV[-]/KS[-] (4.0 log10 copies/mL) participants. All groups had participants with low viral load intermittent shedding and participants with high viral load persistent shedding. Within each group, individual KSHV shedding rate positively correlated with median KSHV log10 copies/mL, and episode duration positively correlated with peak viral load.
CONCLUSIONS: Oral KSHV shedding is highly heterogeneous across Ugandan adults with and without KS and HIV. Persistent shedding is associated with higher median viral loads regardless of HIV and KS status.}, }
@article {pmid39371123, year = {2024}, author = {Dehn, JG and Logan, B and Shaw, BE and Devine, S and Ciurea, SO and Horowitz, M and He, N and Pusic, I and Srour, SA and Arai, S and Juckett, M and Uberti, J and Hill, L and Vasu, S and Hogan, WJ and Hayes-Lattin, B and Westervelt, P and Bashey, A and Farhadfar, N and Grunwald, MR and Leifer, E and Symons, H and Saad, A and Vogel, J and Erickson, C and Buck, K and Lee, SJ and Pidala, J}, title = {Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: An Interventional Trial.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39371123}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, abstract = {IMPORTANCE: Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood.
OBJECTIVE: To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor.
DESIGN: This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months.
SETTINGS: National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers.
PARTICIPANTS: Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkin's and non-Hodgkin's lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available.
INTERVENTION: Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (~25%) to find a matched unrelated donor, were observed under standard center practices, but were not part of the primary objective.
MAIN OUTCOME: Cumulative incidence of transplantation by Search Prognosis arm.
RESULTS: Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Search prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely and 276 (16%) Very Unlikely. 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1,234 patients, the adjusted cumulative incidence (95% CI) of HCT at 6-months was 59.8% (56.7-62.8) in the Very Likely group versus 52.3% (46.1-58.5) in the Very Unlikely (P=0.113).
CONCLUSIONS: A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial. This approach resulted in rapid alternative donor identification and comparable rates of HCT in patients Very Likely and Very Unlikely to find a matched unrelated donor.}, }
@article {pmid39370355, year = {2024}, author = {Choe, M and Summers, C}, title = {The Road More or Less Traveled- Examining the Role of Consolidative Allogeneic Hematopoietic Stem Cell Transplantation After Chimeric Antigen Receptor T Cell Therapy in B-cell ALL.}, journal = {Seminars in hematology}, volume = {61}, number = {5}, pages = {314-320}, doi = {10.1053/j.seminhematol.2024.08.004}, pmid = {39370355}, issn = {1532-8686}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Immunotherapy, Adoptive/methods ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/immunology ; Transplantation, Homologous/methods ; Receptors, Chimeric Antigen/immunology ; Antigens, CD19/immunology ; }, abstract = {Treatment with CD19-targeted chimeric antigen receptor T cell therapy (CD19-CART) has improved salvage rates in children and adults with relapsed and/or refractory B-cell acute lymphoblastic leukemia (ALL). However, not all patients treated with CD19-CAR T cells achieve long-term remission. The role of allogeneic hematopoietic stem cell transplantation as consolidative therapy remains undefined. We aim to review the current literature published to date regarding prognostic markers indicating durable ALL response to CD19-CART and risk factors for relapse after CD19-CART to identify patient cohorts who may benefit from consolidative hematopoietic stem cell transplantation.}, }
@article {pmid39369160, year = {2024}, author = {Zhu, W and Lusk, JA and Pascua, V and Djukovic, D and Raftery, D}, title = {Combination of low glucose and SCD1 inhibition impairs cancer metabolic plasticity and growth in MCF-7 cancer cells: a comprehensive metabolomic and lipidomic analysis.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {20}, number = {5}, pages = {112}, pmid = {39369160}, issn = {1573-3890}, mesh = {Humans ; *Stearoyl-CoA Desaturase/metabolism/antagonists & inhibitors ; *Glucose/metabolism ; MCF-7 Cells ; *Lipidomics/methods ; *Metabolomics/methods ; Lipid Metabolism/drug effects ; Female ; Cell Proliferation/drug effects ; Breast Neoplasms/metabolism/drug therapy ; Metabolome/drug effects ; }, abstract = {BACKGROUND: Cancer cells exhibit remarkable metabolic plasticity, enabling them to adapt to fluctuating nutrient conditions. This study investigates the impact of a combination of low glucose levels and inhibition of stearoyl-CoA desaturase 1 (SCD1) using A939572 on cancer metabolic plasticity and growth.
METHODS: A comprehensive metabolomic and lipidomic analysis was conducted to unravel the intricate changes in cellular metabolites and lipids. MCF-7 cells were subjected to low glucose conditions, and SCD1 was inhibited using A939572. The resulting alterations in metabolic pathways and lipid profiles were explored to elucidate the synergistic effects on cancer cell physiology.
RESULTS: The combination of low glucose and A939572-induced SCD1 inhibition significantly impaired cancer cell metabolic plasticity. Metabolomic analysis highlighted shifts in key glycolytic and amino acid pathways, indicating the cells' struggle to adapt to restricted glucose availability. Lipidomic profiling revealed alterations in lipid composition, implying disruptions in membrane integrity and signaling cascades.
CONCLUSION: Our findings underscore the critical roles of glucose availability and SCD1 activity in sustaining cancer metabolic plasticity and growth. Simultaneously targeting these pathways emerges as a promising strategy to impede cancer progression. The comprehensive metabolomic and lipidomic analysis provides a detailed roadmap of molecular alterations induced by this combination treatment, that may help identify potential therapeutic targets.}, }
@article {pmid39369133, year = {2024}, author = {Basin, MF and Miguel, CM and Jacob, JM and Goldberg, H and Grivas, P and Spiess, PE and Necchi, A and Kamat, AM and Pavlick, DC and Huang, RSP and Lin, DI and Danziger, N and Sokol, ES and Sivakumar, S and Graf, R and Cheng, L and Vasan, N and Ross, J and Basnet, A and Bratslavsky, G}, title = {Single-Hit and Multi-hit PIK3CA Short Variant Genomic Alterations in Clinically Advanced Prostate Cancer: A Genomic Landscape Study.}, journal = {Targeted oncology}, volume = {19}, number = {6}, pages = {981-990}, pmid = {39369133}, issn = {1776-260X}, mesh = {Humans ; Male ; *Class I Phosphatidylinositol 3-Kinases/genetics ; *Prostatic Neoplasms/genetics/pathology ; *Genomics/methods ; Aged ; Middle Aged ; Mutation ; }, abstract = {BACKGROUND: Tumors harboring two or more PIK3CA short variant (SV) ("multi-hit") mutations have been linked to improved outcomes with anti-PIK3CA-targeted therapies in breast cancer. The landscape and clinical implications of multi-hit PIK3CA alterations in clinically advanced prostate cancer (CAPC) remains elusive.
OBJECTIVE: To evaluate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in CAPC.
PATIENTS AND METHODS: The Foundation Medicine FoundationCore database was used to identify 19,978 CAPC tumors that underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA) and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, single-base substitution mutational signatures, and homologous recombination deficiency signature (HRDsig). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3).
RESULTS: 18,741 (93.8%) tumors were PIK3CA wild type (WT), 1155 (5.8%) featured single PIK3CA SV, and 82 (0.4%) featured multi-hit PIK3CA SVs. Single-hit (6.6 versus 3.8; p < 0.0001) and multi-hit (12.8 versus 3.8; p < 0.0001) featured more driver GA per tumor than PIK3CA WT CAPC, as well as higher prevalence of MMR mutational signature, MSI high status, and TMB levels versus PIK3CA WT (p < 0.0001). Other differences in GA included higher frequencies of GA in BRCA2 in multi-hit versus WT (18.3% versus 8.5%; p = 0.0191), ATM in multi-hit versus WT (13.4% versus 5.6%; p = 0.02) and PTEN in single-hit versus WT (40.2% versus 30.1%; p < 0.0001). Homologous recombination deficiency signatures were higher in PIK3CA WT versus single-hit (11.2% versus 7.6%; p = 0.0002). There were no significant differences in PD-L1 expression among the three groups.
CONCLUSIONS: Identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique phenotype that may be associated with response to anti-PIK3CA targeted therapy and checkpoint inhibition, supporting relevant clinical trial designs.}, }
@article {pmid39368804, year = {2024}, author = {Pal, KV and Othus, M and Ali, Z and Russell, K and Shaw, C and Percival, MM and Hendrie, PC and Appelbaum, JS and Walter, RB and Halpern, AB}, title = {Identification of factors predicting low-risk febrile neutropenia admissions in adults with acute myeloid leukemia (AML).}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014291}, pmid = {39368804}, issn = {2473-9537}, abstract = {Febrile neutropenia (FN) is the most common reason for hospital readmission following chemotherapy for AML and is a major driver of healthcare resource utilization. While FN risk models exist, these have largely been developed and validated in solid tumors. We therefore examined whether baseline characteristics could predict which AML patients with FN have a lower risk of progression to severe illness. We identified adults with high-grade myeloid neoplasm ([3]10% blasts in blood/marrow) who received intensive chemotherapy and were admitted for FN from 2016-2023. We collected baseline clinical and disease variables. Outcomes were: infections identified, hospital length of stay (LOS), intensive care unit (ICU) admission, and survival. A "lower-risk [LR]" outcome was defined as LOS <72hrs without ICU admission or inpatient death. Univariate and multivariable (MV) logistic regression models were used to assess covariate associations with outcomes. We identified 397 FN admissions in 248 patients (median age 61 [range: 29-77] years). The median hospital LOS was 6 (range: 1-56) days; 10% required ICU admission and 3.5% died inpatient. Only 15% of admissions were LR. Infection was identified in 59% of admissions. Physiologic parameters including heart rate, blood pressure and fever height were the best predictors of LR admission and infection. We developed MV models to predict LR admission and infection with AUCs of 0.82 and AUC 0.72, respectively. Established FN and critical illness models were not predictive of outcomes in AML, where we could not identify a lower risk group; thus an AML-specific FN risk model requires further development and validation.}, }
@article {pmid39368130, year = {2024}, author = {Pascoe, KM and Bishop, S and Ci, X and Ramirez, M and Perez, G and Ibarra, G and Garza, L and Linde, S and Duran, MC and Chae, HY and Quigley, T and Hassell, L and Garrison, MM and Drain, PK and Shah, PD and Ko, LK}, title = {Factors that shape COVID-19 pediatric vaccine decision-making in rural agricultural communities: A qualitative study.}, journal = {Vaccine}, volume = {42}, number = {26}, pages = {126389}, doi = {10.1016/j.vaccine.2024.126389}, pmid = {39368130}, issn = {1873-2518}, abstract = {While COVID-19 immunizations can improve outcomes from SARS-CoV-2, vaccine rates in the United States have been lowest among children under age 11 and among rural agricultural communities. This study examined factors influencing pediatric COVID-19 vaccine uptake among rural agricultural and predominantly Hispanic communities in Washington State. We conducted in-depth interviews with school district employees and students and held English and Spanish focus group discussions with parents, all of which were audio-recorded and transcribed. We used inductive coding with constant comparison approach to capture emergent themes. We identified five factors that influenced pediatric COVID-19 vaccine uptake in a rural community, including: 1) concerns and misinformation surrounding the new vaccine; 2) witnessing others' vaccine and pandemic experiences; 3) participation in social activities; 4) politicization of and political climate surrounding the vaccine; and 5) health education surrounding the vaccines. To increase pediatric COVID-19 vaccine uptake in rural communities, school districts, students, and parents should receive accurate information and reassurance to dispel health concerns and misinformation, without politicization of the vaccine and fears surrounding vaccine regulations. Social networks can be leveraged to encourage vaccine uptake by sharing positive vaccination vignettes. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04859699https://clinicaltrials.gov/ct2/show/NCT04859699.}, }
@article {pmid39366729, year = {2024}, author = {, }, title = {Forecasting the effects of smoking prevalence scenarios on years of life lost and life expectancy from 2022 to 2050: a systematic analysis for the Global Burden of Disease Study 2021.}, journal = {The Lancet. Public health}, volume = {9}, number = {10}, pages = {e729-e744}, pmid = {39366729}, issn = {2468-2667}, support = {IA/CPHE/17/1/503345/WTDBT_/DBT-Wellcome Trust India Alliance/India ; T32 AG049676/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Life Expectancy/trends ; *Forecasting ; *Smoking/epidemiology ; Prevalence ; Female ; Male ; *Global Burden of Disease ; Adult ; Middle Aged ; Global Health/statistics & numerical data ; Aged ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Smoking is the leading behavioural risk factor for mortality globally, accounting for more than 175 million deaths and nearly 4·30 billion years of life lost (YLLs) from 1990 to 2021. The pace of decline in smoking prevalence has slowed in recent years for many countries, and although strategies have recently been proposed to achieve tobacco-free generations, none have been implemented to date. Assessing what could happen if current trends in smoking prevalence persist, and what could happen if additional smoking prevalence reductions occur, is important for communicating the effect of potential smoking policies.
METHODS: In this analysis, we use the Institute for Health Metrics and Evaluation's Future Health Scenarios platform to forecast the effects of three smoking prevalence scenarios on all-cause and cause-specific YLLs and life expectancy at birth until 2050. YLLs were computed for each scenario using the Global Burden of Disease Study 2021 reference life table and forecasts of cause-specific mortality under each scenario. The reference scenario forecasts what could occur if past smoking prevalence and other risk factor trends continue, the Tobacco Smoking Elimination as of 2023 (Elimination-2023) scenario quantifies the maximum potential future health benefits from assuming zero percent smoking prevalence from 2023 onwards, whereas the Tobacco Smoking Elimination by 2050 (Elimination-2050) scenario provides estimates for countries considering policies to steadily reduce smoking prevalence to 5%. Together, these scenarios underscore the magnitude of health benefits that could be reached by 2050 if countries take decisive action to eliminate smoking. The 95% uncertainty interval (UI) of estimates is based on the 2·5th and 97·5th percentile of draws that were carried through the multistage computational framework.
FINDINGS: Global age-standardised smoking prevalence was estimated to be 28·5% (95% UI 27·9-29·1) among males and 5·96% (5·76-6·21) among females in 2022. In the reference scenario, smoking prevalence declined by 25·9% (25·2-26·6) among males, and 30·0% (26·1-32·1) among females from 2022 to 2050. Under this scenario, we forecast a cumulative 29·3 billion (95% UI 26·8-32·4) overall YLLs among males and 22·2 billion (20·1-24·6) YLLs among females over this period. Life expectancy at birth under this scenario would increase from 73·6 years (95% UI 72·8-74·4) in 2022 to 78·3 years (75·9-80·3) in 2050. Under our Elimination-2023 scenario, we forecast 2·04 billion (95% UI 1·90-2·21) fewer cumulative YLLs by 2050 compared with the reference scenario, and life expectancy at birth would increase to 77·6 years (95% UI 75·1-79·6) among males and 81·0 years (78·5-83·1) among females. Under our Elimination-2050 scenario, we forecast 735 million (675-808) and 141 million (131-154) cumulative YLLs would be avoided among males and females, respectively. Life expectancy in 2050 would increase to 77·1 years (95% UI 74·6-79·0) among males and 80·8 years (78·3-82·9) among females.
INTERPRETATION: Existing tobacco policies must be maintained if smoking prevalence is to continue to decline as forecast by the reference scenario. In addition, substantial smoking-attributable burden can be avoided by accelerating the pace of smoking elimination. Implementation of new tobacco control policies are crucial in avoiding additional smoking-attributable burden in the coming decades and to ensure that the gains won over the past three decades are not lost.
FUNDING: Bloomberg Philanthropies and the Bill & Melinda Gates Foundation.}, }
@article {pmid39365992, year = {2024}, author = {DeFilipp, Z and Kim, HT and Cheng, GS and Hamilton, BK and Chhabra, S and Hamadani, M and Sandhu, KS and Perez, LE and Lee, C and Brennan, TL and Garrelts, C and Brown, BM and Gallagher, KME and Newcomb, RA and El-Jawahri, A and Chen, YB}, title = {A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2024014000}, pmid = {39365992}, issn = {2473-9537}, abstract = {Bronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease. In this prospective, multicenter phase 2 trial (ClinicalTrials.gov, NCT03674047), adult participants with BOS were treated with ruxolitinib 10mg twice daily, continuously in 28-day cycles for up to 12 cycles. Participants enrolled into newly diagnosed (<6 months since BOS diagnosis, cohort A) or established (≥6 months since BOS diagnosis, cohort B) disease cohorts, respectively. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in forced expiratory volume in 1 second (FEV1) at 3 months compared to enrollment. The primary endpoint differed according to cohort (Cohort A: improvement, defined as [3]10% increase in FEV1; Cohort B: stabilization, defined as absence of [3]10% decrease in FEV1). Between 2019 and 2022, 49 participants meeting criteria for BOS were enrolled and treated (cohort A, n=36; cohort B, n=13). The primary endpoint was achieved by 27.8% of participants with new BOS and 92.3% of participants with established BOS. According to the 2014 NIH Consensus Criteria, the best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response, 18.4% partial response), with most responses occurring in mild or moderate disease. Non-infectious severe (grade ≥3) treatment-emergent adverse events were infrequent. Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT.}, }
@article {pmid39365700, year = {2024}, author = {Schmid, S and Russell, ZR and Yamashita, AS and West, ME and Parrish, AG and Walker, J and Rudoy, D and Yan, JZ and Quist, DC and Gessesse, BN and Alvinez, N and Hill, KD and Anderson, LW and Cimino, PJ and Kumasaka, DK and Parchment, RE and Holland, EC and Szulzewsky, F}, title = {ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.}, journal = {Cell reports}, volume = {43}, number = {10}, pages = {114829}, doi = {10.1016/j.celrep.2024.114829}, pmid = {39365700}, issn = {2211-1247}, mesh = {Animals ; *Glioma/genetics/pathology/drug therapy ; *Protein Kinase Inhibitors/pharmacology/therapeutic use ; Mice ; *Disease Models, Animal ; *MAP Kinase Signaling System/drug effects/genetics ; *Receptor, trkA/metabolism/genetics/antagonists & inhibitors ; Humans ; Drug Resistance, Neoplasm/genetics ; Oncogene Proteins, Fusion/metabolism/genetics ; Receptor, trkC/genetics/metabolism/antagonists & inhibitors ; Receptor, trkB/metabolism/genetics ; }, abstract = {Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.}, }
@article {pmid39363864, year = {2024}, author = {Shah, NN and Wang, M and Roeker, LE and Patel, K and Woyach, JA and Wierda, WG and Ujjani, CS and Eyre, TA and Zinzani, PL and Alencar, AJ and Ghia, P and Lamanna, N and Hoffmann, MS and Patel, MR and Flinn, I and Gerson, JN and Ma, S and Coombs, CC and Cheah, CY and Lech-Maranda, E and Fakhri, B and Kim, WS and Barve, MA and Cohen, JB and Jurczak, W and Munir, T and Thompson, MC and Tsai, DE and Bao, K and Cangemi, NA and Kherani, JF and Walgren, RA and Han, H and Ruppert, AS and Brown, JR}, title = {Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.285754}, pmid = {39363864}, issn = {1592-8721}, abstract = {Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.}, }
@article {pmid39363105, year = {2024}, author = {Itell, HL and Guenthoer, J and Humes, D and Baumgarten, NE and Overbaugh, J}, title = {Host cell glycosylation selects for infection with CCR5- versus CXCR4-tropic HIV-1.}, journal = {Nature microbiology}, volume = {9}, number = {11}, pages = {2985-2996}, pmid = {39363105}, issn = {2058-5276}, support = {R01HD103571//U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; T32GM007270//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; F31AI165168//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Humans ; *HIV-1/physiology/genetics/metabolism ; *Receptors, CXCR4/metabolism ; *Receptors, CCR5/metabolism ; Glycosylation ; *HIV Infections/virology/metabolism ; *Viral Tropism ; *CD4-Positive T-Lymphocytes/virology/metabolism ; CRISPR-Cas Systems ; Virus Internalization ; HEK293 Cells ; Polysaccharides/metabolism ; Host-Pathogen Interactions ; }, abstract = {Human immunodeficiency virus type 1 (HIV-1) infection involves a selection bottleneck that leads to transmission of one or a few variants. C-C motif chemokine receptor 5 (CCR5) or C-X-C motif chemokine receptor 4 (CXCR4) can act as coreceptors for HIV-1 viral entry. However, initial infection mostly occurs via CCR5, despite abundant expression of CXCR4 on target cells. The host factors that influence HIV-1 susceptibility and selection during transmission are unclear. Here we conduct CRISPR-Cas9 screens and identify SLC35A2 (a transporter of UDP-galactose expressed in target cells in blood and mucosa) as a potent and specific CXCR4-tropic restriction factor in primary target CD4[+] T cells. SLC35A2 inactivation, which resulted in truncated glycans, not only increased CXCR4-tropic infection levels but also decreased those of CCR5-tropic strains consistently. Single-cycle infections demonstrated that the effect is cell-intrinsic. These data support a role for a host protein that influences glycan structure in regulating HIV-1 infection. Host cell glycosylation may, therefore, affect HIV-1 selection during transmission in vivo.}, }
@article {pmid39363100, year = {2024}, author = {Chu, VT and Glascock, A and Donnell, D and Grabow, C and Brown, CE and Ward, R and Love, C and Kalantar, KL and Cohen, SE and Cannon, C and Woodworth, MH and Kelley, CF and Celum, C and Luetkemeyer, AF and Langelier, CR}, title = {Impact of doxycycline post-exposure prophylaxis for sexually transmitted infections on the gut microbiome and antimicrobial resistome.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {39363100}, issn = {1546-170X}, support = {K23 AI144036/AI/NIAID NIH HHS/United States ; }, abstract = {Doxycycline post-exposure prophylaxis (doxy-PEP) reduces bacterial sexually transmitted infections among men who have sex with men and transgender women. Although poised for widespread clinical implementation, the impact of doxy-PEP on antimicrobial resistance remains a primary concern as its effects on the gut microbiome and resistome, or the antimicrobial resistance genes (ARGs) present in the gut microbiome, are unknown. To investigate these effects, we studied participants from the DoxyPEP trial, a randomized clinical trial comparing doxy-PEP use, a one-time doxycycline 200-mg dose taken after condomless sex (DP arm, n = 100), to standard of care (SOC arm, n = 50) among men who have sex with men and transgender women. From self-collected rectal swabs at enrollment (day-0) and after 6 months (month-6), we performed metagenomic DNA sequencing (DNA-seq) or metatranscriptomic RNA sequencing (RNA-seq). DNA-seq data were analyzable from 127 samples derived from 89 participants, and RNA-seq data were analyzable from 86 samples derived from 70 participants. We compared the bacterial microbiome and resistome between the two study arms and over time. The median number of doxycycline doses taken since enrollment by participants with DNA-seq data was zero (interquartile range (IQR): 0-7 doses) for the SOC arm and 42 (IQR: 27-64 doses) for the DP arm. Tetracycline ARGs were detected in all day-0 DNA-seq samples and in 85% of day-0 RNA-seq samples. The proportional mass of tetracycline ARGs in the resistome increased between day-0 and month-6 in DP participants from 46% to 51% in the metagenome (P = 2.3 × 10[-2]) and from 4% to 15% in the metatranscriptome (P = 4.5 × 10[-6]), but no statistically significant increases in other ARG classes were observed. Exposure to a higher number of doxycycline doses correlated with proportional enrichment of tetracycline ARGs in the metagenome (Spearman's ρ = 0.23, P = 9.0 × 10[-3]) and metatranscriptome (Spearman's ρ = 0.55, P = 3.7 × 10[-8]). Bacterial microbiome alpha diversity, beta diversity and total bacterial mass did not differ between day-0 and month-6 samples from DP participants when assessed by either DNA-seq or RNA-seq. In an abundance-based correlation analysis, we observed an increase over time in the strength of the correlation between tetracycline ARGs and specific bacterial taxa, including some common human pathogens. In sum, doxy-PEP use over a 6-month period was associated with an increase in the proportion of tetracycline ARGs comprising the gut resistome and an increase in the expression of tetracycline ARGs. At 6 months of doxy-PEP use, no residual differences were observed in alpha and beta diversity or taxonomic composition of the gut microbiome. As doxy-PEP is implemented as a public health strategy, further studies and population-level surveillance of doxycycline-resistant pathogens are needed to understand the implications of these findings. ClinicalTrials.gov registration number: NCT03980223 .}, }
@article {pmid39362880, year = {2024}, author = {Hawkes, G and Beaumont, RN and Li, Z and Mandla, R and Li, X and Albert, CM and Arnett, DK and Ashley-Koch, AE and Ashrani, AA and Barnes, KC and Boerwinkle, E and Brody, JA and Carson, AP and Chami, N and Chen, YI and Chung, MK and Curran, JE and Darbar, D and Ellinor, PT and Fornage, M and Gordeuk, VR and Guo, X and He, J and Hwu, CM and Kalyani, RR and Kaplan, R and Kardia, SLR and Kooperberg, C and Loos, RJF and Lubitz, SA and Minster, RL and Naseri, T and Viali, S and Mitchell, BD and Murabito, JM and Palmer, ND and Psaty, BM and Redline, S and Shoemaker, MB and Silverman, EK and Telen, MJ and Weiss, ST and Yanek, LR and Zhou, H and , and Liu, CT and North, KE and Justice, AE and Locke, JM and Owens, N and Murray, A and Patel, K and Frayling, TM and Wright, CF and Wood, AR and Lin, X and Manning, A and Weedon, MN}, title = {Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8549}, pmid = {39362880}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; 875534//Innovative Medicines Initiative (IMI)/ ; }, mesh = {Humans ; *Whole Genome Sequencing ; *Body Height/genetics ; *Polymorphism, Single Nucleotide ; *Genome-Wide Association Study ; Male ; Female ; Gene Frequency ; Genome, Human ; Genetic Variation ; Phenotype ; }, abstract = {The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare (< 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < 6 × 10 - 10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.}, }
@article {pmid39362248, year = {2024}, author = {Wang, ES and Issa, GC and Erba, HP and Altman, JK and Montesinos, P and DeBotton, S and Walter, RB and Pettit, K and Savona, MR and Shah, MV and Kremyanskaya, M and Baer, MR and Foran, JM and Schiller, G and Adès, L and Heiblig, M and Berthon, C and Peterlin, P and Rodríguez-Arbolí, E and Salamero, O and Patnaik, MM and Papayannidis, C and Grembecka, J and Cierpicki, T and Clegg, B and Ray, J and Linhares, BM and Nie, K and Mitra, A and Ahsan, JM and Tabachri, M and Soifer, HS and Corum, D and Leoni, M and Dale, S and Fathi, AT}, title = {Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial.}, journal = {The Lancet. Oncology}, volume = {25}, number = {10}, pages = {1310-1324}, doi = {10.1016/S1470-2045(24)00386-3}, pmid = {39362248}, issn = {1474-5488}, mesh = {Humans ; *Leukemia, Myeloid, Acute/drug therapy/genetics/pathology ; Middle Aged ; Male ; Female ; *Nucleophosmin ; Aged ; Adult ; Neoplasm Recurrence, Local/drug therapy ; Maximum Tolerated Dose ; Drug Resistance, Neoplasm ; Dose-Response Relationship, Drug ; Aged, 80 and over ; }, abstract = {BACKGROUND: Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity.
METHODS: KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41.
FINDINGS: From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission.
INTERPRETATION: Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing.
FUNDING: Kura Oncology.}, }
@article {pmid39361354, year = {2024}, author = {Hazelwood, E and Lopez Manzano, C and Vincent, EE and Albanes, D and Bishop, DT and Le Marchand, L and Ulrich, CM and Peters, U and Murphy, G and Samadder, NJ and Anderson, L and Gunter, MJ and Murphy, N and Van Guelpen, B and Papadimitriou, N}, title = {Plasma ghrelin and risks of sex-specific, site-specific, and early-onset colorectal cancer: A Mendelian randomization analysis.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-0926}, pmid = {39361354}, issn = {1538-7755}, abstract = {BACKGROUND: Epidemiological and laboratory-based studies have provided conflicting evidence for a role of ghrelin in colorectal cancer (CRC) development. We conducted two-sample Mendelian randomization (MR) analyses to evaluate evidence for an association of circulating ghrelin and CRC risk overall and by sex, cancer subsite and age at diagnosis.
METHODS: Genetic instruments proxying plasma total ghrelin levels were obtained from a recent genome-wide association study of 54,219 participants. Summary data for CRC risk were obtained from a recent meta-analysis of several genetic consortia (up to 73,673 cases and 86,854 controls). A two-sample MR approach and several sensitivity analyses were applied.
RESULTS: We found no evidence for an association of genetically-predicted plasma total ghrelin levels and CRC risk (0.95, 95% confidence interval: 0.81-1.12; R2 of ghrelin genetic instruments: 4.6%), with similarly null results observed when stratified by sex, anatomical subsite, and for early-onset CRC.
CONCLUSIONS: Our study suggests that plasma ghrelin levels are unlikely to have a causal relationship with overall, early-onset, and sex- and cancer subsite-stratified CRC risk.
IMPACT: This large-scale analysis adds to the growing body of evidence that plasma total ghrelin levels are not associated with CRC risk.}, }
@article {pmid39361286, year = {2024}, author = {Pizzo, A and Leisenring, WM and Stratton, KL and Lamoureux, É and Flynn, JS and Alschuler, K and Krull, KR and Jibb, LA and Nathan, PC and Olgin, JE and Stinson, JN and Armstrong, GT and Alberts, NM}, title = {Fear of Cancer Recurrence in Adult Survivors of Childhood Cancer.}, journal = {JAMA network open}, volume = {7}, number = {10}, pages = {e2436144}, pmid = {39361286}, issn = {2574-3805}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; U2C EB021881/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors/psychology/statistics & numerical data ; Female ; Male ; *Fear/psychology ; Adult ; Cross-Sectional Studies ; *Neoplasm Recurrence, Local/psychology/epidemiology ; Retrospective Studies ; Neoplasms/psychology/epidemiology ; Risk Factors ; Middle Aged ; Prevalence ; Child ; }, abstract = {IMPORTANCE: Fear of cancer recurrence is common among survivors of adult-onset cancer and associated with increased distress, functional impairment, and health care utilization. However, little is known about the prevalence and risk factors of fear of cancer recurrence among adult survivors of childhood cancer who are also at high risk for subsequent malignant neoplasms.
OBJECTIVE: To characterize the prevalence of and risk factors for clinically significant fear of cancer recurrence in adult survivors of childhood cancer.
This cross-sectional investigation included participants recruited from the Childhood Cancer Survivor Study, a retrospective cohort study of long-term childhood cancer survivors treated at 31 institutions between 1970 and 1999 across North America. Participants were recruited and completed psychosocial measures via online survey between October 2018 and April 2019. Cancer and treatment-related variables were abstracted from medical records. Data were analyzed from May 2023 to July 2024.
MAIN OUTCOMES AND MEASURES: Clinically significant fear of cancer recurrence was assessed via the Fear of Cancer Recurrence Inventory-Short Form. Poisson regression models estimated prevalence ratios (PRs) with 95% CIs adjusted for age and sex to examine the associations of demographic, disease, treatment, and psychosocial variables with fear of cancer recurrence.
RESULTS: The final sample included 229 adult survivors of childhood cancer (115 female [50.2%]; mean [SD] age, 39.6 [9.9] years; mean [SD] time since diagnosis, 31.7 [8.4] years). Among survivors, 38 (16.6%; 95% CI, 11.6%-21.6%) reported clinically significant fear of cancer recurrence, and an additional 36 (15.7%) reported high fear of cancer recurrence. Clinically significant fear of cancer recurrence was associated with unemployment (PR, 2.5; 95% CI, 1.3-4.8), presence of neurologic chronic health conditions (PR, 3.3; 95% CI, 1.8-6.1), treatment with pelvic radiation (PR, 2.9; 95% CI, 1.5-5.6), and amputation or limb sparing surgery (PR, 2.4; 95% CI, 1.2-4.9). Higher risk of clinically significant fear of cancer recurrence was also associated with having either elevated anxiety or depression (PR, 2.6; 95% CI, 1.2-5.9), having both elevated (PR, 3.2; 95% CI, 1.2-8.4), and perceived poor health status (PR, 3.0; 95% CI, 3.1-9.7).
CONCLUSIONS AND RELEVANCE: Decades following treatment, one-third of childhood cancer survivors in this study reported elevated fear their cancer will recur or a subsequent malignant neoplasm will develop. Findings suggest that fear of cancer recurrence should be routinely screened, and clinically significant symptoms intervened upon as a part of survivorship care.}, }
@article {pmid39361281, year = {2024}, author = {Gjesvik, J and Moshina, N and Lee, CI and Miglioretti, DL and Hofvind, S}, title = {Artificial Intelligence Algorithm for Subclinical Breast Cancer Detection.}, journal = {JAMA network open}, volume = {7}, number = {10}, pages = {e2437402}, pmid = {39361281}, issn = {2574-3805}, mesh = {Humans ; *Breast Neoplasms/diagnosis/diagnostic imaging ; Female ; Middle Aged ; *Artificial Intelligence ; *Algorithms ; Aged ; Retrospective Studies ; *Early Detection of Cancer/methods ; *Mammography/methods/statistics & numerical data ; Norway/epidemiology ; }, abstract = {IMPORTANCE: Early breast cancer detection is associated with lower morbidity and mortality.
OBJECTIVE: To examine whether a commercial artificial intelligence (AI) algorithm for breast cancer detection could estimate the development of future cancer.
This retrospective cohort study of 116 495 women aged 50 to 69 years with no prior history of breast cancer before they underwent at least 3 consecutive biennial screening examinations used scores from an AI algorithm (INSIGHT MMG, version 1.1.7.2; Lunit Inc; used September 28, 2022, to April 5, 2023) for breast cancer detection and screening data from multiple, consecutive rounds of mammography performed from September 13, 2004, to December 21, 2018, at 9 breast centers in Norway. The statistical analyses were performed from September 2023 to August 2024.
EXPOSURE: Artificial intelligence algorithm score indicating suspicion for the presence of breast cancer. The algorithm provided a continuous cancer detection score for each examination ranging from 0 to 100, with increasing values indicating a higher likelihood of cancer being present on the current mammogram.
MAIN OUTCOMES AND MEASURES: Maximum AI algorithm score for cancer detection and absolute difference in score among breasts of women developing screening-detected cancer, women with interval cancer, and women who screened negative.
RESULTS: The mean (SD) age at the first study round was 58.5 (4.5) years for 1265 women with screening-detected cancer in the third round, 57.4 (4.6) years for 342 women with interval cancer after 3 negative screening rounds, and 56.4 (4.9) years for 116 495 women without breast cancer all 3 screening rounds. The mean (SD) absolute differences in AI scores among breasts of women developing screening-detected cancer were 21.3 (28.1) at the first study round, 30.7 (32.5) at the second study round, and 79.0 (28.9) at the third study round. The mean (SD) differences prior to interval cancer were 19.7 (27.0) at the first study round, 21.0 (27.7) at the second study round, and 34.0 (33.6) at the third study round. The mean (SD) differences among women who did not develop breast cancer were 9.9 (17.5) at the first study round, 9.6 (17.4) at the second study round, and 9.3 (17.3) at the third study round. Areas under the receiver operating characteristic curve for the absolute difference were 0.63 (95% CI, 0.61-0.65) at the first study round, 0.72 (95% CI, 0.71-0.74) at the second study round, and 0.96 (95% CI, 0.95-0.96) at the third study round for screening-detected cancer and 0.64 (95% CI, 0.61-0.67) at the first study round, 0.65 (95% CI, 0.62-0.68) at the second study round, and 0.77 (95% CI, 0.74-0.79) at the third study round for interval cancers.
CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of women undergoing screening mammography, mean absolute AI scores were higher for breasts developing vs not developing cancer 4 to 6 years before their eventual detection. These findings suggest that commercial AI algorithms developed for breast cancer detection may identify women at high risk of a future breast cancer, offering a pathway for personalized screening approaches that can lead to earlier cancer diagnosis.}, }
@article {pmid39361275, year = {2024}, author = {Kampouri, E and Reynolds, G and Teh, BW and Hill, JA}, title = {Chimeric antigen receptor-T-cell therapies going viral: latent and incidental viral infections.}, journal = {Current opinion in infectious diseases}, volume = {37}, number = {6}, pages = {526-535}, doi = {10.1097/QCO.0000000000001066}, pmid = {39361275}, issn = {1473-6527}, mesh = {Humans ; *Receptors, Chimeric Antigen/immunology ; *Immunotherapy, Adoptive/methods ; *Virus Diseases/prevention & control/immunology/therapy ; }, abstract = {PURPOSE OF REVIEW: Infections are the leading cause of non-relapse mortality following chimeric antigen receptor (CAR)-T-cell therapy, with viral infections being frequent both in the early and late phases post-infusion. We review the epidemiology of viral infections and discuss critical approaches to prevention and management strategies in this setting.
RECENT FINDINGS: Herpesviruses dominate the early period. herpes simplex virus and varicella zoster virus infections are rare due to widespread antiviral prophylaxis, but cytomegalovirus (CMV) reactivation is increasingly observed, particularly in high-risk groups including B cell maturation antigen (BCMA)-CAR-T-cell therapy recipients and patients receiving corticosteroids. While CMV end-organ disease is rare, CMV is associated with increased mortality, emphasizing the need to evaluate the broader impact of CMV on long-term hematological, infection, and survival outcomes. Human herpesvirus-6 (HHV-6) has also emerged as a concern, with its diagnosis complicated by overlapping symptoms with neurotoxicity, underscoring the importance of considering viral encephalitis in differential diagnoses. Respiratory viruses are the most common late infections with a higher incidence after BCMA CAR-T-cell therapy. Vaccination remains a critical preventive measure against respiratory viruses but may be less immunogenic following CAR-T-cell therapy. The optimal timing, type of vaccine, and dosing schedule require further investigation.
SUMMARY: A better understanding of viral epidemiology and preventive trials are needed to improve infection prevention practices and outcomes following CAR-T-cell therapies.}, }
@article {pmid39359003, year = {2024}, author = {Halloran, ME and Struchiner, CJ}, title = {Invited Commentary: Thirty-five Years of Leaky Vaccines.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwae379}, pmid = {39359003}, issn = {1476-6256}, abstract = {Over the past 35 years, the term "leaky vaccine" has gained widespread use in both mathematical modeling and epidemiologic methods for evaluating vaccines. Here we present a short history as we recall it of how the term was coined in the context of the history of sporozoite malaria vaccines that were thought to be possibly leaky in the 1980s. We draw a contrast with the all-or-none vaccine mechanism and review a few consequences for study design and population level effects. We invite readers to contribute information covering the time period preceding our memories in the 1980s as we may have overlooked something.}, }
@article {pmid39357788, year = {2024}, author = {Wisdom, AJ and Yeap, BY and Michalski, JM and Horick, NK and Zietman, AL and Christodouleas, JP and Kamran, SC and Parikh, RR and Vapiwala, N and Mihalcik, S and Miyamoto, DT and Zeng, J and Gay, HA and Pisansky, TM and Mishra, MV and Spratt, DE and Mendenhall, NP and Soffen, EM and Bekelman, JE and Efstathiou, JA}, title = {Setting the Stage: Feasibility and Baseline Characteristics in the PARTIQoL Trial Comparing Proton Therapy Versus Intensity Modulated Radiation Therapy for Localized Prostate Cancer.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2024.09.043}, pmid = {39357788}, issn = {1879-355X}, abstract = {PURPOSE: Men with localized prostate cancer may receive either photon-based intensity modulated radiation therapy (IMRT) or proton beam therapy (PBT). The PARTIQoL trial (NCT01617161) demonstrates the feasibility of performing a large, multicenter phase 3 randomized trial comparing IMRT with PBT for localized prostate cancer. Here, we report baseline features of patients enrolled on this trial and present strategies to improve feasibility of other similar trials.
METHODS AND MATERIALS: Patients with low- or intermediate-risk prostate cancer were randomly assigned to either PBT or IMRT with stratification by institution, age, use of rectal spacer, and fractionation schedule (conventional fractionation: 79.2 Gy in 44 fractions vs moderate hypofractionation: 70.0 Gy in 28 fractions). The primary endpoint is a change from baseline bowel health using the Expanded Prostate Index Composite score 24 months after radiation therapy. Secondary objectives include treatment-related differences in urinary and erectile functions, adverse events, and efficacy endpoints.
RESULTS: Between July 2012 and November 2021, 450 patients were successfully accrued. Patients were randomly assigned to either PBT (N = 226) or to IMRT (N = 224); 13 were ineligible or withdrew before treatment. The median age of 437 analyzed patients was 68 years (range, 46-89 years). A total of 41% of patients had low-risk and 59% had intermediate-risk disease. In total, 49% of patients were treated with conventional fractionation and 51% with moderately hypofractionation. 48% of patients used a rectal spacer. For patients receiving PBT, pencil beam scanning was used in 48%. PBT and IMRT arms were balanced for baseline variables.
CONCLUSIONS: Despite significant challenges, the PARTIQoL trial demonstrated that, with targeted recruitment approaches, multicenter collaboration, payer engagement, and protocol updates to incorporate contemporary techniques, it is feasible to perform a large phase 3 randomized clinical trial to assess whether PBT improves outcomes. We will separately report primary results and continue to monitor participants for longer follow-up and secondary endpoints.}, }
@article {pmid39357459, year = {2024}, author = {Chappidi, MR and Iravani, A and Stambler, N and Baskaran, S and DiPippo, VA and Denes, BS and Lin, DW}, title = {Impact of Baseline Renal Insufficiency on Piflufolastat F-18 Performance and Investigation of Changes in Renal Function Following Piflufolastat F-18 Administration: Results From the OSPREY Trial.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {6}, pages = {102223}, doi = {10.1016/j.clgc.2024.102223}, pmid = {39357459}, issn = {1938-0682}, abstract = {INTRODUCTION: Piflufolastat F-18, a prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, is predominantly eliminated via urinary excretion, and the kidneys have one of the highest absorbed doses. Therefore, this subgroup analysis aimed to investigate the impact of piflufolastat F-18 on renal function and its diagnostic performance in patients stratified by baseline renal function.
PATIENTS AND METHODS: The OSPREY clinical trial enrolled 2 cohorts: A-high-risk patients undergoing radical prostatectomy with pelvic lymphadenectomy, and B-patients with suspected recurrent/metastatic prostate cancer on conventional imaging. Baseline estimated glomerular filtration rates were calculated, and patients were stratified by baseline chronic kidney disease (CKD) stage. Changes in serum creatinine within 28 days postdose and diagnostic performance of piflufolastat F-18 were assessed for each CKD stage group in both cohorts.
RESULTS: 385 patients (cohort A, n = 268; cohort B, n = 117) underwent piflufolastat F-18-PET/CT. Baseline and postpiflufolastat F-18 median creatinine levels (mg/dL) were similar for patients in cohort A (0.95 [n = 264] vs. 0.95 [n = 252], respectively) and cohort B (0.93 [n = 116] vs. 0.96 [n = 84], respectively). Among 332 men (cohort A, n = 249; cohort B, n = 83) with baseline and postpiflufolastat creatinine measurements, there were minimal changes in creatinine across all baseline CKD stage groups (median change ranged from -0.02 to 0.023 in groups with >1 patient). The diagnostic performance of piflufolastat F-18 showed no meaningful differences when stratified by baseline CKD stage.
CONCLUSION: Piflufolastat F-18 appears to be safe and effective for imaging prostate cancer, including men with mild/moderate renal insufficiency.}, }
@article {pmid39353277, year = {2024}, author = {Irajizad, E and Fahrmann, JF and Toumazis, I and Vykoukal, J and Dennison, JB and Shen, Y and Do, KA and Ostrin, EJ and Feng, Z and Hanash, S}, title = {Biomarker trajectory for earlier detection of lung cancer.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105377}, pmid = {39353277}, issn = {2352-3964}, support = {U01 CA086368/CA/NCI NIH HHS/United States ; U01 CA194733/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lung Neoplasms/diagnosis/blood ; *Biomarkers, Tumor/blood ; Male ; Female ; *Early Detection of Cancer/methods ; Middle Aged ; Algorithms ; Aged ; Bayes Theorem ; }, abstract = {BACKGROUND: To determine whether an algorithm based on repeated measurements of a panel of four circulating protein biomarkers (4 MP) for lung cancer risk assessment results in improved performance over a single time measurement.
METHODS: We conducted data analysis of the 4 MP consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in pre-diagnostic sera from 2483 ever-smoker participants (389 cases and 2094 randomly selected non-cases) in the Prostate, Lung, Colorectal, Ovarian (PLCO) Study who had at least two sequential blood collections over 6 years. A parametric empirical Bayes (PEB) algorithm, which incorporates participant biomarker history at each time point, was compared to a single-threshold (ST) method.
FINDINGS: Among ever-smoker participants, the PEB approach yielded an additional 4% improvement in the AUC compared to the ST approach (P-value: 0.009). When considering an ≥10 PY smoking history and at a fixing the specificity corresponding to 1% 6-year lung cancer risk, PEB resulted in significant improvement in the sensitivity (SenPEB:96.3% vs SenST:91.0%; P-value: 6.7e-3). The PEB algorithm identified 17 of the 35 cases that remained ST negative, at an average of 1.26 years before diagnosis. Ten case individuals who were positive based on ST at an average of 1.03 years prior to diagnosis were identified earlier by PEB, at an average of 2.70 years.
INTERPRETATION: An algorithm based on repeated measurements of the 4 MP improves sensitivity and results in an earlier detection of lung cancer compared to a single-threshold method.
FUNDING: This study was supported by NIH Grant Nos. U01CA271888, U01CA194733, U01CA213285, NCI EDRN U01 CA200468, P30CA016672, and U24CA086368; the Cancer Prevention & Research Institute of Texas RP180505 and RP160693; the SPORE P50CA140388; the CCTS TR000371; and the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program and the Lyda Hill Foundation.}, }
@article {pmid39356983, year = {2024}, author = {Lurain, K and Ramaswami, R and Ekwede, I and Eulo, V and Goyal, G and Menon, M and Odeny, TA and Sharon, E and Wagner, MJ and Wang, CJ and Bhardwaj, N and Friedlander, PA and Abdul-Hay, M and Cornejo Castro, EM and Labo, N and Marshall, VA and Miley, W and Moore, K and Roshan, R and Whitby, D and Kask, AS and Kaiser, J and Han, E and Wright, A and Yarchoan, R and Fling, SP and Uldrick, TS}, title = {Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2400640}, doi = {10.1200/JCO.24.00640}, pmid = {39356983}, issn = {1527-7755}, abstract = {PURPOSE: Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort.
METHODS: In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4[+] ≥50 cells/μL and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria.
RESULTS: Thirty-two cisgender men enrolled with baseline median CD4[+] T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4[+] T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable).
CONCLUSION: Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.}, }
@article {pmid39354185, year = {2024}, author = {Armstrong, AJ and Taylor, A and Haffner, MC and Abida, W and Bryce, AH and Karsh, LI and Tagawa, ST and Twardowski, P and Serritella, AV and Lang, JM}, title = {Germline and somatic testing for homologous repair deficiency in patients with prostate cancer (part 1 of 2).}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {39354185}, issn = {1476-5608}, abstract = {BACKGROUND/OBJECTIVES: Unfortunately, not all metastatic castration resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing in prostate cancer.
SUBJECTS/METHODS: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science.
RESULTS/CONCLUSION: We argue for the widespread adoption of germline testing in all patients with prostate cancer and for somatic mutations testing in patients at the time of recurrent/metastatic disease. In this first part, we review how genomic testing is performed. We also review how to overcome certain barriers to integrate genetic and biomarker testing into clinical practice.}, }
@article {pmid39354095, year = {2024}, author = {Zhao, LP and Papadopoulos, GK and Skyler, JS and Pugliese, A and Parikh, HM and Kwok, WW and Lybrand, TP and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, Å}, title = {Progression to type 1 diabetes in the DPT-1 and TN07 clinical trials is critically associated with specific residues in HLA-DQA1-B1 heterodimers.}, journal = {Diabetologia}, volume = {67}, number = {11}, pages = {2481-2493}, pmid = {39354095}, issn = {1432-0428}, support = {R01 DK132406/DK/NIDDK NIH HHS/United States ; R01 DK132406/DK/NIDDK NIH HHS/United States ; }, mesh = {*Diabetes Mellitus, Type 1/genetics/metabolism/immunology ; Humans ; *HLA-DQ alpha-Chains/genetics/metabolism ; *HLA-DQ beta-Chains/genetics/metabolism ; *Haplotypes/genetics ; *Disease Progression ; Female ; Male ; Genetic Predisposition to Disease ; Genotype ; Protein Multimerization ; }, abstract = {AIMS/HYPOTHESIS: The aim of this work was to explore molecular amino acids (AAs) and related structures of HLA-DQA1-DQB1 that underlie its contribution to the progression from stages 1 or 2 to stage 3 type 1 diabetes.
METHODS: Using high-resolution DQA1 and DQB1 genotypes from 1216 participants in the Diabetes Prevention Trial-Type 1 and the Diabetes Prevention Trial, we applied hierarchically organised haplotype association analysis (HOH) to decipher which AAs contributed to the associations of DQ with disease and their structural properties. HOH relied on the Cox regression to quantify the association of DQ with time-to-onset of type 1 diabetes.
RESULTS: By numerating all possible DQ heterodimers of α- and β-chains, we showed that the heterodimerisation increases genetic diversity at the cellular level from 43 empirically observed haplotypes to 186 possible heterodimers. Heterodimerisation turned several neutral haplotypes (DQ2.2, DQ2.3 and DQ4.4) to risk haplotypes (DQ2.2/2.3-DQ4.4 and DQ4.4-DQ2.2). HOH uncovered eight AAs on the α-chain (-16α, -13α, -6α, α22, α23, α44, α72, α157) and six AAs on the β-chain (-18β, β9, β13, β26, β57, β135) that contributed to the association of DQ with progression of type 1 diabetes. The specific AAs concerned the signal peptide (minus sign, possible linkage to expression levels), pockets 1, 4 and 9 in the antigen-binding groove of the α1β1 domain, and the putative homodimerisation of the αβ heterodimers.
CONCLUSIONS/INTERPRETATION: These results unveil the contribution made by DQ to type 1 diabetes progression at individual residues and related protein structures, shedding light on its immunological mechanisms and providing new leads for developing treatment strategies.
DATA AVAILABILITY: Clinical trial data and biospecimen samples are available through the National Institute of Diabetes and Digestive and Kidney Diseases Central Repository portal (https://repository.niddk.nih.gov/studies).}, }
@article {pmid39352173, year = {2024}, author = {Weinstock, LM and Bishop, TM and Bauer, MS and Benware, J and Bossarte, RM and Bradley, J and Dobscha, SK and Gibbs, J and Gildea, SM and Graves, H and Haas, G and House, S and Kennedy, CJ and Landes, SJ and Liu, H and Luedtke, A and Marx, BP and Miller, A and Nock, MK and Owen, RR and Pigeon, WR and Sampson, NA and Santiago-Colon, A and Shivakumar, G and Urosevic, S and Kessler, RC}, title = {Design of a multicenter randomized controlled trial of a post-discharge suicide prevention intervention for high-risk psychiatric inpatients: The Veterans Coordinated Community Care Study.}, journal = {International journal of methods in psychiatric research}, volume = {33}, number = {4}, pages = {e70003}, pmid = {39352173}, issn = {1557-0657}, support = {EBP 22-104//Department of Veterans Affairs Quality Enhancement Research Initiative/ ; PII 18-195//Department of Veterans Affairs Quality Enhancement Research Initiative/ ; QUE 20-026//Department of Veterans Affairs Quality Enhancement Research Initiative/ ; //Warren Alpert Foundation/ ; 36C24122P0883//National Center for PTSD, U.S. Department of Veterans Affairs/ ; 36C24122P0883//VA Boston Healthcare System/ ; UL1 TR003107/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Suicide Prevention ; *Veterans ; United States ; *Patient Discharge ; *Inpatients ; Mental Disorders/prevention & control/therapy ; United States Department of Veterans Affairs ; Adult ; Female ; Male ; Middle Aged ; Follow-Up Studies ; }, abstract = {BACKGROUND: The period after psychiatric hospital discharge is one of elevated risk for suicide-related behaviors (SRBs). Post-discharge clinical outreach, although potentially effective in preventing SRBs, would be more cost-effective if targeted at high-risk patients. To this end, a machine learning model was developed to predict post-discharge suicides among Veterans Health Administration (VHA) psychiatric inpatients and target a high-risk preventive intervention.
METHODS: The Veterans Coordinated Community Care (3C) Study is a multicenter randomized controlled trial using this model to identify high-risk VHA psychiatric inpatients (n = 850) randomized with equal allocation to either the Coping Long Term with Active Suicide Program (CLASP) post-discharge clinical outreach intervention or treatment-as-usual (TAU). The primary outcome is SRBs over a 6-month follow-up. We will estimate average treatment effects adjusted for loss to follow-up and investigate the possibility of heterogeneity of treatment effects.
RESULTS: Recruitment is underway and will end September 2024. Six-month follow-up will end and analysis will begin in Summer 2025.
CONCLUSION: Results will provide information about the effectiveness of CLASP versus TAU in reducing post-discharge SRBs and provide guidance to VHA clinicians and policymakers about the implications of targeted use of CLASP among high-risk psychiatric inpatients in the months after hospital discharge.
CLINICAL TRIALS REGISTRATION: ClinicalTrials.Gov identifier: NCT05272176 (https://www.
CLINICALTRIALS: gov/ct2/show/NCT05272176).}, }
@article {pmid39352001, year = {2024}, author = {Shadman, M and Salkar, M and Srivastava, B and Karve, S and Emond, B and Gogna, P and Manceur, AM and Lafeuille, MH and Rava, A and Sun, H and Howarth, A and Tomicki, S and Agatep, B and Jones, B and Franceschini, E and Saifan, C and Bacchus, S and Roeker, L and Stephens, DM}, title = {Real-world outcomes following ibrutinib dose reduction in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.}, journal = {Leukemia & lymphoma}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/10428194.2024.2402814}, pmid = {39352001}, issn = {1029-2403}, abstract = {This study used real-world data from three separate United States (US) databases to evaluate dosing patterns and time to next treatment (TTNT) following the first-incident adverse event (AE) in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with first-line ibrutinib with and without dose reduction (DR). Median TTNT or death in patients with and without a DR following an AE in each database was as follows: Optum Clinformatics Data Mart (CDM): 59.5 and 30.6 months; ConcertAI: 27.1 and 18.0 months; and Medicare Fee-for-Service (FFS): 49.8 and 22.0 months, respectively. Median TTNT or death in patients with cardiac AEs, with and without a DR, was: Optum CDM: 44.4 and 22.9 months; ConcertAI: 29.9 and 18.3 months; and Medicare FFS: 49.6 and 14.0 months, respectively. Ibrutinib DR was associated with fewer outpatient visits and lower CLL/SLL-related medical costs. These findings suggest that utilizing ibrutinib DR may effectively manage tolerability without compromising clinical efficacy.}, }
@article {pmid39349773, year = {2024}, author = {Liu, S and Zhu, J and Zhong, H and Wu, C and Xue, H and Darst, BF and Guo, X and Durda, P and Tracy, RP and Liu, Y and Johnson, WC and Taylor, KD and Manichaikul, AW and Goodarzi, MO and Gerszten, RE and Clish, CB and Chen, YI and Highland, H and Haiman, CA and Gignoux, CR and Lange, L and Conti, DV and Raffield, LM and Wilkens, L and Marchand, LL and North, KE and Young, KL and Loos, RJ and Buyske, S and Matise, T and Peters, U and Kooperberg, C and Reiner, AP and Yu, B and Boerwinkle, E and Sun, Q and Rooney, MR and Echouffo-Tcheugui, JB and Daviglus, ML and Qi, Q and Mancuso, N and Li, C and Deng, Y and Manning, A and Meigs, JB and Rich, SS and Rotter, JI and Wu, L}, title = {Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations.}, journal = {Diabetologia}, volume = {}, number = {}, pages = {}, pmid = {39349773}, issn = {1432-0428}, support = {R01CA263494/BC/NCI NIH HHS/United States ; U54HG013243//NHGRI/NIMHD/ ; }, abstract = {AIMS/HYPOTHESIS: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European.
METHODS: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs. The models were applied to genome-wide association study summary statistics of 250,127 type 2 diabetes cases and 1,222,941 controls from different racial and ethnic populations.
RESULTS: We identified three, 44 and one protein associated with type 2 diabetes risk in Asian, European and Hispanic/Latino populations, respectively. Meta-analysis identified 40 proteins associated with type 2 diabetes risk across the populations, including well-established as well as novel proteins not yet implicated in type 2 diabetes development.
CONCLUSIONS/INTERPRETATION: Our study improves our understanding of the aetiology of type 2 diabetes in diverse populations.
DATA AVAILABILITY: The summary statistics of multi-ethnic type 2 diabetes GWAS of MVP, DIAMANTE, Biobank Japan and other studies are available from The database of Genotypes and Phenotypes (dbGaP) under accession number phs001672.v3.p1. MESA genetic, proteome and covariate data can be accessed through dbGaP under phs000209.v13.p3. All code is available on GitHub (https://github.com/Arthur1021/MESA-1K-PWAS).}, }
@article {pmid39348623, year = {2024}, author = {Sankaran, S and Banerjee, R}, title = {Smartwatch Biometrics in the Electronic Medical Record: Time for a New Vital Sign?.}, journal = {JCO clinical cancer informatics}, volume = {8}, number = {}, pages = {e2400161}, doi = {10.1200/CCI-24-00161}, pmid = {39348623}, issn = {2473-4276}, mesh = {Humans ; *Electronic Health Records ; *Biometry/methods ; *Smartphone ; Vital Signs ; }, abstract = {Smartphone biometrics in the EMR: is the 5th vital sign here? @JCOCCI_ASCO commentary by Sankaran and @RahulBanerjeeMD here.}, }
@article {pmid39348095, year = {2024}, author = {Harris, HR and Saboda, K and Thomson, CA and Saquib, N and Shadyab, AH and Schnatz, PF and Robles-Morales, R and Qi, L and Roe, DJ and Farland, LV}, title = {History of infertility and risk of endometrial cancer in the Women's Health Initiative.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-24-0717}, pmid = {39348095}, issn = {1538-7755}, abstract = {BACKGROUND: Several studies have suggested an association between infertility and risk of endometrial cancer. However, most studies have evaluated this relationship in premenopausal people, yet the mean age of endometrial cancer is 60 years old, after the average age of menopause.
METHODS: Our study included Women's Health Initiative participants who self-reported whether they had a history of infertility. Cox proportional hazards models were used to examine the association between infertility and incident endometrial cancer. Given that all infertility diagnoses occurred prior to study enrollment, we conducted secondary analyses using logistic regression examining prevalent endometrial cancer cases diagnosed before study baseline.
RESULTS: Approximately 18% of participants reported a history of infertility. No statistically significant association was observed between infertility and risk of incident endometrial cancer overall (incident cases=1622; hazard ratio [HR]=1.12; 95% confidence interval [CI]=0.99-1.26). While point estimates suggested an increase in risk of endometrial cancer among women with BMI ≥25 (HR=1.15; 95% CI=0.99-1.33), none of the associations were statistically significant. There was an association between history of infertility and prevalent endometrial cancer cases (odds ratio [OR]=1.19; 95% CI=1.06-1.34), with the strongest association for infertility diagnosis due to endometriosis (OR=2.42; 95% CI=1.83-3.19).
CONCLUSIONS: In a population of postmenopausal participants, we observed a modest, but not statistically significant, association between overall infertility and incident endometrial cancer, with the suggestion of a higher risk among those with a BMI ≥25.
IMPACT: Our findings highlight, as observed in previous studies, that risk factors for endometrial cancer may vary by body mass index.}, }
@article {pmid39346961, year = {2024}, author = {Zeller, MA and Chang, J and Trevisan, G and Main, RG and Gauger, PC and Zhang, J}, title = {Rapid PRRSV-2 ORF5-based lineage classification using Nextclade.}, journal = {Frontiers in veterinary science}, volume = {11}, number = {}, pages = {1419340}, pmid = {39346961}, issn = {2297-1769}, abstract = {Porcine reproductive and respiratory syndrome virus (PRRSV) continues to be a global challenge for swine health. Yim-Im et al. 2023 provides a standard genetic nomenclature, extending previously published works to better characterize PRRSV-2 ORF5-based genetic lineages on a global scale. To facilitate the use of this nomenclature, scaffold sequences, including historical and contemporary vaccines, were synthesized into a dataset designed for Nextclade v3.0. Metadata from the scaffold sequences representing year, country, and RFLP typing of the sequence were incorporated into the dataset. These scaffold sequences were processed through the Augur pipeline using DQ478308.1 as a reference strain for rooting and comparison. The resultant classifier can be accessed through the Nextclade website (https://clades.nextstrain.org/) or a link on the PRRSView homepage (https://prrsv.vdl.iastate.edu/). The resultant classifier functions the same as other classifiers hosted by the Nextclade core group and can provide phylogenetic-based PRRSV-2 ORF5 classifications on demand. Nextclade provides additional sequence metrics such as classification quality and notable mutations relative to the reference. The submitted sequences are grafted to the reference tree using phylogenetic placement, allowing for comparison to nearby sequences of reference viruses and vaccine strains. Additional comparisons between sequences can be made with metadata incorporated in the dataset. Although Nextclade is hosted as a webtool, the sequences are not uploaded to a server, and all analysis stay strictly confidential to the user. This work provides a standardized, trivial workflow facilitated by Nextclade to rapidly assign lineage classifications to PRRSV-2, identify mutations of interest, and compare contemporary strains to relevant vaccines.}, }
@article {pmid39345789, year = {2024}, author = {Parraga-Leo, A and Oskotsky, TT and Oskotsky, B and Wibrand, C and Roldan, A and Tang, AS and Ha, CWY and Wong, RJ and Minot, SS and Andreoletti, G and Kosti, I and Theis, KR and Ng, S and Lee, YS and Diaz-Gimeno, P and Bennett, PR and MacIntyre, DA and Lynch, SV and Romero, R and Tarca, AL and Stevenson, DK and Aghaeepour, N and Golob, JL and Sirota, M}, title = {VMAP: Vaginal Microbiome Atlas during Pregnancy.}, journal = {JAMIA open}, volume = {7}, number = {3}, pages = {ooae099}, pmid = {39345789}, issn = {2574-2531}, support = {R01 AG058417/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVES: To enable interactive visualization of the vaginal microbiome across the pregnancy and facilitate discovery of novel insights and generation of new hypotheses.
MATERIAL AND METHODS: Vaginal Microbiome Atlas during Pregnancy (VMAP) was created with R shiny to generate visualizations of structured vaginal microbiome data from multiple studies.
RESULTS: VMAP (http://vmapapp.org) visualizes 3880 vaginal microbiome samples of 1402 pregnant individuals from 11 studies, aggregated via open-source tool MaLiAmPi. Visualized features include diversity measures, VALENCIA community state types, and composition (phylotypes, taxonomy) that can be filtered by various categories.
DISCUSSION: This work represents one of the largest and most geographically diverse aggregations of the vaginal microbiome in pregnancy to date and serves as a user-friendly resource to further analyze vaginal microbiome data and better understand pregnancies and associated outcomes.
CONCLUSION: VMAP can be obtained from https://github.com/msirota/vmap.git and is currently deployed as an online app for non-R users.}, }
@article {pmid39345629, year = {2024}, author = {Takenaka, R and Simmerman, SM and Schmidt, CA and Albanese, EH and Rieder, LE and Malik, HS}, title = {The Drosophila maternal-effect gene abnormal oocyte (ao) does not repress histone gene expression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345629}, issn = {2692-8205}, support = {R35 GM142724/GM/NIGMS NIH HHS/United States ; U24 HG013300/HG/NHGRI NIH HHS/United States ; P40 OD010949/OD/NIH HHS/United States ; K12 GM000680/GM/NIGMS NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; R01 GM074108/GM/NIGMS NIH HHS/United States ; R00 HD092625/HD/NICHD NIH HHS/United States ; F32 GM140778/GM/NIGMS NIH HHS/United States ; }, abstract = {The abnormal oocyte (ao) gene of Drosophila melanogaster is a maternal-effect lethal gene previously identified as encoding a transcriptional regulator of core histones. However, background genetic mutations in existing ao mutant strains could compromise their utility in manipulating histone levels. To distinguish the true ao phenotype from background effects, we created two new ao reagents: a CRISPR/Cas9-mediated knockout of the ao allele for genetic and molecular analyses and an epitope-tagged ao allele for cytological experiments. Using these reagents, we confirm previous findings that ao exhibits maternal-effect lethality, which can be rescued by either a decrease in the histone gene copy number or by Y chromosome heterochromatin. We also confirm that the Ao protein localizes to the histone locus bodies in ovaries. Our data also suggest that ao genetically interacts with the histone genes and heterochromatin, as previously suggested. However, contrary to prior findings, we find that ao does not repress core histone transcript levels. Thus, the molecular basis for ao-associated maternal-effect lethality remains unknown.}, }
@article {pmid39345457, year = {2024}, author = {Alencar, GF and Rodriguez, HJ and Pulliam, TH and Remington, AJ and Gilmour, MW and Alam, R and Jabbour, AJ and Mullen, LJ and DeBuysscher, BL and Nghiem, P and Taylor, JJ}, title = {Merkel cell carcinoma-derived macrophage migration inhibitory factor (MIF) may promote persistence of Chronic Lymphocytic Leukemia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39345457}, issn = {2692-8205}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA044579/CA/NCI NIH HHS/United States ; }, abstract = {While concurrent diagnoses of Merkel cell carcinoma (MCC) and other cancers, like Chronic lymphocytic leukemia (CLL), are rare, patients with MCC have a 30-fold higher incidence of CLL. While these increases have been attributed to the ability of CLL to suppress immune responses allowing for the emergence of MCC, here we found evidence that MCC could support the persistence of CLL. Using single cell sequencing approaches and computational analyses of MCC and CLL from a patient where both cancers were present in the same lymph node, we found that production of macrophage migration inhibitory factor (MIF) by MCC could promote the persistence of CLL through stimulation of CD74 and CXCR4. These results may explain why blood cell counts rapidly normalized after treatment for MCC and were maintained at normal levels despite the absence of treatment for CLL.}, }
@article {pmid39343510, year = {2024}, author = {Chae, YK and Othus, M and Patel, S and Powers, B and Hsueh, CT and Govindarajan, R and Bucur, S and Kim, HS and Chung, LI and McLeod, C and Chen, HX and Sharon, E and Streicher, H and Ryan, CW and Blanke, C and Kurzrock, R}, title = {Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the desmoid tumors.}, journal = {Journal for immunotherapy of cancer}, volume = {12}, number = {9}, pages = {}, pmid = {39343510}, issn = {2051-1426}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Adult ; *CTLA-4 Antigen/antagonists & inhibitors ; *Fibromatosis, Aggressive/drug therapy ; Aged ; Young Adult ; Prospective Studies ; Ipilimumab/therapeutic use/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use/pharmacology/adverse effects ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Nivolumab/therapeutic use/pharmacology ; Adolescent ; }, abstract = {BACKGROUND: Dual inhibition using anti-programmed death-1 (PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors has proven effective in many cancers. However, its efficacy in rare solid cancers remains unclear. Desmoid tumors are ultrarare soft-tissue tumors, traditionally treated with surgery. This study reviews the first results of using ipilimumab and nivolumab in the desmoid tumor cohort of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial.
METHODS: DART is a prospective/open-label/multicenter (1,016 US sites)/multicohort phase II trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) that opened at 1,016 US sites. The primary endpoint included overall response rate (ORR) defined as confirmed complete (CR) and partial responses (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. Secondary endpoints include progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; stable disease (SD) ≥6 months plus CR and PR) and toxicity.
RESULTS: Sixteen evaluable patients (median age: 37) with desmoid tumors and a median of 1.5 prior therapies (with no prior exposure to immunotherapy) were analyzed. The tumors varied in location (eight abdomen, three lower limb, two upper limb, two pelvis, and one neck). ORR was 18.8% (3/16; 3 confirmed PR): 40% regression (PFS 30+ months), 83% regression (PFS 16 months) and 71% regression (PFS 8.4 months). Seven additional patients (43.8%) had prolonged SD over 6 months (PFS: 16.5, 22.4+, 22.6, 30.1, 38.2+, 48.3+ and 60.7+ months). Overall CBR was 62.5% (10/16). Median PFS was 19.4 months, with 6-month PFS of 73% and 1-year PFS of 67%. All patients were alive at 1 year; median OS was not assessable, as 13 patients were alive at analysis. Common adverse events included fatigue, nausea and hypothyroidism, with 50% experiencing grade 3-4 events. There were no grade 5 events.
CONCLUSION: Treatment with ipilimumab and nivolumab in desmoid tumors yielded an ORR of 18.8% and a CBR of 62.5% with durable responses seen. This is the first prospective study exploring the efficacy of this combination in this rare disease. Ongoing studies aim to identify markers for response and resistance. Expanded trials are necessary.
TRIAL REGISTRATION NUMBER: NCT02834013.}, }
@article {pmid39341639, year = {2024}, author = {Butler, CD and Combs Bowles, D and Hanigan, IC and Harmer, A and Potter, JD}, title = {The Lancet Countdown on health and climate change: competing interests and optimism bias.}, journal = {Lancet (London, England)}, volume = {404}, number = {10459}, pages = {1196-1197}, doi = {10.1016/S0140-6736(24)01491-0}, pmid = {39341639}, issn = {1474-547X}, mesh = {Humans ; Bias ; *Climate Change ; *Global Health ; *Optimism ; }, }
@article {pmid39339842, year = {2024}, author = {Huang, Y and Alam, S and Andersen-Nissen, E and Carpp, LN and Dintwe, OB and Flach, BS and Grunenberg, N and Laher, F and De Rosa, SC and Ferrari, G and Innes, C and Bekker, LG and Kublin, JG and McElrath, MJ and Tomaras, GD and Gray, GE and Gilbert, PB}, title = {Non-HIV Vaccine-Induced Immune Responses as Potential Baseline Immunogenicity Predictors of ALVAC-HIV and AIDSVAX B/E-Induced Immune Responses.}, journal = {Viruses}, volume = {16}, number = {9}, pages = {}, pmid = {39339842}, issn = {1999-4915}, support = {R01 CA277133/CA/NCI NIH HHS/United States ; R37AI054165//National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)/ ; R01CA277133//National Cancer Institute of the NIH/ ; UM1AI068635//National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *AIDS Vaccines/immunology/administration & dosage ; *HIV Infections/immunology/prevention & control ; *Immunoglobulin G/blood/immunology ; *CD4-Positive T-Lymphocytes/immunology ; Male ; Female ; Adult ; Tetanus Toxoid/immunology/administration & dosage ; Immunogenicity, Vaccine ; HIV Antibodies/blood/immunology ; Hepatitis B Vaccines/immunology/administration & dosage ; HIV-1/immunology ; Young Adult ; Antibodies, Viral/blood/immunology ; Viral Vaccines ; }, abstract = {Identifying correlations between immune responses elicited via HIV and non-HIV vaccines could aid the search for correlates of HIV protection and increase statistical power in HIV vaccine-efficacy trial designs. An exploratory objective of the HVTN 097 phase 1b trial was to assess whether immune responses [focusing on those supported as correlates of risk (CoR) of HIV acquisition] induced via the RV144 pox-prime HIV vaccine regimen correlated with those induced via tetanus toxoid (TT) and/or hepatitis B virus (HBV) vaccines. We measured TT-specific and HBV-specific IgG-binding antibody responses and TT-specific and HBV-specific CD4+ T-cell responses at multiple time points in HVTN 097 participants, and we assessed their correlations at peak time points with HIV vaccine (ALVAC-HIV and AIDSVAX B/E)-induced responses. Four correlations were significant [false discovery rate-adjusted p-value (FDR) ≤ 0.2]. Three of these four were with IgG-binding antibody responses to TT measured one month after TT receipt, with the strongest and most significant correlation [rho = 0.368 (95% CI: 0.096, 0.588; p = 0.008; FDR = 0.137)] being with IgG-binding antibody responses to MN gp120 gDneg (B protein boost) measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. The fourth significant correlation [(rho = 0.361; 95% CI: 0.049, 0.609; p = 0.021; FDR = 0.137)] was between CD4+ T-cell responses to a hepatitis B surface antigen peptide pool, measured 2 weeks after the third HBV vaccination, and IgG-binding antibody responses to gp70BCaseAV1V2 (B V1V2 immune correlate), measured two weeks after the second ALVAC-HIV and AIDSVAX B/E boost. These moderate correlations imply that either vaccine, TT or HBV, could potentially provide a moderately useful immunogenicity predictor for the ALVAC-HIV and AIDSVAX B/E HIV vaccine regimen.}, }
@article {pmid39334347, year = {2024}, author = {Michel, AM and Yi, H and Amenta, J and Collins, N and Vaynrub, A and Umakanth, S and Anderson, G and Arnold, K and Law, C and Pruthi, S and Sandoval-Leon, A and Shirley, R and Perdekamp, MG and Colonna, S and Krisher, S and King, T and Yee, LD and Ballinger, TJ and Braun-Inglis, C and Mangino, DA and Wisinski, K and DeYoung, CA and Ross, M and Floyd, J and Kaster, A and VanderWalde, L and Saphner, TJ and Zarwan, C and Lo, S and Graham, C and Conlin, A and Yost, K and Agnese, D and Jernigan, C and Hershman, DL and Neuhouser, ML and Arun, B and Crew, KD and Kukafka, R}, title = {Use of web-based decision support to improve informed choice for chemoprevention: a qualitative analysis of pre-implementation interviews (SWOG S1904).}, journal = {BMC medical informatics and decision making}, volume = {24}, number = {1}, pages = {272}, pmid = {39334347}, issn = {1472-6947}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Chemoprevention ; *Qualitative Research ; *Breast Neoplasms/prevention & control ; Middle Aged ; Adult ; Internet ; Male ; Decision Support Techniques ; Interviews as Topic ; }, abstract = {BACKGROUND: Women with high-risk breast lesions, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have a 4- to tenfold increased risk of breast cancer compared to women with non-proliferative breast disease. Despite high-quality data supporting chemoprevention, uptake remains low. Interventions are needed to break down barriers.
METHODS: The parent trial, MiCHOICE, is a cluster randomized controlled trial evaluating the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. For this pre-implementation analysis, 25 providers participated in semi-structured interviews prior to accessing decision support tools. Interviews sought to understand attitudes/beliefs and barriers/facilitators to chemoprevention.
RESULTS: Interviews with 25 providers (18 physicians and 7 advanced practice providers) were included. Providers were predominantly female (84%), white (72%), and non-Hispanic (88%). Nearly all providers (96%) had prescribed chemoprevention for eligible patients. Three themes emerged in qualitative analysis. The first theme describes providers' confidence in chemoprevention and the utility of decision support tools. The second theme elucidates barriers to chemoprevention, including time constraints, risk communication and perceptions of patients' fear of side effects and anxiety. The third theme is the need for early implementation of decision support tools.
CONCLUSIONS: This qualitative study suggests that providers were interested in the early inclusion of decision aids (DA) in their chemoprevention discussion workflow. The DAs may help overcome certain barriers which were elucidated in these interviews, including patient level concerns about side effects, clinic time constraints and difficulty communicating risk. A multi-faceted intervention with a DA as one active component may be needed.
TRIAL REGISTRATION: This trial was registered with the NIH clinical trial registry, clinicaltrials.gov, NCT04496739.}, }
@article {pmid39334118, year = {2024}, author = {Ko, LK and Jang, SH and Rodriguez, E and Buta, M and Ibarra, G and Reuland, D}, title = {Dissemination of colorectal cancer information among Hispanic patients and their social network.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {2616}, pmid = {39334118}, issn = {1471-2458}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Colorectal Neoplasms/ethnology/diagnosis ; Decision Support Techniques ; *Early Detection of Cancer/psychology/statistics & numerical data ; *Hispanic or Latino/psychology/statistics & numerical data ; *Information Dissemination ; Social Support ; Washington ; }, abstract = {BACKGROUND: Colorectal cancer (CRC) screening decision aids can inform patients about CRC screening benefits, costs, and procedures. Patients who receive the decision aid report wanting to share the information with their families and friends. We evaluated a CRC screening decision aid on Hispanic patients' communication to their alters and whether patient-alter communication leads to alters' CRC screening intention.
METHODS: We conducted a one-arm pre/post study of Hispanic patients and their alters; patients (n = 42) and their alters (n = 19) were recruited from a clinic site in Yakima County, Washington State. Patients viewed a CRC screening decision aid at the clinic site. Survey data from patients and alters were collected via telephone including patients' communication with their alters about CRC screening after viewing the decision aid and alters' intention to be screened for CRC after talking to the patient.
RESULTS: Most participants reported sharing CRC information with their alters after viewing the decision aid, and most alters confirmed they had received CRC information from participants (68%). The decision aid was associated with participants' own intention to undergo CRC screening and with alters' intention to be screened for CRC using a fecal occult blood test (p = 0.014) and sigmoidoscopy (p = 0.011).
CONCLUSIONS: Patient decision aids have the potential to increase CRC screening behavior beyond the decision aid recipients to their social network.
TRIAL REGISTRATION: Trials Registration Number: NCT04444232 "Retrospectively registered."}, }
@article {pmid39333696, year = {2024}, author = {Serritella, AV and Taylor, A and Haffner, MC and Abida, W and Bryce, A and Karsh, LI and Tagawa, ST and Twardowski, P and Armstrong, AJ and Lang, JM}, title = {Therapeutic implications of homologous repair deficiency testing in patients with prostate cancer (Part 2 of 2).}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {39333696}, issn = {1476-5608}, abstract = {BACKGROUND/OBJECTIVES: Unfortunately, not all metastatic castration-resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing for prostate cancer.
SUBJECTS/METHODS: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science.
RESULTS/CONCLUSIONS: In this second part, we highlight how genetic testing can lead to improved, life-prolonging mCRPC therapeutic strategies based on a review of the recent phase III trials and subsequent regulatory approvals for PARP inhibitors in mCRPC.}, }
@article {pmid39333103, year = {2024}, author = {Fiorenza, S and Zheng, Y and Purushe, J and Bock, TJ and Sarthy, J and Janssens, DH and Sheih, AS and Kimble, EL and Kirchmeier, D and Phi, TD and Gauthier, J and Hirayama, AV and Riddell, SR and Wu, Q and Gottardo, R and Maloney, DG and Yang, JYH and Henikoff, S and Turtle, CJ}, title = {Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8309}, pmid = {39333103}, issn = {2041-1723}, support = {Clinical Fellowship Grant//Haematology Society of Australia and New Zealand (HSANZ)/ ; }, mesh = {Humans ; *Receptors, Chimeric Antigen/metabolism/genetics/immunology ; *Immunotherapy, Adoptive/methods ; *Histone Code ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; Kruppel-Like Transcription Factors/metabolism/genetics ; Transcription Factors/metabolism/genetics ; Histones/metabolism ; Lymphoma/genetics/metabolism/therapy ; Cell Proliferation/genetics ; T-Lymphocyte Subsets/immunology/metabolism ; Immunologic Memory ; }, abstract = {Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionised blood cancer treatment. Parsing the genetic underpinnings of T cell quality and CAR-T efficacy is challenging. Transcriptomics inform CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasises effector and metabolism genes. Here we explore whether analyses of transcriptionally repressive and permissive histone methylation marks describe CAR-T cell functional states and therapeutic potential beyond transcriptomic analyses. Histone mark analyses improve identification of differences between naïve, central memory, and effector memory CD8 + T cell subsets of human origin, and CAR-T derived from these subsets. We find important differences between CAR-T manufactured from central memory cells of healthy donors and of patients. By examining CAR-T products from a clinical trial in lymphoma (NCT01865617), we find a novel association between the activity of the transcription factor KLF7 with in vivo CAR-T accumulation in patients and demonstrate that over-expression of KLF7 increases in vitro CAR-T proliferation and IL-2 production. In conclusion, histone marks provide a rich dataset for identification of functionally relevant genes not apparent by transcriptomics.}, }
@article {pmid39332809, year = {2024}, author = {Amonoo, HL and Guo, M and Keane, EP and Boardman, AC and Song, MT and Wolfe, ED and Cutler, C and Jim, HS and Lee, SJ and Huffman, JC and El-Jawahri, A}, title = {A Peer Support Intervention in Patients With Hematologic Malignancies Undergoing Hematopoietic Stem Cell Transplantation (HSCT): The STEPP Proof-of-Concept Trial.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.09.022}, pmid = {39332809}, issn = {2666-6367}, abstract = {Although peer support interventions are associated with improved patient-reported outcomes in diverse cancer populations, structured peer support programs tailored to the needs of patients undergoing hematopoietic stem cell transplantation (HSCT) are lacking. This single-arm, proof-of-concept trial aimed to refine the Supporting Transplant Experiences with Peer Program (STEPP), a structured, five-session, manualized, phone-delivered peer support intervention for patients undergoing HSCT, informed by qualitative feedback from patients. Adult patients with hematologic malignancies scheduled to undergo allogeneic or autologous HSCT were eligible to participate in the study approximately two weeks prior to their HSCT hospitalization. Participants received the STEPP intervention, which focused on providing informational, emotional, and practical support. To refine the intervention, we conducted semi-structured qualitative exit interviews to gather feedback on the content of STEPP and to identify facilitators and barriers to engagement. Transcribed interviews were analyzed using rapid analytic methods by two coders. Of the 37 eligible patients, 25 enrolled in the study, 20 completed all intervention sessions and 20 completed exit interviews. Participants highlighted that discussions with peer mentors/STEPP interventionists about the transplant journey and processing information provided by the clinical team were the most valuable aspects of STEPP. Positive experiences during the first intervention session facilitated patient engagement with the program. Potential barriers to engagement included logistical challenges in connecting with interventionists while experiencing physical symptoms during inpatient hospitalization and being paired with an interventionist who had a different cancer diagnosis and/or type of transplant. Patients undergoing HSCT reported positive experiences with the structured five-session, phone-delivered peer support intervention administered before and during the HSCT hospitalization. Patients' descriptions of barriers and facilitators to engagement with the STEPP intervention underscore the importance of patient input and programmatic structure in peer support interventions for this population. Insights from this proof-of-concept trial will be incorporated into future trials of STEPP to improve outcomes in HSCT recipients.}, }
@article {pmid39332390, year = {2024}, author = {Drain, PK and Niu, X and Shapiro, AE and Magcaba, ZP and Ngcobo, Z and Ngwane, MW and Thomas, KK and Dalmat, RR and Morton, JF and Budiawan, E and Pinter, A and Cantera, J and Anderson, C and Buchmann, R and Wilson, D and Grant, B and , }, title = {Real-world diagnostic accuracy of lipoarabinomannan in three non-sputum biospecimens for pulmonary tuberculosis disease.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105353}, pmid = {39332390}, issn = {2352-3964}, support = {R01 AI152157/AI/NIAID NIH HHS/United States ; R56 AI171023/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Lipopolysaccharides/urine/blood ; Male ; Female ; Adult ; *Tuberculosis, Pulmonary/diagnosis/urine/blood ; *HIV Infections/complications/diagnosis ; *Biomarkers/urine/blood ; Middle Aged ; Sensitivity and Specificity ; Prospective Studies ; Mycobacterium tuberculosis/immunology ; Sputum/microbiology ; }, abstract = {BACKGROUND: Development of a non-sputum test using readily-obtainable biospecimens remains a global priority for tuberculosis (TB) control. We quantified lipoarabinomannan (LAM) concentrations, a pathogen biomarker for Mycobacterium tuberculosis, in urine, plasma and serum for real-world diagnostic accuracy of pulmonary TB among people living with and without HIV.
METHODS: We conducted a prospective diagnostic study among adults with TB symptoms in South Africa. We measured LAM concentrations in time-matched urine, plasma and serum with an electrochemiluminescence immunoassay using two capture antibodies (FIND 28 and S4-20). From the completed cohort, we randomly selected 210 participants (2 cases: 1 control) based on sensitivity estimates, and we compared diagnostic accuracy of LAM measurements against the microbiological reference standard.
FINDINGS: Urine and blood specimens from 210 of 684 adults enrolled were tested for LAM. Among 138 TB-positive adults (41% female), median urine LAM was 137 pg/mL and 52 pg/mL by FIND 28 and S4-20, respectively. Average LAM concentrations were highest in HIV-positive participants with CD4+ T cells <200 cells/mm[3]. Urine LAM by S4-20 achieved diagnostic sensitivity of 62% (95% CI: 53%-70%) and specificity of 99% (95% CI: 96%-100%). Plasma and serum LAM by FIND 28 showed similar sensitivity (70%, 95% CI: 62%-78%) and comparable specificities (90%, 95% CI: 82%-97%; 94%, 95% CI: 88%-99%). Diagnostic sensitivity of urine LAM by S4-20 was higher among participants without HIV (41%, 95% CI: 24%-61%) compared to HIV-positive participants with CD4 ≥200 cells/mm[3] (20%, 95% CI: 8%-39%).
INTERPRETATION: Detection of LAM was achievable in non-sputum specimens for pulmonary TB, but additional analyte concentration or signal amplification may be required to achieve diagnostic accuracy targets.
FUNDING: Bill and Melinda Gates Foundation.}, }
@article {pmid39331724, year = {2024}, author = {Badros, AZ and Foster, L and Anderson, LD and Chaulagain, CP and Pettijohn, EM and Cowan, AJ and Costello, CL and Larson, S and Sborov, DW and Shain, KH and Silbermann, R and Shah, N and Chung, A and Krevvata, M and Pei, H and Patel, S and Khare, V and Cortoos, A and Carson, R and Lin, T and Voorhees, PM}, title = {Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025746}, pmid = {39331724}, issn = {1528-0020}, abstract = {No randomized trial has directly compared daratumumab and lenalidomide (D-R) maintenance therapy versus standard-of-care lenalidomide (R) alone post-transplant. Here, we report the primary results of the phase 3 AURIGA study evaluating D-R versus R maintenance in NDMM patients who were in ≥very good partial response, minimal residual disease (MRD; threshold 10-5) positive, and anti-CD38 naïve post-transplant. Patients were randomized 1:1 to D-R or R maintenance for up to 36 cycles. Two hundred patients were randomized (D-R, n=99; R, n=101). The primary endpoint, MRD-negative (10-5) conversion rate by 12 months from start of maintenance, was significantly higher for D-R versus R (50.5% vs 18.8%; odds ratio [OR], 4.51; 95% confidence interval [CI], 2.37-8.57; P<0.0001). MRD-negative (10-6) conversion rate was similarly higher with D-R (23.2% vs 5.0%; OR, 5.97; 95% CI, 2.15-16.58; P=0.0002). At 32.3 months' median follow-up, D-R achieved a higher overall MRD-negative (10-5) conversion rate (D-R, 60.6% vs R, 27.7%; OR, 4.12; 95% CI, 2.26-7.52; P<0.0001) and ≥complete response rate (75.8% vs 61.4%; OR, 2.00; 95% CI, 1.08-3.69; P=0.0255) versus R alone. Progression-free survival (PFS) favored D-R versus R (hazard ratio, 0.53; 95% CI, 0.29-0.97); estimated 30-month PFS rates were 82.7% for D-R and 66.4% for R. Incidences of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were slightly higher with D-R versus R. In conclusion, D-R maintenance achieved a higher MRD-negative conversion rate and improved PFS post-transplant versus R alone, with no new safety concerns. This trial was registered at www.ClinicalTrials.gov: #NCT03901963.}, }
@article {pmid39331494, year = {2024}, author = {Unger, JM and Xiao, H and Vaidya, R and LeBlanc, M}, title = {Patient Enrollment to Industry-Sponsored Versus Federally-Sponsored Cancer Clinical Trials.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {33}, pages = {3917-3925}, doi = {10.1200/JCO.24.00843}, pmid = {39331494}, issn = {1527-7755}, abstract = {PURPOSE: The conduct of cancer clinical research in the United States is supported by both private and public sponsors. Industry aims to obtain new drug approvals. Federally-sponsored trials examine a broad set of research questions that are not typically addressed by industry; these trials, which are also more commonly conducted in diverse populations, were recently shown to have contributed to gains of 14 million life-years for patients with cancer. Despite the different mandates, the proportion of patients who might participate in industry-sponsored versus federally-sponsored cancer studies is unknown.
METHODS: We evaluated trial enrollment patterns from 2008 to 2022 using ClinicalTrials.gov data. The ratio of enrollments attributable to industry versus federal sponsors was estimated. A large set of estimates on the basis of different combinations of study characteristics were generated. Point estimates were determined as the mean of combinations and confidence limits by the IQR. Five-year intervals were examined to smooth annual variation.
RESULTS: In total, N = 26,080 studies were examined. The estimated enrollment ratio from 2018 to 2022 for all industry-sponsored versus federally-sponsored trials was 8.1 (IQR, 6.2-9.9). For adult trials, the ratio increased from 4.8 (IQR, 4.4-5.3) during 2008-2012 to 9.6 (IQR, 7.4-11.8) during 2018-2022; for trials in children, the ratio increased from 0.7 (IQR, 0.6-0.7) to 2.3 (IQR, 1.8-2.7). Despite increasing cancer incidence, enrollment counts for federally-sponsored trials were flat over the study period.
CONCLUSION: In the United States, there is a growing reliance on industry to conduct cancer clinical research. Underinvestment in federally-sponsored research comes at a cost for both patients and researchers, with lost opportunities for scientific, clinical, and population advances.}, }
@article {pmid39326063, year = {2024}, author = {Gritti, I and Wan, J and Weeresekara, V and Vaz, JM and Tarantino, G and Bryde, TH and Vijay, V and Kammula, AV and Kattel, P and Zhu, S and Vu, P and Chan, M and Wu, MJ and Gordan, JD and Patra, KC and Silveira, VS and Manguso, RT and Wein, MN and Ott, CJ and Qi, J and Liu, D and Sakamoto, K and Gujral, TS and Bardeesy, N}, title = {DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-24-0634}, pmid = {39326063}, issn = {2159-8290}, support = {P50 CA127003/CA/NCI NIH HHS/United States ; R01 CA215498/CA/NCI NIH HHS/United States ; R01 CA279997/CA/NCI NIH HHS/United States ; }, abstract = {Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer's signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.}, }
@article {pmid39325616, year = {2024}, author = {Kaneko, T and Boulanger-Weill, J and Isabella, AJ and Moens, CB}, title = {Position-independent functional refinement within the vagus motor topographic map.}, journal = {Cell reports}, volume = {43}, number = {10}, pages = {114740}, doi = {10.1016/j.celrep.2024.114740}, pmid = {39325616}, issn = {2211-1247}, support = {R01 NS109425/NS/NINDS NIH HHS/United States ; R21 NS124191/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Zebrafish/physiology ; *Motor Neurons/physiology ; *Vagus Nerve/physiology ; Synaptic Transmission/physiology ; Axons/physiology ; }, abstract = {Motor neurons in the central nervous system often lie in a continuous topographic map, where neurons that innervate different body parts are spatially intermingled. This is the case for the efferent neurons of the vagus nerve, which innervate diverse muscle and organ targets in the head and viscera for brain-body communication. It remains elusive how neighboring motor neurons with different fixed peripheral axon targets develop the separate somatodendritic (input) connectivity they need to generate spatially precise body control. Here, we show that vagus motor neurons in the zebrafish indeed generate spatially appropriate peripheral responses to focal sensory stimulation even when they are transplanted into ectopic positions within the topographic map, indicating that circuit refinement occurs after the establishment of coarse topography. Refinement depends on motor neuron synaptic transmission, suggesting that an experience-dependent periphery-to-brain feedback mechanism establishes specific input connectivity among intermingled motor populations.}, }
@article {pmid39325506, year = {2024}, author = {Fong, Y and Dang, L and Zhang, B and Fintzi, J and Chen, S and Wang, J and Rouphael, NG and Branche, AR and Diemert, DJ and Falsey, AR and Losada, C and Baden, LR and Frey, SE and Whitaker, JA and Little, SJ and Kamidani, S and Walter, EB and Novak, RM and Rupp, R and Jackson, LA and Yu, C and Magaret, CA and Molitor, C and Borate, B and Babu, TM and Kottkamp, AC and Luetkemeyer, AF and Immergluck, LC and Presti, RM and Bäcker, M and Winokur, PL and Mahgoub, SM and Goepfert, PA and Fusco, DN and Atmar, RL and Posavad, CM and Mu, J and Makowski, M and Makhene, MK and Nayak, SU and Roberts, PC and Follmann, D and Gilbert, PB and , }, title = {Neutralizing Antibody Immune Correlates for a Recombinant Protein Vaccine in the COVAIL Trial.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciae465}, pmid = {39325506}, issn = {1537-6591}, support = {UM1 AI148685/AI/NIAID NIH HHS/United States ; }, abstract = {For COVAIL recipients of a COVID-19 Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.}, }
@article {pmid39324163, year = {2024}, author = {McGowan, M and Wairimu, N and Reedy, AM and Mogere, P and Culquichicon, C and Njeru, I and Malen, RC and Jahn, A and Bärnighausen, T and Roche, SD and Ngure, K and Ortblad, KF}, title = {Formalized peer referral to HIV pre-exposure prophylaxis supported with self-testing: a mixed-methods pilot study among young Kenyan women.}, journal = {Frontiers in public health}, volume = {12}, number = {}, pages = {1428609}, pmid = {39324163}, issn = {2296-2565}, mesh = {Humans ; Female ; Kenya ; *Pre-Exposure Prophylaxis ; Pilot Projects ; *HIV Infections/prevention & control/diagnosis ; *Peer Group ; Adolescent ; *Referral and Consultation ; Young Adult ; *Self-Testing ; Anti-HIV Agents/therapeutic use/administration & dosage ; }, abstract = {BACKGROUND: The uptake of daily oral HIV pre-exposure prophylaxis (PrEP)-a highly effective intervention-remains low among African adolescent girls and young women (AGYW) who could benefit. AGYW who initiate PrEP often do so through informal peer referral, which may be enhanced with formalized peer referral and peer-delivered HIV self-testing (HIVST). To understand the feasibility of this PrEP referral model among AGYW, we conducted a pilot study in Kenya.
METHOD: From March to May 2022, we recruited AGYW (≥16-24 years) using PrEP (i.e., "peer providers") from public healthcare clinics in Kiambu County and trained them on HIV prevention, HIVST use, and peer-supported linkage to clinic-based HIV services. Following training, peer providers received eight HIVST kits and were encouraged to refer four peers (i.e., "peer clients") to PrEP. We completed surveys with peer providers and clients one month following intervention delivery to assess PrEP initiation among peer clients. Later, we conducted focus group discussions (FGDs) with peer providers and clients to identify factors that facilitated or challenged intervention outcomes.
RESULTS: We trained 16 peer providers (median age: 23 years, IQR 21-24) who reported delivering the intervention to 56 peer clients; 30 peer clients (median age: 21 years, IQR 19-22) contacted the study team and were enrolled. Most of the enrolled peer clients reported behaviors associated with HIV risk (e.g., condomless sex; 80%, 24/30) and were PrEP-naïve (87%, 26/30). At one-month, PrEP initiation among eligible PrEP-naïve peer clients was high, as reported by providers (78%, 43/55) and clients (85%, 22/26); recent HIVST use was also high among peer clients (provider report: 95%, 53/56; client report: 97%, 29/30). In the FGDs, participants reported that intervention outcomes were facilitated by close preexisting relationships, HIVST assistance, and being escorted to clinic-based HIV services by peer providers; intervention barriers included conflicting priorities and limited HIVST experience.
CONCLUSION: A formalized model of peer referral with HIVST delivery supported PrEP initiation among Kenyan AGYW. These findings demonstrate the potential for peer-delivered interventions to engage AGYW in HIV prevention services; however, more research is needed on the effectiveness and sustainability of this approach at scale.}, }
@article {pmid39322372, year = {2024}, author = {Issaka, RB and Bell-Brown, A and Jewell, T and Jackson, SL and Weiner, BJ}, title = {Interventions to Increase Follow-Up of Abnormal Stool-Based Colorectal Cancer Screening Tests in Safety Net Settings: A Systematic Review.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {22}, number = {10}, pages = {1967-1974.e3}, doi = {10.1016/j.cgh.2024.07.001}, pmid = {39322372}, issn = {1542-7714}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Early Detection of Cancer/methods ; Feces/chemistry ; Occult Blood ; Safety-net Providers ; }, }
@article {pmid39321924, year = {2024}, author = {Rosen, EA and Liu, C}, title = {Author Response to "COVID-19 Outcomes Among Hematopoietic Cell Transplant and Chimeric Antigen Receptor T-cell Recipients: Correspondence".}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.09.019}, pmid = {39321924}, issn = {2666-6367}, }
@article {pmid39321347, year = {2024}, author = {Banerjee, R and Sexton, R and Cowan, AJ and Rosenberg, AS and Ailawadhi, S and Rajkumar, SV and Kumar, SK and Dispenzieri, A and Lonial, S and Durie, BGM and Richardson, PG and Usmani, SZ and Hoering, A and Orlowski, RZ}, title = {Dexamethasone dose intensity does not impact outcomes in newly diagnosed multiple myeloma: a secondary SWOG analysis.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024025939}, pmid = {39321347}, issn = {1528-0020}, abstract = {Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM) despite common toxicities including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 milligrams (mg) once weekly was associated with lower mortality than higher doses of dexamethasone. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM have not been fully characterized. We conducted a secondary pooled analysis of the S0777 and S1211 SWOG studies of NDMM, which employed lenalidomide-dexamethasone (Rd) alone with or without bortezomib (VRd) and with or without elotuzumab (Elo-VRd). Planned dexamethasone intensity was 40-60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for Grade 3+ toxicities per both study protocols). Of 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There was no difference in PFS or OS between the FD-DEX or LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in multivariate models were treatment arm, age ≥70, and thrombocytopenia; FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given dexamethasone's many toxicities and unclear benefit in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective study. NCT00644228, NCT01668719.}, }
@article {pmid39320863, year = {2024}, author = {Kennedy, CJ and Kearns, JC and Geraci, JC and Gildea, SM and Hwang, IH and King, AJ and Liu, H and Luedtke, A and Marx, BP and Papini, S and Petukhova, MV and Sampson, NA and Smoller, JW and Wolock, CJ and Zainal, NH and Stein, MB and Ursano, RJ and Wagner, JR and Kessler, RC}, title = {Predicting Suicides Among US Army Soldiers After Leaving Active Service.}, journal = {JAMA psychiatry}, volume = {}, number = {}, pages = {}, pmid = {39320863}, issn = {2168-6238}, support = {K01 MH135131/MH/NIMH NIH HHS/United States ; }, abstract = {IMPORTANCE: The suicide rate of military servicemembers increases sharply after returning to civilian life. Identifying high-risk servicemembers before they leave service could help target preventive interventions.
OBJECTIVE: To develop a model based on administrative data for regular US Army soldiers that can predict suicides 1 to 120 months after leaving active service.
In this prognostic study, a consolidated administrative database was created for all regular US Army soldiers who left service from 2010 through 2019. Machine learning models were trained to predict suicides over the next 1 to 120 months in a random 70% training sample. Validation was implemented in the remaining 30%. Data were analyzed from March 2023 through March 2024.
MAIN OUTCOME AND MEASURES: The outcome was suicide in the National Death Index. Predictors came from administrative records available before leaving service on sociodemographics, Army career characteristics, psychopathologic risk factors, indicators of physical health, social networks and supports, and stressors.
RESULTS: Of the 800 579 soldiers in the cohort (84.9% male; median [IQR] age at discharge, 26 [23-33] years), 2084 suicides had occurred as of December 31, 2019 (51.6 per 100 000 person-years). A lasso model assuming consistent slopes over time discriminated as well over all but the shortest risk horizons as more complex stacked generalization ensemble machine learning models. Test sample area under the receiver operating characteristic curve ranged from 0.87 (SE = 0.06) for suicides in the first month after leaving service to 0.72 (SE = 0.003) for suicides over 120 months. The 10% of soldiers with highest predicted risk accounted for between 30.7% (SE = 1.8) and 46.6% (SE = 6.6) of all suicides across horizons. Calibration was for the most part better for the lasso model than the super learner model (both estimated over 120-month horizons.) Net benefit of a model-informed prevention strategy was positive compared with intervene-with-all or intervene-with-none strategies over a range of plausible intervention thresholds. Sociodemographics, Army career characteristics, and psychopathologic risk factors were the most important classes of predictors.
CONCLUSIONS AND RELEVANCE: These results demonstrated that a model based on administrative variables available at the time of leaving active Army service can predict suicides with meaningful accuracy over the subsequent decade. However, final determination of cost-effectiveness would require information beyond the scope of this report about intervention content, costs, and effects over relevant horizons in relation to the monetary value placed on preventing suicides.}, }
@article {pmid39320295, year = {2024}, author = {Oved, JH and Russell, A and DeZern, A and Prockop, SE and Bonfim, C and Sharma, A and Purtill, D and Lakkaraja, M and Bidgoli, A and Bhoopalan, SV and Soni, S and Boelens, JJ and Abraham, A}, title = {The role of the conditioning regimen for autologous and ex vivo genetically modified hematopoietic stem cell-based therapies: recommendations from the ISCT stem cell engineering committee.}, journal = {Cytotherapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jcyt.2024.09.001}, pmid = {39320295}, issn = {1477-2566}, abstract = {BACKGROUND: The advent of autologous gene modified cell therapies to treat monogenic disorders has been a major step forward for the field of hematopoietic stem cell transplantation (HCT) and cellular therapies. The need for disease-specific conditioning to enable these products to provide a potential cure has required extrapolation from experience in myeloablative and non-myeloablative HCT for these disorders.
METHODS: In this manuscript, we review the current datasets and clinical experience using different conditioning regimens for autologous gene therapies in hemoglobinopathies, metabolic and lysosomal disorders, inborn errors of immunity (IEI) and bone marrow failure (BMF) syndromes.
RESULTS: The disease specific and unique conditioning requirements of each disorder are considered in order to achieve maximal benefit while minimizing associated toxicities.
CONCLUSIONS: Standardized recommendations based on these data are made for each set of disorders to harmonize treatment. Future directions and the possibility of non-genotoxic conditioning regimens for autologous gene therapies are also discussed. Ethical Statement: The authors followed all relevant ethical considerations in writing this manuscript.}, }
@article {pmid39319780, year = {2024}, author = {Perofsky, AC and Huddleston, J and Hansen, CL and Barnes, JR and Rowe, T and Xu, X and Kondor, R and Wentworth, DE and Lewis, N and Whittaker, L and Ermetal, B and Harvey, R and Galiano, M and Daniels, RS and McCauley, JW and Fujisaki, S and Nakamura, K and Kishida, N and Watanabe, S and Hasegawa, H and Sullivan, SG and Barr, IG and Subbarao, K and Krammer, F and Bedford, T and Viboud, C}, title = {Antigenic drift and subtype interference shape A(H3N2) epidemic dynamics in the United States.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {39319780}, issn = {2050-084X}, support = {10111800//Ministry of Health, Labour and Welfare/ ; 75N93019C00051/NH/NIH HHS/United States ; FC001030/ARC_/Arthritis Research UK/United Kingdom ; 10110400//Ministry of Health, Labour and Welfare/ ; JP22fk0108118//Japan Agency for Medical Research and Development/ ; HHSN272201400008C/NH/NIH HHS/United States ; F31 AI140714/NH/NIH HHS/United States ; 75N93021C00014/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; 75N93019C00051/AI/NIAID NIH HHS/United States ; 75N93021C00014/NH/NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; R01 AI165821/NH/NIH HHS/United States ; HHSN272201400008C/AI/NIAID NIH HHS/United States ; F31 AI140714/AI/NIAID NIH HHS/United States ; 1354890//National Science Foundation/ ; R35 GM119774/GM/NIGMS NIH HHS/United States ; FC001030/WT_/Wellcome Trust/United Kingdom ; R35 GM119774/NH/NIH HHS/United States ; R01 AI127893/NH/NIH HHS/United States ; FC001030/MRC_/Medical Research Council/United Kingdom ; JP23fk0108662//Japan Agency for Medical Research and Development/ ; FC001030/CRUK_/Cancer Research UK/United Kingdom ; R01 AI127893/AI/NIAID NIH HHS/United States ; }, mesh = {*Influenza A Virus, H3N2 Subtype/genetics/immunology ; United States/epidemiology ; *Influenza, Human/epidemiology/virology/immunology ; Humans ; *Hemagglutinin Glycoproteins, Influenza Virus/genetics/immunology ; *Epidemics ; *Antigenic Drift and Shift/genetics ; Child ; Adult ; Neuraminidase/genetics/immunology ; Adolescent ; Child, Preschool ; Antigens, Viral/immunology/genetics ; Young Adult ; Evolution, Molecular ; Seasons ; Middle Aged ; }, abstract = {Influenza viruses continually evolve new antigenic variants, through mutations in epitopes of their major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Antigenic drift potentiates the reinfection of previously infected individuals, but the contribution of this process to variability in annual epidemics is not well understood. Here, we link influenza A(H3N2) virus evolution to regional epidemic dynamics in the United States during 1997-2019. We integrate phenotypic measures of HA antigenic drift and sequence-based measures of HA and NA fitness to infer antigenic and genetic distances between viruses circulating in successive seasons. We estimate the magnitude, severity, timing, transmission rate, age-specific patterns, and subtype dominance of each regional outbreak and find that genetic distance based on broad sets of epitope sites is the strongest evolutionary predictor of A(H3N2) virus epidemiology. Increased HA and NA epitope distance between seasons correlates with larger, more intense epidemics, higher transmission, greater A(H3N2) subtype dominance, and a greater proportion of cases in adults relative to children, consistent with increased population susceptibility. Based on random forest models, A(H1N1) incidence impacts A(H3N2) epidemics to a greater extent than viral evolution, suggesting that subtype interference is a major driver of influenza A virus infection ynamics, presumably via heterosubtypic cross-immunity.}, }
@article {pmid39319420, year = {2024}, author = {Boyle, GE and Sitko, KA and Galloway, JG and Haddox, HK and Bianchi, AH and Dixon, A and Wheelock, MK and Vandi, AJ and Wang, ZR and Thomson, RES and Garge, RK and Rettie, AE and Rubin, AF and Geck, RC and Gillam, EMJ and DeWitt, WS and Matsen, FA and Fowler, DM}, title = {Deep mutational scanning of CYP2C19 in human cells reveals a substrate specificity-abundance tradeoff.}, journal = {Genetics}, volume = {228}, number = {3}, pages = {}, pmid = {39319420}, issn = {1943-2631}, support = {//NIH/ ; //National Human Genome Research Institute Interdisciplinary Training in Genome Sciences/ ; //National Institute of General Medical Sciences of the National Institutes of Health/ ; //Momental Foundation/ ; //Washington Research Foundation Postdoctoral Fellowship/ ; //Australian Government/ ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Humans ; *Cytochrome P-450 CYP2C19/genetics/metabolism ; Substrate Specificity ; *Cytochrome P-450 CYP2C9/genetics/metabolism ; HEK293 Cells ; Mutation ; Amino Acid Substitution ; High-Throughput Nucleotide Sequencing ; }, abstract = {The cytochrome P450s enzyme family metabolizes ∼80% of small molecule drugs. Variants in cytochrome P450s can substantially alter drug metabolism, leading to improper dosing and severe adverse drug reactions. Due to low sequence conservation, predicting variant effects across cytochrome P450s is challenging. Even closely related cytochrome P450s like CYP2C9 and CYP2C19, which share 92% amino acid sequence identity, display distinct phenotypic properties. Using variant abundance by massively parallel sequencing, we measured the steady-state protein abundance of 7,660 single amino acid variants in CYP2C19 expressed in cultured human cells. Our findings confirmed critical positions and structural features essential for cytochrome P450 function, and revealed how variants at conserved positions influence abundance. We jointly analyzed 4,670 variants whose abundance was measured in both CYP2C19 and CYP2C9, finding that the homologs have different variant abundances in substrate recognition sites within the hydrophobic core. We also measured the abundance of all single and some multiple wild type amino acid exchanges between CYP2C19 and CYP2C9. While most exchanges had no effect, substitutions in substrate recognition site 4 reduced abundance in CYP2C19. Double and triple mutants showed distinct interactions, highlighting a region that points to differing thermodynamic properties between the 2 homologs. These positions are known contributors to substrate specificity, suggesting an evolutionary tradeoff between stability and enzymatic function. Finally, we analyzed 368 previously unannotated human variants, finding that 43% had decreased abundance. By comparing variant effects between these homologs, we uncovered regions underlying their functional differences, advancing our understanding of this versatile family of enzymes.}, }
@article {pmid39318685, year = {2024}, author = {Tereshchenko, LG and Haq, KT and Howell, SJ and Mitchell, EC and Martínez, J and Hyde, J and Briceno, G and Pena, J and Pocius, E and Khan, A and Soliman, EZ and Lima, JAC and Kapadia, SR and Misra-Hebert, AD and Kattan, MW and Kansal, MM and Daviglus, ML and Kaplan, R}, title = {Latent profiles of global electrical heterogeneity: the Hispanic Community Health Study/Study of Latinos.}, journal = {European heart journal. Digital health}, volume = {5}, number = {5}, pages = {611-621}, pmid = {39318685}, issn = {2634-3916}, abstract = {AIMS: Despite the highest prevalence of stroke, obesity, and diabetes across races/ethnicities, paradoxically, Hispanic/Latino populations have the lowest prevalence of atrial fibrillation and major Minnesota code-defined ECG abnormalities. We aimed to use Latent Profile Analysis in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) population to obtain insight into epidemiological discrepancies.
METHODS AND RESULTS: We conducted a cross-sectional analysis of baseline HCHS/SOL visit. Global electrical heterogeneity (GEH) was measured as spatial QRS-T angle (QRSTa), spatial ventricular gradient azimuth (SVGaz), elevation (SVGel), magnitude (SVGmag), and sum absolute QRST integral (SAIQRST). Statistical analysis accounted for the stratified two-stage area probability sample design. We fitted a multivariate latent profile generalized structural equation model adjusted for age, sex, ethnic background, education, hypertension, diabetes, smoking, dyslipidaemia, obesity, chronic kidney disease, physical activity, diet quality, average RR' interval, median beat type, and cardiovascular disease (CVD) to gain insight into the GEH profiles. Among 15 684 participants (age 41 years; 53% females; 6% known CVD), 17% had an increased probability of likely abnormal GEH profile (QRSTa 80 ± 27°, SVGaz -4 ± 21°, SVGel 72 ± 12°, SVGmag 45 ± 12 mVms, and SAIQRST 120 ± 23 mVms). There was a 23% probability for a participant of being in Class 1 with a narrow QRSTa (40.0 ± 10.2°) and large SVG (SVGmag 108.3 ± 22.6 mVms; SAIQRST 203.4 ± 39.1 mVms) and a 60% probability of being in intermediate Class 2.
CONCLUSION: A substantial proportion (17%) in the Hispanic/Latino population had an increased probability of altered, likely abnormal GEH profile, whereas 83% of the population was resilient to harmful risk factors exposures.}, }
@article {pmid39317093, year = {2024}, author = {Jones, SMW and Guthrie, KA and Arnold, K and Krouse, R}, title = {The bowel function instrument for rectal cancer survivors with anastomosis and ostomy.}, journal = {Journal of psychosomatic research}, volume = {187}, number = {}, pages = {111931}, doi = {10.1016/j.jpsychores.2024.111931}, pmid = {39317093}, issn = {1879-1360}, abstract = {OBJECTIVE: Rectal cancer is often treated with surgery such as ostomy or anastomosis. The Bowel Function Instrument (BFI) is a valid and reliable 18-item measure of physical bowel symptoms. Some items on the BFI do not apply to those with ostomies. We reanalyzed data from a previous validation study to inform the best method for scoring the BFI for both people with ostomies and anastomosis.
METHODS: People (n = 575) with rectal cancer treated with ostomy (n = 181, 31 %) or anastomosis (n = 394, 69 %) completed the BFI and Short Form 12 (SF12) measure on a mailed survey. The full BFI has three subscales and a total score based on 14 items: soilage/urgency (4 items); frequency of bowel movements (6 items); and dietary changes (4 items). We used confirmatory factor analysis (CFA) to examine two versions (8-item, 11-item) of the BFI adapted for use with both ostomy and anastomosis. We also examined reliability and validity of the version supported by the CFA.
RESULTS: CFA results supported the 8-item BFI that included only the soilage/urgency items and dietary changes items but not the frequency items. The 8-item BFI was reliable (Cronbach's alpha of 0.788). The 8-item BFI score significantly correlated with all SF12 subscales with Pearson correlations ranging from 0.115 (Vitality) to 0.318 (social function).
CONCLUSIONS: The 8-item version of the BFI was valid and reliable as a total score for people with ostomy or anastomosis. The 8-item BFI may be useful for monitoring bowel function during and after treatment for rectal cancer.}, }
@article {pmid39316822, year = {2024}, author = {Thomas, CE and Lin, Y and Kim, M and Kawaguchi, ES and Qu, C and Um, CY and Lynch, BM and Van Guelpen, B and Tsilidis, K and Carreras-Torres, R and van Duijnhoven, FJ and Sakoda, LC and Campbell, PT and Tian, Y and Chang-Claude, J and Bézieau, S and Budiarto, A and Palmer, JR and Newcomb, PA and Casey, G and Le Marchand, L and Giannakis, M and Li, CI and Gsur, A and Newton, C and Obón-Santacana, M and Moreno, V and Vodicka, P and Brenner, H and Hoffmeister, M and Pellatt, AJ and Schoen, RE and Dimou, N and Murphy, N and Gunter, MJ and Castellví-Bel, S and Figueiredo, JC and Chan, AT and Song, M and Li, L and Bishop, DT and Gruber, SB and Baurley, JW and Bien, SA and Conti, DV and Huyghe, JR and Kundaje, A and Su, YR and Wang, J and Keku, TO and Woods, MO and Berndt, SI and Chanock, SJ and Tangen, CM and Wolk, A and Burnett-Hartman, A and Wu, AH and White, E and Devall, MA and Díez-Obrero, V and Drew, DA and Giovannucci, E and Hidaka, A and Kim, AE and Lewinger, JP and Morrison, J and Ose, J and Papadimitriou, N and Pardamean, B and Peoples, AR and Ruiz-Narvaez, EA and Shcherbina, A and Stern, MC and Chen, X and Thomas, DC and Platz, EA and Gauderman, WJ and Peters, U and Hsu, L}, title = {Characterization of additive gene-environment interactions for colorectal cancer risk.}, journal = {Epidemiology (Cambridge, Mass.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/EDE.0000000000001795}, pmid = {39316822}, issn = {1531-5487}, abstract = {BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure.
METHODS: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk.
RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility.
CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.}, }
@article {pmid39316666, year = {2024}, author = {Brown, JR and Eichhorst, B and Lamanna, N and O'Brien, SM and Tam, CS and Qiu, L and Jurczak, W and Zhou, K and Šimkovič, M and Mayer, J and Gillespie-Twardy, A and Ferrajoli, A and Ganly, PS and Weinkove, R and Grosicki, S and Mital, A and Robak, T and Osterborg, A and Yimer, HA and Wang, MY and Salmi, T and Wang, L and Li, J and Wu, K and Cohen, AC and Shadman, M}, title = {Sustained Benefit of Zanubrutinib vs Ibrutinib in Patients With R/R CLL/SLL: Final Comparative Analysis of ALPINE.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024024667}, pmid = {39316666}, issn = {1528-0020}, abstract = {ALPINE (NCT03734016) established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL); here we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n=327) or ibrutinib (n=325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (HR: 0.68 [95% CI, 0.54-0.84]), including in patients with del(17p)/TP53 mutation (HR: 0.51 [95% CI, 0.33-0.78]) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). While median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR: 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common non-hematologic adverse events included COVID-19-related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs six cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile.}, }
@article {pmid39315857, year = {2024}, author = {Ortiz Romero, PL and Kim, YH and Molloy, K and Quaglino, P and Scarisbrick, J and Thornton, S and Sandilands, K and Dent, JE and Nixon, A and Williams, A and Shinohara, MM}, title = {Health-related quality of life in cutaneous T-cell lymphoma: A post hoc analysis of a phase 3 trial in mycosis fungoides and Sézary syndrome.}, journal = {Journal of the European Academy of Dermatology and Venereology : JEADV}, volume = {}, number = {}, pages = {}, doi = {10.1111/jdv.20357}, pmid = {39315857}, issn = {1468-3083}, support = {TD1 1QH//Kyowa Kirin Services Ltd, Galabank Business Park, Galashiels, Scotland/ ; }, abstract = {BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are common subtypes of cutaneous T-cell lymphoma that primarily affect the skin but may spread to the lymph nodes, viscera and blood. The symptom burden may compromise health-related quality of life (HRQL). The phase 3 MAVORIC study (ClinicalTrials.gov identifier NCT01728805) in patients with relapsed/refractory MF/SS reported improved HRQL with mogamulizumab compared with vorinostat.
OBJECTIVES: Use baseline (pre-treatment) data from the MAVORIC study to describe the symptom burden of MF/SS and identify characteristics associated with worse HRQL.
METHODS: Data were from 372 adults with stage IB-IVB histologically confirmed relapsed/ refractory MF or SS. Associations between demographic and medical history variables and worse HRQL (Skindex-29, ItchyQol and Functional Assessment of Cancer Therapy - General [FACT-G]) were determined by regression models.
RESULTS: In the cohort of 372 adults, 70% were white; 42% were female; mean age was 63 (SD 13.0) years. Fifty-five per cent had MF and 45% had SS; 77% had advanced (stage IIB-IV) disease, involving the skin in all patients and the blood and/or nodes in 66%. HRQL scores showed impairment versus normative means (where available), with the greatest impact on Symptoms and Emotions in the Skindex-29, Functioning in the ItchyQol, and Functional Wellbeing in the FACT-G. In regression analysis, worse HRQL across all domains and total score was associated with being female and younger, worse mSWAT score and worse itch for the Skindex-29 (n = 352), and being female, younger, Black/African American, worse performance status and worse itch for the ItchyQol (n = 369). Associations across domains and total score were not found for the FACT-G. Associations between domains and demographic/medical history were seen for all instruments.
CONCLUSIONS: The symptoms of advanced MF/SS compromise all HRQL domains. Treatment goals and therapeutic choice should be informed by individual patients' disease burden.}, }
@article {pmid39315814, year = {2024}, author = {Loes, AN and Tarabi, RAL and Huddleston, J and Touyon, L and Wong, SS and Cheng, SMS and Leung, NHL and Hannon, WW and Bedford, T and Cobey, S and Cowling, BJ and Bloom, JD}, title = {High-throughput sequencing-based neutralization assay reveals how repeated vaccinations impact titers to recent human H1N1 influenza strains.}, journal = {Journal of virology}, volume = {98}, number = {10}, pages = {e0068924}, pmid = {39315814}, issn = {1098-5514}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; T11-712/19-N//Research Grants Council, University Grants Committee ()/ ; U01AI153700//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U01 AI153700/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01AI165821//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; Investigator Support//Howard Hughes Medical Institute (HHMI)/ ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *High-Throughput Nucleotide Sequencing/methods ; *Antibodies, Neutralizing/immunology/blood ; *Influenza A Virus, H1N1 Subtype/immunology/genetics ; *Influenza Vaccines/immunology/administration & dosage ; *Antibodies, Viral/blood/immunology ; *Influenza, Human/prevention & control/immunology/virology ; *Neutralization Tests/methods ; *Vaccination ; *Hemagglutinin Glycoproteins, Influenza Virus/immunology/genetics ; Adult ; Female ; }, abstract = {UNLABELLED: The high genetic diversity of influenza viruses means that traditional serological assays have too low throughput to measure serum antibody neutralization titers against all relevant strains. To overcome this challenge, we developed a sequencing-based neutralization assay that simultaneously measures titers against many viral strains using small serum volumes using a workflow similar to traditional neutralization assays. The key innovation is to incorporate unique nucleotide barcodes into the hemagglutinin (HA) genomic segment, and then pool viruses with numerous different barcoded HA variants and quantify the infectivity of all of them simultaneously using next-generation sequencing. With this approach, a single researcher performed the equivalent of 2,880 traditional neutralization assays (80 serum samples against 36 viral strains) in approximately 1 month. We applied the sequencing-based assay to quantify the impact of influenza vaccination on neutralization titers against recent human H1N1 strains for individuals who had or had not also received a vaccine in the previous year. We found that the viral strain specificities of the neutralizing antibodies elicited by vaccination vary among individuals and that vaccination induced a smaller increase in titers for individuals who had also received a vaccine the previous year-although the titers 6 months after vaccination were similar in individuals with and without the previous-year vaccination. We also identified a subset of individuals with low titers to a subclade of recent H1N1 even after vaccination. We provide an experimental protocol (dx.doi.org/10.17504/protocols.io.kqdg3xdmpg25/v1) and computational pipeline (https://github.com/jbloomlab/seqneut-pipeline) for the sequencing-based neutralization assays to facilitate the use of this method by others.
IMPORTANCE: We describe a new approach that can rapidly measure how the antibodies in human serum inhibit infection by many different influenza strains. This new approach is useful for understanding how viral evolution affects antibody immunity. We apply the approach to study the effect of repeated influenza vaccination.}, }
@article {pmid39315598, year = {2024}, author = {Kwendakwema, CN and Hopkins, T and Bell-Brown, A and Simianu, VV and Shankaran, V and Issaka, RB}, title = {Clinician perceptions on barriers and facilitators to 1-year surveillance colonoscopy completion in survivors of colorectal cancer.}, journal = {Cancer medicine}, volume = {13}, number = {18}, pages = {e70244}, pmid = {39315598}, issn = {2045-7634}, support = {T32CA009515/CA/NCI NIH HHS/United States ; K08CA241296/RC/CCR NIH HHS/United States ; P30 CA015704/RC/CCR NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/psychology/surgery ; *Colonoscopy/psychology ; *Cancer Survivors/psychology ; Male ; Female ; Middle Aged ; Attitude of Health Personnel ; Early Detection of Cancer/psychology ; Health Services Accessibility ; }, abstract = {INTRODUCTION: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Surveillance colonoscopy is recommended 1-year after surgical resection for patients with stage I-III CRC; however, only 18%-61% of CRC survivors complete this test. This study describes clinician-identified barriers and facilitators to surveillance colonoscopy among CRC survivors.
METHODS: We conducted semi-structured interviews with clinicians until thematic saturation was achieved. Interviews were analyzed using the social cognitive theory.
RESULTS: Thirteen clinicians were interviewed, and all identified health system-level barriers to surveillance colonoscopy completion; the most common being fragmented care due to patients receiving care across many health systems. Clinicians also identified social determinants of health barriers (e.g., geographical distance between patients and health systems) to 1-year surveillance colonoscopy completion.
CONCLUSIONS: Clinicians identified several potentially modifiable barriers to 1-year surveillance colonoscopy completion which, if addressed, could improve post-treatment care and outcomes among stage I-III CRC survivors.}, }
@article {pmid39315597, year = {2024}, author = {Rosenthal, EA and Hsu, L and Thomas, M and Peters, U and Kachulis, C and Patterson, K and Jarvik, GP}, title = {Comparing Ancestry Standardization Approaches for a Transancestry Colorectal Cancer Polygenic Risk Score.}, journal = {Genetic epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/gepi.22590}, pmid = {39315597}, issn = {1098-2272}, support = {//This work was funded by the Office of the Director at the National Institute of Health, under award notice 1OT2OD002748-01 and by the NHGRI through the grant U01HG008657./ ; }, abstract = {Colorectal cancer (CRC) is a complex disease with monogenic, polygenic and environmental risk factors. Polygenic risk scores (PRSs) aim to identify high polygenic risk individuals. Due to differences in genetic background, PRS distributions vary by ancestry, necessitating standardization. We compared four post-hoc methods using the All of Us Research Program Whole Genome Sequence data for a transancestry CRC PRS. We contrasted results from linear models trained on A. the entire data or an ancestrally diverse subset AND B. covariates including principal components of ancestry or admixture. Standardization with the training subset also adjusted the variance. All methods performed similarly within ancestry, OR (95% C.I.) per s.d. change in PRS: African 1.5 (1.02, 2.08), Admixed American 2.2 (1.27, 3.85), European 1.6 (1.43, 1.89), and Middle Eastern 1.1 (0.71, 1.63). Using admixture and an ancestrally diverse training set provided distributions closest to standard Normal. Training a model on ancestrally diverse participants, adjusting both the mean and variance using admixture as covariates, created standard Normal z-scores, which can be used to identify patients at high polygenic risk. These scores can be incorporated into comprehensive risk calculation including other known risk factors, allowing for more precise risk estimates.}, }
@article {pmid39314963, year = {2024}, author = {Huddleston, J and Bedford, T}, title = {Timely vaccine strain selection and genomic surveillance improves evolutionary forecast accuracy of seasonal influenza A/H3N2.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39314963}, support = {R01 AI165821/AI/NIAID NIH HHS/United States ; }, abstract = {For the last decade, evolutionary forecasting models have influenced seasonal influenza vaccine design. These models attempt to predict which genetic variants circulating at the time of vaccine strain selection will be dominant 12 months later in the influenza season targeted by vaccination campaign. Forecasting models depend on hemagglutinin (HA) sequences from the WHO's Global Influenza Surveillance and Response System to identify currently circulating groups of related strains (clades) and estimate clade fitness for forecasts. However, the average lag between collection of a clinical sample and the submission of its sequence to the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database is ~3 months. Submission lags complicate the already difficult 12-month forecasting problem by reducing understanding of current clade frequencies at the time of forecasting. These constraints of a 12-month forecast horizon and 3-month average submission lags create an upper bound on the accuracy of any long-term forecasting model. The global response to the SARS-CoV-2 pandemic revealed that modern vaccine technology like mRNA vaccines can reduce how far we need to forecast into the future to 6 months or less and that expanded support for sequencing can reduce submission lags to GISAID to 1 month on average. To determine whether these recent advances could also improve long-term forecasts for seasonal influenza, we quantified the effects of reducing forecast horizons and submission lags on the accuracy of forecasts for A/H3N2 populations. We found that reducing forecast horizons from 12 months to 6 or 3 months reduced average absolute forecasting errors to 25% and 50% of the 12-month average, respectively. Reducing submission lags provided little improvement to forecasting accuracy but decreased the uncertainty in current clade frequencies by 50%. These results show the potential to substantially improve the accuracy of existing influenza forecasting models by modernizing influenza vaccine development and increasing global sequencing capacity.}, }
@article {pmid39314956, year = {2024}, author = {Burns, AC and Zellers, S and Windred, DP and Daghlas, I and Sinnott-Armstrong, N and Rutter, M and Hublin, C and Friligkou, E and Polimanti, R and Phillips, AJK and Cain, SW and Kaprio, J and Ollila, HM and Saxena, R and Lane, JM}, title = {Sleep inertia drives the association of evening chronotype with psychiatric disorders: epidemiological and genetic evidence.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39314956}, support = {R01 HG012810/HG/NHGRI NIH HHS/United States ; }, abstract = {Evening chronotypes (a.k.a. "night-owls") are held to be at greater risk for psychiatric disorders. This is postulated to be due to delayed circadian timing increasing the likelihood of circadian misalignment in an early-oriented society. Circadian misalignment is known to heighten sleep inertia, the difficulty transitioning from sleep to wake characterized by low arousal and cognitive impairment, and evening chronotypes experience greater sleep inertia. Therefore, difficulty awakening may explain the relationship between evening chronotype and psychiatric disorders by acting as a biomarker of circadian misalignment. In analyzing the longitudinal incidence of psychiatric disorders in the UK Biobank (n = 496,820), we found that evening chronotype predicted increased incidence of major depressive disorder, schizophrenia, generalized anxiety disorder and bipolar disorder. Crucially, this effect was dependent on sleep inertia, which was a much stronger predictor of these disorders, such that evening types without sleep inertia were at no higher risk as compared to morning types. Longitudinal analyses of suicide and depressed mood (CES-D score) in the Older Finnish Twin Cohort (n = 23,854) replicated this pattern of results. Twin and genome-wide association analyses of difficulty awakening identified the trait to be heritable (Twin H [2] = 0.40; SNP h [2] = 0.08), enriched for circadian rhythms genes and have substantial shared genetic architecture with chronotype. Marginal and conditional Mendelian randomization analyses mirrored the epidemiological results, such that the causal effect of evening chronotype on psychiatric disorders was driven by shared genetic architecture with difficulty awakening. In contrast, difficult awakening was strongly causally associated with psychiatric disorders independently of chronotype. Psychiatric disorders were only weakly reverse causally linked to difficult awakening. Collectively, these results challenge the notion that evening chronotype is a risk factor for psychiatric disorders per se, suggesting instead that evening types are at greater risk for psychiatric disorders due to circadian misalignment, for which sleep inertia may be acting as a biomarker.}, }
@article {pmid39311908, year = {2024}, author = {Wang, L and Chao, M and Han, RR and Li, L and Dong, L and Chen, F and Jin, MZ and Gao, L and Wang, Y and Feng, DY and Zhu, G and Guo, W and Zhao, WJ and Jin, SJ and Wei, DP and Sun, W and Dai, JX and Jin, WL}, title = {Single-cell map of diverse immune phenotypes in the metastatic brain tumor microenvironment of non-small-cell lung cancer.}, journal = {International journal of surgery (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/JS9.0000000000002088}, pmid = {39311908}, issn = {1743-9159}, }
@article {pmid39311597, year = {2024}, author = {Marzinke, MA and Han, K and Hanscom, B and Guo, X and Piwowar-Manning, E and Hendrix, CW and Rose, S and Spooner, E and Mathew, C and Innes, S and Sekabira, R and Mutambanengwe, M and Rooney, JF and Rinehart, AR and Adeyeye, A and Cohen, MS and Hosseinipour, M and Ford, SL and Delany-Moretlwe, S}, title = {Pharmacologic evaluation of delayed long-acting cabotegravir administration among cisgender women in HPTN 084.}, journal = {Antimicrobial agents and chemotherapy}, volume = {68}, number = {11}, pages = {e0099424}, pmid = {39311597}, issn = {1098-6596}, support = {UM1 AI069423/AI/NIAID NIH HHS/United States ; UM1AI068617//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1AI068613//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; OPP1154174//Bill and Melinda Gates Foundation (GF)/ ; UM1AI068619//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068613/AI/NIAID NIH HHS/United States ; NA//ViiV Healthcare (ViiV Healthcare Limited)/ ; }, mesh = {Humans ; Female ; *Anti-HIV Agents/pharmacokinetics/administration & dosage ; Adult ; *HIV Infections/drug therapy ; *Pyridones/pharmacokinetics/administration & dosage ; Delayed-Action Preparations ; Tenofovir/pharmacokinetics ; Drug Administration Schedule ; Middle Aged ; Diketopiperazines ; }, abstract = {UNLABELLED: HPTN 084 demonstrated the superiority of long-acting injectable cabotegravir (CAB-LA) compared with daily oral tenofovir disoproxil fumarate-emtricitabine (F/TDF) for HIV prevention in women. CAB-LA (600 mg) or placebo injections were administered 4 weeks after an initial dose (loading dose) and every 2 months (Q2M) thereafter; this is the approved regimen. Participants experienced both loading dose and Q2M delays during the trial. CAB concentrations were evaluated before a delay, at the visit associated with the delay, and the visit after a delayed injection was administered. During the blinded phase of the trial, 194 participants randomized to CAB-LA experienced at least one injection delay. Plasma CAB concentrations were maintained above the 4× protein adjusted 90% inhibitory concentration (4× PA-IC90; protocol-specific threshold) for all loading dose and 98% of Q2M delays when injections were administered up to 6 weeks late. The feasibility of shifting to an every 3-month (Q3M) regimen in females was interrogated via simulation studies using a population pharmacokinetic model. Q3M injections in both CAB-naïve (with a loading dose) and previously CAB-exposed females were predicted to yield higher steady-state exposures than in males on the approved Q2M regimen. Although there is observed forgiveness following an isolated delayed CAB-LA injection and simulations suggest acceptable CAB-LA exposures in women with a 600 mg CAB-LA Q3M regimen, empirical efficacy of this regimen has not been established, and transitioning to this dosing schema is not recommended. Future pharmacokinetic bridging studies are aimed at evaluating higher dose CAB-LA formulations administered less frequently.
CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03164564.}, }
@article {pmid39308420, year = {2024}, author = {Damerell, V and Klaassen-Dekker, N and Brezina, S and Ose, J and Ulvik, A and van Roekel, EH and Holowatyj, AN and Baierl, A and Böhm, J and Bours, MJL and Brenner, H and de Wilt, JHW and Grady, WM and Habermann, N and Hoffmeister, M and Keski-Rahkonen, P and Lin, T and Schirmacher, P and Schrotz-King, P and Ulrich, AB and van Duijnhoven, FJB and Warby, CA and Shibata, D and Toriola, AT and Figueiredo, JC and Siegel, EM and Li, CI and Gsur, A and Kampman, E and Schneider, M and Ueland, PM and Weijenberg, MP and Ulrich, CM and Kok, DE and Gigic, B and , }, title = {Circulating tryptophan-kynurenine pathway metabolites are associated with all-cause mortality among patients with stage I-III colorectal cancer.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.35183}, pmid = {39308420}, issn = {1097-0215}, support = {2014/1179//Wereld Kanker Onderzoek Fonds/ ; U01 CA20//NIH/NCI/ ; //VLAG Graduate School/ ; //Rahel-Goitein-Straus-Program, Medical Faculty, Heidelberg University/ ; UM 2012-5653//Dutch Cancer Society/ ; //Listwin Family Foundation/ ; 2016/1620//Wereld Kanker Onderzoek Fonds/ ; //Huntsman Cancer Foundation/ ; R01 CA189184/CA/NCI NIH HHS/United States ; UW 2013-5927//Dutch Cancer Society/ ; //Fred Hutchinson Cancer Center/ ; U01 CA152756/CA/NCI NIH HHS/United States ; //Seattle Translational Tumor Research program/ ; //Research Council Norway/Norwegian Cancer Society/ ; 01KD2101D//Bundesministerium für Bildung und Forschung/ ; //Netherlands Organization for Health Research and Development/ ; //Cottrell Family Fund/ ; R01 CA207371/CA/NCI NIH HHS/United States ; MetaboCCC I 1578-B19//Transcan/ ; //Stichting Alpe d'HuZes/ ; 00005739//Health Foundation Limburg/ ; //Heidelberger Stiftung Chirurgie/ ; UW2014-6877//Dutch Cancer Society/ ; 01KT1503//Bundesministerium für Bildung und Forschung/ ; //Stiftung LebensBlicke/ ; R01 CA220//National Insitutes of Health/ ; U01 CA206110/CA/NCI NIH HHS/United States ; //R.A.C.E. Charities/ ; P30 CA15704//National Insitutes of Health/ ; API02104FW//Austrian Science Fund/ ; //Rodger C. Haggitt Endowed Chair/ ; FOCUS I2104-B26//Transcan/ ; T32 HG008962/HG/NHGRI NIH HHS/United States ; //Matthias-Lackas Foundations/ ; R01 CA194663/CA/NCI NIH HHS/United States ; UW 2015-7//Dutch Cancer Society/ ; }, abstract = {Alterations within the tryptophan-kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan-kynurenine pathway metabolites and all-cause mortality among CRC patients. This study utilizes data from 2102 stage I-III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above-mentioned metabolites with all-cause mortality, adjusted for potential confounders. During a median follow-up of 3.2 years (interquartile range: 2.2-4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all-cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine-to-tryptophan ratio, a marker of cell-mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan-kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.}, }
@article {pmid39307421, year = {2024}, author = {Iftikhar, R and DeFilipp, Z and DeZern, AE and Pulsipher, MA and Bejanyan, N and Burroughs, LM and Kharfan-Dabaja, MA and Arai, S and Kassim, A and Nakamura, R and Saldaña, BJD and Aljurf, M and Hamadani, M and Carpenter, PA and Antin, JH}, title = {Allogeneic Hematopoietic Cell Transplantation for the Treatment of Severe Aplastic Anemia: Evidence-Based Guidelines From the American Society for Transplantation and Cellular Therapy.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.09.017}, pmid = {39307421}, issn = {2666-6367}, abstract = {Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe aplastic anemia (SAA). Existing guidance about HCT in SAA is primarily derived from expert reviews, registry data and societal guidelines; however, transplant-specific guidelines for SAA are lacking. A panel of SAA experts, both pediatric and adult transplant physicians, developed consensus recommendations using Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology employing a GRADE guideline development tool. The panel agrees with previous recommendations for the preferential use of bone marrow as a graft source and the use of rabbit over horse antithymocyte globulin (ATG) for HCT conditioning. Fludarabine containing regimens are preferred for patients at high risk of graft failure and those receiving matched unrelated or haploidentical donor transplant. Given advancements in HCT, the panel does not endorse the historical 40-year age cut-off for considering upfront HCT in adults, acknowledging that fit older patients may also benefit from HCT. The panel also endorses increased utilization of HCT by prioritizing matched unrelated or haploidentical donor HCT over immunosuppressive therapy in children and adults who lack a matched related donor. Finally, the panel suggests either calcineurin inhibitor plus methotrexate or post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis for matched related or matched unrelated donor recipients. These recommendations reflect a significant advancement in transplant strategies for SAA and highlight the importance of ongoing and further research to revisit current evidence in terms of donor choice, conditioning chemotherapy, GVHD prophylaxis and post-transplant immunosuppression.}, }
@article {pmid39306478, year = {2024}, author = {Francini, E and Agarwal, N and Castro, E and Cheng, HH and Chi, KN and Clarke, N and Mateo, J and Rathkopf, D and Saad, F and Tombal, B}, title = {Intensification Approaches and Treatment Sequencing in Metastatic Castration-resistant Prostate Cancer: A Systematic Review.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2024.09.008}, pmid = {39306478}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: Recently, research on treatment intensification has gathered momentum, and three novel therapy combinations were approved for metastatic castration-resistant prostate cancer (mCRPC). This systematic review summarizes the current and emerging evidence around intensified strategies for mCRPC and provides guidance for an ideal therapeutic sequencing.
METHODS: Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines were followed to perform this review. PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials.gov, and major international societies' online proceedings were searched comprehensively until May 15, 2024, for terms related to treatment intensification and sequencing for mCRPC.
KEY FINDINGS AND LIMITATIONS: Overall, 28 clinical trials and 24 ongoing studies of intensification treatments were included in this review. Algorithms of optimal sequencing of approved treatments for mCRPC were outlined according to the use of androgen receptor pathway inhibitors (ARPIs) with or without docetaxel for earlier disease states. In first line, poly(ADP-ribose) polymerase inhibitor + ARPI combinations improve radiographical progression-free survival (rPFS), particularly for those with BRCA1/2 alterations. The AKT inhibitor combination of ipatasertib + abiraterone extends rPFS in those with PTEN loss or PIK3CA/AKT1/PTEN alterations. In those with two or more risk factors for early progression on enzalutamide, radionuclide 177-Lu-PSMA-617 + enzalutamide prolongs progression-free survival. Ongoing research of intensified approaches for mCRPC, and available and potential predictive and prognostic biomarkers are discussed.
Recent approvals and ongoing investigations of single agents and intensification approaches will keep transforming the mCRPC treatment landscape. Improvement of patient profiling applying recognized genomic, molecular, and clinical predictive and prognostic indicators is fundamental to optimize sequential use of available therapies.}, }
@article {pmid39306373, year = {2024}, author = {Issaka, RB and Bell-Brown, A and Jewell, T and Jackson, SL and Weiner, BJ}, title = {Interventions to Increase Follow-Up of Abnormal Stool-Based Colorectal Cancer Screening Tests in Safety Net Settings: A Systematic Review.}, journal = {Gastroenterology}, volume = {167}, number = {5}, pages = {826-833.e3}, doi = {10.1053/j.gastro.2024.08.002}, pmid = {39306373}, issn = {1528-0012}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Early Detection of Cancer/methods ; *Occult Blood ; *Safety-net Providers ; Feces/chemistry ; Colonoscopy ; Mass Screening/methods ; }, }
@article {pmid39298209, year = {2024}, author = {Langer, SL and Romano, JM and Todd, M and Keefe, FJ and Syrjala, KL and Bricker, JB and Burns, J and Bolger, N and Porter, LS}, title = {Couple communication in cancer: A tale of two conceptual models.}, journal = {Health psychology : official journal of the Division of Health Psychology, American Psychological Association}, volume = {}, number = {}, pages = {}, doi = {10.1037/hea0001396}, pmid = {39298209}, issn = {1930-7810}, support = {/CA/NCI NIH HHS/United States ; }, abstract = {UNLABELLED: Cancer poses significant challenges for patients and caregiving partners. Avoidant communication has been linked to poorer psychosocial adjustment to cancer. Two conceptual models have been proposed to account for this linkage: the social-cognitive processing and relationship intimacy models.
OBJECTIVE: To examine the utility of these models in explaining patient and partner psychological and relationship adjustment on a day-to-day basis using ecological momentary assessment.
METHOD: Patients with breast, colorectal, or lung cancer and their partners (286 dyads) were prompted twice daily for 14 days via smartphone to answer questions about communication with their partner, adjustment (psychological distress and relationship satisfaction), and hypothesized mediators (avoidant thoughts and intimacy). Data were collected from 2017 to 2020.
RESULTS: Participants responded to 92% of prompts and completed 91%. Results supported the relationship intimacy but not the social-cognitive processing model. On afternoons when participants (both patients and caregivers) held back or perceived avoidance or criticism from their partner, they reported less intimacy, as did their partners; this lowered intimacy, in turn, led to participants' (both patients' and caregivers') own lowered relationship satisfaction that evening and to patients' lowered relationship satisfaction through caregivers' lowered intimacy (one-tailed Bayesian ps < .025). When distress was the criterion, patients' holding back or perceived avoidance/criticism led to their own increased distress through their own decreased intimacy, and caregivers' holding back or perceived avoidance/criticism led to patients' increased distress through patients' lowered intimacy (one-tailed Bayesian ps < .005).
CONCLUSIONS: Findings offer implications for interventions designed to improve communication and enhance closeness. (PsycInfo Database Record (c) 2024 APA, all rights reserved).}, }
@article {pmid39297845, year = {2024}, author = {McGraw, KE and Schilling, K and Glabonjat, RA and Galvez-Fernandez, M and Domingo-Relloso, A and Martinez-Morata, I and Jones, MR and Nigra, A and Post, WS and Kaufman, J and Tellez-Plaza, M and Valeri, L and Brown, ER and Kronmal, RA and Barr, RG and Shea, S and Navas-Acien, A and Sanchez, TR}, title = {Urinary Metal Levels and Coronary Artery Calcification: Longitudinal Evidence in the Multi-Ethnic Study of Atherosclerosis.}, journal = {Journal of the American College of Cardiology}, volume = {84}, number = {16}, pages = {1545-1557}, doi = {10.1016/j.jacc.2024.07.020}, pmid = {39297845}, issn = {1558-3597}, support = {R01 ES028758/ES/NIEHS NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; T32 ES007322/ES/NIEHS NIH HHS/United States ; R01 HL155576/HL/NHLBI NIH HHS/United States ; R01 ES029967/ES/NIEHS NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; P42 ES033719/ES/NIEHS NIH HHS/United States ; P42 ES023716/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *Coronary Artery Disease/urine/epidemiology/ethnology ; *Atherosclerosis/urine/ethnology/epidemiology ; Cadmium/urine ; Vascular Calcification/urine/epidemiology/diagnostic imaging ; Longitudinal Studies ; Aged, 80 and over ; Tungsten/urine/adverse effects ; Cobalt/urine ; Copper/urine ; Risk Factors ; Zinc/urine ; Disease Progression ; United States/epidemiology ; Metals/urine ; Ethnicity ; }, abstract = {BACKGROUND: Exposure to metals, a newly recognized risk factor for cardiovascular disease (CVD), could be related to atherosclerosis progression.
OBJECTIVES: The authors hypothesized that higher urinary levels of nonessential (cadmium, tungsten, uranium) and essential (cobalt, copper, zinc) metals previously associated with CVD would be associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of CVD in MESA (Multi-Ethnic Study of Atherosclerosis).
METHODS: We analyzed data from 6,418 MESA participants with spot urinary metal levels at baseline (2000-2002) and 1 to 4 repeated, continuous measures of CAC over a 10-year period. We used linear mixed-effect models to assess the association of baseline urinary metal levels with baseline CAC and cumulative change in CAC over a 10-year period. Urinary metals (μg/g creatinine) and CAC were log transformed. Models were adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors.
RESULTS: At baseline, the median CAC was 6.3 (Q1-Q3: 0.7-58.2). Comparing the highest to lowest quartile of urinary cadmium, CAC levels were 51% (95% CI: 32%, 74%) higher at baseline and 75% (95% CI: 47%, 107%) higher over the 10-year period. For urinary tungsten, uranium, and cobalt, the corresponding CAC levels over the 10-year period were 45% (95% CI: 23%, 71%), 39% (95% CI: 17%, 64%), and 47% (95% CI: 25%, 74%) higher, respectively, with no difference for models with and without adjustment for clinical factors. For copper and zinc, the corresponding estimates dropped from 55% to 33% and from 85% to 57%, respectively, after adjustment for clinical factors. The associations of metals with CAC were comparable in magnitude to those for classical CVD risk factors.
CONCLUSIONS: Exposure to metals was generally associated with extent of coronary calcification at baseline and follow-up. These findings support that metals are associated with the progression of atherosclerosis, potentially providing a novel strategy for the prevention and treatment of atherosclerosis progression.}, }
@article {pmid39297750, year = {2024}, author = {Kopmar, NE and Qu, X and Liu, Y and Gooley, TA and Ghiuzeli, CM and Mawad, R and Percival, MM and Fang, M and Cassaday, RD}, title = {Prognostic significance of chromosomal genomic array testing in adults with newly-diagnosed acute lymphoblastic leukemia.}, journal = {Leukemia & lymphoma}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/10428194.2024.2404959}, pmid = {39297750}, issn = {1029-2403}, }
@article {pmid39305480, year = {2024}, author = {Chen, JG and Kensler, TW and Zhu, J and Zhu, YR and Wang, JB and Lu, JH and Muñoz, A and Groopman, JD}, title = {Profound primary prevention of liver cancer following a natural experiment in China: A 50-year perspective and public health implications.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.35198}, pmid = {39305480}, issn = {1097-0215}, support = {MS22019008//Science and Technology Project of Nantong City/ ; P30 CA006973/CA/NCI NIH HHS/United States ; R35 CA197222/CA/NCI NIH HHS/United States ; 2008ZX10002-015//Chinese National Key Projects/ ; 2008ZX10002-017//Chinese National Key Projects/ ; 2012ZX10002009//Chinese National Key Projects/ ; BRA2019030//Project 333 of Jiangsu Province/ ; }, abstract = {Liver cancer causes upwards of 1 million cancer deaths annually and is projected to rise by at least 55% over the next 15 years. Two of the major risk factors contributing to liver cancer have been well documented by multiple epidemiologic studies and the hepatitis B virus (HBV) and aflatoxin show a synergy that increases by more than 8-fold the risk of liver cancer relative to HBV alone. Using the population-based cancer registry established by the Qidong Liver Cancer Institute in 1972 and aflatoxin-specific biomarkers, we document that reduction of aflatoxin exposure has likely contributed to a nearly 70% decline in age-standardized liver cancer incidence over the past 30 years despite an unchanging prevalence of HBV infection in cases. A natural experiment of economic reform in the 1980s drove a rapid switch from consumption of heavily contaminated corn to minimally, if any, contaminated rice and subsequent dietary diversity. Aflatoxin consumption appears to accelerate the time to liver cancer diagnosis; lowering exposure to this carcinogen adds years of life before a cancer diagnosis. Thus, in 1990 the median age of diagnosis was 48 years, while increasing to 67 years by 2021. These findings have important translational public health implications since up to 5 billion people worldwide might be routinely exposed to dietary aflatoxin, especially in societies using corn as the staple food. Interventions against aflatoxin are an achievable outcome leading to a reduction in liver cancer incidence and years of delay of its nearly always fatal diagnosis.}, }
@article {pmid39304265, year = {2024}, author = {, }, title = {Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.}, journal = {The Lancet. Neurology}, volume = {23}, number = {10}, pages = {973-1003}, doi = {10.1016/S1474-4422(24)00369-7}, pmid = {39304265}, issn = {1474-4465}, mesh = {Humans ; *Global Burden of Disease ; Risk Factors ; *Stroke/epidemiology ; *Global Health ; Disability-Adjusted Life Years ; Incidence ; Prevalence ; Quality-Adjusted Life Years ; Male ; Female ; }, abstract = {BACKGROUND: Up-to-date estimates of stroke burden and attributable risks and their trends at global, regional, and national levels are essential for evidence-based health care, prevention, and resource allocation planning. We aimed to provide such estimates for the period 1990-2021.
METHODS: We estimated incidence, prevalence, death, and disability-adjusted life-year (DALY) counts and age-standardised rates per 100 000 people per year for overall stroke, ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage, for 204 countries and territories from 1990 to 2021. We also calculated burden of stroke attributable to 23 risk factors and six risk clusters (air pollution, tobacco smoking, behavioural, dietary, environmental, and metabolic risks) at the global and regional levels (21 GBD regions and Socio-demographic Index [SDI] quintiles), using the standard GBD methodology. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline.
FINDINGS: In 2021, stroke was the third most common GBD level 3 cause of death (7·3 million [95% UI 6·6-7·8] deaths; 10·7% [9·8-11·3] of all deaths) after ischaemic heart disease and COVID-19, and the fourth most common cause of DALYs (160·5 million [147·8-171·6] DALYs; 5·6% [5·0-6·1] of all DALYs). In 2021, there were 93·8 million (89·0-99·3) prevalent and 11·9 million (10·7-13·2) incident strokes. We found disparities in stroke burden and risk factors by GBD region, country or territory, and SDI, as well as a stagnation in the reduction of incidence from 2015 onwards, and even some increases in the stroke incidence, death, prevalence, and DALY rates in southeast Asia, east Asia, and Oceania, countries with lower SDI, and people younger than 70 years. Globally, ischaemic stroke constituted 65·3% (62·4-67·7), intracerebral haemorrhage constituted 28·8% (28·3-28·8), and subarachnoid haemorrhage constituted 5·8% (5·7-6·0) of incident strokes. There were substantial increases in DALYs attributable to high BMI (88·2% [53·4-117·7]), high ambient temperature (72·4% [51·1 to 179·5]), high fasting plasma glucose (32·1% [26·7-38·1]), diet high in sugar-sweetened beverages (23·4% [12·7-35·7]), low physical activity (11·3% [1·8-34·9]), high systolic blood pressure (6·7% [2·5-11·6]), lead exposure (6·5% [4·5-11·2]), and diet low in omega-6 polyunsaturated fatty acids (5·3% [0·5-10·5]).
INTERPRETATION: Stroke burden has increased from 1990 to 2021, and the contribution of several risk factors has also increased. Effective, accessible, and affordable measures to improve stroke surveillance, prevention (with the emphasis on blood pressure, lifestyle, and environmental factors), acute care, and rehabilitation need to be urgently implemented across all countries to reduce stroke burden.
FUNDING: Bill & Melinda Gates Foundation.}, }
@article {pmid39303988, year = {2024}, author = {Taylor, MR and Cole, SW and Bradford, MC and Zhou, C and Fladeboe, KM and Knight, JM and Baker, KS and Yi-Frazier, JP and Rosenberg, AR}, title = {Resilience Intervention Improves Stress-Related Gene Expression in Adolescent and Young Adult HCT Recipients.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.09.014}, pmid = {39303988}, issn = {2666-6367}, abstract = {Overactivation of the stress response can influence cancer outcomes through immune-related pathways. Adolescents and young adults (AYAs) undergoing hematopoietic cell transplantation (HCT) are at risk for poor outcomes, yet there are limited behavioral interventions and no psychosocial biomarker data for this population. The Conserved Transcriptional Response to Adversity (CTRA) is an inflammation-related pattern observed in conditions of heightened stress and is associated with HCT outcomes. The objective of the current study was to explore the CTRA gene regulatory impact of Promoting Resilience in Stress Management (PRISM) intervention among AYAs receiving HCT. We hypothesized that patients who received the intervention would have favorable gene expression signatures compared to those in the control arm. This was an ancillary study within a randomized trial testing the PRISM intervention on psychosocial outcomes among AYAs aged 12 to 24 years receiving HCT (NCT03640325). CTRA was quantified through genome-wide transcriptional profiles obtained from whole blood collected at baseline, 1-, and 3-month post-HCT. Group differences in CTRA gene expression were estimated using mixed-effect linear models. There were no baseline group differences in CTRA expression, but PRISM participants showed a greater decline in CTRA at 1 month compared to controls (β -0.301 ± SE 0.114, P = .016), even when controlling for demographic (Group × Time interaction: F(2, 18) = 7.41, P = .004; β -0.386 ± 0.127, P = .007) and clinical covariates (Group × Time interaction: F(2, 20) = 7.03, P = .005; β -0.480 ± 0.144, P = .003). These differences were not detectable at 3 months (β -0.147 ± SE 0.120, P = .235). There was a change in stress-related gene expression among AYAs randomized to a psychosocial intervention. The stress-inflammation axis may be a targetable pathway in the AYA HCT population.}, }
@article {pmid39303986, year = {2024}, author = {Wickline, MM and Carpenter, PA and Harris, JR and Iribarren, SJ and Reding, KW and Pike, KC and Lee, SJ and Lee, CJ and Oshima, MU and Vo, PT and Berry, DL}, title = {Associations Between Demographic Factors, Clinical Variables, Social Determinants of Health, Vaccine Hesitancy, Vaccine Behavior, and Revaccination Status: A Survey of Adult HCT Survivors in the United States.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.09.012}, pmid = {39303986}, issn = {2666-6367}, abstract = {Comprehensive survivorship care after hematopoietic cell transplantation (HCT) includes revaccination to restore immunity to vaccine-preventable diseases (VPDs). There is complexity to revaccination in this setting, and revaccination rates are sub-optimal. HCT survivors are at high-risk for morbidity and mortality from infections including VPDs, underscoring the importance of interventions to improve revaccination rates among survivors. Determining associations between survivor characteristics and revaccination uptake may guide interventions. The overall study objective was to advance our understanding of factors influencing revaccination uptake among adult HCT survivors living in the United States The specific study aims were to: (1) determine the prevalence of adult survivors who are completely, partially, or not revaccinated at 2 to 8 years after HCT and (2) examine associations between demographic variables, social determinants of health, clinical variables, past vaccination behaviors, vaccine hesitancy (Vaccination Confidence Scale), and revaccination status in adult HCT survivors. This study employed a one-time cross-sectional revaccination survey of adults who were surviving 2 to 8 years after HCT and living in the United States. The survey was sent to eligible survivors in the Fred Hutchinson Cancer Center Long-term Follow-up research cohort. The point prevalence of revaccination outcomes was determined from all the respondents (n = 338), differences in intent to revaccinate for people not yet fully revaccinated were explored using Fisher's exact test (n = 126), and associations were examined between revaccination outcomes and predictors using multivariable logistic regression (n = 292). Survey response rate was 30%. Among respondents, 62% were completely revaccinated, 33% were partially revaccinated, and 4% were not revaccinated. Most respondents (77%) who were not yet fully revaccinated planned to complete the revaccination protocol. However, fewer not-revaccinated respondents than partially revaccinated respondents planned to complete revaccination (50% versus 80%, P = .032). Factors associated with incomplete revaccination were shorter time from HCT, inadequate immune reconstitution, and not having received all childhood vaccines as a child. Our analysis has identified multiple variables associated with revaccination outcomes, indicating the potential for interventions to enhance post-HCT revaccination rates. Since many survivors cannot be revaccinated promptly due to delayed immune recovery, clinicians should iteratively re-evaluate for revaccination readiness as long as it takes to ensure eventual revaccination. Broader efforts by the healthcare community to increase childhood vaccine uptake might eventually support revaccination uptake. Future research that builds on these findings should focus on intervention testing.}, }
@article {pmid39303435, year = {2024}, author = {Boyd, DT and Jones, KV and Quinn, CR and Hill, M and Nelson, LE and Beauchamp, G and Emel, L and Hightow-Weidman, L and Shoptaw, S and Magnus, M and Piwowar-Manning, E and Mayer, KH and Fields, SD and Wheeler, DP and Dyer, TV and Wilton, L}, title = {Ethnic identity and social support as mediators between childhood sexual abuse and depression among black men who have sex with men.}, journal = {Child abuse & neglect}, volume = {157}, number = {}, pages = {107064}, doi = {10.1016/j.chiabu.2024.107064}, pmid = {39303435}, issn = {1873-7757}, support = {P30 AI117970/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Child ; Humans ; Male ; Middle Aged ; Young Adult ; Adult Survivors of Child Abuse/psychology ; *Black or African American/psychology ; *Child Abuse, Sexual/psychology/ethnology ; *Depression/ethnology/psychology ; Social Identification ; *Social Support ; *Sexual and Gender Minorities/psychology ; }, abstract = {BACKGROUND: Survivors of childhood sexual abuse (CSA) often experience long-term adverse mental health effects, a trend that has been observed in research focusing on men who have sex with men (MSM), especially Black MSM.
OBJECTIVE: The aim of this study was to investigate the direct and indirect effects of childhood sexual abuse on depression symptoms among Black MSM through early sexual debut, histories of incarceration, ethnic identity, and social support. In addition, we examine the role of social support and ethnic identity as mediators of depression symptoms.
PARTICIPANTS AND SETTING: The HPTN 073 study enrolled and followed 226 HIV-uninfected Black MSM in three US cities (Los Angeles; Washington, DC; and Chapel Hill, North Carolina) from February 2013 to September 2015. Study participants were offered once-daily oral emtricitabine/tenofovir preexposure prophylaxis combined with counseling and followed for 52 weeks.
METHODS: A path analysis was used to examine direct and indirect effects of CSA experiences on depression symptoms through incarceration, early sexual debut ethnic identity, and social support, and to see whether social support and ethnic identity mediated the relationship between incarceration and depression symptoms.
RESULTS: Our results indicate that childhood sexual abuse was direct and positively associated with early sexual debut (β = 0.21, p < .001). Both ethnic identity (β = -0.14, p < .001) and social support (β = -0.82, p < .001) were direct and negatively associated with depressive symptoms.
CONCLUSION: Our research underscores the significant impact of CSA factors on the life trajectories of some Black MSM, including experiences such as incarceration, sexual debut, and depression symptoms.}, }
@article {pmid39302139, year = {2024}, author = {Zhu, K and Zhao, YQ and Zheng, Y}, title = {Designing cancer screening trials for reduction in late-stage cancer incidence.}, journal = {Biometrics}, volume = {80}, number = {3}, pages = {}, pmid = {39302139}, issn = {1541-0420}, support = {R01 CA236558/NH/NIH HHS/United States ; }, mesh = {Humans ; *Early Detection of Cancer/methods/statistics & numerical data ; Incidence ; *Neoplasms/diagnosis ; Randomized Controlled Trials as Topic ; Models, Statistical ; Research Design ; Biomarkers, Tumor/blood ; Mass Screening/methods/statistics & numerical data ; Computer Simulation ; Biometry/methods ; Sensitivity and Specificity ; }, abstract = {Before implementing a biomarker test for early cancer detection into routine clinical care, the test must demonstrate clinical utility, that is, the test results should lead to clinical actions that positively affect patient-relevant outcomes. Unlike therapeutical trials for patients diagnosed with cancer, designing a randomized controlled trial (RCT) to demonstrate the clinical utility of an early detection biomarker with mortality and related endpoints poses unique challenges. The hurdles stem from the prolonged natural progression of the disease and the lack of information regarding the time-varying screening effect on the target asymptomatic population. To facilitate the study design of screening trials, we propose using a generic multistate disease history model and derive model-based effect sizes. The model links key performance metrics of the test, such as sensitivity, to primary endpoints like the incidence of late-stage cancer. It also incorporates the practical implementation of the biomarker-testing program in real-world scenarios. Based on the chronological time scale aligned with RCT, our method allows the assessment of study powers based on key features of the new program, including the test sensitivity, the length of follow-up, and the number and frequency of repeated tests. The calculation tool from the proposed method will enable practitioners to perform realistic and quick evaluations when strategizing screening trials for specific diseases. We use numerical examples based on the National Lung Screening Trial to demonstrate the method.}, }
@article {pmid39302970, year = {2024}, author = {Cole, JM and Scott, CB and Johnson, MM and Golightly, PR and Carlson, J and Ming, MJ and Harpak, A and Kirkpatrick, M}, title = {The battle of the sexes in humans is highly polygenic.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {39}, pages = {e2412315121}, pmid = {39302970}, issn = {1091-6490}, support = {R01 GM116853/GM/NIGMS NIH HHS/United States ; R35 GM151108/GM/NIGMS NIH HHS/United States ; GM151108//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; GM116853//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {Humans ; Male ; Female ; *Multifactorial Inheritance/genetics ; *Fertility/genetics ; Selection, Genetic ; Haplotypes ; Alleles ; Sex Characteristics ; Genome-Wide Association Study ; Genome, Human ; }, abstract = {Sex-differential selection (SDS), which occurs when the fitness effects of alleles differ between males and females, can have profound impacts on the maintenance of genetic variation, disease risk, and other key aspects of natural populations. Because the sexes mix their autosomal genomes each generation, quantifying SDS is not possible using conventional population genetic approaches. Here, we introduce a method that exploits subtle sex differences in haplotype frequencies resulting from SDS acting in the current generation. Using data from 300K individuals in the UK Biobank, we estimate the strength of SDS throughout the genome. While only a handful of loci under SDS are individually significant, we uncover highly polygenic signals of genome-wide SDS for both viability and fecundity. Selection coefficients of [Formula: see text] may be typical. Despite its ubiquity, SDS may impose a mortality load of less than 1%. An interesting life-history tradeoff emerges: Alleles that increase viability more strongly in females than males tend to increase fecundity more strongly in males than in females. Finally, we find marginal evidence of SDS on fecundity acting on alleles affecting arm fat-free mass. Taken together, our findings connect the long-standing evidence of SDS acting on human phenotypes with its impact on the genome.}, }
@article {pmid39302924, year = {2024}, author = {Naicker, V and Laher, F and Bekker, LG and Seaton, KE and Allen, M and De Rosa, S and Yates, NL and Mkhize, NN and Saunders, K and Heptinstall, J and Malahleha, M and Mngadi, K and Daniels, B and Innes, C and Yu, C and Modise, T and Bekker, V and Grunenberg, N and Furch, B and Miner, MD and Phogat, S and Diazgranados, CA and Gurunathan, S and Koutsoukos, M and Van Der Meeren, O and Roxby, AC and Ferrari, G and Morris, L and Montefiori, D and McElrath, MJ and Tomaras, GD and Moodie, Z}, title = {Safety and immunogenicity after a 30-month boost of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120/MF59 vaccine boost (HVTN 100): A phase 1-2 randomized double-blind placebo-controlled trial.}, journal = {PLOS global public health}, volume = {4}, number = {9}, pages = {e0003319}, pmid = {39302924}, issn = {2767-3375}, abstract = {Induction of broad, durable immune responses is a challenge in HIV vaccine development. HVTN 100 Part A administered subtype C-containing ALVAC-HIV at months 0 and 1, and ALVAC-HIV with bivalent subtype C gp120/MF59 at months 3, 6 and 12. As IgG binding antibody and T-cell responses were similar or greater at month 12.5 vs. month 6.5, but waned by month 18, we investigated vaccine-elicited immune responses after a month 30 boost in this study, HVTN 100 Part B. From 13 September 2017 to 7 August 2018, a subgroup of vaccinees was randomized to receive intramuscular injections of ALVAC+gp120/MF59 (n = 32) or gp120/MF59 alone (n = 31) and a subgroup of placebo recipients was administered placebo (n = 7) at month 30. Primary outcomes were safety, IgG binding antibodies (bAbs) to vaccine-specific and V1V2 Env proteins and vaccine-specific CD4+ T cells at month 30.5. Secondary outcomes included neutralizing and antibody dependent cellular cytotoxicity functions and durability at months 30 and 36. Both vaccine groups had an acceptable safety profile. There were no statistically significant differences in the occurrence or level of IgG bAbs between the vaccine boost groups for any vaccine-specific or V1V2 antigens. IgG responses were higher to vaccine-matched gp120 than to V1V2. The booster vaccination restored the magnitude-breadth IgG bAb response to V1V2 antigens at month 30.5. However, it rapidly waned by month 36. CD4+ T-cell response rates to the 3 vaccine-matched Env antigens for the combined vaccine groups ranged from 37% at month 30, boosted to as high as 91% at month 30.5, and waned by month 36 to as low as 44%, with no significant differences between the vaccine boost groups. Because these responses waned after 6 months, additional strategies may be needed to maintain the durability of prime-boost vaccine regimens and to generate these or other immune responses that confer protection. Trial registration: South African National Clinical Trials Register (SANCTR number: DOH-27-0215-4796) and ClinicalTrials.gov (NCT02404311).}, }
@article {pmid39302431, year = {2024}, author = {Smith, JR and Arellano, AA and Avgousti, DC}, title = {Viral imitation is the sincerest form of epigenetic flattery.}, journal = {Molecular biology of the cell}, volume = {35}, number = {10}, pages = {pe3}, pmid = {39302431}, issn = {1939-4586}, support = {R35 GM133441/GM/NIGMS NIH HHS/United States ; T34 GM136466/GM/NIGMS NIH HHS/United States ; }, mesh = {*Epigenesis, Genetic ; Humans ; *SARS-CoV-2/physiology ; *Histones/metabolism ; Influenza A virus/genetics/physiology ; Chromatin/metabolism ; COVID-19/virology ; Immune Evasion ; Animals ; Host-Pathogen Interactions ; }, abstract = {Viruses use multiple strategies to successfully generate progeny and overcome host defenses. In recent years, it has become increasingly evident that epigenetic mechanisms of host gene regulation are vulnerable to viral manipulation. In the form of histone mimicry, viral invasion of host chromatin is a striking example of how viruses have evolved to invade every aspect of cellular function for viral benefit. In this perspective, we will review how three viruses-influenza A, SARS-CoV-2, and Cotesia plutellae bracovirus-use histone mimicry to promote viral success through immune evasion. These examples highlight the importance of this burgeoning field and point toward the wealth of knowledge we have yet to uncover.}, }
@article {pmid39298738, year = {2024}, author = {Gyurkocza, B and Nath, R and Seropian, S and Choe, H and Litzow, MR and Abboud, C and Koshy, N and Stiff, P and Tomlinson, B and Abhyankar, S and Foran, J and Hari, P and Chen, G and Al-Kadhimi, Z and Kebriaei, P and Sabloff, M and Orozco, JJ and Jamieson, K and Silverman, M and Van Besien, K and Schuster, M and Law, AD and Larkin, K and Pandit-Taskar, N and Rowley, SD and Munshi, P and Cook, R and Levy, MY and Lazarus, HM and Sandmaier, BM and Pagel, JM and Reddy, V and MacDougall, J and McNamara, K and Spross, J and Haeuber, E and Vusirikala, M and Nahar, A and Desai, A and Giralt, S}, title = {Randomized Phase III SIERRA Trial of [131]I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2302018}, doi = {10.1200/JCO.23.02018}, pmid = {39298738}, issn = {1527-7755}, abstract = {PURPOSE: Older patients with relapsed or refractory AML (RR AML) have dismal prognoses without allogeneic hematopoietic cell transplantation (alloHCT). SIERRA compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate [131]I-apamistamab with conventional care.
METHODS: SIERRA (ClinicalTrials.gov identifier: NCT02665065) was a phase III open-label trial. Patients age ≥55 years with active RR AML were randomly assigned 1:1 to either an [131]I-apamistamab-led regimen before alloHCT or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the [131]I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive [131]I-apamistamab followed by alloHCT. The primary end point was durable complete remission (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population.
RESULTS: The ITT population included 153 patients ([131]I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received [131]I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with [131]I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; P < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; P = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring [131]I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the [131]I-apamistamab and conventional care groups, respectively.
CONCLUSION: The [131]I-apamistamab-led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. [131]I-apamistamab was well tolerated and could address an unmet need in this population.}, }
@article {pmid39298390, year = {2024}, author = {Kwan, ML and Pimentel, N and Izano, M and Iribarren, C and Rana, JS and Nguyen-Huynh, M and Cheng, R and Laurent, CA and Lee, VS and Roh, JM and Rillamas-Sun, E and Hershman, DL and Kushi, LH and Greenlee, H and Neugebauer, R}, title = {Adherence to cardiovascular medications and risk of cardiovascular disease in breast cancer patients: A causal inference approach in the Pathways Heart Study.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310531}, pmid = {39298390}, issn = {1932-6203}, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/epidemiology ; *Medication Adherence/statistics & numerical data ; Middle Aged ; *Cardiovascular Diseases/drug therapy/epidemiology ; Aged ; Prospective Studies ; Cardiovascular Agents/therapeutic use ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Risk Factors ; Heart Failure/drug therapy/epidemiology ; }, abstract = {PURPOSE: Women with breast cancer (BC) are at high risk of developing cardiovascular disease (CVD). We examined adherence to CVD medications and their association with major CVD events over 14 years of follow-up in the Pathways Heart Study, a prospective study of 4,776 stage I-III BC patients diagnosed from 2005-2013.
METHODS: Eligibility included being alive 6 months post-BC diagnosis, with dyslipidemia, hypertension, or diabetes at diagnosis along with ≥1 prior outpatient order or dispensing for a statin, anti-hypertensive, or diabetes medication, respectively, in the 30 months prior. Medication adherence was measured from pharmacy data to calculate cumulative average adherence (CAA). Incident heart failure (HF), ischemic heart disease (IHD), and stroke were determined via validated diagnosis and procedure codes. Working marginal structural models (MSM) fitted with inverse probability weighting evaluated the effect of adherence regimens on the hazards for each CVD event, while controlling for baseline and time-varying confounders. MSM parameterizations included: 1) CAA<100% versus CAA = 100% (ref), 2) CAA<80% versus CAA≥80% (ref) and 3) CAA<80% versus 80%≤CAA<100% versus CAA = 100%.
RESULTS: Poor statin adherence (CAA<80%) was associated with higher risk of composite CVD (HR = 2.54; 95% CI: 1.09, 5.94) versus CAA≥80%. Poor statin adherence was also associated with a higher risk of stroke (HR = 8.13; 95% CI: 2.03, 32.51) but not risk of IHD and HF. Further, compared with perfect adherence (CAA = 100%), good adherence (80%≤CAA<100%) was associated with lower risk (HR = 0.35; 95% CI: 0.13, 0.92) while poor adherence (CAA<80%) was associated with higher risk of composite CVD (HR = 2.45; 95% CI: 1.05, 5.70). Levels of adherence to anti-hypertensives and diabetes medications had mixed or null associations with risk of CVD.
CONCLUSIONS: Maintaining good adherence (≥80%) to statins after BC treatment is beneficial for cardiovascular health in patients with dyslipidemia. Future studies should determine factors associated with lower adherence to statins and ways to improve adherence.}, }
@article {pmid39297068, year = {2024}, author = {Guinigundo, A and Baek, G}, title = {Staying Abreast of New Biomarkers in Hematology/Oncology.}, journal = {Journal of the advanced practitioner in oncology}, volume = {15}, number = {3}, pages = {164-169}, pmid = {39297068}, issn = {2150-0878}, abstract = {There has been an increasing number of approvals for targeted therapies in oncology in the past decade, changing the treatment paradigm for many solid tumors and hematologic malignancies. At JADPRO Live 2023, presenters provided an in-depth review of cancer biomarkers, including testing methodology, recommended therapies, and how advanced practitioners can integrate results into clinical decision-making.}, }
@article {pmid39294476, year = {2024}, author = {Luo, K and Zhang, Y and Kaplan, RC and Qi, Q}, title = {Reply to: Milk intake, lactase non-persistence and type 2 diabetes risk in Chinese adults.}, journal = {Nature metabolism}, volume = {}, number = {}, pages = {}, pmid = {39294476}, issn = {2522-5812}, support = {R01-DK119268//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; R01-DK126698//U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)/ ; 23POST1020455//American Heart Association (American Heart Association, Inc.)/ ; R01-MD011389//U.S. Department of Health & Human Services | NIH | National Institute on Minority Health and Health Disparities (NIMHD)/ ; }, }
@article {pmid39294453, year = {2024}, author = {Duggan, C and Carosso, E and Ibarra, G and Neuhouser, ML and Thompson, B}, title = {Developing a Dietary Questionnaire for Rural Mexican Americans.}, journal = {Journal of immigrant and minority health}, volume = {}, number = {}, pages = {}, pmid = {39294453}, issn = {1557-1920}, support = {P30 CA015704-39/NH/NIH HHS/United States ; }, abstract = {Latinos form the largest ethnic population in the United States (18.5%), and the majority are Mexican Americans (61.4%). Many Mexican Americans have unique dietary behaviors, yet few food frequency questionnaires explicitly define Mexican American diets. The objective of this work was to engage with a population of rural Mexican Americans to develop a Mexican American food frequency questionnaire. Because acculturation is linked to dietary intake, we also examined acculturation by diet. We used mixed methods with three phases: (1) a qualitative phase in which a sample of rural Mexican-Americans (N = 15) identified and provided rich data about foods they ate; (2) a developmental phase in which 4 day food records were completed sequentially by two new and different samples of Mexican Americans (N = 19); and 3) a preliminary assessment phase where a new sample of Mexican Americans (N = 49) completed the final food frequency questionnaire. The final questionnaire included many traditional Mexican foods and beverages identified by study participants as part of their typical diet. Traditional Mexican foods and beverages were consumed regularly; little variation in diet was seen by level of acculturation. Respondents perceived diets containing commercial sugar-sweetened beverages as unhealthful, but not those with traditional Mexican drinks, which may represent an unappreciated source of added sugar in the diet. Future work includes studies examining dietary patterns in other urban and rural communities with traditional Mexican diets.}, }
@article {pmid39294153, year = {2024}, author = {Wagner, C and Kistler, KE and Perchetti, GA and Baker, N and Frisbie, LA and Torres, LM and Aragona, F and Yun, C and Figgins, M and Greninger, AL and Cox, A and Oltean, HN and Roychoudhury, P and Bedford, T}, title = {Author Correction: Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8199}, doi = {10.1038/s41467-024-52571-4}, pmid = {39294153}, issn = {2041-1723}, }
@article {pmid39293548, year = {2024}, author = {Marsh, TL and Parikh, ND and Roberts, LR and Schwartz, ME and Nguyen, MH and Befeler, A and Page-Lester, S and Tayob, N and Srivastava, S and Rinaudo, JA and Singal, AG and Reddy, KR and Marrero, JA}, title = {A Phase 3 Biomarker Validation of GALAD for the Detection of Hepatocellular Carcinoma in Cirrhosis.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2024.09.008}, pmid = {39293548}, issn = {1528-0012}, abstract = {BACKGROUND & AIMS: Better surveillance tests for hepatocellular carcinoma (HCC) are needed. The GALAD score (gender, age, α-fetoprotein [AFP] L3, AFP, and des carboxyprothrombin) has been shown to have excellent sensitivity and specificity for HCC in phase 2 studies. We performed a phase 3 biomarker validation study to compare GALAD with AFP in detecting HCC.
METHODS: This is a prospective study of patients with cirrhosis enrolled at 7 centers. Surveillance for HCC was performed every 6 months at each site, and HCC diagnosis was confirmed per American Association for the Study of Liver Diseases guidelines. Blood for biomarker research was obtained at each follow-up visit and stored in a biorepository. Measurements of AFP, AFP-L3, and des-γ carboxyprothrombin) were performed in a FujiFilm laboratory by staff blinded to clinical data. The performance of GALAD in detecting HCC was retrospectively evaluated within 12 months before the clinical diagnosis. All analyses were conducted by an unblinded statistician in the EDRN data management and coordinating center.
RESULTS: A total of 1,558 patients with cirrhosis were enrolled and followed for a median of 2.2 years. A total of 109 patients developed HCC (76 very early or early stage), with an annual incident rate of 2.4%. The areas under the curve for AFP and GALAD within 12 months before HCC were 0.66 and 0.78 (P < .001), respectively. Using a cutoff for GALAD of -1.36, the specificity was 82%, and the sensitivity at 12 months before HCC diagnosis was 62%. For comparison, performance of AFP at 82% specificity showed 41% sensitivity at 12 months before HCC diagnosis (P = .001).
CONCLUSIONS: GALAD score, compared to AFP, improves the detection of HCC within 12 months before the actual diagnosis.}, }
@article {pmid39293545, year = {2024}, author = {Matsumoto, MM and Lee, CI}, title = {Realizing the Potential for Opportunistic Early Detection of Abnormalities on Medical Imaging Using Artificial Intelligence.}, journal = {Journal of the American College of Radiology : JACR}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jacr.2024.09.003}, pmid = {39293545}, issn = {1558-349X}, }
@article {pmid39293515, year = {2024}, author = {Rathkopf, DE and Patel, MR and Choudhury, AD and Rasco, D and Lakhani, N and Hawley, JE and Srinivas, S and Aparicio, A and Narayan, V and Runcie, KD and Emamekhoo, H and Reichert, ZR and Nguyen, MH and Wells, AL and Kandimalla, R and Liu, C and Suryawanshi, S and Han, J and Wu, J and Arora, VK and Pourdehnad, M and Armstrong, AJ}, title = {Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2024.09.005}, pmid = {39293515}, issn = {1569-8041}, abstract = {BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC.
PATIENTS AND METHODS: Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS).
RESULTS: Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations.
CONCLUSIONS: BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status.}, }
@article {pmid39289368, year = {2024}, author = {Walter, M and Haick, AK and Riley, R and Massa, PA and Strongin, DE and Klouser, LM and Loprieno, MA and Stensland, L and Santo, TK and Roychoudhury, P and Aubert, M and Taylor, MP and Jerome, KR and Verdin, E}, title = {Viral gene drive spread during herpes simplex virus 1 infection in mice.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {8161}, pmid = {39289368}, issn = {2041-1723}, support = {R21 AI178255/AI/NIAID NIH HHS/United States ; R21AI178255//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Animals ; *Herpesvirus 1, Human/genetics/physiology ; Mice ; *Herpes Simplex/virology/genetics ; Humans ; Coinfection/virology ; Gene Drive Technology/methods ; Female ; Vero Cells ; Chlorocebus aethiops ; Encephalitis, Herpes Simplex/genetics/virology ; Mice, Inbred C57BL ; Recombination, Genetic/genetics ; Genes, Viral/genetics ; }, abstract = {Gene drives are genetic modifications designed to propagate efficiently through a population. Most applications rely on homologous recombination during sexual reproduction in diploid organisms such as insects, but we recently developed a gene drive in herpesviruses that relies on co-infection of cells by wild-type and engineered viruses. Here, we report on a viral gene drive against human herpes simplex virus 1 (HSV-1) and show that it propagates efficiently in cell culture and during HSV-1 infection in mice. We describe high levels of co-infection and gene drive-mediated recombination in neuronal tissues during herpes encephalitis as the infection progresses from the site of inoculation to the peripheral and central nervous systems. In addition, we show evidence that a superinfecting gene drive virus could recombine with wild-type viruses during latent infection. These findings indicate that HSV-1 achieves high rates of co-infection and recombination during viral infection, a phenomenon that is currently underappreciated. Overall, this study shows that a viral gene drive could spread in vivo during HSV-1 infection, paving the way toward therapeutic applications.}, }
@article {pmid39292927, year = {2024}, author = {Wolff, D and Cutler, C and Lee, SJ and Pusic, I and Bittencourt, H and White, J and Hamadani, M and Arai, S and Salhotra, A and Perez-Simon, JA and Alousi, A and Choe, H and Kwon, M and Bermúdez, A and Kim, I and Socié, G and Chhabra, S and Radojcic, V and O'Toole, T and Tian, C and Ordentlich, P and DeFilipp, Z and Kitko, CL and , }, title = {Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease.}, journal = {The New England journal of medicine}, volume = {391}, number = {11}, pages = {1002-1014}, doi = {10.1056/NEJMoa2401537}, pmid = {39292927}, issn = {1533-4406}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects ; Chronic Disease/drug therapy ; Dose-Response Relationship, Drug ; *Graft vs Host Disease/diagnosis/drug therapy/immunology/metabolism ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Infusions, Intravenous ; *Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors/metabolism ; Recurrence ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R)-dependent monocytes and macrophages are key mediators of chronic graft-versus-host disease (GVHD), a major long-term complication of allogeneic hematopoietic stem-cell transplantation. The CSF1R-blocking antibody axatilimab has shown promising clinical activity in chronic GVHD.
METHODS: In this phase 2, multinational, pivotal, randomized study, we evaluated axatilimab at three different doses in patients with recurrent or refractory chronic GVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group). The primary end point was overall response (complete or partial response) in the first six cycles; the key secondary end point was a patient-reported decrease in chronic GVHD symptom burden, as assessed by a reduction of more than 5 points on the modified Lee Symptom Scale (range, 0 to 100, with higher scores indicating worse symptoms). The primary end point would be met if the lower bound of the 95% confidence interval exceeded 30%.
RESULTS: A total of 241 patients were enrolled (80 patients in the 0.3-mg dose group, 81 in the 1-mg dose group, and 80 in the 3-mg dose group). The primary end point was met in all the groups; an overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group.
CONCLUSIONS: Targeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD. (Funded by Syndax Pharmaceuticals and Incyte; AGAVE-201 ClinicalTrials.gov number, NCT04710576.).}, }
@article {pmid39292670, year = {2024}, author = {Earnest, JT and Kirstein, OD and Mendoza, AC and Barrera-Fuentes, GA and Puerta-Guardo, H and Parra-Cardeña, M and Yam-Trujillo, K and Collins, MH and Pavia-Ruz, N and Ayora-Talavera, G and Gonzalez-Olvera, G and Medina-Barreiro, A and Bibiano-Marin, W and Lenhart, A and Halloran, ME and Longini, I and Dean, N and Waller, LA and Crisp, AM and Correa-Morales, F and Palacio-Vargas, J and Granja-Perez, P and Villanueva, S and Delfın-Gonzalez, H and Gomez-Dantes, H and Manrique-Saide, P and Vazquez-Prokopec, GM}, title = {The TIRS trial: Enrollment procedures and baseline characterization of a pediatric cohort to quantify the epidemiologic impact of targeted indoor residual spraying on Aedes-borne viruses in Merida, Mexico.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310480}, pmid = {39292670}, issn = {1932-6203}, mesh = {Humans ; Child ; *Aedes/virology ; Animals ; Mexico/epidemiology ; Adolescent ; Child, Preschool ; Female ; *Mosquito Control/methods ; Male ; *Mosquito Vectors/virology ; *Dengue/epidemiology/prevention & control/virology ; *Insecticides ; Seroepidemiologic Studies ; Zika Virus Infection/epidemiology/prevention & control ; Zika Virus/immunology/isolation & purification ; Chikungunya Fever/epidemiology/prevention & control ; Dengue Virus/immunology/isolation & purification ; Chikungunya virus/immunology ; }, abstract = {Aedes mosquito-borne viruses (ABVs) place a substantial strain on public health resources in the Americas. Vector control of Aedes mosquitoes is an important public health strategy to decrease or prevent spread of ABVs. The ongoing Targeted Indoor Residual Spraying (TIRS) trial is an NIH-sponsored clinical trial to study the efficacy of a novel, proactive vector control technique to prevent dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV) infections in the endemic city of Merida, Yucatan, Mexico. The primary outcome of the trial is laboratory-confirmed ABV infections in neighborhood clusters. Despite the difficulties caused by the COVID-19 pandemic, by early 2021 the TIRS trial completed enrollment of 4,792 children aged 2-15 years in 50 neighborhood clusters which were allocated to control or intervention arms via a covariate-constrained randomization algorithm. Here, we describe the makeup and ABV seroprevalence of participants and mosquito population characteristics in both arms before TIRS administration. Baseline surveys showed similar distribution of age, sex, and socio-economic factors between the arms. Serum samples from 1,399 children were tested by commercially available ELISAs for presence of anti-ABV antibodies. We found that 45.1% of children were seropositive for one or more flaviviruses and 24.0% were seropositive for CHIKV. Of the flavivirus-positive participants, most were positive for ZIKV-neutralizing antibodies by focus reduction neutralization testing which indicated a higher proportion of participants with previous ZIKV than DENV infections within the cohort. Both study arms had statistically similar seroprevalence for all viruses tested, similar socio-demographic compositions, similar levels of Ae. aegypti infestation, and similar observed mosquito susceptibility to insecticides. These findings describe a population with a high rate of previous exposure to ZIKV and lower titers of neutralizing antibodies against DENV serotypes, suggesting susceptibility to future outbreaks of flaviviruses is possible, but proactive vector control may mitigate these risks.}, }
@article {pmid39291745, year = {2024}, author = {Nagana Gowda, GA and Pascua, V and Hill, L and Djukovic, D and Wang, D and Raftery, D}, title = {Discovery of Hypoxanthine and Inosine as Robust Biomarkers for Predicting the Preanalytical Quality of Human Plasma and Serum for Metabolomics.}, journal = {Analytical chemistry}, volume = {96}, number = {39}, pages = {15754-15764}, doi = {10.1021/acs.analchem.4c03719}, pmid = {39291745}, issn = {1520-6882}, mesh = {Humans ; *Inosine/blood/metabolism ; *Hypoxanthine/blood ; *Metabolomics/methods ; *Biomarkers/blood ; Plasma/chemistry/metabolism ; }, abstract = {In cold human blood, the anomalous dynamics of adenosine triphosphate (ATP) result in the progressive accumulation of adenosine diphosphate (ADP), adenosine monophosphate (AMP), inosine monophosphate (IMP), inosine, and hypoxanthine. While the ATP, ADP, AMP, and IMP are confined to red blood cells (RBCs), inosine and hypoxanthine are excreted into plasma/serum. The plasma/serum levels of inosine and hypoxanthine depend on the temperature of blood and the plasma/serum contact time with the RBCs, and hence they represent robust biomarkers for evaluating the preanalytical quality of plasma/serum. These biomarkers are highly specific since they are generally absent or at very low levels in fresh plasma/serum and are highly sensitive since they are derived from ATP, one of the most abundant metabolites in blood. Further, whether blood was kept at room temperature or on ice could be predicted based on inosine levels. An analysis of >2000 plasma/serum samples processed for metabolomics-centric analyses showed alarmingly high levels of inosine and hypoxanthine. The results highlight the gravity of sample quality challenges with high risk of grossly inaccurate measurements and incorrect study outcomes. The discovery of these robust biomarkers provides new ways to address the longstanding and underappreciated preanalytical sample quality challenges in the blood metabolomics field.}, }
@article {pmid39290875, year = {2024}, author = {Crotty, EE and Paulson, VA and Ronsley, R and Vitanza, NA and Lee, A and Hauptman, J and Goldstein, HE and Lockwood, CM and Leary, SES and Cole, BL}, title = {Cerebrospinal fluid liquid biopsy by low-pass whole genome sequencing for clinical disease monitoring in pediatric embryonal tumors.}, journal = {Neuro-oncology advances}, volume = {6}, number = {1}, pages = {vdae126}, pmid = {39290875}, issn = {2632-2498}, abstract = {BACKGROUND: Liquid biopsy assays that detect cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) are a promising tool for disease monitoring in pediatric patients with primary central nervous system (CNS) tumors. As a compliment to tissue-derived molecular analyses, CSF liquid biopsy has the potential to transform risk stratification, prognostication, and precision medicine approaches.
METHODS: In this pilot study, we evaluated a clinical pipeline to determine feasibility and sensitivity of low-pass whole genome sequencing (LP-WGS) of CSF-derived cfDNA from patients with CNS embryonal tumors. Thirty-two longitudinal CSF samples collected from 17 patients with molecularly characterized medulloblastoma (12), embryonal tumor with multilayered rosettes (2), CNS embryonal tumor, not elsewhere classified (NEC) (2), and atypical teratoid/rhabdoid tumor (1) were analyzed.
RESULTS: Adequate CSF-derived cfDNA for LP-WGS analysis was obtained in 94% of samples (30/32). Copy number variants compatible with neoplasia were detected in 90% (27/30) and included key alterations, such as isodicentric ch17, monosomy 6, and MYCN amplification, among others. Compared to tissue specimens, LP-WGS detected additional aberrations in CSF not previously identified in corresponding primary tumor specimens, suggesting a more comprehensive profile of tumor heterogeneity or evolution of cfDNA profiles over time. Among the 12 CSF samples obtained at initial staging, only 2 (17%) were cytologically positive, compared to 11 (92%) that were copy number positive by LP-WGS.
CONCLUSIONS: LP-WGS of CSF-derived cfDNA is feasible using a clinical platform, with greater sensitivity for tumor detection compared to conventional CSF cytologic analysis at initial staging. Large prospective studies are needed to further evaluate LP-WGS as a predictive biomarker.}, }
@article {pmid39290639, year = {2024}, author = {Eapen, M and Antin, JH and Tolar, J and Arai, S and Horwitz, ME and Kou, J and Leifer, E and McCarty, JM and Nakamura, R and Pulsipher, MA and Rowley, SD and Horowitz, MM and Deeg, HJ}, title = {Long-term survival after unrelated donor marrow transplantation for aplastic anaemia after optimized conditioning regimen: a retrospective multicentre cohort study.}, journal = {EClinicalMedicine}, volume = {76}, number = {}, pages = {102819}, pmid = {39290639}, issn = {2589-5370}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Almost all acquired severe aplastic anaemia is immune mediated and characterised by hypocellular bone marrow and ≥2 affected haematopoietic lineages. The optimal preparartive regimen for unrelated donor transplantation remains to be established. We aimed to study long-term outcomes after unrelated donor transplantation for severe aplastic anaemia with de-escalation of cyclophosphamide (Cy) dose in steps of 50 mg/kg (150, 100, 50, 0 mg/kg) in combination with total body irradiation (TBI) 2 Gy, anti-thymocyte globulin (ATG) and fludarabine.
METHODS: Ninety-six patients with severe aplastic anaemia aged ≤65 years with adequate organ function enrolled on a trial of human leukocyte antigen (HLA)-matched or 1 HLA-locus mismatched unrelated donor marrow transplantation conducted between 02/2006 and 12/2013 in the United States (NCT00326417). Exclusion criteria were Karnofsky performance status of less than 60, clonal cytogenetic abnormalities and inherited marrow failure syndormes. The primary outcome was day-100 engraftment (achievement of absolute neutrophil recovery to at least 0.5 × 10[9]/L without subsequent decline) and day-100 survival. The trial determined the lowest effective Cy dose as 50 mg/kg (n = 38) for day-100 engraftment and survival. Cy dose 100 mg/kg (n = 41) was also acceptable. Accrual to Cy doses 150 mg/kg (n = 15) and 0 mg/kg (n = 3) was terminated early for toxicities. The current study is an extended follow up of patients enrolled on the trial (NCT00326477) and includes 76 of 96 patients alive ≥1 year after transplantation. There were 20 deaths in the first year after transplantation (Cy 0 mg/kg [n = 2], Cy 50 mg/kg [n = 1], Cy 100 mg/kg [n = 10], Cy 150 mg/kg [n = 7]). Patients were followed prospectively from transplantation and data reported using standardized data collection forms until death, loss to follow up or last contact through November 2023. The incidence of graft failure was calculated using the cumulative incidence estimator and the probability of survival using the Kaplan-Meier estimator.
FINDINGS: The median follow up of the cohort is 8.02 (IQR) 5.16-10.12) years. With Cy 50 mg/kg, there was one graft failure and five deaths ≥1 year after transplantation. With Cy 100 mg/kg there was only one late death and no graft failure. The 8-year probabilities of survival were 85.0% (95% CI 67.3-93.5) and 75.6% (95% CI 59.4-86.1) after Cy 50 mg/kg and 100 mg/kg, respectively, P = 0.31. With Cy 0 mg/kg and 150 mg/kg, there were no graft failures or death ≥1 year after transplantation. Regardless of Cy dose 12 of 15 patients aged ≥50 years died.
INTERPRETATION: Cy 50 mg/kg or 100 mg/kg with TBI 2 Gy, ATG and fludarabine are effective conditioning regimens for unrelated donor marrow transplants for aplastic anaemia. Identification of an optimized transplantation approach for patients aged ≥50 years is needed.
FUNDING: US National Institutes of Health.}, }
@article {pmid39290356, year = {2024}, author = {Thomson, TJ and Hu, XJ and Nosyk, B}, title = {Estimating effects of time-varying exposures on mortality risk.}, journal = {Journal of applied statistics}, volume = {51}, number = {13}, pages = {2652-2671}, pmid = {39290356}, issn = {0266-4763}, support = {R01 DA050629/DA/NIDA NIH HHS/United States ; }, abstract = {Administrative databases have become an increasingly popular data source for population-based health research. We explore how mortality risk is associated with some health service utilization process via linked administrative data. A generalized Cox regression model is proposed using a time-dependent stratification variable to summarize lifetime service utilization. Recognizing the service utilization over time as an internal covariate in the survival analysis, conventional likelihood methods are inapplicable. We present an estimating function based procedure for estimating model parameters, and provide a testing procedure for updating the stratification levels. The proposed approach is examined both asymptotically and numerically via simulation. We motivate and illustrate the proposed approach using an on-going program pertaining to opioid agonist treatment (OAT) management for individuals identified with opioid use disorders. Our analysis of the OAT data indicates that the OAT effect on mortality risk decreases in successive OAT attempts, in which two risk classes based on an individual's treatment episode number are established: one with 1-3 OAT episodes, and the other with 4+ OAT episodes.}, }
@article {pmid39290203, year = {2024}, author = {Raychaudhuri, S and Dong, ZM and Knowles, S and Graf, S}, title = {EBV-Positive Classic Hodgkin Lymphoma and Primary Nodal T-Cell/NK-Cell Lymphoma Arising in the Background of Follicular Lymphoma.}, journal = {Case reports in hematology}, volume = {2024}, number = {}, pages = {8810646}, pmid = {39290203}, issn = {2090-6560}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, abstract = {EBV-positive primary nodal T-cell/NK cell lymphoma (TNKL) is a rare diagnosis with a poor prognosis. No relationship with follicular lymphoma (FL), classic Hodgkin lymphoma (cHL), or other non-Hodgkin lymphomas is established. We describe a case of Epstein-Barr virus (EBV)-positive cHL and EBV-positive primary nodal TNKL in the background of an antecedent FL, with all 3 subtypes identified in a single lymph node biopsy from an immunocompetent patient. Intensive frontline therapy achieved only a temporary response, with subsequent rapid progression associated with hemophagocytic lymphohistiocytosis (HLH). We discuss the relationship of the three lymphoma subtypes and the potential roles of EBV and immune dysregulation as contributing factors to this previously undescribed composite lymphoma.}, }
@article {pmid39289635, year = {2024}, author = {Leader, AE and Rebbeck, TR and Oh, WK and Patel, AV and Winer, EP and Bailey, LO and Gomella, LG and Lumpkins, CY and Garraway, IP and Aiello, LB and Baskin, ML and Cheng, HH and Cooney, KA and Ganzak, A and George, DJ and Halabi, S and Hathaway, F and Healy, C and Kim, JW and Leapman, MS and Loeb, S and Maxwell, KN and McNair, C and Morgan, TM and Prindeville, B and Soule, HR and Steward, WL and Suttiratana, SC and Taplin, ME and Yamoah, K and Fortune, T and Bennett, K and Blanding-Godbolt, J and Gross, L and Giri, VN}, title = {Adaptation of the socioecological model to address disparities in engagement of Black men in prostate cancer genetic testing.}, journal = {BMC public health}, volume = {24}, number = {1}, pages = {2533}, pmid = {39289635}, issn = {1471-2458}, mesh = {Humans ; Male ; Africa/ethnology ; Black or African American ; Delphi Technique ; *Genetic Testing ; *Healthcare Disparities ; *Prostatic Neoplasms/diagnosis/genetics ; United States ; *Black People ; }, abstract = {BACKGROUND: Black men consistently have higher rates of prostate cancer (PCA)- related mortality. Advances in PCA treatment, screening, and hereditary cancer assessment center around germline testing (GT). Of concern is the significant under-engagement of Black males in PCA GT, limiting the benefit of precision therapy and tailored cancer screening despite longstanding awareness of these disparities. To address these critical disparities, the Socioecological Model (SEM) was employed to develop comprehensive recommendations to overcome barriers and implement equitable strategies to engage Black males in PCA GT.
METHODS: Clinical/research experts, national organization leaders, and community stakeholders spanning multiple regions in US and Africa participated in developing a framework for equity in PCA GT grounded in the SEM. A novel mixed-methods approach was employed to generate key areas to be addressed and informed statements for consensus consideration utilizing the modified Delphi model. Statements achieving strong consensus (> =75% agreement) were included in final equity frameworks addressing clinical/community engagement and research engagement.
RESULTS: All societal levels of the SEM (interpersonal, institutional, community, and policy/advocacy) must deliver information about PCA GT to Black males that address benefits/limitations, clinical impact, hereditary cancer implications, with acknowledgment of mistrust (mean scores [MS] 4.57-5.00). Interpersonal strategies for information delivery included engagement of family/friends/peers/Black role models to improve education/awareness and overcome mistrust (MS 4.65-5.00). Institutional strategies included diversifying clinical, research, and educational programs and integrating community liaisons into healthcare institutions (MS 4.57-5.00). Community strategies included partnerships with healthcare institutions and visibility of healthcare providers/researchers at community events (MS 4.65-4.91). Policy/advocacy included improving partnerships between advocacy and healthcare/community organizations while protecting patient benefits (MS 4.57-5.00). Media strategies were endorsed for the first time at every level (MS 4.56-5.00).
CONCLUSION: The SEM-based equity frameworks proposed provide the first multidisciplinary strategies dedicated to increase engagement of Black males in PCA GT, which are critical to reduce disparities in PCA-mortality through informing tailored screening, targeted therapy, and cascade testing in families.}, }
@article {pmid39288406, year = {2024}, author = {Chen, X and Soma, L and Murphy, C and Tretiakova, M and Naresh, KN and Fromm, JR}, title = {Utility of CCR7 to differentiate classic Hodgkin lymphoma and other B-cell lymphomas by flow cytometry and immunohistochemistry.}, journal = {American journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcp/aqae119}, pmid = {39288406}, issn = {1943-7722}, abstract = {OBJECTIVES: Classic Hodgkin lymphoma (CHL) is characterized by infrequent neoplastic Hodgkin and Reed-Sternberg (HRS) cells in an inflammatory background. The diagnostic utility of CC-chemokine receptor 7 (CCR7) in CHL was explored using flow cytometry and immunohistochemistry (IHC).
METHODS: Neoplastic specimens and non-neoplastic lymph nodes were immunophenotyped and CCR7 expression was measured semiquantitatively by flow cytometry (clone 3D12) and IHC (clone 150503).
RESULTS: Our results showed that CCR7 was expressed on HRS cells in the vast majority of CHL cases (45/48 by flow cytometry, 57/59 by IHC) but rarely expressed in neoplastic cells in diffuse large B-cell lymphoma, not otherwise specified (1/25 by flow cytometry, 2/40 by IHC) and nodular lymphocyte predominant Hodgkin lymphoma (0/4 by flow cytometry, 1/13 by IHC). Primary mediastinal large B-cell lymphoma (PMLBCL) revealed weak CCR7 expression by flow cytometry in most cases (8/10) but only occasionally by IHC (2/12). Both cases (2/2) of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) also showed CCR7 expression detected by flow cytometry compared with IHC (0/7). The HRS cells demonstrated a greater percentage of positive cells and greater antigen intensity than the other B-cell lymphomas by IHC. The expression identified by flow cytometry in PMLBCL and THRLBCL but not by IHC suggests that there may be differences in the detection capabilities of the 2 techniques or the 2 CCR7 clones used.
CONCLUSIONS: The expression of CCR7 in HRS cells suggests its potential utility in differentiating CHL from other B-cell lymphomas. Incorporating CCR7 into flow cytometry and IHC panels may further enhance the diagnostic sensitivity of CHL.}, }
@article {pmid39287566, year = {2024}, author = {Neary, J and Njuguna, I and Wagner, AD and Richardson, BA and Chebet, D and Langat, A and Ngugi, E and Benki-Nugent, S and Moraa, H and Hawes, SE and Overbaugh, J and Slyker, JA and Lehman, DA and Wamalwa, D and John-Stewart, G}, title = {Brief Report: Group-Based Trajectory Modeling to Determine Long-Term HIV Viral Load Trends Among Children With HIV in Kenya.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {96}, number = {4}, pages = {311-317}, pmid = {39287566}, issn = {1944-7884}, support = {R01 AI076105/AI/NIAID NIH HHS/United States ; F31 HD106261/HD/NICHD NIH HHS/United States ; K01MH121124/MH/NIMH NIH HHS/United States ; K24 HD054314/HD/NICHD NIH HHS/United States ; R01HD094718//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P30 AI027757/AI/NIAID NIH HHS/United States ; K01AI087369//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; K24HD054314//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; K01 AI087369/AI/NIAID NIH HHS/United States ; R01HD23412//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01 HD094718/HD/NICHD NIH HHS/United States ; P30AI027757//Center for AIDS Research, University of Washington/ ; K43 TW 011422-01A1/TW/FIC NIH HHS/United States ; F31HD106261//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01 HD023412/HD/NICHD NIH HHS/United States ; K43 TW011422/TW/FIC NIH HHS/United States ; K01 MH121124/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/drug therapy/virology ; *Viral Load ; Kenya/epidemiology ; Male ; Female ; Child ; Child, Preschool ; Infant ; *Anti-HIV Agents/therapeutic use ; Longitudinal Studies ; Medication Adherence/statistics & numerical data ; }, abstract = {BACKGROUND: Identifying determinants of longitudinal HIV viral load (VL) trajectories using group-based trajectory modeling (GBTM) can inform clinical strategies and mechanisms of nonadherence among children.
METHODS: Children under 12 months old who were newly diagnosed with HIV were enrolled in the Optimizing Pediatric HIV therapy cohort (NCT00428116) from 2007 to 2010. Children initiated antiretroviral therapy at enrollment, and VL was assessed every 3 months for 24 months post-antiretroviral therapy and every 6 months thereafter up to 8 years old. VL trajectory groups were defined using GBTM. Fisher's exact and Kruskal-Wallis tests were used to determine the correlates of each trajectory group compared with the sustained-low VL group.
RESULTS: Five VL trajectory groups were identified among 89 children with 522 VL visits from 6 to 24 months: sustained-low (63% of children), sustained-very-high (16%), sustained-high (9%), low-to-high (7%), and high-with-periods-of-low (6%). Children in the sustained-high group were more frequently on a first-line protease inhibitor (PI)-based regimen (63% vs 38%; P = 0.03) and had younger caregivers (median: 22 vs 28 years; P = 0.02). Among 54 children with 560 VL visits followed from 48 to 96 months, 5 trajectory groups were identified: sustained-low (74%), mid-range (4%), periods-of-low (7%), high-to-low (7%), and sustained-high (7%). Those in the high-to-low group had younger caregivers (21 vs 29 years; P = 0.01).
CONCLUSIONS: GBTM identified unique VL patterns among children with unsuppressed VL. Caregiver and regimen-related characteristics were associated with patterns of nonsuppression. Younger caregivers may benefit from tailored counseling to help them support child antiretroviral therapy adherence. Palatable regimens are necessary for viral suppression among children with HIV.}, }
@article {pmid39286979, year = {2024}, author = {Westaby, D and Jiménez-Vacas, JM and Figueiredo, I and Rekowski, J and Pettinger, C and Gurel, B and Lundberg, A and Bogdan, D and Buroni, L and Neeb, A and Padilha, A and Taylor, J and Zeng, W and Das, S and Hobern, E and Riisnaes, R and Crespo, M and Miranda, S and Ferreira, A and Hanratty, BP and Nava Rodrigues, D and Bertan, C and Seed, G and Fenor de La Maza, MLD and Guo, C and Carmichael, J and Grochot, R and Chandran, K and Stavridi, A and Varkaris, A and Stylianou, N and Hollier, BG and Tunariu, N and Balk, SP and Carreira, S and Yuan, W and Nelson, PS and Corey, E and Haffner, M and de Bono, J and Sharp, A}, title = {BCL2 expression is enriched in advanced prostate cancer with features of lineage plasticity.}, journal = {The Journal of clinical investigation}, volume = {134}, number = {18}, pages = {}, pmid = {39286979}, issn = {1558-8238}, mesh = {Male ; Humans ; *Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; *Prostatic Neoplasms, Castration-Resistant/genetics/pathology/metabolism ; *Gene Expression Regulation, Neoplastic ; Animals ; Cell Line, Tumor ; Receptors, Androgen/metabolism/genetics ; Mice ; DNA Methylation ; Epithelial-Mesenchymal Transition ; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism ; Cell Lineage ; Neoplasm Proteins/genetics/metabolism/biosynthesis ; }, abstract = {The widespread use of potent androgen receptor signaling inhibitors (ARSIs) has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC), typically driven by loss of AR expression, lineage plasticity, and transformation to prostate cancers (PCs) that exhibit phenotypes of neuroendocrine or basal-like cells. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine cancers and may be a therapeutic target for this aggressive PC disease subset. There is an unmet clinical need, therefore, to clinically characterize BCL2 expression in metastatic CRPC (mCRPC), determine its association with AR expression, uncover its mechanisms of regulation, and evaluate BCL2 as a therapeutic target and/or biomarker with clinical utility. Here, using multiple PC biopsy cohorts and models, we demonstrate that BCL2 expression is enriched in AR-negative mCRPC, associating with shorter overall survival and resistance to ARSIs. Moreover, high BCL2 expression associates with lineage plasticity features and neuroendocrine marker positivity. We provide evidence that BCL2 expression is regulated by DNA methylation, associated with epithelial-mesenchymal transition, and increased by the neuronal transcription factor ASCL1. Finally, BCL2 inhibition had antitumor activity in some, but not all, BCL2-positive PC models, highlighting the need for combination strategies to enhance tumor cell apoptosis and enrich response.}, }
@article {pmid39286457, year = {2024}, author = {von Berg, J and McArdle, PF and Häppölä, P and Haessler, J and Kooperberg, C and Lemmens, R and Pezzini, A and Thijs, V and Pulit, SL and Kittner, SJ and Mitchell, BD and de Ridder, J and van der Laan, SW}, title = {Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset.}, journal = {Frontiers in genetics}, volume = {15}, number = {}, pages = {1392061}, pmid = {39286457}, issn = {1664-8021}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 NS100178/NS/NINDS NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; R01 NS105150/NS/NINDS NIH HHS/United States ; I01 BX004672/BX/BLRD VA/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, abstract = {INTRODUCTION: Large genome-wide association studies (GWASs) using case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing the age at onset (AAO) of ischemic stroke.
METHODS: Analyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value <1 x 10[-5] in a sexcombined or sex-stratified analysis using summary data from two additional replication cohorts.
RESULTS: In the women-only meta-analysis, we detected significant evidence for the association of AAO with rs429358, an exonic variant in apolipoprotein E (APOE) that encodes for the APOE-Є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29-year earlier stroke AAO (meta p-value = 2.48 x 10[-11]). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decrease in mortality among APOE-Є4 carriers and have no association to stroke AAO per se. A simulation study showed that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a 2-fold increase in mortality risk would lead to an observed effect of AAO that is comparable to what we found.
DISCUSSION: In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.}, }
@article {pmid39283647, year = {2024}, author = {Church, EC and Bishop, E and Fiore-Gartland, A and Yu, KKQ and Chang, M and Jones, RM and Brache, JK and Ballweber Fleming, L and Phan, JM and Makatsa, MS and Heptinstall, J and Chiong, K and Dintwe, O and Naidoo, A and Voillet, V and Mayer-Blackwell, K and Nwanne, G and Andersen-Nissen, E and Vary, JC and Tomaras, GD and McElrath, MJ and Sherman, DR and Murphy, SC and Kublin, JG and Seshadri, C}, title = {Probing Dermal Immunity to Mycobacteria through a Controlled Human Infection Model.}, journal = {ImmunoHorizons}, volume = {8}, number = {9}, pages = {695-711}, pmid = {39283647}, issn = {2573-7732}, support = {P30 AI168034/AI/NIAID NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; 75N93019C00071/AI/NIAID NIH HHS/United States ; 75N93022D00005/AI/NIAID NIH HHS/United States ; 75N99020D00005/OF/ORFDO NIH HHS/United States ; R01 AI146072/AI/NIAID NIH HHS/United States ; 75N95020D00005/DA/NIDA NIH HHS/United States ; 75N93023D00005/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Mycobacterium bovis/immunology ; *Skin/immunology/microbiology/pathology ; Male ; Adult ; Isoniazid/therapeutic use/pharmacology ; Female ; Tuberculosis/immunology/microbiology ; Young Adult ; Antitubercular Agents/therapeutic use ; }, abstract = {Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections.}, }
@article {pmid39283236, year = {2024}, author = {Presant, CA and Till, C and Vaidya, R and Ashing, KT and Warren, GW and Sun, V and Salgia, R and Massarelli, E and Mortimer, JE and Pal, S and Dorff, T and Amini, A and Erhunmwunsee, L and Phillips, T and Hershman, DL and Unger, JM}, title = {Smoking prevalence and association with sociodemographic variables in cancer clinical trial participants.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.35560}, pmid = {39283236}, issn = {1097-0142}, support = {//Hope Foundation/ ; UG1CA189974//NIH/NCI/NCORP/ ; P30 CA033572/CA/NCI NIH HHS/United States ; R01 CA27989/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Tobacco use (smoking) causes adverse clinical outcomes among patients with cancer, including increased cancer-related mortality. In participants in cancer clinical trials, the prevalence of tobacco use and the factors associated with tobacco use are not well described.
METHODS: Data were examined from participants enrolled in SWOG cancer clinical treatment trials between 2016 and 2022 who reported their smoking status at trial enrollment. Baseline variables (smoking status, insurance type, zip code, and demographic factors) were obtained from patient registration forms. Bivariate and multivariable associations were examined via logistic regression.
RESULTS: Among 4326 patients enrolled in 29 trials, 48.1% reported currently/previously smoking, including 12.4% currently, 4.9% recently, and 30.7% formerly. Ever smoking was more commonly reported in males, patients aged ≥65 years, patients with Medicaid or no insurance, patients from areas of high socioeconomic deprivation, and rural patients. Patients of Hispanic ethnicity and Asian and Pacific Islander patients were less likely to have ever smoked. In multivariable regression, patients with lung cancer were most likely to report ever smoking compared to patients with breast cancer (odds ratio, 4.98; p < .001).
CONCLUSIONS: In the first comprehensive evaluation of smoking status among trial participants enrolled in National Cancer Institute network group treatment trials, nearly half reported ever smoking and one in six reported current or recent smoking. Smoking was more common among vulnerable population patients defined by demographic and socioeconomic factors. Tobacco use should be routinely assessed and reported in clinical trials to help reduce the negative cancer and overall health effects of persistent tobacco use and to address disparities among patients with cancer.}, }
@article {pmid39283073, year = {2024}, author = {Crawford, KHD and Baniecki, ML and Dushin, EG and Tierney, CA and Guan, S and Stensland, LL and Perez-Osorio, AC and Greninger, AL}, title = {Specimen adequacy assay controls in nucleic acid amplification tests do not correlate with nasopharyngeal swab collection method.}, journal = {Journal of clinical microbiology}, volume = {62}, number = {10}, pages = {e0097524}, pmid = {39283073}, issn = {1098-660X}, mesh = {Humans ; *Nasopharynx/virology/microbiology ; *Specimen Handling/methods ; *Nucleic Acid Amplification Techniques/methods ; COVID-19 Nucleic Acid Testing/methods/standards ; }, }
@article {pmid39282902, year = {2024}, author = {Apolo, AB and Ballman, KV and Sonpavde, G and Berg, S and Kim, WY and Parikh, R and Teo, MY and Sweis, RF and Geynisman, DM and Grivas, P and Chatta, G and Reichert, ZR and Kim, JW and Bilen, MA and McGregor, B and Singh, P and Tripathi, A and Cole, S and Simon, N and Niglio, S and Ley, L and Cordes, L and Srinivas, S and Huang, J and Odegaard, M and Watt, C and Petrylak, D and Hoffman-Censits, J and Wen, Y and Hahn, O and Mitchell, C and Tan, A and Streicher, H and Sharon, E and Moon, H and Woods, M and Halabi, S and Perez Burbano, G and Morris, MJ and Rosenberg, JE}, title = {Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2401726}, pmid = {39282902}, issn = {1533-4406}, support = {UG1 CA233160/CA/NCI NIH HHS/United States ; UG1 CA233302/CA/NCI NIH HHS/United States ; UG1 CA233373/CA/NCI NIH HHS/United States ; UG1 CA233193/CA/NCI NIH HHS/United States ; UG1 CA233191/CA/NCI NIH HHS/United States ; U10 CA180882/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; UG1 CA233247/CA/NCI NIH HHS/United States ; UG1 CA233253/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; UG1 CA233290/CA/NCI NIH HHS/United States ; UG1 CA233270/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; UG1 CA233337/CA/NCI NIH HHS/United States ; UG1 CA239767/CA/NCI NIH HHS/United States ; UG1 CA233180/CA/NCI NIH HHS/United States ; UG1 CA233196/CA/NCI NIH HHS/United States ; UG1 CA233327/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery is unknown.
METHODS: In this phase 3 trial, we randomly assigned patients, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomization was stratified according to pathological stage, centrally tested programmed death ligand 1 (PD-L1) status, and previous neoadjuvant chemotherapy. The coprimary end points were disease-free survival and overall survival in the intention-to-treat population. We considered the trial to be successful if either disease-free survival or overall survival was significantly longer with pembrolizumab than with observation.
RESULTS: A total of 702 patients underwent randomization; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of July 5, 2024, the median duration of follow-up for disease-free survival was 44.8 months. The median disease-free survival was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI, 11.0 to 20.2) with observation (hazard ratio for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P = 0.003). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group.
CONCLUSIONS: Among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, disease-free survival was significantly longer with adjuvant pembrolizumab than with observation. (Funded by the National Cancer Institute of the National Institutes of Health and others; Alliance A031501 AMBASSADOR ClinicalTrials.gov number, NCT03244384.).}, }
@article {pmid39282531, year = {2024}, author = {Beresford, SAA and Ornelas, IJ and Garrity, G and Bauer, MC and Bishop, SK and Vreeke, A and Garcia, L and Francis, B and Rillamas-Sun, E and Lombard, KA}, title = {Impact of a school-based intervention and the COVID-19 pandemic on healthy eating in Navajo families: Results from the Yéego! Healthy eating and gardening intervention trial.}, journal = {Preventive medicine reports}, volume = {46}, number = {}, pages = {102858}, pmid = {39282531}, issn = {2211-3355}, support = {U54 CA132381/CA/NCI NIH HHS/United States ; U54 CA132383/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVES: As part of a group randomized trial of a school-based intervention promoting gardening and healthy eating, health behaviors of adult family members were evaluated. The COVID-19 pandemic hit the Navajo Nation in March 2020 and the ongoing Yéego! collaborative study allowed description of adult response to COVID as an ancillary objective.
METHODS: Six elementary schools on the Navajo Nation in Arizona or New Mexico had been randomized to intervention or comparison group. One adult family member for each 3rd and 4th grade student completed surveys at baseline, nine-month and 21-month follow-up. Adult outcomes were fruit and vegetable (F&V) intake, obesogenic dietary index and gardening frequency. COVID-related measures were collected at 21-month follow-up. Differential changes and interactions were examined using repeated measures linear mixed models.
RESULTS: Adult F&V intake increased significantly more in the intervention group than in the comparison group at nine months by 2.26 servings/day (95% CI: 0.45, 4.06). No other changes were associated with the intervention at nine or 21 months. At 21 months, in the subgroup with COVID concerns, the differential change in F&V intake was 2.02 (95% CI: 0.21, 3.84) servings/day. In cross-sectional analyses, only healthy eating measures varied by levels of COVID concerns, stress and resilience.
CONCLUSIONS: The child focused school-based intervention had some impact on adult family members, particularly their F&V intake, suggesting the reach of the intervention extended to students' families. The impact on adult F&V intake persisted among those reporting COVID concerns. Findings have important implications for augmenting healthy eating interventions.}, }
@article {pmid39282444, year = {2024}, author = {Zych, MG and Contreras, M and Vashisth, M and Mammel, AE and Ha, G and Hatch, EM}, title = {RCC1 depletion drives protein transport defects and rupture in micronuclei.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39282444}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM124766/GM/NIGMS NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; DP2 CA280624/CA/NCI NIH HHS/United States ; T32 CA009657/CA/NCI NIH HHS/United States ; }, abstract = {Micronuclei (MN) are a commonly used marker of chromosome instability that form when missegregated chromatin recruits its own nuclear envelope (NE) after mitosis. MN frequently rupture, which results in genome instability, upregulation of metastatic genes, and increased immune signaling. MN rupture is linked to NE defects, but the cause of these defects is poorly understood. Previous work from our lab found that chromosome identity correlates with rupture timing for small MN, i.e. MN containing a short chromosome, with more euchromatic chromosomes forming more stable MN with fewer nuclear lamina gaps. Here we demonstrate that histone methylation promotes rupture and nuclear lamina defects in small MN. This correlates with increased MN size, and we go on to find that all MN have a constitutive nuclear export defect that drives MN growth and nuclear lamina gap expansion, making the MN susceptible to rupture. We demonstrate that these export defects arise from decreased RCC1 levels in MN and that additional loss of RCC1 caused by low histone methylation in small euchromatic MN results in additional import defects that suppress nuclear lamina gaps and MN rupture. Through analysis of mutational signatures associated with early and late rupturing chromosomes in the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset, we identify an enrichment of APOBEC and DNA polymerase E hypermutation signatures in chromothripsis events on early and mid rupturing chromosomes, respectively, suggesting that MN rupture timing could determine the landscape of structural variation in chromothripsis. Our study defines a new model of MN rupture where increased MN growth, caused by defects in protein export, drives gaps in nuclear lamina organization that make the MN susceptible to membrane rupture with long-lasting effects on genome architecture.}, }
@article {pmid39282381, year = {2024}, author = {Shinde, P and Willemsen, L and Anderson, M and Aoki, M and Basu, S and Burel, JG and Cheng, P and Dastidar, SG and Dunleavy, A and Einav, T and Forschmiedt, J and Fourati, S and Garcia, J and Gibson, W and Greenbaum, JA and Guan, L and Guan, W and Gygi, JP and Ha, B and Hou, J and Hsiao, J and Huang, Y and Jansen, R and Kakoty, B and Kang, Z and Kobie, JJ and Kojima, M and Konstorum, A and Lee, J and Lewis, SA and Li, A and Lock, EF and Mahita, J and Mendes, M and Meng, H and Neher, A and Nili, S and Olsen, LR and Orfield, S and Overton, JA and Pai, N and Parker, C and Qian, B and Rasmussen, M and Reyna, J and Richardson, E and Safo, S and Sorenson, J and Srinivasan, A and Thrupp, N and Tippalagama, R and Trevizani, R and Ventz, S and Wang, J and Wu, CC and Ay, F and Grant, B and Kleinstein, SH and Peters, B}, title = {Putting computational models of immunity to the test - an invited challenge to predict B. pertussis vaccination outcomes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39282381}, issn = {2692-8205}, support = {U01 AI141995/AI/NIAID NIH HHS/United States ; U01 AI150753/AI/NIAID NIH HHS/United States ; U19 AI142742/AI/NIAID NIH HHS/United States ; }, abstract = {Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.}, }
@article {pmid39282263, year = {2024}, author = {Banjoko, AW and Ng'uni, T and Naidoo, N and Ramsuran, V and Hyrien, O and Ndhlovu, ZM}, title = {High Resolution Class I HLA -A, -B, and -C Diversity in Eastern and Southern African Populations.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39282263}, issn = {2692-8205}, support = {INV-027090/GATES/Bill & Melinda Gates Foundation/United States ; R01 AI181690/AI/NIAID NIH HHS/United States ; }, abstract = {Africa remains significantly underrepresented in high-resolution Human Leukocyte Antigen (HLA) data, despite being one of the most genetically diverse regions in the world. This critical gap in genetic information poses a substantial barrier to HLA-based research on the continent. In this study, Class I HLA data from Eastern and Southern African populations were analysed to assess genetic diversity across the region. We examined allele and haplotype frequency distributions, deviations from Hardy-Weinberg Equilibrium (HWE), linkage disequilibrium (LD), and conducted neutrality tests of homozygosity across various populations. Additionally, the African HLA data were compared to those of Caucasian and African American populations using the Jaccard index and multidimensional scaling (MDS) methods. The study revealed that South African populations exhibited 50.4% more genetic diversity within the Class I HLA region compared to other African populations. Zambia showed an estimated 36.5% genetic diversity, with Kenya, Rwanda and Uganda showing 35.7%, 34.2%, and 31.1%, respectively. Furthermore, an analysis of in-country diversity among different tribes indicated an average Class I HLA diversity of 25.7% in Kenya, 17% in Rwanda, 2.8% in South Africa, 13.6% in Uganda, and 6.5% in Zambia. The study also highlighted the genetic distinctness of Caucasian and African American populations compared to African populations. Notably, the differential frequencies of disease-promoting and disease-preventing HLA alleles across these populations emphasize the urgent need to generate high-quality HLA data for all regions of Africa and its major ethnic groups. Such efforts will be crucial in enhancing healthcare outcomes across the continent.}, }
@article {pmid39281752, year = {2024}, author = {Zanti, M and O'Mahony, DG and Parsons, MT and Dorling, L and Dennis, J and Boddicker, NJ and Chen, W and Hu, C and Naven, M and Yiangou, K and Ahearn, TU and Ambrosone, CB and Andrulis, IL and Antoniou, AC and Auer, PL and Baynes, C and Bodelon, C and Bogdanova, NV and Bojesen, SE and Bolla, MK and Brantley, KD and Camp, NJ and Campbell, A and Castelao, JE and Cessna, MH and Chang-Claude, J and Chen, F and Chenevix-Trench, G and , and Conroy, DM and Czene, K and De Nicolo, A and Domchek, SM and Dörk, T and Dunning, AM and Eliassen, AH and Evans, DG and Fasching, PA and Figueroa, JD and Flyger, H and Gago-Dominguez, M and García-Closas, M and Glendon, G and González-Neira, A and Grassmann, F and Hadjisavvas, A and Haiman, CA and Hamann, U and Hart, SN and Hartman, MBA and Ho, WK and Hodge, JM and Hoppe, R and Howell, SJ and , and Jakubowska, A and Khusnutdinova, EK and Ko, YD and Kraft, P and Kristensen, VN and Lacey, JV and Li, J and Lim, GH and Lindström, S and Lophatananon, A and Luccarini, C and Mannermaa, A and Martinez, ME and Mavroudis, D and Milne, RL and Muir, K and Nathanson, KL and Nuñez-Torres, R and Obi, N and Olson, JE and Palmer, JR and Panayiotidis, MI and Patel, AV and Pharoah, PDP and Polley, EC and Rashid, MU and Ruddy, KJ and Saloustros, E and Sawyer, EJ and Schmidt, MK and Southey, MC and Tan, VK and Teo, SH and Teras, LR and Torres, D and Trentham-Dietz, A and Truong, T and Vachon, CM and Wang, Q and Weitzel, JN and Yadav, S and Yao, S and Zirpoli, GR and Cline, MS and Devilee, P and Tavtigian, SV and Goldgar, DE and Couch, FJ and Easton, DF and Spurdle, AB and Michailidou, K}, title = {Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {39281752}, support = {/WT_/Wellcome Trust/United Kingdom ; P50 CA116201/CA/NCI NIH HHS/United States ; R01 CA225662/CA/NCI NIH HHS/United States ; R35 CA253187/CA/NCI NIH HHS/United States ; }, abstract = {Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.}, }
@article {pmid39280607, year = {2024}, author = {Qin, G and Zhang, Y and Tyner, JW and Kemp, CJ and Shmulevich, I}, title = {Knowledge graphs facilitate prediction of drug response for acute myeloid leukemia.}, journal = {iScience}, volume = {27}, number = {9}, pages = {110755}, pmid = {39280607}, issn = {2589-0042}, support = {R01 CA270210/CA/NCI NIH HHS/United States ; }, abstract = {Acute myeloid leukemia (AML) is a highly aggressive and heterogeneous disease, underscoring the need for improved therapeutic options and methods to optimally predict responses. With the wealth of available data resources, including clinical features, multiomics analysis, and ex vivo drug screening from AML patients, development of drug response prediction models has become feasible. Knowledge graphs (KGs) embed the relationships between different entities or features, allowing for explanation of a wide breadth of drug sensitivity and resistance mechanisms. We designed AML drug response prediction models guided by KGs. Our models included engineered features, relative gene expression between marker genes for each drug and regulators (e.g., transcription factors). We identified relative gene expression of FGD4-MIR4519, NPC2-GATA2, and BCL2-NFKB2 as predictive features for venetoclax ex vivo drug response. The KG-guided models provided high accuracy in independent test sets, overcame potential platform batch effects, and provided candidate drug sensitivity biomarkers for further validation.}, }
@article {pmid39279497, year = {2024}, author = {Smoljo, T and Lalic, H and Dembitz, V and Tomic, B and Batinic, J and Vrhovac, R and Bedalov, A and Visnjic, D}, title = {Bone marrow stromal cells enhance differentiation of acute myeloid leukemia induced by pyrimidine synthesis inhibitors.}, journal = {American journal of physiology. Cell physiology}, volume = {327}, number = {5}, pages = {C1202-C1218}, pmid = {39279497}, issn = {1522-1563}, support = {GA KK01.1.1.01.0007//EC | European Regional Development Fund (ERDF)/ ; International Award for Research in Leukaemia to Vilma Dembitz//Lady Tata Memorial Trust (LTMT)/ ; DOK-2018-01-9599//Hrvatska Zaklada za Znanost (HRZZ)/ ; R01 GM117446/GM/NIGMS NIH HHS/United States ; R01GM117446//Foundation for the National Institutes of Health (FNIH)/ ; IP-2022-10-9146//Hrvatska Zaklada za Znanost (HRZZ)/ ; DOK-2020-01-2873//Hrvatska Zaklada za Znanost (HRZZ)/ ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/pathology/metabolism/drug therapy ; *Mesenchymal Stem Cells/drug effects/metabolism/pathology ; Animals ; *Cell Differentiation/drug effects ; Mice ; *Aminoimidazole Carboxamide/analogs & derivatives/pharmacology ; *Pyrimidines/pharmacology ; *Ribonucleotides/pharmacology ; Dihydroorotate Dehydrogenase ; Cell Line, Tumor ; AMP-Activated Protein Kinases/metabolism ; Bone Marrow Cells/drug effects/metabolism/pathology ; Biphenyl Compounds ; Quinaldines ; }, abstract = {Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies characterized by differentiation arrest, high relapse rates, and poor survival. The bone marrow (BM) microenvironment is recognized as a critical mediator of drug resistance and a primary site responsible for AML relapse. Our previous study reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induces AML cell differentiation by inhibiting pyrimidine synthesis and activating Checkpoint kinase 1. Although the protective effect of BM stroma on leukemia cells in response to cytotoxic drugs is well-documented, its effect on AML differentiation remains less explored. In this study, we investigated the impact of stromal cell lines and primary mesenchymal stromal cells (MSCs) on AML cell line differentiation triggered by AICAr and brequinar, a known dihydroorotate dehydrogenase (DHODH) inhibitor. Our findings indicate that the mouse MS-5 stromal cell line, known for its cytoprotective effects, does not inhibit AML cell differentiation induced by pyrimidine synthesis inhibitors. Interestingly, AICAr caused morphological changes and growth arrest in MS-5 stromal cells via an AMP-activated protein kinase (AMPK)-dependent pathway. Human stromal cell lines HS-5 and HS-27, as well as primary MSCs isolated from patient bone marrow, were superior in promoting AML differentiation compared with mouse cells in response to AICAr and brequinar, with the inhibitors not significantly affecting the stromal cells themselves. In conclusion, our study highlights the supportive role of human BM MSCs in enhancing the differentiation effects of pyrimidine synthesis inhibitors on AML cells, suggesting that AML treatment strategies focusing on differentiation rather than cell killing may be successful in clinical settings.NEW & NOTEWORTHY This study is the first to demonstrate that human stromal cell lines and primary mesenchymal stromal cells from patients enhance the in vitro differentiation of acute myeloid leukemia (AML) cells induced by pyrimidine synthesis inhibitors, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), and brequinar. Furthermore, this is the first report to show that AICAr affects mouse bone marrow stromal cells by activating AMP-activated protein kinase (AMPK) and that human stromal cells are superior to mouse cells for testing the effects of drugs on AML differentiation.}, }
@article {pmid39279226, year = {2024}, author = {Tandon, PS and Gabert, T and Kuhn, M and Tran, N and Ola, C and Sullivan, E and Zhou, C and Stein, M and Mendoza, JA and Sasser, T and Gonzalez, E}, title = {Modernizing behavioral parent training program for ADHD with mHealth strategies, telehealth groups, and health behavior curriculum: a randomized pilot trial.}, journal = {Journal of pediatric psychology}, volume = {49}, number = {9}, pages = {664-675}, pmid = {39279226}, issn = {1465-735X}, support = {R33 AT010041/AT/NCCIH NIH HHS/United States ; R33AT010041/NH/NIH HHS/United States ; }, mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity/therapy ; Pilot Projects ; Child ; Male ; Female ; *Telemedicine ; *Parents/education ; *Health Behavior ; Feasibility Studies ; Curriculum ; Behavior Therapy/methods ; Adult ; }, abstract = {OBJECTIVE: Parent behavior management training (BMT) is an evidence-based yet underutilized tool to treat children with ADHD and address related health disparities. This pilot study investigated the acceptability and feasibility of a novel, health behavior-, and technology-adapted BMT (LEAP) vs. standard BMT.
METHODS: The weekly 9-session LEAP telemedicine group program is based on a standard BMT curriculum enhanced with strategies for supporting optimal child sleep, problematic media use (PMU), and physical activity, including wrist-worn activity trackers. Children ages 6-10 years with ADHD and their caregivers were randomized to LEAP or standard BMT. Acceptability and feasibility were tracked. Caregivers completed standardized measures, and children wore hip-worn accelerometers for 1 week at baseline, postintervention (10 weeks), and follow-up (20 weeks).
RESULTS: 84 parent/child dyads were randomized to LEAP or standard BMT, with high and comparable acceptability and feasibility. Both treatment groups demonstrated decreased ADHD symptoms and improved executive functions postintervention (p < .0001), maintained at follow-up. Average accelerometer-measured MVPA decreased and sleep duration remained unchanged, while PMU and bedtime resistance improved for both groups.
CONCLUSIONS: LEAP is highly feasible and acceptable, and yielded similar initial clinical and health behavior improvements to standard BMT. Innovative and targeted supports are needed to promote healthy behaviors in children with ADHD.}, }
@article {pmid39278553, year = {2024}, author = {Miranda, MA and Tsalatsanis, A and Trotter, JR and Arnold, DE and Squire, JD and Kidd, S and Parikh, S and Marsh, RA and Griffith, LM and Mallhi, K and Chellapandian, D and Lim, SS and Grunebaum, E and Sullivan, KE and Newburger, PE and Dinauer, MC and Cowan, MJ and Dvorak, CC and Haddad, E and Kohn, DB and Notarangelo, LD and Pai, SY and Puck, JM and Pulsipher, MA and Torgerson, TR and Malech, HL and Kang, EM and Morton, FB and Leiding, JW}, title = {High symptom burden in female X-linked chronic granulomatous disease carriers.}, journal = {Clinical immunology (Orlando, Fla.)}, volume = {268}, number = {}, pages = {110364}, doi = {10.1016/j.clim.2024.110364}, pmid = {39278553}, issn = {1521-7035}, }
@article {pmid39276915, year = {2024}, author = {Haab, B and Qian, L and Staal, B and Jain, M and Fahrmann, J and Worthington, C and Prosser, D and Velokokhatnaya, L and Lopez, C and Tang, R and Hurd, MW and Natarajan, G and Kumar, S and Smith, L and Hanash, S and Batra, SK and Maitra, A and Lokshin, A and Huang, Y and Brand, RE}, title = {A rigorous multi-laboratory study of known PDAC biomarkers identifies increased sensitivity and specificity over CA19-9 alone.}, journal = {Cancer letters}, volume = {604}, number = {}, pages = {217245}, doi = {10.1016/j.canlet.2024.217245}, pmid = {39276915}, issn = {1872-7980}, mesh = {Humans ; *Biomarkers, Tumor/blood ; *Carcinoma, Pancreatic Ductal/blood/diagnosis/pathology ; *Pancreatic Neoplasms/blood/diagnosis/pathology ; Case-Control Studies ; Female ; Male ; *CA-19-9 Antigen/blood ; Middle Aged ; Sensitivity and Specificity ; Aged ; Antigens, Tumor-Associated, Carbohydrate/blood ; }, abstract = {A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial.}, }
@article {pmid39276235, year = {2024}, author = {Miles, RC and Chou, SH and Lamb, LR and Narayan, A and Tran, NT and Lee, JM}, title = {Framework for Successful Integration of Health Services Research Into a Breast Imaging Career.}, journal = {Journal of breast imaging}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbi/wbae042}, pmid = {39276235}, issn = {2631-6129}, abstract = {Health services research (HSR) is a multidisciplinary field of inquiry that examines how health care is structured, providing valuable data on health care outcomes and delivery. Over the past few decades, a shift in the U.S. health care system toward value-based care has placed a priority on health services topics. Health services research has been central to the evolution of breast imaging over this period, with increased emphasis placed on the following: (1) design of appropriate-use criteria for imaging services; (2) determination of cost-effectiveness of imaging protocols and screening regimens guiding policy; and (3) evaluation of policy related to reimbursement for diagnostic imaging and image-guided procedures. Examples of HSR topics that can be applied directly to breast imaging include evaluation of health care availability and accessibility, analysis of health care use patterns, exploration of patient preferences, assessment of technological innovation, development and implementation of clinical practice guidelines and screening strategies, and examination of health care organization and delivery models. Breast imaging radiologists who perform HSR are uniquely positioned to advocate for patients, to promote transformative health care interventions, and to influence policy changes and public health initiatives in breast imaging through analysis of health care data and translation of their research findings. In this Training and Professional Development article, we aim to provide practical approaches to explore interest in HSR and to describe a framework for successful integration of HSR into a breast imaging career.}, }
@article {pmid39271284, year = {2024}, author = {Grover, S and Court, L and Amoo-Mitchual, S and Longo, J and Rodin, D and Scott, AA and Lievens, Y and Yap, ML and Abdel-Wahab, M and Lee, P and Harsdorf, E and Khader, J and Jia, X and Dosanjh, M and Elzawawy, A and Ige, T and Pomper, M and Pistenmaa, D and Hardenbergh, P and Petereit, DG and Sargent, M and Cina, K and Li, B and Anacak, Y and Mayo, C and Prattipati, S and Lasebikan, N and Rendle, K and O'Brien, D and Wendling, E and Coleman, CN}, title = {Global Workforce and Access: Demand, Education, Quality.}, journal = {Seminars in radiation oncology}, volume = {34}, number = {4}, pages = {477-493}, doi = {10.1016/j.semradonc.2024.07.003}, pmid = {39271284}, issn = {1532-9461}, mesh = {Humans ; *Health Services Accessibility ; *Radiation Oncology ; *Neoplasms/radiotherapy ; Global Health ; Developing Countries ; Healthcare Disparities ; Health Services Needs and Demand ; }, abstract = {There has long existed a substantial disparity in access to radiotherapy globally. This issue has only been exacerbated as the growing disparity of cancer incidence between high-income countries (HIC) and low and middle-income countries (LMICs) widens, with a pronounced increase in cancer cases in LMICs. Even within HICs, iniquities within local communities may lead to a lack of access to care. Due to these trends, it is imperative to find solutions to narrow global disparities. This requires the engagement of a diverse cohort of stakeholders, including working professionals, non-governmental organizations, nonprofits, professional societies, academic and training institutions, and industry. This review brings together a diverse group of experts to highlight critical areas that could help reduce the current global disparities in radiation oncology. Advancements in technology and treatment, such as artificial intelligence, brachytherapy, hypofractionation, and digital networks, in combination with implementation science and novel funding mechanisms, offer means for increasing access to care and education globally. Common themes across sections reveal how utilizing these new innovations and strengthening collaborative efforts among stakeholders can help improve access to care globally while setting the framework for the next generation of innovations.}, }
@article {pmid39266311, year = {2024}, author = {Smibert, OC and Trubiano, JA and Kwong, JC and Markey, KA and Slavin, MA}, title = {Protocol for a clinically annotated biorepository of samples from Australian immune-compromised patients to investigate the host-microbiome interaction.}, journal = {BMJ open}, volume = {14}, number = {9}, pages = {e085504}, pmid = {39266311}, issn = {2044-6055}, mesh = {Humans ; Australia ; *Gastrointestinal Microbiome ; Host Microbial Interactions/immunology ; Biological Specimen Banks ; Prospective Studies ; Research Design ; Specimen Handling/methods ; }, abstract = {INTRODUCTION: The human gut microbiota has the potential to modulate the outcomes of several human diseases. This effect is likely to be mediated through interaction with the host immune system. This protocol details the establishment of a biorepository of clinically annotated samples, which we will use to explore correlations between the gut microbiota and the immune system of immune-compromised patients. We aim to identify microbiome-related risk factors for adverse outcomes.
METHODS AND ANALYSES: This is a protocol for the development of a biorepository of clinically annotated samples collected prospectively across three centres in Melbourne, Australia. Participants will be recruited across the following clinical streams: (1) acute leukaemia and allogeneic stem cell transplant; (2) end-stage liver disease and liver transplant; (3) patients receiving any cancer immunotherapies (eg, chimeric antigen receptor therapy); (4) deceased organ donors and (5) healthy adult controls. Participants will be asked to provide paired peripheral blood and microbiota samples (stool and saliva) at either (1) single time point for healthy controls and deceased organ donors or (2) longitudinally over multiple prespecified or event-driven time points for the remaining cohorts. Sampling of fluid from bronchoalveolar lavage and colonoscopy or biopsy of tissues undertaken during routine care will also be performed.
ETHICS AND DISSEMINATION: Ethical approval has been obtained from the relevant local ethics committee (The Royal Melbourne Hospital Human Research Ethics Committee). The results of this study will be disseminated by various scientific platforms including social media, international presentations and publication in peer-reviewed journals.
TRIAL REGISTRATION NUMBER: ACTRN12623001105639. Date registered 20 October 2023.}, }
@article {pmid39266299, year = {2024}, author = {Park, SH and Tsuzuki, S and Contino, KF and Ollodart, J and Eber, MR and Yu, Y and Steele, LR and Inaba, H and Kamata, Y and Kimura, T and Coleman, I and Nelson, PS and Muñoz-Islas, E and Jiménez-Andrade, JM and Martin, TJ and Mackenzie, KD and Stratton, JR and Hsu, FC and Peters, CM and Shiozawa, Y}, title = {Crosstalk between bone metastatic cancer cells and sensory nerves in bone metastatic progression.}, journal = {Life science alliance}, volume = {7}, number = {12}, pages = {}, pmid = {39266299}, issn = {2575-1077}, support = {R21 AR078366/AR/NIAMS NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; P30 CA012197/CA/NCI NIH HHS/United States ; R01 CA238888/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Bone Neoplasms/secondary/metabolism ; Humans ; Mice ; *Calcitonin Gene-Related Peptide/metabolism ; *Disease Progression ; *Sensory Receptor Cells/metabolism ; *Cell Proliferation ; Cell Line, Tumor ; Calcitonin Receptor-Like Protein/metabolism/genetics ; Female ; Male ; Signal Transduction ; }, abstract = {Although the role of peripheral nerves in cancer progression has been appreciated, little is known regarding cancer/sensory nerve crosstalk and its contribution to bone metastasis and associated pain. In this study, we revealed that the cancer/sensory nerve crosstalk plays a crucial role in bone metastatic progression. We found that (i) periosteal sensory nerves expressing calcitonin gene-related peptide (CGRP) are enriched in mice with bone metastasis; (ii) cancer patients with bone metastasis have elevated CGRP serum levels; (iii) bone metastatic patient tumor samples express elevated calcitonin receptor-like receptor (CRLR, a CGRP receptor component); (iv) higher CRLR levels in cancer patients are negatively correlated with recurrence-free survival; (v) CGRP induces cancer cell proliferation through the CRLR/p38/HSP27 pathway; and (vi) blocking sensory neuron-derived CGRP reduces cancer cell proliferation in vitro and bone metastatic progression in vivo. This suggests that CGRP-expressing sensory nerves are involved in bone metastatic progression and that the CGRP/CRLR axis may serve as a potential therapeutic target for bone metastasis.}, }
@article {pmid39265260, year = {2024}, author = {Bakaloudi, DR and Koehne, EL and Diamantopoulos, LN and Holt, SK and Sekar, RR and Ghali, F and Vakar-Lopez, F and Nyame, YA and Psutka, SP and Gore, JL and de la Calle, CM and Lin, DW and Schade, GR and Liao, JJ and Hsieh, AC and Yezefski, T and Hawley, JE and Yu, EY and Montgomery, RB and Grivas, P and Wright, JL}, title = {Small Cell Bladder Cancer: Treatment Patterns for Local Disease and Associated Outcomes. A Retrospective Cohort Study.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {6}, pages = {102208}, doi = {10.1016/j.clgc.2024.102208}, pmid = {39265260}, issn = {1938-0682}, abstract = {BACKGROUND: Small cell bladder cancer (SCBC) is a rare histologic subtype with relative paucity of data regarding treatment response and outcomes. We reviewed 2 databases to compare outcomes in patients with localized SCBC treated with cystectomy versus concurrent chemoradiotherapy (CCRT). We hypothesized that survival would be similar with these therapy approaches.
METHODS: We retrospectively reviewed our institutional and SEER-Medicare databases to identify patients with SCBC. Overall survival (OS) was determined from the date of diagnosis to last follow-up/death. For those with nonmetastatic disease, a multivariate Cox analysis was used to compare locoregional therapy with neoadjuvant chemotherapy (NAC) + cystectomy versus CCRT.
RESULTS: We identified 53 patients in our institutional database and 1166 patients in SEER-Medicare with localized SCBC. Median OS (mOS) with NAC + cystectomy was 46 months (95% CI, 21-72) and 45 months (95% CI, 0-104) in the institutional and SEER-Medicare databases, respectively, whereas mOS with CCRT was 26 months (95% CI, 5-47) and 23 months (95% CI, 18-28) in the 2 series, respectively. In multivariate analysis, NAC followed by cystectomy was associated with an approximately 30% reduction in mortality compared to CCRT in both institutional and national databases but did not reach statistical significance (Institution HR 0.71, 95% CI, 0.22-2.4, P = .58; SEER HR 0.73, 95% CI, 0.49-1.08; P = .11).
CONCLUSIONS: SCBC is very aggressive with limited survival observed in our institutional and SEER-Medicare datasets regardless of locoregional therapy used. There is an unmet need to define the optimal locoregional therapy for nonmetastatic stage and identify novel therapeutic targets.}, }
@article {pmid39264595, year = {2024}, author = {Robbins, HA and Feng, X and Etzioni, R}, title = {Cancer Stage vs Mortality End Points in Randomized Clinical Trials of Cancer Screening.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2024.16365}, pmid = {39264595}, issn = {1538-3598}, }
@article {pmid39264541, year = {2024}, author = {Ratnayake, A and Hernandez, JH and Justman, J and Farley, JE and Hirsch-Moverman, Y and Ho, K and Mayer, S and Oluyomi, A and Sobieszczyk, ME and Swaminathan, S and Skalland, T and Tapsoba, JD and , and Kissinger, PJ}, title = {Vaccine Hesitancy at Nine Community Sites Across the United States, Early in COVID-19 Vaccine Rollout.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {39264541}, issn = {2196-8837}, support = {UM1AI068619//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; }, abstract = {BACKGROUND: Vaccine hesitancy has been a significant concern throughout the COVID-19 pandemic. Vaccine hesitancy can be attributed to lack of confidence in vaccines, complacency about the health threat, or lack of convenience of vaccination. To date, few studies have used methods designed to include populations underrepresented in research when identifying factors associated with vaccine hesitancy.
METHODS: Between January and July 2021, potential participants were recruited from community venues selected through time-location sampling in 15 defined communities in the United States. Study staff administered a questionnaire on demographics, COVID-19 behaviors and attitudes, and vaccination status or intention to consenting individuals. Vaccine hesitancy was analyzed among those age 18 years and older from nine of the 15 sites and was defined as self-reported neutral, unlikely, or very unlikely vaccine intention. Logistic regression modeling, adjusted for site, identified factors associated with vaccine hesitancy.
RESULTS: Among 11,559 individuals, vaccine hesitancy by site ranged from 8.7 to 31.1%. Vaccine hesitancy was associated with being Black compared to White, being White compared to Asian, younger age, unstable housing, being unemployed, lower income, having a disability, providing care in home, not reporting inability to visit sick or elderly relatives during the pandemic, not reporting increased anxiety during the pandemic, and not spending more time with loved ones during the pandemic.
CONCLUSIONS: In these selected US communities, early in vaccine rollout, there were significant racial disparities in vaccine hesitancy. Additionally, individuals who were more marginalized due to their socioeconomic status were more likely to report vaccine hesitancy. Vaccine campaigns should make efforts to remove barriers to vaccination, by improving convenience.}, }
@article {pmid39261482, year = {2024}, author = {Zhang, B and Fong, Y and Fintzi, J and Chu, E and Janes, HE and Kenny, A and Carone, M and Benkeser, D and van der Laan, LWP and Deng, W and Zhou, H and Wang, X and Lu, Y and Yu, C and Borate, B and Chen, H and Reeder, I and Carpp, LN and Houchens, CR and Martins, K and Jayashankar, L and Huynh, C and Fichtenbaum, CJ and Kalams, S and Gay, CL and Andrasik, MP and Kublin, JG and Corey, L and Neuzil, KM and Priddy, F and Das, R and Girard, B and El Sahly, HM and Baden, LR and Jones, T and Donis, RO and Koup, RA and Gilbert, PB and Follmann, D and , and , and , and , }, title = {Omicron COVID-19 immune correlates analysis of a third dose of mRNA-1273 in the COVE trial.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {7954}, pmid = {39261482}, issn = {2041-1723}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/immunology/virology/prevention & control ; *SARS-CoV-2/immunology ; *Antibodies, Neutralizing/immunology ; *Antibodies, Viral/immunology/blood ; *Spike Glycoprotein, Coronavirus/immunology ; *Immunization, Secondary ; *2019-nCoV Vaccine mRNA-1273/administration & dosage/immunology ; COVID-19 Vaccines/immunology/administration & dosage ; Female ; Male ; Adult ; Vaccine Efficacy ; }, abstract = {In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.}, }
@article {pmid39260945, year = {2024}, author = {Barta, JA and Mazzone, PJ and Nair, VS}, title = {Multi-Cancer and Single-Cancer Early Detection Testing: Opportunities and Challenges.}, journal = {Chest}, volume = {166}, number = {3}, pages = {425-428}, doi = {10.1016/j.chest.2024.03.044}, pmid = {39260945}, issn = {1931-3543}, mesh = {Humans ; *Early Detection of Cancer/methods ; *Neoplasms/diagnosis ; Mass Screening/methods ; }, }
@article {pmid39260570, year = {2024}, author = {Kongtim, P and Vittayawacharin, P and Zou, J and Srour, S and Shaffer, B and Shapiro, RM and Varma, A and McGuirk, J and Dholaria, BR and McCurdy, SR and DeZern, AE and Bejanyan, N and Bashey, A and Furst, S and Castagna, L and Mariotti, J and Ruggeri, A and Bailen, R and Teshima, T and Xiao-Jun, H and Bonfim, C and Aung, F and Cao, K and Carpenter, PA and Hamadani, M and Askar, M and Fernandez-Vina, M and Girnita, A and Ciurea, SO}, title = {ASTCT Consensus Recommendations on Testing and Treatment of Patients with Donor-specific Anti-HLA Antibodies.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.09.005}, pmid = {39260570}, issn = {2666-6367}, abstract = {Donor-specific anti-HLA antibodies (DSA) are an important cause of engraftment failure and may negatively impact survival outcomes of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) using an HLA-mismatched allograft. The incidence of DSA varies across studies, depending on individual factors, detection or identification methods and thresholds considered clinically relevant. Although DSA testing by multiplex bead arrays remains semiquantitative, it has been widely adopted as a standard test in most transplant centers. Additional testing to determine risk of allograft rejection may include assays with HLA antigens in natural conformation, such as flow cytometric crossmatch, and/or antibody binding assays, such as C1q testing. Patients with low level of DSA (<2,000 mean fluorescence intensity; MFI) may not require treatment, while others with very high level of DSA (>20,000 MFI) may be at very high-risk for engraftment failure despite current therapies. By contrast, in patients with moderate or high level of DSA, desensitization therapy can successfully mitigate DSA levels and improve donor cell engraftment rate, with comparable outcomes to patients without DSA. Treatment is largely empirical and multimodal, involving the removal, neutralization, and blocking of antibodies, as well as inhibition of antibody production to prevent activation of the complement cascade. Desensitization protocols are based on accumulated multicenter experience, while prospective multicenter studies remain lacking. Most patients require a full intensity protocol that includes plasma exchange, while protocols relying only on rituximab and intravenous immunoglobulin may be sufficient for patients with lower DSA levels and negative C1q and/or flow cytometric crossmatch. Monitoring DSA levels before and after HSCT could guide preemptive treatment when high levels persist after stem cell infusion. This paper aims to standardize current evidence-based practice and formulate future directions to improve upon current knowledge and advance treatment for this relatively rare, but potentially serious complication in allogeneic HSCT recipients.}, }
@article {pmid39259414, year = {2024}, author = {Nuechterlein, N and Cimino, S and Shelbourn, A and Ha, V and Arora, S and Rajan, S and Shapiro, LG and Holland, EC and Aldape, K and McGranahan, T and Gilbert, MR and Cimino, PJ}, title = {HOXD12 defines an age-related aggressive subtype of oligodendroglioma.}, journal = {Acta neuropathologica}, volume = {148}, number = {1}, pages = {41}, pmid = {39259414}, issn = {1432-0533}, support = {DGE-1762114//National Science Foundation Graduate Research Fellowship Program/ ; Intramural Research Program/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Age Factors ; *Brain Neoplasms/genetics/pathology/metabolism ; DNA Methylation ; *Homeodomain Proteins/genetics/metabolism ; Mutation ; *Oligodendroglioma/genetics/pathology ; Transcription Factors/genetics/metabolism ; }, abstract = {Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e-5) and the CGGA (p = 0.03, p < 1e-3). HOXD12 gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (p < 1e-6, p < 0.001, p < 1e-3) and with older age and higher WHO grade in Capper et al. (p < 0.002, p = 0.014). In the TCGA, HOXD12 gene body hypermethylation and elevated expression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with HOXD12 gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.}, }
@article {pmid39259185, year = {2024}, author = {Kalia, SS and Boddicker, NJ and Yadav, S and Huang, H and Na, J and Hu, C and Ambrosone, CB and Yao, S and Haiman, CA and Chen, F and John, EM and Kurian, AW and Guo, B and Lindstrӧm, S and Auer, P and Lacey, JV and Neuhausen, SL and Martinez, ME and Sandler, DP and O'Brien, KM and Taylor, JA and Teras, LR and Hodge, JM and Lori, A and Bodelon, C and Trentham-Dietz, A and Burnside, ES and Vachon, CM and Winham, SJ and Goldgar, DE and Domchek, SM and Nathanson, KL and Weitzel, JN and Couch, FJ and Kraft, P}, title = {Development of a Breast Cancer Risk Prediction Model Integrating Monogenic, Polygenic, and Epidemiologic Risk.}, journal = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {33}, number = {11}, pages = {1490-1499}, pmid = {39259185}, issn = {1538-7755}, support = {//Breast Cancer Research Foundation (BCRF)/ ; P50CA116201//National Institutes of Health (NIH)/ ; R01CA192393//National Institutes of Health (NIH)/ ; Z01ES044005//National Institutes of Health (NIH)/ ; P50 CA116201/CA/NCI NIH HHS/United States ; R35 CA253187/CA/NCI NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; //American Cancer Society (ACS)/ ; R01 CA192393/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/genetics/epidemiology ; *Genetic Predisposition to Disease ; Middle Aged ; Case-Control Studies ; Risk Factors ; Risk Assessment/methods ; Multifactorial Inheritance ; Adult ; Aged ; Prospective Studies ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive, and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited.
METHODS: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium.
RESULTS: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population.
CONCLUSIONS: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification.
IMPACT: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.}, }
@article {pmid39258792, year = {2024}, author = {Anderson, AC and Ho, J and Hall, ET and Hannan, R and Liao, JJ and Louie, AV and Ma, TM and Psutka, SP and Rengan, R and Siva, S and Swaminath, A and Tachiki, L and Tang, C and Teh, BS and Tsai, J and Tykodi, SS and Weg, E and Zaorsky, NG and Lo, SS}, title = {Focal therapy for oligometastatic and oligoprogressive renal cell carcinoma: a narrative review.}, journal = {Future oncology (London, England)}, volume = {20}, number = {33}, pages = {2573-2588}, pmid = {39258792}, issn = {1744-8301}, mesh = {Humans ; *Carcinoma, Renal Cell/therapy/secondary/pathology ; *Kidney Neoplasms/therapy/pathology ; Radiosurgery/methods ; Disease Progression ; Neoplasm Metastasis ; Treatment Outcome ; Combined Modality Therapy/methods ; Disease Management ; }, abstract = {Metastatic renal cell carcinoma (RCC) can present with oligometastatic disease and/or develop oligoprogression following systemic therapy. Cytoreductive and focal metastasis-directed therapy options include resection, stereotactic ablative radiation and thermal ablation. Aggressive focal therapy may allow delay in initiation of or modification to systemic therapy and improve clinical outcomes. In this narrative review we synthesize current practice guidelines and prospective data on focal therapy management options and highlight future research. Patient selection and the choice of focal treatment techniques are controversial due to limited and heterogeneous data and patients may benefit from multidisciplinary evaluation. Prospective comparative trials with clearly defined inclusion criteria and relevant end points are needed to clarify the risks and benefits of different approaches.}, }
@article {pmid39257755, year = {2024}, author = {Gray, CN and Ashokkumar, M and Janssens, DH and Kirchherr, J and Allard, B and Hsieh, E and Hafer, TL and Archin, NM and Browne, EP and Emerman, M}, title = {Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39257755}, issn = {2692-8205}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R61 DA047023/DA/NIDA NIH HHS/United States ; R01 AI143381/AI/NIAID NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R56 AI170226/AI/NIAID NIH HHS/United States ; UM1 AI126619/AI/NIAID NIH HHS/United States ; }, abstract = {The latent HIV reservoir is a major barrier to HIV cure. Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor is appealing towards inducing HIV-1 reactivation. However, even this LRA combination needs improvement as it is inefficient at activating proviruses in cells from people living with HIV (PLWH). We performed a CRISPR screen in conjunction with AZD5582 & I-BET151 and identified a member of the Integrator complex as a target to improve this LRA combination, specifically Integrator complex subunit 12 (INTS12). Integrator functions as a genome-wide attenuator of transcription that acts on elongation through its RNA cleavage and phosphatase modules. Knockout of INTS12 improved latency reactivation at the transcriptional level and is more specific to the HIV-1 provirus than AZD5582 & I-BET151 treatment alone. We found that INTS12 is present on chromatin at the promoter of HIV and therefore its effect on HIV may be direct. Additionally, we observed more RNAPII in the gene body of HIV only with the combination of INTS12 knockout with AZD5582 & I-BET151, indicating that INTS12 induces a transcriptional elongation block to viral reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo. We also detected viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout suggesting that INTS12 prevents full-length HIV RNA production in primary T cells.}, }
@article {pmid39257746, year = {2024}, author = {Owens, K and Rahman, A and Bozic, I}, title = {Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39257746}, issn = {2692-8205}, support = {T32 AI118690/AI/NIAID NIH HHS/United States ; }, abstract = {The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can recapitulate tumor and CAR T-cell data from imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors, which have the lowest average tumor cell density. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.}, }
@article {pmid39255537, year = {2024}, author = {Triner, D and Graf, RP and Madison, RW and Gjoerup, O and Tukachinsky, H and Ross, JS and Quintanilha, JCF and Li, G and Cheng, HH and Pritchard, CC and Zurita, AJ and Qin, Q and Zhang, T and Agarwal, N and Reichert, ZR and Mateo, J and Cieslik, M and Morgan, TM}, title = {Durable benefit from poly(ADP-ribose) polymerase inhibitors in metastatic prostate cancer in routine practice: biomarker associations and implications for optimal clinical next-generation sequencing testing.}, journal = {ESMO open}, volume = {9}, number = {9}, pages = {103684}, pmid = {39255537}, issn = {2059-7029}, mesh = {Humans ; Male ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/pharmacology ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/pathology ; Aged ; *High-Throughput Nucleotide Sequencing/methods ; Biomarkers, Tumor/genetics ; BRCA2 Protein/genetics ; Middle Aged ; Circulating Tumor DNA/genetics ; Liquid Biopsy/methods ; BRCA1 Protein/genetics ; Neoplasm Metastasis ; }, abstract = {BACKGROUND: Controlled trials have consistently demonstrated the efficacy of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1 or BRCA2 alterations (BRCAalt). However, the reported efficacy of PARPi for alterations in other homologous recombination repair (HRR) genes is less consistent. We sought to evaluate the routine practice effectiveness of PARPi between and within these groups.
DESIGN: Patient-level data from a deidentified nationwide (USA-based) cancer clinico-genomic database between January 2011 and September 2023 were extracted. Patients with mCRPC and comprehensive genomic profiling by liquid biopsy [circulating tumor DNA (ctDNA)] or tissue (tumor) biopsy and who received single-agent PARPi were included and grouped by BRCAalt, ATMalt, other HRR, or no HRR. We further subcategorized BRCAalt into homozygous loss (BRCAloss) and all other deleterious BRCAalt (otherBRCAalt).
RESULTS: A total of 445 patients met inclusion criteria: 214 with tumor and 231 with ctDNA. BRCAalt had more favorable outcomes to PARPi compared with ATM, other HRR, and no HRR groups. Within the BRCAalt subgroup, compared with other BRCAalt, BRCAloss had a more favorable time to next treatment (median 9 versus 19.4 months, P = 0.005), time to treatment discontinuation (median 8 versus 14 months, P = 0.006), and routine practice overall survival (median 14.7 versus 19.4 months, P = 0.016). Tumor BRCAloss prevalence (3.1%) was similar to ctDNA prevalence in liquid biopsy specimens with high tumor fraction (>20%). BRCAloss was not detected in orthogonal germline testing.
CONCLUSIONS: PARPi routine practice effectiveness between groups mirrors prospective trials. Within the BRCAalt group, BRCAloss had the best outcomes. Unless the ctDNA tumor fraction is very high, somatic tissue testing (archival or metastatic) should be prioritized to identify patients who may benefit most from PARPi. When tissue testing is not clinically feasible, sufficient ctDNA tumor fraction levels for detection are enriched at clinical timepoints associated with tumor progression.}, }
@article {pmid39255440, year = {2024}, author = {Barata, P and Tangen, C and Plets, M and Thompson, IM and Narayan, V and George, DJ and Heng, DYC and Shuch, B and Stein, M and Gulati, S and Tretiakova, M and Tripathi, A and Bjarnason, GA and Humphrey, P and Adeniran, A and Vaishampayan, U and Alva, A and Zhang, T and Cole, S and Lara, PN and Lerner, SP and Balzer-Haas, N and Pal, SK}, title = {Final Overall Survival Analysis of S1500: A Randomized, Phase II Study Comparing Sunitinib With Cabozantinib, Crizotinib, and Savolitinib in Advanced Papillary Renal Cell Carcinoma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {42}, number = {33}, pages = {3911-3916}, doi = {10.1200/JCO.24.00767}, pmid = {39255440}, issn = {1527-7755}, mesh = {Humans ; *Sunitinib/therapeutic use ; *Pyridines/therapeutic use ; *Carcinoma, Renal Cell/drug therapy/mortality/pathology ; *Kidney Neoplasms/drug therapy/mortality/pathology ; *Anilides/therapeutic use ; Male ; Female ; Middle Aged ; Aged ; *Crizotinib/therapeutic use ; Adult ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Triazines/therapeutic use/adverse effects ; Progression-Free Survival ; Aged, 80 and over ; Pyrazines ; }, abstract = {Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Mesenchymal-epithelial transition (MET) signaling pathway plays a role in the pathogenesis of selected patients with papillary renal cell carcinoma (PRCC). In the phase II PAPMET trial (ClinicalTrials.gov identifier: NCT02761057), cabozantinib significantly prolonged progression-free survival and improved objective response rate compared with sunitinib in patients with advanced PRCC. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized phase II, open-label trial, 147 patients with advanced PRCC who have received up to one previous therapy (excluding vascular endothelial growth factor-directed agents) were assigned to sunitinib, cabozantinib, crizotinib, or savolitinib. Ultimately, savolitinib and crizotinib arms were closed because of futility. With a median follow-up of 17.5 months, the median OS was 21.5 months (95% CI, 12.0 to 28.1) with cabozantinib and 17.3 months (95% CI, 12.8 to 21.8) with sunitinib (hazard ratio, 0.83; 95% CI, 0.51 to 1.36; P = .46). The OS landmark estimates for cabozantinib and sunitinib were 50% versus 39% at 24 months and 32% versus 28% at 36 months. In conclusion, we observed no significant difference in OS across treatment arms. Although cabozantinib represents a well-supported option for advanced PRCC, the lack of survival benefit underscores the need to develop novel therapies for this disease.}, }
@article {pmid39255368, year = {2024}, author = {Li, W and Li, R and Feng, Z and Ning, J and , }, title = {Dynamic and concordance-assisted learning for risk stratification with application to Alzheimer's disease.}, journal = {Biostatistics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/biostatistics/kxae036}, pmid = {39255368}, issn = {1468-4357}, support = {U24 CA230144/CA/NCI NIH HHS/United States ; R01CA269696/NH/NIH HHS/United States ; }, abstract = {Dynamic prediction models capable of retaining accuracy by evolving over time could play a significant role for monitoring disease progression in clinical practice. In biomedical studies with long-term follow up, participants are often monitored through periodic clinical visits with repeat measurements until an occurrence of the event of interest (e.g. disease onset) or the study end. Acknowledging the dynamic nature of disease risk and clinical information contained in the longitudinal markers, we propose an innovative concordance-assisted learning algorithm to derive a real-time risk stratification score. The proposed approach bypasses the need to fit regression models, such as joint models of the longitudinal markers and time-to-event outcome, and hence enjoys the desirable property of model robustness. Simulation studies confirmed that the proposed method has satisfactory performance in dynamically monitoring the risk of developing disease and differentiating high-risk and low-risk population over time. We apply the proposed method to the Alzheimer's Disease Neuroimaging Initiative data and develop a dynamic risk score of Alzheimer's Disease for patients with mild cognitive impairment using multiple longitudinal markers and baseline prognostic factors.}, }
@article {pmid39255259, year = {2024}, author = {Iwu, CD and Cox, SN and Sohlberg, SL and Kim, AE and Logue, J and Han, PD and Sibley, TR and Ilcisin, M and Fay, KA and Lee, J and McCulloch, DJ and Wang, Y and Boeckh, M and Englund, JA and Starita, LM and Hajat, A and Chu, HY}, title = {"I probably shouldn't go in today": Inequitable access to paid sick leave and its impacts on health behaviors during the emergence of COVID-19 in the Seattle area.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0307734}, pmid = {39255259}, issn = {1932-6203}, support = {R01 AG060011/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/epidemiology ; Female ; Male ; Adult ; *Sick Leave/statistics & numerical data/economics ; Middle Aged ; Washington/epidemiology ; Health Behavior ; SARS-CoV-2 ; Socioeconomic Factors ; Income ; Young Adult ; Surveys and Questionnaires ; Adolescent ; }, abstract = {This study examines inequities in access to paid sick leave (PSL) by race/ethnicity, income, and sex and the role of PSL access on leave-taking and care-seeking behaviors among Seattle-area workers in the months leading up to and during the emergence of COVID-19 in the region. Survey responses were collected online and in-person from individuals experiencing acute respiratory illness symptoms between November 2019 and March 2020 as part of a community-based respiratory viral surveillance study. Chi-square tests and log-binomial models were used to assess the association between PSL access and various socioeconomic indicators. A total of 66.6% (n = 2,276) respondents reported access to PSL. Proportionally, access to PSL was highest in respondents identifying as Asian (70.5%), followed by White (68.7%), Latine (58.4%), Multiracial (57.1%), Black (47.1%), and Other (43.1%). Access to PSL increased with household income. Eighty three percent of high-income respondents reported access compared to 52.9% of low-income households. Only 23.3% of the lowest-income households reported access to PSL. Fewer females (65.2%) than males (70.7%) reported access to PSL. Access to PSL is inequitably distributed across income, race/ethnicity, and sex. This study reinforces the vast body of knowledge on how socioeconomic inequalities increase individual and community-level vulnerability to the impacts of infectious disease outbreaks. It also supports the role of labor and economic policy in mitigating (or exacerbating) these impacts. Exemplified by the COVID-19 pandemic, universal access to PSL, especially for marginalized populations, benefits all.}, }
@article {pmid39253895, year = {2024}, author = {Naresh, KN}, title = {Understanding splenic B-cell lymphoma/leukaemia with prominent nucleoli: Diagnosis, underpinnings for disease classification and future directions.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.19754}, pmid = {39253895}, issn = {1365-2141}, abstract = {The 5th edition of the WHO classification of haematolymphoid tumours (WHO-HAEM5) introduced a new category, splenic B-cell lymphoma/leukaemia with prominent nucleoli (SBLPN). The diagnostic entity B-cell prolymphocytic leukaemia (B-PLL) has been discontinued and the category of hairy cell leukaemia variant (HCLv) has been conceptually reframed. B-PLL and HCLv diagnoses were uncommon. Overlap existed between B-PLL and other indolent lymphomas like chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). HCLv lacked consistent cytomorphological, immunophenotypic and genetic features. To address these issues, the WHO-HAEM5 classification has introduced SBLPN to serve as a temporary holding ground for entities that do not neatly fit into the existing classification. Cases previously classified as CD5-negative B-PLL and HCLv fall under the SBLPN category. Some splenic marginal zone lymphoma and splenic diffuse red pulp small B-cell lymphoma cases with higher number of medium or large nucleolated B cells would also be classified as SBLPN under the WHO-HAEM5. This review explores the rationale for discontinuing B-PLL and HCLv diagnoses. It then examines the concept of SBLPN, offers practical guidance for diagnosis and discusses future directions in classifying splenic B-cell lymphomas.}, }
@article {pmid39253833, year = {2024}, author = {Kaplan, RC and Chan, KCG}, title = {Unequal Management and Outcomes Among Asian American Patients With Coronary Heart Disease.}, journal = {Circulation. Cardiovascular quality and outcomes}, volume = {17}, number = {10}, pages = {e011440}, doi = {10.1161/CIRCOUTCOMES.124.011440}, pmid = {39253833}, issn = {1941-7705}, mesh = {Humans ; *Asian ; *Healthcare Disparities/ethnology ; United States/epidemiology ; *Coronary Disease/ethnology/therapy/diagnosis/mortality/epidemiology ; Treatment Outcome ; Male ; Female ; Aged ; Middle Aged ; Risk Assessment ; Race Factors ; Risk Factors ; }, }
@article {pmid39253641, year = {2024}, author = {Brusselmans, M and Carvalho, LM and Hong, SL and Gao, J and Matsen, FA and Rambaut, A and Lemey, P and Suchard, MA and Dudas, G and Baele, G}, title = {On the importance of assessing topological convergence in Bayesian phylogenetic inference.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {39253641}, issn = {2331-8422}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 AI153044/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; }, abstract = {Modern phylogenetics research is often performed within a Bayesian framework, using sampling algorithms such as Markov chain Monte Carlo (MCMC) to approximate the posterior distribution. These algorithms require careful evaluation of the quality of the generated samples. Within the field of phylogenetics, one frequently adopted diagnostic approach is to evaluate the effective sample size (ESS) and to investigate trace graphs of the sampled parameters. A major limitation of these approaches is that they are developed for continuous parameters and therefore incompatible with a crucial parameter in these inferences: the tree topology. Several recent advancements have aimed at extending these diagnostics to topological space. In this reflection paper, we present two case studies - one on Ebola virus and one on HIV - illustrating how these topological diagnostics can contain information not found in standard diagnostics, and how decisions regarding which of these diagnostics to compute can impact inferences regarding MCMC convergence and mixing. Our results show the importance of running multiple replicate analyses and of carefully assessing topological convergence using the output of these replicate analyses. To this end, we illustrate different ways of assessing and visualizing the topological convergence of these replicates. Given the major importance of detecting convergence and mixing issues in Bayesian phylogenetic analyses, the lack of a unified approach to this problem warrants further action, especially now that additional tools are becoming available to researchers.}, }
@article {pmid39253501, year = {2024}, author = {Nanduri, S and Black, A and Bedford, T and Huddleston, J}, title = {Dimensionality reduction distills complex evolutionary relationships in seasonal influenza and SARS-CoV-2.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {39253501}, issn = {2692-8205}, support = {75N93021C00015/AI/NIAID NIH HHS/United States ; F31 AI140714/AI/NIAID NIH HHS/United States ; INV-018979/GATES/Bill & Melinda Gates Foundation/United States ; R35 GM119774/GM/NIGMS NIH HHS/United States ; }, abstract = {Public health researchers and practitioners commonly infer phylogenies from viral genome sequences to understand transmission dynamics and identify clusters of genetically-related samples. However, viruses that reassort or recombine violate phylogenetic assumptions and require more sophisticated methods. Even when phylogenies are appropriate, they can be unnecessary or difficult to interpret without specialty knowledge. For example, pairwise distances between sequences can be enough to identify clusters of related samples or assign new samples to existing phylogenetic clusters. In this work, we tested whether dimensionality reduction methods could capture known genetic groups within two human pathogenic viruses that cause substantial human morbidity and mortality and frequently reassort or recombine, respectively: seasonal influenza A/H3N2 and SARS-CoV-2. We applied principal component analysis (PCA), multidimensional scaling (MDS), t-distributed stochastic neighbor embedding (t-SNE), and uniform manifold approximation and projection (UMAP) to sequences with well-defined phylogenetic clades and either reassortment (H3N2) or recombination (SARS-CoV-2). For each low-dimensional embedding of sequences, we calculated the correlation between pairwise genetic and Euclidean distances in the embedding and applied a hierarchical clustering method to identify clusters in the embedding. We measured the accuracy of clusters compared to previously defined phylogenetic clades, reassortment clusters, or recombinant lineages. We found that MDS embeddings accurately represented pairwise genetic distances including the intermediate placement of recombinant SARS-CoV-2 lineages between parental lineages. Clusters from t-SNE embeddings accurately recapitulated known phylogenetic clades, H3N2 reassortment groups, and SARS-CoV-2 recombinant lineages. We show that simple statistical methods without a biological model can accurately represent known genetic relationships for relevant human pathogenic viruses. Our open source implementation of these methods for analysis of viral genome sequences can be easily applied when phylogenetic methods are either unnecessary or inappropriate.}, }
@article {pmid39251835, year = {2024}, author = {Vo, P and Srinivasan, R and Purev, E and McDuffee, E and Worthy, T and Shalabi, R and Wood, K and Wells, B and Reger, R and Stroncek, D and Geller, N and Aue, G and Tian, X and Childs, R}, title = {Durable remission of refractory and advanced stage mycosis fungoides/sezary syndrome utilizing an "outpatient" alemtuzumab, fludarabine-based reduced intensity allogeneic hematopoietic cell transplantation.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {39251835}, issn = {1476-5365}, }
@article {pmid39251462, year = {2024}, author = {Ronsley, R and Bertrand, KC and Song, EZ and Timpanaro, A and Choe, M and Tlais, D and Vitanza, NA and Park, JR}, title = {CAR T cell therapy for pediatric central nervous system tumors: a review of the literature and current North American trials.}, journal = {Cancer metastasis reviews}, volume = {43}, number = {4}, pages = {1205-1216}, pmid = {39251462}, issn = {1573-7233}, mesh = {Humans ; Child ; *Immunotherapy, Adoptive/methods ; *Central Nervous System Neoplasms/therapy/immunology ; *Receptors, Chimeric Antigen/immunology ; Clinical Trials as Topic ; Animals ; T-Lymphocytes/immunology ; }, abstract = {Central nervous system (CNS) tumors are the leading cause of cancer-related death in children. Typical therapy for CNS tumors in children involves a combination of surgery, radiation, and chemotherapy. While upfront therapy is effective for many high-grade tumors, therapy at the time of relapse remains limited. Furthermore, for diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG), there are currently no curative therapies. Chimeric antigen receptor T (CAR T) cell therapy is a promising novel treatment avenue for these tumors. Here, we review the preclinical evidence for CAR T cell use in pediatric brain tumors, the preliminary clinical experience of CNS CAR T cell trials, toxicity associated with systemic and locoregional CAR T cell therapy for CNS tumors, challenges in disease response evaluation with CAR T cell therapy, and the knowledge gained from correlative biologic studies from these trials in the pediatric and young adult population.}, }
@article {pmid39248500, year = {2024}, author = {Srinivasan, S and Richardson, BA and Wallis, JM and Fiedler, TL and Strenk, SM and Hoffman, NG and Proll, S and Chirenje, ZM and Livant, EW and Fredricks, DN and Hillier, SL and Marrazzo, JM}, title = {Vaginal Bacteria and Proinflammatory Host Immune Mediators as Biomarkers of Human Immunodeficiency Virus Acquisition Risk Among African Women.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiae406}, pmid = {39248500}, issn = {1537-6613}, support = {NCT00705679//VOICE study/ ; UM1AI068633, UM1AI068615, UM1AI106707//National Institute of Allergy and Infectious Diseases/ ; //National Institute of Child Health and Human Development/ ; /MH/NIMH NIH HHS/United States ; /NH/NIH HHS/United States ; P30AI027757//University of Washington's Center for AIDS Research/ ; }, abstract = {BACKGROUND: Few investigations have assessed contributions of both vaginal bacteria and proinflammatory immune mediators to human immunodeficiency virus (HIV) acquisition risk in a prospective cohort.
METHODS: We conducted a nested case-control study of African women who participated in a randomized placebo-controlled trial of daily oral versus vaginal tenofovir-based preexposure prophylaxis for HIV infection. Vaginal concentrations of 23 bacterial taxa and 16 immune mediators were measured. Relationships between individual bacterial concentrations or immune mediators and HIV risk were analyzed using generalized estimating equations in a multivariable model. Factor analysis assessed relationships between combinations of bacterial taxa, immune mediators, and HIV acquisition risk.
RESULTS: We identified 177 HIV pre-seroconversion visits from 150 women who acquired HIV and 531 visits from 436 women who remained HIV uninfected. Fourteen bacterial taxa and 6 proinflammatory cytokines and chemokines were individually associated with greater HIV risk after adjusting for confounders. Women with all 14 taxa versus <14 taxa (adjusted odds ratio [aOR], 4.45 [95% confidence interval {CI}, 2.20-8.98]; P < .001) or all 6 immune mediators versus <6 mediators (aOR, 1.77 [95% CI, 1.24-2.52]; P < .001) had greater risk for HIV acquisition. Factor analysis demonstrated that a bacterial factor comprised of 14 high-risk bacterial taxa (aOR, 1.57 [95% CI, 1.27-1.93]; P < 0.001) and the interferon gamma-induced protein 10 (highest quartile: aOR, 3.19 [95% CI, 1.32-7.72]; P = 0.002) contributed to the highest HIV risk.
CONCLUSIONS: Bacterial and host biomarkers for predicting HIV acquisition risk identify women at greatest risk for HIV infection and can focus prevention efforts.}, }
@article {pmid39245683, year = {2024}, author = {Stathis, CJ and Zhu, H and Carlin, K and Phan, TL and Toomey, D and Hill, JA and Zerr, DM}, title = {A systematic review and meta-analysis of HHV-6 and mortality after hematopoietic cell transplant.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {39245683}, issn = {1476-5365}, abstract = {Human herpesvirus-6B (HHV-6B) reactivation has been associated with non-relapse mortality (NRM) and overall mortality (OM) following allogeneic hematopoietic stem cell transplant (HCT). We performed a systematic review and meta-analysis to better quantify the association. Studies were included if they systematically tested a cohort of HCT recipients for HHV-6 infection or reactivation and described mortality for patients with and without HHV-6B. Random effects models were used to assess the pooled effect of HHV-6B positivity on each outcome of interest. Bayesian aggregation was additionally performed if models included 10 or fewer studies. Eight studies were included in the NRM analysis, which demonstrated a significant association between HHV-6 detection and NRM (pooled effect: 1.84; 95% CI: 1.29-2.62) without significant heterogeneity (I[2] = 0.0%, p = 0.55). A Bayesian aggregation of the raw data used to construct the NRM random effects model supported these findings (95% credible interval: 0.15-1.13). Twenty-five studies were included in OM analysis, which showed a significant positive association (pooled effect: 1.37; 95% CI: 1.07-1.76), though considerable heterogeneity was observed (I[2] = 36.7%, p < 0.05). HHV-6 detection is associated with NRM and OM following HCT. Randomized trials are warranted to evaluate if preventing or treating HHV-6B reactivation improves outcomes.}, }
@article {pmid39243788, year = {2024}, author = {Lama, JR and Duerr, A}, title = {Preventing sexually transmitted infections in the age of PrEP.}, journal = {The lancet. HIV}, volume = {11}, number = {10}, pages = {e651-e653}, doi = {10.1016/S2352-3018(24)00236-4}, pmid = {39243788}, issn = {2352-3018}, mesh = {Humans ; *Pre-Exposure Prophylaxis ; *Sexually Transmitted Diseases/prevention & control/epidemiology ; *HIV Infections/prevention & control/epidemiology ; Anti-HIV Agents/therapeutic use ; Male ; Female ; }, }
@article {pmid39243704, year = {2024}, author = {Puschel, K and Rioseco, A and Soto, M and Paz, S and Martinez, J and Soto, G and Faundez, M and Arenas, E and Vescovi, Z and Fuentes, I and Thompson, B and Emery, J}, title = {Implementation of cancer prevention practices in primary care: results of a cohort study in Chile 2018-2022.}, journal = {Public health}, volume = {236}, number = {}, pages = {168-174}, doi = {10.1016/j.puhe.2024.08.006}, pmid = {39243704}, issn = {1476-5616}, abstract = {OBJECTIVES: The burden of cancer is increasing rapidly in Latin America. Primary care has an essential role in cancer prevention, but implementation levels of prevention practices are not well known. This study evaluated implementation levels and associated factors of cancer preventive practices in primary care over time.
STUDY DESIGN: The study incorporated a retrospective multicentre cohort study.
METHODS: A population of 59,949 patients registered at three primary care clinics was followed from January 2018 to December 2022 in Santiago, Chile. We studied human papillomavirus (HPV) and hepatitis B virus (HBV) immunisation, brief counselling for smoking cessation and alcohol consumption, and cervical and breast cancer screening practices. Standardised electronic medical records were utilised as the source of information. Social, clinical, and organisational factors associated with prevention practices were studied.
RESULTS: The cohort attrition level was 17.1%. Most of the population was of a low socioeconomic status, and 70% visited a primary health centre yearly. Implementation rates of immunisation practices were 90.84% for HPV and 80.94% for HBV in 2022. In contrast, brief counselling for smoking and alcohol consumption was below 20% during the study period. Cervical cancer screening decreased by 25.58% between 2018 and 2022, whereas breast cancer screening reached only 41.71% of the target population. Opportunistic medical visits were strongly associated with brief counselling and breast cancer screening.
CONCLUSION: Implementation practices for cancer prevention in a Chilean primary care cohort are high for immunisation and very low for brief counselling and screening practices. A comprehensive non-medical-based model is needed to improve cancer prevention in primary care.}, }
@article {pmid39241960, year = {2024}, author = {André, F and Cortés, J and Curigliano, G and Modi, S and Li, W and Park, YH and Chung, WP and Kim, SB and Yamashita, T and Pedrini, JL and Im, SA and Tseng, LM and Harbeck, N and Krop, I and Nakatani, S and Tecson, K and Ashfaque, S and Egorov, A and Hurvitz, SA}, title = {A pooled analysis of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with brain metastases.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2024.08.2347}, pmid = {39241960}, issn = {1569-8041}, abstract = {BACKGROUND: This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment.
PATIENTS AND METHODS: T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. The endpoints included intracranial objective response rate (ORR; complete or partial response in the brain) per blinded independent central review (BICR) by RECIST version 1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety.
RESULTS: A total of 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median intracranial DoR was 12.3 [95% confidence interval (CI) 9.1-17.9] months, and for those with untreated/active BMs, it was 17.5 months (95% CI 13.6-31.6 months). The median CNS-PFS and OS were 12.3 months (95% CI 11.1-13.8 months) and not reached (95% CI 22.1 months-not estimable) in those with treated/stable BMs, and 18.5 months (95% CI 13.6-23.3 months) and 30.2 months (95% CI 21.3 months-not estimable) in those with untreated/active BMs, respectively. Drug-related treatment-emergent adverse events grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd.
CONCLUSIONS: T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.}, }
@article {pmid39241315, year = {2024}, author = {Bakaloudi, DR and Talukder, R and Makrakis, D and Diamantopoulos, L and Enright, T and Leary, JB and Patgunarajah, U and Thomas, VM and Swami, U and Agarwal, N and Jindal, T and Koshkin, VS and Brown, JR and Barata, P and Murgić, J and Miletić, M and Johnson, J and Zakharia, Y and Hui, G and Drakaki, A and Duran, I and Buznego, LA and Barrera, RM and Castañeda, DM and Rey-Cárdenas, M and Castellano, D and Nguyen, CB and Park, JJ and Alva, A and McKay, RR and Stewart, TF and Epstein, IB and Bellmunt, J and Wright, JL and Gupta, S and Grivas, P and Khaki, AR}, title = {Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor.}, journal = {Clinical genitourinary cancer}, volume = {22}, number = {6}, pages = {102198}, doi = {10.1016/j.clgc.2024.102198}, pmid = {39241315}, issn = {1938-0682}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI.
METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable.
RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months).
CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.}, }
@article {pmid39241195, year = {2024}, author = {Walter, RB and Potter, V and Craddock, C}, title = {Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in Adults over 70 years old.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2024024247}, pmid = {39241195}, issn = {1528-0020}, abstract = {The advent of reduced-intensity conditioning regimens, improvements in graft-versus-host disease prophylaxis, and better supportive care have permitted increasing use of allogeneic hematopoietic cell transplantation (allo-HCT) in adults age ≥70 with AML. However, while potentially curative, non-relapse mortality and relapse represent the main causes of treatment failure, highlighting the importance of refining both patient selection and transplant strategies. At the same time, continuously evolving non-transplant therapies and transplant technologies mandate prospective trials (re-)examining the role of allo-HCT and its optimal delivery.}, }
@article {pmid39241101, year = {2024}, author = {Abousamra, E and Figgins, M and Bedford, T}, title = {Fitness models provide accurate short-term forecasts of SARS-CoV-2 variant frequency.}, journal = {PLoS computational biology}, volume = {20}, number = {9}, pages = {e1012443}, pmid = {39241101}, issn = {1553-7358}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; }, mesh = {*SARS-CoV-2/genetics ; Humans ; *COVID-19/epidemiology/virology ; *Forecasting/methods ; Computational Biology/methods ; Retrospective Studies ; }, abstract = {Genomic surveillance of pathogen evolution is essential for public health response, treatment strategies, and vaccine development. In the context of SARS-COV-2, multiple models have been developed including Multinomial Logistic Regression (MLR) describing variant frequency growth as well as Fixed Growth Advantage (FGA), Growth Advantage Random Walk (GARW) and Piantham parameterizations describing variant Rt. These models provide estimates of variant fitness and can be used to forecast changes in variant frequency. We introduce a framework for evaluating real-time forecasts of variant frequencies, and apply this framework to the evolution of SARS-CoV-2 during 2022 in which multiple new viral variants emerged and rapidly spread through the population. We compare models across representative countries with different intensities of genomic surveillance. Retrospective assessment of model accuracy highlights that most models of variant frequency perform well and are able to produce reasonable forecasts. We find that the simple MLR model provides ∼0.6% median absolute error and ∼6% mean absolute error when forecasting 30 days out for countries with robust genomic surveillance. We investigate impacts of sequence quantity and quality across countries on forecast accuracy and conduct systematic downsampling to identify that 1000 sequences per week is fully sufficient for accurate short-term forecasts. We conclude that fitness models represent a useful prognostic tool for short-term evolutionary forecasting.}, }
@article {pmid39241078, year = {2024}, author = {Nguyen, TNH and Horowitz, LF and Krilov, T and Lockhart, E and Kenerson, HL and Gujral, TS and Yeung, RS and Arroyo-Currás, N and Folch, A}, title = {Label-free, real-time monitoring of cytochrome C drug responses in microdissected tumor biopsies with a multi-well aptasensor platform.}, journal = {Science advances}, volume = {10}, number = {36}, pages = {eadn5875}, pmid = {39241078}, issn = {2375-2548}, mesh = {*Cytochromes c/metabolism ; Humans ; Animals ; Mice ; *Aptamers, Nucleotide ; Neoplasms/drug therapy/pathology/genetics/metabolism ; Biosensing Techniques/methods ; Biopsy ; Cell Line, Tumor ; Apoptosis/drug effects ; Antineoplastic Agents/pharmacology ; }, abstract = {Functional assays on intact tumor biopsies can complement genomics-based approaches for precision oncology, drug testing, and organs-on-chips cancer disease models by capturing key therapeutic response determinants, such as tissue architecture, tumor heterogeneity, and the tumor microenvironment. Most of these assays rely on fluorescent labeling, a semiquantitative method best suited for single-time-point assays or labor-intensive immunostaining analysis. Here, we report integrated aptamer electrochemical sensors for on-chip, real-time monitoring of cytochrome C, a cell death indicator, from intact microdissected tissues with high affinity and specificity. The platform features a multi-well sensor layout and a multiplexed electronic setup. The aptasensors measure increases in cytochrome C in the supernatant of mouse or human microdissected tumors after exposure to various drug treatments. Because of the sensor's high affinity, it primarily tracks rising concentrations of cytochrome C, capturing dynamic changes during apoptosis. This approach could help develop more advanced cancer disease models and apply to other complex in vitro disease models, such as organs-on-chips and organoids.}, }
@article {pmid39240995, year = {2024}, author = {Williamson, BD and Wu, L and Huang, Y and Hudson, A and Gilbert, PB}, title = {Predicting neutralization susceptibility to combination HIV-1 monoclonal broadly neutralizing antibody regimens.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0310042}, pmid = {39240995}, issn = {1932-6203}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {*HIV-1/immunology/drug effects ; Humans ; *Antibodies, Neutralizing/immunology ; *HIV Antibodies/immunology ; *Antibodies, Monoclonal/immunology ; HIV Infections/immunology/drug therapy/virology ; Neutralization Tests/methods ; }, abstract = {Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 acquisition. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) approach. However, prediction performance for some individual bnAbs has exceeded that for the combination, leading to another possibility: combining the individual-bnAb predicted values and using these to predict combination regimen neutralization; we call this the predict-then-combine (PC) approach. We explore both approaches in both simulated data and data from the Los Alamos National Laboratory's Compile, Neutralize, and Tally NAb Panels repository. The CP approach is superior to the PC approach when the neutralization outcome of interest is binary (e.g., neutralization susceptibility, defined as inhibitory 80% concentration < 1 μg/mL). For continuous outcomes, the CP approach performs nearly as well as the PC approach when the individual-bnAb prediction algorithms have strong performance, and is superior to the PC approach when the individual-bnAb prediction algorithms have poor performance. This knowledge may be used when building prediction models for novel antibody combinations in the absence of in vitro neutralization data for the antibody combination; this, in turn, will aid in the evaluation and down-selection of these antibody combinations into prevention efficacy trials.}, }
@article {pmid39240590, year = {2024}, author = {Nyame, YA}, title = {Editor of the Month.}, journal = {Urology practice}, volume = {}, number = {}, pages = {101097UPJ0000000000000693}, doi = {10.1097/UPJ.0000000000000693}, pmid = {39240590}, issn = {2352-0787}, }
@article {pmid39240291, year = {2024}, author = {Donzella, SM and Deubler, E and Patel, AV and Phipps, AI and Zhong, C}, title = {Sleep and cancer mortality in the Cancer Prevention Study-II.}, journal = {Cancer causes & control : CCC}, volume = {35}, number = {12}, pages = {1541-1555}, pmid = {39240291}, issn = {1573-7225}, mesh = {Humans ; Male ; Female ; *Neoplasms/mortality/epidemiology ; Middle Aged ; *Sleep/physiology ; Adult ; Aged ; Sleep Initiation and Maintenance Disorders/complications ; Risk Factors ; United States/epidemiology ; }, abstract = {PURPOSE: Sleep is a multi-dimensional human function that is associated with cancer outcomes. Previous work on sleep and cancer mortality have not investigated how this relationship varies by sex and cancer site. We investigated the association of sleep duration and perceived insomnia with site-specific and overall cancer mortality among participants in the Cancer Prevention Study-II.
METHODS: Sleep was collected at baseline in 1982 among 1.2 million cancer-free US adults. Cancer-specific mortality was determined through 2018. We used multivariable Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for overall and site-specific cancer mortality, stratified by sex.
RESULTS: Among 983,105 participants (56% female) followed for a median of 27.9 person-years, there were 146,911 primary cancer deaths. Results from the adjusted model showed short (6 h/night) and long (8 h/night and 9-14 h/night) sleep duration, compared to 7 h/night, were associated with a modest 2%, 2%, and 5% higher risk of overall cancer mortality, respectively, and there was a significant non-linear trend (p-trend < 0.01). This non-linear trend was statistically significant among male (p-trend < 0.001) but not female (p-trend 0.71) participants. For male participants, short and long sleep were associated with higher risk of lung cancer mortality and long sleep was associated with higher risk of colorectal cancer mortality. Perceived insomnia was associated with a 3-7% lower risk of overall cancer mortality.
CONCLUSION: Sleep is important to consider in relation to sex- and site-specific cancer mortality. Future research should investigate other components of sleep in relation to cancer mortality.}, }
@article {pmid39240111, year = {2024}, author = {Agrawal, P and Knudsen, ML and MacCamy, A and Hurlburt, NK and Khechaduri, A and Salladay, KR and Kher, GM and Kallur Siddaramaiah, L and Stuart, AB and Bontjer, I and Shen, X and Montefiori, D and Gristick, HB and Bjorkman, PJ and Sanders, RW and Pancera, M and Stamatatos, L}, title = {Short CDRL1 in intermediate VRC01-like mAbs is not sufficient to overcome key glycan barriers on HIV-1 Env.}, journal = {Journal of virology}, volume = {98}, number = {10}, pages = {e0074424}, pmid = {39240111}, issn = {1098-5514}, support = {P01 AI100148/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 GM124169/GM/NIGMS NIH HHS/United States ; //P01 AI1382122/ ; //R01 AI104384/ ; P01 AI138212/AI/NIAID NIH HHS/United States ; P01 AI132122/AI/NIAID NIH HHS/United States ; S10 OD021832/OD/NIH HHS/United States ; R01 AI104384/AI/NIAID NIH HHS/United States ; }, mesh = {*HIV Antibodies/immunology ; *HIV-1/immunology ; Humans ; Animals ; *Antibodies, Neutralizing/immunology ; Mice ; *Polysaccharides/immunology ; *Broadly Neutralizing Antibodies/immunology ; *Antibodies, Monoclonal/immunology ; HIV Envelope Protein gp120/immunology/genetics ; Glycosylation ; AIDS Vaccines/immunology ; HIV Infections/immunology/virology/prevention & control ; Receptors, Antigen, B-Cell/immunology ; Epitopes/immunology ; }, abstract = {UNLABELLED: VRC01-class broadly neutralizing antibodies (bnAbs) have been isolated from people with HIV-1, but they have not yet been elicited by vaccination. They are extensively somatically mutated and sometimes accumulate CDRL1 deletions. Such indels may allow VRC01-class antibodies to accommodate the glycans expressed on a conserved N276 N-linked glycosylation site in loop D of the gp120 subunit. These glycans constitute a major obstacle in the development of VRC01-class antibodies, as unmutated antibody forms are unable to accommodate them. Although immunizations of knock-in mice expressing human VRC01-class B-cell receptors (BCRs) with specifically designed Env-derived immunogens lead to the accumulation of somatic mutations in VRC01-class BCRs, CDRL1 deletions are rarely observed, and the elicited antibodies display narrow neutralizing activities. The lack of broad neutralizing potential could be due to the absence of deletions, the lack of appropriate somatic mutations, or both. To address this point, we modified our previously determined prime-boost immunization with a germline-targeting immunogen nanoparticle (426c.Mod.Core), followed by a heterologous core nanoparticle (HxB2.WT.Core), by adding a final boost with a cocktail of various stabilized soluble Env trimers. We isolated VRC01-like antibodies with extensive somatic mutations and, in one case, a seven-amino acid CDRL1 deletion. We generated chimeric antibodies that combine the vaccine-elicited somatic mutations with CDRL1 deletions present in human mature VRC01 bnAbs. We observed that CDRL1 indels did not improve the neutralizing antibody activities. Our study indicates that CDRL1 length by itself is not sufficient for the broadly neutralizing phenotype of this class of antibodies.
IMPORTANCE: HIV-1 broadly neutralizing antibodies will be a key component of an effective HIV-1 vaccine, as they prevent viral acquisition. Over the past decade, numerous broadly neutralizing antibodies (bnAbs) have been isolated from people with HIV. Despite an in-depth knowledge of their structures, epitopes, ontogenies, and, in a few rare cases, their maturation pathways during infection, bnAbs have, so far, not been elicited by vaccination. This necessitates the identification of key obstacles that prevent their elicitation by immunization and overcoming them. Here we examined whether CDRL1 shortening is a prerequisite for the broadly neutralizing potential of VRC01-class bnAbs, which bind within the CD4 receptor binding site of Env. Our findings indicate that CDRL1 shortening by itself is important but not sufficient for the acquisition of neutralization breadth, and suggest that particular combinations of amino acid mutations, not elicited so far by vaccination, are most likely required for the development of such a feature.}, }
@article {pmid39239793, year = {2024}, author = {Chen, Y and Zhao, L and Jung, SY and Pichardo, MS and Lopez-Pentecost, M and Rohan, TE and Saquib, N and Sun, Y and Tabung, FK and Zheng, T and Wactawski-Wende, J and Manson, JE and Neuhouser, ML and Zhang, X}, title = {Diabetes risk reduction diet and risk of liver cancer and chronic liver disease mortality: A prospective cohort study.}, journal = {Journal of internal medicine}, volume = {296}, number = {5}, pages = {410-421}, doi = {10.1111/joim.20007}, pmid = {39239793}, issn = {1365-2796}, support = {/HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R21 CA238651/CA/NCI NIH HHS/United States ; R21 CA252962/CA/NCI NIH HHS/United States ; R37 CA262299/CA/NCI NIH HHS/United States ; U01 CA259208/CA/NCI NIH HHS/United States ; U01 CA272452/CA/NCI NIH HHS/United States ; RSG-17-190-01-NEC//American Cancer Society Research Scholar Award/ ; PASD-221003396-01//American Cancer Society Interdisciplinary Team Award/ ; /HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R21 CA238651/CA/NCI NIH HHS/United States ; R21 CA252962/CA/NCI NIH HHS/United States ; R37 CA262299/CA/NCI NIH HHS/United States ; U01 CA259208/CA/NCI NIH HHS/United States ; U01 CA272452/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Prospective Studies ; Middle Aged ; Aged ; *Liver Neoplasms/mortality/prevention & control/epidemiology ; Risk Reduction Behavior ; Chronic Disease ; Risk Factors ; Liver Diseases/mortality ; Diet/adverse effects ; Incidence ; Postmenopause ; Proportional Hazards Models ; }, abstract = {BACKGROUND: We aimed to prospectively evaluate the association between a diabetes risk reduction diet (DRRD) score and the risk of liver cancer development and chronic liver disease-specific mortality.
METHODS: We included 98,786 postmenopausal women from the Women's Health Initiative-Observational Study and the usual diet arm of the Diet Modification trial. The DRRD score was derived from eight factors: high intakes of dietary fiber, coffee, nuts, polyunsaturated fatty acids, low intakes of red and processed meat, foods with high glycemic index, sugar-sweetened beverages (SSBs), and trans fat based on a validated Food-Frequency Questionnaire administered at baseline (1993-1998). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for liver cancer incidence and chronic liver disease mortality were estimated using Cox proportional hazards regression models.
RESULTS AND CONCLUSION: After a median follow-up of 22.0 years, 216 incident liver cancer cases and 153 chronic liver disease deaths were confirmed. A higher DRRD score was significantly associated with a reduced risk of developing liver cancer (HRTertile 3 vs. Tertile 1 = 0.69; 95% CI: 0.49-0.97; Ptrend = 0.03) and chronic liver disease mortality (HRT3 vs. T1 = 0.54; 95% CI: 0.35-0.82; Ptrend = 0.003). We further found inverse associations with dietary fiber and coffee, and positive associations with dietary glycemic index, SSBs, and trans fat. A higher DRRD score was associated with reduced risk of developing liver cancer and chronic liver disease mortality among postmenopausal women.}, }
@article {pmid39238853, year = {2024}, author = {Leedy, DJ and Voit, JM and Rillamas-Sun, E and Kwan, ML and Shen, H and Li, S and Laurent, CA and Rana, JS and Lee, VS and Roh, JM and Huang, Y and Greenlee, H and Cheng, RK}, title = {Blood Pressure and Cardiovascular Risk in Women With Breast Cancer: The Pathways Heart Study.}, journal = {JACC. Advances}, volume = {3}, number = {9}, pages = {101207}, pmid = {39238853}, issn = {2772-963X}, abstract = {BACKGROUND: Hypertension is an important contributor to cardiovascular disease (CVD) in breast cancer (BC) survivors; however, research on blood pressure (BP) and CVD outcomes in BC survivors is limited.
OBJECTIVES: The purpose of this study was to better characterize the association between BP and CVD in a large, longitudinal cohort of BC patients.
METHODS: Women with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California were matched 1:5 to women without BC. Patient data were obtained from electronic health records. Multivariable Cox regression and penalized spline models were used to explore the linear and nonlinear relationship of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on CVD outcomes.
RESULTS: BC cases (n = 12,713) and controls (n = 55,886) had median follow-up of 9.6 years (IQR: 5.0-11.9 years). Women with BC had a mean age of 60.6 years; 64.8% were non-Hispanic White. For ischemic heart disease (IHD), every 10 mmHg increase in SBP and DBP was associated with 1.23 (95% CI: 1.14-1.33) and 1.10 (95% CI: 0.98-1.24) risk, respectively, in women with BC. For stroke, every 10 mmHg increase in SBP and DBP was associated with a 1.45 (95% CI: 1.34-1.58) and 1.91 (95% CI: 1.68-2.18) risk, respectively. A U-shaped relationship was observed between heart failure/cardiomyopathy and BP. The associations between BP and risk of IHD, stroke, and any primary CVD were not statistically different comparing women with BC to controls, but risks varied by BC status for heart failure/cardiomyopathy (P for interaction = 0.01).
CONCLUSIONS: Women with and without BC showed similar risks for IHD, stroke, and any primary CVD suggesting similar BP targets should be pursued regardless of BC survivorship status.}, }
@article {pmid39238483, year = {2024}, author = {Vitanza, NA and Choe, M and Brown, C and Beebe, A and Kong, A and Rogers, L and Jacob, S and Mano, E and Abuan, K and Mgebroff, S and Lindgren, C and Gustafson, JA and Wilson, AL and Noll, A and Ronsley, R and Crotty, EE and Leary, SES and Foster, JB and Pinto, N and Gust, J and Gardner, RA and Park, JR and Jensen, MC}, title = {Locoregional CAR T Cells for the Treatment of CNS Tumors in Children: Investigational Drug Service Pharmacy Activities.}, journal = {Journal of hematology oncology pharmacy}, volume = {14}, number = {4}, pages = {148-154}, pmid = {39238483}, issn = {2164-1153}, support = {U01 TR002487/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: A major obstacle in translating the therapeutic potential of chimeric antigen receptor (CAR) T cells to children with central nervous system (CNS) tumors is the blood-brain barrier. To overcome this limitation, preclinical and clinical studies have supported the use of repeated, locoregional intracranial CAR T-cell delivery. However, there is limited literature available describing the process for the involvement of an investigational drug service (IDS) pharmacy, particularly in the setting of a children's hospital with outpatient dosing for CNS tumors.
OBJECTIVES: To describe Seattle Children's Hospital's experience in clinically producing CAR T cells and the implementation of IDS pharmacy practices used to deliver more than 300 intracranial CAR T-cell doses to children, as well as to share how we refined the processing techniques from CAR T-cell generation to the thawing of fractionated doses for intracranial delivery.
METHODS: Autologous CD4+ and CD8+ T cells were collected and transduced to express HER2, EGFR, or B7-H3-specific CAR T cells. Cryopreserved CAR T cells were thawed by the IDS pharmacy before intracranial delivery to patients with recurrent/refractory CNS tumors or with diffuse intrinsic pontine glioma/diffuse midline glioma.
RESULTS: The use of a thaw-and-dilute procedure for cryopreserved individual CAR T-cell doses provides reliable viability and is more efficient than typical thaw-and-wash protocols. Cell viability with the thaw-and-dilute protocol was approximately 75% and was always within 10% of the viability assessed at cryopreservation. Cell viability was preserved through 6 hours after thawing, which exceeded the 1-hour time frame from thawing to infusion.
CONCLUSION: As the field of adoptive immunotherapy grows and continues to bring hope to patients with fatal CNS malignancies, it is critical to focus on improving the preparatory steps for CAR T-cell delivery.}, }
@article {pmid39236759, year = {2024}, author = {Streiff, MB and Holmstrom, B and Angelini, D and Ashrani, A and Buckner, T and Diep, R and Fertrin, KY and Fogerty, AE and Crestani, NG and Gangaraju, R and Rojas-Hernandez, C and Goldhaber, SZ and Ibrahim, I and Kubal, T and Leavitt, AD and Lim, M and Mann, J and Mantha, S and Morton, C and Nester, A and O'Brien, A and Ortel, TL and Pine, A and Pishko, A and Ranade, M and Salmasi, A and Schaefer, J and Williams, E and Wool, G and Wun, T and Montgomery, S and Nguyen, J and Freedman-Cass, D and Sliker, B}, title = {Cancer-Associated Venous Thromboembolic Disease, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {7}, pages = {483-506}, doi = {10.6004/jnccn.2024.0046}, pmid = {39236759}, issn = {1540-1413}, mesh = {Humans ; *Venous Thromboembolism/etiology/diagnosis/therapy/prevention & control ; *Neoplasms/complications/therapy/diagnosis ; Medical Oncology/standards/methods ; Anticoagulants/therapeutic use ; Disease Management ; }, abstract = {The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease provide strategies for the prevention, diagnosis, and treatment of venous thromboembolism (VTE) in adult patients with cancer. VTE is a common and life-threatening condition in patients with cancer, and its management often requires multidisciplinary efforts. The NCCN panel is comprised of specialists spanning various fields, including cardiology, hematology, medical oncology, internal medicine, interventional radiology, and pharmacology. The content featured in this issue specifically addresses the evaluation and recommended treatment options outlined in the NCCN Guidelines for the diverse subtypes of cancer-associated VTE.}, }
@article {pmid39236750, year = {2024}, author = {Ness, RM and Llor, X and Abbass, MA and Bishu, S and Chen, CT and Cooper, G and Early, DS and Friedman, M and Fudman, D and Giardiello, FM and Glaser, K and Gurudu, S and Hall, M and Huang, LC and Issaka, R and Katona, B and Kidambi, T and Lazenby, AJ and Maratt, J and Markowitz, AJ and Marsano, J and May, FP and Mayer, RJ and Olortegui, K and Patel, S and Peter, S and Porter, LD and Shafi, M and Stanich, PP and Terdiman, J and Vu, P and Weiss, JM and Wood, E and Cassara, CJ and Sambandam, V}, title = {NCCN Guidelines® Insights: Colorectal Cancer Screening, Version 1.2024.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {22}, number = {7}, pages = {438-446}, doi = {10.6004/jnccn.2024.0047}, pmid = {39236750}, issn = {1540-1413}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Early Detection of Cancer/standards/methods ; Mass Screening/methods/standards ; }, abstract = {The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age at which to initiate screening in average-risk individuals and those with increased risk based on personal history of childhood, adolescent, and young adult cancer.}, }
@article {pmid39236733, year = {2024}, author = {Isa, F and Gonzalez Ortiz, AM and Meyer, J and Hamilton, JD and Olenchock, BA and Brackin, T and Ganguly, S and Forleo-Neto, E and Faria, L and Heirman, I and Marovich, M and Hutter, J and Polakowski, L and Irvin, SC and Thakur, M and Hooper, AT and Baum, A and Petro, CD and Fakih, FA and McElrath, MJ and De Rosa, SC and Cohen, KW and Williams, LD and Hellman, CA and Odeh, AJ and Patel, AH and Tomaras, GD and Geba, GP and Kyratsous, CA and Musser, B and Yancopoulos, GD and Herman, GA and , }, title = {Effect of timing of casirivimab and imdevimab administration relative to mRNA-1273 COVID-19 vaccination on vaccine-induced SARS-CoV-2 neutralising antibody responses: a prospective, open-label, phase 2, randomised controlled trial.}, journal = {The Lancet. Infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1473-3099(24)00421-3}, pmid = {39236733}, issn = {1474-4457}, abstract = {BACKGROUND: Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes.
METHODS: This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA. Participants were randomly assigned (per prespecified randomisation ratios within enrolment waves) according to a computer-generated randomisation scheme, stratified by age (<65 years and ≥65 years), to various intravenous or subcutaneous doses of casirivimab and imdevimab before, after, or at the same time as mRNA-1273 or to mRNA-1273 only. The doses of casirivimab and imdevimab were chosen to mimic various time intervals between receipt of 1200 mg of the mAb and the first dose of a primary series with mRNA-1273. The primary endpoint was vaccine-induced 50% inhibitory dilution neutralising antibody titres to SARS-CoV-2 spike protein, 56 days after the first vaccination. Secondary endpoints included vaccine-induced total antibodies to SARS-CoV-2 antigens and incidence of treatment-emergent adverse events. Exploratory endpoints included blood-derived T-cell and B-cell responses. The per-protocol set was used for the analysis of the primary endpoint and included all randomly assigned participants who received both doses of the vaccine and completed the injection or infusion of casirivimab and imdevimab per protocol, had no evidence of SARS-CoV-2 infection in the past or in the 56 days after the first dose of vaccine, and did not receive any intervention outside of the study that could alter the immune response. Safety was assessed in the safety analysis set, which included all randomly assigned participants who had received one or more doses of mRNA-1273 or any study drug, and analysed based on treatment received. The study is registered with ClinicalTrials.gov, NCT04852978, and is complete.
FINDINGS: Between April 29, 2021, and Nov 21, 2022, 807 participants were assessed for eligibility and 295 were randomly assigned. 293 participants were included in the safety analysis set and 260 were included in the per-protocol set. All vaccinated participants developed neutralising antibodies to SARS-CoV-2, with median titres above the published protective threshold (100 IU/mL) against the SARS-CoV-2 D614G variant (considered a reference strain at the time the initial COVID-19 vaccines were developed). Titres were decreased up to 4-fold (median titres 280-450 IU/mL for casirivimab and imdevimab vs 1160 IU/mL for vaccine only on day 56) when casirivimab and imdevimab was given 85 days or less before vaccination (150-1200 mg intravenously) or co-administered subcutaneously (600 mg or 1200 mg) with vaccination. Minimal reduction in neutralisation titres was observed in the 48 mg and 12 mg intravenous groups, corresponding to receipt of casirivimab and imdevimab 113 days and 169 days, respectively, before vaccination, and when administering the vaccine 6 days before the mAb. Across all groups, mAbs had a minimal effect on vaccine-induced total antibodies and T-cell responses to the spike protein. Casirivimab and imdevimab plus mRNA-1273 was generally well tolerated; a slight increase in treatment-emergent adverse events was observed in the casirivimab and imdevimab plus vaccine groups versus the vaccine-only group.
INTERPRETATION: Casirivimab and imdevimab administration before or at the time of COVID-19 vaccination reduced the elicitation of SARS-CoV-2 neutralising antibodies, but minimal effect was observed when vaccination occurred before mAb administration. Although the clinical significance of this decrease in neutralisation is unclear, this evidence suggests that further investigation of potential interactions could be warranted before concurrent clinical use of mAbs and vaccines targeting the same viral proteins as their main modes of action for the prevention or treatment of infectious diseases.
FUNDING: Regeneron Pharmaceuticals and F Hoffmann-La Roche.}, }
@article {pmid39236556, year = {2024}, author = {Kenny, A and van Duijn, J and Dintwe, O and Heptinstall, J and Burnham, R and Sawant, S and Zhang, L and Mielke, D and Khuzwayo, S and Omar, FL and Stanfield-Oakley, S and Keyes, T and Dunn, B and Goodman, D and Fong, Y and Benkeser, D and Zou, R and Hural, J and Hyrien, O and Juraska, M and Luedtke, A and van der Laan, L and Giorgi, EE and Magaret, C and Carpp, LN and Pattacini, L and van de Kerkhof, T and Korber, B and Willems, W and Fisher, LH and Schuitemaker, H and Swann, E and Kublin, JG and Pau, MG and Buchbinder, S and Tomaka, F and Nijs, S and Lavreys, L and Gelderblom, HC and Corey, L and Mngadi, K and Gray, GE and Borducchi, E and Hendriks, J and Seaton, KE and Zolla-Pazner, S and Barouch, DH and Ferrari, G and De Rosa, SC and McElrath, MJ and Andersen-Nissen, E and Stieh, DJ and Tomaras, GD and Gilbert, PB and , }, title = {Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.}, journal = {EBioMedicine}, volume = {108}, number = {}, pages = {105320}, pmid = {39236556}, issn = {2352-3964}, support = {R37 AI150590/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; *AIDS Vaccines/immunology/administration & dosage ; *HIV Infections/immunology/prevention & control/virology ; *HIV-1/immunology ; Case-Control Studies ; Male ; Adult ; Vaccine Efficacy ; HIV Antibodies/blood/immunology ; Immunoglobulin G/blood/immunology ; env Gene Products, Human Immunodeficiency Virus/immunology ; Africa, Southern ; Young Adult ; Southern African People ; }, abstract = {BACKGROUND: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models.
METHODS: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions.
FINDINGS: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: -17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: -17.9% to 89.6%), and further increased to 80.9% (95% CI: -17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker.
INTERPRETATION: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen.
FUNDING: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.}, }
@article {pmid39235868, year = {2024}, author = {Piha-Paul, S and Olwill, SA and Hamilton, E and Tolcher, A and Pohlmann, P and Liu, SV and Wurzenberger, C and Hasenkamp, LC and Hansbauer, EM and Shroff, R and Hurvitz, S and Krishnamurthy, A and Patnaik, A and Hahn, N and Kumar, R and Duerr, M and Zettl, M and Aviano, K and Matis, L and Bruns, I and Ku, G}, title = {A First-in-Human Study of cinrebafusp alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-24-1552}, pmid = {39235868}, issn = {1557-3265}, abstract = {PURPOSE: 4-1BB (CD137) is a costimulatory immune receptor expressed on activated T cells, activated B cells, natural killer cells and tumor-infiltrating lymphocytes, making it a promising target for cancer immunotherapy. Cinrebafusp alfa, a monoclonal antibody-like bispecific protein targeting HER2 and 4-1BB, aims to localize 4-1BB activation to HER2-positive tumors. This study evaluated the safety, tolerability, and preliminary efficacy of cinrebafusp alfa in patients with previously treated HER2-positive malignancies.
EXPERIMENTAL DESIGN: This was a multi-center dose escalation study involving patients with HER2-positive malignancies who had received prior treatment. The study assessed the safety and efficacy of cinrebafusp alfa across various dose levels. Patients were assigned to different cohorts, and antitumor responses were evaluated. The study aimed to determine the maximum tolerated dose (MTD) and to observe any clinical activity at different dose levels.
RESULTS: Out of 40 evaluable patients in the 'active dose' efficacy cohorts, 5 showed an antitumor response, resulting in an overall response rate (ORR) of 12.5% and a disease control rate of 52.5%. Clinical activity was observed at the 8 mg/kg and 18 mg/kg dose levels, with confirmed objective response rates of 28.6% and 25.0%, respectively. Cinrebafusp alfa was safe and tolerable, with Grade ≤2 infusion-related reactions being the most frequent treatment-related adverse event. MTD was not reached during the study.
CONCLUSION: Cinrebafusp alfa demonstrates promising activity in patients with HER2-positive malignancies who have progressed on prior HER2-targeting regimens. Its acceptable safety profile suggests it could be a treatment option for patients not responding to existing HER2-directed therapies.}, }
@article {pmid39235529, year = {2024}, author = {Hahn, WO and Parks, KR and Shen, M and Ozorowski, G and Janes, H and Ballweber-Fleming, L and Woodward Davis, AS and Duplessis, C and Tomai, M and Dey, AK and Sagawa, ZK and De Rosa, SC and Seese, A and Kallur Siddaramaiah, L and Stamatatos, L and Lee, WH and Sewall, LM and Karlinsey, D and Turner, HL and Rubin, V and Furth, S and MacPhee, K and Duff, M and Corey, L and Keefer, MC and Edupuganti, S and Frank, I and Maenza, J and Baden, LR and Hyrien, O and Sanders, RW and Moore, JP and Ward, AB and Tomaras, GD and Montefiori, DC and Rouphael, N and McElrath, MJ}, title = {Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies.}, journal = {The Journal of experimental medicine}, volume = {221}, number = {10}, pages = {}, pmid = {39235529}, issn = {1540-9538}, support = {OPP1107954//Gates Foundation/ ; INV-002022/GATES/Bill & Melinda Gates Foundation/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P01 AI110657/AI/NIAID NIH HHS/United States ; UM1 AI069534/AI/NIAID NIH HHS/United States ; INV-002916/GATES/Bill & Melinda Gates Foundation/United States ; }, mesh = {Humans ; *Antibodies, Neutralizing/immunology ; *AIDS Vaccines/immunology/administration & dosage ; *Alum Compounds/administration & dosage ; Adult ; *Adjuvants, Immunologic/administration & dosage ; *env Gene Products, Human Immunodeficiency Virus/immunology ; HIV Antibodies/immunology ; Female ; HIV-1/immunology ; Male ; HIV Infections/immunology/prevention & control ; B-Lymphocytes/immunology ; Adjuvants, Vaccine ; Middle Aged ; Young Adult ; CD4-Positive T-Lymphocytes/immunology ; }, abstract = {Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140 formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding, and immunogenicity in a first-in-healthy adult (n = 17), randomized, and placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, and B cell and CD4+ T cell responses emerged after vaccination. Five vaccinees developed serum autologous tier 2 nAbs (ID50 titer, 1:28-1:8647) after two to three doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/Alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes.}, }
@article {pmid39235112, year = {2024}, author = {Kwendakwema, CN and Sabo, MC and Roberts, ST and Masese, L and McClelland, RS and Shafi, J and Lehman, DA and Overbaugh, J and Graham, SM}, title = {Sexual Violence, Genital Cytokines, and Colposcopy Findings: A Cross-Sectional Study of Women Engaged in Sex Work in Mombasa, Kenya.}, journal = {Sexually transmitted diseases}, volume = {}, number = {}, pages = {}, doi = {10.1097/OLQ.0000000000002070}, pmid = {39235112}, issn = {1537-4521}, abstract = {BACKGROUND: Sexual violence (SV) increases HIV susceptibility in a sustained manner. This study evaluated genital cytokines and colposcopy findings in women reporting both recent and more remote SV.Methods: A cross-sectional study of HIV-1 negative Kenyan women who engage in sex work (WESW) was performed. Cervicovaginal fluid was collected by menstrual cup and cytokines (IFNγ, TNFα, IL-1β, IL-6, IL-10, MIP-1α, MIP-1β and CXCL10) measured using chemiluminescence. Cervical injury was assessed by colposcopy. Associations between recent (≤30 days prior), more remote (>30 days prior) and no (reference category) SV exposure and cytokine concentrations were evaluated using linear regression.
RESULTS: Among 282 participants, 25 (8.9%) reported recent SV and 123 (43.6%) reported more remote SV. Only two cytokines (IL-10 and CXCL10) were associated with the 3-category SV variable in bivariable modeling at the pre-specified cut-off (p < 0.2) and carried forward. In multivariable analyses, more remote SV (β = 0.72, 95% CI 0.06, 1.38; p = 0.03), but not recent SV (β = 0.20, 95%CI -0.99, 1.39; p = 0.74) was associated with cervicovaginal IL-10 compared to no SV. Recent (β = 0.36, 95% CI -0.94, 1.67; p = 0.58) and more remote (β = 0.51, 95% CI -0.21, 1.24; p = 0.16) SV were not associated with CXCL10 compared to no SV. Cervical epithelial friability (χ2 = 1.3, p = 0.51), erythema (χ2 = 2.9, p = 0.24), vascular disruption (χ2 = 1.4; p = 0.50), epithelial disruption (χ2 = 2.6, p = 0.27), or any colposcopy finding (χ2 = 1.2, p = 0.54) were not associated with SV category by chi-square test.
CONCLUSIONS: The mechanism linking SV to sustained increases in HIV susceptibility may not be related to persistent genital inflammation or injury.}, }
@article {pmid39234871, year = {2024}, author = {Mercadal, S and Ahn, KW and Allbee-Johnson, M and Ganguly, S and Geethakumari, PR and Hong, S and Malone, A and Murthy, H and Pawarode, A and Sica, AR and Solh, M and Ustun, C and Shadman, M and Sauter, CS and Hamadani, M and Herrera, AF and Lee, CJ}, title = {Outcomes of patients with primary central nervous system lymphoma following CD19-targeted chimeric antigen receptor T-cell therapy.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2024.285613}, pmid = {39234871}, issn = {1592-8721}, }
@article {pmid39234862, year = {2024}, author = {Phillips, T and Wang, M and Robak, T and Gallinson, D and Stevens, D and Patel, K and Ramadan, S and Wun, CC and Jurczak, W and Smith, SD}, title = {Safety and efficacy of acalabrutinib plus bendamustine and rituximab in patients with treatment-naive or relapsed / refractory mantle cell lymphoma: phase Ib trial.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2023.284896}, pmid = {39234862}, issn = {1592-8721}, abstract = {This multicenter, open-label, phase 1b study (ACE-LY-106) assessed the safety and efficacy of acalabrutinib, bendamustine, and rituximab (ABR) in treatment-naive (TN) and relapsed or refractory (R/R) mantle cell lymphoma (MCL). Patients received acalabrutinib from cycle 1 until disease progression or treatment discontinuation, bendamustine on days 1 and 2 of each cycle for up to 6 cycles, and rituximab on day 1 of each cycle for 6 cycles, continuing every other cycle from cycle 8 for 12 additional doses (TN cohort). Eighteen patients enrolled in the TN and 20 in the R/R cohort. Median duration of exposure to acalabrutinib was 34.0 and 14.6 months in the TN and R/R cohorts, respectively. No new safety risks were identified, and most adverse events (AEs) were grades 1 or 2. Thirteen patients from the TN cohort (72.2%) and 17 patients from the R/R cohort (85.0%) reported grade 3-4 AEs, most commonly neutropenia (TN: 38.9%, R/R: 50.0%). AEs leading to death were pneumonitis (n=1, TN cohort), COVID-19, and cerebrospinal meningitis (n=1 each, R/R cohort). Overall response was 94.4% and 85.0% in the TN and R/R cohorts, respectively; complete response rates were 77.8% and 70.0%, respectively. After a median follow-up of 47.6 months, median progression-free survival (PFS) and overall survival (OS) were not reached in the TN cohort. After a median follow-up of 20.4 months, median PFS was 28.6 months and OS was not reached in the R/R cohort. Results indicate that ABR was safe and efficacious, supporting further study in patients with TN MCL. ClinicalTrials.gov identifier: NCT02717624.}, }
@article {pmid39233917, year = {2024}, author = {Wesselink, E and Gauderman, W and Berndt, SI and Brenner, H and Buchanan, DD and Campbell, PT and Chan, AT and Chang-Claude, J and Cotterchoi, M and Gunter, MJ and Hoffmeister, M and Joshi, AD and Newton, CC and Pai, RK and Pellatt, AJ and Phipps, AI and Song, M and Um, CY and van Guelpen, B and White, E and Peters, U and van Duijnhoven, FJB}, title = {Calcium intake and genetic variants in the calcium sensing receptor in relation to colorectal cancer mortality: an international consortium study of 18,952 patients.}, journal = {BJC reports}, volume = {2}, number = {1}, pages = {63}, pmid = {39233917}, issn = {2731-9377}, support = {R01 CA059045/CA/NCI NIH HHS/United States ; U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; R01 CA248857/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA206279/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {BACKGROUND: Research on calcium intake as well as variants in the calcium sensor receptor (CaSR) gene and their interaction in relation to CRC survival is still limited.
METHODS: Data from 18,952 CRC patients, were included. Associations between primarily pre-diagnostic dietary (n = 13.085), supplemental (n = 11,837), total calcium intake (n = 5970) as well as 325 single nucleotide polymorphisms (SNPs) of the CaSR gene (n = 15,734) in relation to CRC-specific and all-cause mortality were assessed using Cox proportional hazard models. Also interactions between calcium intake and variants in the CaSR gene were assessed.
RESULTS: During a median follow-up of 4.8 years (IQR 2.4-8.4), 6801 deaths occurred, of which 4194 related to CRC. For all-cause mortality, no associations were observed for the highest compared to the lowest sex- and study-specific quartile of dietary (HR 1.00, 95%CI 0.92-1.09), supplemental (HR 0.97, 95%CI 0.89-1.06) and total calcium intake (HR 0.99, 95%CI 0.88-1.11). No associations with CRC-specific mortality were observed either. Interactions were observed between supplemental calcium intake and several SNPs of the CaSR gene.
CONCLUSION: Calcium intake was not associated with all-cause or CRC-specific mortality in CRC patients. The association between supplemental calcium intake and all-cause and CRC-specific mortality may be modified by genetic variants in the CaSR gene.}, }
@article {pmid39233850, year = {2024}, author = {Roos, CR and Bricker, J and Kiluk, B and Trull, TJ and Bowen, S and Witkiewitz, K and Kober, H}, title = {A smartphone app-based mindfulness intervention to enhance recovery from substance use disorders: Protocol for a pilot feasibility randomized controlled trial.}, journal = {Contemporary clinical trials communications}, volume = {41}, number = {}, pages = {101338}, pmid = {39233850}, issn = {2451-8654}, abstract = {BACKGROUND: Poor long-term recovery outcomes after treatment (e.g., readmission to inpatient treatment) are common among individuals with substance use disorders (SUDs). In-person mindfulness-based treatments (MBTs) are efficacious for SUDs and may improve recovery outcomes. However, existing MBTs for SUD have limited public health reach, and thus scalable delivery methods are needed. A digitally-delivered MBT for SUDs may hold promise.
METHODS: We recently developed Mindful Journey, a smartphone app-based adjunctive MBT for improving long-term recovery outcomes. In this paper, we present details on the app and describe the protocol for a single-site pilot feasibility randomized controlled trial of Mindful Journey. In this trial, individuals (n = 34) in an early phase of outpatient treatment for SUDs will be randomized to either treatment-as-usual (TAU) plus Mindful Journey, or TAU only. The trial will focus on testing the feasibility (e.g., engagement) and acceptability of the app (e.g., perceived usability and helpfulness for recovery), as well as feasibility of study procedures (e.g., assessment completion). The trial will incorporate ecological momentary assessment before and after treatment to assess mechanisms in real-time, including mindfulness, craving, difficulties with negative emotion regulation, and savoring. To examine the sensitivity to change of outcomes (substance use, substance-related problems, and psychological distress) and mechanism variables (noted above), we will test within-treatment-condition changes over time.
DISCUSSION: The proposed pilot trial will provide important preliminary data on whether Mindful Journey is feasible and acceptable among individuals with SUDs.
TRIAL REGISTRATION: ClinicalTrials.gov NCT05109507.}, }
@article {pmid39233462, year = {2024}, author = {Reiner, AS and Knight, JA and John, EM and Lynch, CF and Malone, KE and Liang, X and Woods, M and Root, JC and Bernstein, JL}, title = {Reply to "Critical analysis of the study from Reiner et al. on agreement of medical record abstraction and self-report of breast cancer treatment".}, journal = {Cancer}, volume = {130}, number = {23}, pages = {4151-4152}, doi = {10.1002/cncr.35549}, pmid = {39233462}, issn = {1097-0142}, support = {CA097397/NH/NIH HHS/United States ; CA083178/NH/NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; CA008748/NH/NIH HHS/United States ; CA129639/NH/NIH HHS/United States ; CA114236/NH/NIH HHS/United States ; CA008748/NH/NIH HHS/United States ; CA083178/NH/NIH HHS/United States ; CA097397/NH/NIH HHS/United States ; CA114236/NH/NIH HHS/United States ; CA129639/NH/NIH HHS/United States ; }, }
@article {pmid39232161, year = {2024}, author = {Zheng, XF and Sarkar, A and Lotana, H and Syed, A and Nguyen, H and Ivey, RG and Kennedy, JJ and Whiteaker, JR and Tomasik, B and Huang, K and Li, F and D'Andrea, AD and Paulovich, AG and Shah, K and Spektor, A and Chowdhury, D}, title = {CDK5-cyclin B1 regulates mitotic fidelity.}, journal = {Nature}, volume = {633}, number = {8031}, pages = {932-940}, pmid = {39232161}, issn = {1476-4687}, mesh = {Humans ; Coenzymes/metabolism ; *Cyclin B1/metabolism ; *Cyclin-Dependent Kinase 5/antagonists & inhibitors/deficiency/genetics/metabolism ; HeLa Cells ; *Mitosis ; Models, Molecular ; *Multiprotein Complexes/metabolism ; Mutation ; Phosphoproteins/metabolism ; Protein Binding ; Proteome/metabolism ; Reproducibility of Results ; }, abstract = {CDK1 has been known to be the sole cyclin-dependent kinase (CDK) partner of cyclin B1 to drive mitotic progression[1]. Here we demonstrate that CDK5 is active during mitosis and is necessary for maintaining mitotic fidelity. CDK5 is an atypical CDK owing to its high expression in post-mitotic neurons and activation by non-cyclin proteins p35 and p39[2]. Here, using independent chemical genetic approaches, we specifically abrogated CDK5 activity during mitosis, and observed mitotic defects, nuclear atypia and substantial alterations in the mitotic phosphoproteome. Notably, cyclin B1 is a mitotic co-factor of CDK5. Computational modelling, comparison with experimentally derived structures of CDK-cyclin complexes and validation with mutational analysis indicate that CDK5-cyclin B1 can form a functional complex. Disruption of the CDK5-cyclin B1 complex phenocopies CDK5 abrogation in mitosis. Together, our results demonstrate that cyclin B1 partners with both CDK5 and CDK1, and CDK5-cyclin B1 functions as a canonical CDK-cyclin complex to ensure mitotic fidelity.}, }
@article {pmid39230981, year = {2024}, author = {Collett, JA and Flannery, AH and Liu, LJ and Takeuchi, T and Basile, DP and Neyra, JA}, title = {IL-17A Levels and Progression of Kidney Disease Following Hospitalization with and without Acute Kidney Injury.}, journal = {Kidney360}, volume = {}, number = {}, pages = {}, doi = {10.34067/KID.0000000000000559}, pmid = {39230981}, issn = {2641-7650}, support = {R01DK063114/DK/NIDDK NIH HHS/United States ; U54DK137307/DK/NIDDK NIH HHS/United States ; K23DK128562/DK/NIDDK NIH HHS/United States ; R01DK063114/DK/NIDDK NIH HHS/United States ; U54DK137307/DK/NIDDK NIH HHS/United States ; K23DK128562/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Acute kidney injury (AKI) is associated with increased mortality and new or progressive chronic kidney disease (CKD). Inflammatory cells play an important role in acute organ injury. We previously demonstrated that serum IL-17A levels were significantly elevated in critically ill patients with AKI and independently associated with hospital mortality. We hypothesize that IL-17A levels are elevated in hospitalized patients with AKI at diagnosis, and sustained elevation af