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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 23 Aug 2019 at 01:39 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2019-08-22

Dimitrov D, Moore JR, Wood D, et al (2019)

Predicted effectiveness of daily and non-daily PrEP for MSM based on sex and pill-taking patterns from HPTN 067/ADAPT.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5553311 [Epub ahead of print].

BACKGROUND: HPTN 067/ADAPT evaluated the feasibility of daily and non-daily HIV pre-exposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York, U.S. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens.

METHODS: An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the iPrEx trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use.

RESULTS: We estimated that PrEP was highly protective (85%-96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%-88% efficacy) than in Harlem (62%-81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85% and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8-9 percentage points in Harlem and by 5-9 percentage points in Bangkok across regimens.

CONCLUSIONS: Our analysis suggests that PrEP was more effective among MSM in Thailand than in the U.S. as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, non-daily PrEP was less effective than daily PrEP, especially in the U.S. where the sex act coverage associated with daily use was substantially higher.

RevDate: 2019-08-22

Lee C, Lee SJ, S Haneuse (2019)

Time-to-event analysis when the event is defined on a finite time interval.

Statistical methods in medical research [Epub ahead of print].

Acute graft-versus-host disease (GVHD) is a frequent complication following hematopoietic cell transplantation (HCT). Research on risk factors for acute GVHD has tended to ignore two important clinical issues. First, post-transplant mortality is high. In our motivating data, 100-day post-HCT mortality was 15.4%. Second, acute GVHD in its classic form is only diagnosed within 100 days of the transplant; beyond 100 days, a patient may be diagnosed with late onset acute or chronic GVHD. Standard modeling of time-to-event outcomes, however, generally conceive of patients being able to experience the event at any point on the time scale. In this paper, we propose a novel multi-state model that simultaneously: (i) accounts for mortality through joint modeling of acute GVHD and death, and (ii) explicitly acknowledges the finite time interval during which the event of interest can take place. The observed data likelihood is derived, with estimation and inference via maximum likelihood. Additionally, we provide methods for estimating the absolute risk of acute GVHD and death simultaneously. The proposed framework is compared via comprehensive simulations to a number of alternative approaches that each acknowledge some but not all aspects of acute GVHD, and illustrated with an analysis of HCT data that motivated this work.

RevDate: 2019-08-22

Jain RK, Grivas P, SK Pal (2019)

Non-invasive diagnosis and monitoring of urothelial bladder cancer: are we there yet?.

BJU international, 124(3):361-362.

RevDate: 2019-08-22

Kordelas L, Görgens A, Radtke S, et al (2019)

Allogeneic transplantation of peripheral blood stem cell grafts results in a massive decrease of primitive hematopoietic progenitor frequencies in reconstituted bone marrows.

Bone marrow transplantation pii:10.1038/s41409-019-0645-7 [Epub ahead of print].

The success of allogeneic hematopoietic stem cell transplantation (alloSCT) is indicated by the reconstitution of the peripheral blood system of patients after alloSCT and the engraftment of hematopoietic stem and progenitor cells (HSPCs) into their bone marrow (BM). The number of CD34+ cells is commonly used as surrogate for the content of hematopoietic stem cells in the grafts. During the last decade, several antigens (including CD133, CD45RA, CD38, and CD10) were identified allowing discrimination of different HSPC subpopulations within the human CD34+ cell compartment. Although such studies increased our understanding of early human hematopoiesis tremendously, hardly any study dissected the CD34+ compartment in the alloSCT setting. Consequently, we comprehensively analyzed the CD34+ compartment in G-CSF-stimulated peripheral blood stem cell grafts of allogeneic donors, in BM samples of the respective recipients 4 weeks after alloSCT, and in BM samples of healthy donors. We demonstrate that alloSCT is associated with a dramatic shift from primitive to more mature HSPC types. Upon investigating whether the composition of engrafted CD34+ cells has any impact on the incidence and severity of graft-versus-host disease, we did not find any correlation. However, more detailed analyses of the CD34+ compartment may elucidate associations with other transplantation-related complications.

RevDate: 2019-08-22

Li SS, Gilbert PB, Carpp LN, et al (2019)

Fc gamma receptor polymorphisms modulated the vaccine effect on HIV-1 risk in the HVTN 505 HIV vaccine trial.

Journal of virology pii:JVI.02041-18 [Epub ahead of print].

HVTN 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection, yet enhanced HIV infection risk for others. Here we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four FCGR2C single nucleotide polymorphism (SNP) sites) (HR=9.79, p=0.035) but not among participants without the haplotype (HR=0.86, p=0.67); the interaction of vaccine and haplotype effect was significant (p=0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3 FCGR3B SNPs) (HR=2.78, p=0.058) but not among participants without the haplotype (HR=0.73, p=0.44); again, the interaction of vaccine and haplotype was significant (p-value=0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8+ T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an FCGR2A SNP and two FCGR2B SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination.IMPORTANCE By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines.

RevDate: 2019-08-22

Starr K, Greninger AL, Makhsous N, et al (2019)

Comparison of Three Adenovirus Quantitative PCR Assays with ATCC Reference Strains and Clinical Samples.

Journal of clinical microbiology pii:JCM.00735-19 [Epub ahead of print].

Adenoviruses (AdV) have been associated with a variety of human diseases and are recognized as causing significant morbidity and mortality in immunocompromised or transplant patients. Quantification of AdV DNA in plasma is notoriously difficult due to the genetic diversity of the 71 different serotypes identified to date. There is no WHO standard available to harmonize quantitative data so results between labs vary widely. In this study we compared an laboratory-developed multiplex PCR assay with primers and probes specific for each group (A-G) and subgroup E4 (Octaplex) to one with a single primer and probe set (Jothikumar, 2005) and one utilizing bisulfite pre-treatment of DNA to reduce variation prior to amplification (Genetic Signatures). Our Octaplex assay detected all low copy-number clinical samples while the other two assays had subsets of samples that did not amplify. The Jothikumar assay failed to efficiently amplify 3 of the high copy number cultured strains, while the Genetic Signatures (GS) 3base™ assay had a positive bias, resulting in higher copies/mL (> 0.5 log10) for all culture fluids tested. All three assays resulted in end-point detection of the available 51 AdV types. Using two different materials to generate a standard curve revealed that the OctaplexTaqMan assay and the Jothikumar assay both consistently gave adenovirus levels lower than the commercial platform for AdV culture fluids, but not patient samples. This study highlights the differences in detection of AdV between laboratories that can be attributed to both the PCR method as well as the reference material used for quantitation.

RevDate: 2019-08-22

Dvinge H, Guenthoer J, Porter PL, et al (2019)

RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing.

Genome research pii:gr.246678.118 [Epub ahead of print].

Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the trans-acting regulatory proteins that control alternative splicing in both healthy and malignant cells has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here demonstrate that the RNA components of the spliceosome likewise influence alternative splicing decisions and contribute to the establishment of global splicing programs. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and between normal and malignant cells. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing, but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially mis-spliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many solid and liquid tumors, we propose that a full understanding of dysregulated pre-mRNA processing in cancers requires study of the RNA as well as protein components of the splicing machinery.

RevDate: 2019-08-21

Holmberg LA, Green D, Libby E, et al (2019)

Bortezomib and Vorinostat Therapy as Maintenance Therapy after Autologous Transplant for Multiple Myeloma.

Acta haematologica pii:000501298 [Epub ahead of print].

BACKGROUND: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT.

PATIENTS AND METHODS: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles.

RESULTS: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression.

CONCLUSIONS: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.

RevDate: 2019-08-21

Navarro SL, Tarkhan A, Shojaie A, et al (2019)

Plasma metabolomics profiles suggest beneficial effects of a low-glycemic load dietary pattern on inflammation and energy metabolism.

The American journal of clinical nutrition pii:5552380 [Epub ahead of print].

BACKGROUND: Low-glycemic load dietary patterns, characterized by consumption of whole grains, legumes, fruits, and vegetables, are associated with reduced risk of several chronic diseases.

METHODS: Using samples from a randomized, controlled, crossover feeding trial, we evaluated the effects on metabolic profiles of a low-glycemic whole-grain dietary pattern (WG) compared with a dietary pattern high in refined grains and added sugars (RG) for 28 d. LC-MS-based targeted metabolomics analysis was performed on fasting plasma samples from 80 healthy participants (n = 40 men, n = 40 women) aged 18-45 y. Linear mixed models were used to evaluate differences in response between diets for individual metabolites. Kyoto Encyclopedia of Genes and Genomes (KEGG)-defined pathways and 2 novel data-driven analyses were conducted to consider differences at the pathway level.

RESULTS: There were 121 metabolites with detectable signal in >98% of all plasma samples. Eighteen metabolites were significantly different between diets at day 28 [false discovery rate (FDR) < 0.05]. Inositol, hydroxyphenylpyruvate, citrulline, ornithine, 13-hydroxyoctadecadienoic acid, glutamine, and oxaloacetate were higher after the WG diet than after the RG diet, whereas melatonin, betaine, creatine, acetylcholine, aspartate, hydroxyproline, methylhistidine, tryptophan, cystamine, carnitine, and trimethylamine were lower. Analyses using KEGG-defined pathways revealed statistically significant differences in tryptophan metabolism between diets, with kynurenine and melatonin positively associated with serum C-reactive protein concentrations. Novel data-driven methods at the metabolite and network levels found correlations among metabolites involved in branched-chain amino acid (BCAA) degradation, trimethylamine-N-oxide production, and β oxidation of fatty acids (FDR < 0.1) that differed between diets, with more favorable metabolic profiles detected after the WG diet. Higher BCAAs and trimethylamine were positively associated with homeostasis model assessment-insulin resistance.

CONCLUSIONS: These exploratory metabolomics results support beneficial effects of a low-glycemic load dietary pattern characterized by whole grains, legumes, fruits, and vegetables, compared with a diet high in refined grains and added sugars on inflammation and energy metabolism pathways. This trial was registered at clinicaltrials.gov as NCT00622661.

RevDate: 2019-08-21

Chou CK, CJ Turtle (2019)

Insight into mechanisms associated with cytokine release syndrome and neurotoxicity after CD19 CAR-T cell immunotherapy.

Bone marrow transplantation, 54(Suppl 2):780-784.

Adoptive immunotherapy with CD19-targeted chimeric antigen receptor (CAR)-T cells has been successful in producing durable remissions in some patients with relapsed or refractory B cell malignancies. Despite the efficacy of CAR-T cell therapy, significant toxicities can occur. Cytokine release syndrome (CRS) and neurotoxicity are the most common toxicities and can range from self-limited fever to life threatening organ damage and death. Understanding the mechanisms underlying these toxicities can help guide and improve outcomes. In this review we describe CRS and neurotoxicity in patients with B cell malignancies treated with CD19 CAR-T cells in pivotal trials, and also provide insight into potential mechanisms associated with these toxicities based on studies conducted in a phase 1/2 clinical trial at the Fred Hutchinson Cancer Research Center.

RevDate: 2019-08-21

Dembitz V, Tomic B, Kodvanj I, et al (2019)

The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 kinase via pyrimidine depletion.

The Journal of biological chemistry pii:RA119.009396 [Epub ahead of print].

Metabolic pathways play important roles in proliferation and differentiation of malignant cells. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr), a precursor in purine biosynthesis and a well-established activator of AMP-activated protein kinase (AMPK), induces widespread metabolic alterations and is commonly used for dissecting the role of metabolism in cancer. We have previously reported that AICAr promotes differentiation and inhibits proliferation of myeloid leukemia cells. Here, using metabolic assays, immunoblotting, flow cytometry analyses, and siRNA-mediated gene silencing in leukemia cell lines, we show that AICAr-mediated differentiation was independent of the known metabolic effects of AMPK, including glucose consumption, but instead depends on the activation of the DNA damage-associated enzyme checkpoint kinase 1 (Chk1) induced by pyrimidine depletion. LC/MS/MS metabolomics analysis revealed that AICAr increases orotate levels and decreases uridine monophosphate (UMP) levels, consistent with inhibition of UMP synthesis at a step downstream of dihydroorotate dehydrogenase (DHODH). AICAr and the DHODH inhibitor brequinar had similar effects on differentiation markers and S-phase arrest, and genetic or pharmacological Chk1 inactivation abrogated both of these effects. Our results delineate an AMPK-independent effect of AICAr on myeloid leukemia differentiation that involves perturbation of pyrimidine biosynthesis and activation of the DNA damage response network.

RevDate: 2019-08-20

Yang W, Lampe PD, Kensel-Hammes P, et al (2019)

Connexin 43 Functions as a Positive Regulator of Stem Cell Differentiation into Definitive Endoderm and Pancreatic Progenitors.

iScience, 19:450-460 pii:S2589-0042(19)30260-3 [Epub ahead of print].

Efficient stem cell differentiation into pancreatic islet cells is of critical importance for the development of cell replacement therapies for diabetes. Here, we identify the expression pattern of connexin 43 (Cx43), a gap junction (GJ) channel protein, in human embryonic stem cell (hESC)-derived definitive endoderm (DE) and primitive gut tube cells, representing early lineages for posterior foregut (PF), pancreatic progenitors (PP), pancreatic endocrine progenitors (PE), and islet cells. As the function of GJ channels is dependent on their gating status, we tested the impact of supplementing hESC-derived PP cell cultures with AAP10, a peptide that promotes Cx43 GJ channel opening. We found that this treatment promotes the expression of DE markers FoxA2 and Sox17, leads to a more efficient derivation of DE, and improves the yield of PF, PP, and PE cells. These results demonstrate a functional involvement of GJ channels in the differentiation of embryonic stem cells into pancreatic cell lineages.

RevDate: 2019-08-20

Angenendt L, Röllig C, Montesinos P, et al (2019)

Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.

METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1mut/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.

RESULTS: Among 2,426 patients with NPM1mut/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1mut/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.

CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1mut/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1mut share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1mut/FLT3-ITDneg/low AML.

RevDate: 2019-08-20

Cao D, Xu H, Xu X, et al (2019)

High tumor mutation burden predicts better efficacy of immunotherapy: a pooled analysis of 103078 cancer patients.

Oncoimmunology, 8(9):e1629258 pii:1629258.

The relation between tumor mutation burden (TMB) and outcome of cancer patients receiving immunotherapy has been reported. This study aimed to evaluate the prognostic role of TMB in cancer patients receiving immunotherapy. Databases including Embase, PubMed, and the Cochrane library were systematically searched to identify potentially eligible studies until Sep 2018 without language limitation. Studies assessing high versus low TMB in predicting survival of various cancer patients were selected. The pooled analyses were conducted using hazard ratio (HR) of high versus low TMB for overall survival (OS) and progression-free survival (PFS), and the odds ratio (OR) for overall response rate (ORR). The primary endpoint was OS. Secondary outcomes were PFS and ORR. A total of 45 studies consisting of 103078 cancer patients were included. The combined results showed that high TMB was associated with better OS (HR = 0.40; 95% confidence interval (CI):0.30-0.53; p< .00001), PFS (HR = 0.37; 95% CI: 0.26-0.53; p< .00001) and ORR (OR = 4.62; 95%CI: 2.90-7.34; p< .0001) when treated with immunotherapy. In studying patients with high TMB, these patients had improved OS (HR = 0.69; 95%CI: 0.47-1.03; p= .07) when comparing immunotherapy to chemotherapy. Subgroup analyses suggested that the prognostic role of TMB was independent of cancer types and TMB detection methods (all p< .05). Our findings suggest that high TMB is associated with better survival in cancer patients receiving immunotherapy. For cancer patients with high TMB, immunotherapy could be considered.

RevDate: 2019-08-20

Müller NF, Dudas G, T Stadler (2019)

Inferring time-dependent migration and coalescence patterns from genetic sequence and predictor data in structured populations.

Virus evolution, 5(2):vez030 pii:vez030.

Population dynamics can be inferred from genetic sequence data by using phylodynamic methods. These methods typically quantify the dynamics in unstructured populations or assume migration rates and effective population sizes to be constant through time in structured populations. When considering rates to vary through time in structured populations, the number of parameters to infer increases rapidly and the available data might not be sufficient to inform these. Additionally, it is often of interest to know what predicts these parameters rather than knowing the parameters themselves. Here, we introduce a method to infer the predictors for time-varying migration rates and effective population sizes by using a generalized linear model (GLM) approach under the marginal approximation of the structured coalescent. Using simulations, we show that our approach is able to reliably infer the model parameters and its predictors from phylogenetic trees. Furthermore, when simulating trees under the structured coalescent, we show that our new approach outperforms the discrete trait GLM model. We then apply our framework to a previously described Ebola virus dataset, where we infer the parameters and its predictors from genome sequences while accounting for phylogenetic uncertainty. We infer weekly cases to be the strongest predictor for effective population size and geographic distance the strongest predictor for migration. This approach is implemented as part of the BEAST2 package MASCOT, which allows us to jointly infer population dynamics, i.e. the parameters and predictors, within structured populations, the phylogenetic tree, and evolutionary parameters.

RevDate: 2019-08-20

Liu Y, Sun W, Reiner AP, et al (2019)

Statistical inference of genetic pathway analysis in high dimensions.

Biometrika, 106(3):651.

Genetic pathway analysis has become an important tool for investigating the association between a group of genetic variants and traits. With dense genotyping and extensive imputation, the number of genetic variants in biological pathways has increased considerably and sometimes exceeds the sample size [Formula: see text]. Conducting genetic pathway analysis and statistical inference in such settings is challenging. We introduce an approach that can handle pathways whose dimension [Formula: see text] could be greater than [Formula: see text]. Our method can be used to detect pathways that have nonsparse weak signals, as well as pathways that have sparse but stronger signals. We establish the asymptotic distribution for the proposed statistic and conduct theoretical analysis on its power. Simulation studies show that our test has correct Type I error control and is more powerful than existing approaches. An application to a genome-wide association study of high-density lipoproteins demonstrates the proposed approach.

RevDate: 2019-08-20

Bae J, Parayath N, Ma W, et al (2019)

BCMA peptide-engineered nanoparticles enhance induction and function of antigen-specific CD8+ cytotoxic T lymphocytes against multiple myeloma: clinical applications.

Leukemia pii:10.1038/s41375-019-0540-7 [Epub ahead of print].

The purpose of these studies was to develop and characterize B-cell maturation antigen (BCMA)-specific peptide-encapsulated nanoparticle formulations to efficiently evoke BCMA-specific CD8+ cytotoxic T lymphocytes (CTL) with poly-functional immune activities against multiple myeloma (MM). Heteroclitic BCMA72-80 [YLMFLLRKI] peptide-encapsulated liposome or poly(lactic-co-glycolic acid) (PLGA) nanoparticles displayed uniform size distribution and increased peptide delivery to human dendritic cells, which enhanced induction of BCMA-specific CTL. Distinct from liposome-based nanoparticles, PLGA-based nanoparticles demonstrated a gradual increase in peptide uptake by antigen-presenting cells, and induced BCMA-specific CTL with higher anti-tumor activities (CD107a degranulation, CTL proliferation, and IFN-γ/IL-2/TNF-α production) against primary CD138+ tumor cells and MM cell lines. The improved functional activities were associated with increased Tetramer+/CD45RO+ memory CTL, CD28 upregulation on Tetramer+ CTL, and longer maintenance of central memory (CCR7+ CD45RO+) CTL, with the highest anti-MM activity and less differentiation into effector memory (CCR7- CD45RO+) CTL. These results provide the framework for therapeutic application of PLGA-based BCMA immunogenic peptide delivery system, rather than free peptide, to enhance the induction of BCMA-specific CTL with poly-functional Th1-specific anti-MM activities. These results demonstrate the potential clinical utility of PLGA nanotechnology-based cancer vaccine to enhance BCMA-targeted immunotherapy against myeloma.

RevDate: 2019-08-20

Lastwika KJ, Dunn CA, Solan JL, et al (2019)

Phosphorylation of connexin43 at MAPK, PKC or CK1 sites each distinctly alter the kinetics of epidermal wound repair.

Journal of cell science pii:jcs.234633 [Epub ahead of print].

The gap junction protein Connexin 43 (Cx43) is a key player in wound healing and inhibitors of Cx43, which speed epidermal wound healing, are currently in clinical trials. Here, we provide direct in vivo evidence that specific phosphorylation events on Cx43 change the physiological response during wound healing. Blocking phosphorylation by mutation of serines in Cx43 at PKC or CK1 sites significantly slowed the rate of wound closure in vivo and in vitro and resulted in a thicker epidermal layer after reepithelialization. Conversely, preventing Cx43 phosphorylation by MAPK site mutation significantly increased the rate of wound closure in vivo Defects in migration, but not proliferation, in all mutants were partially rescued in vitro by changing serines to aspartic or glutamic acid. These data prove that specific Cx43 phosphorylation events play an important role at different stages of wound healing. Thus, a clear physiological understanding of the spatiotemporal regulation of kinase activation and consequent effects on gap junctions could lead to a more targeted approach to modulating Cx43 expression during wound healing.

RevDate: 2019-08-20

Motzer RJ, Rini BI, McDermott DF, et al (2019)

Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.

The Lancet. Oncology pii:S1470-2045(19)30413-9 [Epub ahead of print].

BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.

METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.

FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.

INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.

FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.

RevDate: 2019-08-20

Moreland BS, Oman KM, R Bundschuh (2019)

A model of pulldown alignments from SssI-treated DNA improves DNA methylation prediction.

BMC bioinformatics, 20(1):431 pii:10.1186/s12859-019-3011-2.

BACKGROUND: Protein pulldown using Methyl-CpG binding domain (MBD) proteins followed by high-throughput sequencing is a common method to determine DNA methylation. Algorithms have been developed to estimate absolute methylation level from read coverage generated by affinity enrichment-based techniques, but the most accurate one for MBD-seq data requires additional data from an SssI-treated Control experiment.

RESULTS: Using our previous characterizations of Methyl-CpG/MBD2 binding in the context of an MBD pulldown experiment, we build a model of expected MBD pulldown reads as drawn from SssI-treated DNA. We use the program BayMeth to evaluate the effectiveness of this model by substituting calculated SssI Control data for the observed SssI Control data. By comparing methylation predictions against those from an RRBS data set, we find that BayMeth run with our modeled SssI Control data performs better than BayMeth run with observed SssI Control data, on both 100 bp and 10 bp windows. Adapting the model to an external data set solely by changing the average fragment length, our calculated data still informs the BayMeth program to a similar level as observed data in predicting methylation state on a pulldown data set with matching WGBS estimates.

CONCLUSION: In both internal and external MBD pulldown data sets tested in this study, BayMeth used with our modeled pulldown coverage performs better than BayMeth run without the inclusion of any estimate of SssI Control pulldown, and is comparable to - and in some cases better than - using observed SssI Control data with the BayMeth program. Thus, our MBD pulldown alignment model can improve methylation predictions without the need to perform additional control experiments.

RevDate: 2019-08-19

Wang Y, McReynolds LJ, Dagnall C, et al (2019)

Pre-transplant short telomeres are associated with high mortality risk after unrelated donor haematopoietic cell transplant for severe aplastic anaemia.

British journal of haematology [Epub ahead of print].

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre-transplant short (<10th percentile-for-age) or very short (<5th or <1st percentile-for-age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre-transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age = 20 years). One hundred and twelve patients (22·86%) had pre-HCT RTL <10th percentile-for-age, with the majority below the 5th percentile (N = 80, 71·43%). RTL <10th percentile-for-age was associated with a higher risk of post-HCT mortality (hazard ratio [HR] = 1·78, 95% confidence interval [CI]=1·18-2·69, P = 0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P > 0·10). Time-dependent effects for post-HCT mortality were only observed in relation to very short RTL; HR comparing RTL <5th versus ≥5th percentile = 1·38, P = 0·15 for the first 12 months after HCT, and HR = 3·91, P < 0·0001, thereafter, P-heterogeneity = 0·008; the corresponding HRs for RTL <1st versus ≥1st percentile = 1·29, P = 0·41, and HR = 5·18, P < 0·0001, P-heterogeneity = 0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.

RevDate: 2019-08-19

Tsamadou C, Fürst D, Wang T, et al (2019)

DONOR HLA-E STATUS ASSOCIATES WITH DISEASE FREE SURVIVAL AND TRANSPLANT RELATED MORTALITY AFTER NON IN VIVO T-CELL DEPLETED HSCT FOR ACUTE LEUKEMIA.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30521-X [Epub ahead of print].

Previous studies have suggested that HLA-E may have a significant role in the outcome of matched unrelated hematopoietic stem cell transplantation (HSCT) especially for patients with acute leukemia. We used CIBMTR data and samples of 1840 adult acute leukemia patients and their 10/10 HLA-matched unrelated donors to investigate the impact of HLA-E matching status as well as of donor/recipient (D/R) HLA-E genotype on post-HSCT outcome. Both, patients and donors were HLA-E genotyped by next generation sequencing. All patients received their first transplant in complete remission between 2000 and 2015. Median follow-up time was 90 months. Overall survival, disease free survival (DFS), transplant-related mortality (TRM) and relapse incidence were primary endpoints with statistical significance set at 0.01. D/R HLA-E genotype analysis revealed a significant association of donor HLA-E*01:03/01:03 genotype with DFS (HR=1.35, p=0.0006) and TRM (HR=1.41, p=0.0058) in patients who received T-cell replete (i.e. without in vivo T-cell depletion) transplants (n=1297). As to D/R HLA-E matching, we did not identify any significant effect on any of the clinical outcome endpoints. In conclusion, this is the largest study to date reporting an improvement of DFS and TRM after matched unrelated HSCT by avoidance of HLA-E*01:03 homozygous donors in patients transplanted with T-cell replete grafts for acute leukemia.

RevDate: 2019-08-19

Fall-Dickson JM, Pavletic SZ, Mays JW, et al (2019)

Oral Complications of Chronic Graft-Versus-Host Disease.

Journal of the National Cancer Institute. Monographs, 2019(53):.

The increasing clinical indications for hematopoietic stem cell transplantation (HSCT) and improved clinical care throughout and following HSCT have led to not only long-term survival but also to an increasing incidence and prevalence of graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT, with increasing incidence in pediatric patients as well. Oral cGVHD specifically has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to significantly decreased caloric intake, oral infections, and increased health service utilization, and may thus affect overall health and survival. The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids, and calcineurin inhibitors. This review of oral complications of cGVHD presents the clinical significance of oral cGVHD to HSCT survivors, our current understanding of the pathobiology of oral cGVHD and gaps in this evidence, and the global targeted interdisciplinary clinical research efforts, including the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Current challenges regarding the management of oral cGVHD and strategies to advance our scientific understanding of this clinically significant chronic oral disease are presented.

RevDate: 2019-08-19

Ahmad K, AE Spens (2019)

Separate Polycomb Response Elements control chromatin state and activation of the vestigial gene.

PLoS genetics, 15(8):e1007877 pii:PGENETICS-D-18-02285 [Epub ahead of print].

Patterned expression of many developmental genes is specified by transcription factor gene expression, but is thought to be refined by chromatin-mediated repression. Regulatory DNA sequences called Polycomb Response Elements (PREs) are required to repress some developmental target genes, and are widespread in genomes, suggesting that they broadly affect developmental programs. While PREs in transgenes can nucleate trimethylation on lysine 27 of the histone H3 tail (H3K27me3), none have been demonstrated to be necessary at endogenous chromatin domains. This failure is thought to be due to the fact that most endogenous H3K27me3 domains contain many PREs, and individual PREs may be redundant. In contrast to these ideas, we show here that PREs near the wing selector gene vestigial have distinctive roles at their endogenous locus, even though both PREs are repressors in transgenes. First, a PRE near the promoter is required for vestigial activation and not for repression. Second, only the distal PRE contributes to H3K27me3, but even removal of both PREs does not eliminate H3K27me3 across the vestigial domain. Thus, endogenous chromatin domains appear to be intrinsically marked by H3K27me3, and PREs appear required to enhance this chromatin modification to high levels at inactive genes.

RevDate: 2019-08-18

Lu AT, Seeboth A, Tsai PC, et al (2019)

DNA methylation-based estimator of telomere length.

Aging pii:102173 [Epub ahead of print].

Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.

RevDate: 2019-08-17

Wang L, Huang Y, Z Feng (2019)

Strategies for validating biomarkers using data from a reference set.

Biostatistics (Oxford, England) pii:5550953 [Epub ahead of print].

Candidate biomarkers discovered in the laboratory need to be rigorously validated before advancing to clinical application. However, it is often expensive and time-consuming to collect the high quality specimens needed for validation; moreover, such specimens are often limited in volume. The Early Detection Research Network has developed valuable specimen reference sets that can be used by multiple labs for biomarker validation. To optimize the chance of successful validation, it is critical to efficiently utilize the limited specimens in these reference sets on promising candidate biomarkers. Towards this end, we propose a novel two-stage validation strategy that partitions the samples in the reference set into two groups for sequential validation. The proposed strategy adopts the group sequential testing method to control for the type I error rate and rotates group membership to maximize the usage of available samples. We develop analytical formulas for performance parameters of this strategy in terms of the expected numbers of biomarkers that can be evaluated and the truly useful biomarkers that can be successfully validated, which can provide valuable guidance for future study design. The performance of our proposed strategy for validating biomarkers with respect to the points on the receiver operating characteristic curve are evaluated via extensive simulation studies and compared with the default strategy of validating each biomarker using all samples in the reference set. Different types of early stopping rules and boundary shapes in the group sequential testing method are considered. Compared with the default strategy, our proposed strategy makes more efficient use of the limited resources in the reference set by allowing more candidate biomarkers to be evaluated, giving a better chance of having truly useful biomarkers successfully validated.

RevDate: 2019-08-17

Li A, Kuderer NM, Garcia DA, et al (2019)

Direct Oral Anticoagulant for the Prevention of Thrombosis in Ambulatory Patients with Cancer: A Systematic Review and Meta-Analysis.

Journal of thrombosis and haemostasis : JTH [Epub ahead of print].

BACKGROUND: It is unclear if direct oral anticoagulant (DOAC) is efficacious and safe for prophylaxis of venous thromboembolism (VTE) in ambulatory patients with cancer.

METHODS: We performed a systematic review using EMBASE, MEDLINE, and CENTRAL. Inclusion criteria included adult ambulatory patients with cancer, prophylactic use of DOAC, and randomized controlled trials (RCT). Exclusion criteria included pediatric patients, inpatient or post-operative setting, therapeutic indication of DOAC, or non-phase III RCT. Two authors screened/reviewed articles and abstracted the data. Meta-analysis was performed using random-effects model. Efficacy outcome included overall and symptomatic VTE incidence during the first six months. Safety outcomes included major bleeding and clinically relevant non-major bleeding (CRNMB) incidence during the on-treatment period. Subgroup analysis was performed for intermediate- and high-risk Khorana Score.

RESULTS: A total of 202 records were identified and 28 full-text articles were assessed. Two studies with 1415 participants were included for meta-analysis. For DOAC versus placebo, the relative risks (RR) for overall and symptomatic VTE incidence by six months were 0.56 (0.35-0.89) and 0.58 (0.29-1.13), respectively. The RR for major bleeding and CRNMB while on-treatment were 1.96 (0.80-4.82) and 1.28 (0.74-2.20), respectively. Patients with high-risk Khorana score (3+) derived the largest absolute risk reduction of VTE.

CONCLUSIONS: Low-dose DOAC reduces the rate of overall VTE in higher-risk cancer patients starting systemic chemotherapy. It may reduce the rate of symptomatic VTE but increase the likelihood of bleeding. This article is protected by copyright. All rights reserved.

RevDate: 2019-08-17

Mell LK, Shen H, Nguyen-Tan PF, et al (2019)

Nomogram to Predict the Benefit of Intensive Treatment for Locoregionally Advanced Head and Neck Cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-1832 [Epub ahead of print].

PURPOSE: Previous studies indicate the benefit of therapy depends on patients' risk for cancer recurrence relative to non-cancer mortality (ω ratio). We sought to test the hypothesis that head and neck cancer (HNC) patients with a higher ω ratio selectively benefit from intensive therapy.

EXPERIMENTAL DESIGN: We analyzed 2688 patients with stage III-IVB HNC undergoing primary radiation therapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio, and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation (AFX) and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score based on tumor, demographic, and health factors. Analysis was by intention-to-treat.

RESULTS: Decreasing age, improved performance status, higher body mass index, node positive status, P16 negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥ 0.80 were more likely to benefit from intensive treatment (5-year OS, 70.0% vs. 56.6%; HR 0.73, 95% CI 0.57-0.94; P=0.016) than those with a ω score < 0.80 (5-year OS, 46.7% vs. 45.3%; HR 1.02, 95% CI 0.92-1.14; P=0.69;P=0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression.

CONCLUSION: HNC patients with a higher ω score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.

RevDate: 2019-08-17

Lindstrom S, Wang L, Smith EN, et al (2019)

Genomic and Transcriptomic Association Studies Identify 16 Novel Susceptibility Loci for Venous Thromboembolism.

Blood pii:blood.2019000435 [Epub ahead of print].

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30,234 VTE cases and 172,122 controls and assessed the association between 12,923,718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new, independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for both novel and previously known regions co-localized with eQTL signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

RevDate: 2019-08-16

Cordeiro A, Bezerra ED, Hirayama AV, et al (2019)

Late events after treatment with CD19-Targeted Chimeric Antigen Receptor Modified T-cells.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30517-8 [Epub ahead of print].

CD19-targeted CAR-T cell therapy has shown excellent anti-tumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy are still unknown. Here we report late adverse events, defined as beginning or persisting beyond 90 days after CAR-T cell infusion, in patients who survived at least one year after therapy. Median follow-up was 28.1 months (range, 12.5-62.6). At last follow-up 73% of patients were still alive, and 24% were in ongoing complete remission [1]. The most common late adverse event was hypogammaglobulinemia (IgG <400 mg/dL or IVIG replacement), observed in 67% of patients with available data. Infection density was 0.55 infections/100 days at risk (2.08/patient year). 80% of the infections were treated in the outpatient setting, and 5% required admission to the intensive care unit. Subsequent malignancies occurred in 15% of patients, including 5% myelodysplastic syndrome (MDS). Among patients with ongoing CR and with no MDS, 16% experienced prolonged cytopenias, requiring transfusions or growth factor support. Graft versus host disease (GVHD) occurred in three of 15 patients (20%) who had a prior allogeneic hematopoietic cell transplantation. Most of the late events observed in this cohort were not severe and many could be related to prior or subsequent therapies, suggesting a safe long-term profile of CD19-targeted CAR-T cell immunotherapy.

RevDate: 2019-08-16

Storb R, Georges GE, TA Gooley (2019)

TBI- VS. Chemotherapy-Based Myeloablative Conditioning for Allogeneic HCT.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30519-1 [Epub ahead of print].

THE QUESTION What is better, myeloablative chemotherapy-based conditioning or total body irradiation (TBI)-based conditioning for younger (<60 years) and medically fit patients with hematologic malignancies in preparation for allogeneic hematopoietic cell transplantation (HCT), has been a recurring question. Why has a universally accepted answer been elusive despite more than 30 years of mainly multi-center, retrospective analyses and a handful of prospective trials?

RevDate: 2019-08-16

Kunkle BW, Grenier-Boley B, Sims R, et al (2019)

Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RevDate: 2019-08-16

Kuhlman B, P Bradley (2019)

Advances in protein structure prediction and design.

Nature reviews. Molecular cell biology pii:10.1038/s41580-019-0163-x [Epub ahead of print].

The prediction of protein three-dimensional structure from amino acid sequence has been a grand challenge problem in computational biophysics for decades, owing to its intrinsic scientific interest and also to the many potential applications for robust protein structure prediction algorithms, from genome interpretation to protein function prediction. More recently, the inverse problem - designing an amino acid sequence that will fold into a specified three-dimensional structure - has attracted growing attention as a potential route to the rational engineering of proteins with functions useful in biotechnology and medicine. Methods for the prediction and design of protein structures have advanced dramatically in the past decade. Increases in computing power and the rapid growth in protein sequence and structure databases have fuelled the development of new data-intensive and computationally demanding approaches for structure prediction. New algorithms for designing protein folds and protein-protein interfaces have been used to engineer novel high-order assemblies and to design from scratch fluorescent proteins with novel or enhanced properties, as well as signalling proteins with therapeutic potential. In this Review, we describe current approaches for protein structure prediction and design and highlight a selection of the successful applications they have enabled.

RevDate: 2019-08-16

Ozog S, Timberlake ND, Hermann K, et al (2019)

Resveratrol trimer enhances gene delivery to hematopoietic stem cells by reducing antiviral restriction at endosomes.

Blood pii:blood.2019000040 [Epub ahead of print].

Therapeutic gene delivery to hematopoietic stem cells (HSCs) holds great potential as a life-saving treatment for a range of monogenic, oncologic, and infectious diseases. However, clinical gene therapy is severely limited by intrinsic HSC resistance to modification with lentiviral vectors (LVs), thus requiring high doses or repeat LV administration to achieve therapeutic gene correction. Here we show that temporary co-application of the cyclic resveratrol trimer caraphenol A enhances LV gene delivery efficiency to human and non-human primate hematopoietic stem and progenitor cells. While significant ex vivo, this effect was most dramatically observed in human lineages derived from HSCs transplanted into immunodeficient mice. We further demonstrate that caraphenol A relieves restriction of LV transduction by altering the levels of interferon-induced transmembrane (IFITM) proteins IFITM2 and IFITM3 and their association with late endosomes, thus augmenting LV core endosomal escape. Caraphenol A-mediated IFITM downregulation did not alter the LV integration pattern or bias lineage differentiation. Taken together, these findings compellingly demonstrate that the pharmacologic modification of intrinsic immune restriction factors is a promising and non-toxic approach for improving LV-mediated gene therapy.

RevDate: 2019-08-16

Hill JA, Giralt S, Torgerson TR, et al (2019)

CAR-T - and a side order of IgG, to go? - Immunoglobulin replacement in patients receiving CAR-T cell therapy.

Blood reviews pii:S0268-960X(19)30067-0 [Epub ahead of print].

The development and regulatory approval of chimeric antigen receptor T cell (CAR-T) therapies targeting the B-lineage surface antigen CD19 represents a major milestone in cancer immunotherapy. This treatment also results in depletion of normal CD19+ B cells and is associated with hypogammaglobulinemia. These on-target, off-tumor toxicities may result in an increased risk for infection, particularly for encapsulated bacteria. Data regarding the efficacy and cost-effectiveness of prophylactic IgG replacement in CD19-targeted CAR-T cell therapy recipients is lacking, and current expert recommendations are extrapolated from the data for individuals with primary immune deficiencies. This article reviews CAR-T cell therapies targeting B-lineage lymphocytes, associated side effects, and considerations for the approach to management of hypogamaglobulinemia in this patient population. Studies are needed to establish evidence-based approaches to prophylactic immunoglobulin administration in this context, and strategies may differ by patient and CAR-T cell product characteristics.

RevDate: 2019-08-15

Lim B, Tsolaki M, Soosaipillai A, et al (2019)

Liquid biopsy of cerebrospinal fluid identifies neuronal pentraxin receptor (NPTXR) as a biomarker of progression of Alzheimer's disease.

Clinical chemistry and laboratory medicine pii:/j/cclm.ahead-of-print/cclm-2019-0428/cclm-2019-0428.xml [Epub ahead of print].

Background Alzheimer's disease (AD) is the most prevalent form of dementia. Currently, the most studied biomarkers of AD are cerebrospinal fluid (CSF) amyloid β 1-42, total tau and phosphorylated tau. However, misdiagnosis can exceed 20%. Recently, we found that CSF amyloid β precursor-like protein-1 (APLP1) and neuronal pentraxin receptor (NPTXR) are promising biomarkers of AD. The aim of the present study is to validate CSF APLP1 and NPTXR as biomarkers of AD severity. Methods APLP1 and NPTXR concentrations were measured in the CSF of patients with mild cognitive impairment (MCI) (n = 14), mild AD (n = 21), moderate AD (n = 43) and severe AD (n = 30) using enzyme-linked immunosorbent assays (ELISAs). Results CSF APLP1 and NPTXR were not associated with age or sex. CSF APLP1 was not different between any of the AD severity groups (p = 0.31). CSF NPTXR was significantly different between MCI and mild AD (p = 0.006), mild and moderate AD (p = 0.016), but not between moderate and severe AD (p = 0.36). NPTXR concentration progressively declined from MCI to mild, to moderate and to severe AD patients (p < 0.0001, Kruskal-Wallis test). CSF NPTXR positively correlated with the Mini-Mental Status Examination (MMSE) score (p < 0.001). Conclusions NPTXR concentration in CSF is a promising biomarker of AD severity and could inform treatment success and disease progression in clinical settings.

RevDate: 2019-08-15

McGuckin Wuertz K, Treuting PM, Hemann EA, et al (2019)

STING is required for host defense against neuropathological West Nile virus infection.

PLoS pathogens, 15(8):e1007899 pii:PPATHOGENS-D-19-00259.

West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.

RevDate: 2019-08-14

Wirsching HG, Arora S, Zhang H, et al (2019)

Cooperation of oncolytic virotherapy with VEGF-neutralizing antibody treatment in IDH wildtype glioblastoma dependends on MMP9.

Neuro-oncology pii:5550114 [Epub ahead of print].

RevDate: 2019-08-14

Matrajt L, Halloran ME, R Antia (2019)

Reply to Lindsey, Höschler and de Silva.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5549961 [Epub ahead of print].

RevDate: 2019-08-14

Patterson K, Prabhu V, Xu R, et al (2018)

Cost-effectiveness of Pembrolizumab for Patients with Advanced, Unresectable, or Metastatic Urothelial Cancer Ineligible for Cisplatin-based Therapy.

European urology oncology pii:S2588-9311(18)30169-X [Epub ahead of print].

BACKGROUND: There is an unmet need for effective therapies for patients with advanced or metastatic urothelial cancer who cannot tolerate cisplatin-based chemotherapy. Cisplatin-ineligible patients experience a high frequency of adverse events from the most commonly used standard of care treatment, carboplatin plus gemcitabine, or alternative treatment with gemcitabine monotherapy. Pembrolizumab is a potent, highly selective humanised monoclonal antibody that releases checkpoint inhibition of the immune response system, and provides a new alternative for these patients.

OBJECTIVE: To assess the cost-effectiveness of pembrolizumab for first-line treatment of urothelial carcinoma ineligible for cisplatin-based therapy in patients with strongly PD-L1-positive tumours in Sweden.

Parametric survival curves were fitted to overall survival, progression-free survival, and time on treatment data from KEYNOTE-052 to extrapolate clinical outcomes. A simulated treatment comparison and a network meta-analysis were conducted to estimate the comparative efficacy of pembrolizumab versus carboplatin plus gemcitabine and gemcitabine monotherapy. EQ-5D data from KEYNOTE-052 were used to estimate utility, while resource use and cost inputs were estimated using Swedish regional pricing lists and clinician opinion.

The model reported costs, life years, and quality-adjusted life years (QALYs), and results were tested using deterministic and probabilistic sensitivity analysis.

RESULTS AND LIMITATIONS: We estimated that pembrolizumab would improve survival by 2.11 and 2.16 years and increase QALYs by 1.71 and 1.75 compared to carboplatin plus gemcitabine and gemcitabine monotherapy, respectively. Pembrolizumab was associated with a cost increase of €90520 versus carboplatin plus gemcitabine and €95055 versus gemcitabine, with corresponding incremental cost-effectiveness ratios of €53055/QALY and €54415/QALY.

CONCLUSIONS: At a willingness-to-pay threshold of €100000/QALY, pembrolizumab is a cost-effective treatment versus carboplatin plus gemcitabine and versus gemcitabine.

PATIENT SUMMARY: This is the first analysis to show that pembrolizumab is a cost-effective option for first-line treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma in Sweden.

RevDate: 2019-08-14

Martinez Chanza N, Werner L, Plimack E, et al (2019)

Incidence, Patterns, and Outcomes with Adjuvant Chemotherapy for Residual Disease After Neoadjuvant Chemotherapy in Muscle-invasive Urinary Tract Cancers.

European urology oncology pii:S2588-9311(19)30001-X [Epub ahead of print].

BACKGROUND: Patients with residual muscle-invasive urinary tract cancer after neoadjuvant chemotherapy (NAC) have a high risk of recurrence.

OBJECTIVE: To retrospectively evaluate whether additional adjuvant chemotherapy (AC) improves outcomes compared with surveillance in patients with significant residual disease despite NAC.

We identified 474 patients who received NAC from the Retrospective International Study of Cancers of the Urothelium database, of whom 129 had adverse residual disease (≥ypT3 and/or ypN+).

Time to relapse (TTR) was the primary endpoint assessed starting from 2mo after surgery to minimize immortal time bias. Secondary endpoints included overall survival (OS), incidence of AC use, and chemotherapy patterns. Kaplan-Meier and Cox regression models estimated TTR, OS, and associations with AC, adjusting for the type of NAC, age, and pathological stage in multivariable analyses.

RESULTS AND LIMITATIONS: A total of 106 patients underwent surveillance, while 23 received AC. Gemcitabine-cisplatin was the most frequent regimen employed in both settings (30.4%), and the majority (82.6%) of the patients switched to a different regimen. Median follow-up was 30mo. Over 50% of patients developed a recurrence. Median TTR was 16mo (range: <1-108mo). Longer median TTR was observed with AC compared with surveillance (18 vs 10mo, p=0.06). Risk of relapse significantly decreased with AC when adjusted in multivariable analyses (p=0.01). The subgroup analyses of ypT4b/ypN+ patients (AC: 19; surveillance: 50) who received AC had significantly greater median TTR (20 vs 9mo; hazard ratio 0.43; 95% confidence interval: 0.21-0.89). No difference in OS was found. Limitations include the retrospective design.

CONCLUSIONS: The utilization of AC after NAC in patients with high-risk residual disease is not frequent in clinical practice but might reduce the risk of recurrence. Further investigation is needed in this high-risk population to identify optimal therapy and to improve clinical outcomes such as the ongoing adjuvant immunotherapy trials.

PATIENT SUMMARY: We found that administering additional chemotherapy in patients who had significant residual disease despite preoperative chemotherapy is not frequent in clinical practice. While it might reduce the risk of recurrence, it did not clearly increase overall survival. We encourage participation in the ongoing immunotherapy trials to see whether we can improve outcomes using a different type of therapy that stimulates the immune system.

RevDate: 2019-08-14

Foerster M, Anderson BO, McKenzie F, et al (2019)

Inequities in breast cancer treatment in sub-Saharan Africa: findings from a prospective multi-country observational study.

Breast cancer research : BCR, 21(1):93 pii:10.1186/s13058-019-1174-4.

BACKGROUND: Improving breast cancer survival in sub-Saharan Africa (SSA) is urgently needed, requiring early diagnosis and improved access to treatment. However, data on the types of and barriers to receiving breast cancer therapy in this region are limited and have not been compared between different SSA countries and treatment settings.

METHODS: In different health care settings across Uganda, Nigeria and Namibian sites of the prospective African Breast Cancer - Disparities in Outcomes cohort study, we assessed the percentage of newly diagnosed breast cancer patients who received treatment (systemic, surgery and/or radiotherapy) for cancer and their socio-demographic and clinical determinants. Treatment data were systematically extracted from medical records, as well as self-reported by women during 6-month follow-up interviews, and were used to generate a binary indicator of treatment received within 12 months of diagnosis (yes/no), which was analysed via logistic regression.

RESULTS: Of 1325 women, cancer treatment had not been initiated treatment within 1 year of diagnosis for 227 (17%) women and 185 (14%) of women with stage I-III disease. Untreated percentages were highest in two Nigerian regional hospitals where 38% of 314 women were not treated (32% among stage I-III). At a national referral hospital in Uganda, 18% of 430 women were not treated (15% among stage I-III). In contrast, at a cancer care centre in Windhoek, Namibia, where treatment is provided free to the patient, all non-black (100%) and almost all (98.7%) black women had initiated treatment. Percentages of untreated women were higher in women from lower socio-economic groups, women who believed in traditional medicine and, in Uganda, in HIV+ women. Self-reported treatment barriers confirmed treatment costs and treatment refusal as contributors to not receiving treatment.

CONCLUSIONS: Financial support to ensure treatment access and education of treatment benefits are needed to improve treatment access for breast cancer patients across sub-Saharan Africa, especially at regional treatment centres, for lower socio-economic groups, and for the HIV-positive woman with breast cancer.

RevDate: 2019-08-14

Ma H, Malone KE, McDonald JA, et al (2019)

Pre-diagnosis alcohol consumption and mortality risk among black women and white women with invasive breast cancer.

BMC cancer, 19(1):800 pii:10.1186/s12885-019-5991-8.

BACKGROUND: Alcohol consumption is associated with increased risk of breast cancer; however, its association with subsequent risk of breast cancer death is unclear.

METHODS: We followed 4523 women with complete information on relevant risk factors for mortality; these women were 35 to 64 years of age when diagnosed with incident invasive breast cancer between 1994 and 1998. During follow up (median, 8.6 years), 1055 women died; 824 died from breast cancer. The information on alcohol consumption before diagnosis was collected shortly after breast cancer diagnosis (average: 5.1 months) during an in-person interview which used a structured questionnaire. Multivariable Cox proportional hazards regression models provided hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific mortality, mortality due to causes other than breast cancer, and all-cause mortality associated with alcohol consumption from age 15 years until breast cancer diagnosis and during recent periods of time prior to breast cancer diagnosis.

RESULTS: Average weekly alcohol consumption from age 15 years until breast cancer diagnosis was inversely associated with breast cancer-specific mortality (Ptrend = 0.01). Compared to non-drinkers, women in the highest average weekly alcohol consumption category (≥7 drinks/week) had 25% lower risk of breast cancer-specific mortality (HR = 0.75, 95% CI = 0.56-1.00). Breast cancer mortality risk was also reduced among women in the highest average weekly alcohol consumption category in two recent time periods (5-year period ending 2-years prior to breast cancer diagnosis, HR = 0.74, 95% CI = 0.57-0.95; 2-year period immediately prior to breast cancer diagnosis: HR = 0.73, 95% CI = 0.56-0.95). Furthermore, analyses of average weekly alcohol consumption by beverage type from age 15 years until breast cancer diagnosis suggested that wine consumption was inversely associated with breast cancer-specific mortality risk (wine Ptrend = 0.06, beer Ptrend = 0.24, liquor Ptrend = 0.74). No association with any of these alcohol consumption variables was observed for mortality risk due to causes other than breast cancer.

CONCLUSIONS: Overall, we found no evidence that alcohol consumption before breast cancer diagnosis increases subsequent risk of death from breast cancer.

RevDate: 2019-08-13

Liu X, Yue Z, Cao Y, et al (2019)

Graft-Versus-Host Disease-Free Antitumoral Signature After Allogeneic Donor Lymphocyte Injection Identified by Proteomics and Systems Biology.

JCO precision oncology, 3:.

PURPOSE: As a tumor immunotherapy, allogeneic hematopoietic cell transplantation with subsequent donor lymphocyte injection (DLI) aims to induce the graft-versus-tumor (GVT) effect but often also leads to acute graft-versus-host disease (GVHD). Plasma tests that can predict the likelihood of GVT without GVHD are still needed.

PATIENTS AND METHODS: We first used an intact-protein analysis system to profile the plasma proteome post-DLI of patients who experienced GVT and acute GVHD for comparison with the proteome of patients who experienced GVT without GVHD in a training set. Our novel six-step systems biology analysis involved removing common proteins and GVHD-specific proteins, creating a protein-protein interaction network, calculating relevance and penalty scores, and visualizing candidate biomarkers in gene networks. We then performed a second proteomics experiment in a validation set of patients who experienced GVT without acute GVHD after DLI for comparison with the proteome of patients before DLI. We next combined the two experiments to define a biologically relevant signature of GVT without GVHD. An independent experiment with single-cell profiling in tumor antigen-activated T cells from a patient with post-hematopoietic cell transplantation relapse was performed.

RESULTS: The approach provided a list of 46 proteins in the training set, and 30 proteins in the validation set were associated with GVT without GVHD. The combination of the two experiments defined a unique 61-protein signature of GVT without GVHD. Finally, the single-cell profiling in activated T cells found 43 of the 61 genes. Novel markers, such as RPL23, ILF2, CD58, and CRTAM, were identified and could be extended to other antitumoral responses.

CONCLUSION: Our multiomic analysis provides, to our knowledge, the first human plasma signature for GVT without GVHD. Risk stratification on the basis of this signature would allow for customized treatment plans.

RevDate: 2019-08-13

Kannan A, Philley JV, Hertweck KL, et al (2019)

Cancer Testis Antigen Promotes Triple Negative Breast Cancer Metastasis and is Traceable in the Circulating Extracellular Vesicles.

Scientific reports, 9(1):11632 pii:10.1038/s41598-019-48064-w.

Triple negative breast cancer (TNBC) has poor survival, exhibits rapid metastases, lacks targeted therapies and reliable prognostic markers. Here, we examined metastasis promoting role of cancer testis antigen SPANXB1 in TNBC and its utility as a therapeutic target and prognostic biomarker. Expression pattern of SPANXB1 was determined using matched primary cancer, lymph node metastatic tissues and circulating small extracellular vesicles (sEVs). cDNA microarray analysis of TNBC cells stably integrated with a metastasis suppressor SH3GL2 identified SPANXB1 as a potential target gene. TNBC cells overexpressing SH3GL2 exhibited decreased levels of both SPANXB1 mRNA and protein. Silencing of SPANXB1 reduced migration, invasion and reactive oxygen species production of TNBC cells. SPANXB1 depletion augmented SH3GL2 expression and decreased RAC-1, FAK, A-Actinin and Vinculin expression. Phenotypic and molecular changes were reversed upon SPANXB1 re-expression. SPANXB1 overexpressing breast cancer cells with an enhanced SPANXB1:SH3GL2 ratio achieved pulmonary metastasis within 5 weeks, whereas controls cells failed to do so. Altered expression of SPANXB1 was detected in the sEVs of SPANXB1 transduced cells. Exclusive expression of SPANXB1 was traceable in circulating sEVs, which was associated with TNBC progression. SPANXB1 represents a novel and ideal therapeutic target for blocking TNBC metastases due to its unique expression pattern and may function as an EV based prognostic marker to improve TNBC survival. Uniquely restricted expression of SPANXB1 in TNBCs, makes it an ideal candidate for targeted therapeutics and prognostication.

RevDate: 2019-08-13

Koch LB, Opoku KN, Deng Y, et al (2019)

Autophosphorylation is sufficient to release Mps1 kinase from native kinetochores.

Proceedings of the National Academy of Sciences of the United States of America pii:1901653116 [Epub ahead of print].

Accurate mitosis depends on a surveillance system called the spindle assembly checkpoint. This checkpoint acts at kinetochores, which attach chromosomes to the dynamic tips of spindle microtubules. When a kinetochore is unattached or improperly attached, the protein kinase Mps1 phosphorylates kinetochore components, catalyzing the generation of a diffusible "wait" signal that delays anaphase and gives the cell time to correct the error. When a kinetochore becomes properly attached, its checkpoint signal is silenced to allow progression into anaphase. Recently, microtubules were found to compete directly against recombinant human Mps1 fragments for binding to the major microtubule-binding kinetochore element Ndc80c, suggesting a direct competition model for silencing the checkpoint signal at properly attached kinetochores. Here, by developing single-particle fluorescence-based assays, we tested whether such direct competition occurs in the context of native kinetochores isolated from yeast. Mps1 levels were not reduced on kinetochore particles bound laterally to the sides of microtubules or on particles tracking processively with disassembling tips. Instead, we found that Mps1 kinase activity was sufficient to promote its release from the isolated kinetochores. Mps1 autophosphorylation, rather than phosphorylation of other kinetochore components, was responsible for this dissociation. Our findings suggest that checkpoint silencing in yeast does not arise from a direct competition between Mps1 and microtubules, and that phosphoregulation of Mps1 may be a critical aspect of the silencing mechanism.

RevDate: 2019-08-12

Molina Y, Henderson V, Ornelas IJ, et al (2019)

Understanding Complex Roles of Family for Latina Health: Evaluating Family Obligation Stress.

Family & community health, 42(4):254-260.

We developed a measure of family obligation stress and compared its relationship to health and unmet health care needs relative to social support among a sample of US-based Latinas. Data come from a randomized controlled trial within 4 clinics to increase mammography among Latinas (n = 539). The 1-factor measure had acceptable reliability and construct validity. Family obligation stress was associated with worse health and greater unmet health care needs. Family obligation stress varied by years in the United States and country of origin. Our measure of family obligation stress contributes new venues to family research among Latino populations.

RevDate: 2019-08-12

Adamson B, Garrison L, Barnabas RV, et al (2019)

Competing biomedical HIV prevention strategies: potential cost-effectiveness of HIV vaccines and PrEP in Seattle, WA.

Journal of the International AIDS Society, 22(8):e25373.

INTRODUCTION: Promising HIV vaccine candidates are steadily progressing through the clinical trial pipeline. Once available, HIV vaccines will be an important complement but also potential competitor to other biomedical prevention tools such as pre-exposure prophylaxis (PrEP). Accordingly, the value of HIV vaccines and the policies for rollout may depend on that interplay and tradeoffs with utilization of existing products. In this economic modelling analysis, we estimate the cost-effectiveness of HIV vaccines considering their potential interaction with PrEP and condom use.

METHODS: We developed a dynamic model of HIV transmission among the men who have sex with men population (MSM), aged 15-64 years, in Seattle, WA offered PrEP and HIV vaccine over a time horizon of 2025-2045. A healthcare sector perspective with annual discount rate of 3% for costs (2017 USD) and quality-adjusted life years (QALYs) was used. The primary economic endpoint is the incremental cost-effectiveness ratio (ICER) when compared to no HIV vaccine availability.

RESULTS: HIV vaccines improved population health and increased healthcare costs. Vaccination campaigns achieving 90% coverage of high-risk men and 60% coverage of other men within five years of introduction are projected to avoid 40% of new HIV infections between 2025 and 2045. This increased total healthcare costs by $30 million, with some PrEP costs shifted to HIV vaccine spending. HIV vaccines are estimated to have an ICER of $42,473/QALY, considered cost-effective using a threshold of $150,000/QALY. Results were most sensitive to HIV vaccine efficacy and future changes in the cost of PrEP drugs. Sensitivity analysis found ranges of 30-70% HIV vaccine efficacy remained cost-effective. Results were also sensitive to reductions in condom use among PrEP and vaccine users.

CONCLUSIONS: Access to an HIV vaccine is desirable as it could increase the overall effectiveness of combination HIV prevention efforts and improve population health. Planning for the rollout and scale-up of HIV vaccines should carefully consider the design of policies that guide interactions between vaccine and PrEP utilization and potential competition.

RevDate: 2019-08-11

Rios A, Durbin EB, Hands I, et al (2019)

Cross-Registry Neural Domain Adaptation to Extract Mutational Test Results from Pathology Reports.

Journal of biomedical informatics pii:S1532-0464(19)30186-8 [Epub ahead of print].

OBJECTIVE: We study the performance of machine learning (ML) methods, including neural networks (NNs), to extract mutational test results from pathology reports collected by cancer registries. Given the lack of hand-labeled datasets for mutational test result extraction, we focus on the particular use-case of extracting Epidermal Growth Factor Receptor mutation results in non-small cell lung cancers. We explore the generalization of NNs across different registries where our goals are two-fold: (1) to assess how well models trained on a registry's data port to test data from a different registry and (2) to assess whether and to what extent such models can be improved using state-of-the-art neural domain adaptation techniques under different assumptions about what is available (labeled vs unlabeled data) at the target registry site.

MATERIALS AND METHODS: We collected data from two registries: the Kentucky Cancer Registry (KCR) and the Fred Hutchinson Cancer Research Center (FH) Cancer Surveillance System. We combine NNs with adversarial domain adaptation to improve cross-registry performance. We compare to other classifiers in the standard supervised classification, unsupervised domain adaptation, and supervised domain adaptation scenarios.

RESULTS: The performance of ML methods varied between registries. To extract positive results, the CNN had an F1 of 71.5% on the KCR dataset and 95.7% on the FH dataset. For the KCR dataset, the CNN F1 results were low when trained on FH data (Positive F1: 23%). Using our proposed adversarial CNN, we match the F1 of the models trained directly on each registry's data. The adversarial CNN F1 improved when trained on FH and applied to KCR dataset (Positive F1: 70.8%). We found similar performance improvements when we trained on KCR and tested on FH reports (Positive F1: 45% to 96%).

CONCLUSION: Adversarial domain adaptation improves the performance of NNs applied to pathology reports. In the unsupervised domain adaptation, we match the performance of models that are trained directly on a registry's data.

RevDate: 2019-08-10

Niu X, Amendola LM, Hart R, et al (2019)

Clinical exome sequencing vs. usual care for hereditary colorectal cancer diagnosis: A pilot comparative effectiveness study.

Contemporary clinical trials pii:S1551-7144(19)30535-X [Epub ahead of print].

BACKGROUND: Clinical exome sequencing (CES) provides the advantage of assessing genetic variation across the human exome compared to a traditional stepwise diagnostic approach or multi-gene panels. Comparative effectiveness research methods offer an approach to better understand the patient-centered and economic outcomes of CES.

PURPOSE: To evaluate CES compared to usual care (UC) in the diagnostic work-up of inherited colorectal cancer/polyposis (CRCP) in a randomized controlled trial (RCT).

METHODS: The primary outcome was clinical sensitivity for the diagnosis of inherited CRCP; secondary outcomes included psychosocial outcomes, family communication, and healthcare resource utilization. Participants were surveyed 2 and 4 weeks after results return and at 3-month intervals up to 1 year.

RESULTS: Evolving outcome measures and standard of care presented critical challenges. The majority of participants in the UC arm received multi-gene panels [94.73%]. Rates of genetic findings supporting the diagnosis of hereditary CRCP were 7.5% [7/93] vs. 5.4% [5/93] in the CES and UC arms, respectively (P = .28). Differences in privacy concerns after receiving CRCP results were identified (0.88 in UC vs 0.38 in CES, P = .05); however, healthcare resource utilization, family communication and psychosocial outcomes were otherwise similar between the two arms. More participants with positive results (17.7%) intended to change their life insurance 1 month after the first return visit compared to participants returned a VUS (variants of uncertain significance) (9.1%) or negative result (4.8%) (P = .09).

CONCLUSION: Our results suggest that CES provides similar clinical benefits to multi-gene panels in the diagnosis of hereditary CRCP.

RevDate: 2019-08-10

Tretiakova MS, Wang W, Wu Y, et al (2019)

Gene fusion analysis in renal cell carcinoma by fusionplex RNA sequencing and correlations of molecular findings with clinicopathological features.

Genes, chromosomes & cancer [Epub ahead of print].

Translocation renal cell carcinoma (tRCC) affects younger patients and often has poor outcomes. Accurate diagnosis is required to guide clinical management. Here we evaluate the RNA-sequencing FusionPlex platform with a 115-gene panel including TFE3 and TFEB for tRCC diagnosis and correlate molecular findings with clinicopathological features. We reviewed 996 consecutive RCC cases from our institution over the preceding 7 years and retrieved 17 cases with histological and immunohistochemical features highly suggestive of either TFE3 (n=16) or TFEB (n=1). Moderate to strong labeling for TFE3 was present in 15 cases; two cases with weak TFE3 expression were melan-A or cathepsin K positive. RNA-sequencing detected gene rearrangements in 8 cases: PRCC-TFE3 (3), ASPSCR1-TFE3 (2), LUC7C3-TFE3 (1), SFPQ-TFE3 (1), and a novel SETD1B-TFE3 (1). FISH assays of 11 tumors verified 6 positive cases concordant with FusionPlex. Two other cases were confirmed by RT-PCR. FusionPlex was superior to FISH by providing precise breakpoints for tRCC-related genes in a single assay and allowing identification of both known and novel fusion partners, thereby facilitating clinicopathological correlations as fusion partners can influence tumor appearance, immunophenotype and behavior. Cases with partner genes PRCC and novel partner SETD1B were associated with prominent papillary architecture while cases with partner genes ASPSCR1and LUC7C3 were associated with a predominantly nested/alveolar pattern. The case with SFPQ-TFE3 fusion was characterized by biphasic morphology mimicking TFEB-like translocation RCC. We recommend FusionPlex analysis of RCC in patients under age 50 or when the histologic appearance suggests tRCC. This article is protected by copyright. All rights reserved.

RevDate: 2019-08-10

Weycker D, Doroff R, Hanau A, et al (2019)

Use and effectiveness of pegfilgrastim prophylaxis in US clinical practice:a retrospective observational study.

BMC cancer, 19(1):792 pii:10.1186/s12885-019-6010-9.

BACKGROUND: Febrile neutropenia (FN) is a serious complication of myelosuppressive chemotherapy. Clinical practice guidelines recommend routine prophylactic coverage with granulocyte colony-stimulating factor (G-CSF)-such as pegfilgrastim-for most patients receiving chemotherapy with an intermediate to high risk for FN. Patterns of pegfilgrastim prophylaxis during the chemotherapy course and associated FN risks in US clinical practice have not been well characterized.

METHODS: A retrospective cohort design and data from two commercial healthcare claims repositories (01/2010-03/2016) and Medicare Claims Research Identifiable Files (01/2007-09/2015) were employed. Study population included patients who had non-metastatic breast cancer or non-Hodgkin's lymphoma and received intermediate/high-risk regimens. Pegfilgrastim prophylaxis use and FN incidence were ascertained in each chemotherapy cycle, and all cycles were pooled for analyses. Adjusted odds ratios for FN were estimated for patients who did versus did not receive pegfilgrastim prophylaxis in that cycle.

RESULTS: Study population included 50,778 commercial patients who received 190,622 cycles of chemotherapy and 71,037 Medicare patients who received 271,944 cycles. In cycle 1, 33% of commercial patients and 28% of Medicare patients did not receive pegfilgrastim prophylaxis, and adjusted odds of FN were 2.6 (95% CI 2.3-2.8) and 1.6 (1.5-1.7), respectively, versus those who received pegfilgrastim prophylaxis. In cycle 2, 28% (commercial) and 26% (Medicare) did not receive pegfilgrastim prophylaxis; corresponding adjusted FN odds were comparably elevated (1.9 [1.6-2.2] and 1.6 [1.5-1.8]). Results in subsequent cycles were similar. Across all cycles, 15% of commercial patients and 23% of Medicare patients did not receive pegfilgrastim prophylaxis despite having FN in a prior cycle, and prior FN increased odds of subsequent FN by 2.1-2.4 times.

CONCLUSIONS: Notwithstanding clinical practice guidelines, a large minority of patients did not receive G-CSF prophylaxis, and FN incidence was substantially higher among this subset of the population. Appropriate use of pegfilgrastim prophylaxis may reduce patient exposure to this potentially fatal but largely preventable complication of myelosuppressive chemotherapy.

RevDate: 2019-08-10

Li JJ, Chew GL, MD Biggin (2019)

Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes.

Genome biology, 20(1):162 pii:10.1186/s13059-019-1761-9.

BACKGROUND: General translational cis-elements are present in the mRNAs of all genes and affect the recruitment, assembly, and progress of preinitiation complexes and the ribosome under many physiological states. These elements include mRNA folding, upstream open reading frames, specific nucleotides flanking the initiating AUG codon, protein coding sequence length, and codon usage. The quantitative contributions of these sequence features and how and why they coordinate to control translation rates are not well understood.

RESULTS: Here, we show that these sequence features specify 42-81% of the variance in translation rates in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Mus musculus, and Homo sapiens. We establish that control by RNA secondary structure is chiefly mediated by highly folded 25-60 nucleotide segments within mRNA 5' regions, that changes in tri-nucleotide frequencies between highly and poorly translated 5' regions are correlated between all species, and that control by distinct biochemical processes is extensively correlated as is regulation by a single process acting in different parts of the same mRNA.

CONCLUSIONS: Our work shows that general features control a much larger fraction of the variance in translation rates than previously realized. We provide a more detailed and accurate understanding of the aspects of RNA structure that directs translation in diverse eukaryotes. In addition, we note that the strongly correlated regulation between and within cis-control features will cause more even densities of translational complexes along each mRNA and therefore more efficient use of the translation machinery by the cell.

RevDate: 2019-08-09

Boonyaratanakornkit J, JJ Taylor (2019)

Techniques to Study Antigen-Specific B Cell Responses.

Frontiers in immunology, 10:1694.

Antibodies against foreign antigens are a critical component of the overall immune response and can facilitate pathogen clearance during a primary infection and also protect against subsequent infections. Dysregulation of the antibody response can lead to an autoimmune disease, malignancy, or enhanced infection. Since the experimental delineation of a distinct B cell lineage in 1965, various methods have been developed to understand antigen-specific B cell responses in the context of autoimmune diseases, primary immunodeficiencies, infection, and vaccination. In this review, we summarize the established techniques and discuss new and emerging technologies for probing the B cell response in vitro and in vivo by taking advantage of the specificity of B cell receptor (BCR)-associated and secreted antibodies. These include ELISPOT, flow cytometry, mass cytometry, and fluorescence microscopy to identify and/or isolate primary antigen-specific B cells. We also present our approach to identify rare antigen-specific B cells using magnetic enrichment followed by flow cytometry. Once these cells are isolated, in vitro proliferation assays and adoptive transfer experiments in mice can be used to further characterize antigen-specific B cell activation, function, and fate. Transgenic mouse models of B cells targeting model antigens and of B cell signaling have also significantly advanced our understanding of antigen-specific B cell responses in vivo.

RevDate: 2019-08-09

Mathsyaraja H, Freie B, Cheng PF, et al (2019)

Max deletion destabilizes MYC protein and abrogates Eµ-Myc lymphomagenesis.

Genes & development pii:gad.325878.119 [Epub ahead of print].

Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell-specific deletion of Max has a modest effect on B-cell development but completely abrogates Eµ-Myc-driven lymphomagenesis. While Max loss affects only a few hundred genes in normal B cells, it leads to the global down-regulation of Myc-activated genes in premalignant Eµ-Myc cells. We show that the balance between MYC-MAX and MNT-MAX interactions in B cells shifts in premalignant B cells toward a MYC-driven transcriptional program. Moreover, we found that MAX loss leads to a significant reduction in MYC protein levels and down-regulation of direct transcriptional targets, including regulators of MYC stability. This phenomenon is also observed in multiple cell lines treated with MYC-MAX dimerization inhibitors. Our work uncovers a layer of Myc autoregulation critical for lymphomagenesis yet partly dispensable for normal development.

RevDate: 2019-08-09

O'Steen S, Comstock ML, Orozco JJ, et al (2019)

The Alpha Emitter Astatine-211 Targeted to CD38 can Eradicate Multiple Myeloma in a Disseminated Disease Model.

Blood pii:blood.2019001250 [Epub ahead of print].

Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD negative to {less than or equal to}10-5, concerning because MRD negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant sub-clones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine‑211 (211At) deposits prodigious energy within three cell diameters, ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At‑CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At‑CD38 at 15-45 µCi at least doubled median survival of mice relative to untreated controls (p <0.003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low burden MRD, three studies demonstrated that single-dose 211At-CD38 at 24-45 µCi produced sustained remission and long-term survival (>150 days) for 50-80% of mice, where all untreated mice died in 20-55 days (p <0.0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low disease burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem-cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients.

RevDate: 2019-08-09

Chen H, Cook LS, Tang MC, et al (2019)

Relationship between diabetes and diabetes medications and risk of different molecular subtypes of breast cancer.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-19-0291 [Epub ahead of print].

BACKGROUND: Type II diabetes and certain diabetes treatments have been observed to impact breast cancer risk. However, their associations with different breast cancer molecular subtype defined by estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor-2 (HER2) status is unclear.

METHODS: We conducted a retrospective multi-center population-based case-case study consisting of 4,557 breast cancer cases to evaluate the impact of type II diabetes and diabetes medications on the risk of different breast cancer molecular subtypes (ER+/HER2-, ER+/HER2+, triple negative (TN, ER-/PR-/HER2-) and HER2-overexpressing (H2E, ER-/PR-/HER2+)). Using ER+/HER2- cases as the reference group, we estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for each subtype using polytomous logistic regression.

RESULTS: Compared to those without a diabetes history, women with type II diabetes had a 38% (95% CI: 1.01-1.89) increased odds of TN breast cancer. Current and longer-term recent metformin use (13-24 months of treatment within the 24-month period prior to breast cancer diagnosis) were associated with elevated odds of TN breast cancer (OR=1.54; 95% CI: 1.07-2.22 and OR=1.80; 95% CI: 1.13-2.85, respectively).

CONCLUSIONS: The odds of having a TN rather than ER+/HER2- breast cancer is greater for women with type II diabetes, and particularly for those who were users of metformin. This finding is supported by some preclinical data suggesting that diabetes may be more strongly associated with risk of TN disease.

IMPACT: Our study provides novel evidence regarding potential differential effects of type II diabetes and metformin use on risk of different molecular subtypes of breast cancer.

RevDate: 2019-08-09

Spence D, Argentieri MA, Andall-Brereton G, et al (2019)

Advancing cancer care and prevention in the Caribbean: a survey of strategies for the region.

The Lancet. Oncology pii:S1470-2045(19)30516-9 [Epub ahead of print].

Cancer is now the second leading cause of death in the Caribbean. Despite this growing burden, many Caribbean small island nations have health systems that struggle to provide optimal cancer care for their populations. In this Series paper, we identify several promising strategies to improve cancer prevention and treatment that have emerged across small island nations that are part of the Caribbean Community. These strategies include the establishment of a Caribbean cancer registry hub, the development of resource-appropriate clinical guidelines, innovations in delivering specialty oncology services (eg, paediatric oncology and palliative care), improving access to opioids, and developing regional training capacity in palliative medicine. These developments emphasise the crucial role of public-private partnerships in improving health care for the region and show how fostering strategic collaborations with colleagues and centres in more developed countries, who can contribute specialised expertise and improve regional collaboration, can improve care across the cancer control continuum.

RevDate: 2019-08-08

Herrera AF, Chen L, Khajavian S, et al (2019)

Allogeneic Stem Cell Transplantation Provides Durable Remission in Patients with Primary Mediastinal Large B-cell Lymphoma.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30513-0 [Epub ahead of print].

Standard therapy for relapsed or refractory (rel/ref) primary mediastinal large B-cell lymphoma (PMBCL) is salvage therapy followed by autologous (auto) hematopoietic stem cell transplant (HSCT). However, many patients have refractory disease and are unable to undergo autoHSCT and a sizable proportion of patients will relapse after autoHSCT. By analogy to diffuse large B-cell lymphoma, those patients may be treated with allogeneic (allo) HSCT with curative intent, but at the risk of significant morbidity and mortality. Given the advent of effective immunotherapy approaches for rel/ref PMBCL, it is important to better understand the toxicity and efficacy of alloHSCT in these patients, to which these new approaches could be an alternative. We therefore retrospectively studied the outcomes of alloHSCT in a multicenter cohort of 28 patients with rel/ref PMBCL who underwent transplant at 4 centers. Most (79%) patients were sensitive to pre-transplant therapy and 86% received reduced intensity conditioning. The overall progression-free survival (PFS), overall survival (OS) and cumulative incidences of non-relapse mortality and relapse in the cohort at 5 years were 34%, 45%, 32%, and 33%, respectively. Outcomes were significantly better in patients with pre-transplant responsive disease (2-year PFS and OS of 50% and 58%) as compared with refractory patients (2-year PFS and OS of 0%). In our multicenter retrospective study, alloHSCT produced durable remissions in a proportion of patients with treatment-sensitive disease prior to transplantation (5-year PFS 44%) and should be considered in the treatment of patients with rel/ref PMBCL.

RevDate: 2019-08-08

Pergam SA, Englund JA, Kamboj M, et al (2019)

Preventing Measles among Immunosuppressed Cancer and Hematopoietic Cell Transplant Patients: A Position Statement by the American Society for Transplantation and Cellular Therapy.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30506-3 [Epub ahead of print].

Until recently, measles exposures were relatively rare, and so consequently, were an afterthought for cancer and/or blood and marrow transplant recipients and their providers. Declines in measles herd immunity have reached critical levels in many communities throughout the US, due to increasing vaccine hesitancy, so that community-based outbreaks have occurred. The reemergence of measles as a clinical disease has raised serious concern among immunocompromised patients and those who work within the cancer and hematopoietic cell transplant (HCT) community. Since live attenuated vaccines such as measles mumps rubella (MMR) are contraindicated in immunocompromised patients and without approved antiviral therapies for measles, community exposures in these patients can lead to life-threatening infection. The lack of data regarding measles prevention in this population poses a number of clinical dilemmas. Herein, specialists in Infectious Diseases and HCT/cellular therapy endorsed by the American Society of Transplant and Cellular Therapy, address frequently asked questions about measles in these high-risk cancer and HCT patients, and provide their expert opinion based on the limited available data.

RevDate: 2019-08-08

Cohen YZ, Butler AL, Millard K, et al (2019)

Safety, pharmacokinetics, and immunogenicity of the combination of the broadly neutralizing anti-HIV-1 antibodies 3BNC117 and 10-1074 in healthy adults: A randomized, phase 1 study.

PloS one, 14(8):e0219142 pii:PONE-D-19-02668.

BACKGROUND: Additional forms of pre-exposure prophylaxis are needed to prevent HIV-1 infection. 3BNC117 and 10-1074 are broadly neutralizing anti-HIV-1 antibodies that target non-overlapping epitopes on the HIV-1 envelope. We investigated the safety, tolerability, pharmacokinetics, and immunogenicity of the intravenous administration of the combination of 3BNC117 and 10-1074 in healthy adults.

METHODS: This randomized, double-blind, placebo-controlled, single center, phase 1 study enrolled healthy adults aged 18-65 years to receive one infusion of 3BNC117 immediately followed by 10-1074 at 10 mg/kg, three infusions of 3BNC117 followed by 10-1074 at 3 mg/kg or 10 mg/kg every 8 weeks, or placebo infusions. The primary outcomes were safety and pharmacokinetics. This trial is registered with ClinicalTrials.gov, number NCT02824536.

FINDINGS: Twenty-four participants were enrolled in a 3:1 ratio to receive the study products or placebo. The combination of 3BNC117 and 10-1074 was safe and generally well tolerated. There were no serious adverse events considered related to the infusions. The mean elimination half-lives of 3BNC117 and 10-1074 were 16.4 ± 4.6 days and 23.0 ± 5.4 days, respectively, similar to what was observed in previous studies in which each antibody was administered alone. Anti-drug antibody responses were rare and without evidence of related adverse events or impact on elimination kinetics.

INTERPRETATION: Single and repeated doses of the combination of 3BNC117 and 10-1074 were well tolerated in healthy adults. These data support the further development of the combination of 3BNC117 and 10-1074 as a long-acting injectable form of pre-exposure prophylaxis for the prevention of HIV-1 infection.

RevDate: 2019-08-08

Han CJ, Pike K, Jarrett ME, et al (2019)

Symptom-based latent classes of persons with irritable bowel syndrome.

Research in nursing & health [Epub ahead of print].

A large amount of interindividual variability exists in symptom experiences of persons with irritable bowel syndrome (IBS). Thus, consideration of multiple symptoms to identify distinct symptom subgroups may be useful in directing personalized health strategies for symptom management. We aimed to identify latent classes (i.e., subgroups) of persons with IBS who share similar patterns of symptoms using symptom-related variables (six groups of daily diary symptoms, cognitive beliefs about IBS, and IBS quality of life [QOL]); and to examine how subgroups differed in patient characteristics. Data were derived from a baseline assessment of men and women enrolled in two cognitively-focused intervention trials (N = 332). Using latent class analysis, four latent classes were identified: Class 1 (low symptoms and good QOL, n = 153), Class 2 (low symptoms and moderate QOL, n = 106), Class 3 (high symptoms with diarrhea and poor QOL, n = 38), and Class 4 (high symptoms with low diarrhea and moderate QOL, n = 35). Diarrhea, being female, less formal education, unemployment, and previous history of major depressive disorder were associated with membership in Class 3. Using these distinct symptom profiles, the next step is to explore underlying mechanisms accounting for symptom burden with the goal of designing tailored interventions to reduce that burden.

RevDate: 2019-08-08

Kitcher SR, Kirkwood NK, Camci ED, et al (2019)

ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity.

JCI insight, 4(15): pii:126764.

Aminoglycoside (AG) antibiotics are widely used to prevent life-threatening infections, and cisplatin is used in the treatment of various cancers, but both are ototoxic and result in loss of sensory hair cells from the inner ear. ORC-13661 is a new drug that was derived from PROTO-1, a compound first identified as protective in a large-scale screen utilizing hair cells in the lateral line organs of zebrafish larvae. Here, we demonstrate, in zebrafish larvae and in mouse cochlear cultures, that ORC-13661 provides robust protection of hair cells against both ototoxins, the AGs and cisplatin. ORC-13661 also prevents both hearing loss in a dose-dependent manner in rats treated with amikacin and the loading of neomycin-Texas Red into lateral line hair cells. In addition, patch-clamp recordings in mouse cochlear cultures reveal that ORC-13661 is a high-affinity permeant blocker of the mechanoelectrical transducer (MET) channel in outer hair cells, suggesting that it may reduce the toxicity of AGs by directly competing for entry at the level of the MET channel and of cisplatin by a MET-dependent mechanism. ORC-13661 is therefore a promising and versatile protectant that reversibly blocks the hair cell MET channel and operates across multiple species and toxins.

RevDate: 2019-08-07

Guo Y, Ayers JL, Carter KT, et al (2019)

Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15.

Aging cell [Epub ahead of print].

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence-associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence-associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.

RevDate: 2019-08-07

McDavid A, Gottardo R, Simon N, et al (2019)

GRAPHICAL MODELS FOR ZERO-INFLATED SINGLE CELL GENE EXPRESSION.

The annals of applied statistics, 13(2):848-873.

Bulk gene expression experiments relied on aggregations of thousands of cells to measure the average expression in an organism. Advances in microfluidic and droplet sequencing now permit expression profiling in single cells. This study of cell-to-cell variation reveals that individual cells lack detectable expression of transcripts that appear abundant on a population level, giving rise to zero-inflated expression patterns. To infer gene co-regulatory networks from such data, we propose a multivariate Hurdle model. It is comprised of a mixture of singular Gaussian distributions. We employ neighborhood selection with the pseudo-likelihood and a group lasso penalty to select and fit undirected graphical models that capture conditional independences between genes. The proposed method is more sensitive than existing approaches in simulations, even under departures from our Hurdle model. The method is applied to data for T follicular helper cells, and a high-dimensional profile of mouse dendritic cells. It infers network structure not revealed by other methods; or in bulk data sets. An R implementation is available at https://github.com/amcdavid/HurdleNormal.

RevDate: 2019-08-06

Potter GE, Wong J, Sugimoto J, et al (2019)

Networks of face-to-face social contacts in Niakhar, Senegal.

PloS one, 14(8):e0220443 pii:PONE-D-18-27976.

We present the first analysis of face-to-face contact network data from Niakhar, Senegal. Participants in a cluster-randomized influenza vaccine trial were interviewed about their contact patterns when they reported symptoms during their weekly household surveillance visit. We employ a negative binomial model to estimate effects of covariates on contact degree. We estimate the mean contact degree for asymptomatic Niakhar residents to be 16.5 (95% C.I. 14.3, 18.7) in the morning and 14.8 in the afternoon (95% C.I. 12.7, 16.9). We estimate that symptomatic people make 10% fewer contacts than asymptomatic people (95% C.I. 5%, 16%; p = 0.006), and those aged 0-5 make 33% fewer contacts than adults (95% C.I. 29%, 37%; p < 0.001). By explicitly modelling the partial rounding pattern observed in our data, we make inference for both the underlying (true) distribution of contacts as well as for the reported distribution. We created an estimator for homophily by compound (household) membership and estimate that 48% of contacts by symptomatic people are made to their own compound members in the morning (95% CI, 45%, 52%) and 60% in the afternoon/evening (95% CI, 56%, 64%). We did not find a significant effect of symptom status on compound homophily. We compare our findings to those from other countries and make design recommendations for future surveys.

RevDate: 2019-08-06

Maruvada P, Lampe JW, Wishart DS, et al (2019)

Perspective: Dietaryiomarkers of Intake and Exposure-Exploration with Omics Approaches.

Advances in nutrition (Bethesda, Md.) pii:5544358 [Epub ahead of print].

While conventional nutrition research has yielded biomarkers such as doubly labeled water for energy metabolism and 24-h urinary nitrogen for protein intake, a critical need exists for additional, equally robust biomarkers that allow for objective assessment of specific food intake and dietary exposure. Recent advances in high-throughput MS combined with improved metabolomics techniques and bioinformatic tools provide new opportunities for dietary biomarker development. In September 2018, the NIH organized a 2-d workshop to engage nutrition and omics researchers and explore the potential of multiomics approaches in nutritional biomarker research. The current Perspective summarizes key gaps and challenges identified, as well as the recommendations from the workshop that could serve as a guide for scientists interested in dietary biomarkers research. Topics addressed included study designs for biomarker development, analytical and bioinformatic considerations, and integration of dietary biomarkers with other omics techniques. Several clear needs were identified, including larger controlled feeding studies, testing a variety of foods and dietary patterns across diverse populations, improved reporting standards to support study replication, more chemical standards covering a broader range of food constituents and human metabolites, standardized approaches for biomarker validation, comprehensive and accessible food composition databases, a common ontology for dietary biomarker literature, and methodologic work on statistical procedures for intake biomarker discovery. Multidisciplinary research teams with appropriate expertise are critical to moving forward the field of dietary biomarkers and producing robust, reproducible biomarkers that can be used in public health and clinical research.

RevDate: 2019-08-06

Roxby AC, Yuhas K, Farquhar C, et al (2019)

Mycoplasma genitalium infection among HIV-infected pregnant African women and implications for mother-to-child transmission of HIV.

AIDS (London, England) [Epub ahead of print].

OBJECTIVE: Many sexually transmitted infections (STIs) increase risk of mother-to-child transmission (MTCT) of HIV, but the effect of Mycoplasma genitalium (MG) is not known. We hypothesized that MG infection would be common among HIV-infected pregnant women and could be associated with in utero and intrapartum MTCT.

DESIGN: Observational case-cohort study METHODS:: This study used specimens from a Kenyan perinatal MTCT cohort (1999-2005) involving HIV-infected women and their infants, who received short-course zidovudine for prevention of MTCT. Vaginal swabs collected at 32 weeks gestation were tested for MG using a transcription-mediated amplification assay. Infant perinatal HIV infection was determined at birth and 4 weeks of age by DNA PCR. Using a case-cohort design, a random sample was generated with 3:1 control: case ratio; prevalence and correlates of MG were assessed with Chi-squared and t-tests; predictors of infant outcomes were analyzed using logistic regression.

RESULTS: Among 220 HIV-infected pregnant women evaluated, 47 women (21.4%) had MG. Antenatal MG infection was associated with higher HIV RNA in plasma (5.0 vs. 4.6 log10 copies/ml in MG-positive vs. MG-negative women, p = 0.02) at 32 weeks. Women with MG were less likely to report prior STIs and genital ulcers (both p = 0.05). There was no association found between exposure to MG and perinatal MTCT (OR = 0.72, 95% CI 0.35, 1.51, p = 0.39).

CONCLUSIONS: Vaginal MG infection was frequently detected among Kenyan HIV-infected pregnant women and was associated with higher plasma HIV levels, but was not associated with perinatal transmission of HIV.

RevDate: 2019-08-06

Bell SM, Katzelnick L, T Bedford (2019)

Dengue genetic divergence generates within-serotype antigenic variation, but serotypes dominate evolutionary dynamics.

eLife, 8: pii:42496 [Epub ahead of print].

Dengue virus (DENV) exists as four genetically distinct serotypes, each of which is historically assumed to be antigenically uniform. However, recent analyses suggest that antigenic heterogeneity may exist within each serotype, but its source, extent and impact remain unclear. Here, we construct a sequence-based model to directly map antigenic change to underlying genetic divergence. We identify 49 specific substitutions and four colinear substitution clusters that robustly predict dengue antigenic relationships. We report moderate antigenic diversity within each serotype, resulting in variation in genotype-specific patterns of heterotypic cross-neutralization. We also quantify the impact of antigenic variation on real-world DENV population dynamics, and find that serotype-level antigenic fitness is a dominant driver of dengue clade turnover. These results provide a more nuanced understanding of the relationship between dengue genetic and antigenic evolution, and quantify the effect of antigenic fitness on dengue evolutionary dynamics.

RevDate: 2019-08-06

Rillamas-Sun E, Bishop S, Cisneros O, et al (2019)

Psychosocial Factors of Diet and Physical Activity among Rural, Hispanic Children: Findings from a Multilevel Health Intervention Study.

Journal of racial and ethnic health disparities pii:10.1007/s40615-019-00623-7 [Epub ahead of print].

OBJECTIVE: To examine the relationship of psychosocial factors, such as self-efficacy, family role modeling, and perceptions of the environment, on diet, physical activity, and sedentary behavior in Hispanic children living in rural Washington State.

METHODS: Gender, heights, and weights were obtained from Hispanic 8-12 year olds (n = 553) from two rural communities in Lower Yakima, Washington. A subsample of 179 children provided psychosocial measures, diet, and screen time via questionnaire and physical activity via accelerometer. Body mass index percentiles were used to calculate the prevalence of obesity. The association of demographic and psychosocial measures on the mean difference (95% confidence interval (CI)) of fruit, vegetable, and sugar consumption and minutes spent active was estimated using linear regression models.

RESULTS: Prevalence of obesity was 35%. Children with obesity consumed one-fifth (- 0.3, - 0.02) fewer cups of fruits, 2.2 (0.1, 4.2) more teaspoons of total added sugars, and spent 16.1 (- 22.0, - 10.2) fewer minutes in moderate-to-vigorous physical activity per day compared with children with healthy weights. Males consumed more added sugars and reported more screen time than females, but spent more daily minutes in moderate-to-vigorous physical activity. Higher fruit and vegetable self-efficacy scores were associated with more consumption of fruits and vegetables, more engagement in light physical activity, and less time spent sedentary per day.

CONCLUSION: Male gender and some psychosocial measures were associated with obesogenic behaviors. Insight about factors associated with obesity-related behaviors in rural, Hispanic children may help the development of successful and effective behavioral health interventions for this understudied population.

RevDate: 2019-08-06

Vantaku V, Putluri V, Bader DA, et al (2019)

Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression.

Oncogene pii:10.1038/s41388-019-0902-7 [Epub ahead of print].

Advanced Bladder Cancer (BLCA) remains a clinical challenge that lacks effective therapeutic measures. Here, we show that distinct, stage-wise metabolic alterations in BLCA are associated with the loss of function of aldehyde oxidase (AOX1). AOX1 associated metabolites have a high predictive value for advanced BLCA and our findings demonstrate that AOX1 is epigenetically silenced during BLCA progression by the methyltransferase activity of EZH2. Knockdown (KD) of AOX1 in normal bladder epithelial cells re-wires the tryptophan-kynurenine pathway resulting in elevated NADP levels which may increase metabolic flux through the pentose phosphate (PPP) pathway, enabling increased nucleotide synthesis, and promoting cell invasion. Inhibition of NADP synthesis rescues the metabolic effects of AOX1 KD. Ectopic AOX1 expression decreases NADP production, PPP flux and nucleotide synthesis, while decreasing invasion in cell line models and suppressing growth in tumor xenografts. Further gain and loss of AOX1 confirm the EZH2-dependent activation, metabolic deregulation, and tumor growth in BLCA. Our findings highlight the therapeutic potential of AOX1 and provide a basis for the development of prognostic markers for advanced BLCA.

RevDate: 2019-08-05

Sun S, Stewart JD, Eliot MN, et al (2019)

Short-term exposure to air pollution and incidence of stroke in the Women's Health Initiative.

Environment international, 132:105065 pii:S0160-4120(19)31766-0 [Epub ahead of print].

BACKGROUND: Evidence of the association between daily variation in air pollution and risk of stroke is inconsistent, potentially due to the heterogeneity in stroke etiology.

OBJECTIVES: To estimate the associations between daily variation in ambient air pollution and risk of stroke and its subtypes among participants of the Women's Health Initiative, a large prospective cohort study in the United States.

METHODS: We used national-scale, log-normal ordinary kriging models to estimate daily concentrations of fine particulate matter (PM2.5), respirable particulate matter (PM10), nitrogen dioxide (NO2), nitrogen oxides (NOx), sulphur dioxide, and ozone at participant addresses. Stroke was adjudicated by trained neurologists and classified as ischemic or hemorrhagic. Ischemic strokes were further classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. We used a time-stratified case-crossover approach to estimate the odds ratio (OR) of the risk of stroke associated with an interquartile range (IQR) increase in concentrations of each air pollutant. We performed stratified analysis to examine whether associations varied across subgroups defined by age at stroke onset, US census region, smoking status, body mass index, and prior history of diabetes mellitus, hypertension, heart or circulation problems, or arterial fibrillation at enrollment.

RESULTS: Among 5417 confirmed strokes between 1993 and 2012, 4300 (79.4%) were classified as ischemic and 924 (17.1%) as hemorrhagic. No association was observed between day-to-day variation in any pollutant and risk of total stroke, ischemic stroke, or specific etiologies of ischemic stroke. We observed a positive association between risk of hemorrhagic stroke and NO2 and NOx in the 3 days prior to stroke with OR of 1.24 (95% CI: 1.01, 1.52) and 1.18 (95% CI: 1.03, 1.34) per IQR increase, respectively. The observed associations with hemorrhagic stroke were more pronounced among non-obese participants.

CONCLUSIONS: In this large cohort of post-menopausal US women, daily NO2 and NOx were associated with higher risk of hemorrhagic stroke, but ambient levels of four other air pollutants were not associated with higher risk of total stroke, ischemic stroke, or ischemic stroke subtypes.

RevDate: 2019-08-05

Bethancourt HJ, Kratz M, K O'Connor (2019)

A short-term religious "fast" from animal products has a minimal impact on cardiometabolic health biomarkers irrespective of concurrent shifts in distinct plant-based food groups.

The American journal of clinical nutrition pii:5543705 [Epub ahead of print].

BACKGROUND: Plant-based diets may help improve measures of body fat, blood cholesterol, glucose metabolism, and inflammation. However, limited evidence suggests that the health effects of reducing animal products may depend on the quality of plant-based foods consumed as caloric replacements.

OBJECTIVE: This study examined how temporarily restricting consumption of meat, dairy, and egg (MDE) products for religious purposes influences cardiometabolic health biomarkers and whether any effects of MDE restriction on biomarkers are modified by concurrent shifts in calories, fish, and distinct plant-based foods.

DESIGN: This study followed a sample of 99 individuals in the United States with varying degrees of adherence to Orthodox Christian (OC) guidance to abstain from MDE products during Lent, the 48-d period prior to Easter. Dietary composition was estimated from FFQs and 7-d food records; measures of body fat, blood lipids, glucose metabolism, and inflammation were collected prior to and at the end of Lent.

RESULTS: Each serving decrease in MDE products was associated with an average -3.7% (95% CI: -5.5%, -2.0%; P < 0.0001) and -3.6% (95% CI: -5.8%, -1.3%; P = 0.003) change in fasting total and LDL blood cholesterol, respectively, which were partly explained by minor weight loss. However, the total/HDL cholesterol ratio did not significantly decrease due to an average -3.2% (95% CI: -5.8%, -0.6%; P = 0.02) change in HDL cholesterol. No associations between MDE restrictions and shifts in measures of body fat, glucose, insulin, or C-reactive protein were observed. The data could not provide evidence that changes in cardiometabolic health biomarkers in relation to MDE restriction were modified by concurrent shifts in calories, fish, or plant-based foods.

CONCLUSION: Temporary MDE restrictions practiced by this sample of OCs in the United States during Lent had minimal effects on cardiometabolic disease risk factors. Further research among larger samples of OCs is needed to understand how nutritionally distinct and complex combinations of plant-based foods may modify the health effects of religious fasting from MDE products.

RevDate: 2019-08-05

Morgans AK, CS Higano (2019)

Back to Basics: Addressing Bone Health in Men with Prostate Cancer on Androgen Deprivation Therapy.

RevDate: 2019-08-03

Kaipainen A, Zhang A, Gil da Costa RM, et al (2019)

Testosterone accumulation in prostate cancer cells is enhanced by facilitated diffusion.

The Prostate [Epub ahead of print].

BACKGROUND: Testosterone is a driver of prostate cancer (PC) growth via ligand-mediated activation of the androgen receptor (AR). Tumors that have escaped systemic androgen deprivation, castration-resistant prostate cancers (CRPC), have measurable intratumoral levels of testosterone, suggesting that a resistance mechanism still depends on androgen-simulated growth. However, AR activation requires an optimal intracellular concentration of androgens, a situation challenged by low circulating testosterone concentrations. Notably, PC cells may optimize their androgen levels by regulating the expression of steroid metabolism enzymes that convert androgen precursors into androgens. Here we propose that testosterone entry into the cell could be another control point.

METHODS: To determine whether testosterone enters cells via a transporter, we performed in vitro 3 H-testosterone uptake assays in androgen-dependent LNCaP and androgen and AR-independent PC3 cells. To determine if the uptake mechanism depended on a concentration gradient, we modified UGT2B17 levels in LNCaP cells and measured androgen levels by liquid-liquid extraction-mass spectrometry. We also analyzed CRPC metastases for expression of AKR1C3 to determine whether this enzyme that converts adrenal androgens to testosterone was present in the tumor stroma (microenvironment) in addition to its expression in the tumor epithelium.

RESULTS: Testosterone uptake followed a concentration gradient but unlike in passive diffusion, was saturable and temperature-dependent, thus suggesting facilitated transport. Suppression of UGT2B17 to abrogate a testosterone gradient reduced testosterone transport while overexpression of the enzyme enhanced it. The facilitated transport suggests a paracrine route of testosterone uptake for maintaining optimal intracellular levels. We found that AKR1C3 was expressed in the tumor microenvironment of CRPC metastases in addition to epithelial cells and the pattern of relative abundance of the enzyme in epithelium vs stroma varied substantially between the metastatic sites.

CONCLUSIONS: Our findings suggest that in addition to testosterone transport and metabolism by tumor epithelium, testosterone could also be produced by components of the tumor microenvironment. Facilitated testosterone uptake by tumor cells supports a cell nonautonomous mechanism for testosterone signaling in CRPC.

RevDate: 2019-08-03

Cheng A, Zhao S, FitzGerald LM, et al (2019)

A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer: Development and validation studies.

The Prostate [Epub ahead of print].

BACKGROUND: Molecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed.

METHODS: Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic-lethal events from those who remained recurrence-free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan-Meier curves and receiver operating characteristic analyses to evaluate the model's performance.

RESULTS: Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10-11). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69-0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56-0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment-Surgery).

CONCLUSION: Our validated 4GT score has prognostic value for metastatic-lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.

RevDate: 2019-08-03

Marsh RA, Leiding JW, Logan BR, et al (2019)

Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

Journal of clinical immunology pii:10.1007/s10875-019-00659-8 [Epub ahead of print].

INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.

METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.

RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT.

CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

RevDate: 2019-08-02

Livingstone MC, Johnson NM, Roebuck BD, et al (2019)

Serum miR-182 is a predictive biomarker for dichotomization of risk of hepatocellular carcinoma in rats.

Molecular carcinogenesis [Epub ahead of print].

Exploration of animal models leads to discoveries that can reveal candidate biomarkers for translation to human populations. Herein, a model of hepatocarcinogenesis and protection was used in which rats treated with aflatoxin (AFB1) daily for 28 days (200 µg/kg BW) developed tumors compared with rats completely protected from tumors by concurrent administration of the chemoprotective agent, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im). Differential expression of miRNAs in tumors (AFB1) and nontumor (AFB1 + CDDO-Im) bearing livers and their levels in sera over the life-course of the animals was determined. miRNA transcriptome analysis identified 17 miRNAs significantly upregulated at greater than five-fold in the tumors. The ten most dysregulated miRNAs judged by fold-change and biological significance were selected for further study, including liver-specific miR-122-5p. Validation of sequencing results by real-time PCR confirmed the upregulation of the majority of these miRNAs in tumors, including miR-182, as well as miR-224-5p as the most dysregulated of these miRNAs (over 400-fold). The longitudinal analysis of levels of miR-182 in sera demonstrated significant and persistent increases (5.13-fold; 95% CI: 4.59-5.70). The increase in miR-182 was detected months before any clinical symptoms were present in the animals. By the terminal time point of the study, in addition to elevated levels of serum miR-182, serum miR-122-5p was also found to be increased (>1.5-fold) in animals that developed hepatocarcinomas. Thus, using the data from an unbiased discovery approach of the tissue findings, serum miR-182 was found to track across the complex, multistage process of hepatocarcinogenesis opening an opportunity for translation to human populations.

RevDate: 2019-08-02

Kofuji S, Hirayama A, Eberhardt AO, et al (2019)

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.

Nature cell biology, 21(8):1003-1014.

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

RevDate: 2019-08-01

Zhang H, Wilmot B, Bottomly D, et al (2019)

Genomic landscape of Neutrophilic Leukemias of Ambiguous Diagnosis.

Blood pii:blood.2019000611 [Epub ahead of print].

Chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are a group of rare, heterogeneous myeloid disorders. There is strong morphologic resemblance amongst these distinct diagnostic entities as well as lack of specific molecular markers and limited understanding of disease pathogenesis, which has made diagnosis challenging in certain cases. The treatment has remained empirical, resulting in dismal outcomes. We, therefore, performed whole exome and RNA-sequencing of these rare hematologic malignancies and present the most complete survey of the genomic landscape of these diseases to date. We observed a diversity of combinatorial mutational patterns that generally do not cluster within any one diagnosis. Gene expression analysis reveals enrichment, but not co-segregation of clinical and genetic disease features with transcriptional clusters. In conclusion, these group of diseases represent a continuum of related diseases rather than discrete diagnostic entities.

RevDate: 2019-08-01

Liu Y, Horn JL, Banda K, et al (2019)

The androgen receptor regulates a druggable translational regulon in advanced prostate cancer.

Science translational medicine, 11(503):.

The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer.

RevDate: 2019-08-01

Humbert O, Radtke S, Samuelson C, et al (2019)

Therapeutically relevant engraftment of a CRISPR-Cas9-edited HSC-enriched population with HbF reactivation in nonhuman primates.

Science translational medicine, 11(503):.

Reactivation of fetal hemoglobin (HbF) is being pursued as a treatment strategy for hemoglobinopathies. Here, we evaluated the therapeutic potential of hematopoietic stem and progenitor cells (HSPCs) edited with the CRISPR-Cas9 nuclease platform to recapitulate naturally occurring mutations identified in individuals who express increased amounts of HbF, a condition known as hereditary persistence of HbF. CRISPR-Cas9 treatment and transplantation of HSPCs purified on the basis of surface expression of the CD34 receptor in a nonhuman primate (NHP) autologous transplantation model resulted in up to 30% engraftment of gene-edited cells for >1 year. Edited cells effectively and stably reactivated HbF, as evidenced by up to 18% HbF-expressing erythrocytes in peripheral blood. Similar results were obtained by editing highly enriched stem cells, defined by the markers CD34+CD90+CD45RA-, allowing for a 10-fold reduction in the number of transplanted target cells, thus considerably reducing the need for editing reagents. The frequency of engrafted, gene-edited cells persisting in vivo using this approach may be sufficient to ameliorate the phenotype for a number of genetic diseases.

RevDate: 2019-07-31

Cotter ML, Boitano S, Lampe PD, et al (2019)

The lipidated connexin mimetic peptide, SRPTEKT-Hdc, is a potent inhibitor of Cx43 channels with specificity for the pS368 phospho-isoform.

American journal of physiology. Cell physiology [Epub ahead of print].

Connexin (Cx) mimetic peptides derived from extracellular loop II sequences (e.g. Gap 27: SRPTEKTIFII; Peptide5: VDCFLSRPTEKT) have been used as reversible, Cx-specific blockers of hemichannel (HCh) and gap junction channel (GJCh) function. These blockers typically require high concentrations (HCh: ~5 µM, < 1 hour; GJCh: ~100 µM, > 1 hour) to achieve inhibition. We have shown that addition of a hexadecyl (Hdc) lipid tail to the conserved SRPTEKT peptide sequence, SRPTEKT-Hdc, results in a novel, highly efficacious and potent inhibitor of mechanically-induced Ca2+-wave propagation (IC50: 64.8 pM) and HCh-mediated dye uptake (IC50: 45.0 pM) in Madin-Darby canine kidney cells expressing rCx43 (MDCK43). The lack of similar effect on dye coupling (NBD-MTMA) suggested channel conformation-specific inhibition. Here we report that SRPTEKT-Hdc inhibition of Ca2+-wave propagation, dye coupling, and dye uptake depended on the functional configuration of Cx43 as determined by phosphorylation at serine 368. Ca2+-wave propagation was enhanced in MDCK cells expressing single site mutants of Cx43 that mimicked (MDCK43-S368D) or favored (MDCK43-S365A) phosphorylation at S368. Further, SRPTEKT-Hdc potently inhibited GJCh-mediated Ca2+-wave propagation (IC50: 230.4 pM), dye coupling, and HCh-mediated dye uptake in MDCK43-S368D and -S365A cells. In contrast, Ca2+-wave propagation, dye coupling, and dye uptake were largely unaffected (IC50: 12.3 μM) by SRPTEKT-Hdc in MDCK43-S368A and -S365D cells, mutations that mimic or favor dephosphorylation at S368. Together, these data indicate that SRPTEKT-Hdc is a potent inhibitor of physiologic Ca2+-wave signaling mediated specifically by the pS368 phospho-form of Cx43.

RevDate: 2019-07-31

Gulati R, Psutka SP, R Etzioni (2019)

Reply by Authors.

The Journal of urology [Epub ahead of print].

RevDate: 2019-07-31

Han S, Chi NC, Han C, et al (2019)

Adapting the Resilience Framework for Family Caregivers of Hospice Patients With Dementia.

American journal of Alzheimer's disease and other dementias, 34(6):399-411.

Family caregivers face ongoing, formidable stress and burden. Caregivers need sustainable support to maintain resilience. We aim to identify challenges, possible solutions that are resources for resilience, and expected consequences from the perspective of 39 family caregivers of hospice patients with dementia. The resilience framework was used to guide the coding and synthesis of the qualitative data. Identified challenges included difficulties in communication, providing care and decision-making, lack of knowledge, emotional challenges, concern about care facility selection, death with dignity, and lack of public awareness. Resilience resources for caregiving challenges were identified at the individual, community, and societal levels. Anticipated benefits of using these resources included the ability to provide better care and have a better quality of life for both patients and caregivers. The findings of this study can guide the design and implementation of supportive interventions designed for family caregivers of hospice patients with dementia to bolster available resilience resources.

RevDate: 2019-07-31

Beltran H, Hruszkewycz A, Scher HI, et al (2019)

The role of lineage plasticity in prostate cancer therapy resistance.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-1423 [Epub ahead of print].

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer (PC). Treatment refractory PCs are increasingly associated with loss of luminal prostate markers, and in many cases induction of developmental programs, stem cell-like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low prostate specific antigen (PSA) progression, resistance to AR pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell/neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology, few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the National Cancer Institute (NCI) Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.

RevDate: 2019-07-31

Lubwama M, Phipps W, Najjuka CF, et al (2019)

Bacteremia in febrile cancer patients in Uganda.

BMC research notes, 12(1):464 pii:10.1186/s13104-019-4520-9.

OBJECTIVE: The aim of this study was to determine the predominant bacterial species causing bacteremia among febrile cancer patients, and their antibacterial resistance profiles at the Uganda Cancer Institute.

RESULTS: We enrolled in-patients with a documented fever (≥ 37.5 °C). Bacteria from positive blood cultures were identified using standard methods biochemically. Antibacterial susceptibility testing was performed with the Kirby-Bauer disc diffusion method. From a total of 170 febrile episodes, positive blood cultures were obtained from 24 (14.1%). A positive culture was more likely to be obtained from a patient with neutropenia (P = 0.017). Of 22 (66.7%) Gram-negative bacteria isolated, half were E. coli (n = 11). Gram-negative compared to Gram-positive bacteria were most likely to be isolated from patients with a hematologic malignancy (P = 0.02) or patients with neutropenia (P = 0.006). Of the isolated Enterobacteriaceae 85% (n = 20) were resistant to three or more classes of antibiotic and 41% (n = 7) had extended spectrum beta-lactamases. Of the 11 Gram-positive bacteria isolated, the S. aureus isolate was methicillin resistant but susceptible to vancomycin. Multidrug resistant Gram-negative bacteria are the main cause of bacteremia in febrile cancer patients at the Uganda Cancer Institute. There is need for ongoing microbial surveillance, infection prevention and control, and antibiotic stewardship programs.

RevDate: 2019-07-30

Flanagan MR, Tang MC, Baglia ML, et al (2018)

Relationship Between Anthropometric Factors and Risk of Second Breast Cancer Among Women With a History of Ductal Carcinoma In Situ.

JNCI cancer spectrum, 2(2):pky020 pii:pky020.

Background: Women with ductal carcinoma in situ (DCIS) have an elevated risk of a second breast cancer, but few data are available regarding the impact of modifiable lifestyle factors on this risk.

Methods: In a population-based case-control patient study of women with a history of DCIS in western Washington diagnosed between 1996 and 2013, 497 patients diagnosed with DCIS and a second ipsilateral or contralateral invasive or in situ breast cancer were enrolled. There were 965 matched control patients with one DCIS diagnosis. Associations between anthropometric factors and risk of an invasive or in situ second breast cancer event were evaluated using conditional logistic regression. Statistical tests were two-sided.

Results: Obesity (body mass index [BMI] ≥ 30 kg/m2) at initial DCIS diagnosis was associated with a 1.6-fold (95% confidence interval [CI] = 1.2 to 2.2) increased risk of any second breast cancer and a 2.2-fold increased risk of a contralateral second breast cancer (95% CI = 1.4 to 3.3) compared with normal weight women (BMI < 25 kg/m2). BMI and weight, both at initial DCIS diagnosis and at the time of the second breast cancer diagnosis, were positively associated with risk of any second and second invasive breast cancers (odds ratio = 1.01-1.04, all P ≤ .03).

Conclusions: Although additional confirmatory studies are needed, obesity appears to be an important contributor to the risk of second breast cancers within the growing population of women with DCIS. This has potential clinical relevance with respect to identifying which women with a history of DCIS may require more careful monitoring and who may benefit from lifestyle modifications.

RevDate: 2019-07-30

Passarelli MN, PA Newcomb (2017)

Survival Benefits of Smoking Cessation After Breast Cancer Diagnosis.

JNCI cancer spectrum, 1(1):pkx005 pii:pkx005.

RevDate: 2019-07-29

Newcomb PA, Adams SV, Mayer S, et al (2018)

Postmenopausal Fracture History and Survival After Reproductive Cancer Diagnosis.

JNCI cancer spectrum, 2(1):pky001.

Background: Postmenopausal bone fracture's have been proposed as a marker of lifetime estrogen exposure and have been associated with decreased risk of breast and endometrial cancer. It is plausible that prediagnostic fractures may be related to survival of estrogen-sensitive cancers.

Methods: We evaluated a cohort of breast (n = 6411), endometrial (n = 1127), and ovarian (n = 658) cancer cases diagnosed between 1992 and 2010 while participating in the Women's Health Initiative. Postmenopausal fracture history was assessed from baseline reports of fractures after age 55 years and incident fractures that occurred at least one year prior to cancer diagnosis during study follow-up. Using Cox regression, we compared women with and without a history of fractures with respect to overall and cancer-specific survival. Estimates were adjusted for participant factors, including hormone therapy use; hormone receptor status was not included in our analysis.

Results: Among women with breast cancer, a history of prediagnostic fractures at any site was associated with poorer overall survival (hazard ratio [HR] = 1.22, 95% confidence interval [CI] = 1.05 to 1.43). A history of hip, forearm, or spine fractures, or hip fracture alone, was associated with increased risk of mortality (HR = 1.26, 95% CI = 1.01 to 1.58, and HR = 2.05, 95% CI = 1.27 to 3.32, respectively). Fracture history was associated neither with cancer-specific survival among breast cancer survivors, nor with overall or disease-specific mortality among endometrial and ovarian cancer survivors.

Conclusions: Postmenopausal breast cancer patients with a history of fractures, especially of the hip, are more likely to die of any cause than breast cancer survivors without a fracture history. Identifying and intervening in fracture risk factors should be standard of care for all women diagnosed with breast cancer.

RevDate: 2019-07-30

Chlebowski RT, Anderson GL, Manson JE, et al (2018)

Low-Fat Dietary Pattern and Cancer Mortality in the Women's Health Initiative (WHI) Randomized Controlled Trial.

JNCI cancer spectrum, 2(4):pky065 pii:pky065.

Background: In the Women's Health Initiative Dietary Modification trial, a low-fat dietary pattern reduced deaths after breast cancer. Mortality from other cancer sites has not been reported.

Methods: A low-fat dietary pattern influence on deaths from and after site-specific cancers was examined during 8.5 years (median) of dietary intervention and cumulatively during 17.7 years (median) of follow-up. A total 48 835 postmenopausal women, ages 50-79 years, were randomly assigned from 1993 to 1998 at 40 US clinical centers to dietary intervention (40%, n = 19 541 or a usual diet comparison group (60%, n = 29 294). Dietary intervention influence on mortality from protocol-specified cancers (breast, colon and rectum, endometrium and ovary), individually and as a composite, represented the primary analyses.

Results: During the dietary intervention period, a reduction in deaths after breast cancer (HR = 0.65 95% CI = 0.45 to 0.94, P = .02) was the only statistically significant cancer mortality finding. During intervention, the HRs for deaths after the protocol-specified cancer composite were 0.90 (95% CI = 0.73 to 1.10) and 0.95 (95% CI = 0.85 to 1.06) for deaths after all cancers. During 17.7 years of follow-up with 3867 deaths after all cancers, reduction in deaths after breast cancer continued in the dietary intervention group (HR = 0.85, 95% CI = 0.74 to 0.99, P = .03). However, no dietary intervention influence on deaths from or after any other cancer or cancer composite was seen.

Conclusions: A low-fat dietary pattern reduced deaths after breast cancer. No reduction in mortality from or after any other cancer or cancer composite was seen.

RevDate: 2019-07-30

Sulakvelidze N, Burdick B, Kaklamani V, et al (2019)

Evaluating the Effect of a Video Education Curriculum for First Time Breast Cancer Patients: a Prospective RCT Feasibility Study.

Journal of cancer education : the official journal of the American Association for Cancer Education pii:10.1007/s13187-019-01578-3 [Epub ahead of print].

Newly diagnosed breast cancer patients seek information through a variety of sources. In this small pilot study, we evaluated the feasibility of providing personalizable breast cancer video education prior to the first oncology consultation and compared outcomes to patients receiving standard of care educational materials. Personalized videos included detailed information on a patient's specific grade, stage, and tumor subtype (e.g., grade 2, stage 3, triple negative breast cancer) in addition to general videos that defined the terms of grade, stage, and cancer subtype. Newly diagnosed breast cancer patients who were scheduled for an initial oncology appointment at two sites were enrolled in this prospective, randomized control trial. Twenty-eight patients were assigned to receive either video education (experimental group) with the possibility of personalization or a video explaining how to view cancer education materials at the cancer center website (control group). Sixteen oncologists at the two centers also participated in evaluating patient outcomes. Pre- and post-education surveys queried patient-perceived understanding of breast cancer and treatment, perceived ability for decision-making, confidence in providers, and anxiety and depression symptoms. We observed that patients given video education had greater improvements in some of these areas, with the biggest improvement seen in patients who received a personalized video on their specific tumor subtype (based on tumor receptor status). Overall, however, there were no statistically significant differences between the study groups. We conclude that providing personalized video education during the time prior to first oncologic consultation is feasible and may provide benefit for patients, especially for explaining complex components of a diagnosis, such as a cancer subtype. Further research is needed to determine how to optimally provide education tailored to a given patient and tumor type, and how to leverage patients' electronic devices as an education delivery vehicle.

RevDate: 2019-07-30

Clynes M, Corbett A, J Overbaugh (2019)

Why we need good mentoring.

Nature reviews. Cancer pii:10.1038/s41568-019-0173-1 [Epub ahead of print].

Cancer research relies on key values such as creativity, collaboration, research integrity and resource sharing. A positive research environment which fosters these key values is becoming a decisive factor for some funders and research institutions. To create a supportive research culture in laboratories, the training and mentoring of young scientists is important. However, the fast-paced and fierce competition for funding and jobs can present a challenge to the younger generation of scientists who depend on the guidance and mentorship of scientific leaders. The annual Nature Awards for Mentoring in Science have been created to bring attention to one of the most essential but least recognized skills in scientific leadership. Thus far, 35 scientists from across the world, who are working in a range of disciplines, have been recognized by this award for their outstanding scientific mentorship. In this Viewpoint, we have asked three recipients of this award who work in fields associated with cancer research about their views on good mentoring, and how a revised approach to mentorship can help to achieve a positive research culture and contribute to scientific discovery.

RevDate: 2019-07-30

Kim H, Oh H, Oh YS, et al (2019)

SPIN90, an adaptor protein, alters the proximity between Rab5 and Gapex5 and facilitates Rab5 activation during EGF endocytosis.

Experimental & molecular medicine, 51(7):85 pii:10.1038/s12276-019-0284-5.

During ligand-mediated receptor endocytosis, the small GTPase Rab5 functions in vesicle fusion and trafficking. Rab5 activation is known to require interactions with its guanine nucleotide-exchange factors (GEFs); however, the mechanism regulating Rab5 interactions with GEFs remains unclear. Here, we show that the SH3-adapter protein SPIN90 participates in the activation of Rab5 through the recruitment of both Rab5 and its GEF, Gapex5, to endosomal membranes during epidermal growth factor (EGF)-mediated endocytosis. SPIN90 strongly interacts with the inactive Rab5/GDI2 complex through its C-terminus. In response to EGF signaling, extracellular signal-regulated kinase (ERK)-mediated phosphorylation of SPIN90 at Thr-242 enables SPIN90 to bind Gapex5 through its N-terminal SH3 domain. Gapex5 is a determinant of Rab5 membrane targeting, while SPIN90 mediates the interaction between Gapex5 and Rab5 in a phosphorylation-dependent manner. Collectively, our findings suggest that SPIN90, as an adaptor protein, simultaneously binds inactive Rab5 and Gapex5, thereby altering their spatial proximity and facilitating Rab5 activation.

RevDate: 2019-07-30

Zomerdijk N, Turner J, Hill GR, et al (2019)

Adult related haematopoietic stem cell donor care: Views of Transplant Nurses.

European journal of oncology nursing : the official journal of European Oncology Nursing Society, 41:56-63.

PURPOSE: The objective of this mixed-methods study was to explore the experiences and perspectives of Transplant Nurses (TNs) in caring for related donors (RDs).

METHOD: In this mixed-methods study, both quantitative and qualitative data were collected from semi-structured interviews with seven TNs from two clinical hospitals. Closed and multiple-choice questions regarding the organisation of RD care were administered in addition to an in-depth exploration of TN experiences and perspectives of RD care. Interviews were audio-recorded, transcribed, and qualitative data was subjected to thematic analyses.

RESULTS: The analysis identified 5 themes relating to RD care: managing complex family dynamics and ambivalence; concerns about RD psychological adjustment; identifying and correcting RD misperceptions; limited guidelines and structured processes; limited training for the role and access to supervision. Five themes were identified describing the barriers to delivering RD care: RDs unwilling to express their concerns; language; time constraints; medical priority of clinicians; biomedical focus of TNs. All TNs agreed they would like additional training in the psychosocial management of RDs. TNs identified key areas for improvement, including psychosocial support and educational material.

CONCLUSIONS: Our results highlight the significant role of TNs in RD care, and underline issues specific to the current RD care environment. Lack of training for the role and limited guidelines addressing RD care management are key issues which may detrimentally affect RD care. The pivotal role of TNs must be acknowledged and supported by improving TN training and implementing clear guidelines for the management of RDs. The trial has been registered on the publicly accessible register: www.clinicaltrials.gov site with the identifier ACTRN12617000407392.

RevDate: 2019-07-29

Chambers LC, Hughes JP, Glick SN, et al (2019)

Resolution of symptoms and resumption of sex after diagnosis of nongonococcal urethritis among men who have sex with men.

Sexually transmitted diseases [Epub ahead of print].

BACKGROUND: Standard counseling at nongonococcal urethritis (NGU) diagnosis includes advice to abstain from sex for ≥7 days and until symptoms resolve.

METHODS: From 12/2014 to 07/2018, we enrolled men who have sex with men and received azithromycin (1g) for NGU at the Public Health-Seattle and King County STD Clinic. Over 12 weeks of follow-up, participants reported daily urethral symptoms and sexual activity on web-based diaries. NGU was defined as urethral symptoms or visible urethral discharge plus ≥5 polymorphonuclear leukocytes per high-power field. Time of symptom resolution was defined as the first of five consecutive asymptomatic days.

RESULTS: Of 100 participants with NGU and no Chlamydia trachomatis (CT)/Mycoplasma genitalium (MG) co-infections, 36 (36%), 22 (22%), and 42 (42%) had CT-NGU, MG-NGU, and non-CT/non-MG NGU, respectively. Among men with MG-NGU, 94% had a macrolide resistance mutation. For all etiologies, median time to symptom resolution after azithromycin was seven days (95% confidence interval [CI]=5-9); 37% had symptoms lasting >7 days. For men with CT-NGU, MG-NGU, and non-CT/non-MG NGU, median time to symptom resolution was four (95%CI=2-6, 16% >7 days), undefined (95%CI=7-undefined, 60% >7 days), and seven (95%CI=5-11, 46% >7 days) days, respectively. Median time to first sexual activity (any type) was 12 days (95%CI=11-17); it was 16 days (95%CI=12-18) to first urethral sexual exposure. Twenty-seven percent did not avoid urethral exposure for the recommended period.

CONCLUSIONS: Counseling at NGU diagnosis should educate patients that symptoms may persist >7 days, particularly for non-CT NGU, and emphasize the rationale for the 7-day abstinence period.

RevDate: 2019-07-29

Giovenco D, Pettifor A, MacPhail C, et al (2019)

Assessing risk for HIV infection among adolescent girls in South Africa: an evaluation of the VOICE risk score (HPTN 068).

Journal of the International AIDS Society, 22(7):e25359.

INTRODUCTION: To maximize impact and minimize costs, antiretroviral pre-exposure prophylaxis (PrEP) interventions should be offered to those at highest risk for HIV infection. The risk score derived from the VOICE trial is one tool currently being utilized to determine eligibility in adolescent PrEP trials in sub-Saharan Africa. This study is aimed at evaluating the utility of the risk score in predicting HIV incidence among a cohort of adolescent girls in rural South Africa.

METHODS: We utilized data from HIV Prevention Trials Network (HPTN) 068, a phase III randomized controlled trial conducted in rural Mpumalanga province, South Africa. School-attending young women aged 13 to 20 years were enrolled into the trial from 2011 to 2012 and followed for up to three years. A risk score based on individual-level risk factors measured at enrolment was calculated for HPTN 068 participants who completed a one-year follow-up visit and were HIV seronegative at enrolment. Possible scores ranged from 0 to 10. A proportional hazards model was then used to determine if risk score at enrolment was predictive of incident HIV infection at follow-up and an area under the curve analysis was used to examine the predictive ability of the score.

RESULTS AND DISCUSSION: The risk score had limited variability in the HPTN 068 sample. Scores ≥5 identified 85% of incident infections from 94% of the sample, compared to the VOICE sample in which scores ≥5 identified 91% of incident infections from only 64% of participants. The risk score did not predict HIV incidence after one year of follow-up (hazard ratio = 1.029; 95% confidence interval (CI): 0.704, 1.503, p = .884) and showed poor predictive ability (area under the curve = 0.55; 95% CI: 0.44, 0.65). Certain individual risk factors that comprise the risk score may be context specific or not relevant for adolescent populations. Additional factors should be considered when assessing risk for the purposes of determining PrEP eligibility.

CONCLUSIONS: The VOICE risk score demonstrated low utility to predict HIV incidence in the HPTN 068 sample. Findings highlight the need for an age and developmentally appropriate tool for assessing risk for HIV infection among adolescents. Use of the VOICE risk score for determining PrEP eligibility in younger populations should be carefully considered.

RevDate: 2019-07-29

Bach M, Moon J, Moore R, et al (2019)

A Neutrophil Activation Biomarker Panel in Prognosis and Monitoring of Patients with Rheumatoid Arthritis.

Arthritis & rheumatology (Hoboken, N.J.) [Epub ahead of print].

OBJECTIVE: Exaggerated neutrophil activation and formation of neutrophil extracellular traps (NETs) are linked to inflammation and autoimmunity, including rheumatoid arthritis (RA). However, whether NETs are present in the circulation of RA patients and contribute to inflammation and disease progression has not been carefully addressed. Here we assess markers of neutrophil activation and NET formation in plasma samples, asking whether they add clinical value in improving on determination of prognosis and monitoring in RA patients.

METHODS: Markers of neutrophil activation (calprotectin) and cell death (NET) were analyzed in plasma from three cross-sectional RA cohorts and healthy individuals using ELISA. A longitudinal inception cohort (n=247), seen for follow-up a median of 8 years later was used for predictive analyses.

RESULTS: Markers of neutrophil activation and cell death were increased in RA patients compared to healthy individuals (p<0.0001). Calprotectin levels correlated with CDAI (r=0.53, p<0.0001) and distinguished between patients in remission and active disease, an observation not seen with CRP. A biomarker panel consisting of ACPA and calprotectin could predict erosive disease (OR=7.5, p<0.0001) and joint space narrowing (OR=4.9, p=0.001). Levels of NETs were associated with heightened levels of cell-free citrulline (p=0.02) and inflammation (p=0.0002). Furthermore, NETs, and a 'neutrophil activation signature' biomarker panel, had good predictive value in identifying patients developing extra-articular nodules (OR=5.6, p=0.006).

CONCLUSION: Neutrophils undergo marked activation and cell death in RA. Neutrophil biomarkers provide added clinical value in monitoring and prognosis of RA patients, and may allow for early preventive treatment intervention. This article is protected by copyright. All rights reserved.

RevDate: 2019-07-29

Adler D, Abar B, Durham DD, et al (2019)

Validation of the Emergency Severity Index (Version 4) for the Triage of Adult Emergency Department Patients With Active Cancer.

The Journal of emergency medicine pii:S0736-4679(19)30418-4 [Epub ahead of print].

BACKGROUND: Patients with active cancer account for a growing percentage of all emergency department (ED) visits and have a unique set of risks related to their disease and its treatments. Effective triage for this population is fundamental to facilitating their emergency care.

OBJECTIVES: We evaluated the validity of the Emergency Severity Index (ESI; version 4) triage tool to predict ED-relevant outcomes among adult patients with active cancer.

METHODS: We conducted a prespecified analysis of the observational cohort established by the National Cancer Institute-supported Comprehensive Oncologic Emergencies Research Network's multicenter (18 sites) study of ED visits by patients with active cancer (N = 1075). We used a series of χ2 tests for independence to relate ESI scores with 1) disposition, 2) ED resource use, 3) hospital length of stay, and 4) 30-day mortality.

RESULTS: Among the 1008 subjects included in this analysis, the ESI distribution skewed heavily toward high acuity (>95% of subjects had an ESI level of 1, 2, or 3). ESI was significantly associated with patient disposition and ED resource use (p values < 0.05). No significant associations were observed between ESI and the non-ED based outcomes of hospital length of stay or 30-day mortality.

CONCLUSION: ESI scores among ED patients with active cancer indicate higher acuity than the general ED population and are predictive of disposition and ED resource use. These findings show that the ESI is a valid triage tool for use in this population for outcomes directly relevant to ED care.

RevDate: 2019-07-28

Scott H, Vittinghoff E, Irvin R, et al (2019)

Development and Validation of the Personalized Sexual Health Promotion (SexPro) HIV Risk Prediction Model for Men Who Have Sex with Men in the United States.

AIDS and behavior pii:10.1007/s10461-019-02616-3 [Epub ahead of print].

Accurate HIV risk assessment among men who have sex with men (MSM) is important to help providers assess risk, and target HIV prevention interventions. We sought to develop an evidence-based HIV risk assessment tool for US MSM that is inclusive of Black MSM. Data from four large longitudinal cohorts of MSM were used to develop (EXPLORE), and validate (VAX004, HPTN061, and HVTN505). These data included visits in which participants self-reported HIV risk behavior and underwent HIV testing. We developed a pooled logistic model for incident HIV infection based on self-reported risk behaviors during the 6 months before each study visit. A total of 4069 MSM were used for the development cohort, and 8047 MSM in the three validation cohorts through 2013. The final model includes age (< 35, ≥ 35); Black race and Latino ethnicity; numbers of HIV-negative anal sex partners; number of insertive or receptive anal intercourse episodes; having 1 HIV-negative partner only; self-reported substance use; and bacterial sexually transmitted infection diagnosis. The model showed good discrimination in internal validation (C-statistic = 79.5). The external validation cohorts also showed good discrimination, with C-statistics of 73.1, 71.0, 71.9 in VAX004, HPTN061, and HVTN505 respectively, and acceptable calibration. We developed and validated an HIV risk assessment tool for MSM, which showed good predictive ability, including among the largest cohort of HIV-uninfected Black MSM in the US. This tool is available online (mysexpro.org) and can be used by providers to support targeting of HIV prevention interventions such as pre-exposure prophylaxis for MSM.

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ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

Biographies

Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )