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26 Jun 2019 at 01:32
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Bibliography on: Publications by FHCRC Researchers


Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 26 Jun 2019 at 01:32 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: 2019-06-24

Kessler RC, Bossarte RM, Luedtke A, et al (2019)

Machine learning methods for developing precision treatment rules with observational data.

Behaviour research and therapy, 120:103412 pii:S0005-7967(19)30098-1 [Epub ahead of print].

Clinical trials have identified a variety of predictor variables for use in precision treatment protocols, ranging from clinical biomarkers and symptom profiles to self-report measures of various sorts. Although such variables are informative collectively, none has proven sufficiently powerful to guide optimal treatment selection individually. This has prompted growing interest in the development of composite precision treatment rules (PTRs) that are constructed by combining information across a range of predictors. But this work has been hampered by the generally small samples in randomized clinical trials and the use of suboptimal analysis methods to analyze the resulting data. In this paper, we propose to address the sample size problem by: working with large observational electronic medical record databases rather than controlled clinical trials to develop preliminary PTRs; validating these preliminary PTRs in subsequent pragmatic trials; and using ensemble machine learning methods rather than individual algorithms to carry out statistical analyses to develop the PTRs. The major challenges in this proposed approach are that treatment are not randomly assigned in observational databases and that these databases often lack measures of key prescriptive predictors and mental disorder treatment outcomes. We proposed a tiered case-cohort design approach that uses innovative methods for measuring and balancing baseline covariates and estimating PTRs to address these challenges.

RevDate: 2019-06-24

Ramsey SD, Shankaran V, SD Sullivan (2019)

Basket Cases: How Real-World Testing for Drugs Approved Based on Basket Trials Might Lead to False Diagnoses, Patient Risks, and Squandered Resources.

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

RevDate: 2019-06-24

Meers MP, Bryson TD, Henikoff JG, et al (2019)

Improved CUT&RUN chromatin profiling tools.

eLife, 8: pii:46314 [Epub ahead of print].

Previously we described a novel alternative to Chromatin Immunoprecipitation, CUT&RUN, in which unfixed permeabilized cells are incubated with antibody, followed by binding of a Protein A-Micrococcal Nuclease (pA/MNase) fusion protein (Skene and Henikoff, 2017). Here we introduce three enhancements to CUT&RUN: A hybrid Protein A-Protein G-MNase construct that expands antibody compatibility and simplifies purification, a modified digestion protocol that inhibits premature release of the nuclease-bound complex, and a calibration strategy based on carry-over of E. coli DNA introduced with the fusion protein. These new features, coupled with the previously described low-cost, high efficiency, high reproducibility and high-throughput capability of CUT&RUN make it the method of choice for routine epigenomic profiling.

RevDate: 2019-06-24

Jordahl KM, Phipps AI, Randolph TW, et al (2019)

Differential DNA methylation in blood as a mediator of the association between cigarette smoking and bladder cancer risk among postmenopausal women.

Epigenetics [Epub ahead of print].

Smoking accounts for approximately 52% of bladder cancer incidence among postmenopausal women, but the underlying mechanism is poorly understood. Our study investigates whether changes in DNA methylation, as measured in blood, mediate the impact of smoking on bladder cancer risk among postmenopausal women. We conducted analyses among 206 cases and 251 controls that were current or never smokers at baseline from a previous case-control study of bladder cancer and genome-wide DNA methylation nested within the Women's Health Initiative. Separate mediation analyses were conducted for three CpG sites demonstrating robust associations with smoking in prior methylome-wide association studies: cg05575921 (AhRR), cg03636183 (F2RL3), and cg19859270 (GPR15). We estimated causal effects using the regression-based, four-way decomposition approach, which addresses the interaction between smoking and each CpG site. The overall proportion of the excess relative risk mediated by cg05575921 was 92% (p-value = 0.004) and by cg19859270 was 79% (p-value = 0.02). The largest component of the excess relative risk of bladder cancer due to 30 pack-years of smoking history in current smokers was the mediated interaction for both cg05575921 (72%, p = 0.02) and cg19859270 (72%, p-value = 0.04), where the mediated interaction is the effect of smoking on bladder cancer that both acts through differential methylation and depends on smoking history. There was little evidence that smoking was mediated through cg03636183. Our results suggest that differential methylation of cg05575921 and cg19859270 mediate the effects of smoking on bladder cancer, potentially revealing downstream effects of smoking relevant for carcinogenesis.

RevDate: 2019-06-24

Ris MD, Leisenring WM, Goodman P, et al (2019)

Neuropsychological and socioeconomic outcomes in adult survivors of pediatric low-grade glioma.

Cancer [Epub ahead of print].

BACKGROUND: Current estimates suggest that 75% of children diagnosed with a central nervous system (CNS) tumor will become 5-year survivors. However, survivors of childhood CNS tumors are at increased risk for long-term morbidity.

METHODS: To determine long-term neuropsychological and socioeconomic status (SES) outcomes, adult survivors of pediatric low-grade gliomas (n = 181) in the Childhood Cancer Survivor Study and a sibling comparison group that was frequency-matched by age and sex (n = 105) completed a comprehensive battery of standardized neuropsychological tests and an SES assessment. Multivariable regression models compared treatment-specific groups for neuropsychological and SES outcomes and evaluated associations with tumor location, age at diagnosis, sex, and age at evaluation.

RESULTS: In adjusted models, survivors treated with surgery and radiotherapy (surgery+RT; median age at diagnosis, 7 years; median age at assessment, 41 years) scored lower on estimated IQ than survivors treated with surgery only, who scored lower than siblings (surgery+RT, 93.9; surgery only, 101.2; siblings, 108.5; all P values <.0001). Survivors diagnosed at younger ages had low scores for all outcomes (P < .05) except for attention/processing speed. For SES outcomes, survivors treated with surgery+RT had lower occupation scores (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.1-5.9), lower income (OR, 2.6; 95% CI, 1.3-5.0), and less education (OR, 2.1; 95% CI, 1.1-4.0) than those treated with surgery only.

CONCLUSIONS: Decades after treatment, survivors treated with radiotherapy and at younger ages had poorer neuropsychological and SES outcomes. Lifelong surveillance of survivors of pediatric low-grade gliomas may be warranted as life events, stages, and transitions (employment, family, and aging) present new challenges and risks.

RevDate: 2019-06-24

Laskar RS, Muller DC, Li P, et al (2019)

Sex specific associations in genome wide association analysis of renal cell carcinoma.

European journal of human genetics : EJHG pii:10.1038/s41431-019-0455-9 [Epub ahead of print].

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

RevDate: 2019-06-24

Kobayashi M, Tarnawsky SP, Wei H, et al (2019)

Hemogenic Endothelial Cells Can Transition to Hematopoietic Stem Cells through a B-1 Lymphocyte-Biased State during Maturation in the Mouse Embryo.

Stem cell reports pii:S2213-6711(19)30193-6 [Epub ahead of print].

Precursors of hematopoietic stem cells (pre-HSCs) have been identified as intermediate precursors during the maturation process from hemogenic endothelial cells to HSCs in the aorta-gonad-mesonephros (AGM) region of the mouse embryo at embryonic day 10.5. Although pre-HSCs acquire an efficient adult-repopulating ability after ex vivo co-culture, their native hematopoietic capacity remains unknown. Here, we employed direct transplantation assays of CD45-VE-cadherin(VC)+KIT+(V+K+) cells (containing pre-HSCs) into immunodeficient neonatal mice that permit engraftment of embryonic hematopoietic precursors. We found that freshly isolated V+K+ cells exhibited significantly greater B-1 lymphocyte-biased repopulating capacity than multilineage repopulating capacity. Additionally, B cell colony-forming assays demonstrated the predominant B-1 progenitor colony-forming ability of these cells; however, increased B-2 progenitor colony-forming ability emerged after co-culture with Akt-expressing AGM endothelial cells, conditions that support pre-HSC maturation into HSCs. Our studies revealed an unexpected B-1 lymphocyte bias of the V+K+ population and acquisition of B-2 potential during commitment to the HSC fate.

RevDate: 2019-06-23

Chen H, Kichaev G, Bien SA, et al (2019)

Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues.

Human genetics pii:10.1007/s00439-019-02041-5 [Epub ahead of print].

Although genome-wide association studies (GWAS) have identified hundreds of risk loci for breast and prostate cancer, only a few studies have characterized the GWAS association signals across functional genomic annotations with a particular focus on single nucleotide polymorphisms (SNPs) located in DNA regulatory elements. In this study, we investigated the enrichment pattern of GWAS signals for breast and prostate cancer in genomic functional regions located in normal tissue and cancer cell lines. We quantified the overall enrichment of SNPs with breast and prostate cancer association p values < 1 × 10-8 across regulatory categories. We then obtained annotations for DNaseI hypersensitive sites (DHS), typical enhancers, and super enhancers across multiple tissue types, to assess if significant GWAS signals were selectively enriched in annotations found in disease-related tissue. Finally, we quantified the enrichment of breast and prostate cancer SNP heritability in regulatory regions, and compared the enrichment pattern of SNP heritability with GWAS signals. DHS, typical enhancers, and super enhancers identified in the breast cancer cell line MCF-7 were observed with the highest enrichment of genome-wide significant variants for breast cancer. For prostate cancer, GWAS signals were mostly enriched in DHS and typical enhancers identified in the prostate cancer cell line LNCaP. With progressively stringent GWAS p value thresholds, an increasing trend of enrichment was observed for both diseases in DHS, typical enhancers, and super enhancers located in disease-related tissue. Results from heritability enrichment analysis supported the selective enrichment pattern of functional genomic regions in disease-related cell lines for both breast and prostate cancer. Our results suggest the importance of studying functional annotations identified in disease-related tissues when characterizing GWAS results, and further demonstrate the role of germline DNA regulatory elements from disease-related tissue in breast and prostate carcinogenesis.

RevDate: 2019-06-22

Lam HM, Nguyen HM, Labrecque MP, et al (2019)

Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts.

European urology pii:S0302-2838(19)30449-X [Epub ahead of print].

BACKGROUND: Androgen deprivation therapy improves the survival of castration-resistant prostate cancer (CRPC) patients, yet ultimately fails with debilitating side effects. Supraphysiological testosterone (SPT)-based therapy produces clinical responses with improved quality of life in a subset of patients. Currently, no information defines a durable response to SPT.

OBJECTIVE: To identify key molecular phenotypes underlying SPT response to improve patient selection and guide combination treatment to achieve a durable response.

A patient-derived xenograft (PDX) preclinical trial was performed with 13 CRPC PDXs to identify molecular features associated with SPT response. Comprehensive intratumoral androgen, tumor growth, and integrated transcriptomic and protein analyses were performed in three PDXs resistant to the newer androgen receptor (AR) pathway inhibitor enzalutamide (ENZ) to define SPT response and resistance.

INTERVENTION: Testosterone cypionate.

SPT efficacy was evaluated by PDX growth, prostate-specific antigen (PSA) change, and survival. Intratumoral androgens were analyzed using mass spectrometry. Global transcriptome analysis was performed using RNA sequencing, and confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Log-rank and Mann-Whitney tests were used for survival and molecular analyses, respectively.

RESULTS AND LIMITATIONS: A durable SPT responder was identified, presenting robust repressions of ARv7 and E2F transcriptional outputs, and a DNA damage response (DDR) transcriptomic program that were altogether restored upon SPT resistance in the transient responder. ENZ rechallenge of SPT-relapsed PDXs resulted in PSA decreases but tumor progression.

CONCLUSIONS: SPT produces a durable response in AR-pathway inhibitor ENZ CRPC that is associated with sustained suppression of ARv7 and E2F transcriptional outputs, and the DDR transcriptome, highlighting the potential of combination treatments that maintain suppression of these programs to drive a durable response to SPT.

PATIENT SUMMARY: Patients with ENZ-resistant prostate cancer have very limited treatment options. Supraphysiological testosterone presents a prominent option for improved quality of life and a potential durable response in patients with sustained suppression on ARv7/E2F transcriptional outputs and DNA repair program.

RevDate: 2019-06-22

Chu ND, Bi HS, Emerson RO, et al (2019)

Longitudinal immunosequencing in healthy people reveals persistent T cell receptors rich in highly public receptors.

BMC immunology, 20(1):19 pii:10.1186/s12865-019-0300-5.

BACKGROUND: The adaptive immune system maintains a diversity of T cells capable of recognizing a broad array of antigens. Each T cell's specificity for antigens is determined by its T cell receptors (TCRs), which together across all T cells form a repertoire of millions of unique receptors in each individual. Although many studies have examined how TCR repertoires change in response to disease or drugs, few have explored the temporal dynamics of the TCR repertoire in healthy individuals.

RESULTS: Here we report immunosequencing of TCR β chains (TCRβ) from the blood of three healthy individuals at eight time points over one year. TCRβ repertoires of all peripheral-blood T cells and sorted memory T cells clustered clearly by individual, systematically demonstrating that TCRβ repertoires are specific to individuals across time. This individuality was absent from TCRβs from naive T cells, suggesting that the differences resulted from an individual's antigen exposure history, not genetic background. Many characteristics of the TCRβ repertoire (e.g., diversity, clonality) were stable across time, although we found evidence of T cell expansion dynamics even within healthy individuals. We further identified a subset of "persistent" TCRβs present across all time points. These receptors were rich in clonal and highly public receptors and may play a key role in immune system maintenance.

CONCLUSIONS: Our results highlight the importance of longitudinal sampling of the immune system, providing a much-needed baseline for TCRβ dynamics in healthy individuals. Such a baseline will improve interpretation of changes in the TCRβ repertoire during disease or treatment.

RevDate: 2019-06-22

Panizza CE, Lim U, Yonemori KM, et al (2019)

Effects of Intermittent Energy Restriction Combined with a Mediterranean Diet on Reducing Visceral Adiposity: A Randomized Active Comparator Pilot Study.

Nutrients, 11(6): pii:nu11061386.

Intermittent energy restriction combined with a Mediterranean diet (IER+MED) has shown promise to reduce body fat and insulin resistance. In the Multiethnic Cohort Adiposity Phenotype Study, Japanese Americans had the highest visceral adipose tissue (VAT) when adjusting for total adiposity. We conducted this pilot study to demonstrate feasibility and explore efficacy of following IER+MED for 12 weeks to reduce VAT among East Asians in Hawaii. Sixty volunteers (aged 35-55, BMI 25-40 kg/m2, VAT ≥ 90 cm2 for men and ≥ 80 cm2 for women) were randomized to IER+MED (two consecutive days with 70% energy restriction and 5 days euenergetic MED) or an active comparator (euenergetic Dietary Approaches to Stop Hypertension (DASH) diet). Participants and clinic staff (except dietitians) were blinded to group assignments. IER+MED had significantly larger reductions in DXA-measured VAT and total fat mass (-22.6 ± 3.6 cm2 and -3.3 ± 0.4 kg, respectively) vs. DASH (-10.7 ± 3.5 cm2 and -1.6 ± 0.4 kg) (p = 0.02 and p = 0.005). However, after adjusting for total fat mass, change in VAT was not statistically different between groups; whereas, improvement in alanine transaminase remained significantly greater for IER+MED vs. DASH (-16.2 ± 3.8 U/L vs. -4.0 ± 3.6 U/L, respectively, p = 0.02). Attrition rate was 10%, and participants adhered well to study prescriptions with no reported major adverse effect. Results demonstrate IER+MED is acceptable, lowers visceral and total adiposity among East Asian Americans, and may improve liver function more effectively than a healthful diet pattern. ClinicalTrials.gov Identifier: NCT03639350.

RevDate: 2019-06-21

Chappell CA, Harkoo I, Szydlo DW, et al (2019)

Contraceptive method switching among women living in sub-Saharan Africa participating in an HIV-1 prevention trial: a prospective cohort study.

Contraception pii:S0010-7824(19)30206-9 [Epub ahead of print].

OBJECTIVE: Long-acting reversible contraceptive (LARC) method uptake has been low within the context of HIV prevention trials. Within a multinational study (MTN-020/ASPIRE), the Contraceptive Action Team improved LARC accessibility and uptake. In this secondary analysis, we determined the rate of contraceptive method continuation among the women enrolled.

STUDY DESIGN: ASPIRE was a randomized, double-blinded, placebo-controlled phase III safety and effectiveness study of the Dapivirine Vaginal Ring for HIV-1 prevention. Between 2012-2014, sexually active women aged 18-45 from Malawi, South Africa, Uganda, and Zimbabwe were enrolled. All participants were required to use contraception for enrollment to the study and could choose between all highly effective contraceptive methods available in their respective countries. Women were seen monthly and could change methods at any time. Continuation rates from study enrollment to 6 and 12months was determined.

RESULTS: The overall contraceptive method continuation rate was 77% (1972/2551) at 6months and 66% (1694/2551) at 12months. The 6 and 12-month continuation rates were highest for implantable contraceptives (89%, 82%) followed by copper IUD (83%, 77%). Rates of continuation for injectable contraceptives depot medroxyprogesterone acetate (80%, 69%) and norethisterone enanthate (71%, 54%) were higher than for oral contraceptives, which were continued at 47% at 6months and 35% at 12months. The continuation rates of all methods did not differ by users with and without previous contraceptive experience.

CONCLUSIONS: LARC methods have the highest rates of continuation at 12months and should be routinely offered in the context of HIV prevention trials in sub-Saharan Africa.

IMPLICATIONS: Intrauterine devices and contraceptive implant continuation was high at 12months among women participating in an HIV prevention trial in sub-Saharan Africa and LARCs should be routinely offered.

RevDate: 2019-06-21

Haffa M, Lin T, Holowatyj AN, et al (2019)

Transcriptome profiling of adipose tissue reveals depot-specific metabolic alterations among colorectal cancer patients.

The Journal of clinical endocrinology and metabolism pii:5520799 [Epub ahead of print].

CONTEXT: Adipose tissue inflammation and dysregulated energy homeostasis are key mechanisms linking obesity and cancer. Distinct adipose tissue depots strongly differ in their metabolic profiles, however comprehensive studies of depot-specific perturbations among cancer patients are lacking.

OBJECTIVE: We compared transcriptome profiles of visceral (VAT) and subcutaneous (SAT) adipose tissue from colorectal cancer patients, and assessed the associations of different anthropometric measures with depot-specific gene expression.

DESIGN: Whole transcriptomes of VAT and SAT were measured in 233 patients from the ColoCare Study and visceral and subcutaneous fat area were quantified via computed tomography.

RESULTS: VAT compared to SAT showed elevated gene expression of cytokines, cell adhesion molecules and key regulators of metabolic homeostasis. Increased fat area was associated with downregulated lipid and small molecule metabolism and upregulated inflammatory pathways in both compartments. Comparing these patterns between depots proved specific and more pronounced gene expression alterations in SAT and identified unique associations of integrins and lipid metabolism-related enzymes. VAT gene expression patterns that were associated with visceral fat area poorly overlapped with patterns associated with self-reported body mass index (BMI). However, subcutaneous fat area and BMI showed similar associations with SAT gene expression.

CONCLUSIONS: This large-scale human study demonstrates pronounced disparities between distinct adipose tissue depots and reveals that BMI poorly correlates with fat mass-associated changes in VAT. Together, these results provide crucial evidence for the necessity to differentiate between distinct adipose tissue depots for a correct characterization of gene expression profiles that may affect metabolic health of colorectal cancer patients.

RevDate: 2019-06-21

Gulati R, Morgan TM, A'mar T, et al (2019)

Overdiagnosis and lives saved due to reflex testing men with intermediate prostate-specific antigen levels.

Journal of the National Cancer Institute pii:5521572 [Epub ahead of print].

BACKGROUND: Several prostate cancer early detection biomarkers are available for reflex testing in men with intermediate prostate-specific antigen (PSA) levels. Studies of these biomarkers typically provide information about diagnostic performance but not about overdiagnosis and lives saved, the primary drivers of associated harm and benefit.

METHODS: We projected overdiagnoses and lives saved using an established microsimulation model of prostate cancer incidence and mortality with screening and treatment efficacy based on randomized trials. We used this framework to evaluate four urinary reflex biomarkers (measured in 1,112 men presenting for prostate biopsy at 10 U.S. academic/community clinics) and two hypothetical ideal biomarkers (with 100% sensitivity/specificity for any or for high-grade prostate cancer) at one-time screening tests at ages 55 and 65.

RESULTS: Compared to biopsying all men with elevated PSA, reflex testing reduced overdiagnoses (range across ages and biomarkers = 8.8%-60.6%) but also reduced lives saved (by 7.3%-64.9%), producing similar overdiagnoses per life saved. The ideal biomarker for high-grade disease improved this ratio (by 35.2% at age 55 and 42.0% at age 65). Results were similar under continued screening for men not diagnosed at age 55, but the ideal biomarker for high-grade disease produced smaller incremental improvement.

CONCLUSIONS: Modeling is a useful tool for projecting the implications of using reflex biomarkers for long-term prostate cancer outcomes. Under simplified conditions, reflex testing with urinary biomarkers is expected to reduce overdiagnoses but also produce commensurate reductions in lives saved. Reflex testing that accurately identifies high-grade prostate cancer could improve the net benefit of screening.

RevDate: 2019-06-21

Moghadam SD, Krieger JW, D Louden (2019)

A Systematic Review of the Effectiveness of Promoting Water Intake to Reduce Sugar-sweetened Beverage Consumption (P04-005-19).

Current developments in nutrition, 3(Suppl 1): pii:nzz051.P04-005-19.

Objectives: To examine whether promotion of water intake in the general population in and of itself reduces sugar-sweetened beverage (SSB) consumption independent from interventions that target SSBs.

Methods: Seven electronic databases were systematically searched: PubMed, Embase, PsycInfo, CINAHL Complete, Cochrane Central Register of Controlled Trials, CAB Direct, and Web of Science. The search hedge included concepts of drinking water, sweetened beverages, and clinical or controlled or longitudinal studies. Selected studies included a primary water promotion intervention and were published between 1 January 2000 and 6 January 2019, while those with more than a minimal SSB reduction intervention were excluded. We identified 5652 publications, chose 107 for full-text review and selected 17 for this review. Two authors independently extracted data using predefined data fields and rated study quality.

Results: Nine of the 17 studies were randomized controlled trials, six were non-randomized controlled trials, and two were single-group pre-post studies. Participants were primarily children and adolescents. Seven studies reported a decrease in sugar-sweetened beverage consumption. Among the eight studies that successfully increased water intake, five reported beneficial effects on SSB intake while three did not. Of the five positive studies, three were at serious or high risk of bias. Studies with decrease in sugar-sweetened beverage consumption tended to include a home-based or individually focused intervention.

Conclusions: This review found little evidence that interventions aimed solely at increasing water consumption reduce sugar-sweetened beverage intake. Further research is needed to investigate whether interventions that combine water promotion and SSB reduction strategies could be synergistic for reducing SSB intake. SSB reduction approaches at this time should focus directly on SSBs.

Funding Sources: Healthy Eating Research Program, Robert Wood Johnson Foundation.

RevDate: 2019-06-21

Moghadam SD, Navarro S, Shojaie A, et al (2019)

Plasma Lipidomics Profiles After a Diet Characterized by Whole Grains Compared to a Diet High in Refined Grains and Added Sugars (FS03-07-19).

Current developments in nutrition, 3(Suppl 1): pii:nzz046.FS03-07-19.

Objectives: Dietary patterns high in fiber from sources including whole grains, legumes, fruits, vegetables, nuts and seeds, are associated with lower risk of chronic disease, such as cardiovascular disease and cancer. We investigated how plasma lipidomics profiles differed between a diet high in whole grains (WG) versus a diet high in refined grains and added sugars (RG).

Methods: Using a randomized, crossover, controlled feeding study, 80 healthy participants (n = 40 men, n = 40 women, 40 normal weight, 40 overweight/obese), 18-45 y, were randomized to receive either a WG or RG diet for 28 days. After a 28-day washout period where participants resumed their habitual diet, they crossed over to the other diet. Targeted, differential mobility mass spectrometry was performed on fasting plasma samples collected at the baseline and end of each diet period and quantified the concentrations of 863 lipids from 13 classes. Paired t-tests and pairwise partial least squares-discriminant analysis (PLS-DA) were used to evaluate differences in lipid profiles between the two diets.

Results: At a class level, only ceramides were significantly different when comparing the two diets. After removing lipid species with > 20% missing values or CVs < 25%, 606 were retained for species analysis. Sixty-seven lipid species were significantly different between diets at day 28 (FDR < 0.05): 38 of 414 detected triglycerides, 9 of 59 phosphatidylethanolamines, 9 of 63 phosphatidylcholines, 4 of 22 cholesterol esters, 3 of 11 sphingomyelins, 2 of 13 lysophosphatidylcholines, and 1 of 5 ceramides. The majority of significant lipids were higher in plasma after the WG diet. PLSDA analysis showed the first and second components explaining 49% and 8.4%, respectively. Based on the selected components, lipidomic profiles showed fair separation for the two groups of diet. R2 values were 0.07 and 0.43, and Q2 values were -0.03 and 0.04 for components 1 and 2, respectively.

Conclusions: Higher concentrations of some lipid species such as cholesterol ester 12:0, a carrier of high-density lipoprotein, could indicate a favorable shift in lipid profiles. Further investigation using more complex models are being conducted.

Funding Sources: National Cancer Institute - National Institutes of Health.

RevDate: 2019-06-21

Pilande E, So S, Lim U, et al (2019)

Proton Magnetic Resonance Spectroscopy (1H-MRS)-Based Neurometabolite Levels and Cognitive Function in Relation to Visceral Obesity and Non-Alcoholic Fatty Liver Disease (P14-019-19).

Current developments in nutrition, 3(Suppl 1): pii:nzz052.P14-019-19.

Objectives: Intra-abdominal adiposity in the viscera and liver, compared to total adiposity, carries a higher metabolic risk, and it varies substantially by sex and race. We examined the association of neurometabolites and cognitive function with visceral obesity and non-alcoholic fatty liver disease (NAFLD) in multiethnic older adults.

Methods: The Multiethnic Cohort Brain-Gut-Adiposity Study included 100 participants aged 61-77 years, who were recruited into balanced strata by sex, ancestry (Japanese, Native Hawaiian or white) and body mass index (BMI) levels (range: 18.0-44.9 kg/m2). We measured the concentration of key brain metabolites in the frontal and parietal gray matter (GM) and frontal white matter using 1H-MRS and assessed cognitive function using the Modified Mini-Mental State (3MS) and the NIH Toolbox (NIHTB) tests. Mean neurometabolite levels and cognition scores were compared by visceral obesity (visceral fat area at L1-L5 > 150 cm2) and NAFLD (liver fat >5.0%) status determined by abdominal MR imaging, while adjusting for age, sex, race, education, dual energy X-ray absorptiometry-based total adiposity and other confounders.

Results: The prevalence of visceral obesity was 52%, NAFLD 32%, and both conditions 27%. Participants with visceral obesity had higher adjusted mean levels of total glutamate [11.6 (11.3, 12.0) vs. 10.8 (10.4, 11.2) mM/kg; P = 0.01] and myo-inositol [5.2 (5.0, 5.4) vs. 4.7 (4.6, 4.9) mM/kg; P = 0.004] in the parietal GM but had similar levels of total choline, total creatine and N-acetylaspartate. NAFLD status was not significantly associated with the levels of neurometabolites. No significant interaction was detected between the two conditions: participants with either condition compared to those with neither showed a trend toward higher levels of myo-inositol [5.2 (4.9, 5.5) vs. 4.8 (4.5, 5.0) mM/kg; P = 0.07]. Further, participants with NAFLD scored lower for crystallized cognition for language [113 (110, 117) vs. 118 (116, 120); P = 0.02], in particular for reading ability [113 (109, 117) vs. 119 (117, 123); P = 0.03].

Conclusions: Results of this comprehensive, pilot imaging study suggest that, regardless of total adiposity and race/ethnicity, high visceral adiposity is associated with elevated concentrations of inflammatory neurometabolites, and NAFLD is associated with reduced language abilities.

Funding Sources: National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute).

RevDate: 2019-06-21

Kikani C, Xiao M, Wu X, et al (2019)

PASsing on Signals: PAS Kinase (PASK)-mTOR Signaling Conveys Nutrient Sufficiency Signals to Epigenetic (COMPASS) Complexes to Activate Stem Cell Differentiation Program (P15-009-19).

Current developments in nutrition, 3(Suppl 1): pii:nzz037.P15-009-19.

Objectives: To determine how nutrient signaling impacts stem cell functions.

Methods: PASK phosphorylation: We measured in situ phosphorylation of PASK by metabolic 32P labeling of stem cells expressing WT or mutant versions of PASK. PASK Activation: PASK activation was measured using in vitro kinase assay using radio-labeled ATP. Myogenesis: Myogenesis was measured by immunohistological, and immunofluorescent analysis of differentiating muscle stem cells. Antibodies used were: Myogenin (F5D-Developmental Hybridoma), MF20 (Myosin heavy chain), Pax7 and MyoD.

Results: Stem cell fate in the tissue niche is intimately connected with intracellular metabolic state and the extracellular hormonal stimulations. We have identified PAS domain containing Kinase (PASK) as a stem cell enriched protein kinase that is required for establishment of the differentiation program in many stem cell paradigms. For this function, PASK phosphorylates Wdr5, a member of the COMPASS family of histone methyltransferases, to activate the epigenetic processes required for the stem cell differentiation (eLife, 2016). Here we show that a master nutrient sensor, mTOR complex 1 (mTORC1) activates PASK via multi-site phosphorylation during stem cell differentiation. This phosphorylation of PASK by mTORC1 is required for epigenetic activation of the Myogenin transcription, exit from the self-renewal and induction of the myogenesis program. Our data suggest that mTORC1-PASK signaling generates MyoG + committed myoblasts (epigenetically - an early stage of myogenesis), whereas mTORC1-S6K1 signaling is required for myoblast fusion (translationally - later stage of myogenesis).

Conclusions: Our discoveries show that nutrient signaling can partition stem cell fates during different stages of the myogenesis program downstream of mTOR signaling via activation of two distinct protein kinases.

Funding Sources: NIH R01 (Chintan Kikani), HHMI (Jared Rutter).

RevDate: 2019-06-21

Halloran ME, MG Hudgens (2018)

Comment on Laber et al.

Journal of the Royal Statistical Society. Series C, Applied statistics, 67(4):776.

RevDate: 2019-06-21

Yohe ME, Heske CM, Stewart E, et al (2019)

Insights into pediatric rhabdomyosarcoma research: Challenges and goals.

Pediatric blood & cancer [Epub ahead of print].

Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.

RevDate: 2019-06-21

Dawson-Hahn E, Koceja L, Stein E, et al (2019)

Perspectives of Caregivers on the Effects of Migration on the Nutrition, Health and Physical Activity of their Young Children: A Qualitative Study with Immigrant and Refugee Families.

Journal of immigrant and minority health pii:10.1007/s10903-019-00905-6 [Epub ahead of print].

To explore perspectives on nutrition, health and physical activity among immigrant parents with young children before and after migration. We conducted focus groups in five languages (Arabic, Somali, Dari, Burmese and Nepali), then conducted a phenomenological analysis of the transcripts. Fifty caregivers participated; 42% spent time in a refugee camp. Within the domain Change in Environment, four themes emerged: (1) food access; (2) family experiences with weight and growth; (3) differences in physical activity and perceptions of safety; and (4) health care experience. Within the domain of Parenting Behaviors and Experiences, two themes emerged: (1) Sociocultural differences in early feeding behaviors and (2) concern about feeding behaviors. To support health outcomes for refugee and immigrant families with young children, key focus areas for programming would include access to fresh foods, safe places for physical activity, and feeding practices following a family history of food scarcity.

RevDate: 2019-06-20

Sharp JW, Hippe DS, Nakigudde G, et al (2019)

Modifiable patient-related barriers and their association with breast cancer detection practices among Ugandan women without a diagnosis of breast cancer.

PloS one, 14(6):e0217938 pii:PONE-D-19-04486.

Most women with breast cancer in sub-Saharan Africa (SSA) are diagnosed with late-staged disease. The current study assesses patient-related barriers among women from a general SSA population to better understand how patient-related barriers contribute to diagnostic delays. Using convenience-based sampling, 401 Ugandan women without breast cancer were surveyed to determine how prior participation in cancer detection practices correlate with patient-related barriers to prompt diagnosis. In a predominantly poor (76%) and rural population (75%), the median age of the participants was 38. Of the women surveyed, 155 (46%) had prior exposure to breast cancer education, 92 (27%) performed breast self-examination (BSE) and 68 (20%) had undergone a recent clinical breast examination (CBE), breast ultrasound or breast biopsy. The most commonly identified barriers to prompt diagnosis were knowledge deficits regarding early diagnosis (79%), economic barriers to accessing care (68%), fear (37%) and poor social support (24%). However, only women who reported knowledge deficits-a modifiable barrier-were less likely to participate in cancer detection practices (p<0.05). Women in urban and rural areas were similarly likely to report economic barriers, knowledge deficits and/or poor social support, but rural women were less likely than urban women to have received breast cancer education and/or perform BSE (p<0.001). Women who have had prior breast cancer education (p<0.001) and/or who perform BSE (p = 0.02) were more likely to know where she can go to receive a diagnostic breast evaluation. These findings suggest that SSA countries developing early breast cancer detection programs should specifically address modifiable knowledge deficits among women less likely to achieve a diagnostic work-up to reduce diagnostic delays and improve breast cancer outcomes.

RevDate: 2019-06-20

Shore RE, Beck HL, Boice JD, et al (2019)

Response to Letter by Moghissi and Calderone.

Health physics, 117(2):224-225.

RevDate: 2019-06-20

Lupo PJ, Schraw JM, Desrosiers TA, et al (2019)

Association Between Birth Defects and Cancer Risk Among Children and Adolescents in a Population-Based Assessment of 10 Million Live Births.

JAMA oncology pii:2736368 [Epub ahead of print].

Importance: Birth defects affect approximately 1 in 33 children. Some birth defects are known to be strongly associated with childhood cancer (eg, trisomy 21 and acute leukemia). However, comprehensive evaluations of childhood cancer risk in those with birth defects have been limited in previous studies by insufficient sample sizes.

Objectives: To identify specific birth defect-childhood cancer (BD-CC) associations and characterize cancer risk in children by increasing number of nonchromosomal birth defects.

This multistate, population-based registry linkage study pooled statewide data on births, birth defects, and cancer from Texas, Arkansas, Michigan, and North Carolina on 10 181 074 children born from January 1, 1992, to December 31, 2013. Children were followed up to 18 years of age for a diagnosis of cancer. Data were retrieved between September 26, 2016, and September 21, 2017, and data analysis was performed from September 2, 2017, to March 21, 2019.

Exposures: Birth defects diagnoses (chromosomal anomalies and nonchromosomal birth defects) recorded by statewide, population-based birth defects registries.

Main Outcomes and Measures: Cancer diagnosis before age 18 years, as recorded in state cancer registries. Cox regression models were used to generate hazard ratios (HRs) and 95% CIs to evaluate BD-CC associations and the association between number of nonchromosomal defects and cancer risk.

Results: Compared with children without any birth defects (n = 10 181 074), children with chromosomal anomalies (n = 539 567) were 11.6 (95% CI, 10.4-12.9) times more likely to be diagnosed with cancer, whereas children with nonchromosomal birth defects (n = 2123) were 2.5 (95% CI, 2.4-2.6) times more likely to be diagnosed with cancer before 18 years of age. An increasing number of nonchromosomal birth defects was associated with a corresponding increase in the risk of cancer. Children with 4 or more major birth defects were 5.9 (95% CI, 5.4-6.5) times more likely to be diagnosed with cancer compared with those without a birth defect. In the analysis of 72 specific BD-CC patterns, 40 HRs were statistically significant (adjusted P < .05) after accounting for multiple comparisons. Cancers most frequently associated with nonchromosomal defects were hepatoblastoma and neuroblastoma.

Conclusions and Relevance: Several significant and novel associations were observed between specific birth defects and cancers. Among children with nonchromosomal birth defects, the number of major birth defects diagnosed was significantly and directly associated with cancer risk. These findings could inform clinical treatment for children with birth defects and may elucidate mechanisms that lead to these complex outcomes.

RevDate: 2019-06-20

Watson NL, Heffner JL, Mull KE, et al (2019)

Comparing Treatment Acceptability and 12-Month Cessation Rates in Response to Web-Based Smoking Interventions Among Smokers Who Do and Do Not Screen Positive for Affective Disorders: Secondary Analysis.

Journal of medical Internet research, 21(6):e13500 pii:v21i6e13500.

BACKGROUND: Web-based cessation programs are now common for intervening with smokers. However, it remains unclear how acceptable or effective these interventions are among people with affective disorders and symptoms (ADS; eg, depression and anxiety). Research examining this is extremely limited, with mixed results on cessation rates. Additional large studies are needed to more fully understand whether Web-based interventions are similarly used and equally effective among people with and without affective disorder symptomology. If not, more targeted Web-based interventions may be required.

OBJECTIVE: The goal of the research was to compare Web-based treatment acceptability (defined by satisfaction and use) and 12-month cessation outcomes between smokers with and without ADS.

METHODS: Participants (N=2512) were adult smokers enrolled in a randomized, comparative effectiveness trial of two Web-based smoking interventions designed for the general population of smokers. At baseline, participants reported demographic and smoking characteristics and completed measures assessing ADS. Participants were then classified into subgroups based on their self-reported ADS-either into a no ADS group or into six nonmutually exclusive subgroups: depression, posttraumatic stress disorder (PTSD), panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and more than one ADS. Surveys at 12 months postrandomization included subjective ratings of treatment acceptability and self-reported smoking cessation. Treatment use (ie, number of log-ins and total duration of exposure) was assessed via automated records.

RESULTS: Relative to the no ADS group, all six ADS subgroups reported significantly greater satisfaction with their assigned Web treatment program, but they spent less time logged in than those with no ADS. For number of log-ins, a treatment arm by ADS group interaction was observed across all ADS subgroups except GAD, suggesting that relative to the no ADS group, they logged in less to one website but not the other. At the 12-month follow-up, abstinence rates in the no ADS group (153/520, 29.42%) were significantly higher than for participants who screened positive for depression (306/1267, 24.15%; P=.03), PTSD (294/1215, 24.19%; P=.03), PD (229/1003, 23.83%; P=.009), and two or more ADS (323/1332, 24.25%; P=.03). Post hoc analyses suggest the lower quit rates may be associated with differences in baseline nicotine dependence and levels of commitment to resist smoking in difficult situations. Website use did not explain the differential abstinence rates.

CONCLUSIONS: Despite reporting higher levels of treatment satisfaction, most smokers with ADS used their assigned intervention less often and had lower quit rates than smokers with no ADS at treatment onset. The results support the need for developing more targeted interventions for smokers with ADS.

TRIAL REGISTRATION: Clinical Trials.gov NCT01812278; https://clinicaltrials.gov/ct2/show/NCT01812278 (Archived by WebCite at http://www.webcitation.org/78L9cNdG4).

RevDate: 2019-06-20

Fabian KE, Huh D, Kemp CG, et al (2019)

Moderating Factors in an Anti-stigma Intervention for African American Women with HIV in the United States: A Secondary Analysis of the UNITY Trial.

AIDS and behavior pii:10.1007/s10461-019-02557-x [Epub ahead of print].

African American women experience higher rates of HIV than other women in the United States, and stigma has been identified as an important determinant of engagement in HIV care. Our study examined whether key variables moderated the effect of an anti-stigma intervention on outcomes among African American women receiving treatment for HIV. Twelve potential moderators included: age, years lived with HIV, marital status, employment status, education level, PTSD diagnosis, alcohol use, social support, baseline CD4 count, baseline viral load, and number of children. Outcomes included changes in: HIV-related stigma, social support, depressive symptoms, PTSD symptoms, alcohol use, viral load, and engagement in HIV care. Results suggest that the intervention is associated with greater improvement in engagement in care among participants with PTSD or depression at baseline, and may help maintain engagement in care among participants experiencing certain mental health conditions. This provides opportunities to address discriminatory structural barriers that lead to stigma and drop-offs in HIV care.

RevDate: 2019-06-20

Karas M, Brzyski D, Dzemidzic M, et al (2019)

Brain connectivity-informed regularization methods for regression.

Statistics in biosciences, 11(1):47-90.

One of the challenging problems in brain imaging research is a principled incorporation of information from different imaging modalities. Frequently, each modality is analyzed separately using, for instance, dimensionality reduction techniques, which result in a loss of mutual information. We propose a novel regularization-method to estimate the association between the brain structure features and a scalar outcome within the linear regression framework. Our regularization technique provides a principled approach to use external information from the structural brain connectivity and inform the estimation of the regression coefficients. Our proposal extends the classical Tikhonov regularization framework by defining a penalty term based on the structural connectivity-derived Laplacian matrix. Here, we address both theoretical and computational issues. The approach is first illustrated using simulated data and compared with other penalized regression methods. We then apply our regularization method to study the associations between the alcoholism phenotypes and brain cortical thickness using a diffusion imaging derived measure of structural connectivity. Using the proposed methodology in 148 young male subjects with a risk for alcoholism, we found a negative associations between cortical thickness and drinks per drinking day in bilateral caudal anterior cingulate cortex, left lateral OFC and left precentral gyrus.

RevDate: 2019-06-20

Wojcik GL, Graff M, Nishimura KK, et al (2019)

Genetic analyses of diverse populations improves discovery for complex traits.

Nature pii:10.1038/s41586-019-1310-4 [Epub ahead of print].

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

RevDate: 2019-06-20

Sojar H, Baron S, Sullivan JT, et al (2019)

Monoclonal antibody 2C6 targets cross-clade conformational epitope in gp41 with highly active antibody dependent cell cytotoxicity.

Journal of virology pii:JVI.00772-19 [Epub ahead of print].

Previous studies in our laboratory have characterized a panel of highly mutated HIV-specific conformational epitope targeting antibodies (Abs) from a panel of HIV-infected long-term non-progressors (LTNPs). Despite binding HIV envelope protein and having a high number of somatic amino acid mutations, these Abs had poor neutralizing activity. Because of the evidence of antigen driven selection and the long CDR3 region (21 amino acids), we further characterized the epitope targeting of monoclonal Ab (mAb) 76-Q3-2C6 (2C6). We confirmed that 2C6 binds preferentially to trimeric envelope and recognizes the clades A, B and C SOSIP trimers. 2C6 binds gp140 constructs of clades A, B C, and D, suggesting a conserved binding site that we localized to the ectodomain of gp41. Ab competition with mAb 50-69 suggested this epitope localizes near AA 579-613 (referenced to HXB2 gp160). Peptide library scanning showed consistent binding in this region, but to only a single peptide. Lack of overlapping peptide binding supported a non-linear epitope structure. The significance of this site is supported by 2C6 having Ab dependent cell cytotoxicity (ADCC) against envelope proteins from two clades. Using 2C6 and variants, alanine scanning mutagenesis identified three amino acids (AA 592, 595 and 596) in the overlapping region of the previously identified peptide. Additional amino acids at sites 524 and 579 were also identified, helping explain its conformational requirement. The fact that different amino acids were included in the epitope depending on the targeted protein supports the conclusion that 2C6 targets a native conformational epitope. When we mapped these amino acids on the trimerized structure, they spanned across oligomers, supporting the notion that the epitope targeted by 2C6 may lie in a recessed pocket between two gp41 oligomers. A complete understanding of the epitope specificity of Ab dependent cell cytotoxicity (ADCC)-mediating Abs is essential for developing effective immunization strategies that optimize protection by these Abs.Importance: This paper further defines the function and area of the HIV trimeric envelope protein targeted by the monoclonal antibody 2C6. 2C6 binding is influenced by amino acid mutations across two separate gp41 sections of the envelope trimer. This epitope is recognized on multiple clades (variant groups of circulating viruses) of gp41, gp140 trimers, and SOSIP trimers. For the clades tested, 2C6 has robust antibody dependent cell cytotoxicity (ADCC). As the target of 2C6 is available in the major clades of HIV and has robust ADCC activity, further definition and appreciation of targeting of antibodies similar to 2C6 during vaccine development should be considered.

RevDate: 2019-06-19

Carcioppolo N, Christy KR, Jensen JD, et al (2019)

Biomarker profiling for breast cancer detection: translational research to determine acceptance of a novel breast cancer screening technique.

Health systems (Basingstoke, England), 8(1):44-51 pii:1414740.

The current study seeks to determine how the psychosocial predictors of the health belief model are related to willingness to adopt biomarker screening practices among women above and below current screening age recommendations, as biomarker profiling can potentially detect cancer much earlier than current breast cancer detection methods. Patients (N = 205) at an Obstetrician/Gynaecology office in a mid-sized Midwest city. Participants completed a survey in the waiting room before their doctor appointment. Results revealed that benefits (p < .001), barriers (p = .02), cancer worry severity (p = .01), and self-efficacy (p = .002) were significant predictors of willingness to adopt biomarker profiling, and susceptibility was marginally related (p = .09). The direct effects are qualified by two interactions between psychosocial predictors of the health belief model and participants' age. The model predicted willingness to adopt biomarker screening well (R2 = 28%), and may be used successfully as a framework to assess the diffusion of biomarker screening acceptability.

RevDate: 2019-06-20

Mughal TI, Pemmaraju N, Radich JP, et al (2019)

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms.

Hematological oncology [Epub ahead of print].

The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post-ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin.

RevDate: 2019-06-19

He Z, Y Fong (2019)

Maximum diversity weighting for biomarkers with application in HIV-1 vaccine studies.

Statistics in medicine [Epub ahead of print].

While studying the association between risk of HIV-1 infection and vaccine-elicited immune responses in preventative HIV-1 vaccine recipients, we encountered a need to combine a collection of biomarkers in an unsupervised fashion with the goal of preserving signal diversity within that collection. Inspired by methods for weighting protein sequences from the biological sequence analysis literature, we propose novel methods for weighting biomarkers, which we call maximum diversity weights. These weights are defined as the weights that maximize measures of signal diversity within a collection of biomarkers. While the optimization problems do not admit analytical solutions, they are convex and hence can be solved efficiently using iterative search algorithms. Through Monte Carlo studies and a real data example from HIV-1 vaccine research, we show that using maximum diversity weights in association studies can lead to an increase in power over other commonly used weights such as uniform weights or principal component-based weights.

RevDate: 2019-06-19

Cox TC, Lidral AC, McCoy JC, et al (2019)

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans.

Human mutation [Epub ahead of print].

Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.

RevDate: 2019-06-19

Moon JY, Louie TL, Jain D, et al (2019)

A Genome-Wide Association Study Identifies Blood Disorder-Related Variants Influencing Hemoglobin A1c With Implications for Glycemic Status in U.S. Hispanics/Latinos.

Diabetes care pii:dc19-0168 [Epub ahead of print].

OBJECTIVE: We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/Latinos with diverse genetic ancestries.

RESEARCH DESIGN AND METHODS: We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies.

RESULTS: Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (β = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibrating the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28).

CONCLUSIONS: This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.

RevDate: 2019-06-19

Zhang P, Holowatyj AN, Ulrich CM, et al (2019)

Tumor suppressive autophagy in intestinal stem cells controls gut homeostasis.

Autophagy [Epub ahead of print].

We recently found that re-routing intracellular vesicle traffic by suppressing macroautophagy/autophagy or endocytosis genes drastically deregulates Drosophila intestinal stem cell (ISC) proliferation, leading to massive gut hyperplasia that has a negative impact upon lifespan. Beginning with the poorly characterized Snx (sorting nexin) genes, we surveyed a broad set of genes in the endocytosis-autophagy network and found that most of them have this effect. We then discovered that deregulated Egfr-Ras85D/Ras1-mitogen-activated protein kinase signaling is the primary trigger for ISC proliferation upon disruption of this network and determined that in the mutants, ligand-activated receptors were stabilized and recycled to the cell surface via Rab11-dependent endosomes, rather than being degraded via autophagosomes. We profiled the mutational landscape for orthologous network genes in human cancers using The Cancer Genome Atlas (TCGA), and revealed strong, novel associations with distinct genomic and epigenomic subtypes of colorectal cancer.

RevDate: 2019-06-18

Porter LH, Lawrence MG, Wang H, et al (2019)

Establishing a cryopreservation protocol for patient-derived xenografts of prostate cancer.

The Prostate [Epub ahead of print].

BACKGROUND: Serially transplantable patient-derived xenografts (PDXs) are invaluable preclinical models for studying tumor biology and evaluating therapeutic agents. As these models are challenging to establish from prostate cancer specimens, the ability to preserve them through cryopreservation has several advantages for ongoing research. Despite this, there is still uncertainty about the ability to cryopreserve PDXs of prostate cancer. This study compared three different cryopreservation protocols to identify a method that can be used to reproducibly cryopreserve a diverse cohort of prostate cancer PDX models.

METHODS: One serially transplantable prostate cancer PDX from the Melbourne Urological Research Alliance cohort was used to compare three cryopreservation protocols: slow freezing in fetal calf serum (FCS) with 10% dimethyl sulfoxide (DMSO), FCS with 10% DMSO supplemented with the Rho-associated kinase (ROCK) inhibitor Y-27632 and vitrification. The efficiency of the slow freezing protocols was then assessed in 17 additional prostate cancer PDXs. Following cryopreservation, PDXs were re-established in host mice that were either intact and supplemented with testosterone or castrated. Graft take rate, tumor growth, histological features, and transcriptome profiles before and after cryopreservation were compared.

RESULTS: Slow freezing maintained the viability and histological features of prostate cancer PDXs, and the addition of a ROCK inhibitor increased their growth following cryopreservation. Using the slow freezing method, we re-established 100% of PDXs grown in either testosterone-supplemented or castrated host mice. Importantly, the long-term tumor growth rate and transcriptome profile were maintained following cryopreservation.

CONCLUSION: This study has identified a protocol to reliably cryopreserve and re-establish a diverse cohort of serially transplantable PDXs of prostate cancer. This study has the potential to significantly improve the practicality of maintaining PDX models. Cryopreservation may also increase the accessibility of these important resources and provide new opportunities for preclinical studies on a broader spectrum of prostate tumors.

RevDate: 2019-06-18

Harris HR, Cushing-Haugen KL, Webb PM, et al (2019)

Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study.

International journal of epidemiology pii:5520000 [Epub ahead of print].

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer.

METHODS: Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls).

RESULTS: An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations.

CONCLUSION: Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.

RevDate: 2019-06-18

Pardini B, Corrado A, Paolicchi E, et al (2019)

DNA repair and cancer in colon and rectum: novel players in genetic susceptibility.

International journal of cancer [Epub ahead of print].

Inter-individual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value=3.5x10-6) and rs2189517 (in RAD51B) with rectal cancer risk (p-value=5.7x10-6). The results had statistical significance close to the Bonferroni corrected p-value of 5.8x10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g. rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis. This article is protected by copyright. All rights reserved.

RevDate: 2019-06-18

Lee JK, SJ Priceman (2019)

Precision Medicine-Enabled Cancer Immunotherapy.

Cancer treatment and research, 178:189-205.

Repairing defects in anti-tumor immunity has been a longstanding challenge in cancer therapy, and in recent years, immunotherapy has emerged as a promising approach for treating advanced disease. While the interactions between the immune system and cancer have been studied for more than a century, only in recent years has the field realized the tremendous potential in stimulating the immune system to eradicate cancer. From early investigations by William Coley in using bacteria to treat cancer patients to more recent work in adoptively transferred engineered T cells to identify and kill cancer cells has opened up an entire field dedicated to re-educating the immune system in a cancer patient. A multitude of immunotherapy strategies have been proposed and tested in clinical trials, from recombinant proteins, agonistic antibodies, and checkpoint inhibitors designed to re-invigorate anti-tumor immunity, to vaccine approaches and adoptive T-cell strategies, we are now on the cusp of an exciting revolution that will ultimately become an arsenal of therapies to treat any cancer type, at any stage, with the hope of robust and durable responses in cancer patients. In this chapter, we will examine the various immunotherapy strategies under active clinical investigation, with a particular focus on the latest advances in cellular immunotherapies and the future of precision medicine-enabled immunotherapy.

RevDate: 2019-06-18

Zettlitz KA, Tsai WK, Knowles SM, et al (2019)

[89Zr]A2cDb Immuno-PET of Prostate Cancer in a Human Prostate Stem Cell Antigen Knock-in (hPSCA KI) Syngeneic Model.

Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging pii:10.1007/s11307-019-01386-7 [Epub ahead of print].

PURPOSE: A great challenge in the diagnosis and treatment of prostate cancer is distinguishing between indolent or local disease and aggressive or metastatic disease. Antibody-based positron emission tomography (immuno-PET) as a cancer-specific imaging modality could improve diagnosis of primary disease, aid the detection of metastases to regional lymph nodes as well as to distant sites (e.g., bone), and monitor response to therapy.

PROCEDURE: In search for a more physiologically relevant disease model, a human prostate stem cell antigen knock-in (hPSCA KI) mouse model was generated. The use of a syngeneic prostate cancer cell line transduced to express human PSCA (RM-9-hPSCA) enabled the evaluation of anti-PSCA immuno-PET in immunocompetent mice and in the context of normal tissue expression of PSCA. Two PSCA-specific humanized antibody fragments, A11 minibody and A2 cys-diabody, were radiolabeled with positron emitters iodine-124 and zirconium-89, respectively ([124I]A11 Mb and [89Zr]A2cDb), and used for immuno-PET in wild-type, hPSCA KI and tumor-bearing mice.

RESULTS: The hPSCA KI mice express PSCA at low levels in the normal prostate, bladder and stomach, reproducing the expression pattern seen in humans. [124I]A11 Mb immuno-PET detected increased levels of PSCA expression in the stomach, and because I-124 is non-residualizing, very little activity was seen in organs of clearance (liver, kidney, spleen). However, due to the longer half-life of the 80 kDa protein, blood activity (and thus urine activity) at 20 h postinjection remains high. The smaller 50 kDa [89Zr]A2cDb cleared faster, resulting in lower blood and background activity, despite the use of a residualizing radiometal. Importantly, [89Zr]A2cDb immuno-PET showed antigen-specific targeting of PSCA-expressing tumors and minimal nonspecific uptake in PSCA-negative controls.

CONCLUSION: Tracer biodistribution was not significantly impacted by normal tissue expression of PSCA. [89Zr]A2cDb immuno-PET yielded high tumor-to-blood ratio at early time points. Rapid renal clearance of the 50 kDa tracer resulted in an unobstructed view of the pelvic region at 20 h postinjection that would allow the detection of cancer in the prostate.

RevDate: 2019-06-18

Jenkins MA, Win AK, Dowty JG, et al (2019)

Ability of known susceptibility SNPs to predict colorectal cancer risk for persons with and without a family history.

Familial cancer pii:10.1007/s10689-019-00136-6 [Epub ahead of print].

Before SNP-based risk can be incorporated in colorectal cancer (CRC) screening, the ability of these SNPs to estimate CRC risk for persons with and without a family history of CRC, and the screening implications need to be determined. We estimated the association with CRC of a 45 SNP-based risk using 1181 cases and 999 controls, and its correlation with CRC risk predicted from detailed family history. We estimated the predicted change in the distribution across predefined risk categories, and implications for recommended screening commencement age, from adding SNP-based risk to family history. The inter-quintile risk ratio for colorectal cancer risk of the SNP-based risk was 3.28 (95% CI 2.54-4.22). SNP-based and family history-based risks were not correlated (r = 0.02). For persons with no first-degree relatives with CRC, screening could commence 4 years earlier for women (5 years for men) in the highest quintile of SNP-based risk. For persons with two first-degree relatives with CRC, screening could commence 16 years earlier for men and women in the highest quintile, and 7 years earlier for the lowest quintile. This 45 SNP panel in conjunction with family history, can identify people who could benefit from earlier screening. Risk reclassification by 45 SNPs could inform targeted screening for CRC prevention, particularly in clinical genetics settings when mutations in high-risk genes cannot be identified. Yet to be determined is cost-effectiveness, resources requirements, community, patient and clinician acceptance, and feasibility with potentially ethical, legal and insurance implications.

RevDate: 2019-06-18

Carbone LD, Vasan S, Prentice RL, et al (2019)

The renin-angiotensin aldosterone system and osteoporosis: findings from the Women's Health Initiative.

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA pii:10.1007/s00198-019-05041-3 [Epub ahead of print].

New users of RAAS inhibitors, including ACE inhibitors and ARBs, have a small increased risk for fracture in the first 3 years of use, with a reduced risk of fracture with longer duration of use.

INTRODUCTION: Pharmacological inhibitors of the renin-angiotensin aldosterone system (RAAS) are used to treat hypertension. However, the relationship of these medications to osteoporosis is inconsistent, and no study has included simultaneous measurements of both incident fractures and bone mineral density (BMD).

METHODS: The association of RAAS inhibitor use (n = 131,793) with incident fractures in new users of these medications in women in the Women's Health Initiative over a minimum median follow-up of 6.5 years was assessed by Cox proportional hazard models. The association of incident fractures by a cumulative duration of use of these medications (< 3 years.) and (> 3 years.) was also estimated. Subgroup analysis of fracture risk by RAAS inhibitor use confined to women with hypertension was also performed (n = 33,820). The association of RAAS inhibitor use with changes in BMD of the hip was estimated by linear regression in 8940 women with dual energy X-ray absorptiometry measurements.

RESULTS: There was no significant association between RAAS inhibitor use and all fractures in the final adjusted multivariable models including hip BMD (HR 0.86 (0.59, 1.24)). However, among users of RAAS inhibitors, including ACE inhibitors and angiotensin receptor blockers (ARBs), hazard ratios for all incident fracture sites in final multivariable models including hip BMD showed dramatic differences by duration of use, with short duration of use (3 years or less) associated with a marked increased risk for fracture (HR 3.28 (1.66, 6.48)) to (HR 6.23 (3.11, 12.46)) and use for more than 3 years associated with a reduced fracture risk (HR 0.40 (0.24, 0.68) to (HR 0.44 (0.20, 0.97)) . Findings were similar in the subgroup of women with a history of hypertension. There was no significant change in BMD of the hip by RAAS inhibitor use.

CONCLUSIONS: In postmenopausal women, use of RAAS inhibitors, including ACE inhibitors and ARBs, is associated with an increased risk for fracture among new users of these medications in the first 3 years of use. However, long-term use (> 3 years) is associated with a reduced risk. Consideration for fracture risk may be part of the decision-making process for initiation of these medications for other disease states.

RevDate: 2019-06-18

Salter AI, SR Riddell (2019)

Tinkering in the garage - tuning CARs for safety.

Nature reviews. Clinical oncology pii:10.1038/s41571-019-0240-2 [Epub ahead of print].

RevDate: 2019-06-18

Branford S, Kim DDH, Apperley JF, et al (2019)

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia.

Leukemia pii:10.1038/s41375-019-0512-y [Epub ahead of print].

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.

RevDate: 2019-06-18

Acham M, Wesselius A, van Osch FHM, et al (2019)

Intake of milk and other dairy products and the risk of bladder cancer: a pooled analysis of 13 cohort studies.

European journal of clinical nutrition pii:10.1038/s41430-019-0453-6 [Epub ahead of print].

BACKGROUND: Inconsistent associations between milk and other dairy product consumption and bladder cancer (BC) have been reported. We aimed to investigate possible associations with BC risk for total and individual dairy products by bringing together the world's data on this topic.

METHODS: Thirteen cohort studies, included in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study, provided data for 3590 BC cases and 593,637 non-cases. Associations between milk and other dairy product consumption and BC risk were investigated using Cox proportional hazard regression analyses stratified by study center and adjusted for potential confounders.

RESULTS: Overall, total 'other' dairy product consumption was not associated with BC risk (HR comparing highest with lowest tertile: 0.97 (95% CI: 0.87-1.07; ptrend = 0.52) and likewise no association was observed for either liquid milk, processed milk, cream, cheese or icecream. However, an inverse association was observed between yoghurt consumption and BC risk when comparing those in the moderate (25-85 g/day) and high categories (>85 g/day) with non-consumers, with multivariate HR of 0.85 (95% CI: 0.75-0.96) and 0.88 (95% CI: 0.78-0.98), respectively.

CONCLUSIONS: We found no evidence of association between either total or individual dairy products and BC risk, but suggestive evidence that consumption of yoghurt may be associated with a decreased risk.

RevDate: 2019-06-18

Brusniak MY, Ramos H, Lee B, et al (2019)

Laboratory information management software for engineered mini-protein therapeutic workflow.

BMC bioinformatics, 20(1):343 pii:10.1186/s12859-019-2935-x.

BACKGROUND: Protein based therapeutics are one of the fastest growing classes of novel medical interventions in areas such as cancer, infectious disease, and inflammation. Protein engineering plays an important role in the optimization of desired therapeutic properties such as reducing immunogenicity, increasing stability for storage, increasing target specificity, etc. One category of protein therapeutics is nature-inspired bioengineered cystine-dense peptides (CDPs) for various biological targets. These engineered proteins are often further modified by synthetic chemistry. For example, candidate mini-proteins can be conjugated into active small molecule drugs. We refer to modified mini-proteins as "Optides" (Optimized peptides). To efficiently serve the multidisciplinary lab scientists with varied therapeutic portfolio research goals in a non-commercial setting, a cost effective extendable laboratory information management system (LIMS) is/was needed.

RESULTS: We have developed a LIMS named Optide-Hunter for a generalized engineered protein compounds workflow that tracks entities and assays from creation to preclinical experiments. The implementation and custom modules are built using LabKey server, which is an Open Source platform for scientific data integration and analysis. Optide-Hunter contains a compound registry, in-silico assays, high throughput production, large-scale production, in vivo assays and data extraction from a specimen-tracking database. It is used to store, extract, and view data for various therapeutics projects. Optide-Hunter also includes external processing stand-alone software (HPLCPeakClassifierApp) for automated chromatogram classification. The HPLCPeakClassifierApp is used for pre-processing of HPLC data prior to loading to Optide-Hunter. The custom implementation is done using data transformation modules in R, SQL, javascript, and java and is Open Source to assist new users in customizing it for their unique workflows. Instructions for exploring a deployed version of Optide-Hunter can be found at https://www.labkey.com/case%20study/optide-hunter CONCLUSION: The Optide-Hunter LIMS system is designed and built to track the process of engineering, producing and prioritizing protein therapeutic candidates. It can be easily adapted and extended for use in small or large research laboratories where multidisciplinary scientists are collaborating to engineer compounds for potential therapeutic or protein science applications. Open Source exploration of Optide-Hunter can help any bioinformatics scientist adapt, extend, and deploy an equivalent system tailored to each laboratory's workflow.

RevDate: 2019-06-17

Czechowska K, Lannigan J, Wang L, et al (2019)

Cyt-Geist: Current and Future Challenges in Cytometry: Reports of the CYTO 2018 Conference Workshops.

Cytometry. Part A : the journal of the International Society for Analytical Cytology, 95(6):598-644.

RevDate: 2019-06-17

Taylor JA, Sichel SR, NR Salama (2019)

Bent Bacteria: A Comparison of Cell Shape Mechanisms in Proteobacteria.

Annual review of microbiology [Epub ahead of print].

Helical cell shape appears throughout the bacterial phylogenetic tree. Recent exciting work characterizing cell shape mutants in a number of curved and helical Proteobacteria is beginning to suggest possible mechanisms and provide tools to assess functional significance. We focus here on Caulobacter crescentus, Vibrio cholerae, Helicobacter pylori, and Campylobacter jejuni, organisms from three classes of Proteobacteria that live in diverse environments, from freshwater and saltwater to distinct compartments within the gastrointestinal tract of humans and birds. Comparisons among these bacteria reveal common themes as well as unique solutions to the task of maintaining cell curvature. While motility appears to be influenced in all these bacteria when cell shape is perturbed, consequences on niche colonization are diverse, suggesting the need to consider additional selective pressures.

RevDate: 2019-06-17

Mutyaba I, Wabinga HR, Orem J, et al (2019)

Presentation and Outcomes of Childhood Cancer Patients at Uganda Cancer Institute.

Global pediatric health, 6:2333794X19849749 pii:10.1177_2333794X19849749.

Introduction. Limited data suggest that children with cancer in sub-Saharan Africa have poor survival. We aimed to describe the presentation, treatment outcomes, and factors associated with survival among children with cancer managed at Uganda Cancer Institute. Methods. We retrospectively evaluated patients with childhood cancer (age ≤19 years) from Kyadondo County treated at Uganda Cancer Institute from 2006 to 2009. Cox's regression and Kaplan-Meier methods were used to study 1-year survival. Results. Among 310 patients studied, median age was 7 years (range = 0.25-19 years), 64% were boys, and 92% had histological confirmation of cancer diagnosis. The commonest diagnoses were Burkitt lymphoma (BL, N = 87), Kaposi sarcoma (KS, N = 68), non-BL non-Hodgkin lymphoma (NHL, N = 32), acute lymphoblastic leukemia (ALL, N = 28), Wilms (N = 28), and Hodgkin disease (HD, N = 20). Advanced disease at diagnosis was common for all cancers (ranging from 45% for KS to 83% for non-BL NHL). Overall, 33.2% abandoned treatment. One-year survival was 68% for HD (95% confidence interval [CI] = 11.3-40.6), 67% for KS (95% CI = 52.1-77.9), 55% for BL (95% CI = 42-66.9), 44% for Wilms (95% CI = 22.5-63), 43% for non-BL NHL (95% CI = 23.3-61.3), and 20% for ALL (95% CI = 6.4-38.7). In univariate and multivariate analysis, anemia and thrombocytopenia were associated with mortality for several cancers. Conclusion. Survival among children with cancer in Uganda is poor. Advanced stage disease and loss to follow-up likely contribute to poor outcomes. Anemia and thrombocytopenia may augment traditional staging methods to provide better prognostic factors in Uganda and warrant further evaluation.

RevDate: 2019-06-17

Chiorean EG, Cheung WY, Giordano G, et al (2019)

Real-world comparative effectiveness of nab-paclitaxel plus gemcitabine versus FOLFIRINOX in advanced pancreatic cancer: a systematic review.

Therapeutic advances in medical oncology, 11:1758835919850367 pii:10.1177_1758835919850367.

Background: No clinical trial has directly compared nab-paclitaxel/gemcitabine (nab-P/G) with FOLFIRINOX (fluorouracil/leucovorin/oxaliplatin/irinotecan) in metastatic or advanced pancreatic cancer (mPC or aPC). We conducted a systematic review of real-world studies comparing these regimens in the first-line setting.

Methods: Embase and MEDLINE databases through 22 January 2019, and Gastrointestinal Cancers Symposium 2019 abstracts were searched for real-world, retrospective studies comparing first-line nab-P/G versus FOLFIRINOX in mPC or aPC that met specific parameters. Studies with radiotherapy were excluded. Study quality was assessed using the Newcastle-Ottawa Scale.

Results: Of 818 records initially identified, 35 were duplicates and 749 did not meet the eligibility criteria, mostly because they were either not comparative (n = 356) or not first line (n = 245). The remaining 34 studies (21 mPC; 13 aPC) assessed >6915 patients who received nab-P/G or FOLFIRINOX. In the studies identified, the median overall survival (OS) reached 14.4 and 15.9 months with nab-P/G and FOLFIRINOX, respectively, and median progression-free survival reached 8.5 and 11.7 months, respectively. Safety data were reported in 14 studies (2205 patients), including 8 single-institutional studies. In most single-institutional studies that reported safety data, rates were higher with FOLFIRINOX versus nab-P/G for grade 3/4 neutropenia (five of six studies) and febrile neutropenia (all three studies), while rates of grade 3/4 peripheral neuropathy were higher with nab-P/G in four of seven studies.

Conclusions: Although FOLFIRINOX was associated with slightly longer median OS in more studies, the differences, when available, were not statistically significant. Therefore, a randomized, controlled trial is warranted. Toxicity profile differences represent key considerations for treatment decisions.

RevDate: 2019-06-17

Peterson CW, Adair JE, Wohlfahrt ME, et al (2019)

Autologous, Gene-Modified Hematopoietic Stem and Progenitor Cells Repopulate the Central Nervous System with Distinct Clonal Variants.

Stem cell reports pii:S2213-6711(19)30183-3 [Epub ahead of print].

Myeloid-differentiated hematopoietic stem cells (HSCs) have contributed to a number of novel treatment approaches for lysosomal storage diseases of the central nervous system (CNS), and may also be applied to patients infected with HIV. We quantified hematopoietic stem and progenitor cell (HSPC) trafficking to 20 tissues including lymph nodes, spleen, liver, gastrointestinal tract, CNS, and reproductive tissues. We observed efficient marking of multiple macrophage subsets, including CNS-associated myeloid cells, suggesting that HSPC-derived macrophages are a viable approach to target gene-modified cells to tissues. Gene-marked cells in the CNS were unique from gene-marked cells at any other physiological sites including peripheral blood. This novel finding suggests that these cells were derived from HSPCs, migrated to the brain, were compartmentalized, established myeloid progeny, and could be targeted for lifelong delivery of therapeutic molecules. Our findings have highly relevant implications for the development of novel therapies for genetic and infectious diseases of the CNS.

RevDate: 2019-06-17

Martinez DR, Fong Y, Li SH, et al (2019)

Fc Characteristics Mediate Selective Placental Transfer of IgG in HIV-Infected Women.

Cell pii:S0092-8674(19)30617-8 [Epub ahead of print].

The placental transfer of maternal IgG is critical for infant protection against infectious pathogens. However, factors that modulate the placental transfer of IgG remain largely undefined. HIV-infected women have impaired placental IgG transfer, presenting a unique "disruption model" to define factors that modulate placental IgG transfer. We measured the placental transfer efficiency of maternal HIV and pathogen-specific IgG in US and Malawian HIV-infected mothers and their HIV-exposed uninfected and infected infants. We examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, IgG subclass, and glycan signatures and their association with placental IgG transfer efficiency. Maternal IgG characteristics, such as binding to placentally expressed Fc receptors FcγRIIa and FcγRIIIa, and Fc region glycan profiles were associated with placental IgG transfer efficiency. Our findings suggest that Fc region characteristics modulate the selective placental transfer of IgG, with implications for maternal vaccine design and infant health.

RevDate: 2019-06-17

Morsink LM, RB Walter (2019)

Novel monoclonal antibody-based therapies for acute myeloid leukemia.

Best practice & research. Clinical haematology, 32(2):116-126.

There has been long-standing interest in using monoclonal antibodies to improve outcomes of people with acute myeloid leukemia (AML). While several candidate therapeutics have failed at various stages of clinical testing, improved survival of some patients receiving the CD33 antibody-drug conjugate gemtuzumab ozogamicin has provided first evidence that monoclonal antibodies have a role in the armamentarium against AML. Over the last several years, work to improve the success of monoclonal antibody-based therapies in AML has focused on the identification and exploration of new antigen targets as much as on the development of novel treatment formats such as use of unconjugated engineered monoclonal antibodies and conjugated antibodies, delivering highly potent small molecule drugs or radionuclides to AML cells. Here, we will provide a brief overview of current efforts with such investigational monoclonal antibody-based therapeutics.

RevDate: 2019-06-15

Vertii A, Ou J, Yu J, et al (2019)

Two contrasting classes of nucleolus-associated domains in mouse fibroblast heterochromatin.

Genome research pii:gr.247072.118 [Epub ahead of print].

In interphase eukaryotic cells, almost all heterochromatin is located adjacent to the nucleolus or to the nuclear lamina, thus defining Nucleolus-Associated Domains (NADs) and Lamina-Associated Domains (LADs), respectively. Here, we determined the first genome-scale map of murine NADs in mouse embryonic fibroblasts (MEFs) via deep sequencing of chromatin associated with purified nucleoli. We developed a Bioconductor package called NADfinder and demonstrated that it identifies NADs more accurately than other peak-calling tools, due to its critical feature of chromosome-level local baseline correction. We detected two distinct classes of NADs. Type I NADs associate frequently with both the nucleolar periphery and with the nuclear lamina, and generally display characteristics of constitutive heterochromatin, including late DNA replication, enrichment of H3K9me3 and little gene expression. In contrast, Type II NADs associate with nucleoli but do not overlap with LADs. Type II NADs tend to replicate earlier, display greater gene expression, and are more often enriched in H3K27me3 than Type I NADs. The nucleolar associations of both classes of NADs were confirmed via DNA-FISH, which also detected Type I but not Type II probes enriched at the nuclear lamina. Type II NADs are enriched in distinct gene classes, notably factors important for differentiation and development. In keeping with this, we observed that a Type II NAD is developmentally regulated, present in MEFs but not in undifferentiated embryonic stem (ES) cells.

RevDate: 2019-06-15

Rashidi A, Hamadani M, Zhang MJ, et al (2019)

Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission.

Blood advances, 3(12):1826-1836.

HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy-based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease-donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy-based Haplo-HCT vs MSD using calcineurin inhibitor-based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

RevDate: 2019-06-14

Kennedy LC, Bhatia S, Thompson JA, et al (2019)

Preexisting Autoimmune Disease: Implications for Immune Checkpoint Inhibitor Therapy in Solid Tumors.

Journal of the National Comprehensive Cancer Network : JNCCN, 17(6):750-757.

The use of immune checkpoint inhibitors (ICIs) is rapidly expanding to the treatment of many cancer types, both in the metastatic setting and as an adjuvant to other therapies. Clinical trials using ICIs have largely excluded patients with preexisting autoimmune diseases due to concerns for increased toxicity. However, emerging evidence shows that ICIs may be considered in some patients with autoimmunity. This review discusses the commonalities between clinical autoimmune diseases and ICI-induced immunotherapy-related adverse events, and summarizes the existing case series that describes patients with solid tumors who have a preexisting autoimmune disease. This review also discusses which patients with autoimmunity could be considered reasonable candidates for ICI therapy.

RevDate: 2019-06-14

Li A, Manohar PM, Garcia DA, et al (2019)

Cost effectiveness analysis of direct oral anticoagulant (DOAC) versus dalteparin for the treatment of cancer associated thrombosis (CAT) in the United States.

Thrombosis research, 180:37-42 pii:S0049-3848(19)30247-6 [Epub ahead of print].

INTRODUCTION: While trials have demonstrated non-inferiority of direct oral anticoagulant drugs (DOAC) to low-molecular-weight heparins (LMWH) for the treatment of cancer associated thrombosis (CAT), it is unclear if the newer intervention is cost-effective.

METHODS: We performed a cost-utility analysis using a Markov state-transition model over a time horizon of 60 months in a hypothetical cohort of 65-year-old patients with active malignancy and first acute symptomatic CAT who were eligible to receive either rivaroxaban/edoxaban or dalteparin. We obtained transition probability, relative risk, cost, and utility inputs from the literature. We estimated the differential impact on costs and quality-adjusted life years (QALYs) per patient and performed one-way and probabilistic sensitivity analyses to test the robustness of results.

RESULTS: Using the base-case analysis over 60 months, DOAC versus dalteparin was associated with an incremental cost reduction of $24,129 with an incremental QALY reduction of 0.04. In the one-way sensitivity analysis, the cost of dalteparin contributed the most to the incremental cost difference; relative risk of death related to underlying cancer contributed the most of the incremental QALY difference. The probabilistic sensitivity analysis confirmed the base-case analysis, with a large reduction in cost but small reduction in QALYs.

CONCLUSION: Rivaroxaban or edoxaban as compared to dalteparin is cost saving from a payer's perspective for the treatment of CAT. Professional organizations and healthcare systems may want to consider this analysis in future practice recommendations.

RevDate: 2019-06-14

Sabo MC, Lehman DA, Wang B, et al (2019)

Associations between vaginal bacteria implicated in HIV acquisition risk and proinflammatory cytokines and chemokines.

Sexually transmitted infections pii:sextrans-2018-053949 [Epub ahead of print].

OBJECTIVES: Recent studies have identified vaginal bacterial taxa associated with increased HIV risk. A possible mechanism to explain these results is that individual taxa differentially promote cervicovaginal inflammation. This study aimed to explore relationships between concentrations of bacteria previously linked to HIV acquisition and vaginal concentrations of proinflammatory cytokines and chemokines.

METHODS: In this cross-sectional analysis, concentrations of 17 bacterial taxa and four proinflammatory cytokines (interleukin (IL)-1β, IL-6, IL-10 and tumour necrosis factor alpha (TNFα)) and two proinflammatory chemokines (IL-8 and interferon gamma-induced protein 10) were measured in vaginal swabs collected from 80 HIV-uninfected women. Cytokine and chemokine concentrations were compared between women with bacterial concentrations above or below the lower limit of detection as determined by quantitative PCR for each taxon. Principal component analysis was used to create a summary score for closely correlated bacteria, and linear regression analysis was used to evaluate associations between this score and increasing concentrations of TNFα and IL-1β.

RESULTS: Detection of Dialister micraerophilus (p=0.01), Eggerthella sp type 1 (p=0.05) or Mycoplasma hominis (p=0.03) was associated with higher TNFα concentrations, and detection of D. micraerophilus (p<0.01), Eggerthella sp type 1 (p=0.04), M. hominis (p=0.02) or Parvimonas sp type 2 (p=0.05) was associated with significantly higher IL-1β concentrations. Seven bacterial taxa (D. micraerophilus, Eggerthella sp type 1, Gemella asaccharolytica, Sneathia sp, Megasphaera sp, M. hominis and Parvimonas sp type 2) were found to be highly correlated by principal component analysis (eigenvalue 5.24, explaining 74.92% of variability). Linear regression analysis demonstrated associations between this principal component and concentrations of TNFα (β=0.55, 95% CI 0.01 to 1.08; p=0.048) and IL-1β (β=0.96, 95% CI 0.19 to 1.74; p=0.016).

CONCLUSIONS: This study provides evidence that several highly correlated vaginal bacterial taxa may influence vaginal cytokine and chemokine concentrations. These results suggest a mechanism where the presence of specific bacterial taxa could influence HIV susceptibility by increasing vaginal inflammation.

RevDate: 2019-06-13

Heffner JL, Evins AE, Russ C, et al (2019)

Safety and efficacy of first-line smoking cessation pharmacotherapies in bipolar disorders: Subgroup analysis of a randomized clinical trial.

Journal of affective disorders, 256:267-277 pii:S0165-0327(19)30286-1 [Epub ahead of print].

OBJECTIVES: Post hoc analyses of EAGLES data to examine safety and efficacy of first-line smoking cessation pharmacotherapies in smokers with bipolar disorders (BD).

METHODS: Smokers with BD I/II (n = 285; 81.4% with BD I) and a comparison nonpsychiatric cohort (NPC; n = 2794) were randomly assigned to varenicline, bupropion, nicotine replacement therapy (NRT), or placebo for 12 weeks, plus weekly counseling. Primary outcomes were occurrence of moderate to severe neuropsychiatric adverse events (NPSAEs) and Weeks 9-12 biochemically-confirmed continuous abstinence (CA) rates.

RESULTS: For BD smokers, NPSAE risk differences versus placebo were: varenicline, 6.17 (95% CI: -7.84 to 20.18); bupropion, 4.09 (-8.82 to 16.99); NRT, -0.56 (-12.34 to 11.22). ORs for Weeks 9-12 CA, comparing active medication to placebo among BD smokers were: varenicline, 2.61 (0.68-9.95); bupropion, 1.29 (0.31-5.37), NRT, 0.71 (0.14-3.74). Pooling across treatments, NPSAE occurrence was higher (10.7% versus 2.3%; P < 0.001) and CA rates were lower (22.8% versus 13.3%; P = 0.008) in BD than NPC.

LIMITATIONS: Study not powered to detect differences in safety and efficacy in the BD subcohort; generalizability limited to stably treated BD without current substance use disorders.

CONCLUSIONS: Smokers with BD had higher risk of NPSAEs and were less likely to quit overall than NPC smokers. Among smokers with BD, NPSAE risk difference estimates for active treatments versus placebo ranged from 1% lower to 6% higher. Efficacy of varenicline in smokers with BD was similar to EAGLES main outcomes; bupropion and NRT effect sizes were descriptively lower. Varenicline may be a tolerable and effective cessation treatment for smokers with BD.

TRIAL REGISTRATION: ClinicalTrials.gov identifier (https://clinicaltrials.gov/): NCT01456936.

RevDate: 2019-06-13

Aggarwal C, Redman MW, Lara PN, et al (2019)

Brief Report: SWOG S1400D (NCT02965378), a Phase II Study of the Fibroblast Growth Factor Receptor Inhibitor AZD4547 in Previously-treated Patients with Fibroblast Growth Factor Pathway-Activated Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study).

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(19)30462-9 [Epub ahead of print].

BACKGROUND: S1400D is a biomarker-driven therapeutic sub-study of Lung-MAP evaluating the fibroblast growth factor receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell non-small cell lung cancer (SqNSCLC). This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered SqNSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting.

METHODS: Eligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least 1 line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by RECIST 1.1; secondary endpoints included progression-free survival (PFS), overall survival (OS) and duration of response (DoR).

RESULTS: Ninety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n=24, 89%), median age 66 y (49-88), female (n=7, 26%). FGFR alterations included FGFR1 amplification (n=23; 85%); FGFR3 amplification (n=2; 7%); FGFR3 S249C (n=2; 7%); and FGFR3 fusion (n=1; 4%). Treatment with ADZ4547 was well tolerated, grade 3 adverse events (AEs) were seen in six patients; one patient had Grade 4 sepsis. Of 27 response evaluable patients, one patient with FGFR3 S249C had unconfirmed partial response with DoR of 1.5 months and one patient with FGFR1 amplification had a confirmed partial response with DoR of 2.9 months (7%, 95% CI 0-17%). Median PFS and OS for the AZD4547-treated cohort were 2.7 mos (95% CI 1.4 - 4.5 mos) and 7.5 mos (95% CI 3.7-9.3 mos).

CONCLUSIONS: AZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR 1/3 amplified cohort. Evaluation of other targeted agents in Lung-MAP is currently ongoing. ClinicalTrials.gov Identifier: NCT02965378.

RevDate: 2019-06-13

El-Sadr WM, Beauchamp G, Hall HI, et al (2019)

Brief Report: Durability of the Effect of Financial Incentives on HIV Viral Load Suppression and Continuity in Care: HPTN 065 Study.

Journal of acquired immune deficiency syndromes (1999), 81(3):300-303.

BACKGROUND: Results from the HPTN 065 study showed that financial incentives (FI) were associated with significantly higher viral load suppression and higher levels of engagement in care among patients at HIV care sites randomized to FI versus sites randomized to standard of care (SOC). We assessed HIV viral suppression and continuity in care after intervention withdrawal to determine the durability of FI on these outcomes.

SETTING: A total of 37 HIV test and 39 HIV care sites in the Bronx, New York, and Washington, DC, participated in the study.

METHODS: Laboratory data reported to the US National HIV Surveillance System were used to determine site-level viral suppression and continuity in care outcomes. Postintervention effects were assessed for the 3 quarters after discontinuation of FI. Generalized estimation equations were used to compare FI and SOC site-level outcomes after intervention withdrawal.

RESULTS: After FI withdrawal, a trend remained for an increase in viral suppression by 2.7% (-0.3%, 5.6%, P = 0.076) at FI versus SOC sites, decreasing from the 3.8% increase noted during implementation of the intervention. The significant increase in continuity in care during the FI intervention was sustained after intervention with 7.5% (P = 0.007) higher continuity in care at FI versus SOC sites.

CONCLUSIONS: After the withdrawal of FI, findings at the 9-months postintervention withdrawal from this large study showed evidence of durable effects of FI on continuity in care, with trend for continued higher viral suppression. These findings are promising for adoption of such interventions to enhance key HIV-related care outcomes.

RevDate: 2019-06-13

Vinayak S, Tolaney SM, Schwartzberg L, et al (2019)

Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer.

JAMA oncology pii:2735888 [Epub ahead of print].

Importance: Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC).

Objective: To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC.

This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019.

Interventions: Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle.

Main Outcomes and Measures: The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival.

Results: Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected.

Conclusions and Relevance: Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation.

Trial Registration: ClinicalTrials.gov identifier: NCT02657889.

RevDate: 2019-06-13

Progovac AM, Pettinger M, Donohue JM, et al (2019)

Optimism may moderate screening mammogram frequency in Medicare: A longitudinal study.

Medicine, 98(24):e15869.

Higher trait optimism and/or lower cynical hostility are associated with healthier behaviors and lower risk of morbidity and mortality, yet their association with health care utilization has been understudied. Whether these psychological attitudes are associated with breast cancer screening behavior is unknown. To assess the association of optimism and cynical hostility with screening mammography in older women and whether sociodemographic factors acted as mediators of these relationships, we used Women's Health Initiative (WHI) observational cohort survey data linked to Medicare claims. The sample includes WHI participants without history of breast cancer who were enrolled in Medicare Parts A and B for ≥2 years from 2005-2010, and who completed WHI baseline attitudinal questionnaires (n = 48,291). We used survival modeling to examine whether screening frequency varied by psychological attitudes (measured at study baseline) after adjusting for sociodemographic characteristics, health conditions, and healthcare-related variables. Psychological attitudes included trait optimism (Life Orientation Test-Revised) and cynical hostility (Cook Medley subscale), which were self-reported at study baseline. Sociodemographic, health conditions, and healthcare variables were self-reported at baseline and updated through 2005 as available. Contrary to our hypotheses, repeated events survival models showed that women with the lowest optimism scores (i.e., more pessimistic tendencies) received 5% more frequent screenings after complete covariate adjustment (p < .01) compared to the most optimistic group, and showed no association between cynical hostility and frequency of screening mammograms. Sociodemographic factors did not appear to mediate the relationship between optimism and screenings. However, higher levels of education and higher levels of income were associated with more frequent screenings (both p < .01). We also found that results for optimism were primarily driven by women who were aged 75 or older after January 2009, when changes to clinical guidelines lead to uncertainty about risks and benefits of screening in this age group. The study demonstrated that lower optimism, higher education, and higher income were all associated with more frequent screening mammograms in this sample after repeated events survival modeling and covariate adjustment.

RevDate: 2019-06-13

Dashti HS, Merino J, Lane JM, et al (2019)

Genome-wide association study of breakfast skipping links clock regulation with food timing.

The American journal of clinical nutrition pii:5514151 [Epub ahead of print].

BACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits.

OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait.

METHODS: We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963).

RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095).

CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

RevDate: 2019-06-13

Oliva J, Galasinski S, Richey A, et al (2019)

Clinically advanced p38 inhibitors suppress DUX4 expression in cellular and animal models of facioscapulohumeral muscular dystrophy.

The Journal of pharmacology and experimental therapeutics pii:jpet.119.259663 [Epub ahead of print].

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by mis-expression of the DUX4 developmental transcription factor in mature skeletal muscle where it is responsible for muscle degeneration. Preventing expression of DUX4 mRNA is a disease-modifying therapeutic strategy with the potential to halt or reverse the course of disease. We previously reported that agonists of the beta-2 adrenergic receptor suppress DUX4 expression by activating adenylate cyclase to increase cAMP levels. Efforts to further explore this signaling pathway led to the identification of p38 MAP kinase as a major regulator of DUX4 expression. In vitro experiments demonstrate that clinically advanced p38 inhibitors suppress DUX4 expression in FSHD type 1 (FSHD1) and FSHD2 myoblasts and differentiating myocytes in vitro with exquisite potency. Individual siRNA-mediated knockdown of either p38alpha or p38beta suppresses DUX4 expression, demonstrating that each kinase isoform plays a distinct requisite role in activating DUX4. Finally, p38 inhibitors effectively suppress DUX4 expression in a mouse xenograft model of human FSHD gene regulation. These data support the repurposing of existing clinical p38 inhibitors as potential therapeutics for FSHD. The surprise finding that p38 alpha and beta isoforms each independently contribute to DUX4 expression offers a unique opportunity to explore the utility of p38 isoform-selective inhibitors to balance efficacy and safety in skeletal muscle. We propose p38 inhibition as a disease-modifying therapeutic strategy for FSHD. SIGNIFICANCE STATEMENT: Facioscapulohumeral muscular dystrophy (FSHD) currently has no treatment options. This work provides evidence that repurposing a clinically advanced p38 inhibitor may provide the first disease-modifying drug for FSHD by suppressing toxic DUX4 expression, the root cause of muscle degeneration in this disease.

RevDate: 2019-06-13

Zolla-Pazner S, PB Gilbert (2019)


Journal of virology pii:JVI.00629-19 [Epub ahead of print].

The RV144 vaccine trial is the only clinical study to have shown a modest but statistically significant decrease in HIV infection risk. RV144 and the subsequent studies identifying the level of V1V2-specific antibodies as a correlate of reduced infection risk are still controversial despite many papers supporting and expanding the initial study. We address these controversies and summarize active and passive immunization experiments in non-human primates that support the initial finding.

RevDate: 2019-06-13

Solan JL, Marquez-Rosado L, PD Lampe (2019)

Cx43 phosphorylation mediated effects on ERK and Akt protect against ischemia reperfusion injury and alter stability of stress-inducible protein NDRG1.

The Journal of biological chemistry pii:RA119.009162 [Epub ahead of print].

Gap junctions contain intercellular channels that enable intercellular communication of small molecules while also serving as a signaling scaffold. Connexins, the proteins that form gap junctions in vertebrates, the connexins, are highly regulated and typically have short (<2 h) half-lives. Connexin43 (Cx43), the predominate connexin in the myocardium and epithelial tissues, is phosphorylated on more than a dozen serine residues and interacts with a variety of protein kinases. These interactions regulate Cx43 and gap junction formation and stability. Casein kinase 1 (CK1)-mediated phosphorylation of Cx43 promotes gap junction assembly. Using murine knock-in technology and quantitative PCR, immunoblotting, and immunoprecipitation assays, we show here that mutation of the CK1 phosphorylation sites in Cx43 reduce the levels of total Cx43 in myocardium and increase Cx43 phosphorylation on sites phosphorylated by extracellular signal-regulated kinase (ERK). In aged myocardium, we found that compared with wildtype Cx43, mutant Cx43 expression increases ERK activation, phosphorylation of Akt substrates and protection from ischemia induced injury (IRI). Our findings also uncovered that Cx43 interacts with the hypoxia-inducible protein N-Myc downstream regulated gene 1 protein (NDRG1), and that Cx43 phosphorylation status controls this interaction and dramatically affects NDRG1 stability. We propose that in addition to altering gap junction stability, Cx43 phosphorylation directly and dynamically regulates cellular signaling through ERK and Akt in response to ischemic injury. We conclude that gap junction-dependent NDRG1 regulation might explain some cellular responses to hypoxia.

RevDate: 2019-06-13

Natesampillai S, Paim AC, Cummins NW, et al (2019)

TRAILshort Protects against CD4 T Cell Death during Acute HIV Infection.

Journal of immunology (Baltimore, Md. : 1950) pii:jimmunol.1900271 [Epub ahead of print].

CD4 T cells from HIV-1 infected patients die at excessive rates compared to those from uninfected patients, causing immunodeficiency. We previously identified a dominant negative ligand that antagonizes the TRAIL-dependent pathway of cell death, which we called TRAILshort. Because the TRAIL pathway has been implicated in CD4 T cell death occurring during HIV-1 infection, we used short hairpin RNA knockdown, CRISPR deletion, or Abs specific for TRAILshort to determine the effect of inhibiting TRAILshort on the outcome of experimental acute HIV infection in vitro. Strikingly, all three approaches to TRAILshort deletion/inhibition enhanced HIV-induced death of both infected and uninfected human CD4 T cells. Thus, TRAILshort impacts T cell dynamics during HIV infection, and inhibiting TRAILshort causes more HIV-infected and uninfected bystander cells to die. TRAILshort is, therefore, a host-derived, host-adaptive mechanism to limit the effects of TRAIL-induced cell death. Further studies on the effects of TRAILshort in other disease states are warranted.

RevDate: 2019-06-12

Maskarinec G, Hullar MAJ, Monroe KR, et al (2019)

Fecal Microbial Diversity and Structure Are Associated with Diet Quality in the Multiethnic Cohort Adiposity Phenotype Study.

The Journal of nutrition pii:5514145 [Epub ahead of print].

BACKGROUND: Variation in gut microbial community structure is partly attributed to variations in diet. A priori dietary indexes capture diet quality and have been associated with chronic disease risk.

OBJECTIVES: The aim of this study was to examine the association of diet quality, as assessed by the Healthy Eating Index, Alternative Healthy Eating Index-2010, alternate Mediterranean Diet, and the Dietary Approaches to Stop Hypertension Trial, with measures of fecal microbial community structure assessed in the Adiposity Phenotype Study (APS), an ethnically diverse study population with varied food intakes.

METHODS: Multiethnic Cohort Study members completed a validated quantitative food frequency questionnaire (QFFQ) at cohort entry (1993-1996) and, for the APS subset, at clinic visit (2013-2015), when they also provided a stool sample. DNA was extracted from stool, and the V1-V3 region of the 16S rRNA gene was amplified and sequenced. Dietary index scores were computed based on the QFFQ and an extensive nutritional database. Using linear regression adjusted for relevant covariates, we estimated associations of dietary quality with microbiome measures and computed adjusted mean values of microbial measures by tertiles of dietary index scores.

RESULTS: The 858 men and 877 women of white, Japanese American, Latino, Native Hawaiian, and African American ancestry had a mean age of 69.2 years at stool collection. Alpha diversity according to the Shannon index increased by 1-2% across tertiles of all 4 diet indexes measured at clinic visit. The mean relative abundance of the phylum Actinobacteria was 13-19% lower with higher diet quality across all 4 indexes (difference between tertile 3 and tertile 1 divided by tertile 1). Of the 104 bacterial genera tested, 21 (primarily from the phylum Firmicutes) were positively associated with at least 1 index after Bonferroni adjustment.

CONCLUSION: Diet quality was strongly associated with fecal microbial alpha diversity and beta diversity and several genera previously associated with human health.

RevDate: 2019-06-12

Somsouk M, Rachocki C, Mannalithara A, et al (2019)

Effectiveness and cost of organized outreach for colorectal cancer screening: A Randomized Controlled Trial.

Journal of the National Cancer Institute pii:5513785 [Epub ahead of print].

BACKGROUND: Colorectal cancer (CRC) screening remains underutilized especially in safety-net systems. The objective of this study was to determine the effectiveness, costs, and cost-effectiveness of organized outreach using fecal immunochemical tests (FIT) compared with usual care.

METHODS: Patients aged 50-75 years eligible for CRC screening from eight participating primary care safety-net clinics were randomized to outreach intervention with usual care versus usual care alone. The intervention included a mailed postcard and call, followed by a mailed FIT kit, and a reminder phone call if the FIT kit was not returned. The primary outcome was screening participation at one year and a microcosting analysis of the outreach activities with embedded long-term cost-effectiveness of outreach. All statistical tests were two-sided.

RESULTS: 5,386 patients were randomized to the intervention group and 5,434 to usual care. FIT screening was statistically significantly higher in the intervention group than in the control group (57.9% vs. 37.4%, P < 0.001; difference 20.5%, 95% CI 18.6-22.4%). In the intervention group, FIT completion rate was higher in patients who had previously completed a FIT versus those who had not (71.9% vs. 35.7%, P < 0.001). There was evidence of effect modification of the intervention by race/ethnicity, marital status, language, and clinic. Outreach cost approximately $23/patient and $112/additional patient screened. Projecting long-term outcomes, outreach was estimated to cost $9,200/quality-adjusted life-year gained vs. usual care.

CONCLUSION: Population-based management with organized FIT outreach statistically significantly increased CRC screening and was cost-effective in a safety-net system. The sustainability of the program and any impact of economies of scale remains to be determined.

RevDate: 2019-06-12

Irungu EM, Sharma M, Maronga C, et al (2019)

The Incremental Cost of Delivering PrEP as a Bridge to ART for HIV Serodiscordant Couples in Public HIV Care Clinics in Kenya.

AIDS research and treatment, 2019:4170615.

Background: In 2016, the Kenyan Ministry of Health (MOH) released guidelines that recommend preexposure prophylaxis (PrEP) for persons with substantial ongoing HIV risk, including those in HIV serodiscordant partnerships. Estimates of the costs of delivering PrEP within Kenyan public health facilities are needed for planning for PrEP scale up.

Methods: We estimated the incremental annual costs of providing PrEP to HIV uninfected partners as a time-limited "bridge" until the infected partner is virally suppressed on ART within HIV serodiscordant couples as part of routine clinic care in Thika, Kenya. Costs were collected from the Partners Demonstration Project, a prospective evaluation of integrated delivery of preexposure prophylaxis (PrEP) and antiretroviral therapy (ART) to high-risk HIV serodiscordant couples. We conducted time and motion studies to distinguish between activities related to research, routine clinical care, and PrEP delivery. Costs (2015 US dollars) were collected from the MOH perspective and divided into staff, transportation, equipment, supplies, buildings and overhead, and start-up.

Results: PrEP related activities conducted during the screening, enrollment, and follow-up visits took an average of 13 minutes, 51 minutes, and 12 minutes, respectively. Assuming a staff structure of 3 counselors, 1 nurse, and 2 clinicians, we estimate that 3,178 couples can be screened, 1,444 couples offered PrEP and ART, and 6,138 couples followed up annually in an average HIV care clinic. Using costs incurred by the MOH for personnel, drug, and laboratory tests, we estimate that the incremental cost of offering PrEP to HIV uninfected partners within existing ART programs is $86.79 per couple per year. Personnel and PrEP medication made up the largest portion of the costs. We estimate that the total cost to Ministry of Health of delivering integrated PrEP and ART program in public health facilities is $250.19 per HIV serodiscordant couple per year.

Conclusions: Time-limited provision of PrEP to the HIV uninfected partner within HIV serodiscordant couples can be an affordable delivery model implemented in HIV care programs in Kenya and similar settings. These costs can be used for budgetary planning and cost effectiveness analyses.

RevDate: 2019-06-12

Bender Ignacio RA, Dasgupta S, Stevens-Ayers T, et al (2019)

Comprehensive Virome-wide Antibody Responses by Systematic Epitope Scanning After Hematopoietic Cell Transplantation.

Blood pii:blood.2019897405 [Epub ahead of print].

Further insight into humoral viral immunity after hematopoietic cell transplantation (HCT) could have potential impact on donor selection or monitoring of patients. Currently, estimation of humoral immune recovery is inferred from lymphocyte counts or immunoglobulin levels and does not address vulnerability to specific viral infections. We interrogated the viral antibody repertoire before and after HCT using a novel serosurvey (VirScan) that detects immunoglobulin G responses to 206 viruses. We performed VirScan on cryopreserved serum from pre-HCT and 30, 100, and 365 days after myeloablative HCT from 37 donor-recipient pairs. We applied ecologic metrics (a- and b-diversity) and evaluated predictors of metrics and changes over time. Donor age and donor/recipient CMV serostatus and receipt systemic glucocorticoids were most strongly associated with VirScan metrics at d100. Other clinical characteristics, including pre-HCT treatment and conditioning, did not affect anti-viral repertoire metrics. The recipient repertoire was most similar (pairwise b-diversity) to that of donor at d100, but more similar to pre-HCT self by day 365. Gain or loss of epitopes to common viruses over the year post-HCT differed by donor and recipient pre-HCT serostatus, with highest gains in naïve donors to seropositive recipients for several human herpesviruses and adenoviruses. We used VirScan to highlight contributions of donor and recipient to anti-viral humoral immunity and evaluate longitudinal changes. This work builds a foundation to test whether such systematic profiling could serve as a biomarker of immune reconstitution, predict clinical events after HCT, or help refine selection of optimal donors.

RevDate: 2019-06-11

Kreimer AR, Ferreiro-Iglesias A, Nygard M, et al (2019)

Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium.

Annals of oncology : official journal of the European Society for Medical Oncology pii:5510170 [Epub ahead of print].

BACKGROUND: Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown.

PATIENTS AND METHODS: We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6-11 years, range = 0-40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay).

RESULTS: HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1-155.4) in whites and 17.2-fold (95% CI 1.7-170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years (N = 24), 20-30 years (N = 148), 10-20 years (N = 228), and <10 years (N = 301 cases) (p-trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis.

CONCLUSIONS: The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.

RevDate: 2019-06-11

Pan K, Nelson RA, Wactawski-Wende J, et al (2019)

Insulin Resistance and Cancer-Specific and All-Cause Mortality in Postmenopausal Women: The Women's Health Initiative.

Journal of the National Cancer Institute pii:5480168 [Epub ahead of print].

BACKGROUND: Insulin resistance has been proposed as a mediator of the increased cancer incidence and mortality associated with obesity. However, prior studies included limited cancer deaths and had inconsistent findings. Therefore, we evaluated insulin resistance and cancer-specific and all-cause mortality in postmenopausal women participating in the Women's Health Initiative (WHI).

METHODS: Eligible were a subsample of 22 837 WHI participants aged 50-79 years enrolled at 40 US clinical centers from 1993 to 1998 who had baseline fasting glucose and insulin levels. Baseline insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Cancers were verified by central medical record review and deaths verified by medical record and death certificate review enhanced by National Death Index queries. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific and all-cause mortality. All statistical tests were two-sided.

RESULTS: During a median of 18.9 years of follow-up, 1820 cancer deaths and 7415 total deaths occurred. Higher HOMA-IR quartile was associated with higher cancer-specific mortality (Q4 vs Q1, HR = 1.26, 95% CI = 1.09 to 1.47; Ptrend = .003) and all-cause mortality (Q4 vs Q1, HR = 1.63, 95% CI = 1.51 to 1.76; Ptrend < .001). A sensitivity analysis for diabetes status did not change findings. Among women with body mass index less than 25 kg/m2, higher HOMA-IR quartile was associated with higher cancer mortality (Fine and Gray, P = .004).

CONCLUSIONS: High insulin resistance, as measured by HOMA-IR, identifies postmenopausal women at higher risk for cancer-specific and all-cause mortality who could potentially benefit from early intervention.

RevDate: 2019-06-11

Tarlock K, Alonzo TA, Wang YC, et al (2019)

Functional Properties of KIT Mutations are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-18-1897 [Epub ahead of print].

PURPOSE: KIT mutations (KIT+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KIT mutations in CBF pediatric AML.

EXPERIMENTAL DESIGN: Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status (KIT+ vs wild type KIT (KIT-)) and mutation location (E8 vs. E17).

RESULTS: KIT mutations were detected in 63/205(31%) patients; 22 (35%) involved only E8, 32(51%) only E17, 6(10%) both exons, and 3(5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly impacted growth of E17, but not E8, transfected cells. KIT+ CBF AML patients had comparable overall survival (OS) to that of KIT- (78%, vs. 81%, p=0.905) but higher relapse rates (RR 43% vs. 21%, p=0.005). E17 KIT+ outcomes were inferior to KIT- patients [disease free survival (DFS) 51% vs. 73%, p=0.027; RR 21% vs. 46%, p=0.007)] although GO abrogated this negative prognostic impact. E8 mutations lacked significant prognostic impact and GO failed to significantly improve outcome.

CONCLUSIONS: E17 mutations impact prognosis in CBF AML, as well as response to GO and TKIs, thus clinical trials utilizing both agents should be considered for KIT+ patients.

RevDate: 2019-06-10

Lin BM, Nadkarni GN, Tao R, et al (2019)

Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study.

Frontiers in genetics, 10:494.

Background: Chronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study.

Methods: We assembled multi-ethnic genome-wide imputed data on CKD non-overlapping cases [4,150 mild to moderate CKD, 1,105 end-stage kidney disease (ESKD)] and non-CKD controls for up to 41,041 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian, and American Indians). We implemented a generalized estimating equation approach for GWAS using ancestry combined data while adjusting for age, sex, principal components, study, and ethnicity.

Results: The GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby NMT2 (rs10906850, p = 3.7 × 10-8) that replicated in the United Kingdom Biobank white British (p = 0.008). Several variants at the APOL1 locus were associated with ESKD including the APOL1 G1 rs73885319 (p = 1.2 × 10-9). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported APOL1 locus (p = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at p-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry.

Conclusion: Our genetic study identified a novel association at NMT2 for CKD and showed for the first time strong associations of the APOL1 variants with ESKD across multi-ethnic populations. Our findings suggest differences in genetic effects across CKD severity and provide information for study design of genetic studies of CKD in diverse populations.

RevDate: 2019-06-10

Di Credico G, Edefonti V, Polesel J, et al (2019)

Joint effects of intensity and duration of cigarette smoking on the risk of head and neck cancer: A bivariate spline model approach.

Oral oncology, 94:47-57.

OBJECTIVES: This study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as interacting continuous exposures.

MATERIALS AND METHODS: We pooled individual-level data from 33 case-control studies (18,260 HNC cases and 29,844 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. In bivariate regression spline models, exposures to cigarette smoking intensity and duration (compared with never smokers) were modeled as a linear piecewise function within a logistic regression also including potential confounders. We jointly estimated the optimal knot locations and regression parameters within the Bayesian framework.

RESULTS: For oral-cavity/pharyngeal (OCP) cancers, an odds ratio (OR) >5 was reached after 30 years in current smokers of ∼20 or more cigarettes/day. Patterns of OCP cancer risk in current smokers differed across strata of alcohol intensity. For laryngeal cancer, ORs >20 were found for current smokers of ≥20 cigarettes/day for ≥30 years. In former smokers who quit ≥10 years ago, the ORs were approximately halved for OCP cancers, and ∼1/3 for laryngeal cancer, as compared to the same levels of intensity and duration in current smokers.

CONCLUSION: Referring to bivariate spline models, this study better quantified the joint effect of intensity and duration of cigarette smoking on HNC risk, further stressing the need of smoking cessation policies.

RevDate: 2019-06-10

Spracklen CN, Karaderi T, Yaghootkar H, et al (2019)

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

American journal of human genetics pii:S0002-9297(19)30188-0 [Epub ahead of print].

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

RevDate: 2019-06-09

Andrasik M, Grove D, Broder G, et al (2019)

A descriptive analysis of transgender participants in phase 1-2a trials of the HIV Vaccine Trials Network (HVTN) in the United States and Peru.

Vaccine pii:S0264-410X(19)30630-9 [Epub ahead of print].

BACKGROUND: HIV disproportionately impacts transgender populations globally, creating challenges to inclusion in trials requiring low HIV risk profiles (LHRP) for acquisition. Our knowledge of transgender individuals with LHRP is limited. We conducted an analysis of transgender and cisgender individuals in HVTN trials enrolling individuals with LHRP.

METHODS: We analyzed data from 694 participants enrolled in the phase 1-2a HVTN trials in the US and Peru from 2009 to 2014 that included individuals who reported gender identity (GI) differing from assigned birth sex (transgender [TG]), and compared them with those who reported a congruent GI (cisgender [CG]).

RESULTS: 681 participants (98%) were CG and 13 (2%) were TG. Mean age was 25 years. 16% were Hispanic and most (69%) were White. Reasons for enrolling included to help find an effective vaccine (TG 100%; CG 98%) and help their community (TG 100%; CG 96%). Significant differences by GI were observed in reported pre-existing conditions (p = 0.004); however, approximately 10% of pre-existing conditions reported by TG were GI-related (e.g., gender dysphoria). Significant differences were observed in hormone therapy use (p < 0.001) and mental health medications (p = 0.007). Retention was excellent with 2.1% missed visits and no discontinuations of vaccination for TG and 3% missed visits and 7.1% discontinuations among CG. There was no statistically significant difference in HIV incidence.

CONCLUSIONS: Primary reasons for participation were altruistic for all participants. Comparable to CG counterparts, TG participants maintained LHRP, followed trial procedures, and had high retention, facilitating meaningful early phase HIV preventive vaccine trial contributions.

RevDate: 2019-06-09

Balgansuren G, Regen L, Sprague M, et al (2019)

Identification of the rs9277534 HLA-DP expression marker by next generation sequencing for the selection of unrelated donors for hematopoietic cell transplantation.

Human immunology pii:S0198-8859(19)30273-3 [Epub ahead of print].

Mismatching of an unrelated donor against a high-expression HLA-DPB1 recipient allele is associated with a high risk of graft-versus-host disease and mortality. The Seattle Cancer Care Alliance (SCCA) and Fred Hutchinson Cancer Research Center transplant program employs an algorithm to match for HLA-A, B, C, DRB1, DQB1 and DPB1 alleles (12/12) and to avoid, whenever possible, donor mismatching against a recipient high-expression HLA-DPB1 allele. HLA-DPB1 expression is associated with the rs9277534 A/G polymorphism located in the 3'UTR of the HLA-DPB1 gene. Next generation sequencing of HLA-DPB1 using the Illumina TruSight HLA V2 Sequencing Panel and Conexio Assign software analyses provides information on rs9277534 variants without the need for any additional SNP testing. Here we present the molecular location of rs9277534 in NGS data and discuss the challenges to resolve HLA-DPB1 ambiguities.

RevDate: 2019-06-08

Prentice RL, Aragaki AK, Howard BV, et al (2019)

Low-Fat Dietary Pattern among Postmenopausal Women Influences Long-Term Cancer, Cardiovascular Disease, and Diabetes Outcomes.

The Journal of nutrition pii:5512736 [Epub ahead of print].

BACKGROUND: The preferred macronutrient dietary composition, and the health consequences of dietary fat reduction specifically, have been debated for decades. Here we provide a comprehensive overview of long-term health outcomes in the Women's Health Initiative Dietary Modification (DM) trial.

OBJECTIVE: The DM trial aimed to examine whether a low-fat dietary pattern would reduce the risk of invasive breast cancer, colorectal cancer, and, secondarily, coronary heart disease (CHD), with various other health outcomes also considered.

METHODS: The DM trial is a randomized controlled trial conducted at 40 centers in the US, among 48,835 postmenopausal women aged 50-79 y with baseline intake of ≥32% energy from fat. Participants were randomly assigned to a low-fat dietary pattern intervention group or to a usual-diet comparison group, during 1993-1998. Intervention goals were to reduce fat intake from ∼35% to 20% of total energy, in conjunction with increasing vegetables and fruit to 5 servings/d and grains to 6 servings/d.

RESULTS: Over an 8.5-y (median) intervention period, intervention and comparison group differences included lower fat by 8-10%, and higher carbohydrate by 8-10%, of total energy, in conjunction with higher consumption of vegetables, fruit, and grains. Time-to-outcome analyses did not show significant differences between intervention and comparison groups for invasive breast cancer, colorectal cancer, or CHD, either over the intervention period or over longer-term cumulative follow-up. Additional analyses showed significant intervention group benefits related to breast cancer, CHD, and diabetes, without adverse effects. Over a 19.6-y (median) follow-up period, HRs (95% CIs) were 0.84 (0.74, 0.96) for breast cancer followed by death, and 0.87 (0.77, 0.98) for diabetes requiring insulin.

CONCLUSIONS: Reduction in dietary fat with corresponding increase in vegetables, fruit, and grains led to benefits related to breast cancer, CHD, and diabetes, without adverse effects, among healthy postmenopausal US women.

This trial was registered at clinicaltrials.gov as NCT00000611.

RevDate: 2019-06-08

Lampe JW, Kim E, Levy L, et al (2019)

Colonic mucosal and exfoliome transcriptomic profiling and fecal microbiome response to a flaxseed lignan extract intervention in humans.

The American journal of clinical nutrition pii:5512737 [Epub ahead of print].

BACKGROUND: Microbial metabolism of lignans from high-fiber plant foods produces bioactive enterolignans, such as enterolactone (ENL) and enterodiol (END). Enterolignan exposure influences cellular pathways important to cancer risk and is associated with reduced colon tumorigenesis in animal models and lower colorectal cancer risk in humans.

OBJECTIVES: The aim of this study was to test the effects of a flaxseed lignan supplement (50 mg secoisolariciresinol diglucoside/d) compared with placebo on host gene expression in colon biopsies and exfoliated colonocyte RNA in feces and fecal microbial community composition, and to compare responses in relation to ENL excretion.

METHODS: We conducted a 2-period randomized, crossover intervention in 42 healthy men and women (20-45 y). We used RNA-seq to measure differentially expressed (DE) genes in colonic mucosa and fecal exfoliated cells through the use of edgeR and functional analysis with Ingenuity Pathway Analysis. We used 16S ribosomal RNA gene (V1-V3) analysis to characterize the fecal microbiome, and measured END and ENL in 24-h urine samples by gas chromatography-mass spectrometry.

RESULTS: We detected 32 DE genes (false discovery rate <0.05) in the exfoliome, but none in the mucosal biopsies, in response to 60 d of lignan supplement compared with placebo. Statistically significant associations were detected between ENL excretion and fecal microbiome measured at baseline and at the end of the intervention periods. Further, we detected DE genes in colonic mucosa and exfoliome between low- and high-ENL excreters. Analysis of biopsy samples indicated that several anti-inflammatory upstream regulators, including transforming growth factor β and interleukin 10 receptor, were suppressed in low-ENL excreters. Complementary analyses in exfoliated cells also suggested that low-ENL excreters may be predisposed to proinflammatory cellular events due to upregulation of nuclear transcription factor κB and NOS2, and an inhibition of the peroxisome proliferator-activated receptor γ network.

CONCLUSIONS: These results suggest that ENL or other activities of the associated gut microbial consortia may modulate response to a dietary lignan intervention. This has important implications for dietary recommendations and chemoprevention strategies. This study was registered at clinicaltrials.gov as NCT01619020.

RevDate: 2019-06-08

Rudin CM, Poirier JT, Byers LA, et al (2019)

Author Correction: Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.

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

RevDate: 2019-06-08

Puttur F, Denney L, Gregory LG, et al (2019)

Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans.

Science immunology, 4(36):.

Group 2 innate lymphoid cells (ILC2s) are enriched in mucosal tissues (e.g., lung) and respond to epithelial cell-derived cytokines initiating type 2 inflammation. During inflammation, ILC2 numbers are increased in the lung. However, the mechanisms controlling ILC2 trafficking and motility within inflamed lungs remain unclear and are crucial for understanding ILC2 function in pulmonary immunity. Using several approaches, including lung intravital microscopy, we demonstrate that pulmonary ILC2s are highly dynamic, exhibit amoeboid-like movement, and aggregate in the lung peribronchial and perivascular spaces. They express distinct chemokine receptors, including CCR8, and actively home to CCL8 deposits located around the airway epithelium. Within lung tissue, ILC2s were particularly motile in extracellular matrix-enriched regions. We show that collagen-I drives ILC2 to markedly change their morphology by remodeling their actin cytoskeleton to promote environmental exploration critical for regulating eosinophilic inflammation. Our study provides previously unappreciated insights into ILC2 migratory patterns during inflammation and highlights the importance of environmental guidance cues in the lung in controlling ILC2 dynamics.

RevDate: 2019-06-08

Mrugala MM, Kim B, Sharma A, et al (2019)

Phase II Study of Systemic High-dose Methotrexate and Intrathecal Liposomal Cytarabine for Treatment of Leptomeningeal Carcinomatosis From Breast Cancer.

Clinical breast cancer pii:S1526-8209(19)30099-0 [Epub ahead of print].

Metastatic breast cancer frequently leads to brain metastases and, less commonly, leptomeningeal carcinomatosis (LC). Once cerebrospinal fluid involvement occurs, the prognosis is poor. There are limited treatment options available, but none offer significant survival benefit. Methotrexate, given systemically at high doses (3.5-8 gm/m2), achieves cytotoxic concentrations in the CSF and has been shown to prolong survival in patients with LC. Intrathecal liposomal cytarabine has been shown to increase time to neurologic progression in patients with breast cancer and LC. The combination of these 2 agents in LC has not been studied extensively. Here, we present the results of the phase II study with this combination showing promising efficacy and very good tolerability.

RevDate: 2019-06-07

Casey DL, Chi YY, Donaldson SS, et al (2019)

Increased local failure for patients with intermediate-risk rhabdomyosarcoma on ARST0531: A report from the Children's Oncology Group.

Cancer [Epub ahead of print].

BACKGROUND: The objective of this study was to evaluate local control for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531.

METHODS: This study analyzed 424 patients with intermediate-risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24 months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate-risk study, D9803.

RESULTS: For patients with group I/II alveolar RMS (n = 55), the 5-year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n = 141), it was 20.2%; and for group III embryonal RMS (n = 228), it was 27.9% (P = .03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5 cm (32.3% vs 16.7%; P = .001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P = .03). After the exclusion of patients 24 months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 (P = .02). After adjustments for clinical prognostic factors, event-free survival and overall survival were worse on ARST0531 (P = .004 and P = .05, respectively).

CONCLUSIONS: Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531.

RevDate: 2019-06-07

Tate WR, Abraham I, LD Cranmer (2019)

Center-Specific Modeling Predicts Cancer Trial Accrual More Accurately Than Investigators and Random Effects Modeling at 16 Cancer Centers.

JCO clinical cancer informatics, 3:1-12.

PURPOSE: Clinical trials often exceed their anticipated enrollment periods, and study sites often do not meet accrual goals. We previously reported the development and validation of a single-site accrual prediction model. Here, we describe the expansion of this methodology at 16 cancer centers (CCs) and compare an overall model versus site-specific models.

METHODS: This retrospective cohort study used data from treatment and supportive care intervention studies permanently closed to accrual between 2009 and 2015 at 16 United States-based CCs. Center and ClinicalTrials.gov data were used to generate both site-specific and random effects mixed models (random effect: institution). Accrual predictions were generated from each model and compared with the accrual prediction of the disease team (DT).

RESULTS: Sixteen institutions submitted 5,787 eligible trials (range, 93 to 697 trials per institution). Local accrual ranged from 363 to 6,716 participants; 1,053 studies (18%) accrued no participants. Actual average accrual was 8.5 participants (median, four participants). Site-specific models predicted accrual at 99% of actual and correctly predicted whether a study would accrue four or more participants 73% of the time versus DT prediction of 58%. Correlation at the category level was 30%; model sensitivity and specificity were 83% and 62%, respectively. The overall model predicted accrual 93% of actual and correctly predicted accrual of four or more participants 66% of the time, with a correlation at the category level of 28%.

CONCLUSION: Both regression models predicted clinical trial accrual at least as or more accurately than DT at all but one center. Site-specific models generally performed slightly better than the random effects model. This study confirms the previous finding that this method is an accurate and objective metric that can be easily implemented to improve clinical research resource allocation across multiple centers.

RevDate: 2019-06-07

Crawford J, Denduluri N, Patt D, et al (2019)

Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-019-04875-1 [Epub ahead of print].

PURPOSE: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC.

METHODS: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models.

RESULTS: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays ≥ 7 days, 50.1% experienced dose reductions ≥ 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS ≥ 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays ≥ 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays ≥ 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI ≥ 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality.

CONCLUSIONS: Dose delays, dose reductions, and reduced RDI were common, and dose delays ≥ 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

RevDate: 2019-06-07

Zhang S, Kohli K, Black RG, et al (2019)

Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial.

Cancer immunology research pii:2326-6066.CIR-18-0940 [Epub ahead of print].

Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer-testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and post-treatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (p<0.05). Gene expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into "hot" tumors will work in concert with anti-PD1 therapy to provide patient benefit.

RevDate: 2019-06-07

Paller CJ, Antonarakis ES, Beer TM, et al (2019)

Germline Genetic Testing in Advanced Prostate Cancer; Practices and Barriers: Survey Results from the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium.

Clinical genitourinary cancer pii:S1558-7673(19)30139-9 [Epub ahead of print].

BACKGROUND: Germline genetic testing increasingly identifies advanced prostate cancer (PCa) patients who are candidates for precision therapies. The Prostate Cancer Clinical Trials Consortium (PCCTC) established the Germline Genetics Working Group to provide guidance and resources to expand effective use of germline genetic testing.

MATERIALS AND METHODS: A 14-item questionnaire was e-mailed to academic oncologists at 43 PCCTC sites to collect information on germline genetic testing patterns, including patients considered, choice of assays, barriers slowing adoption, and actions to overcome barriers.

RESULTS: Twenty-six genitourinary oncologists from 19 institutions responded. Less than 40% (10 of 26) reported referring patients to a genetics department, whereas the remainder take personal responsibility for genetic testing and counseling; 16 (62%) consider testing all metastatic PCa patients, whereas 3 (12%) consider testing all patients with high-risk local disease; and 7 (27%) use multigene comprehensive pan-cancer panels, and 14 (54%) use smaller or targeted cancer gene panels. Barriers to widespread use are: (1) delayed or limited access to genetic counseling; (2) no insurance coverage; (3) lack of effective workflows; (4) insufficient educational materials; and (5) time and space constraints in busy clinics. The primary limitation was the <50% (19 of 43) response from PCCTC sites and no coverage of nonacademic cancer treatment facilities.

CONCLUSION: Joint efforts by urologists, oncologists, genetics counselors, insurers, and cancer centers can accelerate implementation of integrated germline genetic services for personalized treatment and clinical trial eligibility for PCa patients.

RevDate: 2019-06-06

Unger JM, ME Fleury (2019)

Reimbursing Patients for Participation in Cancer Clinical Trials.

JAMA oncology pii:2735331 [Epub ahead of print].

RevDate: 2019-06-10

Nguyen N, Powers KA, Miller WC, et al (2019)

Sexual Partner Types and Incident HIV Infection among Rural South African Adolescent Girls and Young Women Enrolled in HPTN 068: A Latent Class Analysis.

Journal of acquired immune deficiency syndromes (1999) [Epub ahead of print].

BACKGROUND: Sexual partners are the primary source of incident HIV infection among adolescent girls and young women (AGYW) in sub-Saharan Africa. Identifying partner types at greatest risk of HIV transmission could guide the design of tailored HIV prevention interventions.

METHODS: We conducted a secondary analysis of data from AGYW (ages 13-23) enrolled in a randomized controlled trial of cash transfers for HIV prevention in South Africa. Annually, AGYW reported behavioral and demographic characteristics of their three most recent sexual partners, categorized each partner using pre-specified labels, and received HIV testing. We used latent class analysis (LCA) to identify partner types from reported characteristics, and generalized estimating equations to estimate the relationship between both LCA-identified and pre-specified partner types and incident HIV infection.

RESULTS: Across 2140 AGYW-visits, 1034 AGYW made 2968 partner-reports, and 63 AGYW acquired HIV infection. We identified five LCA partner types, which we named monogamous HIV-negative peer partner; one-time protected in-school peer partner; out-of-school older partner; anonymous out-of-school peer partner; and cohabiting with children in-school peer partner. Compared to AGYW with only monogamous HIV-negative peer partners, AGYW with out-of-school older partners had 2.56 times the annual risk of HIV infection (95% CI: 1.23, 5.33), while AGYW with anonymous out-of-school peer partners had 1.72 times the risk (95% CI: 0.82, 3.59). Pre-specified partner types were not associated with incident HIV.

CONCLUSION: By identifying meaningful combinations of partner characteristics and predicting the corresponding risk of HIV acquisition among AGYW, LCA-identified partner types may provide new insights for the design of tailored HIV prevention interventions.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

RevDate: 2019-06-06

Victoria D O, Rivet AK, James P H, et al (2019)

Low Disclosure of PrEP nonadherence and HIV risk behaviors associated with poor HIV PrEP adherence in the HPTN 067/ADAPT Study.

Journal of acquired immune deficiency syndromes (1999) [Epub ahead of print].

OBJECTIVE: We evaluated the relationship between two types of social relationships (i.e., 1) external support for use of HIV pre-exposure prophylaxis [PrEP] and related study supplies 2) participants' disclosure of PrEP use and condom use and HIV PrEP adherence among daily-dosing regimen participants in HPTN 067, an open-label trial of oral tenofovir (TFV) disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg.

METHODS: Using HPTN-067 survey data, we developed scales examining 1) Low Perceived External Support for PrEP: low perceived support by others for PrEP use or perceived negative reactions to the pill case (scoring ranges from 0 to 2) and 2) Participant-Staff Disclosure Challenges Scale which identifies challenges to sharing non-use of PrEP or condoms to study staff (scoring ranges from 0 to 4); these scales are the primary independent variables. Adherence, the dependent variable, was determined using log-transformed plasma TFV concentrations. GEE linear regression was used to assess the association between both scales and adherence.

RESULTS: Participants (n=161) included HIV-uninfected women in South Africa, and men who have sex with men and transgender women, in Thailand and the U.S. In multivariable analyses, higher scores in the Participant-Staff Disclosure Challenges Scale were significantly associated with lower PrEP adherence (exp(β) = 0.62, 95% CI (0.46- 0.84); p=0.002) as were increased days since the last PrEP dose (exp(β) = 0.73, 95% CI (0.65- 0.83); p≤0.001).

CONCLUSIONS: Given the association with adherence, study staff-participant interactions and participants' disclosure of PrEP challenges may be worthwhile intervention targets for improving PrEP adherence in confirmatory studies.

RevDate: 2019-06-06

Khalighi PR, Martens KL, White AA, et al (2019)

Utilization patterns and clinical outcomes of rasburicase administration according to tumor risk stratification.

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners [Epub ahead of print].

PURPOSE: Current guidelines for tumor lysis syndrome management recommend rasburicase for high-risk patients. Adherence to guidelines has not been well studied, and the correlation between uric acid reduction and clinically relevant outcomes, such as acute kidney injury, remains unclear. Our study aims to describe rasburicase utilization patterns and outcomes in cancer patients with varying risks for tumor lysis syndrome.

METHODS: In this retrospective cohort study, we included cancer inpatients who received rasburicase for tumor lysis syndrome management at two affiliated academic hospitals from 2009 to 2015. Patients were classified by tumor lysis syndrome risk categories prior to drug administration. Primary outcomes included acute kidney injury incidence and renal recovery. Secondary outcomes included uric acid nadir, mortality, and hospital length-of-stay.

RESULTS: Among 164 patients, 42 (26%) had high-, 63 (38%) had intermediate-, and 59 (36%) had low-risk for tumor lysis syndrome. A total of 94 patients (57%) had existing renal dysfunction prior to rasburicase use. This occurred more frequently in low- (68%) compared to intermediate- (57%) and high- (43%) risk patients (p = 0.044). A greater proportion of patients in the high-risk group (78%) had renal recovery when compared to the intermediate- (61%) or low- (45%) risk groups (p = 0.056). Despite a similar length of stay, the high-risk group had a significantly lower 30-day mortality (10%) when compared to intermediate- (25%) or low- (32%) risk groups (p = 0.029).

CONCLUSIONS: Our results suggest that rasburicase may be frequently prescribed to treat hyperuricemia unrelated to tumor lysis syndrome in cancer patients. Improved education and adherence to guidelines may improve clinical and economic outcomes associated with rasburicase administration.

RevDate: 2019-06-06

Maloney E, DuFort CC, Provenzano PP, et al (2019)

Non-Invasive Monitoring of Stromal Biophysics with Targeted Depletion of Hyaluronan in Pancreatic Ductal Adenocarcinoma.

Cancers, 11(6): pii:cancers11060772.

Pancreatic ductal adenocarcinoma (PDA) is characterized by a pronounced fibroinflammatory stromal reaction consisting of inordinate levels of hyaluronan (HA), collagen, immune cells, and activated fibroblasts that work in concert to generate a robust physical barrier to the perfusion and diffusion of small molecule therapeutics. The targeted depletion of hyaluronan with a PEGylated recombinant human hyaluronidase (PEGPH20) lowers interstitial gel-fluid pressures and re-expands collapsed intratumoral vasculature, improving the delivery of concurrently administered agents. Here we report a non-invasive means of assessing biophysical responses to stromal intervention with quantitative multiparametric magnetic resonance imaging (MRI) at 14 Tesla (T). We found that spin-spin relaxation time T2 values and glycosaminoglycan chemical exchange saturation transfer (GagCEST) values decreased at 24 h, reflecting depletion of intratumoral HA content, and that these parameters recovered at 7 days concurrent with replenishment of intratumoral HA. This was also reflected in an increase in low-b apparent diffusion coefficient (ADC) at 24 h, consistent with improved tumor perfusion that again normalized at 7 days after treatment. Phantom imaging suggests that the GagCEST signal is driven by changes in HA versus other glycosaminoglycans. Thus, multiparametric magnetic resonance imaging (MRI) can be used as a non-invasive tool to assess therapeutic responses to targeted stromal therapy in PDA and likely other stroma-rich solid tumors that have high levels of hyaluronan and collagen.

RevDate: 2019-06-05

Moore JR, Ahmed H, McGuire D, et al (2019)

Dependence of CD8 T Cell Response upon Antigen Load During Primary Infection : Analysis of Data from Yellow Fever Vaccination.

Bulletin of mathematical biology pii:10.1007/s11538-019-00618-9 [Epub ahead of print].

A major question in immunology is what role antigen load plays in determining the size of the CD8 immune response. Is the amount of antigen important during recruitment, proliferation, and/or memory formation? Animal studies have shown that antigen is only strictly required early during activation of T cells, but the importance of antigen at later timepoints is unclear. Using data from 24 volunteers infected with the yellow fever vaccine virus (YFV), we analyzed the dependence of T cell proliferation upon viral load. We found that volunteers with high viral load initially have greater T cell responses, but by 28 days post-vaccination those with lower viral load are able to 'catch-up.' Using differential equation modeling we show that this pattern is consistent with viral load only affecting recruitment (i.e., programmed proliferation) as opposed to affecting recruitment and proliferation (i.e., antigen-dependent proliferation). A quantitative understanding of the dependence of T cell dynamics on antigen load will be of use to modelers studying not only vaccination, but also cancer immunology and autoimmune disorders.

RevDate: 2019-06-10

Shepshelovich D, Xu W, Lu L, et al (2019)

Body mass index (BMI), BMI change, and overall survival in small cell and non-small cell lung cancer patients: a pooled analysis of the International Lung Cancer Consortium.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(19)30416-2 [Epub ahead of print].

BACKGROUND: The relationships between morbid obesity, changes in body mass index (BMI) prior to cancer diagnosis, and lung cancer outcomes by histology (small-cell lung cancer (SCLC) and non-SCLC (NSCLC)) have not been well studied.

METHODS: Individual level data analysis was performed on 25,430 NSCLC and 2,787 SCLC patients from sixteen studies of the International Lung Cancer Consortium (ILCCO) evaluating the association between various BMI variables and lung cancer overall survival (OS), reported as adjusted hazard ratios (aHR) from Cox proportional hazard models and adjusted penalized smoothing spline plots.

RESULTS: OS of NSCLC had putative U-shaped hazard ratio relationships with BMI, based on spline plots: being underweight (BMI<18.5-kg/m2; aHR=1.56; 95%CI:1.43-1.70) or morbidly overweight (BMI>40; aHR=1.09; 95%CI:0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, while being overweight (25≤BMI<30; aHR=0.89; 95%CI:0.85-0.95) or obese (30≤BMI≤40; aHR=0.86; 95%CI:0.82-0.91)) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the time-period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR=1.24; 95%CI:1.2-1.3) and SCLC patients (aHR=1.26 (95%CI:1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinico-demographic subsets.

CONCLUSIONS: Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.

RevDate: 2019-06-04

Pergam SA, Limaye AP, AST Infectious Diseases Community of Practice (2019)

Varicella Zoster Virus (VZV) in Solid Organ Transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

Clinical transplantation [Epub ahead of print].

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the diagnosis, prevention and management of varicella zoster virus (VZV) in the pre- and post-transplant period. Primary varicella is an uncommon complication post-solid-organ transplant (SOT), except among pediatric transplant patients and those seronegative for VZV. As the majority of SOT recipients are seropositive for VZV, herpes zoster (HZ) occurs frequently following SOT, particularly among recipients who are older (≥65 years of age) and those receiving more intensive immunosuppression. Transplant providers should aware of the increased risk for HZ-related complications such as dissemination, organ-specific involvement and post-herpetic neuralgia. Treatment for localized zoster is primarily given as oral regimens, but those with more complicated presentations or those at risk for dissemination should be treated initially with IV therapy. Available antiviral prophylaxis regimens and vaccination strategies for varicella and HZ among these immunosuppressed patients remain a mainstay for prevention in the pre and post-transplant periods. Finally, we discuss important approaches to addressing post-exposure prophylaxis and infection control practices for those SOT patients with documented VZV infections. This article is protected by copyright. All rights reserved.

RevDate: 2019-06-04

Tordoff D, Andrasik M, A Hajat (2019)

Misclassification of Sex Assigned at Birth in the Behavioral Risk Factor Surveillance System and Transgender Reproductive Health: A Quantitative Bias Analysis.

Epidemiology (Cambridge, Mass.) [Epub ahead of print].

BACKGROUND: National surveys based on probability sampling methods, such as the Behavior Risk Factor and Surveillance System (BRFSS), are crucial tools for unbiased estimates of health disparities. In 2014, the BRFSS began offering a module to capture transgender and gender nonconforming identity. Although the BRFSS provides much needed data on the this population, these respondents are vulnerable to misclassification of sex assigned at birth.

METHODS: We applied quantitative bias analysis to explore the magnitude and direction of the systematic bias present as a result of this misclassification. We use multivariate Poisson regression with robust standard errors to estimate the association between gender and four sex-specific outcomes: prostate-specific antigen (PSA) testing, Pap testing, hysterectomy, and pregnancy. We applied single and multiple imputation methods, and probabilistic adjustments to explore bias present in these estimates.

RESULTS: Combined BRFSS data from 2014, 2015, and 2016 included 1,078 transgender women, 701 transgender men, and 450 gender nonconforming individuals. Sex assigned at birth was misclassified among 29.6% of transgender women and 30.2% of transgender men. Transgender and gender nonconforming individuals excluded due to sex-based skip patterns are demographically distinct from those who were asked reproductive health questions, suggesting that there is noteworthy selection bias present in the data. Estimates for gender nonconforming respondents are vulnerable to small degrees of bias, while estimates for cancer screenings among transgender women and men are more robust to moderate degrees of bias.

CONCLUSION: Our results demonstrate that the BRFSS methodology introduces substantial uncertainty into reproductive health measures, which could bias population-based estimates. These findings emphasize the importance of implementing validated sex and gender questions in health surveillance surveys.

RevDate: 2019-06-04

Hart SFM, Pineda JMB, Chen CC, et al (2019)

Disentangling strictly self-serving mutations from win-win mutations in a mutualistic microbial community.

eLife, 8: pii:44812.

Mutualisms can be promoted by pleiotropic win-win mutations which directly benefit self (self-serving) and partner (partner-serving). Intuitively, partner-serving phenotype could be quantified as an individual's benefit supply rate to partners. Here, we demonstrate the inadequacy of this thinking, and propose an alternative. Specifically, we evolved well-mixed mutualistic communities where two engineered yeast strains exchanged essential metabolites lysine and hypoxanthine. Among cells that consumed lysine and released hypoxanthine, a chromosome duplication mutation seemed win-win: it improved cell's affinity for lysine (self-serving), and increased hypoxanthine release rate per cell (partner-serving). However, increased release rate was due to increased cell size accompanied by increased lysine utilization per birth. Consequently, total hypoxanthine release rate per lysine utilization (defined as 'exchange ratio') remained unchanged. Indeed, this mutation did not increase the steady state growth rate of partner, and is thus solely self-serving during long-term growth. By extension, reduced benefit production rate by an individual may not imply cheating.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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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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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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