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Bibliography on: Publications by FHCRC Researchers

The Electronic Scholarly Publishing Project: Providing world-wide, free access to classic scientific papers and other scholarly materials, since 1993.


ESP: PubMed Auto Bibliography 16 Jan 2019 at 01:36 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: 2019-01-14

Chen H, Huffman JE, Brody JA, et al (2018)

Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies.

American journal of human genetics pii:S0002-9297(18)30465-8 [Epub ahead of print].

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.

RevDate: 2019-01-14

McKinnon LR, Achilles S, Bradshaw CS, et al (2019)

The evolving facets of bacterial vaginosis: implications for HIV transmission.

AIDS research and human retroviruses [Epub ahead of print].

Bacterial vaginosis (BV) is a common yet poorly understood vaginal condition that has become a major focus of HIV transmission and immunology research. Varied terminologies are used by clinicians and researchers to describe microbial communities that reside in the female reproductive tract, which is driven in part by microbial genetic and metabolic complexity, evolving diagnostic and molecular techniques, and multidisciplinary perspectives of clinicians, epidemiologists, microbiologists, and immunologists who all appreciate the scientific importance of understanding mechanisms that underlie "BV". This Perspectives article aims to clarify the varied terms used to describe the cervicovaginal microbiota and its "non-optimal" state, under the overarching term of BV. The ultimate goal is to move toward language standardization in future literature that facilitates a better understanding of the impact of BV on female reproductive tract immunology and risk of sexually transmitted infections including HIV.

RevDate: 2019-01-12

Hoang VT, Verma D, Godavarthy PS, et al (2019)

The transcriptional regulator FUBP1 influences disease outcome in murine and human myeloid leukemia.

Leukemia pii:10.1038/s41375-018-0358-8 [Epub ahead of print].

The transcriptional regulator far upstream element binding protein 1 (FUBP1) acts as an oncoprotein in solid tumor entities and plays a role in the maintenance of hematopoietic stem cells. However, its potential function in leukemia is unknown. In murine models of chronic (CML) and acute myeloid leukemia (AML) induced by BCR-ABL1 and MLL-AF9, respectively, knockdown of Fubp1 resulted in prolonged survival, decreased numbers of CML progenitor cells, decreased cell cycle activity and increased apoptosis. Knockdown of FUBP1 in CML and AML cell lines recapitulated these findings and revealed enhanced DNA damage compared to leukemia cells expressing wild type FUBP1 levels. FUBP1 was more highly expressed in human CML compared to normal bone marrow cells and its expression correlated with disease progression. In AML, higher FUBP1 expression in patient leukemia cells was observed with a trend toward correlation with shorter overall survival. Treatment of mice with AML with irinotecan, known to inhibit topoisomerase I and FUBP1, significantly prolonged survival alone or in combination with cytarabine. In summary, our data suggest that FUBP1 acts as cell cycle regulator and apoptosis inhibitor in leukemia. We demonstrated that FUBP1 might play a role in DNA repair, and its inhibition may improve outcome in leukemia patients.

RevDate: 2019-01-11

Monaco F, Scott BL, Chauncey TR, et al (2019)

Total body irradiation dose escalation decreases risk of progression and graft rejection after hematopoietic cell transplantation for myelodysplastic syndromes or myeloproliferative neoplasms.

Haematologica pii:haematol.2018.199398 [Epub ahead of print].

A nonmyeloablative regimen of fludarabine and 200 cGy total body irradiation combined with post-grafting immunosuppression with mycophenolate mofetil and a calcineurin inhibitor facilitates allogeneic hematopoietic cell transplantation from HLA-matched related or unrelated donors in older patients and/or those with comorbidities. However, outcomes of prior studies have been disappointing in patients with myelodysplastic syndromes or myeloproliferative neoplasms due to high incidences of progression or graft failure (together termed hematopoietic cell transplantation-failure). We hypothesized that escalating the total body irradiation dose may improve the outcomes and subsequently performed a phase II total body irradiation dose-escalation trial. Patients with median age 66 years were enrolled in two arms to receive nonmyeloablative conditioning followed by hematopoietic cell transplantation with total body irradiation dose escalation for excessive hematopoietic cell transplantation-failure: Arm A: myeloproliferative neoplasm/myelodysplastic syndrome low-risk (n=36) and Arm B: myelodysplastic syndrome high-risk/chronic myelomonocytic leukemia (n=41). Total body irradiation dose levels were: Level-1 (300 cGy), Level-2 (400 cGy), or Level-3 (450 cGy). Patients received intravenous fludarabine 30 mg/m2 x3 days. Total body irradiation was administered on day 0 followed by infusion of peripheral blood stem cells from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with mycophenolate mofetil and cyclosporine was administered. The primary endpoint was day 200 hematopoietic cell transplant failure, with the objective of reducing the incidence to <20%. Primary endpoint was reached on Arm A at dose Level-1 (300 cGy total body irradiation) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 11%, and on Arm B at dose Level-3 (450 cGy) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 9%. Increasing the total body irradiation dose leads to a higher success rate with nonmyeloablative conditioning by reducing relapse and rejection. Further studies are necessary to decrease nonrelapse mortality, especially among patients with high-risk disease. Trial registered under No. NCT00397813 .

RevDate: 2019-01-10

Greenlee H, Z Shi (2019)

Implementing Integrative Oncology: Hopes and Challenges.

Journal of oncology practice, 15(1):17-18.

RevDate: 2019-01-10

Lyman GH (2019)

Febrile Neutropenia: An Ounce of Prevention or a Pound of Cure.

Journal of oncology practice, 15(1):27-29.

RevDate: 2019-01-10

Stoddard BL, KR Fox (2019)

Editorial: Preprints, citations and Nucleic Acids Research.

Nucleic acids research, 47(1):1-2.

RevDate: 2019-01-10

Reeves KW, Santana MD, Manson JE, et al (2019)

Urinary Phthalate Biomarker Concentrations and Postmenopausal Breast Cancer Risk.

Journal of the National Cancer Institute pii:5284913 [Epub ahead of print].

Background: Growing laboratory and animal model evidence supports the potentially carcinogenic effects of some phthalates, chemicals used as plasticizers in a wide variety of consumer products, including cosmetics, medications, and vinyl flooring. However, prospective data on whether phthalates are associated with human breast cancer risk are lacking.

Methods: We conducted a nested case-control study within the Women's Health Initiative (WHI) prospective cohort (N = 419 invasive cases and 838 controls). Controls were matched 2:1 to cases on age, enrollment date, follow-up time, and WHI study group. We quantified thirteen phthalate metabolites and creatinine in two or three urine samples per participant over one to three years. Multivariable conditional logistic regression analysis was used to estimate odds ratios and 95% confidence intervals (OR, 95% CI) for breast cancer risk associated with each phthalate biomarker over up to 19 years of follow-up.

Results: Overall, we did not observe statistically significant positive associations between phthalate biomarkers and breast cancer risk in multivariable analyses (e.g. 4th vs 1st quartile of diethylhexyl phthalate OR 1.03, 95% CI 0.91 - 1.17). Results were generally similar in analyses restricted to disease subtypes, to non-users of postmenopausal hormone therapy, stratified by body mass index, or to cases diagnosed within three, five, or ten years.

Conclusions: In the first prospective analysis of phthalates and postmenopausal breast cancer, phthalate biomarker concentrations did not result in an increased risk of developing invasive breast cancer.

RevDate: 2019-01-10

Unger JM, Hershman DL, Fleury ME, et al (2019)

Association of Patient Comorbid Conditions With Cancer Clinical Trial Participation.

JAMA oncology pii:2720475 [Epub ahead of print].

Importance: The American Society of Clinical Oncology (ASCO), Friends of Cancer Research, and the US Food and Drug Administration recently recommended modernizing criteria related to comorbidities routinely used to exclude patients from cancer clinical trials. The goal was to design clinical trial eligibility such that trial results better reflect real-world cancer patient populations, to improve clinical trial participation, and to increase patient access to new treatments in trials. Yet despite the assumed influence of comorbidities on trial participation, the relationship between patients' comorbidity profile at diagnosis and trial participation has not been explicitly examined using patient-level data.

Objectives: To investigate the association between comorbidities, clinical trial decision-making, and clinical trial participation; and to estimate the potential impact of reducing comorbidity exclusion criteria on trial participation, to provide a benchmark for changing criteria.

A national survey was embedded within a web-based cancer treatment-decision tool accessible on multiple cancer-oriented websites. Participants must have received a diagnosis of breast, lung, colorectal, or prostate cancer. In total, 5499 surveyed patients who made a treatment decision within the past 3 months were analyzed using logistic regression analysis and simulations.

Exposures: Cancer diagnosis and 1 or more of 18 comorbidities.

Main Outcomes and Measures: Patient discussion of a clinical trial with their physician (yes vs no); if a trial was discussed, the offer of trial participation (yes vs no); and, if trial participation was offered, trial participation (yes vs no).

Results: Of the 5499 patients who participated in the survey, 3420 (62.6%) were women and 2079 (37.8%) were men (mean [SD] age, 56.63 [10.05] years). Most patients (65.6%; n = 3610) had 1 or more comorbidities. The most common comorbid condition was hypertension (35.0%; n = 1924). Compared with the absence of comorbidities, the presence of 1 or more comorbidities was associated with a decreased risk of trial discussions (44.1% vs 37.2%; OR, 0.86; 95% CI, 0.75-0.97; P = .02), trial offers (21.7% vs 15.7%; OR, 0.82; 95% CI, 0.70-0.96; P = .02), and trial participation (11.3% vs 7.8%; OR, 0.76; 95% CI, 0.61-0.94; P = .01). The removal of the ASCO-recommended comorbidity restrictions could generate up to 6317 additional patient trial registrations every year.

Conclusions and Relevance: Independent of sociodemographic variables, the presence of comorbidities is adversely associated with trial discussions, trial offers, and trial participation itself. Updating trial eligibility criteria could provide an opportunity for several thousand more patients with well-managed comorbidities to participate in clinical trials each year.

RevDate: 2019-01-10

Fries CA, Lawson SD, Wang LC, et al (2019)

Composite Graft Pretreatment With Hydrogen Sulfide Delays the Onset of Acute Rejection.

Annals of plastic surgery [Epub ahead of print].

INTRODUCTION: Vascularized composite allotransplantation can reconstruct devastating tissue loss by replacing like-with-like tissues, most commonly in the form of hand or face transplantation. Unresolved technical and ethical challenges have meant that such transplants remain experimental treatments. The most significant barrier to expansion of this field is the requirement for systemic immunosuppression, its toxicity and effect on longevity.Hydrogen sulfide (H2S) has been shown experimentally to ameliorate the ischemia reperfusion injury associated with composite tissue autotransplantation, which has been linked to acute rejection in solid organ transplantation. In this protocol, a large-animal model was used to evaluate the effect of H2S on acute rejection after composite tissue allotransplantation.

MATERIALS AND METHODS: A musculocutaneous flap model in SLA-mismatched swine was used to evaluate acute rejection of allotransplants in 2 groups: control animals (n = 8) and a treatment group in which the allografts were pretreated with hydrogen sulfide (n = 8). Neither group was treated with systemic immunosuppression. Acute rejection was graded clinically and histopathologically by an independent, blinded pathologist. Data were analyzed by t tests with correction for multiple comparisons by the Holm-Šídák method.

RESULTS: Clinically, H2S-treated tissue composites showed a delay in the onset of rejection that was statistically significant from postoperative day 6. Histopathologically, this difference between groups was also apparent, although evidence of a difference in groups disappeared beyond day 10.

CONCLUSIONS: Targeted hydrogen sulfide treatment of vascularized composite allografts immediately before transplantation can delay acute rejection. This may, in turn, reduce or obviate the requirement for systemic immunosuppression.

RevDate: 2019-01-10

Estey E (2019)

'Looking beyond survival to define therapeutic value in acute myeloid leukemia'.

Leukemia & lymphoma [Epub ahead of print].

RevDate: 2019-01-10

Lange JM, Gulati R, Leonardson AS, et al (2018)


The annals of applied statistics, 12(3):1773-1795.

Outcomes after cancer diagnosis and treatment are often observed at discrete times via doctor-patient encounters or specialized diagnostic examinations. Despite their ubiquity as endpoints in cancer studies, such outcomes pose challenges for analysis. In particular, comparisons between studies or patient populations with different surveillance schema may be confounded by differences in visit frequencies. We present a statistical framework based on multistate and hidden Markov models that represents events on a continuous time scale given data with discrete observation times. To demonstrate this framework, we consider the problem of comparing risks of prostate cancer progression across multiple active surveillance cohorts with different surveillance frequencies. We show that the different surveillance schedules partially explain observed differences in the progression risks between cohorts. Our application permits the conclusion that differences in underlying cancer progression risks across cohorts persist after accounting for different surveillance frequencies.

RevDate: 2019-01-10

Silva DA, Yu S, Ulge UY, et al (2019)

De novo design of potent and selective mimics of IL-2 and IL-15.

Nature, 565(7738):186-191.

We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor βγc heterodimer (IL-2Rβγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rβγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rβγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.

RevDate: 2019-01-09

Burnett-Hartman AN, Hua X, Rue TC, et al (2019)

Risk interval analysis of emergency room visits following colonoscopy in patients with inflammatory bowel disease.

PloS one, 14(1):e0210262 pii:PONE-D-18-11080.

BACKGROUND AND AIMS: Prior studies suggest that colonoscopy may exacerbate inflammatory bowel disease (IBD) symptoms. Thus, our study aimed to determine risk of emergency room (ER) visits associated with colonoscopy among IBD patients and evaluate potential modifiers of this risk.

METHODS: The study population included IBD patients in the Multi-Payer Claims Database who were >20 years old and had a colonoscopy from 2007-2010. We used a self-controlled risk interval design and mixed-effects Poisson regression models to calculate risk ratios (RR) and 95% confidence intervals (CI) comparing the incidence of ER visits in the 1-4 weeks following colonoscopy (risk interval) to the incidence of ER visits in the 7-10 weeks after colonoscopy (control interval). We also conducted stratified analyses by patient characteristics, bowel preparation type, and medication.

RESULTS: There were 212,205 IBD patients with at least 1 colonoscopy from 2007-2010, and 3,699 had an ER visit during the risk and/or control interval. The risk of an ER visit was higher in the 4-week risk interval following colonoscopy compared to the control interval (RR = 1.24; 95% CI: 1.17-1.32). The effect was strongest in those <41 years old (RR = 1.60; 95% CI: 1.21-2.11), in women (RR = 1.32; 95% CI: 1.21-1.44), and in those with sodium phosphate bowel preparation (RR = 2.09; 95% CI: 1.02-4.29). Patients using immunomodulators had no increased risk of ER visits (RR = 0.75; 95% CI: 0.35-1.59).

CONCLUSIONS: Our results suggest that there is an increased risk of ER visits following colonoscopy among IBD patients, but that immunomodulators and mild bowel preparation agents may mitigate this risk.

RevDate: 2019-01-09

Peebles K, Velloza J, Balkus JE, et al (2019)

High Global Burden and Costs of Bacterial Vaginosis: A Systematic Review and Meta-Analysis.

Sexually transmitted diseases [Epub ahead of print].

BACKGROUND: Bacterial vaginosis (BV) is the most common vaginal infection among women of reproductive age and is associated with important adverse health outcomes. Estimates of the burden of BV and associated costs are needed to inform research priorities.

METHODS: We conducted a systematic review and meta-analysis of global BV prevalence among reproductive-aged women in the general population. We searched PubMed and Embase, and used random effects models to estimate BV prevalence by global regions. We estimated the direct medical costs of treating symptomatic BV. Assuming a causal relationship, we also estimated the potential costs of BV-associated preterm births and HIV cases in the United States.

RESULTS: General population prevalence of BV is high globally, ranging from 23% to 29% across regions (Europe and Central Asia: 23%; East Asia and Pacific: 24%; Latin America and Caribbean: 24%; Middle East and North Africa: 25%; sub-Saharan Africa: 25%; North America 27%; South Asia: 29%). Within North America, Black and Hispanic women have significantly higher (33% and 31%, respectively) prevalence compared to other racial groups (White: 23%; Asian: 11%) (p<0.01).The estimated annual global economic burden of treating symptomatic BV is $4.8 (95% CI: $3.7, $6.1) billion. The US economic burden of BV is nearly tripled when including costs of BV-associated preterm births and HIV cases.

CONCLUSIONS: BV prevalence is high globally, with a concomitant high economic burden and marked racial disparities in prevalence. Research to determine the etiology of BV and corresponding prevention and sustainable treatment strategies are urgently needed to reduce the burden of BV among women. Additionally, the exceptionally high cost of BV-associated sequelae highlights the need for research to understand potential causal linkages between BV and adverse health outcomes.

RevDate: 2019-01-09

Bennett B, Workman T, Smith MN, et al (2019)

Longitudinal, Seasonal, and Occupational Trends of Multiple Pesticides in House Dust.

Environmental health perspectives, 127(1):17003.

BACKGROUND: Children are especially vulnerable to pesticide exposure and can suffer lasting health effects. Because children of farmworkers are exposed to a variety of pesticides throughout development, it is important to explore temporal patterns of coexposures.

OBJECTIVES: The objectives of this study were to characterize the pesticide co-exposures, determine how they change over time, and assess differences between farmworker and nonfarmworker households.

METHODS: Dust collected from 40 farmworker and 35 nonfarmworker households in the Yakima Valley of the State of Washington in 2005 and then again in 2011 was analyzed for 99 pesticides. Eighty-seven pesticides representing over 28 classes were detected. Pesticides were grouped into classes using U.S. EPA pesticide chemical classifications, and trends in concentrations were analyzed at the class level.

RESULTS: Levels of organophosphates, pyridazinones, and phenols significantly decreased between 2005 and 2011 in both farmworker and nonfarmworker households. Levels of anilides, 2,6-dinitroanilines, chlorophenols, triclosan, and guanidines significantly increased in both farmworker and nonfarmworker households in 2011 vs. 2005. Among farmworkers alone, there were significantly lower levels of N-methyl carbamates and neonicotinoids in 2011.

CONCLUSIONS: We observed significant reductions in the concentrations of many pesticides over time in both farmworker and nonfarmworker households. Although nonfarmworker households generally had lower concentrations of pesticides, it is important to note that in comparison with NHANES participants, nonfarmworkers and their families still had significantly higher concentrations of urinary pesticide metabolites. This finding highlights the importance of detailed longitudinal exposure monitoring to capture changes in agricultural and residential pesticide use over time. This foundation provides an avenue to track longitudinal pesticide exposures in an intervention or regulatory context.

RevDate: 2019-01-09

Westling T, Juraska M, Seaton KE, et al (2019)

Methods for comparing durability of immune responses between vaccine regimens in early-phase trials.

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

The ability to produce a long-lasting, or durable, immune response is a crucial characteristic of many highly effective vaccines. A goal of early-phase vaccine trials is often to compare the immune response durability of multiple tested vaccine regimens. One parameter for measuring immune response durability is the area under the mean post-peak log immune response profile. In this paper, we compare immune response durability across vaccine regimens within and between two phase I trials of DNA-primed HIV vaccine regimens, HVTN 094 and HVTN 096. We compare four estimators of this durability parameter and the resulting statistical inferences for comparing vaccine regimens. Two of these estimators use the trapezoid rule as an empirical approximation of the area under the marginal log response curve, and the other two estimators are based on linear and nonlinear models for the marginal mean log response. We conduct a simulation study to compare the four estimators, provide guidance on estimator selection, and use the nonlinear marginal mean model to analyze immunogenicity data from the two HIV vaccine trials.

RevDate: 2019-01-09

Cassady K, Martin PJ, D Zeng (2018)

Regulation of GVHD and GVL Activity via PD-L1 Interaction With PD-1 and CD80.

Frontiers in immunology, 9:3061.

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies (i.e. leukemia and lymphoma), because graft-versus-leukemia (GVL) activity mediated by alloreactive T cells can eliminate residual malignant cells and prevent relapse. However, the same alloreactive T cells also mediate a severe side effect, graft-versus-host disease (GVHD), and prevention of GVHD while preserving GVL activity remains an elusive goal. The immune checkpoint molecule PD-L1 and its interaction with PD-1 receptor in regulating cancer immunity is under intensive and wide-spread study, but knowledge about this interaction in regulating GVHD and GVL activity is very limited. In this review, we summarize the literature exploring how PD-L1 interaction with its receptors PD-1 and CD80 regulate GVHD and GVL activities, how PD-L1 signaling regulates T cell metabolic profiles, and how a differential role of PD-L1 interaction with PD-1, CD80 or both may provide a novel avenue to prevent GVHD while preserving strong GVL effects.

RevDate: 2019-01-09

Schumacher FR, Olama AAA, Berndt SI, et al (2019)

Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.

RevDate: 2019-01-08

Yang J, Jing L, James EA, et al (2018)

A Novel Approach of Identifying Immunodominant Self and Viral Antigen Cross-Reactive T Cells and Defining the Epitopes They Recognize.

Frontiers in immunology, 9:2811.

Infection and vaccination can lead to activation of autoreactive T cells, including the activation of cross-reactive T cells. However, detecting these cross-reactive T cells and identifying the non-self and self-antigen epitopes is difficult. The current study demonstrates the utility of a novel approach that effectively accomplishes both. We utilized surface expression of CD38 on newly activated CD4 memory T cells as a strategy to identify type 1 diabetes associated autoreactive T cells activated by influenza vaccination in healthy subjects. We identified an influenza A matrix protein (MP) specific CD4+ T cell clone that cross-recognizes an immunodominant epitope from Glutamic Acid Decarboxylase 65 (GAD65) protein. The sequences of the MP and GAD65 peptides are rather distinct, with only 2 identical amino acids within the HLA-DR binding region. This result suggests that activation of autoreactive T cells by microbial infection under certain physiological conditions can occur amongst peptides with minimum amino acid sequence homology. This novel strategy also provides a new research pathway in which to examine activation of autoreactive CD4+ T cells after vaccination or natural infection.

RevDate: 2019-01-08

Skapek SX, Ferrari A, Gupta AA, et al (2019)


Nature reviews. Disease primers, 5(1):1 pii:10.1038/s41572-018-0051-2.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and represents a high-grade neoplasm of skeletal myoblast-like cells. Decades of clinical and basic research have gradually improved our understanding of the pathophysiology of RMS and helped to optimize clinical care. The two major subtypes of RMS, originally characterized on the basis of light microscopic features, are driven by fundamentally different molecular mechanisms and pose distinct clinical challenges. Curative therapy depends on control of the primary tumour, which can arise at many distinct anatomical sites, as well as controlling disseminated disease that is known or assumed to be present in every case. Sophisticated risk stratification for children with RMS incorporates various clinical, pathological and molecular features, and that information is used to guide the application of multifaceted therapy. Such therapy has historically included cytotoxic chemotherapy as well as surgery, ionizing radiation or both. This Primer describes our current understanding of RMS epidemiology, disease susceptibility factors, disease mechanisms and elements of clinical care, including diagnostics, risk-based care of newly diagnosed and relapsed disease and the prevention and management of late effects in survivors. We also outline potential opportunities to further translate new biological insights into improved clinical outcomes.

RevDate: 2019-01-08

Erzurumluoglu AM, Liu M, Jackson VE, et al (2019)

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

Molecular psychiatry pii:10.1038/s41380-018-0313-0 [Epub ahead of print].

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

RevDate: 2019-01-08

Haab BB, Staal B, Barnett D, et al (2019)

The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy over CA19-9 in Pancreatic Cancer Diagnosis.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-18-3310 [Epub ahead of print].

PURPOSE: The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic ductal adenocarcinoma (PDAC), but not enough to be reliable for the detection or diagnosis of the disease. We hypothesized that a glycan called sTRA is a biomarker for PDAC that improves upon CA19-9.

EXPERIMENTAL DESIGN: We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed candidate biomarkers from sTRA and CA19-9 in a training set of 147 plasma samples and used the panels to make case/control calls, based on predetermined thresholds, in a 50-sample validation set and a blinded, 147-sample test set.

RESULTS: The sTRA glycan was produced and secreted by pancreatic tumors and models that did not produce and secrete CA19-9. Two biomarker panels improved upon CA19-9 in the training set, one optimized for specificity, which included CA19-9 and two versions of the sTRA assay, and another optimized for sensitivity, which included two sTRA assays. Both panels achieved statistical improvement (p < 0.001) over CA19-9 in the validation set, and the specificity-optimized panel achieved statistical improvement (p < 0.001) in the blinded set: 95% specificity and 54% sensitivity (75% accuracy), compared to 97%/30% (65% accuracy). Unblinding produced further improvements and revealed independent, complementary contributions from each marker.

CONCLUSIONS: sTRA is a validated serological biomarker of PDAC that yields improved performance over CA19-9. The new panels may enable surveillance for PDAC among people with elevated risk, or improved differential diagnosis among patients with suspected pancreatic cancer.

RevDate: 2019-01-08

Ramchandren R, Advani RH, Ansell SM, et al (2019)

Brentuximab Vedotin Plus Chemotherapy in North American Patients with Newly Diagnosed Stage III or IV Hodgkin Lymphoma.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-18-2435 [Epub ahead of print].

PURPOSE: To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA).

EXPERIMENTAL DESIGN: ECHELON-1 is a global, open-label, randomized phase 3 study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD+bleomycin) as frontline therapy in subjects with Stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on Days 1 and 15 of each 28‑day cycle for up to 6 cycles.

RESULTS: The NA subgroup consisted of 497 subjects in the A+AVD (n=250) and ABVD (n=247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint (modified progression-free survival [PFS] per independent review) demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR=0.60; P=.012). For PFS, the risk of progression or death was also reduced (HR=0.50; P=.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared to ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD.

CONCLUSIONS: The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for Stage III or IV cHL patients.

RevDate: 2019-01-08

Stone SA, Han CJ, Senn T, et al (2019)

Sex Hormones in Women With Elevated Breast Cancer Risk Undergoing Weight Loss.

Western journal of nursing research [Epub ahead of print].

Sedentary lifestyles and obesity are known risk factors for breast cancer. Elevated estrogen levels correlate with obesity and, independently, with increased breast cancer risk. Lifestyle interventions that reduce obesity may mitigate this risk, potentially via estrogen pathways. In a 6-month lifestyle intervention, overweight/obese women with high breast cancer risk were randomized to control (n = 7) or intervention (n = 6) and analyzed for sex hormone levels. Serum and urine hormones were evaluated by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and sex hormone binding globulin (SHBG) by enzyme-linked immunosorbent assay (ELISA). Serum estrone (E1) and estradiol (E2) were reduced by 12.1% and 50.8%, respectively, at 9 months in the intervention group, which differed from controls (p = .043 and .020). This contrasted with a 73.3% increase in urine E1 at 6 months in the intervention group (p = .035). These results suggest that a lifestyle intervention led to a favorable estrogen profile in relation to breast cancer risk.

RevDate: 2019-01-08

Andersen MR, Sweet E, Hager S, et al (2019)

Effects of Vitamin D Use on Health-Related Quality of Life of Breast Cancer Patients in Early Survivorship.

Integrative cancer therapies [Epub ahead of print].

BACKGROUND: Vitamin D supplements may prevent recurrence, prolong survival, and improve mood for women with breast cancer, although evidence for these effects is preliminary.

METHODS: This report describes vitamin D supplement use by 553 breast cancer patient/survivors (193 who used a naturopathic oncology [NO] provider and 360 who did not) participating in a matched cohort study of breast cancer outcomes.

RESULTS: We found that more than half of breast cancer patients reported using vitamin D supplements. Women who received care from NO providers in early survivorship may be more likely to use vitamin D supplements (P < .05). Approximately 30% of breast cancer patients with blood levels recorded in their medical chart were potentially vitamin D deficient (<30 ng/mL). Vitamin D supplement use at study enrollment was associated with higher levels of self-reported health-related quality of life (HRQOL) at enrollment (P < .05) and predicted better HRQOL at 6-month follow-up (P < .05). Sufficient blood levels of vitamin D recorded between enrollment and follow-up were also associated with better HRQOL at follow-up (P < .05).

CONCLUSIONS: Vitamin D supplementation by breast cancer patients is common both during and after treatment for breast cancer, but deficiency may also be common. NO and conventional providers may be able to promote vitamin D sufficiency through vitamin D supplementation and by encouraging healthy solar exposure. Further studies should be undertaken examining whether vitamin D supplementation and higher blood levels might improve HRQOL among women with breast cancer in early survivorship.

RevDate: 2019-01-08

Molina Y, Ulrich A, Greer AC, et al (2019)

Impact of pre-diagnosis awareness of HIV-related stigma and dispositional coping on linkage to HIV care among newly diagnosed HIV+ Peruvian patients.

AIDS care [Epub ahead of print].

A substantial body of literature has characterized how psychosocial factors, including HIV-related stigma and coping, are associated with HIV testing and HIV care utilization post-diagnosis. Less is known about if certain psychosocial characteristics pre-diagnosis may also predict linkage to care among individuals who receive an HIV-positive diagnosis. We examined if pre-diagnosis awareness/perception about HIV-related stigma and dispositional coping styles predicted linkage to HIV care within three months post-diagnosis with a secondary analysis of 604 patients from a randomized controlled trial (Sabes Study). Awareness/perception about HIV-related stigma, dispositional maladaptive and adaptive coping were measured before patients underwent an HIV test. Linkage to care was measured as receipt of care within three months of receiving the diagnosis. After adjusting for covariates, individuals who reported greater dispositional maladaptive coping pre-diagnosis had lower odds of linking to care, OR = 0.82, 95%CI [0.67, 1.00], p = .05. There was also a non-significant inverse association between dispositional adaptive coping pre-diagnosis and linkage to care. These preliminary data suggest the need for further longitudinal research and highlight the potential utility of pre-diagnosis psychosocial assessment and tailored counseling when providing positive HIV diagnosis results.

RevDate: 2019-01-08

Himbert C, Ose J, Nattenmüller J, et al (2019)

Body Fatness, Adipose Tissue Compartments, and Biomarkers of Inflammation and Angiogenesis in Colorectal Cancer: The ColoCare Study.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 28(1):76-82.

BACKGROUND: Adiposity has been linked to both risk and prognosis of colorectal cancer; however, the impact of different fat areas [visceral (VFA) vs. subcutaneous fat area (SFA)] is unclear. We investigated associations between adiposity and biomarkers of inflammation and angiogenesis among patients with colorectal cancer.

METHODS: Preoperative serum samples and computed tomography scans were obtained from 188 patients diagnosed with primary invasive stage I-IV colorectal cancer enrolled in the ColoCare Study. Adiposity was assessed by area-based quantification of VFA, SFA, and VFA:SFA ratio on spinal levels L3/L4 and L4/L5. Circulating levels of inflammation (CRP, SAA, sICAM-1, and sVCAM-1) and angiogenesis (VEGF-A and VEGF-D) were assessed from patient sera on the Meso Scale Discovery platform. Partial correlations and regression analyses, adjusted for age, sex, and tumor stage, were performed.

RESULTS: VFA was moderately correlated with CRP and SAA (CRP: L3/L4 and L4/L5:r = 0.21, P = 0.01; SAA: L3/L4:r = 0.17, P = 0.04). The correlation between SFA and the measured biomarkers were weak (r ≤ 0.13, not significant). The ratio of VFA:SFA at L3/L4 was moderately correlated with VEGF-A (r = 0.28, P = 0.0008) and SAA (r = 0.24, P = 0.006), and less so with CRP (r = 0.18, P = 0.04) and sICAM-1 (r = 0.18, P = 0.04). Similar correlations were found for the VFA:SFA ratio at L4/L5.

CONCLUSIONS: We observed an association between visceral adiposity and biomarkers of inflammation and angiogenesis in colorectal cancer. In particular, the VFA:SFA ratio was correlated with circulating levels of the proangiogenic biomarker VEGF-A.

IMPACT: Our findings support a direct association of visceral adipose tissue with inflammatory and angiogenic processes, which play fundamental roles in the development and progression of colorectal cancer.

RevDate: 2019-01-07

Hightow-Weidman LB, Magnus M, Beauchamp G, et al (2019)

Incidence and Correlates of STIs among Black Men who have Sex with Men Participating in the HPTN 073 PrEP Study.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5274674 [Epub ahead of print].

Background: HPTN 073 assessed the feasibility, acceptability, and safety of pre-exposure prophylaxis (PrEP) for Black men who have sex with men (BMSM). The purpose of this analysis was to characterize the relationship between PrEP uptake and use, and incident STIs among participants enrolled in HPTN 073.

Methods: 226 HIV-uninfected BMSM were enrolled in three US cities; all participants received client-centered care coordination (C4) and were offered daily oral PrEP. Participants were followed for 12 months with STI testing (rectal and urine NAAT for gonorrhea and chlamydia, RPR for syphilis) conducted at baseline, week 26 and week 52. Logistic regression was used to examine associations between STI incidence and PrEP uptake. Generalized estimating equations (GEE) evaluated associations between age, PrEP acceptance, sexual behaviors, and incident STI cases.

Results: Baseline STI prevalence was 14.2%. Men <25 were more likely to have a baseline STI (25.3% vs. 6.7%; OR 4.39; 95% CI: 1.91, 10.11). Sixty participants (26.5%) acquired ≥1 STI during follow-up; the incidence rate was 34.2 cases per 100 person-years (95% CI: 27.4, 42.9). In adjusted analyses, baseline STI diagnosis (OR 4.23, 95% CI: 1.82, 9.87; p<0.001) and additional C4 time (OR 1.03, 95% CI: 1.00, 1.06; p=0.027) were associated with having an incident STI. STI incidence was not associated with PrEP acceptance or adherence.

Discussion: While we found higher rates of STIs in younger BMSM, the overall rates of STI in this trial were lower than in prior PrEP trials with no increase over time. BMSM with STIs at PrEP initiation may require additional interventions targeting STI acquisition risk.

RevDate: 2019-01-07

Galldiks N, Langen KJ, Albert NL, et al (2019)

PET Imaging in Patients with Brain Metastasis - Report of the RANO/PET Group.

Neuro-oncology pii:5274178 [Epub ahead of print].

Brain metastases (BM) from extracranial cancer are associated with significant morbidity and mortality. Effective local treatment options are stereotactic radiotherapy, including radiosurgery or fractionated external beam radiotherapy, and surgical resection. The use of systemic treatment for intracranial disease control also is improving. BM diagnosis, treatment planning and follow-up is most often based on contrast-enhanced magnetic resonance imaging (MRI). However, anatomic imaging modalities including standard MRI have limitations in accurately characterizing post-therapeutic reactive changes and treatment response. Molecular imaging techniques such as positron emission tomography (PET) characterize specific metabolic and cellular features of metastases, potentially providing clinically relevant information supplementing anatomic MRI. Here, the RANO working group provides recommendations for the use of PET imaging in the clinical management of patients with BM based on evidence from studies validated by histology and/or clinical outcome.

RevDate: 2019-01-07

Spearman P, Tomaras GD, Montefiori DC, et al (2019)

Rapid Boosting of HIV-1 Neutralizing Antibody Responses in Humans Following a Prolonged Immunologic Rest.

The Journal of infectious diseases pii:5280104 [Epub ahead of print].

Background: Durability and breadth of HIV-1-specific immune responses elicited through vaccination are important considerations in the development of an effective HIV-1 vaccine. Responses to HIV-1 envelope subunit protein (Env) immunization in humans are often described as short-lived.

Methods: We identified 16 healthy volunteers who had received priming with an HIV-1 subtype B Env protein vaccine given with MF59 adjuvant 5-17 years previously, and administered three booster immunizations with a heterologous subtype C trimeric gp140 protein vaccine. We enrolled 20 healthy unprimed volunteers and administered the same vaccination regimen.

Results: Binding antibodies and neutralizing antibodies to Tier 1 viral isolates were detected in the majority of previously-primed subjects. Remarkably, a single dose of protein boosted binding and neutralizing antibody titers in 100% of primed subjects following this prolonged immunologic rest period, and CD4+ T cell responses were boosted in 75% of primed individuals.

Conclusions: These results demonstrate that HIV-1 protein immunogens can elicit durable memory T and B cell responses, and that strong Tier 1 virus neutralizing responses can be elicited by a single booster dose of protein following a long immunologic rest period. However, we found no evidence that cross-clade boosting led to a significantly broadened neutralizing antibody response.

RevDate: 2019-01-07

Margolis KL, Buchner DM, LaMonte MJ, et al (2019)

Hypertension Treatment and Control and Risk of Falls in Older Women.

Journal of the American Geriatrics Society [Epub ahead of print].

BACKGROUND/OBJECTIVES: A lower risk of falls is commonly cited as a reason to treat hypertension conservatively in older individuals. We examined the effect of hypertension treatment and control status and measured blood pressure (BP) level on the risk of falls in older women.

DESIGN/SETTING: Prospective cohort study.

PARTICIPANTS: A total of 5971 women (mean age 79 years; 50.4% white, 33.1% black, 16.5% Hispanic/Latina) enrolled in the Women's Health Initiative and Objective Physical Activity and Cardiovascular Health study.

MEASUREMENTS: BP was measured by trained nurses, and hypertension treatment was assessed by medication inventory. Participants mailed in monthly calendars to self-report falls for 1 year.

RESULTS: Overall, 70% of women had hypertension at baseline (53% treated and controlled, 12% treated and uncontrolled, 5% untreated). There were 2582 women (43%) who reported falls in the 1 year of surveillance. Compared with nonhypertensive women, when adjusted for fall risk factors and lower limb physical function, the incidence rate ratio (IRR) for falls was 0.82 (confidence interval [CI] = 0.74-0.92) in women with treated controlled hypertension (p = .0008) and 0.73 (CI = 0.62-0.87) in women with treated uncontrolled hypertension (p = .0004). Neither measured systolic nor diastolic BP was associated with falls in the overall cohort. In women treated with antihypertensive medication, higher diastolic BP was associated with a lower risk of falls in a model adjusted for fall risk factors (IRR = 0.993 per mm Hg; 95% CI = 0.987-1.000; p = .04). The only class of antihypertensive medication associated with an increased risk of falls compared with all other types of antihypertensive drugs was β-blockers.

CONCLUSION: Women in this long-term research study with treated hypertension had a lower risk of falls compared with nonhypertensive women. Diastolic BP (but not systolic BP) is weakly associated with fall risk in women on antihypertensive treatment (<1% decrease in risk per mm Hg increase). J Am Geriatr Soc, 2019.

RevDate: 2019-01-07

Martins F, Sykiotis GP, Maillard M, et al (2019)

New therapeutic perspectives to manage refractory immune checkpoint-related toxicities.

The Lancet. Oncology, 20(1):e54-e64.

Immune checkpoint inhibitors are reshaping the prognosis of many cancer and are progressively becoming the standard of care in the treatment of many tumour types. Immunotherapy is bringing new hope to patients, but also a whole new spectrum of toxicities for healthcare practitioners to manage. Oncologists and specialists involved in the pluridisciplinary management of patients with cancer are increasingly confronted with the therapeutic challenge of treating patients with severe and refractory immune-related adverse events. In this Personal View, we summarise the therapeutic strategies that have been used to manage such toxicities resulting from immune checkpoint inhibitor treatment. On the basis of current knowledge about their pathogenesis, we discuss the use of new biological and non-biological immunosuppressive drugs to treat severe and steroid refractory immune-related adverse events. Depending on the immune infiltrate type that is predominant, we propose a treatment algorithm for personalised management that goes beyond typical corticosteroid use. We propose a so-called shut-off strategy that aims at inhibiting key inflammatory components involved in the pathophysiological processes of immune-related adverse events, and limits potential adverse effects of drug immunosuppression on tumour response. This approach develops on current guidelines and challenges the step-by-step increase approach to drug immunosuppression.

RevDate: 2019-01-07

Kennedy LC, V Gadi (2018)

Dasatinib in breast cancer: Src-ing for response in all the wrong kinases.

Annals of translational medicine, 6(Suppl 1):S60.

RevDate: 2019-01-06

Bajema KL, Bassett IV, Coleman SM, et al (2019)

Subclinical tuberculosis among adults with HIV: clinical features and outcomes in a South African cohort.

BMC infectious diseases, 19(1):14 pii:10.1186/s12879-018-3614-7.

BACKGROUND: Subclinical tuberculosis is an asymptomatic disease phase with important relevance to persons living with HIV. We describe the prevalence, clinical characteristics, and risk of mortality for HIV-infected adults with subclinical tuberculosis.

METHODS: Untreated adults with HIV presenting for outpatient care in Durban, South Africa were screened for tuberculosis-related symptoms and had sputum tested by acid-fast bacilli smear and tuberculosis culture. Active tuberculosis and subclinical tuberculosis were defined as having any tuberculosis symptom or no tuberculosis symptoms with culture-positive sputum. We evaluated the association between tuberculosis disease category and 12-month survival using Cox regression, adjusting for age, sex, and CD4 count.

RESULTS: Among 654 participants, 96 were diagnosed with active tuberculosis disease and 28 with subclinical disease. The median CD4 count was 68 (interquartile range 39-161) cells/mm3 in patients with active tuberculosis, 136 (72-312) cells/mm3 in patients with subclinical disease, and 249 (125-394) cells/mm3 in those without tuberculosis disease (P < 0.001). The proportion of smear positive cases did not differ significantly between the subclinical (29%) and active tuberculosis groups (14%, P 0.08). Risk of mortality was not increased in individuals with subclinical tuberculosis relative to no tuberculosis (adjusted hazard ratio 0.84, 95% confidence interval 0.26-2.73).

CONCLUSIONS: Nearly one-quarter of tuberculosis cases among HIV-infected adults were subclinical, which was characterized by an intermediate degree of immunosuppression. Although there was no significant difference in survival, anti-tuberculous treatment of subclinical cases was common.

TRIAL REGISTRATION: Prospectively registered on , NCT01188941 (August 26, 2010).

RevDate: 2019-01-05

Cuadrado A, Rojo AI, Wells G, et al (2019)

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.

Nature reviews. Drug discovery pii:10.1038/s41573-018-0008-x [Epub ahead of print].

The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.

RevDate: 2019-01-04

Weiss NS (2019)

Observational Studies That Seek to Emulate a Randomized Trial of Screening to Reduce the Incidence of Cancer: Do They Address the Question to Which We'd Like to Have an Answer?.

American journal of epidemiology pii:5273257 [Epub ahead of print].

Some forms of cancer screening have the potential to reduce cancer incidence, if the screening modality can identify not only a malignancy but a treatable pre-malignant condition (such as a colon polyp) as well. Cohort studies of the efficacy of these forms of screening in reducing the incidence of cancer face many challenges, notably the difficulty in distinguishing whether a test performed in a given individual was screening or diagnostic in nature. Downward bias in the estimated efficacy of screening resulting from misclassification of test indication is a particular problem in cohort studies that seek to gauge cancer incidence beginning at the time of screening (and a corresponding point in time among unscreened persons). The downward bias is accentuated in those cohort studies that have sought to mimic the "intention-to-treat" analytic approach used in randomized trials, in which initially unscreened persons are retained in this category even if later they themselves undergo screening.

RevDate: 2019-01-04

Lemaitre RN, McKnight B, Sotoodehnia N, et al (2018)

Circulating Very Long-Chain Saturated Fatty Acids and Heart Failure: The Cardiovascular Health Study.

Journal of the American Heart Association, 7(21):e010019.

Background Circulating very-long-chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism that may point to new risk pathways and potential targets for heart failure (HF) prevention. The associations of VLSFA to HF in humans are not known. Methods and Results Using a cohort study design, we studied the associations of serially measured plasma phospholipid VLSFA with incident HF in the Cardiovascular Health Study. We investigated the associations of time-varying levels of the 3 major circulating VLSFAs , lignoceric acid (24:0), behenic acid (22:0), and arachidic acid (20:0), with the risk of incident HF using Cox regression. During 45030 person-years among 4249 participants, we identified 1304 cases of incident HF , including 489 with preserved and 310 with reduced ejection fraction. Adjusting for major HF risk factors and other circulating fatty acids, higher levels of each VLSFAs were associated with lower risk of incident HF (P trend≤0.0007 each). The hazard ratio comparing the highest quintile to the lowest quintile was 0.67 (95% confidence interval, 0.55-0.81) for 24:0, 0.72 (95% confidence interval, 0.60-0.87) for 22:0 and 0.72 (95% confidence interval, 0.59-0.88) for 20:0. The associations were similar in subgroups defined by sex, age, body mass index, coronary heart disease, and diabetes mellitus. Among those with ejection fraction data, the associations appeared similar for those with preserved and with reduced ejection fraction. Conclusions Higher levels of circulating VLSFAs are associated with lower risk of incident HF in older adults. These novel associations should prompt further research on the role of VLSFA in HF , including relevant new risk pathways. Clinical Trial Registration URL : . Unique identifier: NCT 00005133.

RevDate: 2019-01-04

Muller DC, Larose TL, Hodge A, et al (2019)

Circulating high sensitivity C reactive protein concentrations and risk of lung cancer: nested case-control study within Lung Cancer Cohort Consortium.

BMJ (Clinical research ed.), 364:k4981.

OBJECTIVES: To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type.

DESIGN: Nested case-control study.

SETTING: 20 population based cohort studies in Asia, Europe, Australia, and the United States.

PARTICIPANTS: 5299 patients with incident lung cancer, with individually incidence density matched controls.

EXPOSURE: Circulating hsCRP concentrations in prediagnostic serum or plasma samples.

MAIN OUTCOME MEASURE: Incident lung cancer diagnosis.

RESULTS: A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.

CONCLUSIONS: Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.

RevDate: 2019-01-03

Pulsipher MA, Logan BR, Kiefer DM, et al (2018)

Higher risks of toxicity and incomplete recovery in 13-17 year old females after marrow donation: RDSafe peds results.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(18)31698-7 [Epub ahead of print].

Although donation of bone marrow (BM) or peripheral blood stem cells (PBSC) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this, we prospectively enrolled 294 donors age <18 at 25 pediatric transplant centers in North America, assessing them pre-donation, peri-donation, 1 month, 6 months, and 1 year after donation. We noted that 71% of children reported pain and 59% other symptoms peri-donation, with resolution to 14% and 12% at 1 month. Both older age (age 13-17 vs. younger) and female sex were associated with higher levels of pain peri-donation, with the highest rates in older females (57% and 17% reporting grades 2-4 and 3-4 pain, respectively). Multivariate analyses showed a 4-fold increase in risk for older females compared to males <13 (p<0.001)). At 1 year, 11% of 13-17 year old females reported grade 2-4 pain compared to 3%, 0%, and 1% of males aged 13-17, females <13, and males <13 (p=0.01). Males and females 13-17 years old failed to return to pre-donation pain levels at 1 year 22% and 23% of the time compared to 3% and 10% in males and females <13 (p=0.002). In conclusion, females age 13-17 are at increased risk for grade 2-4 pain at 1 year and more than 20% of females and males 13-17 do not return to baseline pain levels 1 year after BM donation. Studies aimed at decreasing symptoms and improving recovery in older children are warranted.

RevDate: 2019-01-03

Johansson M, Carreras-Torres R, Scelo G, et al (2019)

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

PLoS medicine, 16(1):e1002724 pii:PMEDICINE-D-18-01768.

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

RevDate: 2019-01-03

Morris AP, Le TH, Wu H, et al (2019)

Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies.

Nature communications, 10(1):29 pii:10.1038/s41467-018-07867-7.

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

RevDate: 2019-01-02

Liu C, Strnad L, Beekmann SE, et al (2019)

Clinical Practice Variation Among Adult Infectious Diseases Physicians in the Management of Staphylococcus aureus Bacteremia.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5270151 [Epub ahead of print].

Infectious disease management of Staphylococcus aureus bacteremia (SAB) was surveyed through the Emerging Infections Network. While there were areas of consensus, we found substantial practice variation in diagnostic evaluation and management of adult patients with SAB. These findings highlight opportunities for further research and guidance to define best practices.

RevDate: 2019-01-02

Fogel JM, Zhang Y, Palumbo PJ, et al (2019)

Use of Antiretroviral Drug Testing to Assess the Accuracy of Self-reported Data from HIV-Infected People Who Inject Drugs.

AIDS and behavior pii:10.1007/s10461-018-2379-8 [Epub ahead of print].

We used antiretroviral (ARV) drug testing to evaluate the accuracy of self-reported data for HIV status and antiretroviral treatment (ART) among people who inject drugs enrolled in an HIV prevention trial. ARV drugs were detected in enrollment samples from 72/482 = 14.9% HIV-infected participants (39/52 = 75.0% who reported being on ART; 33/430 = 7.7% who reported not being on ART). Overall, 213/482 = 44.2% participants indicated that they were not aware of their HIV-positive status prior to study entry; of those, 30 had ARV drugs detected at enrollment, including 15 who also had ARV drugs detected at the screening visit. These participants were likely aware of their HIV-positive status at study entry but did not report this to study staff. This study shows that self-reported data on HIV testing history and ART may not be accurate and that ARV drug testing can help identify persons who are aware of their HIV-positive status and are on ART.

RevDate: 2019-01-01

Ueda M, El-Jurdi N, Cooper B, et al (2018)

Low-dose azacitidine with DNMT1 level monitoring to treat posttransplant AML or MDS relapse.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(18)31697-5 [Epub ahead of print].

Patients with early AML/MDS relapse after hematopoietic cell transplantation have poor prognosis and no standard treatment. Twenty-nine patients with early disease recurrence posttransplant were treated with azacitidine (median dose 40 mg/m2/day x 5-7 days). At a median follow-up of 6.3 (range 1.3-41.1) months, 7 (27%) had response to azacitidine defined as complete remission, hematologic improvement, or improved donor chimerism. Response occurred at a median of 3 cycles, and median duration of response was 70 (range 26-464) days. Median survival was 6.8 months (95% CI 3.8-11.1). Patients receiving azacitidine dose ≤40 or >40 mg/m2 had similar survival. Six patients receiving donor lymphocyte infusion with azacitidine had response or stable disease without worsening graft-versus-host-disease. We retrospectively used a flow cytometry assay to explore DNA-methyltransferase-1 in blood mononuclear cells as a potential pharmacodynamic marker to assess intracellular drug targeting in 8 patients. No correlation with azacitidine dose or response was observed. Low-dose azacitidine appears to be comparable to higher doses in efficacy posttransplant. A significant proportion of this poor-risk population responded to low-dose azacitidine, suggesting a dose-independent, non-cytotoxic mechanism for anti-leukemic activity.

RevDate: 2019-01-01

Hitzler J, E Estey (2019)

Gemtuzumab ozogamicin in acute myeloid leukemia: act 2, with perhaps more to come.

Haematologica, 104(1):7-9.

RevDate: 2018-12-31

Jin Ha M, W Sun (2018)

Estimation of high-dimensional directed acyclic graphs with surrogate intervention.

Biostatistics (Oxford, England) pii:5268842 [Epub ahead of print].

Directed acyclic graphs (DAGs) have been used to describe causal relationships between variables. The standard method for determining such relations uses interventional data. For complex systems with high-dimensional data, however, such interventional data are often not available. Therefore, it is desirable to estimate causal structure from observational data without subjecting variables to interventions. Observational data can be used to estimate the skeleton of a DAG and the directions of a limited number of edges. We develop a Bayesian framework to estimate a DAG using surrogate interventional data, where the interventions are applied to a set of external variables, and thus such interventions are considered to be surrogate interventions on the variables of interest. Our work is motivated by expression quantitative trait locus (eQTL) studies, where the variables of interest are the expression of genes, the external variables are DNA variations, and interventions are applied to DNA variants during the process of a randomly selected DNA allele being passed to a child from either parent. Our method, surrogate intervention recovery of a DAG ($\texttt{sirDAG}$), first constructs a DAG skeleton using penalized regressions and the subsequent partial correlation tests, and then estimates the posterior probabilities of all the edge directions after incorporating DNA variant data. We demonstrate the utilities of $\texttt{sirDAG}$ by simulation and an application to an eQTL study for 550 breast cancer patients.

RevDate: 2018-12-31

Budde LE, Wu D, Martin DB, et al (2018)

Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial.

British journal of haematology, 183(4):601-607.

We sought to develop a safe and effective outpatient salvage regimen by replacing ifosfamide within the (R)ICE (rituximab, ifosfomide, carboplatin, etoposide) regimen with bendamustine (T(R)EC) via a multicentre phase I/II study for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). Therapy consisted of 60-120 mg/m2 per day bendamustine on days 1 and 2 in combination with carboplatin, etoposide and rituximab (only for CD20+ lymphoma) used in the (R)ICE regimen for up to 2 cycles. The objectives were to define a maximally tolerated dose (MTD) of bendamustine, determine safety and toxicity, assess efficacy, and evaluate impact on stem cell collection. Forty-eight patients were treated of which 71% had refractory disease. No dose-limiting toxicities were observed. The recommended phase II dose of bendamustine was 120 mg/m2 per day on days 1 and 2. Response rates were 85% (70% complete response, CR) in HL, and 65% (40% CR) in DLBCL. Stem cell collection was successful in 30 of 32 patients. The most common non-haematological toxicities ≥grade 3 were febrile neutropenia (8%) and dehydration (8%). The T(R)EC regimen safely yields high response rates, successfully mobilizes peripheral blood stem cells and compares favourably to RICE, offering an effective outpatient treatment option for patients with relapsed or refractory DLBCL and HL.

RevDate: 2018-12-31

Swygert SG, Kim S, Wu X, et al (2018)

Condensin-Dependent Chromatin Compaction Represses Transcription Globally during Quiescence.

Molecular cell pii:S1097-2765(18)30990-0 [Epub ahead of print].

Quiescence is a stress-resistant state in which cells reversibly exit the cell cycle and suspend most processes. Quiescence is essential for stem cell maintenance, and its misregulation is implicated in tumor formation. One of the hallmarks of quiescent cells is highly condensed chromatin. Because condensed chromatin often correlates with transcriptional silencing, it has been hypothesized that chromatin compaction represses transcription during quiescence. However, the technology to test this model by determining chromatin structure within cells at gene resolution has not previously been available. Here, we use Micro-C XL to map chromatin contacts at single-nucleosome resolution genome-wide in quiescent Saccharomyces cerevisiae cells. We describe chromatin domains on the order of 10-60 kilobases that, only in quiescent cells, are formed by condensin-mediated loops. Condensin depletion prevents the compaction of chromatin within domains and leads to widespread transcriptional de-repression. Finally, we demonstrate that condensin-dependent chromatin compaction is conserved in quiescent human fibroblasts.

RevDate: 2018-12-30

Ko LK, Taylor VM, Mohamed FB, et al (2018)

"We brought our culture here with us": A qualitative study of perceptions of HPV vaccine and vaccine uptake among East African immigrant mothers.

Papillomavirus research (Amsterdam, Netherlands) pii:S2405-8521(18)30019-3 [Epub ahead of print].

BACKGROUND: HPV vaccine studies in East African communities are few and focus mainly on Somali women and girls. We examined how HPV vaccine perceptions and uptake are shaped among Somali, Ethiopian, and Eritrean mothers.

METHODS: We convened three focus groups in Somali, Amharic, and Tigrinya with mothers of 11-17 year old children. The Socio-Context Framework (social, cultural, and religious factors) and Andersen's Behavioral Model (predisposing, enabling, and need for care factors) informed question development.

RESULTS: Negative vaccine perceptions, lack of HPV vaccine knowledge, and concerns about side effects emerged as predisposing factors. Having a provider who engages parents on HPV vaccination and takes responsibility for vaccine-related risks emerged as enabling factors. Availability of vaccine information resources (e.g., person-to-person, word of mouth education for parents) were also enabling factors. Need for care factors included having comprehensive vaccine information, strong recommendation from a doctor, and validation from a co-ethnic medical professional. Women exerted strong social influence on vaccine uptake (social), had concerns about pork gelatin in vaccines (religious), and felt discussions about sex with children were culturally unacceptable (cultural).

CONCLUSION: Strategies for vaccine uptake among East African immigrants need to address factors that shape HPV vaccine perceptions for adolescents, caregivers, and providers.

RevDate: 2018-12-30

Doll KM, Goff BA, SD Ramsey (2018)

In Reply: Are early screening biomarkers for endometrial cancer needed to reduce health disparities?.

RevDate: 2018-12-30

Bachanova V, Weisdorf DJ, Wang T, et al (2018)

Donor killer-cell immunoglobulin-like receptor (KIR) genotype does not improve graft-versus-leukemia responses in chronic lymphocytic leukemia (CLL) after unrelated donor transplant: a CIBMTR analysis.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(18)31696-3 [Epub ahead of print].

Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with CLL leading to 40-45% long-term survival. The impact of donor KIR genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown.

METHODS: We examined 573 adult (URD)-CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival.

RESULTS: Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved OS were reduced intensity conditioning (HR of death 0.76) and good performance status (HR 0.46), while allo-HCT in non-remission (HR 1.96) and mismatched donors (HR 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A vs B/x KIR haplotypes and those with KIR gene content scores of 0 vs 1 vs ≥2 yielded similar rates of non-relapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival (PFS) and overall survival (OS). Relapse risk was not different with grafts from donors with KIR3DL1 transplanted into HLA C1/1 vs C2 recipients.

CONCLUSION: This large analysis failed to demonstrate an association between unrelated donor KIR genotype and transplant outcome for patients with CLL and thus KIR genotyping should not be used as a donor selection criterion in this setting.

RevDate: 2018-12-29

Brown JR, O'Brien S, Kingsley CD, et al (2018)

Durable remissions with obinutuzumab-based chemoimmunotherapy: long-term follow-up of the phase 1b GALTON trial in CLL.

Blood pii:blood-2018-06-857714 [Epub ahead of print].

RevDate: 2018-12-28

Lee DW, Santomasso BD, Locke FL, et al (2018)

ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(18)31691-4 [Epub ahead of print].

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematological malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients with relapsed or refractory B-cell acute lymphoblastic leukemia up to the age of 25 years and/or adults with large B-cell lymphoma. Many more CAR T products as well as other immunotherapies including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurological toxicity. The assessment and grading of these toxicities have varied considerably across clinical trials and across institutions, making it difficult to compare safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement widely across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20-21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT) in Arlington, VA. Here, we report the consensus of the group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to use, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the post-approval clinical setting.

RevDate: 2018-12-28

Poston JN, Fromm JR, Rasmussen HA, et al (2018)

A pilot study of weekly brentuximab vedotin in patients with CD30+ malignancies resistant to brentuximab vedotin every 3 weeks.

RevDate: 2018-12-27

McClure JB, Bricker J, Mull K, et al (2018)

Comparative-Effectiveness of Group-Delivered Acceptance and Commitment Therapy vs. Cognitive Behavioral Therapy for Smoking Cessation: A Randomized Controlled Trial.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:5258090 [Epub ahead of print].

Introduction: Preliminary trial data suggests group-delivered Acceptance and Commitment Therapy (ACT) might be effective for smoking cessation. If so, this could offer a viable alternative to mainstream behavioral therapies, such as those grounded in Cognitive Behavioral Therapy (CBT). The goal of the current study was to compare the effectiveness of group-delivered ACT versus group-delivered CBT in a rigorous randomized trial design with long term follow-up.

Methods: Participants (n = 450) were recruited from the Kaiser Permanente Washington health care system and randomized to either ACT-based group counseling or an attention-matched CBT-based group program. All were prescribed an 8-week course of nicotine patches. The primary outcome was self-reported 30-day point prevalence abstinence (PPA) at 12 months post-randomization assessed with missing values imputed as smoking. Sensitivity analyses using multiple imputation and complete cases were examined, as were biochemically-confirmed and 6-month outcomes.

Results: Thirty-day point prevalence abstinence rates at the 12-month follow up did not differ between study arms in the primary analysis (13.8% ACT vs. 18.1% CBT, adjusted OR 0.68 [0.35, 1.27], p = 0.23) or the sensitivity analyses.

Conclusions: Group-based ACT and CBT had similar long-term quit rates in this methodologically rigorous randomized trial. Group-based ACT is a reasonable alternative to group-based CBT for smoking cessation.

Implications: This study compared the effectiveness of group-based ACT with group-based CBT for smoking cessation using a rigorous, large-scale, attention-matched, randomized trial with one-year follow-up. One-year cessation rates did not differ between group-based ACT and CBT, suggesting ACT-based intervention is a reasonable alternative to CBT-based counseling for smoking cessation. The results add to the nascent but growing literature assessing ACT and other mindfulness-based treatments for smoking cessation.

RevDate: 2018-12-27

Rose R, Hall M, Redd AD, et al (2018)

Phylogenetic methods inconsistently predict direction of HIV transmission among heterosexual pairs in the HPTN052 cohort.

The Journal of infectious diseases pii:5259209 [Epub ahead of print].

Background: We evaluated use of phylogenetic methods to predict the direction of HIV transmission.

Methods: For 33 index-partner pairs with genetically-linked infection, samples were collected from partners and indexes close to time of partners' seroconversion (SC); 31 indexes also had an earlier sample. Phylogenies were inferred using env next-generation sequences (one tree per pair/subtype). Direction of transmission (DoT) predicted from each tree was classified as correct or incorrect based on which sequences (index or partner) were closest to the root. DoT was also assessed using maximum-parsimony to infer ancestral node states for 100 bootstrap trees.

Results: DoT was predicted correctly for both single pair and subtype-specific trees in 22 pairs (67%) using SC samples and 23 pairs (74%) using early index samples. DoT was predicted incorrectly for four pairs (15%) using SC or early index samples. In the bootstrap analysis, DoT was predicted correctly for 18 pairs (55%) using SC samples and 24 pairs (73%) using early index samples. DoT was predicted incorrectly for seven pairs (21%) using SC samples and four pairs (13%) using early index samples.

Conclusions: Phylogenetic methods based solely on tree topology of HIV env sequences, particularly without consideration of phylogenetic uncertainty, may be insufficient for determining DoT.

RevDate: 2018-12-27

Chan AK, Ammanuel SG, Chan AY, et al (2018)

Chlorhexidine Showers are Associated With a Reduction in Surgical Site Infection Following Spine Surgery: An Analysis of 4266 Consecutive Surgeries.

Neurosurgery pii:5257779 [Epub ahead of print].

BACKGROUND: Surgical site infection (SSI) is a common complication following spinal surgery. Prevention is critical to maintaining safe patient care and reducing additional costs associated with treatment.

OBJECTIVE: To determine the efficacy of preoperative chlorhexidine (CHG) showers on SSI rates following fusion and nonfusion spine surgery.

METHODS: A mandatory preoperative CHG shower protocol was implemented at our institution in November 2013. A cohort comparison of 4266 consecutive patients assessed differences in SSI rates for the pre- and postimplementation periods. Subgroup analysis was performed on the type of spinal surgery (eg, fusion vs nonfusion). Data represent all spine surgeries performed between April 2012 and April 2016.

RESULTS: The overall mean SSI rate was 0.4%. There was no significant difference between the pre- (0.7%) and postimplementation periods (0.2%; P = .08). Subgroup analysis stratified by procedure type showed that the SSI rate for the nonfusion patients was significantly lower in the post- (0.1%) than the preimplementation group (0.7%; P = .02). There was no significant difference between SSI rates for the pre- (0.8%) and postimplementation groups (0.3%) for the fusion cohort (P = .21). In multivariate analysis, the implementation of preoperative CHG showers were associated with significantly decreased odds of SSI (odds ratio = 0.15, 95% confidence interval [0.03-0.55], P < .01).

CONCLUSION: This is the largest study investigating the efficacy of preoperative CHG showers on SSI following spinal surgery. In adjusted multivariate analysis, CHG showering was associated with a significant decrease in SSI following spinal surgery.

RevDate: 2018-12-27

Wang L, Luedtke AR, Y Huang (2018)

Assessing the incremental value of new biomarkers based on OR rules.

Biostatistics (Oxford, England) pii:5261271 [Epub ahead of print].

In early detection of disease, a single biomarker often has inadequate classification performance, making it important to identify new biomarkers to combine with the existing marker for improved performance. A biologically natural method for combining biomarkers is to use logic rules, e.g., the OR/AND rules. In our motivating example of early detection of pancreatic cancer, the established biomarker CA19-9 is only present in a subclass of cancers; it is of interest to identify new biomarkers present in the other subclasses and declare disease when either marker is positive. While there has been research on developing biomarker combinations using the OR/AND rules, inference regarding the incremental value of the new marker within this framework is lacking and challenging due to statistical non-regularity. In this article, we aim to answer the inferential question of whether combining the new biomarker achieves better classification performance than using the existing biomarker alone, based on a nonparametrically estimated OR rule that maximizes the weighted average of sensitivity and specificity. We propose and compare various procedures for testing the incremental value of the new biomarker and constructing its confidence interval, using bootstrap, cross-validation, and a novel fuzzy p-value-based technique. We compare the performance of different methods via extensive simulation studies and apply them to the pancreatic cancer example.

RevDate: 2018-12-27

Juraska M, Huang Y, PB Gilbert (2018)

Inference on treatment effect modification by biomarker response in a three-phase sampling design.

Biostatistics (Oxford, England) pii:5261270 [Epub ahead of print].

An objective in randomized clinical trials is the evaluation of "principal surrogates," which consists of analyzing how the treatment effect on a clinical endpoint varies over principal strata subgroups defined by an intermediate response outcome under both or one of the treatment assignments. The latter effect modification estimand has been termed the marginal causal effect predictiveness (mCEP) curve. This objective was addressed in two randomized placebo-controlled Phase 3 dengue vaccine trials for an antibody response biomarker whose sampling design rendered previously developed inferential methods highly inefficient due to a three-phase sampling design. In this design, the biomarker was measured in a case-cohort sample and a key baseline auxiliary strongly associated with the biomarker (the "baseline surrogate measure") was only measured in a further sub-sample. We propose a novel approach to estimation of the mCEP curve in such three-phase sampling designs that avoids the restrictive "placebo structural risk" modeling assumption common to past methods and that further improves robustness by the use of non-parametric kernel smoothing for biomarker density estimation. Additionally, we develop bootstrap-based procedures for pointwise and simultaneous confidence intervals and testing of four relevant hypotheses about the mCEP curve. We investigate the finite-sample properties of the proposed methods and compare them to those of an alternative method making the placebo structural risk assumption. Finally, we apply the novel and alternative procedures to the two dengue vaccine trial data sets.

RevDate: 2018-12-27

Fong Y, Huang Y, Lemos MP, et al (2018)

Response to Guo et al.'s Letter to the Editor.

Biostatistics (Oxford, England) pii:5261265 [Epub ahead of print].

RevDate: 2018-12-27

Dai J, Li Z, Amos CI, et al (2018)

Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci.

Carcinogenesis pii:5259175 [Epub ahead of print].

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In the current study, we performed a large-scale case-control study with 20,871 lung cancer cases and 15,971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The eQTL (expression quantitative trait loci) analysis and pathway enrichment analysis were performed to identify the possible target genes and pathways. Additionally, we performed motif-based analysis to explore the lung cancer related motifs using sequence kernel association test (SKAT). Two novel variants, rs186332 in 20q13.3 (C>T, OR = 1.17, 95% CI: 1.10-1.24, P = 8.45×10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02×10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1 respectively. What's more, the expression of both MRGBP and SLC16A1 were aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71×10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS related genetic variants for lung cancer.

RevDate: 2018-12-27

Sauter CS, DeFilipp Z, Inamoto Y, et al (2018)

ASBMT Statement on Routine Prophylaxis for Central Nervous System Recurrence of Acute Lymphoblastic Leukemia following Allogeneic Hematopoietic Cell Transplantation.

Hematologic malignancies treated with allogeneic hematopoietic cell transplantation (allo-HCT) have varying incidences of posttransplant central nervous system (CNS) relapse, with acute lymphoblastic leukemia (ALL) representing the most common disease histology. While data supporting posttransplant CNS prophylaxis for ALL in the pre-CNS penetrant systemic therapy-era established this as standard practice, controversy exists regarding the role of posttransplant CNS prophylaxis in the contemporary era. Herein we review the most relevant, albeit exclusively retrospective, literature to date for the role of posttransplant CNS prophylaxis in ALL. Given the paucity of data supporting the routine practice of posttransplant CNS prophylaxis for ALL in the contemporary era, this position statement is anticipated to further stoke controversy and discussion within the transplantation community. Ultimately, only well-designed prospective clinical studies will elucidate the role of routine posttransplant CNS prophylaxis.

RevDate: 2018-12-27

Radtke S, Chan YY, Sippel TR, et al (2018)

MISTRG mice support engraftment and assessment of nonhuman primate hematopoietic stem and progenitor cells.

Experimental hematology pii:S0301-472X(18)30988-3 [Epub ahead of print].

Pre-clinical feasibility, safety, and efficacy testing of hematopoietic stem cell (HSC)-mediated gene therapy approaches is commonly performed in large animal models such as nonhuman primates (NHPs). Here we wished to determine whether mouse models would allow engraftment of NHP HSPCs which would enable more facile and less costly evaluation of promising strategies. In this study, we comprehensively tested two mouse strains for the engraftment of NHP CD34+ hematopoietic stem and progenitor cells. No engraftment of NHP HSPCs was observed in NSG mice, whereas the humanized MISTRG model did demonstrate dose-dependent multilineage engraftment of NHP cells in the peripheral blood, bone marrow, spleen, and thymus. Most importantly and closely mimicking the hematopoietic recovery of autologous stem cell transplants in the NHP, only HSC-enriched CD34+CD90+CD45RA- cell fractions did engraft and reconstituted the bone marrow stem cell niche in MISTRG mice. In summary, we here report the first "monkeynized" mouse xenograft model that closely recapitulates the autologous hematopoietic reconstitution in the NHP stem and progenitor cell transplantation and gene therapy model. Availability of this model has the potential to pre-evaluate novel HSC-mediated gene therapy approaches, inform studies in the NHP, and improve the overall outcome of large-animal experiments.

RevDate: 2018-12-26

Kapadia SN, Wu C, Mayer KH, et al (2018)

No change in health-related quality of life for at-risk U.S. women and men starting HIV pre-exposure prophylaxis (PrEP): Findings from HPTN 069/ACTG A5305.

PloS one, 13(12):e0206577 pii:PONE-D-17-43167.

INTRODUCTION: Tenofovir (TDF)-containing PrEP is effective for HIV prevention, but its effect on health-related quality of life (QOL) is unknown. Using data from HPTN 069/ACTG A5305, a randomized study of potential PrEP regimens comparing maraviroc alone, or together with TDF or emtricitabine (FTC), to TDF + FTC (control), we evaluated the impact of these regimens on QOL in at-risk HIV-uninfected U.S. women and men.

METHODS: QOL was measured at baseline (before starting medications) and every 8 weeks through week 48 using the EQ-5D-3L. Responses were converted to a scale from 0.0 (death) to 1.0 (perfect health), using published valuation weights. Mean scores were compared between groups at each time point using nonparametric testing. Multivariable linear regression was used to adjust for potential confounders.

RESULTS: We analyzed 186 women (median age 35 years, 65% black, 17% Hispanic) and 405 men (median age 30 years, 28% black, 22% Hispanic), including 9 transgender participants analyzed based on sex-at-birth. Mean baseline QOL was 0.91 for women and 0.95 for men. There were minimal changes in mean QOL over time for any regimen (women: p = 0.29; men: p = 0.14). There were no significant differences between participants who continued the regimen compared to participants who discontinued early (women: p = 0.61; men: p = 0.1). Mean QOL did not differ significantly by regimen at any time point, both unadjusted and after adjustment for age, race/ethnicity, adherence, and use of alcohol, marijuana, opiates, and other substances.

CONCLUSIONS: QOL in at-risk individuals starting candidate PrEP regimens in a clinical trial is similar to the general population and maintained over time. This finding did not vary among regimens or when adjusted for demographics, adherence, and substance use. Our findings are the first to show that starting a candidate PrEP regimen in at-risk HIV-uninfected U.S. women and men was not associated with significant changes in QOL.


RevDate: 2018-12-26

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

Recent Epidemiologic Studies and the Linear No-Threshold Model For Radiation Protection-Considerations Regarding NCRP Commentary 27.

Health physics, 116(2):235-246.

National Council on Radiation Protection and Measurements Commentary 27 examines recent epidemiologic data primarily from low-dose or low dose-rate studies of low linear-energy-transfer radiation and cancer to assess whether they support the linear no-threshold model as used in radiation protection. The commentary provides a critical review of low-dose or low dose-rate studies, most published within the last 10 y, that are applicable to current occupational, environmental, and medical radiation exposures. The strengths and weaknesses of the epidemiologic methods, dosimetry assessments, and statistical modeling of 29 epidemiologic studies of total solid cancer, leukemia, breast cancer, and thyroid cancer, as well as heritable effects and a few nonmalignant conditions, were evaluated. An appraisal of the degree to which the low-dose or low dose-rate studies supported a linear no-threshold model for radiation protection or on the contrary, demonstrated sufficient evidence that the linear no-threshold model is inappropriate for the purposes of radiation protection was also included. The review found that many, though not all, studies of solid cancer supported the continued use of the linear no-threshold model in radiation protection. Evaluations of the principal studies of leukemia and low-dose or low dose-rate radiation exposure also lent support for the linear no-threshold model as used in protection. Ischemic heart disease, a major type of cardiovascular disease, was examined briefly, but the results of recent studies were considered too weak or inconsistent to allow firm conclusions regarding support of the linear no-threshold model. It is acknowledged that the possible risks from very low doses of low linear-energy-transfer radiation are small and uncertain and that it may never be possible to prove or disprove the validity of the linear no-threshold assumption by epidemiologic means. Nonetheless, the preponderance of recent epidemiologic data on solid cancer is supportive of the continued use of the linear no-threshold model for the purposes of radiation protection. This conclusion is in accord with judgments by other national and international scientific committees, based on somewhat older data. Currently, no alternative dose-response relationship appears more pragmatic or prudent for radiation protection purposes than the linear no-threshold model.

RevDate: 2018-12-26

Halpern AB, Walter RB, EH Estey (2018)

Outpatient induction and consolidation care strategies in acute myeloid leukemia.

Current opinion in hematology [Epub ahead of print].

PURPOSE OF REVIEW: Patients with acute myeloid leukemia (AML) are almost invariably kept in the hospital until resolution of cytopenias following intensive induction chemotherapy. This care approach is costly and may further contribute to the reduced qualify of life of these patients. This has raised interest in moving at least part of this care to the outpatient setting. Reimbursement challenges for inpatient administration of some of the new drugs approved for AML in the last 2 years adds to this interest.

RECENT FINDINGS: Retrospective and smaller prospective studies have shown that outpatient management following intensive induction chemotherapy ('Early Hospital Discharge') is feasible and may be well tolerated and cost-effective. Reported experience is more limited regarding administration of intensive chemotherapy in the outpatient setting.

SUMMARY: Although of interest, barriers to the successful implementation of outpatient care models, such as limited outpatient infrastructure or geographical limitations, will have to be overcome in many cancer centers. Importantly, before wide-spread introduction, the safety and 'efficacy' (e.g. reduction in medical resources and/or cost and improvement in quality of life) of outpatient care strategies will need to be further evaluated in a prospective - and ideally randomized - manner across more heterogeneous types of oncology and geographical settings.

RevDate: 2018-12-26

Davis JL, Lockwood CM, Stohr B, et al (2018)

Expanding the Spectrum of Pediatric NTRK-rearranged Mesenchymal Tumors.

The American journal of surgical pathology [Epub ahead of print].

Pediatric mesenchymal tumors harboring variant NTRK fusions (ETV6-negative) are being increasingly described; however, the histologic and clinical features of these variant NTRK tumors and their relationship to classic infantile fibrosarcoma are not well characterized. A better understanding of the clinicopathologic features of these tumors is necessary, and would aid in both early diagnosis and treatment. Therefore, the aim of this study was to characterize a series of pediatric NTRK-rearranged mesenchymal tumors, including classic ETV6-NTRK3 fused tumors and tumors with variant (non-ETV6) NTRK fusions. The clinical features, morphology, immunophenotype, and genetics of 12 classic ETV6-NTRK3 fused infantile fibrosarcoma and 18 variant NTRK-rearranged mesenchymal tumors were evaluated. For both classic and variant groups, the age at diagnosis ranged from birth to 15 years (median, 4 mo) with no sex predilection; the most common sites involved were the extremities and trunk. The rate of local recurrence and metastasis were not significantly different (recurrence rate: 11% classic, 40% variant; metastatic rate: 18% classic, 25% variant). Classic and variant NTRK tumors had an overlapping spectrum of histologic features, containing haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles. Both groups showed diffuse pan-TRK expression by immunohistochemistry. Otherwise, the immunoprofile was nonspecific, but similar between both groups. No statistical difference was seen in any clinicopathologic feature between the classic ETV6-NTRK3 and variant fusion cohorts. Pediatric NTRK-rearranged mesenchymal tumors with both classic and variant fusions likely represent a spectrum of disease with shared, recognizable cliniopathologic features.

RevDate: 2018-12-26

Kraft SA, Duenas DM, Kublin JG, et al (2018)

Exploring Ethical Concerns About Human Challenge Studies: A Qualitative Study of Controlled Human Malaria Infection Study Participants' Motivations and Attitudes.

Journal of empirical research on human research ethics : JERHRE [Epub ahead of print].

Controlled human malaria infection (CHMI) studies deliberately infect healthy participants with malaria to test interventions faster and more efficiently. Some argue the study design and high payments offered raise ethical concerns about participants' understanding of risks and undue inducement. We conducted baseline and exit interviews with 16 CHMI study participants to explore these concerns. Participants described themes including decision-making tension with friends and family, mixed motivations for participating, low study risks but high burdens, fair compensation, sacrificing values, deceiving researchers, and perceived benefits. Our findings do not support concerns that high payments limit understanding of study risks, but suggest participants may lack appreciation of study burdens, withhold information or engage in deception, and experience conflict with others regarding study participation.

RevDate: 2018-12-24

Viscoli CM, Kent DM, Conwit R, et al (2018)

Scoring System to Optimize Pioglitazone Therapy After Stroke Based on Fracture Risk.

Stroke [Epub ahead of print].

Background and Purpose- The insulin sensitizer, pioglitazone, reduces cardiovascular risk in patients after an ischemic stroke or transient ischemic attack but increases bone fracture risk. We conducted a secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke) to assess the effect of pretreatment risk for fracture on the net benefits of pioglitazone therapy. Methods- IRIS was a randomized placebo-controlled trial of pioglitazone that enrolled patients with insulin resistance but without diabetes mellitus within 180 days of an ischemic stroke or transient ischemic attack. Participants were recruited at 179 international centers from February 2005 to January 2013 and followed for a median of 4.8 years. Fracture risk models were developed from patient characteristics at entry. Within fracture risk strata, we quantified the effects of pioglitazone compared with placebo by estimating the relative risks and absolute 5-year risk differences for fracture and stroke or myocardial infarction. Results- The fracture risk model included points for age, race-ethnicity, sex, body mass index, disability, and medications. The relative increment in fracture risk with pioglitazone was similar in the lower (

RevDate: 2018-12-22

Azenkot T, Zaniello B, Green ML, et al (2018)

Cytomegalovirus shedding from breastmilk and mucosal sites in healthy post-partum women: a pilot study.

Journal of medical virology [Epub ahead of print].

Mother-to-child cytomegalovirus (CMV) breastmilk transmission can occur in the postnatal period. In a pilot study, we measured daily CMV detection by PCR in breastmilk, vaginal, and saliva samples from 9 healthy CMV-seropositive postpartum women for 28 days. CMV was found in 7 of 9 women and t 171 of 253 breastmilk samples (67.6%). In 4 women, all breast milk samples were positive. CMV was less frequently detected in the vagina (39 of 258, 15.1%) and saliva (53 of 258, 20.5%). Daily breastmilk, oral and genital collection is feasible and demonstrates high variability between women. Further study of the dynamics of CMV in distinct anatomic compartments is warranted. This article is protected by copyright. All rights reserved.

RevDate: 2018-12-22

Janssens DH, Wu SJ, Sarthy JF, et al (2018)

Automated in situ chromatin profiling efficiently resolves cell types and gene regulatory programs.

Epigenetics & chromatin, 11(1):74 pii:10.1186/s13072-018-0243-8.

BACKGROUND: Our understanding of eukaryotic gene regulation is limited by the complexity of protein-DNA interactions that comprise the chromatin landscape and by inefficient methods for characterizing these interactions. We recently introduced CUT&RUN, an antibody-targeted nuclease cleavage method that profiles DNA-binding proteins, histones and chromatin-modifying proteins in situ with exceptional sensitivity and resolution.

RESULTS: Here, we describe an automated CUT&RUN platform and apply it to characterize the chromatin landscapes of human cells. We find that automated CUT&RUN profiles of histone modifications crisply demarcate active and repressed chromatin regions, and we develop a continuous metric to identify cell-type-specific promoter and enhancer activities. We test the ability of automated CUT&RUN to profile frozen tumor samples and find that our method readily distinguishes two pediatric glioma xenografts by their subtype-specific gene expression programs.

CONCLUSIONS: The easy, cost-effective workflow makes automated CUT&RUN an attractive tool for high-throughput characterization of cell types and patient samples.

RevDate: 2018-12-22

Pender A, Jones RL, S Pollack (2018)

Optimising Cancer Vaccine Design in Sarcoma.

Cancers, 11(1): pii:cancers11010001.

Immunotherapeutics are increasingly recognized as a key tool in the armamentarium against malignancy. The success of immune checkpoint-targeting drugs and adoptive cell therapy has refocused attention on the potential anti-cancer effect of eliciting a tumour-specific immunological response. Sarcomas are a rare and diverse group of tumours with a limited prognosis in advanced disease despite systemic therapeutics. Various vaccine strategies including peptide vaccines against cancer testis antigens, dendritic cell vaccines, and viral vectors have been trialled in sarcoma with growing evidence of efficacy. Here, we review the principles of successful vaccine development and how these have been applied thus far to the treatment of sarcoma.

RevDate: 2018-12-21

Kansagra AJ, Frey NV, Bar M, et al (2018)

Clinical utilization of Chimeric Antigen Receptors T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL) - an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT).

On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor - T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

RevDate: 2018-12-21

Ene CI, Macomber MW, Barber JK, et al (2018)

Patterns of Failure After Stereotactic Radiosurgery for Recurrent High-Grade Glioma: A Single Institution Experience of 10 Years.

Neurosurgery pii:5253912 [Epub ahead of print].

BACKGROUND: Stereotactic radiosurgery (SRS) is a treatment modality that is frequently used as salvage therapy for small nodular recurrent high-grade gliomas (HGG). Due to the infiltrative nature of HGG, it is unclear if this highly focused technique provides a durable local control benefit.

OBJECTIVE: To determine how demographic or clinical factors influence the pattern of failure following SRS for recurrent high-grade gliomas.

METHODS: We retrospectively reviewed clinical, radiographic, and follow-up information for 47 consecutive patients receiving SRS for recurrent HGG at our institution between June 2006 and July 2016. All patients initially presented with an HGG (WHO grade III and IV). Following SRS for recurrence, all patients experienced treatment failure, and we evaluated patterns of local, regional, and distant failure in relation to the SRS 50% isodose line.

RESULTS: Most patients with recurrent HGG developed "in-field" treatment failure following SRS (n = 40; 85%). Higher SRS doses were associated with longer time to failure (hazards ratio = 0.80 per 1 Gy increase; 95% confidence interval 0.67-0.96; P = .016). There was a statistically significant increase in distant versus in-field failure among older patients (P = .035). This effect was independent of bevacizumab use (odds ratio = 0.54, P = 1.0).

CONCLUSION: Based on our experience, the majority of treatment failures after SRS for recurrent HGG were "in-field." Older patients, however, presented with more distant failures. Our results indicate that higher SRS doses delivered to a larger area as fractioned or unfractioned regimen may prolong time to failure, especially in the older population.

RevDate: 2018-12-21

Halabi S, Dutta S, Tangen CM, et al (2018)

Overall Survival of Black and White Men With Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel.

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

PURPOSE: Several studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen.

METHODS: Individual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined. Race was based on self-report. The primary end point was OS. The Cox proportional hazards regression model was used to assess the prognostic importance of race (black v white) adjusted for established risk factors common across the trials (age, prostate-specific antigen, performance status, alkaline phosphatase, hemoglobin, and sites of metastases).

RESULTS: Of 8,820 men, 7,528 (85%) were white, 500 (6%) were black, 424 (5%) were Asian, and 368 (4%) were of unknown race. Black men were younger and had worse performance status, higher testosterone and prostate-specific antigen, and lower hemoglobin than white men. Despite these differences, the median OS was 21.0 months (95% CI, 19.4 to 22.5 months) versus 21.2 months (95% CI, 20.8 to 21.7 months) in black and white men, respectively. The pooled multivariable hazard ratio of 0.81 (95% CI, 0.72 to 0.91) demonstrates that overall, black men have a statistically significant decreased risk of death compared with white men (P < .001).

CONCLUSION: When adjusted for known prognostic factors, we observed a statistically significant increased OS in black versus white men with mCRPC who were enrolled in these clinical trials. The mechanism for these differences is not known.

RevDate: 2018-12-21

Kuzma JN, Hagman DK, Cromer G, et al (2018)

Intra-individual variation in markers of intestinal permeability and adipose tissue inflammation in healthy normal weight to obese adults.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-18-0641 [Epub ahead of print].

BACKGROUND: Intestinal permeability and adipose tissue inflammation are considered mechanistic links in the relationship between diet, obesity, and chronic disease. However, methods to measure both are not well standardized, and the reliability of commonly used measures is not known.

METHODS: We calculated the intraclass correlation coefficient (ICC) for several common measures of intestinal permeability and adipose tissue inflammation from a randomized clinical trial of cross-over design in which normal weight (n=12) or overweight/obese (n=12) individuals each completed three 8-day dietary intervention periods.

RESULTS: For biomarkers of intestinal permeability, plasma zonulin and lipopolysaccharide binding protein, ICCs were 'excellent' (i.e., > 0.9). The direct measure of intestinal permeability, the lactulose/mannitol test, exhibited 'fair' reliability (ICC=0.53). A wider range of ICCs (0.6-0.9), suggesting 'good' to 'excellent' reliability, were obtained for measures of adipose tissue expression of genes encoding major mediators of inflammation. Similarly, individual immune cell populations isolated from adipose tissue, expressed as a percentage of all CD45+ cells, also had 'good' to 'excellent' ICCs. However, when these populations were expressed as number of cells per gram of tissue, ICC values were 'fair', falling below 0.6.

CONCLUSION: Due to the repeated measures design, our study offered a unique opportunity to assess reliability of commonly used biomarkers of intestinal permeability and adipose tissue inflammation. Our findings suggest that these measures were generally highly reliable in the short-term.

IMPACT: Along with other factors, particularly validity, the demonstrated reliabilities can help inform the choice of endpoints in studies of intestinal permeability and adipose tissue inflammation.

RevDate: 2018-12-21

Chandrasekaran S, Hunt H, Melhorn S, et al (2018)

Adipokine profiles in preeclampsia.

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians [Epub ahead of print].

OBJECTIVES: Hypertensive disorders of pregnancy (HDP), including preeclampsia (PE), are associated with short- and long-term maternal health complications, and obesity is a leading attributable risk factor for HDP. Yet, most women identified as obese (by body mass index [BMI] ≥ 30 kg/m2) do not develop HDP, indicating limited predictability of BMI alone. In nonpregnant populations, increased visceral fat mass (VFM) is an obesity-associated phenotype increasing the risk for developing hypertension. We sought to assess whether in pregnancy, obese women with PE would have a higher circulating levels of adipokines preferential to VFM compared to obese women without PE.

STUDY DESIGN: We performed a case control study of women with and without PE, including obese (n = 65; BMI ≥ 30 kg/m2) and normal weight (n = 52; BMI 18.4-24.9 kg/m2) women. Plasma concentrations of adipokines preferential to VFM (visfatin, resistin), adipokines reflecting overall adiposity (leptin, adiponectin), and inflammatory cytokines were compared.

RESULTS: We found that among obese women, cases had significantly higher levels of visceral fat mass (VFM)-associated adipokines and cytokines compared to controls [visfatin (p < 0.01, t = -3.8), resistin (p = 0.002, t = 1.12), IFN gamma (p = 0.04, t = -2.0), IL-6 (p < 0.01, t = -2.65), IL1-beta (p < 0.01, t = -4.1), IL-2 (p < 0.01, t = -3.9)]. Interestingly, however, obese and normal weight cases had similar VFM-adipokine and cytokine levels [visfatin (p = 0.34, t = -0.35), resistin (p = 0.55, t = -0.25)], and inflammatory marker concentrations [IFN gamma (p = 0.86, t = -0.76), IL-6 (p = 0.91, t = -0.53), IL-1beta (p = 0.67, t = 1.18), and IL-2 (p = 0.45, t = -1.16)]. These data possibly suggest an association between VFM and preeclampsia (PE) that is present independent of BMI.

CONCLUSION: In summary, we demonstrated that, in normal-weight and obese women, PE was associated with higher concentrations of VFM-preferential adipokines compared to normal-weight and obese controls without PE.

RevDate: 2018-12-20

Jiang X, Zeleznik OA, Lindström S, et al (2018)

Metabolites Associated With the Risk of Incident Venous Thromboembolism: A Metabolomic Analysis.

Journal of the American Heart Association, 7(22):e010317.

Background Venous thromboembolism (VTE) is a complex thrombotic disorder that constitutes a major source of mortality and morbidity. To improve understanding of the cause of VTE , we conducted a metabolomic analysis in a case-control study including 240 incident VTE cases and 6963 controls nested within 3 large prospective population-based cohorts, the Nurses' Health Study, the Nurses' Health Study II , and the Health Professionals Follow-Up Study. Methods and Results For each individual, we measured 211 metabolites and collected detailed information on lifestyle factors. We performed logistic regression and enrichment analysis to identify metabolites and biological categories associated with incident VTE risk, accounting for key confounders, such as age, sex, smoking, alcohol consumption, body mass index, and comorbid diseases (eg, cancers). We performed analyses of all VTEs and separate analyses of pulmonary embolism. Using the basic model controlling for age, sex, and primary disease, we identified 60 nominally significant VTE - or pulmonary embolism-associated metabolites (P<0.05). These metabolites were enriched for diacylglycerols (Ppermutation<0.05). However, after controlling for multiple testing, only 1 metabolite (C5 carnitine; odds ratio, 1.25; 95% confidence interval, 1.10-1.41; Pcorrected=0.03) remained significantly associated with VTE . After further adjustment for body mass index, no metabolites were significantly associated with disease after accounting for multiple testing, and no metabolite classes were enriched for nominally significant associations. Conclusions Although our findings suggest that circulating metabolites may influence the risk of incident VTE , the associations we observed were confounded by body mass index. Larger studies involving additional individuals and with broader metabolomics coverage are needed to confirm our findings.

RevDate: 2018-12-19

Day AL, Greisen P, Doyle L, et al (2018)

Unintended specificity of an engineered ligand-binding protein facilitated by unpredicted plasticity of the protein fold.

Protein engineering, design & selection : PEDS pii:5253233 [Epub ahead of print].

Attempts to create novel ligand-binding proteins often focus on formation of a binding pocket with shape complementarity against the desired ligand (particularly for compounds that lack distinct polar moieties). Although designed proteins often exhibit binding of the desired ligand, in some cases they display unintended recognition behavior. One such designed protein, that was originally intended to bind tetrahydrocannabinol (THC), was found instead to display binding of 25-hydroxy-cholecalciferol (25-D3) and was subjected to biochemical characterization, further selections for enhanced 25-D3 binding affinity and crystallographic analyses. The deviation in specificity is due in part to unexpected altertion of its conformation, corresponding to a significant change of the orientation of an α-helix and an equally large movement of a loop, both of which flank the designed ligand-binding pocket. Those changes led to engineered protein constructs that exhibit significantly more contacts and complementarity towards the 25-D3 ligand than the initial designed protein had been predicted to form towards its intended THC ligand. Molecular dynamics simulations imply that the initial computationally designed mutations may contribute to the movement of the helix. These analyses collectively indicate that accurate prediction and control of backbone dynamics conformation, through a combination of improved conformational sampling and/or de novo structure design, represents a key area of further development for the design and optimization of engineered ligand-binding proteins.

RevDate: 2018-12-19

Webb PM, Na R, Weiderpass E, et al (2018)

Use of aspirin, other nonsteroidal anti-inflammatory drugs and acetaminophen and risk of endometrial cancer: the Epidemiology of Endometrial Cancer Consortium.

Annals of oncology : official journal of the European Society for Medical Oncology pii:5253175 [Epub ahead of print].

Background: Regular use of aspirin has been associated with a reduced risk of cancer at several sites but the data for endometrial cancer are conflicting. Evidence regarding use of other analgesics is limited.

Patients and methods: We pooled individual-level data from seven cohort and five case-control studies participating in the Epidemiology of Endometrial Cancer Consortium including 7,120 women with endometrial cancer and 16,069 controls. For overall analyses, study-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression and combined using random-effects meta-analysis; for stratified analyses we used mixed-effects logistic regression with study as a random effect.

Results: At least weekly use of aspirin and non-aspirin (NA) NSAIDs was associated with an approximately 15% reduced risk of endometrial cancer among both overweight and obese women (OR = 0.86 [95%CI 0.76-0.98] and 0.86 [0.76-0.97], respectively, for aspirin; 0.87 [0.76-1.00] and 0.84 [0.74-0.96], respectively, for NA-NSAIDs). There was no association among women of normal weight (BMI <25 kg/m2, PHeterogeneity=0.04 for aspirin, PHeterogeneity=0.003 for NSAIDs). Among overweight and obese women, the inverse association with aspirin was stronger for use 2-6 times/week (OR = 0.81, 95%CI 0.68-0.96) than for daily use (0.91, 0.80-1.03), possibly because a high proportion of daily users use low-dose formulations. There was no clear association with use of acetaminophen.

Conclusion: Our pooled analysis provides further evidence that use of standard-dose aspirin or other NSAIDs may reduce risk of endometrial cancer among overweight and obese women.

RevDate: 2018-12-19

Triplette M, Crothers K, Mahale P, et al (2018)

Risk of lung cancer in lung transplant recipients in the United States.

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons [Epub ahead of print].

Lung transplant recipients have an increased risk of lung cancer that is poorly understood. Prior studies are largely descriptive and single-center, and have not examined risk factors or outcomes in this population. This registry-linkage study utilized matched transplant and cancer registry data from 17 US states/regions during 1987-2012. We used standardized incidence ratios (SIRs) to compare incidence with the general population, Poisson models to identify lung cancer risk factors, and Cox models to compare survival after diagnosis. Lung cancer risk was increased among lung recipients (SIR 4.8, 95% confidence interval [CI] 4.1-5.5). Those with single lung transplant had 13-fold (95% CI 11-15) increased risk in the native lung. Native lung cancer risk factors included age, prior smoking, time since transplant, and idiopathic pulmonary fibrosis. Compared with cases in the general population, lung cancers in recipients were more frequently localized stage (P = .02) and treated surgically (P = .05). However, recipients had higher all-cause (adjusted hazard ratio 1.90, 95% CI 1.52-2.37) and cancer-specific mortality (adjusted hazard ratio 1.67, 95% CI 1.28-2.18). In conclusion, lung cancer risk is increased after lung transplant, especially in the native lung of single lung recipients. Traditional risk factors are associated with lung cancer in these patients. Lung cancer survival is worse among lung recipients despite earlier diagnosis.

RevDate: 2018-12-19

Halpern AB, RB Walter (2018)

CLAG-M with dose-escalated mitoxantrone for adults with acute myeloid leukemia.

Oncotarget, 9(93):36543-36544 pii:26383.

RevDate: 2018-12-19

Collins CJ, Chang IJ, Jung S, et al (2018)

Rapid Multiplexed Proteomic Screening for Primary Immunodeficiency Disorders From Dried Blood Spots.

Frontiers in immunology, 9:2756.

Background: Primary immunodeficiency disorders (PIDD) comprise a group of life-threatening congenital diseases characterized by absent or impaired immune responses. Despite the fact that effective, curative treatments are available with optimal clinical outcomes when diagnosed early, newborn screening does not exist for the majority of these diseases due to the lack of detectable, specific biomarkers or validated methods for population-based screening. Peptide immunoaffinity enrichment coupled with selected reaction monitoring mass spectrometry (immuno-SRM) is a sensitive proteomic assay, involving antibody-mediated peptide capture, that allows for concurrent quantification of multiple analytes. This assay has promise for use in potential newborn screening of PIDDs that lead to diminished or absent target proteins in the majority of cases. Objective: To determine and evaluate if a multiplex assay based on immuno-SRM is able to reliably and precisely distinguish affected patients with X-linked agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), and CD3ϵ-associated severe combined immunodeficiency (SCID) from one another and from unaffected normal control dried blood spot (DBS) samples. Methods: We performed a blinded, multiplexed analysis of proteolytically-generated peptides from WASp, BTK, and CD3ϵ (for WAS, XLA, and SCID, respectively) in DBS samples from 42 PIDD patients, 40 normal adult controls, and 62 normal newborns. The peptide ATPase copper transporting protein (ATP7B) 1056 was simultaneously monitored for quality assurance purposes. Results: The immuno-SRM assays reliably quantified the target peptides in DBS and accurately distinguished affected patients from normal controls. Analysis of signature peptides found statistically significant reduction or absence of peptide levels in affected patients compared to control groups in each case (WASp and BTK: p = 0.0001, SCID: p = 0.05). Intra and inter-assay precision ranged from 11 to 22% and 11 to 43% respectively; linearity (1.39-2000 fmol peptide), and stability (≤ 0.09% difference in 72 h) showed high precision for the multiplexed assay. Inter-laboratory assay comparison showed high concordance for measured peptide concentrations, with R2 linearity ≥ 0.97 for the WASp 274, CD3ϵ 197, BTK 407, and ATP7B 1056 peptides. Conclusion: Immuno-SRM-based quantification of proteotypic peptides from WASp, BTK, and CD3ϵ in DBS distinguishes relevant PIDD cases from one another and from controls, raising the possibility of employing this approach for large-scale multiplexed newborn screening of selective PIDDs.

RevDate: 2018-12-18

Fortner RT, Poole EM, Wentzensen NA, et al (2018)

Ovarian cancer risk factors by tumor aggressiveness: an analysis from the Ovarian Cancer Cohort Consortium.

International journal of cancer [Epub ahead of print].

Ovarian cancer risk factors differ by histotype; however, within subtype there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n=864), very aggressive (death in 1-<3 years, n=1,390), moderately aggressive (death in 3-<5 years, n=639), and less aggressive (lived 5+ years, n=1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet =0.01), family history of ovarian cancer (phet =0.02), body mass index (BMI; phet ≤0.04) and smoking (phet <0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20-<25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted. This article is protected by copyright. All rights reserved.

RevDate: 2018-12-18

Cathcart-Rake EJ, Zemla T, Jatoi A, et al (2018)

Acquisition of sexual orientation and gender identity data among NCI Community Oncology Research Program practice groups.

Cancer [Epub ahead of print].

BACKGROUND: Sexual and gender minority individuals face numerous cancer-related inequities, many of which appear to be underreported. However, to the best of the authors' knowledge, no one has assessed rates of acquisition of sexual orientation and gender identity (SOGI) data within community oncology settings.

METHODS: Community oncology practices that were part of the NCI Community Oncology Research Program (NCORP) network were asked whether they routinely collected SOGI information and coded this information in their electronic medical records. The proportion of practice groups reporting routine collection of sexual and/or gender minority information was calculated. Potential associations between the collection of SOGI information and practice group-level and state-level characteristics (from Gallup poll data) were also provided.

RESULTS: Twenty-four percent of the responding NCORP practice groups reported routine collection of sexual orientation information, and 10% reported collection of gender identity information. Practices located in western regions of the United States, practices in states with higher proportions of sexual and gender minority-identifying individuals, and practices with lower proportions of non-Hispanic patients were more likely to ask patients about sexual orientation and/or gender identity.

CONCLUSIONS: US oncology practices that participate in research do not frequently collect SOGI information from patients with cancer. Educational initiatives should inform oncology staff and providers about the importance of collecting gender identity and sexual orientation information to improve existent disparities faced by sexual and gender minority patients.

RevDate: 2018-12-18

Zhang X, Zhang Y, Zhu X, et al (2018)

Local and global chromatin interactions are altered by large genomic deletions associated with human brain development.

Nature communications, 9(1):5356 pii:10.1038/s41467-018-07766-x.

Large copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Here we report on the epigenomic effects of the prominent large deletion CNVs on chromosome 22q11.2 and on chromosome 1q21.1. We use Hi-C analysis of long-range chromosome interactions, including haplotype-specific Hi-C analysis, ChIP-Seq analysis of regulatory histone marks, and RNA-Seq analysis of gene expression patterns. We observe changes on all the levels of analysis, within the deletion boundaries, in the deletion flanking regions, along chromosome 22q, and genome wide. We detect gene expression changes as well as pronounced and multilayered effects on chromatin states, chromosome folding and on the topological domains of the chromatin, that emanate from the large CNV locus. These findings suggest basic principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity.

RevDate: 2018-12-18

Yang Y, Wu L, Shu X, et al (2018)

Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk.

Cancer research pii:0008-5472.CAN-18-2726 [Epub ahead of print].

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N=1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P<7.94×10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27 and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression.

RevDate: 2018-12-18

You R, Dai J, Zhang P, et al (2018)

Dynamic Metabolic Response to Adriamycin-Induced Senescence in Breast Cancer Cells.

Metabolites, 8(4): pii:metabo8040095.

Cellular senescence displays a heterogeneous set of phenotypes linked to tumor suppression; however, after drug treatment, senescence may also be involved in stable or recurrent cancer. Metabolic changes during senescence can provide detailed information on cellular status and may also have implications for the development of effective treatment strategies. The metabolic response to Adriamycin (ADR) treatment, which causes senescence as well as cell death, was obtained with the aid of metabolic profiling and isotope tracing in two human breast cancer cell lines, MCF7 and MDA-MB-231. After 5 days of ADR treatment, more than 60% of remaining, intact cells entered into a senescent state, characterized by enlarged and flattened morphology and positive blue staining using SA-β-gal. Metabolic trajectory analysis showed that the two cell lines' responses were significantly different and were divided into two distinct stages. The metabolic shift from the first stage to the second was reflected by a partial recovery of the TCA cycle, as well as amino acid and lipid metabolisms. Isotope tracing analysis indicated that the higher level of glutamine metabolism helped maintain senescence. The results suggest that the dynamic changes during senescence indicate a multi-step process involving important metabolic pathways which might allow breast cancer cells to adapt to persistent ADR treatment, while the higher level of anapleurosis may be important for maintaining the senescent state. Ultimately, a better understanding of metabolic changes during senescence might provide targets for cancer therapy and tumor eradication.

RevDate: 2018-12-18

Greenlee H, Shi Z, Hibshoosh H, et al (2018)

Obesity-associated Breast Inflammation among Hispanic/Latina Breast Cancer Patients.

Cancer prevention research (Philadelphia, Pa.) pii:1940-6207.CAPR-18-0207 [Epub ahead of print].

Breast white adipose tissue inflammation (BWATi) is associated with obesity and higher breast cancer risk among non-Hispanic white women. Obesity is prevalent in Hispanic/Latina patients with breast cancer, and the occurrence of BWATi in this population is not well-characterized. The association between BWATi and body mass index (BMI) was evaluated in Hispanic/Latina patients with breast cancer who underwent mastectomy. BWATi was defined as the presence of crown-like structures of the breast (CLS-B), detected by CD68 IHC in nontumor breast tissue. BWATi severity was quantified as number of CLS-B/cm2 Adipocyte diameter was measured using hematoxylin and eosin-stained breast tissue sections. Preoperative BMI (within 1 week prior to mastectomy) was categorized as normal (18.5-<25.0 kg/m2), overweight (25.0-<30.0 kg/m2), class I obesity (30.0-<35.0 kg/m2), and class II-III obesity (35.0 kg/m2 or above). Patient charts were abstracted to record clinicopathologic features and liver function tests <90 days before mastectomy. The study included 91 women (mean age 69 years; range 36-96 years). Prevalence of BWATi increased with BMI (24% in normal weight, 34% in overweight, 57% in class I obesity, and 65% in class II-III obesity; Ptrend <0.01). Severe BWATi (>0.27 CLS-B/cm2) was associated with higher BMI (Ptrend = 0.046) and greater adipocyte diameter (P = 0.04). Adjusting for BMI, neoadjuvant chemotherapy, and elevated alanine aminotransferase were associated with severe BWATi, and current smoking was associated with mild BWATi (all P < 0.05). BWATi was associated with higher BMI in Hispanic/Latina patients with breast cancer, consistent with previously described associations in other populations.

RevDate: 2018-12-17

Rose TM, Bruce AG, Barcy S, et al (2018)

Quantitative RNAseq analysis of Ugandan KS tumors reveals KSHV gene expression dominated by transcription from the LTd downstream latency promoter.

PLoS pathogens, 14(12):e1007441 pii:PPATHOGENS-D-18-01451 [Epub ahead of print].

KSHV is endemic in Uganda and the HIV epidemic has dramatically increased the incidence of Kaposi sarcoma (KS). To investigate the role of KSHV in the development of KS, we obtained KS biopsies from ART-naïve, HIV-positive individuals in Uganda and analyzed the tumors using RNAseq to globally characterize the KSHV transcriptome. Phylogenetic analysis of ORF75 sequences from 23 tumors revealed 6 distinct genetic clusters with KSHV strains exhibiting M, N or P alleles. RNA reads mapping to specific unique coding sequence (UCDS) features were quantitated using a gene feature file previously developed to globally analyze and quantitate KSHV transcription in infected endothelial cells. A pattern of high level expression was detected in the KSHV latency region that was common to all KS tumors. The clear majority of transcription was derived from the downstream latency transcript promoter P3(LTd) flanking ORF72, with little evidence of transcription from the P1(LTc) latency promoter, which is constitutive in KSHV-infected lymphomas and tissue-culture cells. RNAseq data provided evidence of alternate P3(LTd) transcript editing, splicing and termination resulting in multiple gene products, with 90% of the P3(LTd) transcripts spliced to release the intronic source of the microRNAs K1-9 and 11. The spliced transcripts encode a regulatory uORF upstream of Kaposin A with alterations in intervening repeat sequences yielding novel or deleted Kaposin B/C-like sequences. Hierarchical clustering and PCA analysis of KSHV transcripts revealed three clusters of tumors with different latent and lytic gene expression profiles. Paradoxically, tumors with a latent phenotype had high levels of total KSHV transcription, while tumors with a lytic phenotype had low levels of total KSHV transcription. Morphologically distinct KS tumors from the same individual showed similar KSHV gene expression profiles suggesting that the tumor microenvironment and host response play important roles in the activation level of KSHV within the infected tumor cells.

RevDate: 2018-12-17

Elmore JG, Elder DE, Barnhill RL, et al (2018)

Concordance and Reproducibility of Melanoma Staging According to the 7th vs 8th Edition of the AJCC Cancer Staging Manual.

JAMA network open, 1(1):.

IMPORTANCE: The recently updated American Joint Committee on Cancer (AJCC) classification of cancer staging, the AJCC Cancer Staging Manual, 8th edition (AJCC 8), includes revisions to definitions of T1a vs T1b or greater. The Melanoma Pathology Study database affords a comparison,of pathologists' concordance and reproducibility in the microstaging of melanoma according to both the existing 7th edition (AJCC 7) and the new AJCC 8.

OBJECTIVE: To compare AJCC 7 and AJCC 8 to examine whether changes to the definitions of T1a and T1b or greater are associated with changes in concordance and reproducibility.

In this diagnostic study conducted as part of the national Melanoma Pathology Study across US states, 187 pathologists interpreting melanocytic skin lesions in practice completed 4342 independent case interpretations of 116 invasive melanoma cases. A consensus reference diagnosis and participating pathologists' interpretations were classified into the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis class IV (T1a) or class V (T1b) using both the AJCC 7 and AJCC 8 criteria.

MAIN OUTCOMES AND MEASURES: Concordance with consensus reference diagnosis, interobserver reproducibility, and intraobserver reproducibility.

RESULTS: For T1a diagnoses, participating pathologists' concordance with the consensus reference diagnosis increased from 44% (95% CI, 41%-48%) to 54% (95% CI, 51%-57%) using AJCC 7 and AJCC 8 criteria, respectively. The concordance for cases of T1b or greater increased from 72% (95% CI, 69%-75%) to 78% (95% CI, 75%-80%). Intraobserver reproducibility of diagnoses also improved, increasing from 59% (95% CI, 56%-63%) to 64% (95% CI, 62%-67%) for T1a invasive melanoma, and from 74% (95% CI, 71%-76%) to 77% (95% CI, 74%-79%) for T1b or greater invasive melanoma cases.

CONCLUSIONS AND RELEVANCE: Melanoma staging in AJCC 8 shows greater reproducibility and higher concordance with a reference standard. Improved classification of invasive melanoma can be expected after implementation of AJCC 8, suggesting a positive impact on patients. However, despite improvement, concordance and reproducibility remain low.

RevDate: 2018-12-17

Liu D, Cai T, Lok A, et al (2018)

Nonparametric Maximum Likelihood Estimators of Time-Dependent Accuracy Measures for Survival Outcome Under Two-Stage Sampling Designs.

Journal of the American Statistical Association, 113(522):882-892.

Large prospective cohort studies of rare chronic diseases require thoughtful planning of study designs, especially for biomarker studies when measurements are based on stored tissue or blood specimens. Two-phase designs, including nested case-control (Thomas, 1977) and case-cohort (Prentice, 1986) sampling designs, provide cost-effective strategies for conducting biomarker evaluation studies. Existing literature for biomarker assessment under two-phase designs largely focuses on simple inverse probability weighting (IPW) estimators (Cai and Zheng, 2011; Liu et al., 2012). Drawing on recent theoretical development on the maximum likelihood estimators for relative risk parameters in two-phase studies (Scheike and Martinussen, 2004; Zeng et al., 2006), we propose nonparametric maximum likelihood based estimators to evaluate the accuracy and predictiveness of a risk prediction biomarker under both types of two-phase designs. In addition, hybrid estimators that combine IPW estimators and maximum likelihood estimation procedure are proposed to improve efficiency and alleviate computational burden. We derive large sample properties of proposed estimators and evaluate their finite sample performance using numerical studies. We illustrate new procedures using a two-phase biomarker study aiming to evaluate the accuracy of a novel biomarker, des-γ-carboxy prothrombin, for early detection of hepatocellular carcinoma (Lok et al., 2010).

RevDate: 2018-12-17

Brahma S, S Henikoff (2018)

RSC-Associated Subnucleosomes Define MNase-Sensitive Promoters in Yeast.

Molecular cell pii:S1097-2765(18)30940-7 [Epub ahead of print].

The classic view of nucleosome organization at active promoters is that two well-positioned nucleosomes flank a nucleosome-depleted region (NDR). However, this view has been recently disputed by contradictory reports as to whether wider (≳150 bp) NDRs instead contain unstable, micrococcal nuclease-sensitive ("fragile") nucleosomal particles. To determine the composition of fragile particles, we introduce CUT&RUN.ChIP, in which targeted nuclease cleavage and release is followed by chromatin immunoprecipitation. We find that fragile particles represent the occupancy of the RSC (remodeling the structure of chromatin) nucleosome remodeling complex and RSC-bound, partially unwrapped nucleosomal intermediates. We also find that general regulatory factors (GRFs) bind to partially unwrapped nucleosomes at these promoters. We propose that RSC binding and its action cause nucleosomes to unravel, facilitate subsequent binding of GRFs, and constitute a dynamic cycle of nucleosome deposition and clearance at the subset of wide Pol II promoter NDRs.

RevDate: 2018-12-17

Mavaddat N, Michailidou K, Dennis J, et al (2018)

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

American journal of human genetics pii:S0002-9297(18)30405-1 [Epub ahead of print].

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

RevDate: 2018-12-15

Kisalu NK, Idris AH, Weidle C, et al (2018)

Author Correction: A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite.

In the version of this article originally published, data were incorrectly ascribed to monoclonal antibody CIS34 because of a labeling error. The data were generated with monoclonal antibody CIS04. Full details can be found in the correction notice.

RevDate: 2018-12-15

Hourigan CS, Gale RP, RB Walter (2018)

Refining AML outcome prediction.

RevDate: 2018-12-15

Sharifian R, Okamura DM, Denisenko O, et al (2018)

Distinct patterns of transcriptional and epigenetic alterations characterize acute and chronic kidney injury.

Scientific reports, 8(1):17870 pii:10.1038/s41598-018-35943-x.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered early and late phases of a pathologic continuum of interconnected disease states. Although changes in gene expression patterns have recently been elucidated for the transition of AKI to CKD, the epigenetic regulation of key kidney injury related genes remains poorly understood. We used multiplex RT-qPCR, ChIP-qPCR and integrative analysis to compare transcriptional and epigenetic changes at renal disease-associated genes across mouse AKI and CKD models. These studies showed that: (i) there are subsets of genes with distinct transcriptional and epigenetically profiles shared by AKI and CKD but also subsets that are specific to either the early or late stages of renal injury; (ii) differences in expression of a small number of genes is sufficient to distinguish AKI from CKD; (iii) transcription plays a key role in the upregulation of both AKI and CKD genes while post-transcriptional regulation appears to play a more significant role in decreased expression of both AKI and CKD genes; and (iv) subsets of transcriptionally upregulated genes share epigenetic similarities while downregulated genes do not. Collectively, our study suggests that identified common transcriptional and epigenetic profiles of kidney injury loci could be exploited for therapeutic targeting in AKI and CKD.

RevDate: 2018-12-15

Bonsignori M, Scott E, Wiehe K, et al (2018)

Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier.

Immunity pii:S1074-7613(18)30480-1 [Epub ahead of print].

Elicitation of VRC01-class broadly neutralizing antibodies (bnAbs) is an appealing approach for a preventative HIV-1 vaccine. Despite extensive investigations, strategies to induce VRC01-class bnAbs and overcome the barrier posed by the envelope N276 glycan have not been successful. Here, we inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation. Env immunogens designed on reverted VRC01-class bnAbs bound to VRC01 UCA with affinity sufficient to activate naive B cells. Early mutations defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B cell maturation toward the development of neutralization breadth. Finally, VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan.

RevDate: 2018-12-14

Finak G (2018)

The Computational article format: Software as a research output.

Cytometry. Part A : the journal of the International Society for Analytical Cytology, 93(12):1187-1188.


ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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


Order from Amazon

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

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Papers in Classical Genetics

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

Digital Books

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


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


Biographical information about many key scientists.

Selected Bibliographies

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

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