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Bibliography on: Publications by FHCRC Researchers

RJR-3x

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

RJR: Recommended Bibliography 18 Aug 2019 at 01:33 Created: 

Publications by FHCRC Researchers

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

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

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

Citations The Papers (from PubMed®)

RevDate: 2019-08-16

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

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

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

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

RevDate: 2019-08-16

Storb R, Georges GE, TA Gooley (2019)

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

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

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

RevDate: 2019-08-16

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

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

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

RevDate: 2019-08-16

Kuhlman B, P Bradley (2019)

Advances in protein structure prediction and design.

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

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

RevDate: 2019-08-16

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

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

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

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

RevDate: 2019-08-16

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

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

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

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

RevDate: 2019-08-15

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

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

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

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

RevDate: 2019-08-15

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

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

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

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

RevDate: 2019-08-14

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

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

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

RevDate: 2019-08-14

Matrajt L, Halloran ME, R Antia (2019)

Reply to Lindsey, Höschler and de Silva.

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

RevDate: 2019-08-14

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

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

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

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

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

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

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

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

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

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

RevDate: 2019-08-14

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

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

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

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

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

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

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

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

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

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

RevDate: 2019-08-14

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

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

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

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

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

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

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

RevDate: 2019-08-14

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

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

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

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

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

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

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

RevDate: 2019-08-13

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

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

JCO precision oncology, 3:.

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

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

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

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

RevDate: 2019-08-13

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

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

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

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

RevDate: 2019-08-13

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

Autophosphorylation is sufficient to release Mps1 kinase from native kinetochores.

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

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

RevDate: 2019-08-12

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

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

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

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

RevDate: 2019-08-12

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

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

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

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

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

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

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

RevDate: 2019-08-11

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

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

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

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

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

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

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

RevDate: 2019-08-10

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

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

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

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

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

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

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

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

RevDate: 2019-08-10

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

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

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

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

RevDate: 2019-08-10

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

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

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

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

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

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

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

RevDate: 2019-08-10

Li JJ, Chew GL, MD Biggin (2019)

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

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

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

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

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

RevDate: 2019-08-09

Boonyaratanakornkit J, JJ Taylor (2019)

Techniques to Study Antigen-Specific B Cell Responses.

Frontiers in immunology, 10:1694.

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

RevDate: 2019-08-09

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

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

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

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

RevDate: 2019-08-09

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

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

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

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

RevDate: 2019-08-09

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

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

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

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

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

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

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

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

RevDate: 2019-08-09

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

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

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

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

RevDate: 2019-08-08

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

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

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

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

RevDate: 2019-08-08

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

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

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

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

RevDate: 2019-08-08

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

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

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

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

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

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

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

RevDate: 2019-08-08

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

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

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

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

RevDate: 2019-08-08

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

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

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

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

RevDate: 2019-08-07

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

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

Aging cell [Epub ahead of print].

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

RevDate: 2019-08-07

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

GRAPHICAL MODELS FOR ZERO-INFLATED SINGLE CELL GENE EXPRESSION.

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

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

RevDate: 2019-08-06

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

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

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

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

RevDate: 2019-08-06

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

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

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

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

RevDate: 2019-08-06

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

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

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

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

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

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

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

RevDate: 2019-08-06

Bell SM, Katzelnick L, T Bedford (2019)

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

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

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

RevDate: 2019-08-06

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

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

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

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

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

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

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

RevDate: 2019-08-06

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

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

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

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

RevDate: 2019-08-05

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

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

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

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

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

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

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

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

RevDate: 2019-08-05

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

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

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

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

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

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

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

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

RevDate: 2019-08-05

Morgans AK, CS Higano (2019)

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

RevDate: 2019-08-03

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

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

The Prostate [Epub ahead of print].

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

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

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

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

RevDate: 2019-08-03

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

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

The Prostate [Epub ahead of print].

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

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

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

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

RevDate: 2019-08-03

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

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

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

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

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

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

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

RevDate: 2019-08-02

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

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

Molecular carcinogenesis [Epub ahead of print].

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

RevDate: 2019-08-02

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

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

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

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

RevDate: 2019-08-01

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

Genomic landscape of Neutrophilic Leukemias of Ambiguous Diagnosis.

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

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

RevDate: 2019-08-01

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

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

Science translational medicine, 11(503):.

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

RevDate: 2019-08-01

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

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

Science translational medicine, 11(503):.

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

RevDate: 2019-07-31

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

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

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

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

RevDate: 2019-07-31

Gulati R, Psutka SP, R Etzioni (2019)

Reply by Authors.

The Journal of urology [Epub ahead of print].

RevDate: 2019-07-31

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

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

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

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

RevDate: 2019-07-31

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

The role of lineage plasticity in prostate cancer therapy resistance.

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

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

RevDate: 2019-07-31

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

Bacteremia in febrile cancer patients in Uganda.

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

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

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

RevDate: 2019-07-30

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

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

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

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

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

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

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

RevDate: 2019-07-30

Passarelli MN, PA Newcomb (2017)

Survival Benefits of Smoking Cessation After Breast Cancer Diagnosis.

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

RevDate: 2019-07-29

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

Postmenopausal Fracture History and Survival After Reproductive Cancer Diagnosis.

JNCI cancer spectrum, 2(1):pky001.

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

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

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

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

RevDate: 2019-07-30

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

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

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

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

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

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

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

RevDate: 2019-07-30

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

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

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

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

RevDate: 2019-07-30

Clynes M, Corbett A, J Overbaugh (2019)

Why we need good mentoring.

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

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

RevDate: 2019-07-30

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

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

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

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

RevDate: 2019-07-30

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

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

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

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

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

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

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

RevDate: 2019-07-29

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

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

Sexually transmitted diseases [Epub ahead of print].

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

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

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

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

RevDate: 2019-07-29

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

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

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

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

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

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

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

RevDate: 2019-07-29

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

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

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

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

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

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

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

RevDate: 2019-07-29

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

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

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

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

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

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

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

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

RevDate: 2019-07-28

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

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

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

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

RevDate: 2019-07-28

Barzi A, Hershman DL, Till C, et al (2019)

Osteoporosis in colorectal cancer survivors: analysis of the linkage between SWOG trial enrollees and Medicare claims.

Archives of osteoporosis, 14(1):83 pii:10.1007/s11657-019-0629-7.

To explore the rates of osteoporosis (diagnosis and screening) and fractures in colorectal cancer survivors (CRCS), records of clinical trial enrollees was linked to Medicare. Female/male risk of fracture in CRCS is 74% higher than general population. Less than 30% of male and female CRCS receive osteoporosis screening. Osteoporosis is a significant morbidity in CRCS.

INTRODUCTION: In the USA, the population of colorectal cancer survivors (CRCS) is on the rise. Calcium and vitamin D are the common thread between colorectal cancer and osteoporosis. We set to explore the patterns and prevalence of osteoporosis (OP) and osteoporotic fractures (OF) in CRCS who received fluorouracil-based therapy on SWOG trials.

METHODS: Data for CRCS from three SWOG phase III treatment trials between 1994 and 2000 (N = 3775) were linked to Medicare claims (N = 1233). OP was identified using ICD9 and HCPCS codes; OF was defined using a more restricted set of codes. We compared patterns of OP, OF, and screening for OP by gender in CRCS. Given the gender disparities in the rates of OP and OF, we used data from the National Health Interview Survey (NHIS) and the National Hospital Discharge Survey (NHDS) to assess the ratio of OF in females and males in general population.

RESULTS: Forty-seven percent of females and 15% of men CRCS had OP claims. Female CRCS were more likely than males to have OP (HR = 4.76 [3.77-6.01], p < 0.0001) and OF (HR = 2.64 [2.04-3.42], p < 0.0001). In the general population, the female to male ratio of OF was 1.67 as opposed to 2.90 in CRCS, indicating a significantly larger gender disparity of OF in CRCS (p < 0.001). Only 7% of men and 27% of women CRCS had OP screening.

CONCLUSION: Despite a low rate of OP screening, the gender disparity of OF in CRCS is more pronounced than the general population. These findings provide an impetus for studying OP and OF in CRCS.

RevDate: 2019-07-27

Brown AL, de Smith AJ, Gant VU, et al (2019)

Inherited genetic susceptibility of acute lymphoblastic leukemia in Down syndrome.

Blood pii:blood.2018890764 [Epub ahead of print].

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and demonstrate distinct somatic features, including CRLF2 rearrangement in approximately 50% of cases; however, the role of inherited genetic variation in ALL susceptibility among children with DS is unknown. Here, we report the first genome-wide association study of DS-ALL, comprising a meta-analysis of four independent studies, with 542 DS-ALL cases and 1,192 DS controls. We identified four susceptibility loci at genome-wide statistical significance: single nucleotide polymorphisms rs58923657 near IKZF1 (odds ratio [OR]=2.02, Pmeta =5.32x10-15), rs3731249 in CDKN2A (OR=3.63, Pmeta =3.91x10-10), rs7090445 in ARID5B (OR=1.60, Pmeta =8.44x10-9), and rs3781093 in GATA3 (OR=1.73, Pmeta =2.89x10-8). We performed DS-ALL versus non-DS ALL case-case analyses, comparing possible associations at these and three other established ALL susceptibility loci (BMI1, PIP4K2A, CEBPE) and found significant association with DS status for CDKN2A (OR=1.58, Pmeta =4.1x10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression, high hyperdiploidy, ETV6-RUNX1, and B-other subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 susceptibility locus. It maps to a B-cell super-enhancer, and the risk allele is associated with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation rates in Down syndrome- than non-Down syndrome lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of a known ALL risk locus in children with DS and serve as a basis for further biological insights into the etiology of this disease.

RevDate: 2019-07-26

McDermott CL, Engelberg RA, Woo C, et al (2019)

Novel Data Linkages to Characterize Palliative and End-of-Life Care: Challenges and Considerations.

Journal of pain and symptom management pii:S0885-3924(19)30390-2 [Epub ahead of print].

CONTEXT: Working groups have called for linkages of existing and diverse databases to improve quality measurement in palliative and end-of-life care, but limited data are available on the challenges of using different data sources to measure such care.

OBJECTIVES: To assess data concordance obtained from different sources in a novel linkage of death certificates, electronic health records (EHR), cancer registry data, and insurance claims for patients who died with cancer.

METHODS: We joined a database of Washington State death certificates and EHR to a data repository of commercial health plan enrollment and claims files linked to registry records from Puget Sound Cancer Surveillance System. We assessed care in the last month including hospitalizations, ICU admissions, emergency department (ED) visits, imaging scans, radiation, and hospice, plus chemotherapy in the last 14 days. We used a chi-square test to compare differences between healthcare in EHR and claims.

RESULTS: Records of hospitalization, ICU, and ED use were 33%, 15% and 33% lower in EHR versus claims. Radiation, hospice, and imaging were 6%, 14% and 28% lower in EHR, but chemotherapy was 4% higher compared to claims. These differences were statistically different for hospice (p<0.02), hospitalization, ICU, ER, and imaging (all p<0.01) but not radiation (p=0.12) or chemotherapy (p=0.29).

CONCLUSION: We found substantial variation between EHR and claims for end-of-life healthcare use. Reliance on EHR will miss some healthcare use while claims will not capture the complex clinical details in EHR that can help define the quality of palliative care and EOL healthcare utilization.

RevDate: 2019-07-26

Kerwin BA, Bennett C, Brodsky Y, et al (2019)

Framework mutations of the 10-1074 bnAb increase conformational stability, manufacturability and stability while preserving full neutralization activity.

Journal of pharmaceutical sciences pii:S0022-3549(19)30444-7 [Epub ahead of print].

The broadly neutralizing anti-HIV antibody, 10-1074, is a highly somatically hypermutated IgG1 being developed for prophylaxis in Sub-Saharan Africa. A series of algorithms were applied to identify potentially destabilizing residues in the framework of the Fv region. Of seventeen residues defined, a variant was identified encompassing one light and three heavy chain residues. with significantly increased conformational stability while maintaining full neutralization activity. Central to the stabilization was the replacement of the heavy chain residue T108 with R108 at the base of the CDR3 loop which allowed for the formation of a nascent salt bridge with heavy chain residue D137. Three additional mutations were necessary to confer increased conformational stability as evidenced by differential scanning fluorimetry and isothermal chemical unfolding. Additionally, we observed increased stability during low pH incubation in which 40% of the parental monomer aggregated while the combinatorial variant showed no increase in aggregation. Incubation of the variant at 100 mg/mL for 6 weeks at 40°C showed a 9-fold decrease in subvisible particles ≥ 2μm relative to the parental molecule. Stability-based designs have also translated to improved pharmacokinetics. Together, these data show that increasing conformational stability of the Fab can have profound effects on the manufacturability and long-term stability of a monoclonal antibody.

RevDate: 2019-07-26

Kong R, Duan H, Sheng Z, et al (2019)

Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.

Cell, 178(3):567-584.e19.

The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.

RevDate: 2019-07-26

Nash SH, Peters U, D Redwood (2019)

Developing an Epidemiologic Study to Investigate Risk Factors for Colorectal Cancer Among Alaska Native People.

Journal of public health management and practice : JPHMP, 25 Suppl 5, Tribal Epidemiology Centers: Advancing Public Health in Indian Country for Over 20 Years:S54-S60.

Alaska Native (AN) people have among the highest rates of colorectal cancer (CRC) recorded globally. Preventing CRC is an important health priority of AN tribal health leaders and communities. Lifestyle and genetic risk and protective factors for CRC among AN people remain understudied. We have been working to establish a tribally led, community-based, comprehensive investigation of lifestyle and genetic risk and protective factors for CRC among AN people. We describe the process of initiating this research study, including conversations with key tribal health system staff. We discuss themes that arose during these conversations and literature review and describe how those themes were used during the study design and protocol development phase. This description is intended to provide guidance to other researchers working to establish community-based studies of cancer risk, particularly among tribal communities.

RevDate: 2019-07-26

Zueger PM, Holmes HM, Calip GS, et al (2019)

Older Medicare Beneficiaries Frequently Continue Medications with Limited Benefit Following Hospice Admission.

Journal of general internal medicine pii:10.1007/s11606-019-05152-x [Epub ahead of print].

BACKGROUND: The use of medications not relieving symptoms or maximizing quality of life should be minimized following hospice enrollment.

OBJECTIVE: To evaluate the frequency of and predictive factors for continuation of medications with limited benefit after hospice admission among those admitted for cancer- and non-cancer-related causes.

DESIGN: Cohort study using the Surveillance, Epidemiology and End Results-Medicare linked database.

PATIENTS: Medicare Part D-enrolled beneficiaries 66 years and older who were admitted to and died under hospice care between January 1, 2008, and December 31, 2013 (N = 70,035).

MAIN MEASURES: Patients were followed from hospice enrollment through death for Part D dispensing of limited benefit medications (LBMs) they had used in the 6 months prior to hospice admission, including anti-hyperlipidemics, anti-hypertensives, oral anti-diabetics, anti-platelets, anti-dementia medications, anti-osteoporotic medications, and proton pump inhibitors. The proportion of patients continuing an LBM after hospice admission was evaluated. Adjusted relative risks (RRs) were estimated for factors associated with LBM continuation.

KEY RESULTS: Overall, 29.8% and 30.5% of patients admitted to hospice for a cancer- and non-cancer-related cause, respectively, continued at least one LBM after hospice admission. Anti-dementia medications were continued most frequently (29.3%) while anti-osteoporotic medications were continued least often (14.1%). Compared to home hospice, LBM continuation was greater in hospice patients residing in skilled nursing (RR 1.25, 95% CI 1.20-1.29), non-skilled nursing (RR 1.29, 95% CI 1.25-1.32), and assisted living facilities (RR 1.28, 95% CI 1.24-1.32). Patients with hospice stays ≥ 180 days were more likely to continue at least one LBM compared to those with stays of 1 week or less (RR 13.11, 95% CI 12.25-14.02).

CONCLUSIONS: A substantial proportion of Medicare hospice beneficiaries continued to receive LBMs following hospice enrollment. Providers should evaluate the necessity of continuing non-palliative medications at the end of life through a careful, patient-centric consideration of their potential risks and benefits.

RevDate: 2019-07-26

Dosenovic P, Pettersson AK, Wall A, et al (2019)

Anti-idiotypic antibodies elicit anti-HIV-1-specific B cell responses.

The Journal of experimental medicine pii:jem.20190446 [Epub ahead of print].

Human anti-HIV-1 broadly neutralizing antibodies (bNAbs) protect against infection in animal models. However, bNAbs have not been elicited by vaccination in diverse wild-type animals or humans, in part because B cells expressing the precursors of these antibodies do not recognize most HIV-1 envelopes (Envs). Immunogens have been designed that activate these B cell precursors in vivo, but they also activate competing off-target responses. Here we report on a complementary approach to expand specific B cells using an anti-idiotypic antibody, iv8, that selects for naive human B cells expressing immunoglobulin light chains with 5-amino acid complementarity determining region 3s, a key feature of anti-CD4 binding site (CD4bs)-specific VRC01-class antibodies. In mice, iv8 induced target cells to expand and mature in the context of a polyclonal immune system and produced serologic responses targeting the CD4bs on Env. In summary, the results demonstrate that an anti-idiotypic antibody can specifically recognize and expand rare B cells that express VRC01-class antibodies against HIV-1.

RevDate: 2019-07-26

Bancroft T, DeBuysscher BL, Weidle C, et al (2019)

Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes.

The Journal of experimental medicine pii:jem.20190164 [Epub ahead of print].

Many tested vaccines fail to provide protection against disease despite the induction of antibodies that bind the pathogen of interest. In light of this, there is much interest in rationally designed subunit vaccines that direct the antibody response to protective epitopes. Here, we produced a panel of anti-idiotype antibodies able to specifically recognize the inferred germline version of the human immunodeficiency virus 1 (HIV-1) broadly neutralizing antibody b12 (iglb12). We determined the crystal structure of two anti-idiotypes in complex with iglb12 and used these anti-idiotypes to identify rare naive human B cells expressing B cell receptors with similarity to iglb12. Immunization with a multimerized version of this anti-idiotype induced the proliferation of transgenic murine B cells expressing the iglb12 heavy chain in vivo, despite the presence of deletion and anergy within this population. Together, our data indicate that anti-idiotypes are a valuable tool for the study and induction of potentially protective antibodies.

RevDate: 2019-07-26

Waller EK, Logan BR, Fei M, et al (2019)

Kinetics of immune cell reconstitution predict survival in allogeneic bone marrow and G-CSF-mobilized stem cell transplantation.

Blood advances, 3(15):2250-2263.

The clinical utility of monitoring immune reconstitution after allotransplant was evaluated using data from Blood and Marrow Transplant Clinical Trials Network BMT CTN 0201 (NCT00075816), a multicenter randomized study of unrelated donor bone marrow (BM) vs granulocyte colony-stimulating factor (G-CSF)-mobilized blood stem cell (G-PB) grafts. Among 410 patients with posttransplant flow cytometry measurements of immune cell subsets, recipients of G-PB grafts had faster T-cell reconstitution than BM recipients, including more naive CD4+ T cells and T-cell receptor excision circle-positive CD4+ and CD8+ T cells at 3 months, consistent with better thymic function. Faster reconstitution of CD4+ T cells and naive CD4+ T cells at 1 month and CD8+ T cells at 3 months predicted more chronic graft-versus-host disease (GVHD) but better survival in G-PB recipients, but consistent associations of T-cell amounts with GVHD or survival were not seen in BM recipients. In contrast, a higher number of classical dendritic cells (cDCs) in blood samples at 3 months predicted better survival in BM recipients. Functional T-cell immunity measured in vitro by cytokine secretion in response to stimulation with cytomegalovirus peptides was similar when comparing blood samples from BM and G-PB recipients, but the degree to which acute GVHD suppressed immune reconstitution varied according to graft source. BM, but not G-PB, recipients with a history of grades 2-4 acute GVHD had lower numbers of B cells, plasmacytoid dendritic cells, and cDCs at 3 months. Thus, early measurements of T-cell reconstitution are predictive cellular biomarkers for long-term survival and response to GVHD therapy in G-PB recipients, whereas more robust DC reconstitution predicted better survival in BM recipients.

RevDate: 2019-07-26

Nambiar M, Chuang YC, GR Smith (2019)

Distributing meiotic crossovers for optimal fertility and evolution.

DNA repair pii:S1568-7864(19)30201-0 [Epub ahead of print].

During meiosis, homologous chromosomes of a diploid cell are replicated and, without a second replication, are segregated during two nuclear divisions to produce four haploid cells (including discarded polar bodies in females of many species). Proper segregation of chromosomes at the first division requires in most species that homologous chromosomes be physically connected. Tension generated by connected chromosomes moving to opposite sides of the cell signals proper segregation. In the absence of the required connections, called crossovers, chromosomes often segregate randomly and produce aneuploid gametes and, thus, dead or disabled progeny. To be effective, crossovers must be properly distributed along chromosomes. Crossovers within or too near the centromere interfere with proper segregation; crossovers too near each other can ablate the required tension; and crossovers too concentrated in only one or a few regions would not re-assort most genetic characters important for evolution. Here, we discuss current knowledge of how the optimal distribution of crossovers is achieved in the fission yeast Schizosaccharomyces pombe, with reference to other well-studied species for comparison and illustration of the diversity of biology.

RevDate: 2019-07-25

Ortblad KF, Baeten JM, Cherutich P, et al (2019)

The arc of HIV epidemics in sub-Saharan Africa: new challenges with concentrating epidemics in the era of 90-90-90.

Current opinion in HIV and AIDS [Epub ahead of print].

PURPOSE OF REVIEW: The aim of this review is to examine the emerging results from the HIV universal test and treat (UTT) cluster-randomized trials in sub-Saharan Africa, discuss how expanding access to HIV clinical services is likely to reshape the arc of HIV epidemics, and consider implications for HIV prevention and control strategies in the coming decade.

RECENT FINDINGS: The effect of universal HIV testing followed by immediate antiretroviral treatment (ART) on community-level HIV incidence remains unclear upon completion of five randomized trials. Only two of the four trials that measured HIV incidence found significant reductions in community-level incidence. Even in these trials, HIV incidence remained above levels required for epidemic control (≤1 case per 1000 person-years) despite high levels of ART coverage and viral suppression. These findings may indicate that community-delivered HIV services are not reaching the high-frequency transmitters who sustain HIV epidemics and are likely members of marginalized or hard to engage core groups.

SUMMARY: With expanded access to HIV services in sub-Saharan Africa, HIV epidemics are transitioning from hyperendemic to declining/endemic epidemic phases, characterized increasingly by the reconcentration of HIV in marginalized or hard to engage core groups. To move toward epidemic control, novel HIV service delivery models and technologies are needed to engage those who continue to drive HIV incidence in this new epidemic phase.

RevDate: 2019-07-25

Tretiakova MS, Kehr EL, Gore JL, et al (2019)

Thyroid-Like Follicular Renal Cell Carcinoma Arising Within Benign Mixed Epithelial and Stromal Tumor.

International journal of surgical pathology [Epub ahead of print].

Thyroid-like follicular renal cell carcinoma (TLF-RCC) is an extremely rare tumor with less than 40 published reports. These tumors are morphologically distinct with striking resemblance to thyroid follicular tumors, but immunohistochemically different due to lack of thyroglobulin and thyroid transcription factor 1 expression. TLF-RCCs arise in younger patients (mean age = 41 years) with female predominance and in all reported cases were solitary tumors without coexisting epithelial or mesenchymal kidney neoplasms. In this article, we report a case of a 42-year-old woman who presented with an incidental 4-cm solid and cystic left renal mass of the upper pole, which was resected. A detailed imaging assessment, pathologic findings, and immunohistochemical studies revealed a partially encapsulated TLF-RCC arising in a background of mixed epithelial and stromal tumor.

RevDate: 2019-07-25

Chowning JT, Wu R, Brinkema C, et al (2019)

A new twist on DNA extraction: Collaborative argumentation and student protocol design.

Science teacher (Normal, Ill.), 86(6):20-27.

RevDate: 2019-07-24

Anderson KG, Voillet V, Bates B, et al (2019)

Engineered adoptive T-cell therapy prolongs survival in a preclinical model of advanced stage ovarian cancer.

Cancer immunology research pii:2326-6066.CIR-19-0258 [Epub ahead of print].

Adoptive T-cell therapy using high-affinity T-cell receptors (TCRs) to target tumor antigens has potential for improving outcomes in high-grade serous ovarian cancer (HGSOC) patients. Ovarian tumors develop a hostile, multicomponent tumor microenvironment containing suppressive cells, inhibitory ligands, and soluble factors that facilitate evasion of antitumor immune responses. Developing and validating an immunocompetent mouse model of metastatic ovarian cancer that shares antigenic and immunosuppressive qualities of human disease would facilitate establishing effective T-cell therapies. We used deep transcriptome profiling and immunohistochemical analysis of human HGSOC tumors and disseminated mouse ID8VEGF tumors to compare immunologic features. We then evaluated the ability of CD8 T cells engineered to express a high-affinity TCR specific for mesothelin, an ovarian cancer antigen, to infiltrate advanced ID8VEGF murine ovarian tumors and control tumor growth. Human CD8 T cells engineered to target mesothelin were also evaluated for ability to kill HLA-A2+ HGSOC lines. Immunohistochemistry and gene expression profiling revealed striking similarities between tumors of both species, including processing/presentation of a leading candidate target antigen, suppressive immune cell infiltration, and expression of molecules that inhibit T-cell function. Engineered T cells targeting mesothelin infiltrated mouse tumors but became progressively dysfunctional and failed to persist. Treatment with repeated doses of T cells maintained functional activity, significantly prolonging survival of mice harboring late-stage disease at treatment onset. Human CD8 T cells engineered to target mesothelin were tumoricidal for three HGSOC lines. Treatment with engineered T cells may have clinical applicability in patients with advanced-stage HGSOC.

RevDate: 2019-07-24

Burd A, Schilsky RL, Byrd JC, et al (2019)

Challenges and approaches to implementing master/basket trials in oncology.

Blood advances, 3(14):2237-2243.

The appetite for cutting-edge cancer research, across medical institutions, scientific researchers, and health care providers, is increasing based on the promise of true breakthroughs and cures with new therapeutics available for investigation. At the same time, the barriers for advancing clinical research are impacting how quickly drug development efforts are conducted. For example, we know now that under a microscope, patients with the same type of cancer and histology might look the same; however, the reality is that most cancers are driven by genomic, transcriptional, and epigenetic changes that make each patient unique. Additionally, the immunologic reaction to different tumor types is distinct among patients. The challenge for researchers developing new therapies today is vastly different than it was in the era of cytotoxics. Today, we must identify a sufficient number of patients harboring a rare mutation or other characteristic and match this to the right therapeutic option. This summary provides a guide to help inform the scientific cancer community about the benefits and challenges of conducting umbrella or basket trials (master trials), and to create a roadmap to help make this new and evolving form of clinical trial design as effective as possible.

RevDate: 2019-07-24

Sun Y, Liu B, Snetselaar LG, et al (2019)

Association of Normal-Weight Central Obesity With All-Cause and Cause-Specific Mortality Among Postmenopausal Women.

JAMA network open, 2(7):e197337 pii:2738622.

Importance: Current public health guidelines for obesity prevention and control focus on promoting a normal body mass index (BMI), rarely addressing central obesity, which is reflected by high waist circumference (WC) and common in the general population. Studies of the association of normal-weight central obesity with long-term health outcomes are sparse.

Objective: To examine associations of normal-weight central obesity with all-cause and cause-specific mortality in postmenopausal women in the United States.

A nationwide prospective cohort study of 156 624 postmenopausal women enrolled in the Women's Health Initiative at 40 clinical centers in the United States between 1993 and 1998. These women were observed through February 2017. Data analysis was performed from September 15, 2017, to March 13, 2019.

Exposures: Different combinations of BMI (calculated as weight in kilograms divided by height in meters squared; normal weight: BMI, 18.5-24.9; overweight: BMI, 25.0-29.9; and obesity: BMI, ≥30) and WC (normal: WC, ≤88 cm and high: WC, >88 cm).

Main Outcomes and Measures: Mortality from all causes, cardiovascular disease, and cancer.

Results: Of the 156 624 women (mean [SD] age, 63.2 [7.2] years), during 2 811 187 person-years of follow-up, 43 838 deaths occurred, including 12 965 deaths from cardiovascular disease (29.6%) and 11 828 deaths from cancer (27.0%). Compared with women with normal weight and no central obesity and adjusted for demographic characteristics, socioeconomic status, lifestyle factors, and hormone use, the hazard ratio for all-cause mortality was 1.31 (95% CI, 1.20-1.42) among women with normal weight and central obesity, 0.91 (95% CI, 0.89-0.94) among women with overweight and no central obesity, 1.16 (95% CI, 1.13-1.20) for women with overweight and central obesity, 0.93 (95% CI, 0.89-0.94) for women with obesity and no central obesity, and 1.30 (95% CI, 1.27-1.34) for women with obesity and central obesity. Compared with normal weight without central obesity, normal-weight central obesity was associated with higher risk of cardiovascular disease mortality (hazard ratio, 1.25; 95% CI, 1.05-1.46) and cancer mortality (hazard ratio, 1.20; 95% CI, 1.01-1.43).

Conclusions and Relevance: Normal-weight central obesity in women was associated with excess risk of mortality, similar to that of women with BMI-defined obesity with central obesity. These findings underscore the need for future public health guidelines to include the prevention and control of central obesity, even in individuals with normal BMI.

RevDate: 2019-07-24

Dominguez-Valentin M, Sampson JR, Seppälä TT, et al (2019)

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Genetics in medicine : official journal of the American College of Medical Genetics pii:10.1038/s41436-019-0596-9 [Epub ahead of print].

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.

METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.

RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.

CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

RevDate: 2019-07-22

Carnevale Neto F, Andreo MA, Raftery D, et al (2019)

Characterization of aporphine alkaloids by electrospray ionization tandem mass spectrometry and DFT calculations.

Rapid communications in mass spectrometry : RCM [Epub ahead of print].

RATIONALE: Aporphine alkaloids represent a large group of isoquinoline natural products with important roles in biological and biomedical areas. Their characterization by electrospray ionization tandem mass spectrometry (ESI-MS/MS) can contribute to the rapid identification in complex biological matrices.

METHODS: We report the fragmentation of protonated 7,7-dimethyl aporphine alkaloids by ESI-MS/MS, and the putative annotation of aporphine alkaloids in plant extracts. We have used low- and high-resolution MS/MS analyses to rationalize the fragmentation pathways, and employed the B3LYP/6-31+G(d,p) density functional theory (DFT) model to provide thermochemical parameters and to obtain the reactive sites.

RESULTS: DFT calculations of a set of 7,7-dimethyl aporphine alkaloids suggested the heterocyclic amino group as the most basic site due to the proton affinity of the nitrogen atom. Collision induced dissociation (CID) experiments promoted ● OCH3 elimination instead of the expected neutral loss of the heterocyclic amino group, pointing to the ion [M-15+H]●+ as the diagnostic fragment for 7,7-dimethyl aporphine alkaloids. The analysis of plant extracts led to the annotation of 25 aporphine alkaloids. Their fragmentation initiated with the loss of the amino group followed by formation of a cyclic carbocation. Further reactions derived from consecutive charge-remote and/or charge-induced fragmentations of the substituents attached to the aromatic system. The mechanisms were re-examined based on plausible gas-phase ion chemistry reactions.

CONCLUSIONS: Taken together, the diagnostic product ions and the series of radical and neutral eliminations provided information about the location of methylenedioxy, aromatic methoxy, and methoxy-hydroxy groups in aporphine alkaloids, assisting their characterization via MS/MS.

RevDate: 2019-07-22

Ralph DK, FA Matsen (4th) (2019)

Per-sample immunoglobulin germline inference from B cell receptor deep sequencing data.

PLoS computational biology, 15(7):e1007133 pii:PCOMPBIOL-D-17-02122 [Epub ahead of print].

The collection of immunoglobulin genes in an individual's germline, which gives rise to B cell receptors via recombination, is known to vary significantly across individuals. In humans, for example, each individual has only a fraction of the several hundred known V alleles. Furthermore, the currently-accepted set of known V alleles is both incomplete (particularly for non-European samples), and contains a significant number of spurious alleles. The resulting uncertainty as to which immunoglobulin alleles are present in any given sample results in inaccurate B cell receptor sequence annotations, and in particular inaccurate inferred naive ancestors. In this paper we first show that the currently widespread practice of aligning each sequence to its closest match in the full set of IMGT alleles results in a very large number of spurious alleles that are not in the sample's true set of germline V alleles. We then describe a new method for inferring each individual's germline gene set from deep sequencing data, and show that it improves upon existing methods by making a detailed comparison on a variety of simulated and real data samples. This new method has been integrated into the partis annotation and clonal family inference package, available at https://github.com/psathyrella/partis, and is run by default without affecting overall run time.

RevDate: 2019-07-22

Friedman DN, Moskowitz CS, Hilden P, et al (2019)

Radiation Dose and Volume to the Pancreas and Subsequent Risk of Diabetes Mellitus.

Journal of the National Cancer Institute pii:5536877 [Epub ahead of print].

BACKGROUND: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for diabetes mellitus but the association between risk and radiation dose and volume is unclear.

METHODS: Participants included 20,762 five-year survivors of childhood cancer (4,568 exposed to abdRT) and 4,853 siblings. For abdRT, we estimated maximum dose to abdomen, mean doses for whole pancreas, pancreatic head, body, tail, and percent pancreas volume receiving ≥10, ≥20, and ≥30Gy. Relative risks (RRs) were estimated with a Poisson model using generalized estimating equations, adjusted for attained age. All statistical tests were two-sided.

RESULTS: Survivors exposed to abdRT (median age=31.6 years, range=10.2-58.3) were 2.92-fold more likely than siblings (95% confidence interval [CI]=2.02 to 4.23) and 1.60-times more likely than survivors not exposed to abdRT (95%CI=1.24 to 2.05) to develop diabetes. Among survivors treated with abdRT, greater attained age (RR(per 10 years)=2.11, 95%CI=1.70 to 2.62), higher body mass index (RR(BMI 30+)=5.00, 95%CI=3.19 to 7.83 with reference(BMI 18.5-24.9)), and increasing pancreatic tail dose were associated with increased diabetes risk in a multivariable model; an interaction was identified between younger age at cancer diagnosis and pancreatic tail dose with much higher diabetes risk associated with increasing pancreatic tail dose among those diagnosed at the youngest ages (p<.001). Radiation dose and volume to other regions of the pancreas were not statistically significantly associated with risk.

CONCLUSIONS: Among survivors treated with abdRT, diabetes risk was associated with higher pancreatic tail dose, especially at younger ages. Targeted interventions are needed to improve cardiometabolic health among those at highest risk.

RevDate: 2019-07-22

Chew GL, Campbell AE, De Neef E, et al (2019)

DUX4 Suppresses MHC Class I to Promote Cancer Immune Evasion and Resistance to Checkpoint Blockade.

Developmental cell pii:S1534-5807(19)30529-5 [Epub ahead of print].

Advances in cancer immunotherapies make it critical to identify genes that modulate antigen presentation and tumor-immune interactions. We report that DUX4, an early embryonic transcription factor that is normally silenced in somatic tissues, is re-expressed in diverse solid cancers. Both cis-acting inherited genetic variation and somatically acquired mutations in trans-acting repressors contribute to DUX4 re-expression in cancer. Although many DUX4 target genes encode self-antigens, DUX4-expressing cancers were paradoxically characterized by reduced markers of anti-tumor cytolytic activity and lower major histocompatibility complex (MHC) class I gene expression. We demonstrate that DUX4 expression blocks interferon-γ-mediated induction of MHC class I, implicating suppressed antigen presentation in DUX4-mediated immune evasion. Clinical data in metastatic melanoma confirmed that DUX4 expression was associated with significantly reduced progression-free and overall survival in response to anti-CTLA-4. Our results demonstrate that cancers can escape immune surveillance by reactivating a normal developmental pathway and identify a therapeutically relevant mechanism of cell-intrinsic immune evasion.

RevDate: 2019-07-22

Ermoian RP, NA Vitanza (2019)

No Further Therapy.

International journal of radiation oncology, biology, physics, 104(5):969-970.

RevDate: 2019-07-21

Yeung CCS, M Shadman (2019)

How to Choose the Best Treatment and Testing for Chronic Lymphocytic Leukemia in the Tsunami of New Treatment Options.

Current oncology reports, 21(8):74 pii:10.1007/s11912-019-0819-x.

PURPOSE OF REVIEW: Treatment of chronic lymphocytic leukemia (CLL) has undergone a major shift since introduction of multiple targeted agents. B cell receptor inhibitors that target either bruton tyrosine kinase (ibrutinib) or phosphatidylinositol 3-kinases (idelalisib and duvelisib) and BCL-2 inhibitor venetoclax have become the mainstay of treatment.

RECENT FINDINGS: Newer generations of monoclonal antibodies targeting CD20 (obinutuzumab and ofatumumab) are commonly used with novel drugs or chemotherapy agents and result in improved efficacy. At the same time, chemoimmunotherapy remains a reasonable option for selected patients. Therefore, with variety of reasonable options, choice of treatment in first-line or relapsed setting has become more challenging. Better understanding of the molecular and cytogenetics data for each patient is critical to improve management of patients with CLL. Herein, we review our approach to diagnosis and treatment of CLL in the era of novel therapeutic agents.

RevDate: 2019-07-21

Liao GJ, Hippe DS, Chen LE, et al (2019)

Physician Ordering of Screening Ultrasound: National Rates and Association With State-Level Breast Density Reporting Laws.

Journal of the American College of Radiology : JACR pii:S1546-1440(19)30822-1 [Epub ahead of print].

PURPOSE: To describe factors associated with screening ultrasound ordering and determine whether adoption of state-level breast density reporting laws was associated with changes in ordering rates.

MATERIALS AND METHODS: We performed a cohort study using National Ambulatory Medical Care Survey data for 2007 to 2015. We included preventive office visits for women aged 40 to 74 years without breast symptoms and signs or additional reasons requiring ultrasound ordering. Multivariate logistic regression was used to identify changes in ultrasound ordering rates pre- versus post-state-level density reporting laws, accounting for patient-, physician-, and practice-level characteristics. Analyses were weighted to account for the multistage probability sampling design of National Ambulatory Medical Care Survey.

RESULTS: Our sample included 12,787 visits over the 9-year study period. Overall, 28.9% (3,370 of 12,787) of women underwent a breast examination and 22.1% (2,442 of 12,787) had a screening mammogram ordered. Only 3.3% (379 of 12,787) had screening ultrasound ordered. Screening ultrasounds were ordered more frequently for younger women (rate ratio [RR] 0.8 per 10-year increase in age, 95% confidence interval [CI]: 0.6-0.9, P = .003), at urban practices (RR 2.3, 95% CI: 1.1-5.0, P = .028), and less frequently in practices with computer reminders for ordering screening tests (RR 0.6, 95% CI: 0.3-0.9, P = .024). In multivariate analyses, the rate of ultrasound ordering did not change after adoption of density notification laws (RR 0.7, 95% CI: 0.3-2.0, P = .57).

CONCLUSION: The rate of screening ultrasound ordering remains low over time. There was no observed association between adoption of state-level density reporting laws and overall changes in ultrasound ordering.

RevDate: 2019-07-20

Kaley TJ, Panageas KS, Mellinghoff IK, et al (2019)

Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma.

Journal of neuro-oncology pii:10.1007/s11060-019-03243-7 [Epub ahead of print].

PURPOSE: Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades of biologic importance in glioblastoma, and has promising pre-clinical activity in vitro and in vivo. Therefore, we conducted a phase II open-label single-arm clinical trial of perifosine for patients with recurrent glioblastoma (GBM).

METHODS: We planned to accrue up to 30 adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy. Concurrent p450 stimulating hepatic enzyme inducing anticonvulsants were prohibited. Patients were treated with a loading dose of 600 mg PRF (in 4 divided doses on day 1) followed by 100 mg daily until either disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS6) rate, with at least 20% considered promising. Accrual was continuous but if 0 of the first 12 patients with GBM reached PFS6, then further accrual would terminate for futility. Patients with other high grade gliomas were accrued concurrently to an exploratory cohort.

RESULTS: Treatment was generally well tolerated; gastrointestinal toxicities were the most common side effects, although none resulted in treatment discontinuation. However, there was limited to no efficacy in GBM (n = 16): the PFS6 rate was 0%, median PFS was 1.58 months [95% CI (1.08, 1.84)], median overall survival was 3.68 months [95% CI (2.50, 7.79)], with no radiographic responses. There was a confirmed partial response in one patient with anaplastic astrocytoma (n = 14).

CONCLUSIONS: PRF is tolerable but ineffective as monotherapy for GBM. Preclinical data suggests synergistic effects of PRF in combination with other approaches, and further study is ongoing.

RevDate: 2019-07-20

Pan TD, Mueller BA, Dugowson CE, et al (2019)

Disease progression in relation to pre-onset parity among women with rheumatoid arthritis.

Seminars in arthritis and rheumatism pii:S0049-0172(18)30748-0 [Epub ahead of print].

OBJECTIVE: Rheumatoid arthritis (RA) often ameliorates during pregnancy and flares postpartum, but the relationship of pregnancy and childbirth to RA prognosis is unclear. We examined RA severity for association with parity prior to RA onset and asked whether time from birth (latency) and/or the mother's HLA genotype influenced results.

METHODS: A cohort study was conducted of 222 women previously identified in a prospective study of newly diagnosed RA, who returned for follow-up evaluation a median of 8 years later. Stratified analyses using Mantel-Haenszel methods were conducted to evaluate 5 RA severity measures based on hand and wrist radiographs, physical exams, and Health Assessment Questionnaires for association with parity.

RESULTS: Overall, we observed little evidence of altered risk of progression to severe RA in relation to pre-onset parity, adjusting for RA onset age and time to follow-up. Stratifying parous women who had only live births by latency (<15 years/15+ years) showed no difference in risk of severe RA compared to nulligravid women. Live birth deliveries were significantly protective for women with 0 but not for those with 1 or 2 copies of the RA risk-associated HLA-DRB1 shared epitope sequence for erosion score (RR 0.26 95% CI 0.09-0.89) and joint count (RR 0.28 95% CI 0.09-0.87).

CONCLUSION: We observed little evidence of difference in severe RA by pre-onset parity overall. However, among women not predisposed to RA by possessing the risk-associated HLA genotype, parous women who had only live births had lower risk of progression to severe RA as measured by erosion score and joint count.

RevDate: 2019-07-19

Feldstein LR, Ellis EM, Rowhani-Rahbar A, et al (2019)

Estimating the cost of illness and burden of disease associated with the 2014-2015 chikungunya outbreak in the U.S. Virgin Islands.

PLoS neglected tropical diseases, 13(7):e0007563 pii:PNTD-D-19-00592 [Epub ahead of print].

Chikungunya virus (CHIKV), an alphavirus that causes fever and severe polyarthralgia, swept through the Americas in 2014 with almost 2 million suspected or confirmed cases reported by April 2016. In this study, we estimate the direct medical costs, cost of lost wages due to absenteeism, and years lived with disability (YLD) associated with the 2014-2015 CHIKV outbreak in the U.S. Virgin Islands (USVI). For this analysis, we used surveillance data from the USVI Department of Health, medical cost data from three public hospitals in USVI, and data from two studies of laboratory-positive cases up to 12 months post illness. On average, employed case-patients missed 9 days of work in the 12 months following their disease onset, which resulted in an estimated cost of $15.5 million. Estimated direct healthcare costs were $2.9 million for the first 2 months and $0.6 million for 3-12 months following the outbreak. The total estimated cost associated with the outbreak ranged from $14.8 to $33.4 million (approximately 1% of gross domestic product), depending on the proportion of the population infected with symptomatic disease, degree of underreporting, and proportion of cases who were employed. The estimated YLDs associated with long-term sequelae from the CHIKV outbreak in the USVI ranged from 599-1,322. These findings highlight the significant economic burden of the recent CHIKV outbreak in the USVI and will aid policy-makers in making informed decisions about prevention and control measures for inevitable, future CHIKV outbreaks.

RevDate: 2019-07-18

Li A, Wu Q, Luo S, et al (2019)

Derivation and Validation of a Risk Assessment Model for Immunomodulatory Drug-Associated Thrombosis Among Patients With Multiple Myeloma.

Journal of the National Comprehensive Cancer Network : JNCCN, 17(7):840-847.

BACKGROUND: Although venous thromboembolism (VTE) is a significant complication for patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), no validated clinical model predicts VTE in this population. This study aimed to derive and validate a new risk assessment model (RAM) for IMiD-associated VTE.

METHODS: Patients with newly diagnosed MM receiving IMiDs were selected from the SEER-Medicare database (n=2,397) to derive a RAM and then data from the Veterans Health Administration database (n=1,251) were used to externally validate the model. A multivariable cause-specific Cox regression model was used for model development.

RESULTS: The final RAM, named the "SAVED" score, included 5 clinical variables: prior surgery, Asian race, VTE history, age ≥80 years, and dexamethasone dose. The model stratified approximately 30% of patients in both the derivation and the validation cohorts as high-risk. Hazard ratios (HRs) were 1.85 (P<.01) and 1.98 (P<.01) for high- versus low-risk groups in the derivation and validation cohorts, respectively. In contrast, the method of stratification recommended in the current NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease had HRs of 1.21 (P=.17) and 1.41 (P=.07) for the corresponding risk groups in the 2 datasets.

CONCLUSIONS: The SAVED score outperformed the current NCCN Guidelines in risk-stratification of patients with MM receiving IMiD therapy. This clinical model can help inform providers and patients of VTE risk before IMiD initiation and provides a simplified clinical backbone for further prognostic biomarker development in this population.

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RJR Experience and Expertise

Researcher

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

Educator

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

Administrator

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

Technologist

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

Publisher

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

Speaker

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

Facilitator

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

Designer

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

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

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