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Bibliography on: Publications by FHCRC Researchers

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


ESP: PubMed Auto Bibliography 20 Nov 2019 at 01:38 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: 2019-11-19

Hill JA, Krantz EM, Hay KA, et al (2019)

Durable preservation of antiviral antibodies after CD19-directed chimeric antigen receptor T-cell immunotherapy.

Blood advances, 3(22):3590-3601.

The long-term effects of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy (CD19-CARTx) for B-cell malignancies on humoral immunity are unclear. We examined antiviral humoral immunity in 39 adults with B-cell malignancies who achieved durable complete remission without additional therapy for >6 months after CD19-CARTx. Despite CD19+ B-cell aplasia in all patients, the incidence of viral infections occurring >90 days post-CD19-CARTx was low (0.91 infections per person-year). Because long-lived plasma cells are CD19- and should not be direct targets of CD19-targeted chimeric antigen receptor T cells, we tested the hypothesis that humoral immunity was preserved after CD19-CARTx based on linear mixed-effects models of changes in serum total immunoglobulin G (IgG) concentration, measles IgG concentration, and the number of viruses or viral epitopes to which serum IgG was directed (the "antivirome") using the novel VirScan assay. Samples were tested pre-CD19-CARTx and ∼1, 6, and 12 months post-CD19-CARTx. Although total IgG concentration was lower post-CD19-CARTx (mean change, -17.5%), measles IgG concentration was similar (mean change, 1.2%). Only 1 participant lost measles seroprotection post-CD19-CARTx but had undergone allogeneic hematopoietic cell transplantation before CD19-CARTx. The antivirome was also preserved, with mean absolute losses of 0.3 viruses and 6 viral epitopes detected between pre- and post-CD19-CARTx samples. Most participants gained IgG to ≥2 epitopes for ≥2 viruses, suggesting that humoral immunity to some viruses may be maintained or recover after successful CD19-CARTx. These findings may differ in children. Studies of immunoglobulin replacement and vaccination after CARTx are warranted.

RevDate: 2019-11-19

Sivakumar R, Chan M, Shin JS, et al (2019)

Organotypic tumor slice cultures provide a versatile platform for immuno-oncology and drug discovery.

Oncoimmunology, 8(12):e1670019 pii:1670019.

Organotypic tumor slices represent a physiologically-relevant culture system for studying the tumor microenvironment. Systematic characterization of the tumor slice culture system will enable its effective application for translational research. Here, using flow cytometry-based immunophenotyping, we performed a comprehensive characterization of the immune cell composition in organotypic tumor slices prepared from four syngeneic mouse tumor models and a human liver tumor. We found that the immune cell compositions of organotypic tumor slices prepared on the same day as the tumor cores were harvested are similar. Differences were primarily observed in the lymphocyte population of a clinical hepatocellular carcinoma case. Viable populations of immune cells persisted in the tumor slices for 7 days. Despite some changes in the immune cell populations, we showed the utility of mouse tumor slices for assessing responses to immune-modulatory agents. Further, we demonstrated the ability to use patient-derived xenograft tumor slices for assessing responses to targeted and cytotoxic drugs. Overall, tumor slices provide a broadly useful platform for studying the tumor microenvironment and evaluating the preclinical efficacy of cancer therapeutics.

RevDate: 2019-11-19

Neuhouser ML (2019)

Red and processed meat: more with less?.

The American journal of clinical nutrition pii:5628900 [Epub ahead of print].

RevDate: 2019-11-19

Majhail NS, Mau LW, Chitphakdithai P, et al (2019)

Transplant center characteristics and survival after allogeneic hematopoietic cell transplantation in adults.

Bone marrow transplantation pii:10.1038/s41409-019-0748-1 [Epub ahead of print].

Allogeneic hematopoietic cell transplantation (alloHCT) is a highly specialized procedure. We surveyed adult transplant centers in the United States (US) and then used data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2010) to evaluate associations of center volume, infrastructure, and care delivery models with survival post alloHCT. Based on their 2010 alloHCT volume, centers were categorized as low-volume (≤40 alloHCTs; N = 42 centers, 1900 recipients) or high-volume (>40 alloHCTs; N = 41 centers, 9637 recipients). 100-day survival was 86% (95% CI, 85-87%) in high-volume compared with 83% (95% CI, 81-85%) in low-volume centers (difference 3%; P < 0.001). One-year survival was 62% (95% CI, 61-63%) and 56% (95% CI, 54-58%), respectively (difference 6%; P < 0.001). Logistic regression analyses adjusted for patient and center characteristics; alloHCT at high-volume centers (odds ratio [OR] 1.32; P < 0.001) and presence of a survivorship program dedicated to HCT recipients (OR 1.23; P = 0.009) were associated with favorable 1-year survival compared to low-volume centers. Similar findings were observed in a CIBMTR validation cohort (2012-2014); high-volume centers had better 1-year survival (OR 1.24, P < 0.001). Among US adult transplant centers, alloHCT at high-volume centers and at centers with survivorship programs is associated with higher 1-year survival.

RevDate: 2019-11-18

Pidala J, Hamadani M, Dawson P, et al (2019)

Randomized Multicenter Trial of Sirolimus vs. Prednisone as Initial Therapy for Standard Risk Acute GVHD: BMT CTN 1501.

Blood pii:428815 [Epub ahead of print].

Clinical- and biomarker-based tools may identify a lower risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted an NHLBI/NCI-funded Blood and Marrow Transplant Clinical Trials Network (CTN) multi-center, open label, randomized phase II trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs. prednisone as initial treatment for patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA 1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus n=58, prednisone n=64). Others were AA3 (n=4), or AA status missing (n=1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% CI 54.1%-75.5%) vs. 73% (90% CI 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone {less than or equal to} 0.25mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs. 31.7%, p < 0.001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, non-relapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2-3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based standard risk acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. Additionally, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life.

RevDate: 2019-11-18

Olson BJ, Moghimi P, Schramm CA, et al (2019)

sumrep: A Summary Statistic Framework for Immune Receptor Repertoire Comparison and Model Validation.

Frontiers in immunology, 10:2533.

The adaptive immune system generates an incredible diversity of antigen receptors for B and T cells to keep dangerous pathogens at bay. The DNA sequences coding for these receptors arise by a complex recombination process followed by a series of productivity-based filters, as well as affinity maturation for B cells, giving considerable diversity to the circulating pool of receptor sequences. Although these datasets hold considerable promise for medical and public health applications, the complex structure of the resulting adaptive immune receptor repertoire sequencing (AIRR-seq) datasets makes analysis difficult. In this paper we introduce sumrep, an R package that efficiently performs a wide variety of repertoire summaries and comparisons, and show how sumrep can be used to perform model validation. We find that summaries vary in their ability to differentiate between datasets, although many are able to distinguish between covariates such as donor, timepoint, and cell type for BCR and TCR repertoires. We show that deletion and insertion lengths resulting from V(D)J recombination tend to be more discriminative characterizations of a repertoire than summaries that describe the amino acid composition of the CDR3 region. We also find that state-of-the-art generative models excel at recapitulating gene usage and recombination statistics in a given experimental repertoire, but struggle to capture many physiochemical properties of real repertoires.

RevDate: 2019-11-17

Zamora D, Krantz EM, Green ML, et al (2019)

The Cytomegalovirus Humoral Response Against Epithelial Cell Entry-mediated Infection in the Primary Infection Setting after Hematopoietic Cell Transplantation.

The Journal of infectious diseases pii:5627782 [Epub ahead of print].

BACKGROUND: The influence of humoral immunity on the prevention of primary cytomegalovirus (CMV) infection after hematopoietic cell transplantation (HCT) is poorly understood.

METHODS: To determine whether neutralizing antibodies (nAb) against CMV pentameric complex (PC)-mediated epithelial cell entry decrease CMV infection after HCT, samples were analyzed from a randomized controlled trial conducted by Bowden et al. (1991) of CMV intravenous immunoglobulin (IVIG) prophylaxis. Weekly serum from 61 CMV donor positive / recipient negative (D+/R-) HCT patients (33 control, 28 CMV IVIG) was tested using a PC-entry nAb assay and quantitative CMV polymerase chain reaction (PCR).

RESULTS: There was a trend toward higher weekly PC-entry nAb titers (p=0.07) and decreased CMV infection by PCR at viral load cutoffs of ≥ 1,000 IU/mL and ≥ 10,000 IU/mL in the CMV IVIG arm. High nAb titers were not significantly protective against CMV infection later after HCT in both study arms. Among CMV-infected patients, each log2 increase in nAb titer was associated with an average 0.2 log10 decrease in concurrent CMV viral load after infection (p=0.001; adjusted for study arm).

CONCLUSIONS: This study provides initial support that CMV IVIG prophylaxis moderately enhances PC-entry nAB activity in D+/R- HCT recipients.

RevDate: 2019-11-17

Narayan V, Harrison M, Cheng H, et al (2019)

Improving research for prostate cancer survivorship: A statement from the Survivorship Research in Prostate Cancer (SuRECaP) working group.

Urologic oncology pii:S1078-1439(19)30410-7 [Epub ahead of print].

Survivorship care for patients with prostate cancer requires careful consideration of unique disease-specific factors, including the prolonged natural disease history, the potential for competing health risks, and the consequences of long-term androgen deprivation therapy. However, current prostate cancer survivorship research is unfortunately limited by the lack of a robust supportive evidence base, variability in the definitions and measurement of survivorship outcomes, and a heavy reliance on expert opinion. As a result, the conduct of quality prostate cancer survivorship research is of increasing importance for patients, medical providers, and other key stakeholders. This manuscript harmonizes a path forward for improving prostate cancer survivorship by defining prostate cancer survivorship and survivorship research, as well as by highlighting key research priorities and cooperative mechanisms for survivorship studies within prostate cancer, with a particular focus on men with advanced disease.

RevDate: 2019-11-16

Marsh TL, Janes H, MS Pepe (2019)

Statistical inference for net benefit measures in biomarker validation studies.

Biometrics [Epub ahead of print].

Referral strategies based on risk scores and medical tests are commonly proposed. Direct assessment of their clinical utility requires implementing the strategy and is not possible in early phases of biomarker research. Prior to late-phase studies, net benefit measures can be used to assess the potential clinical impact of a proposed strategy. Validation studies, in which the biomarker defines a prespecified referral strategy, are a gold standard approach to evaluating biomarker potential. Uncertainty, quantified by a confidence interval, is important to consider when deciding whether a biomarker warrants an impact study, does not demonstrate clinical potential, or that more data are needed. We establish distribution theory for empirical estimators of net benefit and propose empirical estimators of variance. The primary results are for the most commonly employed estimators of net benefit: from cohort and unmatched case-control samples, and for point estimates and net benefit curves. Novel estimators of net benefit under stratified two-phase and categorically matched case-control sampling are proposed and distribution theory developed. Results for common variants of net benefit and for estimation from right-censored outcomes are also presented. We motivate and demonstrate the methodology with examples from lung cancer research and highlight its application to study design. This article is protected by copyright. All rights reserved.

RevDate: 2019-11-16

Glumac PM, Gallant JP, Shapovalova M, et al (2019)

Exploitation of CD133 for the targeted imaging of lethal prostate cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-1659 [Epub ahead of print].

PURPOSE: Aggressive variant prostate cancer (AVPC) is a non-androgen receptor-driven form of disease that arises in men who have failed standard-of-care therapies. Therapeutic options for AVPC are limited, and the development of novel therapeutics is significantly hindered by the inability to accurately quantify patient response to therapy by imaging. Imaging modalities that accurately and sensitively detect the bone and visceral metastases associated with AVPC do not exist.

EXPERIMENTAL DESIGN: This study investigated the transmembrane protein CD133 as a targetable cell surface antigen in AVPC. We evaluated the expression of CD133 by microarray and immunohistochemistry analysis. The imaging potential of the CD133-targeted IgG (HA10 IgG) was evaluated in preclinical prostate cancer models using two different imaging modalities: near-infrared and positron emission tomography (PET) imaging.

RESULTS: Evaluation of the patient data demonstrated that CD133 is overexpressed in a specific phenotype of AVPC that is androgen receptor-indifferent and neuroendocrine differentiated. Additionally, HA10 IgG was selective for CD133-expressing tumors in all preclinical imaging studies. PET imaging with [89Zr]Zr-HA10 IgG revealed a mean %ID/g of 24.30±3.19 in CD133-positive metastatic lesions as compared to 11.82±0.57 in CD133-negative lesions after 72 hours (p=0.0069). Ex vivo biodistribution showed similar trends as signals were increased by nearly 3-fold in CD133-positive tumors (p<0.0001).

CONCLUSIONS: To our knowledge, this is the first study to define CD133 as a targetable marker of AVPC. Similarly, we have developed a novel imaging agent which is selective for CD133-expressing tumors, resulting in a non-invasive PET imaging approach to more effectively detect and monitor AVPC.

RevDate: 2019-11-16

Dubrovskaya V, Tran K, Ozorowski G, et al (2019)

Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability.

Immunity pii:S1074-7613(19)30452-2 [Epub ahead of print].

The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.

RevDate: 2019-11-15

Richter DJ, TC Levin (2019)

The origin and evolution of cell-intrinsic antibacterial defenses in eukaryotes.

Current opinion in genetics & development, 58-59:111-122 pii:S0959-437X(19)30013-9 [Epub ahead of print].

To survive in a world dominated by bacteria, eukaryotes have evolved numerous self-defense strategies. While some defenses are recent evolutionary innovations, others are ancient, with roots early in eukaryotic history. With a focus on antibacterial immunity, we highlight the evolution of pattern recognition receptors that detect bacteria, where diverse functional classes have been formed from the repeated use and reuse of a small set of protein domains. Next, we discuss core microbicidal strategies shared across eukaryotes, and how these systems may have been co-opted from ancient cellular mechanisms. We propose that studying antibacterial responses across diverse eukaryotes can reveal novel modes of defense, while highlighting the critical innovations that occurred early in the evolution of our own immune systems.

RevDate: 2019-11-15

Kopmar NE, EH Estey (2019)

New drug approvals in acute myeloid leukemia: an unprecedented paradigm shift.

Clinical advances in hematology & oncology : H&O, 17(10):569-575.

We are witnessing an unprecedented paradigm shift in the treatment of acute myeloid leukemia (AML). For nearly 4 decades-since the introduction of cytarabine- and anthracycline-based induction chemotherapy in the 1970s-treatment options for patients with AML have remained limited, and outcomes remain poor for the majority of patients, particularly the elderly. Over the past 10 to 15 years, we have better elucidated the genetic and molecular basis of AML, which has led to our current understanding of disease heterogeneity. We now appreciate that numerous distinct disease subtypes exist, each with their own disease characteristics and risk profile. In keeping with this improved understanding, we have seen the introduction of numerous new agents that are mechanistically targeted against a specific mutation, a deranged cellular pathway, and/or a specific AML disease subset. Within the last 3 years alone, the US Food and Drug Administration has approved 8 new targeted agents for the treatment of AML. With their introduction comes a new sense of optimism, along with questions about how to best use these agents. In this article, we discuss the recently approved agents in AML, the rationale behind their development and the trials that served as the basis for their approval, and the implications of their introduction into the treatment armamentarium.

RevDate: 2019-11-15

Montgomery B (2019)

Prostate cancer in military veterans.

Clinical advances in hematology & oncology : H&O, 17(10):552-554.

RevDate: 2019-11-15

Lyman GH (2019)

How biosimilars will impact costs and care in oncology.

Clinical advances in hematology & oncology : H&O, 17(10):544-547.

RevDate: 2019-11-15

Baker KS (2019)

Insights into survivorship care for cancer patients.

Clinical advances in hematology & oncology : H&O, 17(10):541-543.

RevDate: 2019-11-15

Khera N, Deeg HJ, Kodish E, et al (2019)

Allogeneic Hematopoietic Cell Transplantation and Other Expensive Cellular Therapies: A Miracle for the Few but Off Limits to Many?.

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

RevDate: 2019-11-15

Preussler JM, Denzen EM, Majhail NS, et al (2019)

Engaging hematopoietic cell transplantation patients and caregivers in the design of print and mobile application individualized survivorship care plan tools.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-019-05114-3 [Epub ahead of print].

PURPOSE: INSPIRE (INteractive Survivorship Program with Information and REsources) is an online health program that includes a mobile app, website, health action plan, and individualized survivorship care plans for adult hematopoietic cell transplant (HCT) survivors. The INSPIRE program integrates two previously effective randomized control trials that tested an internet-based program and patient-centered survivorship care plans for HCT survivors.

METHODS: Three focus groups were conducted with a total of 22 participants (20 patients, 2 caregivers/patient advocates) to explore patient and caregiver preferences and to optimize the patient-centered emphasis of INSPIRE. Adult (age > 18 years at the time of study entry) HCT recipients had to be at least 1-year post-HCT to participate; caregivers/patient advocates were also eligible. Participants had to be able to communicate in English, could have any diagnosis, transplant type, or donor source, and could have had multiple transplants.

RESULTS: All patient participants received an allogeneic HCT; average time since HCT was 8 years (range 2-22 years). The majority of participants were female (77.3%). Overall, the tools were well received by participants in this study, particularly the personalized features of all the tools. Major themes included interest in having the ability to tailor features to individual needs, and an interest in tracking information over time.

DISCUSSION: Engaging patients and caregivers is invaluable to optimize tools designed to improve HCT survivorship care. Print, online, and mobile-based tools, tailored to individual patients' treatment history and requisite follow-up care, can provide otherwise unavailable expertise and guidelines for care.

RevDate: 2019-11-15

Brusca RM, Hanna DB, Wada NI, et al (2019)

Subclinical cardiovascular disease in HIV controller and long-term nonprogressor populations.

HIV medicine [Epub ahead of print].

OBJECTIVES: Elite controllers (ECs), viraemic controllers (VCs), and long-term nonprogressors (LTNPs) control HIV viral replication or maintain CD4 T-cell counts without antiretroviral therapy, but may have increased cardiovascular disease (CVD) risk compared to HIV-uninfected persons. We evaluated subclinical carotid and coronary atherosclerosis and inflammatory biomarker levels among HIV controllers, LTNPs and noncontrollers and HIV-uninfected individuals in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS).

METHODS: We measured carotid plaque presence and common carotid artery intima-media thickness (IMT) in 1729 women and 1308 men, and the presence of coronary artery calcium and plaque in a subgroup of men. Associations between HIV control category and carotid and coronary plaque prevalences were assessed by multivariable regression analyses adjusting for demographics and CVD risk factors. Serum inflammatory biomarker concentrations [soluble CD163 (sCD163), soluble CD14 (sCD14), galectin-3 (Gal-3), galectin-3 binding protein (Gal-3BP) and interleukin (IL)-6] were measured and associations with HIV control category assessed.

RESULTS: We included 135 HIV controllers (30 ECs) and 135 LTNPs in the study. Carotid plaque prevalence and carotid IMT were similar in HIV controllers, LTNPs and HIV-uninfected individuals. HIV controllers and LTNPs had lower prevalences of carotid plaque compared to viraemic HIV-infected individuals. The prevalence of coronary atherosclerosis was similar in HIV controllers/LTNPs compared to HIV-uninfected and viraemic HIV-infected men. Controllers and LTNPs had higher concentrations of sCD163 and sCD14 compared to HIV-uninfected persons.

CONCLUSIONS: Subclinical CVD was similar in HIV controllers, LTNPs and HIV-uninfected individuals despite elevated levels of some inflammatory biomarkers. Future studies of HIV controllers and LTNPs are needed to characterize the risk of CVD among HIV-infected persons.

RevDate: 2019-11-15

Li C, Course MM, McNeish IA, et al (2019)

Prophylactic in vivo hematopoietic stem cell gene therapy with an immune checkpoint inhibitor reverses tumor growth in syngeneic mouse tumor models.

Cancer research pii:0008-5472.CAN-19-1044 [Epub ahead of print].

Population-wide testing for cancer-associated mutations has established that more than one-fifth of ovarian and breast carcinomas are associated with inherited risk. Salpingo-oophorectomy and/or mastectomy are currently the only effective options offered to women with high-risk germ-line mutations. Our goal here is to develop a long-lasting approach that provides immuno-prophylaxis for mutation carriers. Our approach leverages the fact that at early stages, tumors recruit hematopoietic stem/progenitor cells (HSPCs) from the bone marrow and differentiate them into tumor-supporting cells. We developed a technically simple technology to genetically modify HSPCs in vivo. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. In vivo HSPC transduction with a GFP-expressing vector and subsequent implantation of syngeneic tumor cells showed >80% GFP-marking in tumor infiltrating leukocytes. To control expression of transgenes, we developed a miRNA regulation system that is activated only when HSPCs are recruited to and differentiated by the tumor. We tested our approach using the immune checkpoint inhibitor antiPD-L1-gamma1 as an effector gene. In in vivo HSPC-transduced mice with implanted mouse mammary carcinoma (MMC) tumors, after initial tumor growth, tumors regressed and did not recur. Conventional treatment with an anti-PD-L1 monoclonal antibody had no significant anti-tumor effect, indicating that early, self-activating expression of antiPD-L1-gamma1 can overcome the immunosuppressive environment in MMC tumors. The efficacy and safety of this approach was further validated in an ovarian cancer model with typical germ-line mutations (ID8 p53-/- brca2-/-), both in a prophylactic and therapeutic setting. This HSPC gene therapy approach has potential for clinical translation.

RevDate: 2019-11-14

Hanash SM, Feng Z, A Taguchi (2019)

Failure to Disclose Potential Conflict of Interest-Letter of Explanation.

JAMA oncology pii:2755636 [Epub ahead of print].

RevDate: 2019-11-14

Guadamuz JS, Ozenberger K, Qato DM, et al (2019)

Mediation analyses of socioeconomic factors determining racial differences in the treatment of diffuse large B-cell lymphoma in a cohort of older adults.

Medicine, 98(46):e17960.

Despite near universal health coverage under Medicare, racial disparities persist in the treatment of diffuse large B-cell lymphoma (DLBCL) among older patients in the United States. Studies evaluating DLBCL outcomes often treat socioeconomic status (SES) measures as confounders, potentially introducing biases when SES factors are mediators of disparities in cancer treatment.To examine differences in DLBCL treatment, we performed causal mediation analyses of SES measures, including: metropolitan statistical area (MSA) of residence; census-tract poverty level; and private Medicare supplementation using the Surveillance, Epidemiology and End Results-Medicare linked database between 2001 and 2011. In this retrospective cohort study of DLBCL patients ages 66+ years, we conducted a series of multivariable logistic regression analyses estimating odds ratios (OR) and 95% confidence intervals (CI) relating chemo- and/or immuno-therapy treatment and each SES measure, comparing non-Hispanic (NH)-black, Hispanic/Latino, and Asian/Pacific Islander (API) to NH-white patients.Compared to NH-white patients, racial/ethnic minority patients had lower odds of receiving chemo- and/or immuno-therapy treatment (NH-black: OR 0.84, 95% CI 0.65, 1.08; API: OR 0.80, 95% CI 0.64, 1.01; Hispanic/Latino: OR 0.78, 95% CI 0.64, 0.96) and higher odds of lacking private Medicare supplementation and residence within an urban MSA and poor census tracts. Adjustment for SES measures as confounders nullified observed racial differences. In causal mediation analyses, between 31% and 38% of race/ethnicity differences were mediated by having private Medicare supplementation.Providing equitable access to Medicare supplementation may reduce disparities in receipt of chemo- and/or immuno-therapy treatment in older DLBCL patients.

RevDate: 2019-11-14

Li A, Wu QV, Hilton T, et al (2019)

Soluble C5b-9 As a Prognostic Biomarker for Thrombotic Microangiopathy at the Onset of Graft-Versus-Host Disease.

Blood, 134(Supplement_1):40.

DISCLOSURES: Schmidt: Kypha Inc: Employment, Equity Ownership. Lee:Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding.

RevDate: 2019-11-14

Schuster SJ, Bartlett NL, Assouline S, et al (2019)

Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines.

Blood, 134(Supplement_1):6.

DISCLOSURES: Schuster: Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Nordic Nanovector: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding. Bartlett:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yoon:Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MSD: Consultancy; Janssen: Consultancy; Yuhan Pharma: Research Funding. Bosch:Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sehn:Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Apobiologix: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria; TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Cheah:Janssen: Honoraria; Acerta: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Gilead: Honoraria; Loxo: Honoraria. Shadman:Mustang Biopharma: Research Funding; Gilead: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Atara: Consultancy; Bigene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Verastem: Consultancy; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Merck: Research Funding. Gregory:MSD: Other: grant pending, Research Funding; Beigene: Other: Grant pending, Research Funding; Celgene: Other: grant pending, Research Funding; Monash University: Research Funding; Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: grant pending, Research Funding; Janssen: Other: grant pending, Research Funding; Melbourne Haematology: Consultancy, Honoraria, Other: Travel fees and conference support, Speakers Bureau. Wei:Genentech, Inc./F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Yin:Genentech, Inc: Employment, Equity Ownership. Kwan:Genentech, Inc: Employment, Equity Ownership. Yousefi:F. Hoffmann-La Roche Ltd: Employment. Hernandez:Genentech, Inc.: Employment, Equity Ownership. Li:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. O'Hear:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Budde:F. Hoffmann-La Roche Ltd: Consultancy.

OFF LABEL DISCLOSURE: Mosunetuzumab (RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

RevDate: 2019-11-13

Resnick R, Wong CJ, Hamm DC, et al (2019)

DUX4-Induced Histone Variants H3.X and H3.Y Mark DUX4 Target Genes for Expression.

Cell reports, 29(7):1812-1820.e5.

The DUX4 transcription factor is briefly expressed in the early cleavage-stage embryo, where it induces an early wave of zygotic gene transcription, whereas its mis-expression in skeletal muscle causes the muscular dystrophy facioscapulohumeral dystrophy (FSHD). Here, we show that DUX4 induces the expression of the histone variants H3.X and H3.Y. We have used a myoblast cell line with doxycycline-inducible DUX4 to show that these histone variants are incorporated throughout the body of DUX4-induced genes. Following a brief pulse of DUX4, these histones contribute to greater perdurance and to enhanced re-activation of DUX4 target gene expression. These findings provide a model for H3.X/Y as a chromatin mechanism that facilitates the expression of DUX4 target genes subsequent to a brief pulse of DUX4 expression.

RevDate: 2019-11-13

Hsieh AL, Zheng X, Yue Z, et al (2019)

Misregulation of Drosophila Myc Disrupts Circadian Behavior and Metabolism.

Cell reports, 29(7):1778-1788.e4.

Drosophila Myc (dMyc) is highly conserved and functions as a transcription factor similar to mammalian Myc. We previously found that oncogenic Myc disrupts the molecular clock in cancer cells. Here, we demonstrate that misregulation of dMyc expression affects Drosophila circadian behavior. dMyc overexpression results in a high percentage of arrhythmic flies, concomitant with increases in the expression of clock genes cyc, tim, cry, and cwo. Conversely, flies with hypomorphic mutations in dMyc exhibit considerable arrhythmia, which can be rescued by loss of dMnt, a suppressor of dMyc activity. Metabolic profiling of fly heads revealed that loss of dMyc and its overexpression alter steady-state metabolite levels and have opposing effects on histidine, the histamine precursor, which is rescued in dMyc mutants by ablation of dMnt and could contribute to effects of dMyc on locomotor behavior. Our results demonstrate a role of dMyc in modulating Drosophila circadian clock, behavior, and metabolism.

RevDate: 2019-11-13

Paulson KG, Gupta D, Kim TS, et al (2019)

Age-Specific Incidence of Melanoma in the United States.

JAMA dermatology pii:2754716 [Epub ahead of print].

Importance: Melanoma is epidemiologically linked to UV exposure, particularly childhood sunburn. Public health campaigns are increasing sun-protective behavior in the United States, but the effect on melanoma incidence is unknown.

Objective: To examine the incidence of melanoma in the United States and whether any age-specific differences are present.

Observational, population-based registry data were extracted on July 3, 2018, from the combined National Program of Cancer Registries-Surveillance Epidemiology and End Results United States Cancer Statistics database for 2001-2015. Deidentified data for 988 103 cases of invasive melanoma, with International Classification of Diseases for Oncology histologic categorization codes 8720 to 8790, were used for analysis. Data analysis was performed from July 1, 2018, to March 1, 2019.

Main Outcomes and Measures: The annual rates of melanoma in pediatric, adolescent, young adult, and adult age groups were determined. Analyses were stratified by sex, and incidence rates were age-adjusted to the 2000 US standard population. Annual percentage change (APC) in incidence rate was calculated over the most recent decade for which data were available (2006-2015) using the weighted least squares method.

Results: In 2015, 83 362 cases of invasive melanoma were reported in the United States, including 67 in children younger than 10 years, 251 in adolescents (10-19 years), and 1973 in young adults (20-29 years). Between 2006 and 2015, the overall incidence rate increased from 200.1 to 229.1 cases per million person-years. In adults aged 40 years or older, melanoma rates increased by an APC of 1.8% in both men (95% CI, 1.4%-2.1%) and women (95% CI, 1.4%-2.2%). In contrast, clinically and statistically significant decreases were seen in melanoma incidence for adolescents and young adults. Specifically, incidence rates decreased by an APC of -4.4% for male adolescents (95% CI, -1.7% to -7.0%), -5.4% for female adolescents (95% CI, -3.3% to -7.4%), -3.7% for male young adults (95% CI, -2.5% to -4.8%), and -3.6% for female young adults (95% CI, -2.8% to -4.5%). Data on skin pigmentation and sun protection history were unavailable; similar trends were observed with data limited to non-Hispanic whites. Young adult women appeared to have twice the risk of melanoma as young adult men.

Conclusions and Relevance: The incidence of invasive melanoma in the United States appeared to decrease in adolescents and young adults from 2006 to 2015, and this finding contrasted with increases in older populations. These incidence trends suggest that public health efforts may be favorably influencing melanoma incidence in the United States.

RevDate: 2019-11-13

Khan HM, Gardner KM, Shaw C, et al (2019)

Need for routine examination of left ventricular ejection fraction in patients with AML.

RevDate: 2019-11-13

Noordam R, Bos MM, Wang H, et al (2019)

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Nature communications, 10(1):5121 pii:10.1038/s41467-019-12958-0.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

RevDate: 2019-11-13

Huang T, Townsend MK, Wentzensen N, et al (2019)

Reproductive and hormonal factors and risk of ovarian cancer by tumor dominance: results from the Ovarian Cancer Cohort Consortium (OC3).

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-19-0734 [Epub ahead of print].

BACKGROUND: Laterality of epithelial ovarian tumors may reflect the underlying carcinogenic pathways and origins of tumor cells.

METHODS: We pooled data from 9 prospective studies participating in the Ovarian Cancer Cohort Consortium. Information on measures of tumor size or tumor dominance was extracted from surgical pathology reports or obtained through cancer registries. We defined dominant tumors as those restricted to one ovary or where the dimension of one ovary was at least twice as large as the other, and non-dominant tumors as those with similar dimensions across the two ovaries or peritoneal tumors. Competing risks Cox models were used to examine whether associations with reproductive and hormonal risk factors differed by ovarian tumor dominance.

RESULTS: Of 1,058 ovarian cancer cases with tumor dominance information, 401 were left-dominant, 363 were right-dominant, and 294 were non-dominant. Parity was more strongly inversely associated with risk of dominant than non-dominant ovarian cancer (p-heterogeneity=0.004). Ever use of oral contraceptives (OCs) was associated with lower risk of dominant tumors, but was not associated with non-dominant tumors (p-heterogeneity=0.01). Higher body mass index was associated with higher risk of left-dominant tumors, but not significantly associated with risk of right-dominant or non-dominant tumors (p-heterogeneity=0.08).

CONCLUSIONS: These data suggest that reproductive and hormonal risk factors appear to have a stronger impact on dominant tumors, which may have an ovarian or endometriosis origin.

IMPACT: Examining the associations of ovarian cancer risk factors by tumor dominance may help elucidate the mechanisms through which these factors influence ovarian cancer risk.

RevDate: 2019-11-13

Smith JL, Ries RE, Hylkema T, et al (2019)

Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-positive AML Defines Novel Therapeutic Options - A COG and TARGET Pediatric AML Study.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-1800 [Epub ahead of print].

PURPOSE: A cryptic inv(16)(p13.3q24.3) encoding the CBFA2T3-GLIS2 fusion is associated with poor outcome in infants with acute megakaryocytic leukemia. We aimed to broaden our understanding of the pathogenesis of this fusion through transcriptome profiling.

EXPERIMENTAL DESIGN: Available RNA from children and young adults with de novo AML (N=1,049) underwent transcriptome sequencing (mRNA and miRNA). Transcriptome profiles for those with the CBFA2T3-GLIS2 fusion (N=24) and without (N=1,025) were contrasted to define fusion-specific miRNAs, genes, and pathways. Clinical annotations defined distinct fusion-associated disease characteristics and outcomes.

RESULTS: The CBFA2T3-GLIS2 fusion was restricted to infants < 3 years-old (p<0.001) and presence of this fusion was highly associated with adverse outcome (p<0.001) across all morphological classifications. Further, there was a striking paucity of recurrent cooperating mutations and transduction of cord blood stem cells with this fusion was sufficient for malignant transformation. CBFA2T3-GLIS2 positive cases displayed marked up-regulation of genes with cell membrane/extracellular matrix localization potential, including NCAM1 and GABRE. Additionally, miRNA profiling revealed significant over-expression of mature miR-224 and miR-452, which are intronic miRNAs transcribed from the GABRE locus. Gene-set enrichment identified dysregulated Hippo, TGFβ, and hedgehog signaling, as well as NCAM1 (CD56) Interaction pathways. Therapeutic targeting of fusion-positive leukemic cells with CD56-directed ADC caused significant cytotoxicity in leukemic blasts.

CONCLUSIONS: The CBFA2T3-GLIS2 fusion defines a highly refractory entity limited to infants that appears to be sufficient for malignant transformation. Transcriptome profiling elucidated several highly targetable genes and pathways, including the identification of CD56, providing a highly plausible target for therapeutic intervention.

RevDate: 2019-11-12

Bader P, Salzmann-Manrique E, Balduzzi A, et al (2019)

More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling.

Blood advances, 3(21):3393-3405.

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.

RevDate: 2019-11-12

Ranganathan M, Kilburn K, Stoner MCD, et al (2019)

The mediating role of partner selection in the association between transactional sex and HIV incidence among young women.

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

OBJECTIVE: In sub-Saharan Africa, transactional sex is associated with an increased risk of HIV infection in adolescent girls and young women, but the mechanisms for this relationship remain unclear. We hypothesise that young women who report transactional sex may have multiple partners and older partners, thereby increasing their HIV risk.

SETTING: We used longitudinal data from the HPTN 068 trial in rural South Africa where young women aged 13-20 who were HIV-negative at enrolment (n=2362) were followed approximately annually for up to 6 years.

METHODS: We used the parametric g-formula to estimate the total effect of time-varying, frequent transactional sex (receipt of gifts/money at least weekly vs monthly or less) on HIV incidence and the controlled direct effect for mediation in a simulated cohort using 20,000 bootstrapped observations. We calculated rates and hazard ratios over the entire study period.

RESULTS: The hazard ratio for the total effect of frequent transactional sex on HIV incidence was 1.56 (95% CI: 1.28, 1.85). However, this effect was mediated by partner age (>5+) and number of partners (>1) and the hazard ratio was attenuated to 1.09 (95% CI: 0.90, 1.28) when setting both partner age and partner number constant.

CONCLUSION: Both partner age difference and partner number mediate the relationship between transactional sex and incident HIV infection. Through this mediation analysis, we provide important longitudinal evidence to suggest that young women who engage in frequent transactional sex select multiple partners, often older male partners that may be part of higher risk sexual networks.

RevDate: 2019-11-12

Williams-Nguyen J, Hawes SE, Nance RM, et al (2019)

Association of Infection with Chronic Hepatitis C Virus and Myocardial Infarction in People Living with HIV in the United States.

American journal of epidemiology pii:5622678 [Epub ahead of print].

Hepatitis C virus (HCV) is common among people living with human immunodeficiency virus (PLWH). Extrahepatic manifestations of HCV, including myocardial infarction (MI), are a topic of active research. MI is classified into types, predominantly atheroembolic Type 1 MI (T1MI) and supply-demand mismatch Type 2 MI (T2MI). We examined the association between HCV and MI in the Centers for Acquired Immunodeficiency Syndrome Research Network of Integrated Clinical Systems, a multi-center clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Universal MI definition. We estimated the association between chronic HCV (RNA+) and time to MI adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics and history of injecting drug use. Among 23,407 PLWH aged ≥18, there were 336 T1MI and 330 T2MI during a median of 4.7 years of follow-up during 1998 through 2016. HCV was associated with a 46% greater risk of T2MI (adjusted hazard ratio (aHR) 1.46, 95% CI: 1.09, 1.97) but not T1MI (aHR 0.87, 95% CI: 0.58, 1.29). In an exploratory cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR 2.01, 95% CI: 1.25, 3.24). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research.

RevDate: 2019-11-12

Lai HTM, de Oliveira Otto MC, Lee Y, et al (2019)

Serial Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway and Total Mortality, Cause-Specific Mortality, and Cardiovascular Diseases in the Cardiovascular Health Study.

Journal of the American Heart Association, 8(22):e012881.

Background Synthesized fatty acids (FAs) from de novo lipogenesis may affect cardiometabolic health, but longitudinal associations between serially measured de novo lipogenesis-related fatty acid biomarkers and mortality or cardiovascular disease (CVD) are not well established. Methods and Results We investigated longitudinal associations between de novo lipogenesis-related fatty acids with all-cause mortality, cause-specific mortality, and incident CVD among 3869 older US adults, mean (SD) age 75 (5) years and free of prevalent CVD at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n-7), stearic (18:0), oleic acid (18:1n-9), and other risk factors were serially measured at baseline, 6 years, and 13 years. All-cause mortality, cause-specific mortality, and incident fatal and nonfatal CVD were centrally adjudicated. Risk was assessed in multivariable-adjusted Cox models with time-varying FAs and covariates. During 13 years, median follow-up (maximum 22.4 years), participants experienced 3227 deaths (1131 CVD, 2096 non-CVD) and 1753 incident CVD events. After multivariable adjustment, higher cumulative levels of 16:0, 16:1n-7, and 18:1n-9 were associated with higher all-cause mortality, with extreme-quintile hazard ratios (95% CIs) of 1.35 (1.17-1.56), 1.40 (1.21-1.62), and 1.56 (1.35-1.80), respectively, whereas higher levels of 18:0 were associated with lower mortality (hazard ratio=0.76; 95% CI=0.66-0.88). Associations were generally similar for CVD mortality versus non-CVD mortality, as well as total incident CVD. Changes in levels of 16:0 were positively, and 18:0 inversely, associated with all-cause mortality (hazard ratio=1.23, 95% CI=1.08-1.41; and hazard ratio=0.78, 95% CI=0.68-0.90). Conclusions Higher long-term levels of 16:0, 16:1n-7, and 18:1n-9 and changes in 16:0 were positively, whereas long-term levels and changes in 18:0 were inversely, associated with all-cause mortality in older adults.

RevDate: 2019-11-11

Tripathi A, P Grivas (2019)

The utility of next generation sequencing in advanced urothelial carcinoma.

European urology focus pii:S2405-4569(19)30274-3 [Epub ahead of print].

Biomarker-driven clinical trials are crucial for improving outcomes in patients with advanced urothelial carcinoma (aUC). Multiplatform genomic analyses utilizing next generation sequencing of tumor tissue and cell-free circulating tumor DNA have provided novel insights into the biology of UC and identified several molecular subtypes with potential therapeutic implications. Several "targetable" genomic alterations have been identified, such as those involving Fibroblast Growth Factor Receptor (FGFR), Human Epidermal growth factor Receptors, DNA damage response pathway, among others. Agents targeting those pathways have demonstrated encouraging efficacy in early clinical trials, while the FGFR inhibitor erdafitinib received accelerated approval by the FDA for platinum-refractory metastatic bladder cancer harboring FGFR2/3 alterations. Identification and validation of targets and potential biomarkers predictive of response will be crucial for successfully incorporating novel therapeutic strategies in the evolving treatment landscape of aUC. Standardization of molecular profiling, regarding assay, timing, origin of tumor specimen and other parameters may enable a more systematic assessment of clinical utility. PATIENT SUMMARY: 'Personalized cancer therapy' aims to tailor treatments to the characteristics of an individual patient's tumor. Next generation sequencing analyzes genes in a patient's tumor sample to identify abnormalities unique to his/her cancer. Clinicians can attempt to use this information to select the best treatment at the right time. This approach has shown significant promise and resulted in the approval of a new therapy for certain patients with advanced urothelial cancer; however, more work is required for broader impact and added value in patient care overall.

RevDate: 2019-11-09

Radtke S, Humbert O, HP Kiem (2019)

Mouse Models in Hematopoietic Stem Cell Gene Therapy and Genome Editing.

Biochemical pharmacology pii:S0006-2952(19)30391-0 [Epub ahead of print].

Gene therapy has become an important treatment option for a variety of hematological diseases. The biggest advances have been made with CAR T cells and many of those studies are now FDA approved as a routine treatment for some hematologic malignancies. Hematopoietic stem cell (HSC) gene therapy is not far behind with treatment approvals granted for beta-hemoglobinopathies and adenosine deaminase severe combined immune deficiency (ADA-SCID), and additional approbations currently being sought. With the current pace of research, the significant investment of biotech companies, and the continuously growing toolbox of viral as well as non-viral gene delivery methods, the development of new ex vivo and in vivo gene therapy approaches is at an all-time high. Research in the field of gene therapy has been ongoing for more than 4 decades with big success stories as well as devastating drawbacks along the way. In particular, the damaging effect of uncontrolled viral vector integration observed in the initial gene therapy applications in the 90s led to a more comprehensive upfront safety assessment of treatment strategies. Since the late 90s, an important read-out to comprehensively assess the quality and safety of cell products has come forward with the mouse xenograft model. Here, we review the use of mouse models across the different stages of basic, pre-clinical and translational research towards the clinical application of HSC-mediated gene therapy and editing approaches.

RevDate: 2019-11-09

Nie L, Wei Y, Zhang F, et al (2019)

CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

Nature communications, 10(1):5114 pii:10.1038/s41467-019-13105-5.

Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.

RevDate: 2019-11-09

Phad GE, Pushparaj P, Tran K, et al (2019)

Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses.

The Journal of experimental medicine pii:jem.20191155 [Epub ahead of print].

Well-ordered HIV-1 envelope glycoprotein (Env) trimers are prioritized for clinical evaluation, and there is a need for an improved understanding about how elicited B cell responses evolve following immunization. To accomplish this, we prime-boosted rhesus macaques with clade C NFL trimers and identified 180 unique Ab lineages from ∼1,000 single-sorted Env-specific memory B cells. We traced all lineages in high-throughput heavy chain (HC) repertoire (Rep-seq) data generated from multiple immune compartments and time points and expressed several as monoclonal Abs (mAbs). Our results revealed broad dissemination and high levels of somatic hypermutation (SHM) of most lineages, including tier 2 virus neutralizing lineages, following boosting. SHM was highest in the Ab complementarity determining regions (CDRs) but also surprisingly high in the framework regions (FRs), especially FR3. Our results demonstrate the capacity of the immune system to affinity-mature large numbers of Env-specific B cell lineages simultaneously, supporting the use of regimens consisting of repeated boosts to improve each Ab, even those belonging to less expanded lineages.

RevDate: 2019-11-09

Salipante SJ, KR Jerome (2019)

Digital PCR-An Emerging Technology with Broad Applications in Microbiology.

Clinical chemistry pii:clinchem.2019.304048 [Epub ahead of print].

BACKGROUND: The PCR and its variant, quantitative PCR (qPCR), have revolutionized the practice of clinical microbiology. Continued advancements in PCR have led to a new derivative, digital PCR (dPCR), which promises to address certain limitations inherent to qPCR.

CONTENT: Here we highlight the important technical differences between qPCR and dPCR, and the potential advantages and disadvantages of each. We then review specific situations in which dPCR has been implemented in clinical microbiology and the results of such applications. Finally, we attempt to place dPCR in the context of other emerging technologies relevant to the clinical laboratory, including next-generation sequencing.

SUMMARY: dPCR offers certain clear advantages over traditional qPCR, but these are to some degree offset by limitations of the technology, at least as currently practiced. Laboratories considering implementation of dPCR should carefully weigh the potential advantages and disadvantages of this powerful technique for each specific application planned.

RevDate: 2019-11-08

Dertinger SD, Totsuka Y, Bielas JH, et al (2019)

High information content assays for genetic toxicology testing: A report of the International Workshops on Genotoxicity Testing (IWGT).

Mutation research, 847:403022.

We live in an era of 'big data', where the volume, velocity, and variety of the data being generated is increasingly influencing the way toxicological sciences are practiced. With this in mind, a workgroup was formed for the 2017 International Workshops on Genotoxicity Testing (IWGT) to consider the use of high information content data in genetic toxicology assessments. Presentations were given on adductomics, global transcriptional profiling, error-reduced single-molecule sequencing, and cellular phenotype-based assays, which were identified as methodologies that are relevant to present-day genetic toxicology assessments. Presenters and workgroup members discussed the state of the science for these methodologies, their potential use in genetic toxicology, current limitations, and the future work necessary to advance their utility and application. The session culminated with audience-assisted SWOT (strength, weakness, opportunities, and threats) analyses. The summary report described herein is structured similarly. A major conclusion of the workgroup is that while conventional regulatory genetic toxicology testing has served the public well over the last several decades, it does not provide the throughput that has become necessary in modern times, and it does not generate the mechanistic information that risk assessments ideally take into consideration. The high information content assay platforms that were discussed in this session, as well as others under development, have the potential to address aspect(s) of these issues and to meet new expectations in the field of genetic toxicology.

RevDate: 2019-11-07

Koyama M, GR Hill (2019)

The primacy of gastrointestinal tract antigen presenting cells in lethal graft-versus-host disease.

Blood pii:422723 [Epub ahead of print].

Allogeneic stem cell transplantation remains a cornerstone of curative therapy for high-risk and/or advanced hematological malignancies but remains limited by graft-versus-host disease (GVHD). GVHD is initiated by the interaction between recipient antigen presenting cells (APC) and donor T-cells, culminating in T-cell differentiation along pathogenic type-1 (Th1/Tc1) and type-17 (Th17/Tc17) paradigms, at the expense of tolerogenic regulatory T-cell (Treg/Tr1) patterns. Type-1 and type-17 T-cells secrete cytokines (e.g. GM-CSF and IFNg) critical to the cytokine storm that amplifies donor APC expansion and their alloantigen presentation. It is become increasingly clear that pathogenic donor T-cell differentiation is initiated by both professional recipient APC (e.g. dendritic cells (DC)) and non-professional APC (e.g. epithelial and mesenchymal), particularly within the GI-tract. In the immediate peri-transplant period, these APC are profoundly modified by PAMP/DAMP signals derived from conditioning and intestinal microbiota. Subsequently donor DC in the GI-tract are activated by DAMP/PAMP signals in the colon that gain access to the lamina propria once the mucosal barrier mucosa is compromised by GVHD. This results in donor DC expansion and alloantigen presentation in the colon, and their subsequent migration into the mesenteric lymph nodes. Here, new donor T-cells are primed, expanded, differentiated and imprinted with gut-homing integrins permissive of migration into the damaged GI-tract, resulting in the lethal feed-forward cascade of GVHD. These new insights into our understanding of the cellular and molecular factors initiating GVHD, both spatially and temporally, give rise to a number of logical therapeutic targets, focusing on the inhibition of APC function in the GI-tract.

RevDate: 2019-11-07

Thangavelu G, Du J, Paz KG, et al (2019)

Inhibition of Inositol kinase B controls acute and chronic graft-versus-host disease.

Blood pii:387148 [Epub ahead of print].

T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation, differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T-cells, and can control T-cell mediated autoimmunity. Here, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine induced Itpkb deleted (Itpkb-/-) T-cells had attenuated acute GVHD in two models without eliminating A20-luciferase B-cell lymphoma graft-versus-leukemia (GVL). A highly potent, selective inhibitor, GNF362, ameliorated acute GVHD without impairing GVL against two acute myeloid leukemia lines (MLL-AF9-eGFP; C1498-luciferase). Compared to FK506, GNF362 more selectively deleted donor alloreactive versus nominal antigen responsive T-cells. Consistent with these data and as compared to FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a distinct pathophysiology from acute GVHD, Itpkb-/- donor T-cells reduced active chronic GVHD in a multi-organ system model with bronchiolitis obliterans (BO) driven by germinal center reactions, resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is required to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.

RevDate: 2019-11-07

Schroeder CM, Valenzuela JR, Natividad IM, et al (2019)

A burst of genetic innovation in Drosophila actin-related proteins for testis-specific function.

Molecular biology and evolution pii:5614436 [Epub ahead of print].

Many cytoskeletal proteins perform fundamental biological processes and are evolutionarily ancient. For example, the superfamily of actin-related proteins (Arps) specialized early in eukaryotic evolution for diverse cellular roles in the cytoplasm and the nucleus. Despite its strict conservation across eukaryotes, we find that the Arp superfamily has undergone dramatic lineage-specific diversification in Drosophila. Our phylogenomic analyses reveal four independent Arp gene duplications that occurred in the common ancestor of the obscura group of Drosophila and have been mostly preserved in this lineage. All four obscura-specific Arp paralogs are predominantly expressed in the male germline and have evolved under positive selection. We focus our analyses on the divergent Arp2D paralog, which arose via a retroduplication event from Arp2, a component of the Arp2/3 complex that polymerizes branched actin networks. Computational modeling analyses suggests that Arp2D can replace Arp2 in the Arp2/3 complex and bind actin monomers. Together with the signature of positive selection, our findings suggest that Arp2D may augment Arp2's functions in the male germline. Indeed, we find that Arp2D is expressed during and following male meiosis, where it localizes to distinct locations such as actin cones-specialized cytoskeletal structures that separate bundled spermatids into individual mature sperm. We hypothesize that this unprecedented burst of genetic innovation in cytoskeletal proteins may have been driven by the evolution of sperm heteromorphism in the obscura group of Drosophila.

RevDate: 2019-11-06

Rossi A, Gauvrit S, Marass M, et al (2016)

Regulation of Vegf signaling by natural and synthetic ligands.

Blood, 128(19):2359-2366.

The mechanisms that allow cells to bypass anti-vascular endothelial growth factor A (VEGFA) therapy remain poorly understood. Here we use zebrafish to investigate this question and first show that vegfaa mutants display a severe vascular phenotype that can surprisingly be rescued to viability by vegfaa messenger RNA injections at the 1-cell stage. Using vegfaa mutants as an in vivo test tube, we found that zebrafish Vegfbb, Vegfd, and Pgfb can also rescue these animals to viability. Taking advantage of a new vegfr1 tyrosine kinase-deficient mutant, we determined that Pgfb rescues vegfaa mutants via Vegfr1. Altogether, these data reveal potential resistance routes against current anti-VEGFA therapies. In order to circumvent this resistance, we engineered and validated new dominant negative Vegfa molecules that by trapping Vegf family members can block vascular development. Thus, our results show that Vegfbb, Vegfd, and Pgfb can sustain vascular development in the absence of VegfA, and our newly engineered Vegf molecules expand the toolbox for basic research and antiangiogenic therapy.

RevDate: 2019-11-07

Bossé Y, Li Z, Xia J, et al (2019)

Transcriptome-wide association study reveals candidate causal genes for lung cancer.

International journal of cancer [Epub ahead of print].

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of this study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n=1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma, small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (PTWAS =1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (PTWAS =3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (PTWAS =6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influence lung cancer risk. This article is protected by copyright. All rights reserved.

RevDate: 2019-11-07

Yu M, Hazelton WD, Luebeck GE, et al (2019)

Epigenetic aging: more than just a clock when it comes to cancer.

Cancer research pii:0008-5472.CAN-19-0924 [Epub ahead of print].

The incidence of cancer, adjusted for secular trends, is directly related to age, and advanced chronological age is one of the most significant risk factors for cancer. Organismal aging is associated with changes at the molecular, cellular and tissue levels and is affected by both genetic and environmental factors. The specific mechanisms through which these age-associated molecular changes contribute to the increased risk of aging-related disease, such as cancer, are incompletely understood. DNA methylation, a prominent epigenetic mark, also changes over a lifetime as part of an 'epigenetic aging' process. Here, we give an update and review of epigenetic aging, in particular the phenomena of epigenetic drift and epigenetic clock, with regard to its implication in cancer etiology. We discuss the discovery of the DNA methylation-based biomarkers for biological tissue age and the construction of various epigenetic age-estimators for human clinical outcomes and health/life span. Recent studies in various types of cancer point to the significance of epigenetic aging in tumorigenesis, and its potential use for cancer risk prediction. Future studies are needed to assess the potential clinical impact of strategies focused on lowering cancer risk by preventing premature aging or promoting healthy aging.

RevDate: 2019-11-06

Gralow JR, Barlow WE, Paterson AHG, et al (2019)

Phase III randomized trial of bisphosphonates as adjuvant therapy in breast cancer: S0307.

Journal of the National Cancer Institute pii:5613900 [Epub ahead of print].

BACKGROUND: Adjuvant bisphosphonates, when given in a low estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early stage breast cancer.

METHODS: Patients with stage I-III breast cancer were randomized to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival (OS) a secondary outcome. All statistical tests were two-sided.

RESULTS: 6,097 patients enrolled. Median age was 52.7 years. Prior to randomization, 73.2% of patients indicated preference for oral versus intravenous formulation. DFS did not differ across arms in a log-rank test (p = 0.49). 5-year DFS was 88.3% (zoledronic acid, 95% CI 86.9%-89.6%), 87.6% (clodronate, 95% CI 86.1%-88.9%), and 87.4% (ibandronate, 95% CI 85.6%-88.9%). 5-year OS also did not differ between arms (log rank p = 0.50) and was 92.6% (zoledronic acid, 95% CI 91.4%-93.6%), 92.4% (clodronate 95% CI 91.2%-93.5%), and 92.9%% (ibandronate 95% CI 91.5%-94.1%). Bone as first site of recurrence did not differ between arms (P = 0.93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the Jaw (ONJ) was highest for zoledronic acid (1.26%), compared to clodronate (0.36%) and ibandronate (0.77%).

CONCLUSIONS: We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of ONJ with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the U.S. should be considered.

RevDate: 2019-11-06

Crochet E, Tyc VL, Wang M, et al (2019)

Posttraumatic stress as a contributor to behavioral health outcomes and healthcare utilization in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

Journal of cancer survivorship : research and practice pii:10.1007/s11764-019-00822-5 [Epub ahead of print].

PURPOSE: To examine the association between posttraumatic stress symptoms (PTSS), neurocognitive and psychosocial late-effects, health behaviors, and healthcare utilization in long-term survivors of childhood cancer.

METHODS: Participants included individuals (N = 6844; 52.5% female; mean [SD] age at diagnosis = 7.6 [5.8], at follow-up = 34.9 [7.5]) in the Childhood Cancer Survivor Study (CCSS). Follow-up included the Posttraumatic Stress Scale, Brief Symptom Inventory-18, Short-form 36 Health-related quality of life (HRQOL) survey, CCSS Neurocognitive Questionnaire, and questions about sociodemographics, physical health, health behaviors, and healthcare utilization. Modified Poisson regression and multinomial logistic regression models examined associations between posttraumatic stress symptoms (PTSS) and neurocognitive, HRQOL, health behavior, and healthcare outcomes when adjusting for sociodemographics, disease, and treatment.

RESULTS: Long-term survivors with PTSS (N = 995, 14.5%) reported more impairment in mental (relative risk [RR] 3.42, 95% confidence interval [CI] 3.05-3.85), and physical (RR = 2.26, CI = 1.96-2.61) HRQOL. PTSS was also associated with increased impairment in task efficiency (RR = 3.09, CI = 2.72-3.51), working memory (RR = 2.55, CI = 2.30-2.83), organization (RR = 2.11, CI = 1.78-2.50), and emotional regulation (RR = 3.67, CI = 3.30-4.09). Survivors with PTSS were significantly more likely to attend cancer-specific health visits in the past 2 years (OR = 1.89, CI = 1.50-2.39), and showed greater likelihood of either high frequency (OR = 1.89, CI = 1.50-2.39) or complete lack of (OR = 1.63, CI = 1.32-2.01) primary care visits compared to survivors without PTSS.

CONCLUSIONS: Survivors with PTSS reported significantly more psychosocial and neurocognitive late effects, and were more likely to engage in variable use of healthcare.

PTSS is associated with additional challenges for a population vulnerable to adverse late effects. Inclusion of integrative services during follow-up visits may benefit functional outcomes.

RevDate: 2019-11-06

Mohty M, Gautier J, Malard F, et al (2019)

CD19 chimeric antigen receptor-T cells in B-cell leukemia and lymphoma: current status and perspectives.

Leukemia pii:10.1038/s41375-019-0615-5 [Epub ahead of print].

The approval of tisagenlecleucel and axicabtagene ciloleucel represents a breakthrough in the field of immune and cellular therapy for hematologic malignancies. These anti-CD19 chimeric antigen receptor-T cells (CAR) proved to be highly effective in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and specific histologic subtypes of B-cell non-Hodgkin lymphomas. This expert review aims to summarize the current available research evidence in this field, with a special focus on the different challenges faced by treating physicians, and we also provide future perspectives.

RevDate: 2019-11-05

Danila DC, Szmulewitz RZ, Vaishampayan U, et al (2019)

Phase I Study of DSTP3086S, an Antibody-Drug Conjugate Targeting Six-Transmembrane Epithelial Antigen of Prostate 1, in Metastatic Castration-Resistant Prostate Cancer.

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

PURPOSE: Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is highly expressed in prostate cancers. DSTP3086S is a humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody linked to the potent antimitotic agent monomethyl auristatin E. This study evaluated the safety and activity of DSTP3086S in patients with metastatic castration-resistant prostate cancer.

METHODS: Patients were enrolled in a 3 + 3 dose escalation study to evaluate DSTP3086S (0.3 to 2.8 mg/kg intravenously) given once every 3 weeks followed by cohort expansion at the recommended phase II dose or weekly (0.8 to 1.0 mg/kg).

RESULTS: Seventy-seven patients were given DSTP3086S once every 3 weeks, and seven were treated weekly. Two patients in the once-every-3-weeks dose escalation had dose-limiting grade 3 transaminitis. Grade 3 hyperglycemia and grade 4 hypophosphatemia were dose-limiting toxicities in one patient treated at 1.0 mg/kg weekly. Initial cohort expansion evaluated dosing at 2.8 mg/kg once every 3 weeks (n = 10), but frequent dose reductions led to testing of 2.4 mg/kg (n = 39) in the expansion phase. Common related adverse events (> 20%) across doses (once every 3 weeks) were fatigue, peripheral neuropathy, nausea, constipation, anorexia, diarrhea, and vomiting. DSTP3086S pharmacokinetics were linear. Among 62 patients who received > 2 mg/kg DSTP3086S once every 3 weeks, 11 (18%) demonstrated a ≥ 50% decline in prostate-specific antigen; two (6%) of 36 with measurable disease at baseline achieved a radiographic partial response; and of 27 patients with informative unfavorable baseline circulating tumor cells ≥ 5/7.5 mL of blood, 16 (59%) showed conversions to favorable circulating tumor cells < 5. No prostate-specific antigen or RECIST responses were seen with weekly dosing.

CONCLUSION: DSTP3086S has acceptable safety at the recommended phase II dose level of 2.4 mg/kg once every 3 weeks. Antitumor activity at doses between 2.25 and 2.8 mg/kg once every 3 weeks supports the potential benefit of treating STEAP1-expressing metastatic castration-resistant prostate cancer with an STEAP1-targeting antibody-drug conjugate.

RevDate: 2019-11-05

Dabestani N, Katz DA, Dombrowski J, et al (2019)

Time Trends in First Episode Genital Herpes Simplex Virus Infections in an Urban STD Clinic.

Sexually transmitted diseases [Epub ahead of print].

BACKGROUND: Genital herpes simplex virus type-1 (HSV-1) has emerged as the leading cause of first episode genital herpes among specific populations in the U.S., such as adolescents, young adult women, and men who have sex with men (MSM). We examined trends in the etiology of first episode genital herpes diagnoses over time in an STD clinic population.

METHODS: Using an electronic database, we identified persons diagnosed with first episode genital herpes at Public Health Seattle & King County STD Clinic from 1993 through 2014 and compared risk factors for genital HSV-1 versus HSV-2 infection.

RESULTS: Of 52,030 patients with genital ulcers, 3,065 (6.15%) had first episode genital herpes infection: 1,022 (33.3%) with HSV-1 and 2,043 (67.7%) with HSV-2. Overall, 1,154 (37.7%) were women, the median age was 28 (IQR 24 to 36) years, 1,875 (61.2%) patients were white, and 353 (11.5%) were MSM. The number of patients diagnosed with first episode genital HSV-2 declined on average by 5.5 persons per year - from 208 in 1993 to 35 in 2014 (change of -5.6 per year, 95% CI=-6.9 to -4.1), while HSV-1 diagnoses remained stable at approximately 50 per year (change of 0.2; 95% CI: -0.4 to 0.9). In a multivariate model, persons diagnosed with first episode genital HSV-1 rather than genital HSV-2 infection were more likely to be younger (age <30 years (RR=1.38; 95% CI: 1.22, 1.55)), white (RR=3.16; 95% CI: 2.57, 3.88), and MSM (RR=1.50; 95% CI: 1.31, 1.71).

CONCLUSIONS: We observed a significant decrease in the frequency of first episode genital HSV-2 and a stable number of first episode genital HSV-1 infections in an STD clinic over the last 2 decades.

RevDate: 2019-11-05

Symonds LK, SA Cohen (2019)

Use of perioperative chemotherapy in colorectal cancer metastatic to the liver.

Gastroenterology report, 7(5):301-311 pii:goz035.

A curative-intent approach may improve survival in carefully selected patients with oligometastatic colorectal cancer. Aggressive treatments are most frequently administered to patients with isolated liver metastasis, though they may be judiciously considered for other sites of metastasis. To be considered for curative intent with surgery, patients must have disease that can be definitively treated while leaving a sufficient functional liver remnant. Neoadjuvant chemotherapy may be used for upfront resectable disease as a test of tumor biology and/or for upfront unresectable disease to increase the likelihood of resectability (so-called 'conversion' chemotherapy). While conversion chemotherapy in this setting aims to improve survival, the choice of a regimen remains a complex and highly individualized decision. In this review, we discuss the role of RAS status, primary site, sidedness, and other clinical features that affect chemotherapy treatment selection as well as key factors of patients that guide individualized patient-treatment recommendations for colorectal-cancer patients being considered for definitive treatment with metastasectomy.

RevDate: 2019-11-05

Xu Y, Morales AJ, Cargill MJ, et al (2019)

Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma.

Cancer immunology, immunotherapy : CII pii:10.1007/s00262-019-02419-4 [Epub ahead of print].

5T4 (trophoblast glycoprotein, TPBG) is a transmembrane tumor antigen expressed on more than 90% of primary renal cell carcinomas (RCC) and a wide range of human carcinomas but not on most somatic adult tissues. The favorable expression pattern has encouraged the development and clinical testing of 5T4-targeted antibody and vaccine therapies. 5T4 also represents a compelling and unexplored target for T-cell receptor (TCR)-engineered T-cell therapy. Our group has previously isolated high-avidity CD8+ T-cell clones specific for an HLA-A2-restricted 5T4 epitope (residues 17-25; 5T4p17). In this report, targeted single-cell RNA sequencing was performed on 5T4p17-specific T-cell clones to sequence the highly variable complementarity-determining region 3 (CDR3) of T-cell receptor α chain (TRA) and β chain (TRB) genes. Full-length TRA and TRB sequences were cloned into lentiviral vectors and transduced into CD8+ T-cells from healthy donors. Redirected effector T-cell function against 5T4p17 was measured by cytotoxicity and cytokine release assays. Seven unique TRA-TRB pairs were identified. All seven TCRs exhibited high expression on CD8+ T-cells with transduction efficiencies from 59 to 89%. TCR-transduced CD8+ T-cells demonstrated redirected cytotoxicity and cytokine release in response to 5T4p17 on target-cells and killed 5T4+/HLA-A2+ kidney-, breast-, and colorectal-tumor cell lines as well as primary RCC tumor cells in vitro. TCR-transduced CD8+ T-cells also detected presentation of 5T4p17 in TAP1/2-deficient T2 target-cells. TCR-transduced T-cells redirected to recognize the 5T4p17 epitope from a broadly shared tumor antigen are of interest for future testing as a cellular immunotherapy strategy for HLA-A2+ subjects with 5T4+ tumors.

RevDate: 2019-11-05

Rodrigues G, Hoshino A, Kenific CM, et al (2019)

Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis.

Nature cell biology pii:10.1038/s41556-019-0404-4 [Epub ahead of print].

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

RevDate: 2019-11-04

Cheng GS, Bondeelle L, Gooley T, et al (2019)

Azithromycin use and increased cancer risk among patients with bronchiolitis obliterans after hematopoietic cell transplantation.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30707-4 [Epub ahead of print].

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematological relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT, who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of BOS patients from two large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio in patients exposed to azithromycin versus unexposed was HR = 1.51 (95% CI, 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR= 0.54, 95%CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.

RevDate: 2019-11-04

Burnett-Hartman AN, Newcomb PA, U Peters (2019)

Challenges with colorectal cancer family history assessment: motivation to translate polygenic risk scores into practice.

Gastroenterology pii:S0016-5085(19)41483-2 [Epub ahead of print].

RevDate: 2019-11-04

Eyre TA, Roeker LE, Fox CP, et al (2019)

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

British journal of haematology [Epub ahead of print].

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.

RevDate: 2019-11-04

Kriner MA, AR Subramaniam (2019)

The serine transporter SdaC prevents cell lysis upon glucose depletion in Escherichia coli.

MicrobiologyOpen [Epub ahead of print].

The amino acid serine plays diverse metabolic roles, yet bacteria actively degrade exogenously provided serine via deamination to pyruvate. Serine deamination is thought to be a detoxification mechanism due to the ability of serine to inhibit several biosynthetic reactions, but this pathway remains highly active even in nutrient-replete conditions. While investigating the physiological roles of serine deamination in different growth conditions, we discovered that Escherichia coli cells lacking the sdaCB operon, which encodes the serine transporter SdaC and the serine deaminase SdaB, lyse upon glucose depletion in a medium containing no exogenous serine but all other amino acids and nucleobases. Unexpectedly, this lysis phenotype can be recapitulated by deleting sdaC alone and can be rescued by heterologous expression of SdaC. Lysis of ΔsdaC cells can be prevented by omitting glycine from the medium, inhibiting the glycine cleavage system, or by increasing alanine availability. Together, our results reveal that the serine transporter SdaC plays a critical role in maintaining amino acid homeostasis during shifts in nutrient availability in E. coli.

RevDate: 2019-11-03

Wockner LF, Hoffmann I, Webb L, et al (2019)

Growth Rate of Plasmodium falciparum: Analysis of Parasite Growth Data from Malaria Volunteer Infection Studies.

The Journal of infectious diseases pii:5611305 [Epub ahead of print].

BACKGROUND: Growth rate of malaria parasites in the blood of infected subjects is an important measure of efficacy of drugs and vaccines.

METHODS: We used log-linear and sine-wave models to estimate the parasite growth rate of the 3D7 strain of Plasmodium falciparum using data from 177 subjects from 14 induced blood stage malaria (IBSM) studies conducted at QIMR Berghofer. We estimated parasite multiplication rate per 48 hour (PMR48), PMR per life-cycle (PMRLC), and parasite life-cycle duration. We compared these parameters to those from studies conducted elsewhere with infections induced by IBSM (n=66), sporozoites via mosquito bite (n=336) or injection (n=51).

RESULTS: The parasite growth rate of 3D7 in QIMR Berghofer studies was 0.75/day (95% CI: 0.73-0.77/day), PMR48 was 31.9 (95% CI: 28.7-35.4), PMRLC was 16.4 (95% CI: 15.1-17.8) and parasite life-cycle was 38.8 hour (95% CI: 38.3-39.2 hour). These parameters were similar to estimates from IBSM studies elsewhere (0.71/day, 95% CI: 0.67-0.75/day; PMR48 26.6, 95% CI: 22.2-31.8), but significantly higher (P < 0.001) than in sporozoite studies (0.47/day, 95% CI: 0.43-0.50/day; PMR48 8.6, 95% CI: 7.3-10.1).

CONCLUSION: Parasite growth rates were similar across different IBSM studies and higher than infections induced by sporozoite.

RevDate: 2019-11-03

Weschke DP, Leisenring WM, Lawler RL, et al (2019)

Inflammatory Cytokine Profile in Individuals with Inherited Chromosomally Integrated Human Herpesvirus 6.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30705-0 [Epub ahead of print].

Acute graft-versus-host-disease (aGVHD) is a major complication following hematopoietic cell transplantations (HCT). We have shown that HCT recipients in which either the donor or patient had inherited chromosomally-integrated human herpesvirus 6 (iciHHV-6) have a higher incidence of developing more severe aGVHD. Previous studies established that increased proinflammatory cytokines are associated with increased risk for aGVHD and non-relapse mortality post-HCT. We hypothesized that HCT recipients with donor or recipient iciHHV-6 (iciHHV-6pos HCT cases) will have higher cytokine levels compared to HCT recipients without iciHHV-6 (iciHHV-6neg HCT controls). We identified 64 iciHHV-6pos HCT cases with plasma from days 7, 14, and/or 21 post-HCT and before aGVHD onset in patients who developed aGVHD. We identified 64 iciHHV-6neg HCT controls matched for aGVHD risk factors. We also identified 28 donors with iciHHV-6 and 56 matched donors without iciHHV-6. We measured plasma cytokine concentrations for IL-6, ST2, TIM3, TNFα, TNFRp55, and CRP. We used Mann-Whitney tests and repeated measures models to compare cytokine levels. iciHHV-6pos HCT cases had higher CRP levels on day 7 and day 21 and higher TNFRp55 levels on day 14 and day 21 compared to iciHHV-6neg HCT controls. These findings were recapitulated in a repeated measures model. The differences were most evident among patients who subsequently developed aGVHD grades 2-4. Additionally, iciHHV-6pos HCT cases had earlier-onset aGVHD (median, 20 versus 27 days post-HCT; p=0.02). There were no differences in cytokine levels among healthy donors with or without iciHHV-6. This study demonstrates that HCT recipients with iciHHV-6 have higher proinflammatory cytokines that may be associated with increased risk for aGVHD.

RevDate: 2019-11-04

Adesina OO, Jenkins IC, Wu QV, et al (2019)

Urinary cross-linked carboxyterminal telopeptide, a bone resorption marker, decreases after vaso-occlusive crises in adults with sickle cell disease.

Blood cells, molecules & diseases, 80:102369 pii:S1079-9796(19)30311-0 [Epub ahead of print].

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 μg/mmol during vaso-occlusive crises to 2.62 μg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

RevDate: 2019-11-02

Muñoz E, Gallo LC, Hua S, et al (2019)

Stress is Associated with Neurocognitive Function in Hispanic/Latino Adults: Results from HCHS/SOL Socio-Cultural Ancillary Study.

The journals of gerontology. Series B, Psychological sciences and social sciences pii:5611171 [Epub ahead of print].

OBJECTIVES: The purpose of this study was to evaluate the hypothesis that chronic and acculturative stress would be negatively associated with neurocognitive function among middle aged to older Hispanics/Latinos.

METHOD: Our analytic sample consisted of 3,265 participants (mean age = 56.7 (+/-0.24)) from the Hispanic Community Health Study/Study of Latinos who participated in its Sociocultural Ancillary Study. During the baseline phase of this project, participants were assessed on multiple domains of neurocognitive function, and completed self-report measures of chronic and acculturative stress.

RESULTS: Each standard deviation increase in chronic stress was associated with lower performance in a verbal learning task (B = -.17, 95% CI [-.32, -.01]); this association was no longer significant after adjusting for mental and physical health symptoms, including depression and anxiety symptoms, and cardiovascular health. A standard deviation increase in acculturative stress was associated with poorer performance in all cognitive measures (Bs range = -.13 to -1.03). Associations of acculturation stress with psychomotor speed, verbal learning, and word fluency remained significant after adjusting for mental and physical health symptoms.

DISCUSSION: Our results suggest that mental and physical health may help explain some cross-sectional associations between stress and cognition and highlight the need to examine culture-specific psychosocial stressors to better understand the context of psychosocial risk factors for neurocognitive performance.

RevDate: 2019-11-02

McKay SL, Guo A, Pergam SA, et al (2019)

Herpes zoster risk in immunocompromised adults in the United States: A systematic review.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5611148 [Epub ahead of print].

BACKGROUND: The primary reported risk factors for herpes zoster (HZ) are increasing age and immunodeficiency yet estimates of HZ risk by immunocompromising condition have not been well characterized. We undertook a systematic review of the literature to estimate HZ risk in five categories of immunocompromised patients.

METHODS: We systematically reviewed studies examining risk of HZ and its complications in adult patients with hematopoietic cell transplants (HCT), cancer (hematologic and solid tumor), HIV, and solid organ transplant (SOT; kidney and other). We identified studies in Pubmed, Embase, Cochrane, Scopus, and that presented original data from studies in the United States published after 1992 (1996 for HIV). We assessed risk of bias with Cochrane or GRADE methods.

RESULTS: We identified and screened 3,765 records and synthesized 34 studies with low or moderate risk of bias. The majority of studies included (32/34) reported at least one estimate of HZ cumulative incidence (range=0%-41%). Twelve studies reported HZ incidence, which varied widely within and between immunocompromised populations. Incidence estimates ranged between 9 and 92 HZ cases/1,000 patient-years and were highest in HCT, followed by hematologic malignancies, SOT, solid tumor malignancies, and lowest in HIV patients. Among 17 studies of HCT patients, absent or <1 year of post-transplant antiviral prophylaxis were associated with higher HZ cumulative incidence.

CONCLUSIONS: HZ is common among all immunocompromised populations studied-exceeding expected HZ incidence among immunocompetent adults ≥60 years. Better evidence of incidence of HZ complications and severity in immunocompromised populations are needed to inform economic and HZ vaccine policy analyses.

RevDate: 2019-11-02

Klarin D, Busenkell E, Judy R, et al (2019)

Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease.

Nature genetics pii:10.1038/s41588-019-0519-3 [Epub ahead of print].

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.

RevDate: 2019-11-02

Maurice NJ, McElrath MJ, Andersen-Nissen E, et al (2019)

CXCR3 enables recruitment and site-specific bystander activation of memory CD8+ T cells.

Nature communications, 10(1):4987 pii:10.1038/s41467-019-12980-2.

Bystander activation of memory T cells occurs in the absence of cognate antigen during infections that elicit strong systemic inflammatory responses, which subsequently affect host immune responses. Here we report that memory T cell bystander activation is not limited to induction by systemic inflammation. We initially observe potential T cell bystander activation in a cohort of human vaccine recipients. Using a mouse model system, we then find that memory CD8+ T cells are specifically recruited to sites with activated antigen-presenting cells (APCs) in a CXCR3-dependent manner. In addition, CXCR3 is also necessary for T cell clustering around APCs and T cell bystander activation, which temporospatially overlaps with the subsequent antigen-specific T cell response. Our data thus suggest that bystander activation is part of the initial localized immune response, and is mediated by a site-specific recruitment process of memory T cells.

RevDate: 2019-11-02

Goossens R, van den Boogaard ML, Lemmers RJLF, et al (2019)

Intronic SMCHD1 variants in FSHD: testing the potential for CRISPR-Cas9 genome editing.

Journal of medical genetics pii:jmedgenet-2019-106402 [Epub ahead of print].

BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is associated with partial chromatin relaxation of the DUX4 retrogene containing D4Z4 macrosatellite repeats on chromosome 4, and transcriptional de-repression of DUX4 in skeletal muscle. The common form of FSHD, FSHD1, is caused by a D4Z4 repeat array contraction. The less common form, FSHD2, is generally caused by heterozygous variants in SMCHD1.

METHODS: We employed whole exome sequencing combined with Sanger sequencing to screen uncharacterised FSHD2 patients for extra-exonic SMCHD1 mutations. We also used CRISPR-Cas9 genome editing to repair a pathogenic intronic SMCHD1 variant from patient myoblasts.

RESULTS: We identified intronic SMCHD1 variants in two FSHD families. In the first family, an intronic variant resulted in partial intron retention and inclusion of the distal 14 nucleotides of intron 13 into the transcript. In the second family, a deep intronic variant in intron 34 resulted in exonisation of 53 nucleotides of intron 34. In both families, the aberrant transcripts are predicted to be non-functional. Deleting the pseudo-exon by CRISPR-Cas9 mediated genome editing in primary and immortalised myoblasts from the index case of the second family restored wild-type SMCHD1 expression to a level that resulted in efficient suppression of DUX4.

CONCLUSIONS: The estimated intronic mutation frequency of almost 2% in FSHD2, as exemplified by the two novel intronic SMCHD1 variants identified here, emphasises the importance of screening for intronic variants in SMCHD1. Furthermore, the efficient suppression of DUX4 after restoring SMCHD1 levels by genome editing of the mutant allele provides further guidance for therapeutic strategies.

RevDate: 2019-11-02

Black AJ, Zargar H, Zargar-Shoshtari K, et al (2019)

The prognostic value of the neutrophil-to-lymphocyte ratio in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy.

Urologic oncology pii:S1078-1439(19)30374-6 [Epub ahead of print].

INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) is an attractive marker because it is derived from routine bloodwork. NLR has shown promise as a prognostic factor in muscle invasive bladder cancer (MIBC) but its value in patients receiving neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is not yet established. Since NLR is related to an oncogenic environment and poor antitumor host response, we hypothesized that a high NLR would be associated with a poor response to NAC and would remain a poor prognostic indicator in patients receiving NAC.

METHODS: A retrospective analysis was performed on patients with nonmetastatic MIBC (cT2-4aN0M0) who received NAC prior to RC between 2000 and 2013 at 1 of 19 centers across Europe and North America. The pre-NAC NLR was used to split patients into a low (NLR ≤ 3) and high (NLR > 3) group. Demographic and clinical parameters were compared between the groups using Student's t test, chi-squared, or Fisher's exact test. Putative risk factors for disease-specific and overall survival were analyzed using Cox regression, while predictors of response to NAC (defined as absence of MIBC in RC specimen) were investigated using logistic regression.

RESULTS: Data were available for 340 patients (199 NLR ≤ 3, 141 NLR > 3). Other than age and rate of lymphovascular invasion, demographic and pretreatment characteristics did not differ significantly. More patients in the NLR > 3 group had residual MIBC after NAC than the NLR ≤ 3 group (70.8% vs. 58.3%, P = 0.049). NLR was the only significant predictor of response (odds ratio: 0.36, P = 0.003) in logistic regression. NLR was a significant risk factor for both disease-specific (hazard ratio (HR): 2.4, P = 0.006) and overall survival (HR:1.8, P = 0.02).

CONCLUSION: NLR > 3 was associated with a decreased response to NAC and shorter disease-specific and overall survival. This suggests that NLR is a simple tool that can aid in MIBC risk stratification in clinical practice.

RevDate: 2019-11-01

Gurdasani D, Carstensen T, Fatumo S, et al (2019)

Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Cell, 179(4):984-1002.e36.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

RevDate: 2019-11-01

Perez HR, Starrels JL, Gonzalez S, et al (2019)

Prescription Opioid Use Among Hispanics/Latinos With Arthritis Symptoms: Results From the Hispanic Community Health Study/Study of Latinos.

Hispanic health care international : the official journal of the National Association of Hispanic Nurses [Epub ahead of print].

INTRODUCTION: To determine the prevalence of prescription opioid (PO) use among Hispanics/Latinos with arthritis symptoms and to characterize how demographic and cultural factors are associated with PO use.

METHOD: Cross-sectional analysis of baseline visit data during 2008 to 2011 from the Hispanic Community Health Study/Study of Latinos, a population-based cohort study of 16,415 Hispanics/Latinos living in Chicago, Illinois, Miami, Florida, Bronx, New York, and San Diego, California. Included participants self-reported painful inflammation or swelling in one or more joints. Multivariate models controlling for physical and mental health scores were constructed to assess how demographic and cultural factors were associated with PO use.

RESULTS: A total of 9.3% were using POs at the time of the baseline visit. In multivariate models, persons of Cuban background (adjusted odds ratio [AOR] = 0.42, 95% confidence interval [CI; 0.21, 0.81]) and of Dominican background (AOR = 0.38, 95% CI [0.18, 0.80]) were significantly less likely to use POs compared with a reference group of persons of Mexican background. Greater language acculturation was also negatively associated with PO use (AOR = 0.68, 95% CI [0.53, 0.87]).

CONCLUSION: POs were used relatively uncommonly, and use showed marked variation between Hispanic/Latino groups. Future study should determine mechanisms for why greater use of English among Hispanics/Latinos might influence PO use.

RevDate: 2019-11-01

Payne TH, Lovis C, Gutteridge C, et al (2019)

Status of health information exchange: a comparison of six countries.

Journal of global health, 9(2):0204279.

Background: Health information exchange (HIE) is frequently cited as an important objective of health information technology investment because of its potential to improve quality, reduce cost, and increase patient satisfaction. In this paper we examine the status and practices of HIE in six countries, drawn from a range of higher and lower income regions.

Methods: For each of the countries represented - China, England, India, Scotland, Switzerland, and the United States - we describe the state of current practice of HIE with reference to two scenarios: transfer of care and referral. For each country we discuss national objectives, barriers and plans for further advancing clinical information exchange.

Results: The countries vary widely in levels of adoption of EHRs, availability of health information in electronic form suitable for HIE, and in the information technology infrastructure to be used for transmission. Common themes emerged, however, including an expectation that information will be exchanged rather than gathered anew, the need for incentives to promote information exchange, and concerns about data security and patient confidentiality.

Conclusions: Although the ability to transfer health information to where it is most needed is nearly always mentioned as an advantage of HIE adoption, there are wide differences in the degree to which this has been achieved to support the scenarios used in this study. Nevertheless, these differences indicate varying stages of progress along a comparable pathway, with similar barriers being identified in the countries described. In some cases, these have been partially surmounted while elsewhere work is needed. We reflect on contextual factors influencing the status and direction of HIE efforts in different global regions and their implications for progress.

RevDate: 2019-11-01

Di Meo A, Brown MD, Finelli A, et al (2019)

Prognostic Urinary miRNAs for the Assessment of Small Renal Masses.

Clinical biochemistry pii:S0009-9120(19)30825-2 [Epub ahead of print].

BACKGROUND: Renal cell carcinoma (RCC) is often detected incidentally as a small renal mass (SRM; pT1a, ≤ 4 cm). It is clinically challenging to predict progression in patients with SRMs. This is largely due to the recent recognition of clinically progressive and non-progressive RCC-SRMs. It is critical to accurately stratify SRM patients according to risk to avoid unnecessary treatment. This is especially significant for elderly and infirm patients, where the risk of surgery outweighs mortality from SRMs.

METHODS: We employed a qRT-PCR array-based approach and targeted qRT-PCR to identify and validate early, non-invasive diagnostic and prognostic biomarkers of RCC-SRMs. In total, we evaluated eighty urine samples, including 30 renal oncocytoma (≤ 4 cm) cases, 26 progressive and 24 non-progressive clear cell RCC-SRM (ccRCC-SRM) cases.

RESULTS: We identified nine urinary miRNAs which displayed significantly elevated expression in ccRCC-SRMs (pT1a; ≤ 4 cm) relative to renal oncocytoma (≤ 4 cm). Additionally, miR-328-3p displayed significantly down-regulated expression in progressive relative to non-progressive ccRCC-SRMs. Patients with elevated miR-328-3p expression had significantly longer overall survival (HR =0.29, 95% CI =0.08 to 1.03, p = 0.042) compared to patients with low miR-328-3p expression. We also found no significant association between miR-328-3p expression levels and gender, age, laterality, tumor size, or grade, suggesting that miR-328-3p is an independent prognostic biomarker.

CONCLUSIONS: Our in-depth miRNA profiling approach identified novel biomarkers for early-stage ccRCC-SRMs. Pretreatment characterization of urinary miRNAs may provide insight into early RCC progression and could potentially aid clinical decision-making, improving patient management and reducing overtreatment.

RevDate: 2019-11-01

Barnard M, Mostaghel EA, Auchus RJ, et al (2019)

The role of adrenal derived androgens in castration resistant prostate cancer.

The Journal of steroid biochemistry and molecular biology pii:S0960-0760(19)30514-X [Epub ahead of print].

Castration resistant prostate cancer (CRPC) remains androgen dependant despite castrate levels of circulating testosterone following androgen deprivation therapy, the first line of treatment for advanced metstatic prostate cancer. CRPC is characterized by alterations in the expression levels of steroidgenic enzymes that enable the tumour to derive potent androgens from circulating adrenal androgen precursors. Intratumoral androgen biosynthesis leads to the localized production of both canonical androgens such as 5α-dihydrotestosterone (DHT) as well as less well characterized 11-oxygenated androgens, which until recently have been overlooked in the context of CRPC. In this review we discuss the contribution of both canonical and 11-oxygenated androgen precursors to the intratumoral androgen pool in CRPC. We present evidence that CRPC remains androgen dependent and discuss the alterations in steroidogenic enzyme expression and how these affect the various pathways to intratumoral androgen biosynthesis. Finally we summarize the current treatment strategies for targeting adrenal derived androgen biosynthesis.

RevDate: 2019-11-01

Kaplan RC, Wang Z, Usyk M, et al (2019)

Gut microbiome composition in the Hispanic Community Health Study/Study of Latinos is shaped by geographic relocation, environmental factors, and obesity.

Genome biology, 20(1):219 pii:10.1186/s13059-019-1831-z.

BACKGROUND: Hispanics living in the USA may have unrecognized potential birthplace and lifestyle influences on the gut microbiome. We report a cross-sectional analysis of 1674 participants from four centers of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), aged 18 to 74 years old at recruitment.

RESULTS: Amplicon sequencing of 16S rRNA gene V4 and fungal ITS1 fragments from self-collected stool samples indicate that the host microbiome is determined by sociodemographic and migration-related variables. Those who relocate from Latin America to the USA at an early age have reductions in Prevotella to Bacteroides ratios that persist across the life course. Shannon index of alpha diversity in fungi and bacteria is low in those who relocate to the USA in early life. In contrast, those who relocate to the USA during adulthood, over 45 years old, have high bacterial and fungal diversity and high Prevotella to Bacteroides ratios, compared to USA-born and childhood arrivals. Low bacterial diversity is associated in turn with obesity. Contrasting with prior studies, our study of the Latino population shows increasing Prevotella to Bacteroides ratio with greater obesity. Taxa within Acidaminococcus, Megasphaera, Ruminococcaceae, Coriobacteriaceae, Clostridiales, Christensenellaceae, YS2 (Cyanobacteria), and Victivallaceae are significantly associated with both obesity and earlier exposure to the USA, while Oscillospira and Anaerotruncus show paradoxical associations with both obesity and late-life introduction to the USA.

CONCLUSIONS: Our analysis of the gut microbiome of Latinos demonstrates unique features that might be responsible for health disparities affecting Hispanics living in the USA.

RevDate: 2019-11-01

Chang YM, Sevekari T, Duerr A, et al (2019)

HIV self-testing in Pune, India: perspectives and recommendations of female sex workers and peer educators.

AIDS care [Epub ahead of print].

Female sex workers (FSW) represent a focal point of the HIV epidemic in India. HIV self-testing (HIVST) could mitigate under-diagnosis of HIV and reduce disease transmission in this population. This study assessed the acceptability of HIVST through focus group discussions (FGD) with FSW. FSW expressed willingness to use HIVST and preference for saliva-based HIVST over blood-based HIVST and preferred that HIVST education, administration, and storage take place in trusted community centers and not in brothels. We provide preliminary recommendations for the implementation of an acceptable and feasible HIVST program for FSW in India.

RevDate: 2019-10-31

Hadfield J, Brito AF, Swetnam DM, et al (2019)

Twenty years of West Nile virus spread and evolution in the Americas visualized by Nextstrain.

PLoS pathogens, 15(10):e1008042 pii:PPATHOGENS-D-19-01212.

It has been 20 years since West Nile virus first emerged in the Americas, and since then, little progress has been made to control outbreaks caused by this virus. After its first detection in New York in 1999, West Nile virus quickly spread across the continent, causing an epidemic of human disease and massive bird die-offs. Now the virus has become endemic to the United States, where an estimated 7 million human infections have occurred, making it the leading mosquito-borne virus infection and the most common cause of viral encephalitis in the country. To bring new attention to one of the most important mosquito-borne viruses in the Americas, we provide an interactive review using Nextstrain: a visualization tool for real-time tracking of pathogen evolution ( Nextstrain utilizes a growing database of more than 2,000 West Nile virus genomes and harnesses the power of phylogenetics for students, educators, public health workers, and researchers to visualize key aspects of virus spread and evolution. Using Nextstrain, we use virus genomics to investigate the emergence of West Nile virus in the U S, followed by its rapid spread, evolution in a new environment, establishment of endemic transmission, and subsequent international spread. For each figure, we include a link to Nextstrain to allow the readers to directly interact with and explore the underlying data in new ways. We also provide a brief online narrative that parallels this review to further explain the data and highlight key epidemiological and evolutionary features ( Mirroring the dynamic nature of outbreaks, the Nextstrain links provided within this paper are constantly updated as new West Nile virus genomes are shared publicly, helping to stay current with the research. Overall, our review showcases how genomics can track West Nile virus spread and evolution, as well as potentially uncover novel targeted control measures to help alleviate its public health burden.

RevDate: 2019-10-31

Pilon AC, Gu H, Raftery D, et al (2019)

Correction to Mass Spectral Similarity Networking and Gas-Phase Fragmentation Reactions in the Structural Analysis of Flavonoid Glycoconjugates.

RevDate: 2019-10-31

Cardozo EF, Ji D, Lau G, et al (2019)

Disentangling the life-spans of hepatitis C virus infected cells and intracellular vRNA replication-complexes during direct acting antiviral therapy.

Journal of viral hepatitis [Epub ahead of print].

The decay rate of hepatitis C virus (HCV) infected cells during therapy has been used to determine the duration of treatment needed to attain a sustained virologic response, but with direct acting antivirals (DAA) this rate has been difficult to estimate. Here we show that it is possible to estimate it, by simultaneously analyzing the viral load and alanine aminotransferase (ALT) kinetics during combination DAA therapy.We modeled the HCV RNA and ALT serum kinetics in 26 patients with chronic HCV genotype 1b infection, under four different sofosbuvir based combination treatments. In all patients, ALT decayed exponentially to a set-point in the normal range by 1-3 weeks after initiation of therapy. The model indicates that the ALT decay rate during the first few weeks after initiation of therapy reflects the death rate of infected cells, with an estimated median half-life of 2.5 days in this patient population. This information allows independent estimation of the rate of loss of intracellular replication complexes during therapy. Our model also predicts that the final ALT set-point is not related to the release of ALT by dying HCV infected cells. Using ALT data, one can separately obtain information about the rate of "cure" of HCV infected cells versus their rate of death, something not possible when analyzing only HCV RNA data. This information can be used to compare the effects of different DAA combinations, and to rationally evaluate their antiviral effects.

RevDate: 2019-10-31

Petersdorf EW, Carrington M, O'hUigin C, et al (2019)

Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study.

The Lancet. Haematology pii:S2352-3026(19)30208-X [Epub ahead of print].

BACKGROUND: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT.

METHODS: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors.

FINDINGS: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype.

INTERPRETATION: The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials.

FUNDING: The National Institutes of Health, USA.

RevDate: 2019-10-31

Othus M, Gale RP, Hourigan CS, et al (2019)

Statistics and measurable residual disease (MRD) testing: uses and abuses in hematopoietic cell transplantation.

SERIES EDITORS' NOTE: The decision whether to recommend a transplant to someone with acute leukemia in first remission is complex and challenging. Diverse, often confounded co-variates interact to influence one's recommendation. Briefly, the decision metric can be viewed in three spheres: (1) subject-; (2) transplant-; and (3) disease-related co-variates. Subject-related co-variates include items such as age and comorbidities. Transplant-related co-variates include items such as donor-types, graft source, proposed conditioning and pre- and post-transplant immune suppression.But what of disease-related variables? Previously haematologists relied on co-variates such as WBC at diagnosis, chemotherapy cycles to achieve first remission, cytogenetics and most recently, mutation topography. However, these co-variates have largely been replaced by results of measurable residual disease (MRD)-testing. Many chemotherapy-only and transplant studies report strong correlations between results of MRD-testing on therapy outcomes such as cumulative incidence of relapse (CIR), leukemia-free survival (LFS) or survival. (CIR makes biological sense in a transplant context whereas LFS and survival do not give competing causes of death such as transplant-related mortality (TRM), graft-versus-host disease and interstitial pneumonia unrelated to relapse probability).This raises the question of how useful results are of MRD-testing in predicting CIR after transplants. Elsewhere we discussed accuracy and precision of MRD-testing in predicting outcomes of therapy of acute myeloid leukemia (Estey E, Gale RP. Leukemia 31:1255-1258, 2017; Hourigan CS, Gale RP, Gormley NJ, Ossenkoppele GJ, Walter RB. Leukemia 31:1482-1490, 2017). Briefly put, not terribly good. Although results of MRD-testing are often the most powerful predictor of CIR in multivariable analyses, the C-statistic (a measure of prediction accuracy) is often only about 0.75. This is much better than flipping a fair coin but far from ideal.In the typescript which follows, Othus and colleagues discuss statistical issues underlying MRD-testing in the context of haematopoietic cell transplants. We hope readers, especially haematologists who often need to make transplant recommendations to people with acute leukemia in first remission, will read it carefully and critically. The bottom line is MRD-test data are useful but considerable uncertainty is unavoidable with substantial false-positive and -negative rates. We need to acknowledge this uncertainty to ourselves and to the people we counsel. The authors quote Voltaire who said: Doubt is not a pleasant condition, but certainty is an absurd one. Sadly so, but we do the best we can. Robert Peter Gale, Imperial College London, and Mei-Jie Zhang, Medical College of Wisconsin and CIBMTR.

RevDate: 2019-10-30

Herting CJ, Chen Z, Maximov V, et al (2019)

Tumour-associated macrophage-derived interleukin-1 mediates glioblastoma-associated cerebral oedema.

Brain : a journal of neurology pii:5610123 [Epub ahead of print].

Glioblastoma is the most common and uncompromising primary brain tumour and is characterized by a dismal prognosis despite aggressive treatment regimens. At the cellular level, these tumours are composed of a mixture of neoplastic cells and non-neoplastic cells, including tumour-associated macrophages and endothelial cells. Cerebral oedema is a near-universal occurrence in patients afflicted with glioblastoma and it is almost exclusively managed with the corticosteroid dexamethasone despite significant drawbacks associated with its use. Here, we demonstrate that dexamethasone blocks interleukin-1 production in both bone marrow-derived and brain resident macrophage populations following stimulation with lipopolysaccharide and interferon gamma. Additionally, dexamethasone is shown to inhibit downstream effectors of interleukin-1 signalling in both macrophage populations. Co-culture of bone marrow-derived macrophages with organotypic tumour slices results in an upregulation of interleukin-1 cytokines, an effect that is absent in co-cultured microglia. Genetic ablation of interleukin-1 ligands or receptor in mice bearing RCAS/tv-a-induced platelet-derived growth factor B-overexpressing glioblastoma results in reduced oedema and partial restoration of the integrity of the blood-brain barrier, respectively; similar to results obtained with vascular endothelial growth factor neutralization. We establish that tumours from dexamethasone-treated mice exhibit reduced infiltration of cells of the myeloid and lymphoid compartments, an effect that should be considered during clinical trials for immunotherapy in glioblastoma patients. Additionally, we emphasize that caution should be used when immune profiling and single-cell RNA sequencing data are interpreted from fresh glioblastoma patient samples, as nearly all patients receive dexamethasone after diagnosis. Collectively, this evidence suggests that interleukin-1 signalling inhibition and dexamethasone treatment share therapeutic efficacies and establishes interleukin-1 signalling as an attractive and specific therapeutic target for the management of glioblastoma-associated cerebral oedema.

RevDate: 2019-10-30

Suzuki H, Kumar SA, Shuai S, et al (2019)

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

Nature, 574(7780):707-711.

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

RevDate: 2019-10-30

Nazha A, Sekeres MA, Bejar R, et al (2019)

Genomic Biomarkers to Predict Resistance to Hypomethylating Agents in Patients With Myelodysplastic Syndromes Using Artificial Intelligence.

JCO precision oncology, 3:.

PURPOSE: We developed an unbiased framework to study the association of several mutations in predicting resistance to hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS), analogous to consumer and commercial recommender systems in which customers who bought products A and B are likely to buy C: patients who have a mutation in gene A and gene B are likely to respond or not respond to HMAs.

METHODS: We screened a cohort of 433 patients with MDS who received HMAs for the presence of common myeloid mutations in 29 genes that were obtained before the patients started therapy. The association between mutations and response was evaluated by the Apriori market basket analysis algorithm. Rules with the highest confidence (confidence that the association exists) and the highest lift (strength of the association) were chosen. We validated our biomarkers in samples from patients enrolled in the S1117 trial.

RESULTS: Among 433 patients, 193 (45%) received azacitidine, 176 (40%) received decitabine, and 64 (15%) received HMA alone or in combination. The median age was 70 years (range, 31 to 100 years), and 28% were female. The median number of mutations per sample was three (range, zero to nine), and 176 patients (41%) had three or more mutations per sample. Association rules identified several genomic combinations as being highly associated with no response. These molecular signatures were present in 30% of patients with three or more mutations/sample with an accuracy rate of 87% in the training cohort and 93% in the validation cohort.

CONCLUSION: Genomic biomarkers can identify, with high accuracy, approximately one third of patients with MDS who will not respond to HMAs. This study highlights the importance of machine learning technologies such as the recommender system algorithm in translating genomic data into useful clinical tools.

RevDate: 2019-10-29

Romieu I, Biessy C, Torres-Mejía G, et al (2019)

Project profile: a multicenter study on breast cancer in young women in Latin America (PRECAMA study).

Salud publica de Mexico, 61(5):601-608.

OBJECTIVE: To describe the rationale and the methodology of a multicenter project to study the etiology of breast cancer in young Latin American women.

MATERIALS AND METHODS: The International Agency for Research on Cancer has established an international collaborative population-based case-control study in four countries in Latin America: Chile, Colombia, Costa Rica, and Mexico (the PRECAMA study). Standardized methodologies were developed to collect information on reproductive variables, lifestyle, anthropometry, diet, clinical and pathological data, and biological specimens. The study will be extended to other countries in the region.

CONCLUSIONS: PRECAMA is unique in its multidisciplinary approach that combines genetics, genomics, and metabolomics with lifestyle factors. Then data generated through this project will be instrumental to identify major risk factors for molecular subtypes of breast cancer in young women, which will be important for pre- vention and targeted screening programs in Latin America.

RevDate: 2019-10-28

Voelker L, Upadhyaya B, Ferkey DM, et al (2019)

INX-18 and INX-19 play distinct roles in electrical synapses that modulate aversive behavior in Caenorhabditis elegans.

PLoS genetics, 15(10):e1008341 pii:PGENETICS-D-19-01262 [Epub ahead of print].

In order to respond to changing environments and fluctuations in internal states, animals adjust their behavior through diverse neuromodulatory mechanisms. In this study we show that electrical synapses between the ASH primary quinine-detecting sensory neurons and the neighboring ASK neurons are required for modulating the aversive response to the bitter tastant quinine in C. elegans. Mutant worms that lack the electrical synapse proteins INX-18 and INX-19 become hypersensitive to dilute quinine. Cell-specific rescue experiments indicate that inx-18 operates in ASK while inx-19 is required in both ASK and ASH for proper quinine sensitivity. Imaging analyses find that INX-19 in ASK and ASH localizes to the same regions in the nerve ring, suggesting that both sides of ASK-ASH electrical synapses contain INX-19. While inx-18 and inx-19 mutant animals have a similar behavioral phenotype, several lines of evidence suggest the proteins encoded by these genes play different roles in modulating the aversive quinine response. First, INX-18 and INX-19 localize to different regions of the nerve ring, indicating that they are not present in the same synapses. Second, removing inx-18 disrupts the distribution of INX-19, while removing inx-19 does not alter INX-18 localization. Finally, by using a fluorescent cGMP reporter, we find that INX-18 and INX-19 have distinct roles in establishing cGMP levels in ASK and ASH. Together, these results demonstrate that electrical synapses containing INX-18 and INX-19 facilitate modulation of ASH nociceptive signaling. Our findings support the idea that a network of electrical synapses mediates cGMP exchange between neurons, enabling modulation of sensory responses and behavior.

RevDate: 2019-10-28

Sharma P, Barlow WE, Godwin AK, et al (2019)

Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial.

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

PURPOSE: To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313.

METHODS: Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size.

RESULTS: Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated (r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively.

CONCLUSION: The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

RevDate: 2019-10-28

Veiga LH, Curtis RE, Morton LM, et al (2019)

Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use: A Report From the Childhood Cancer Survivor Study.

JAMA pediatrics pii:2753619 [Epub ahead of print].

Importance: Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied.

Objectives: To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status.

In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018.

Exposures: Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents.

Main Outcomes and Measures: Odds ratios (ORs) for subsequent breast cancer by ER status.

Results: A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use.

Conclusions and Relevance: This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.

RevDate: 2019-10-25

Zhu K, Huang Y, XH Zhou (2017)

Tree-based Ensemble Methods For Individualized Treatment Rules.

Biostatistics & epidemiology, 2(1):61-83.

There is a growing interest in development of statistical methods for personalized medicine or precision medicine, especially for deriving optimal individualized treatment rules (ITRs). An ITR recommends a patient to a treatment based on the patient's characteristics. The common parametric methods for deriving an optimal ITR, which model the clinical endpoint as a function of the patient's characteristics, can have suboptimal performance when the conditional mean model is misspecified. Recent methodology development has cast the problem of deriving optimal ITR under a weighted classification framework. Under this weighted classification framework, we develop a weighted random forests (W-RF) algorithm that derives an optimal ITR nonparametrically. In addition, with the W-RF algorithm, we propose the variable importance measures for quantifying relative relevance of the patient's characteristics to treatment selection, and the out-of-bag estimator for the population average outcome under the estimated optimal ITR. Our proposed methods are evaluated through intensive simulation studies. We illustrate the application of our methods using data from Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimers Disease Study (CATIE-AD).

RevDate: 2019-10-28

Zahoor H, P Grivas (2019)

The importance of not only living longer but also better in the setting of advanced urothelial cancer.

Annals of translational medicine, 7(Suppl 6):S187.

RevDate: 2019-10-26

Herr MM, Curtis RE, Tucker MA, et al (2019)

Risk factors for the development of cutaneous melanoma after allogeneic hematopoietic cell transplantation.

Journal of the American Academy of Dermatology pii:S0190-9622(19)32952-4 [Epub ahead of print].

Melanoma risk is increased after allogeneic hematopoietic cell transplantation (HCT), but specific risk factors are unknown. We conducted a nested case-control study of 140 melanoma cases and 557 controls (matched by age at HCT, sex, primary disease, survival time) through the Center for International Blood and Marrow Transplant Research. Melanoma risk was significantly increased among HCT survivors who received total body irradiation-based myeloablative conditioning (multivariable adjusted odds ratio [OR]=1.77; 95% confidence interval [CI]=1.00-3.15) or reduced-intensity conditioning containing melphalan (OR=2.60; 95%CI=1.13-6.02) or fludarabine (OR=2.72; 95%CI=1.02-7.30) versus busulfan-based myeloablative regimens; were diagnosed with acute graft-versus-host disease (GVHD) with stage 2+ skin involvement (OR=1.92; 95%CI=1.19-3.10), chronic GvHD without skin involvement (OR=1.91; 95%CI=1.03-3.57), or keratinocytic carcinoma (OR=2.37; 95%CI=1.16-4.83); and resided in areas with higher ambient ultraviolet radiation (ORtertile3=1.64; 95%CI=1.01-2.67). These results emphasize the importance of adherence to current surveillance guidelines (routine skin examination, photoprotection recommendations), particularly for HCT survivors at highest risk.

RevDate: 2019-10-25

LaMonte MJ, Wactawski-Wende J, Larson JC, et al (2019)

Association of Physical Activity and Fracture Risk Among Postmenopausal Women.

JAMA network open, 2(10):e1914084 pii:2753526.

Importance: Physical activity is inversely associated with hip fracture risk in older women. However, the association of physical activity with fracture at other sites and the role of sedentary behavior remain unclear.

Objective: To assess the associations of physical activity and sedentary behavior with fracture incidence among postmenopausal women.

The Women's Health Initiative prospective cohort study enrolled 77 206 postmenopausal women aged 50 to 79 years between October 1993 and December 1998 at 40 US clinical centers. Participants were observed for outcomes through September 2015, with data analysis conducted from June 2017 to August 2019.

Exposures: Self-reported physical activity and sedentary time.

Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for total and site-specific fracture incidence.

Results: During a mean (SD) follow-up period of 14.0 (5.2) years among 77 206 women (mean [SD] age, 63.4 [7.3] years; 66 072 [85.6%] white), 25 516 (33.1%) reported a first incident fracture. Total physical activity was inversely associated with the multivariable-adjusted risk of hip fracture (>17.7 metabolic equivalent [MET] h/wk vs none: HR, 0.82; 95% CI, 0.72-0.95; P for trend < .001). Inverse associations with hip fracture were also observed for walking (>7.5 MET h/wk vs none: HR, 0.88; 95% CI, 0.78-0.98; P for trend = .01), mild activity (HR, 0.82; 95% CI, 0.73-0.93; P for trend = .003), moderate to vigorous activity (HR, 0.88; 95% CI, 0.81-0.96; P for trend = .002), and yard work (HR, 0.90; 95% CI, 0.82-0.99; P for trend = .04). Total activity was positively associated with knee fracture (>17.7 MET h/wk vs none: HR, 1.26; 95% CI, 1.05-1.50; P for trend = .08). Mild activity was associated with lower risks of clinical vertebral fracture (HR, 0.87; 95% CI, 0.78-0.96; P for trend = .006) and total fractures (HR, 0.91; 95% CI, 0.87-0.94; P for trend < .001). Moderate to vigorous activity was positively associated with wrist or forearm fracture (HR, 1.09; 95% CI, 1.03-1.15; P for trend = .004). After controlling for covariates and total physical activity, sedentary time was positively associated with total fracture risk (>9.5 h/d vs <6.5 h/d: HR, 1.04; 95% CI, 1.01-1.07; P for trend = .01). When analyzed jointly, higher total activity mitigated some of the total fracture risk associated with sedentary behavior. Analysis of time-varying exposures resulted in somewhat stronger associations for total physical activity, whereas those for sedentary time were materially unchanged.

Conclusions and Relevance: In older ambulatory women, higher total physical activity was associated with lower total and hip fracture risk but higher knee fracture risk. Mild activity and walking were associated with lower hip fracture risk, a finding with important public health implications because these activities are common in older adults. The positive association between sedentary time and total fracture risk requires further investigation.

RevDate: 2019-10-25

Schenk JM, Newcomb LF, Zheng Y, et al (2019)

African American Race is Not Associated with Risk of Reclassification during Active Surveillance: Results from the Canary Prostate Cancer Active Surveillance Study (PASS).

The Journal of urology [Epub ahead of print].

OBJECTIVE: To evaluate whether African American (AA) men are at higher risk of reclassification in a large, prospective multi-institutional active surveillance (AS) cohort.

METHODS: The Canary Prostate Active Surveillance Study (PASS) is a protocol-driven active surveillance cohort with pre-specified prostate-specific antigen (PSA) and surveillance biopsies regimen. Men included in this study had Gleason Grade Group 1 or 2 at diagnosis, < 5 years between diagnosis and enrollment, and had undergone ≥ 1 surveillance biopsy. Risk of reclassification, defined as an increase in Gleason score on subsequent biopsy, was compared between AA and CA using cox proportional hazards models. For the subset of men undergoing delayed prostatectomy, rates of adverse pathology, defined as pT3a or greater or Gleason Grade Group 3 or greater, were compared for AA and CA.

RESULTS: Of 1,315 men, there were 89 (7%) AA and 1,226 (93%) CA. There were no differences in the rate of treatment for AA and CA. In multivariate models, AA race was not associated with the risk of reclassification (HR=1.16, 95% CI: 0.78-1.72). Among 441 men who had a prostatectomy after a period of AS, rate of adverse pathology was similar for AA and CA (46% vs 47%, p=0.99).

CONCLUSIONS: Among men on AS who follow a standardized protocol of regular PSA and biopsy, AA men were not at increased risk of pathologic reclassification on AS or adverse pathology at prostatectomy. AS appears to be an appropriate management strategy for AA men with favorable risk prostate cancer.

RevDate: 2019-10-25

Tolley EE, Li S, Zangeneh SZ, et al (2019)

Acceptability of a long-acting injectable HIV prevention product among US and African women: findings from a phase 2 clinical Trial (HPTN 076).

Journal of the International AIDS Society, 22(10):e25408.

INTRODUCTION: High HIV incidence and low adherence to daily oral PrEP among women underscore the need for more acceptable and easier to use HIV prevention products. Global demand for injectable contraception suggests that new, long-acting, injectable formulations could meet this need. We examine acceptability of a long-acting injectable PrEP among HIV-uninfected women in Zimbabwe, South Africa and two United States phase 2 trial sites.

METHODS: Quantitative surveys were administered at the first, fourth and sixth injection visits. Focus group discussions (FGD) were conducted after the sixth injection visit. We compared the acceptability of injectable product attributes, prevention preferences and future interest in injectable PrEP by site and arm and ran longitudinal ordinal logistic regression models to identify determinants of future interest in injectable PrEP.

RESULTS: Between April 2015 and February 2017, the trial enrolled 136 (100 African, 36 US) women with a median age of 31 years. Most participants (>75%) rated injectable attributes as very acceptable. While few reported rash or other side effects, 56% to 67% reported injection pain, with nonsignificant differences over time and between arms. During FGDs, participants described initial fear of the injectable and variable experiences with pain. Most US and African participants preferred injectable PrEP to daily oral pills (56% to 96% vs. 4% to 25%). Future interest in using injectable PrEP was associated with acceptability of product attributes and was higher in African than US sites. In FGDs, participants described multiple reasons for trial participation, including a combination of monetary, health-related and altruistic motivations. While associated with future interest in use in univariate models, neither altruistic nor personal motivations remained significant in the multivariate model.

CONCLUSIONS: This study found that long-acting injectable PrEP is acceptable among African and US women experiencing product use. Acceptability of product attributes better predicted future interest in injectable use than experience of pain. This is reassuring as a single-dose regimen of a different product has advanced to phase 3 trials. Finally, the study suggests that future demand for an injectable PrEP by women may be greater in African than US settings, where the risk of HIV is highest.

RevDate: 2019-10-25

Sulakvelidze N, Burdick B, Gelfand E, et al (2019)

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

The original version of this article unfortunately contained a mistake. The name of "Eric Gelfand" was omitted.

RevDate: 2019-10-25

Benkeser D, Gilbert PB, M Carone (2019)

Estimating and Testing Vaccine Sieve Effects Using Machine Learning.

Journal of the American Statistical Association, 114(527):1038-1049.

When available, vaccines are an effective means of disease prevention. Unfortunately, efficacious vaccines have not yet been developed for several major infectious diseases, including HIV and malaria. Vaccine sieve analysis studies whether and how the efficacy of a vaccine varies with the genetics of the pathogen of interest, which can guide subsequent vaccine development and deployment. In sieve analyses, the effect of the vaccine on the cumulative incidence corresponding to each of several possible genotypes is often assessed within a competing risks framework. In the context of clinical trials, the estimators employed in these analyses generally do not account for covariates, even though the latter may be predictive of the study endpoint or censoring. Motivated by two recent preventive vaccine efficacy trials for HIV and malaria, we develop new methodology for vaccine sieve analysis. Our approach offers improved validity and efficiency relative to existing approaches by allowing covariate adjustment through ensemble machine learning. We derive results that indicate how to perform statistical inference using our estimators. Our analysis of the HIV and malaria trials shows markedly increased precision -- up to doubled efficiency in both trials -- under more plausible assumptions compared with standard methodology. Our findings provide greater evidence for vaccine sieve effects in both trials.

RevDate: 2019-10-25

Gallagher CS, Mäkinen N, Harris HR, et al (2019)

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Nature communications, 10(1):4857 pii:10.1038/s41467-019-12536-4.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

RevDate: 2019-10-25

Bezerra ED, Othus M, Shawn C, et al (2019)

Independent Associations Between Glomerular Filtration Rate and Serum Bilirubin Level and Early Mortality in Acute Myeloid Leukemia.

RevDate: 2019-10-24

Bejanyan N, Kim S, Hebert KM, et al (2019)

Choice of conditioning regimens for bone marrow transplantation in severe aplastic anemia.

Blood advances, 3(20):3123-3131.

Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

RevDate: 2019-10-24

Shadman M, Gauthier J, Hay KA, et al (2019)

Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy.

Blood advances, 3(20):3062-3069.

Allogeneic hematopoietic cell transplantation (allo-HCT) is offered to selected patients after chimeric antigen receptor-modified T-cell (CAR-T) therapy. Lymphodepleting chemotherapy and CAR-T therapy have immunosuppressive and immunomodulatory effects that could alter the safety profile of subsequent allo-HCT. We reviewed our experience with 32 adults (acute lymphoblastic leukemia [ALL], n = 19; B-cell non-Hodgkin lymphoma [NHL]/chronic lymphocytic leukemia [CLL], n = 13) who received an allo-HCT after CAR-T therapy, with a focus on posttransplant toxicities. Myeloablative conditioning (MAC) was used in 74% of ALL patients and 39% of NHL/CLL patients. The median time from CAR-T therapy to allo-HCT was 72 days in ALL patients and 122 days in NHL/CLL patients. Cumulative incidences of grade 3-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 25% and 10%, respectively. All patients had neutrophil recovery (median, 18.5 days) and all but 3 had platelet recovery (median, 12 days). Twenty-two percent had viral or systemic fungal infection within 100 days after allo-HCT. The 100-day and 1-year cumulative incidences of NRM were 16% and 21%, respectively, for ALL patients and 15% and 33%, respectively, for NHL/CLL patients. In ALL patients, later utilization of allo-HCT after CAR-T therapy was associated with higher mortality. In NHL/CLL patients, MAC was associated with higher mortality. Toxicities did not exceed the expected incidences in this high-risk population.

RevDate: 2019-10-24

Kamdar M, Li H, Chen RW, et al (2019)

Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma.

Blood advances, 3(20):3132-3135.


ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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


Order from Amazon

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

Electronic Scholarly Publishing
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Papers in Classical Genetics

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

Digital Books

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


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


Biographical information about many key scientists.

Selected Bibliographies

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

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