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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 19 Nov 2018 at 01:33 Created: 

Publications by FHCRC Researchers

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

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

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

Citations The Papers (from PubMed®)

RevDate: 2018-11-18

Kearns JT, Winters BD, Holt SK, et al (2018)

Pathologic Nodal Involvement in Patients With Penile Cancer With Cavernosal Versus Spongiosal Involvement.

Clinical genitourinary cancer pii:S1558-7673(18)30103-4 [Epub ahead of print].

BACKGROUND: The American Joint Committee on Cancer recently proposed new TNM staging for penile cancer, with proposed T2 as spongiosal invasion and T3 as cavernosal invasion. We sought to validate the proposed staging system for predicting pathologic nodal involvement using the National Cancer Data Base.

PATIENTS AND METHODS: Invasive penile cancer cases from 2010 to 2012 were identified. Differences in demographic and pathologic factors between T2 and T3 tumors were compared using χ2 and t tests. Logistic regression was performed to determine the odds of pathologically involved lymph nodes (pN+) by T classification.

RESULTS: There were 378 T2 and 524 T3 patients with penile cancer. Compared with T2 tumors, T3 tumors were larger (mean size, 5.8 cm vs. 4.3 cm), had higher positive surgical margin rates (12% vs. 9%), and were more likely to have lymphovascular invasion (42% vs. 31%) (all P < .05). In multivariable analysis, both T2 (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.3) and T3 (OR, 2.3; 95% CI, 1.4-3.6) remained significantly associated with risk of positive lymph nodes compared with T1 disease, but there was no increase in risk between T2 and T3 disease (OR, 1.1; 95% CI, 0.7-1.8; P = .56).

CONCLUSION: The proposed new American Joint Committee on Cancer staging system for the penile cancer distinguishes spongiosal (T2) from cavernosal (T3) involvement. There does not appear to be a difference in positive lymph node status between the 2 grades when other clinical and pathologic variables are considered.

RevDate: 2018-11-17

Reeves KW, Santana MD, Manson JE, et al (2018)

Predictors of urinary phthalate biomarker concentrations in postmenopausal women.

Environmental research, 169:122-130 pii:S0013-9351(18)30558-9 [Epub ahead of print].

BACKGROUND: Phthalates are ubiquitous endocrine disrupting chemicals present in a wide variety of consumer products. However, the personal characteristics associated with phthalate exposure are unclear.

OBJECTIVES: We sought to describe personal, behavioral, and reproductive characteristics associated with phthalate metabolite concentrations in an ongoing study nested within the Women's Health Initiative (WHI).

MATERIALS AND METHODS: We measured thirteen phthalate metabolites in two or three archived urine samples collected in 1993-2001 from each of 1257 WHI participants (2991 observations). We fit multivariable generalized estimating equation models to predict urinary biomarker concentrations from personal, behavioral, and reproductive characteristics.

RESULTS: Older age was predictive of lower concentrations of monobenzyl phthalate (MBzP), mono-carboxyoctyl phthalate (MCOP), mono-3-carboxypropyl phthalate (MCPP), and the sum of di-n-butyl phthalate metabolites (ΣDBP). Phthalate metabolite concentrations varied by race/region, with generally higher concentrations observed among non-Whites and women from the West region. Higher neighborhood socioeconomic status predicted lower MBzP concentrations, and higher education predicted lower monoethyl phthalate (MEP) and higher concentrations of the sum of metabolites of di-isobutyl phthalate (ΣDiBP). Overweight/obesity predicted higher MBzP, MCOP, monocarboxynonyl phthalate (MCNP), MCPP, and the sum of metabolites of di(2-ethylhexyl) phthalate (ΣDEHP) and lower MEP concentrations. Alcohol consumption predicted higher concentrations of MEP and ΣDBP, while current smokers had higher ΣDBP concentrations. Better diet quality as assessed by Healthy Eating Index 2005 scores predicted lower concentrations of MBzP, ΣDiBP, and ΣDEHP.

CONCLUSION: Factors predictive of lower biomarker concentrations included increased age and healthy behaviors (e.g. lower alcohol intake, lower body mass index, not smoking, higher quality diet, and moderate physical activity). Racial group (generally higher among non-Whites) and geographic regions (generally higher in Northeast and West compared to South regions) also were predictive of phthalate biomarker concentrations.

RevDate: 2018-11-17

Rozmus J, Kariminia A, Abdossamadi S, et al (2018)

Comprehensive B Cell Phenotyping Profile for Chronic Graft-Versus-Host Disease Diagnosis.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(18)30701-8 [Epub ahead of print].

Previous studies have reported single B cell related chronic graft-versus-host disease diagnostic (cGvHD) biomarkers such as B cell activating factor (BAFF), CD21low and immature B cells, but research on the performance of biomarker combinations and the covariate effect of steroids is lacking. The primary objective of this study was to determine the most accurate combination of B cell populations using cell surface staining flow cytometry in an independent cGvHD cohort. Secondary objectives included assessing the effect of corticosteroid use at sample collection on the make-up and accuracy of the diagnostic panel and identifying the mechanism underlying low surface expression of BAFF receptor (BAFF-R) on B cells in cGvHD. Flow cytometric analysis was performed in an adult cohort of post-HCT patients with cGvHD onset (n = 44) and time-matched recipients without cGvHD (n = 63). We confirmed that the onset of cGvHD was associated with higher soluble BAFF (sBAFF) levels, elevated numbers of CD27-CD10-CD21low CD19+ B cells and classical switched memory B cells, and reduced numbers of transitional and naïve B cells. The highest single B cell population area under the Receiver Operator Characteristic (ROC) curve (AUC) was 0.72 for transitional type 1 CD21low B cells. We also showed a significant inverse relationship between sBAFF and surface BAFF-R expression caused by sBAFF modulation of BAFF-R. Steroid use at sample collection influenced the significance of the sBAFF: B cell ratio, naïve and marginal zone-like B cells. The optimal combination of B cell subsets most significantly associated with cGvHD onset with or without concurrent corticosteroid use resulted in ROC AUC of 0.87 and 0.84 respectively. Transitional and CD21low B cells were the only populations present in both panels; however only analyzing them resulted in ROC AUC of 0.79 and 0.78 respectively. This suggests that the inclusion of other populations and use of different panels depending on steroid use is necessary to achieve better accuracy. Soluble BAFF was not part of either panel. These novel B cell profiles could be prospectively tested in patients post-HSCT and lead to focused mechanistic studies.

RevDate: 2018-11-17

Reeves DB, Duke ER, Wagner TA, et al (2018)

A majority of HIV persistence during antiretroviral therapy is due to infected cell proliferation.

Nature communications, 9(1):4811 pii:10.1038/s41467-018-06843-5.

Antiretroviral therapy (ART) suppresses viral replication in people living with HIV. Yet, infected cells persist for decades on ART and viremia returns if ART is stopped. Persistence has been attributed to viral replication in an ART sanctuary and long-lived and/or proliferating latently infected cells. Using ecological methods and existing data, we infer that >99% of infected cells are members of clonal populations after one year of ART. We reconcile our results with observations from the first months of ART, demonstrating mathematically how a fossil record of historic HIV replication permits observed viral evolution even while most new infected cells arise from proliferation. Together, our results imply cellular proliferation generates a majority of infected cells during ART. Therefore, reducing proliferation could decrease the size of the HIV reservoir and help achieve a functional cure.

RevDate: 2018-11-17

Qu X, Li H, Braziel RM, et al (2018)

Genomic alterations important for the prognosis in patients with follicular lymphoma treated on SWOG study S0016.

Blood pii:blood-2018-07-865428 [Epub ahead of print].

Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy number aberrations (CNAs) and copy neutral loss of heterozygosity (cnLOH) identified by chromosome genomic array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in SWOG S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (i.e., the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: while early progression was correlated with 2p gain [P=0.007, OR=2.55 (1.29, 5.03)] and 2p cnLOH [P=0.005, OR=10.9 (2.08, 57.2)], 2p gain specifically encompassing VRK2 and FANCL predicted PFS [P=0.01, HR=1.80 (1.14, 2.68)] as well as OS [P=0.005, 2.40 (1.30, 4.40)]; CDKN2A/B (9p) deletion correlated with worse PFS [P=0.004, 3.50 (1.51, 8.28)]; whereas CREBBP (16p) [P<0.001, 6.70 (2.52, 17.58)] and TP53 (17p) [P<0.001, 3.90 (1.85, 8.31)] deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.

RevDate: 2018-11-16

Heuvel AVD, Mahfouz A, Kloet SL, et al (2018)

Single-cell RNA-sequencing in facioscapulohumeral muscular dystrophy disease etiology and development.

Human molecular genetics pii:5185122 [Epub ahead of print].

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by sporadic de-repression of the transcription factor DUX4 in skeletal muscle. DUX4 activates a cascade of muscle disrupting events, eventually leading to muscle atrophy and apoptosis. Yet, how sporadic DUX4 expression leads to the generalized muscle wasting remains unclear. Transcriptome analyses have systematically been challenged by the majority of nuclei being DUX4neg, weakening the DUX4 transcriptome signature. Moreover, DUX4 has been shown to be expressed in a highly dynamic burst-like manner, likely resulting in the detection of the downstream cascade of events long after DUX4 expression itself has faded. Identifying the FSHD-transcriptome in individual cells and unraveling the cascade of events leading to FSHD development, may therefore provide important insights in the disease process.We employed single-cell RNA-sequencing, combined with pseudotime trajectory modeling, to study FSHD disease etiology and cellular progression in human primary myocytes. We identified a small FSHD-specific cell population in all tested patient-derived cultures and detected new genes associated with DUX4 de-repression. We furthermore generated an FSHD cellular progression model, reflecting both the early burst-like DUX4 expression as well as the downstream activation of various FSHD-associated pathways, which allowed us to correlate DUX4 expression signature dynamics with that of regulatory complexes, thereby facilitating the prioritization of epigenetic targets for DUX4 silencing.Single-cell transcriptomics combined with pseudotime modeling thus holds valuable information on FSHD disease etiology and progression which can potentially guide biomarker and target selection for therapy.

RevDate: 2018-11-16

Amundsen SK, GR Smith (2018)

The RecB helicase-nuclease tether mediates Chi hotspot control of RecBCD enzyme.

Nucleic acids research pii:5184714 [Epub ahead of print].

In bacteria, repair of DNA double-strand breaks uses a highly conserved helicase-nuclease complex to unwind DNA from a broken end and cut it at specific DNA sequences called Chi. In Escherichia coli the RecBCD enzyme also loads the DNA strand-exchange protein RecA onto the newly formed end, resulting in a recombination hotspot at Chi. Chi hotspots regulate multiple RecBCD activities by altering RecBCD's conformation, which is proposed to include the swinging of the RecB nuclease domain on the 19-amino-acid tether connecting the helicase and nuclease domains. Here, we altered the tether and tested multiple RecBCD activities, genetically in cells and enzymatically in cell-free extracts. Randomizing the amino-acid sequence or lengthening it had little effect. However, shortening it by as little as two residues or making substitutions of ≥10 proline or ≥9 glycine residues dramatically lowered Chi-dependent activities. These results indicate that proper control of RecBCD by Chi requires that the tether be long enough and appropriately flexible. We discuss a model in which the swing-time of the nuclease domain determines the position of Chi-dependent and Chi-independent cuts and Chi hotspot activity.

RevDate: 2018-11-16

Lim U, Monroe KR, Buchthal S, et al (2018)

Propensity for Intra-abdominal and Hepatic Adiposity Varies Among Ethnic Groups.

Gastroenterology pii:S0016-5085(18)35263-6 [Epub ahead of print].

BACKGROUND & AIMS: We compared fat storage in the abdominal region among individuals from 5 different ethnic/racial groups to determine whether fat storage is associated with disparities observed in the metabolic syndrome and other obesity-associated diseases.

METHODS: We collected data from 1794 participants in the Multiethnic Cohort Study (60-77 years old; of African, European (white), Japanese, Latino, or Native Hawaiian ancestry) with body mass index values of 17.1-46.2 kg/m2. From May 2013 through April 2016, participants visited the study clinic to undergo body measurements, an interview, and a blood collection. Participants were evaluated by dual energy X-ray absorptiometry and abdominal magnetic resonance imaging. Among the ethnic groups, we compared adiposity of trunk, intra-abdominal visceral cavity, and liver, adjusting for total fat mass; we evaluated the association of adult weight change with abdominal adiposity; and we examined the prevalence of the metabolic syndrome mediated by abdominal adiposity.

RESULTS: Relative amounts of trunk, visceral, and liver fat varied significantly with ethnicity-they were highest in Japanese Americans, lowest in African Americans, and intermediate in the other groups. Compared with African Americans, the mean visceral fat area was 45% and 73% greater in Japanese American men and women, respectively, and the mean measurements of liver fat were 61% and 122% greater in Japanese American men and women. The visceral and hepatic adiposity associated with weight gain since participants were 21 years old varied in a similar pattern among ethnic/racial groups. In the mediation analysis, visceral and liver fat jointly accounted for a statistically significant fraction of the difference in metabolic syndrome prevalence, in comparison to white persons, for African Americans, Japanese Americans, and Native Hawaiian women, independently of total fat mass.

CONCLUSIONS: In an analysis of data from the participants in the Multiethnic Cohort Study, we found extensive differences among ethnic/racial groups in the propensity to store fat intra-abdominally. This observation should be considered by clinicians in the prevention and early detection of metabolic disorders.

RevDate: 2018-11-16

Ludwig DS, Willett WC, Volek JS, et al (2018)

Dietary fat: From foe to friend?.

Science (New York, N.Y.), 362(6416):764-770.

For decades, dietary advice was based on the premise that high intakes of fat cause obesity, diabetes, heart disease, and possibly cancer. Recently, evidence for the adverse metabolic effects of processed carbohydrate has led to a resurgence in interest in lower-carbohydrate and ketogenic diets with high fat content. However, some argue that the relative quantity of dietary fat and carbohydrate has little relevance to health and that focus should instead be placed on which particular fat or carbohydrate sources are consumed. This review, by nutrition scientists with widely varying perspectives, summarizes existing evidence to identify areas of broad consensus amid ongoing controversy regarding macronutrients and chronic disease.

RevDate: 2018-11-16

Patel AB, Louder RK, Greber BJ, et al (2018)

Structure of human TFIID and mechanism of TBP loading onto promoter DNA.

Science (New York, N.Y.) pii:science.aau8872 [Epub ahead of print].

The general transcription factor IID (TFIID) is a critical component of the eukaryotic transcription preinitiation complex (PIC) and is responsible for recognizing the core promoter DNA and initiating PIC assembly. We used cryo-electron microscopy (cryo-EM), chemical crosslinking-mass spectrometry (CX-MS) and biochemical reconstitution to determine the complete molecular architecture of TFIID and define the conformational landscape of TFIID in the process of TATA-box binding protein (TBP) loading onto promoter DNA. Our structural analysis revealed five structural states of TFIID in the presence of TFIIA and promoter DNA, showing that the initial binding of TFIID to the downstream promoter positions the upstream DNA and facilitates scanning of TBP for a TATA-box and the subsequent engagement of the promoter. Our findings provide a mechanistic model for the specific loading of TBP by TFIID onto the promoter.

RevDate: 2018-11-16

Streiff MB, Holmstrom B, Angelini D, et al (2018)

NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018.

Journal of the National Comprehensive Cancer Network : JNCCN, 16(11):1289-1303.

Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE.

RevDate: 2018-11-16

Fatobene G, Storer BE, Salit RB, et al (2018)

Disability related to chronic graft-versus-host disease after alternative donor hematopoietic cell transplantation.

Haematologica pii:haematol.2018.202754 [Epub ahead of print].

We determined the incidence of disability related to chronic graft-versus-host disease (bronchiolitis obliterans, grade ≥ 2 keratoconjunctivitis sicca, sclerotic features or esophageal stricture) for 3 categories of alternative donor: cord blood, haplorelated marrow or peripheral blood with posttransplant cyclophosphamide, and unrelated single HLA-allele mismatched peripheral blood. Among 396 consecutive hematopoietic cell transplantation recipients, 129 developed chronic graft-versus-host disease with incidences in each group of 18% for cord blood, 24% for haplorelated, and 55% for unrelated single HLA-allele mismatched peripheral blood; after a median follow-up of 48, 60, and 46 months, respectively, from diagnosis. Disability rates were significantly lower for cord blood (hazard ratio 0.13; 95% cumulative incidence (CI): 0.1-0.4) and for the haplorelated group (HR 0.31; 95%CI: 0.1-0.7) compared to unrelated single HLA-allele mismatched peripheral blood. Cord blood recipients were also >2-fold more likely to return to work/school by 3 years from chronic graft-versus-host disease onset (HR 2.54; 95%CI: 1.1-5.7, p=.02), and the haplorelated group trended similarly (HR 2.38; 95%CI: 1.0-5.9, p=.06). Cord blood recipients were more likely to discontinue immunosuppression than unrelated single HLA-allele mismatched peripheral blood (HR 3.96; 95%CI: 1.9-8.4, p=.0003), similar to the haplorelated group (HR 4.93; 95%CI: 2.2-11.1, p=.0001). Progression-free survival and non-relapse mortality did not differ between donor groups. Our observations that compared to unrelated single HLA-allele mismatched peripheral blood, recipients of cord blood and haplorelated grafts less often developed disability related to chronic graft-versus-host disease, and more likely resumed work/school, should help better counsel pre-hematopoietic cell transplant candidates.

RevDate: 2018-11-16

Piper CL, Scheel JR, Lee CI, et al (2018)

Representation of Women on Radiology Journal Editorial Boards: A 40-Year Analysis.

Academic radiology pii:S1076-6332(18)30182-X [Epub ahead of print].

RATIONALE AND OBJECTIVES: We examined female representation on editorial boards of four prominent radiology journals. We compared editorial board representation to female academic radiology career advancement and the proportion of female authorship in three journals over four decades.

METHODS: We collected data on the gender of editorial board members as listed on mastheads of Radiology, American Journal of Roentgenology (AJR), Academic Radiology, and the Journal of the American College of Radiology in 5-year intervals plus the most recent year available (1973-2017), and the gender of their editors-in-chief for all years since each journal's inception. We compared Radiology, AJR, and Academic Radiology data to published data on gender of the journals' authors, all US medical students, and academic radiologists over time.

RESULTS: Gender was determined for 171 editors-in-chief (100%) and 2139 (100%) editorial board members listed in the selected journals for each of the study years. The proportion of women on editorial boards increased from 1.4% (1 of 69) in 1978 to 18.8% (73 of 388) in 2013 (P < .001), but remained below the proportion of female first authors (7.5% in 1978 and 27.1% in 2013) and female faculty in radiology (11.5% in 1978 and 28.1% in 2013). None of the four general radiology journals had a female editor-in-chief during the study period.

CONCLUSIONS: Female representation on editorial boards has increased over time, but still lags behind increases seen in female first authorship in radiology journals and radiology faculty appointments over the last four decades. There was no female editor-in-chief during the study period.

RevDate: 2018-11-15

Iovino L, Mazziotta F, Buda G, et al (2018)

The Onset of Monoclonal and Oligoclonal Gammopathies Is a Good Prognostic Factor after Allogeneic Stem Cell Transplantation.

Acta haematologica, 141(1):7-11 pii:000493416 [Epub ahead of print].

RevDate: 2018-11-15

Borges KA, Dai J, Parikh ND, et al (2018)

Rationale and design of the Hepatocellular carcinoma Early Detection Strategy study: A multi-center longitudinal initiative of the National Cancer Institute's early Detection Research Network.

Contemporary clinical trials pii:S1551-7144(18)30564-0 [Epub ahead of print].

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity.

METHODS: The Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in six clinical centers across the country. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository.

RESULTS: The database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis.

CONCLUSIONS: The HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers. Trial registry URL:

RevDate: 2018-11-15

Koch MA (2018)

Sex Bias in Sepsis.

Cell host & microbe, 24(5):613-615.

Though critical for preventing fatal sepsis, the mechanisms mediating the capture of bloodstream bacteria are incompletely understood. New work by Zeng et al. (2018) demonstrates that estrogen-regulated innate antibodies protect females and newborns from death following bloodstream infection with enteropathogenic Eschericia coli.

RevDate: 2018-11-15

Andersen MR, Karlan BY, Drescher CW, et al (2018)

False-positive screening events and worry influence decisions about surgery among high-risk women.

Health psychology : official journal of the Division of Health Psychology, American Psychological Association pii:2018-57423-001 [Epub ahead of print].

OBJECTIVE: Studies of cancer screening have found that false positive screening events (FPSE) can affect worry about cancer risk and screening program use, we sought to further explore this.

METHOD: In a study of 1,100 women at high risk for ovarian cancer who participated in a previously published randomized controlled trial (RCT), we sought to explore whether worry might also influence the use of risk-reducing surgical procedures by women. Participants included 234 women with BRCA1/2 mutations and 866 women with high-risk pedigrees. We followed the women for up to 6 years.

RESULTS: Worry predicted risk reducing prophylactic bilateral salpingo-oophorectomy (pBSO) for both mutation carriers (HR = 1.74; p = .02), and women with high-risk pedigree (HR = 3.41; p < .001). FPSE also predicted subsequent pBSO among women with a high-risk pedigree (HR 2.31; p < .01). While screening may reduce worry among those who never receive a positive result, FPSE increase worry at least temporarily. Worry about ovarian cancer risk predicted use of preventative pBSO among high-risk women including those with BRCA1/2 mutations enrolled in an ovarian cancer-screening program. FPSE also predicted risk-reducing ovarian surgery among high-risk women without a known mutation at the time of screening program enrollment.

CONCLUSIONS: Physicians who offer screening should know that false positive results may increase use of pBSO, how this should effect clinical practice is unclear. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

RevDate: 2018-11-15

Zhao N, Zhang H, Clark JJ, et al (2018)

Composite Kernel Machine Regression based on Likelihood Ratio Test for Joint Testing of Genetic and Gene-environment Interaction Effect.

Biometrics [Epub ahead of print].

Most common human diseases are a result from the combined effect of genes, the environmental factors and their interactions such that including gene-environment (GE) interactions can improve power in gene mapping studies. The standard strategy is to test the SNPs, one-by-one, using a regression model that includes both the SNP effect and the GE interaction. However, the SNP-by-SNP approach has serious limitations, such as the inability to model epistatic SNP effects, biased estimation and reduced power. Thus, in this paper, we develop a kernel machine regression framework to model the overall genetic effect of a SNP-set, considering the possible GE interaction. Specifically, we use a composite kernel to specify the overall genetic effect via a nonparametric function and we model additional covariates parametrically within the regression framework. The composite kernel is constructed as a weighted average of two kernels, one corresponding to the genetic main effect and one corresponding to the GE interaction effect. We propose a likelihood ratio test (LRT) and a restricted likelihood ratio test (RLRT) for statistical significance. We derive a Monte Carlo approach for the finite sample distributions of LRT and RLRT statistics. Extensive simulations and real data analysis show that our proposed method has correct type I error and can have higher power than score-based approaches under many situations. This article is protected by copyright. All rights reserved.

RevDate: 2018-11-15

Davidsen K, FA Matsen (4th) (2018)

Benchmarking Tree and Ancestral Sequence Inference for B Cell Receptor Sequences.

Frontiers in immunology, 9:2451.

B cell receptor sequences evolve during affinity maturation according to a Darwinian process of mutation and selection. Phylogenetic tools are used extensively to reconstruct ancestral sequences and phylogenetic trees from affinity-matured sequences. In addition to using general-purpose phylogenetic methods, researchers have developed new tools to accommodate the special features of B cell sequence evolution. However, the performance of classical phylogenetic techniques in the presence of B cell-specific features is not well understood, nor how much the newer generation of B cell specific tools represent an improvement over classical methods. In this paper we benchmark the performance of classical phylogenetic and new B cell-specific tools when applied to B cell receptor sequences simulated from a forward-time model of B cell receptor affinity maturation toward a mature receptor. We show that the currently used tools vary substantially in terms of tree structure and ancestral sequence inference accuracy. Furthermore, we show that there are still large performance gains to be achieved by modeling the special mutation process of B cell receptors. These conclusions are further strengthened with real data using the rules of isotype switching to count possible violations within each inferred phylogeny.

RevDate: 2018-11-15

Asbach B, Kibler KV, Köstler J, et al (2018)

Priming with a potent HIV-1 DNA vaccine frames the quality of immune responses prior to a poxvirus and protein boost.

Journal of virology pii:JVI.01529-18 [Epub ahead of print].

The use of heterologous immunization regimens and improved vector systems has led to increases in immunogenicity of HIV-1 vaccine candidates in non-human primates. In order to resolve interrelations between different delivery modalities, three different poxvirus boost regimens were compared. Three groups of rhesus macaques were each primed with the same DNA vaccine encoding for Gag, PolNef, and gp140. The groups were then boosted either with the vaccinia virus strain NYVAC or a variant with improved replication competence in human cells termed NYVAC-KC. The latter was either administered by scarification or intramuscularly. Finally, macaques were boosted with adjuvanted gp120 protein to enhance humoral responses. The regimen elicited very potent CD4+ and CD8+ T cell responses in a well-balanced manner, peaking two weeks after the boost. T cells were broadly reactive and polyfunctional. All animals exhibited antigen-specific humoral responses already after the poxvirus boost that further increased following protein administration. Polyclonal reactivity of IgG antibodies was highest against HIV-1 clade C Env-proteins with considerable cross-reactivity to other clades. Substantial effector functional activities (ADCC and ADCVI) were observed in sera obtained after the last protein boost. Notably, major differences between the groups were absent, indicating that the potent priming induced by the DNA vaccine initially framed the immune responses in such a way that the subsequent boosts with NYVAC and protein only led to an increase in the response magnitudes without skewing the quality. This study highlights the importance of selecting the best combination of vector systems in heterologous prime-boost vaccination regimens.ImportanceThe evaluation of HIV vaccine efficacy trials indicates that protection would most likely correlate with a polyfunctional immune response involving several effector functions from all arms of the immune system. Heterologous prime-boost regimens have been shown to elicit vigorous T cell and antibody responses in non-human primates that, however, qualitatively and quantitatively differ depending on the respective vector systems used. The present study evaluated a DNA prime, poxvirus and protein boost regimen, and compared how two poxvirus vectors with varying degrees of replication capacity and two different delivery modalities - conventional intramuscular delivery and percutaneous delivery by scarification - impact several immune effectors. It was found that despite the different poxvirus boosts, the overall immune responses in the three groups were similar, suggesting the potent DNA priming as the major determining factor of immune responses. These findings emphasize the importance of selecting optimal priming agents in heterologous prime-boost vaccination settings.

RevDate: 2018-11-15

Kibler KV, Asbach B, Perdiguero B, et al (2018)

Replication-competent NYVAC-KC yields improved immunogenicity to HIV-1 antigens in rhesus macaques, compared to non-replicating NYVAC.

Journal of virology pii:JVI.01513-18 [Epub ahead of print].

As part of the continuing effort to develop an effective HIV vaccine, we generated a poxviral vaccine vector (previously described) designed to improve on the results of the RV144 Phase III clinical trial. The construct, NYVAC-KC, is a replication-competent, attenuated recombinant of the vaccinia virus strain, NYVAC. NYVAC is a vector that has been used in many previous clinical studies but is replication deficient. Here we report a side-by-side comparison of replication-restricted NYVAC and replication-competent NYVAC-KC in a non-human primate study, which utilized a prime-boost regimen similar to that of RV144. NYVAC-C and NYVAC-C-KC express the HIV-1 antigens gp140 and Gag/Gag-Pol-Nef-derived VLPs from clade C and were used as the prime, with recombinant virus plus envelope protein as the boost. In nearly every T and B cell immune assay against HIV-1, including neutralization and antibody binding, NYVAC-C-KC induced a greater immune response than did NYVAC-C, indicating that replication competence in a poxvirus may improve upon the modestly successful regimen used in the RV144 clinical trial.ImportanceThough the RV144 Phase III clinical trial showed promise that an effective vaccine against HIV-1 is possible, a successful vaccine will require improvement over the vaccine candidate (ALVAC) used in the RV144 study. With that goal in mind, we have tested in non-human primates an attenuated, but replication-competent vector, NYVAC-KC, in direct comparison to its parental vector, NYVAC, which is replication-restricted in human cells, similar to the ALVAC vector used in RV144. We have utilized a prime-boost regimen for administration of the vaccine candidate that is similar to the one used in the RV144 study. The results of this study indicate that a replication-competent poxvirus vector may improve upon the effectiveness of the RV144 clinical trial vaccine candidate.

RevDate: 2018-11-15

Hill JA, Ikoma M, Zerr DM, et al (2018)

RNA sequencing of the in vivo human herpesvirus 6B transcriptome to identify targets for clinical assays distinguishing between latent and active infections.

Journal of virology pii:JVI.01419-18 [Epub ahead of print].

Human herpesvirus 6B (HHV-6B) DNA is frequently detected in human samples. Diagnostic assays distinguishing HHV-6B reactivation from latency are limited. This has impaired strategies to diagnose and treat HHV-6B-associated diseases. We used RNA sequencing to characterize and compare the HHV-6B transcriptome in multiple sample types, including 1) whole blood from hematopoietic cell transplant (HCT) recipients with and without HHV-6B plasma viremia; 2) tumor tissue samples from subjects with large B cell lymphoma infected with HHV-6B; 3) lymphoblastoid cell lines (LCLs) from subjects with inherited chromosomally integrated HHV-6B or latent infection with HHV-6B; and 4) HHV-6B Z29 infected SupT1 CD4+ T cells. We demonstrated substantial overlap in the HHV-6B transcriptome observed in in vivo and in vitro samples, although there was variability in the breadth and quantity of gene expression across samples. The HHV-6B viral polymerase gene U38 was the only HHV-6B transcript detected in all RNA-seq data sets and was one of the most highly expressed genes. We developed a novel reverse transcription PCR assay targeting HHV-6B U38, which identified U38 messenger RNA in all tested whole blood samples from patients with concurrent HHV-6B viremia. No HHV-6B U38 transcripts were detected by RNA-seq or RT-qPCR in whole blood samples from subjects without HHV-6B plasma detection or from latently infected LCLs. A RT-qPCR assay for HHV-6B U38 may be useful to identify lytic HHV-6B infection in non-plasma samples and samples from individuals with inherited chromosomally integrated HHV-6B. This study also demonstrates the feasibility of transcriptomic analyses in HCT recipients.IMPORTANCE Human herpesvirus 6B (HHV-6B) is a DNA virus that infects most children within the first few years of life. After primary infection, HHV-6B persists as a chronic, latent infection in many cell types. Additionally, HHV-6B can integrate into germline chromosomes, resulting in individuals with viral DNA in every nucleated cell. Given that PCR to detect viral DNA is the mainstay for diagnosing HHV-6B infection, the characteristics of HHV-6B infection complicate efforts to distinguish between latent and active viral infection, particularly in immunocompromised patients who have frequent HHV-6B reactivation. In this study, we used RNA sequencing to characterize the HHV-6B gene expression profile in multiple sample types, and our findings identified evidence-based targets for diagnostic tests that distinguish between latent and active viral infection.

RevDate: 2018-11-14

Munshi PN, C Ujjani (2018)

The Acceleration of CAR-T therapy in Non-Hodgkin Lymphoma.

Hematological oncology [Epub ahead of print].

Recent advances in diffuse large B-cell lymphomas have included both identification of high-risk subtypes characterized by multiply relapsed and/or refractory disease as well as novel treatment in the form of cellular therapy. Chimeric antigen receptor (CAR)-T cell therapy is a recently developed approach to address the poor outcomes in this patient population. The CAR-T cell construct has evolved though several iterations as it transitioned from the lab to the clinic. Three major studies have evaluated the efficacy of CD19-directed CAR-T cell therapy in aggressive B-cell non-Hodgkin lymphoma; each demonstrating durable complete remissions in heavily pretreated patients. The cost of this remarkable therapy, however, includes cytokine release syndrome and neurotoxicity shortly after administration as well as delayed infectious complications due to B-cell aplasia. Future investigations are focused on the optimizing both safety and efficacy of CAR T cell therapy.

RevDate: 2018-11-14

Hilton SK, JD Bloom (2018)

Modeling site-specific amino-acid preferences deepens phylogenetic estimates of viral sequence divergence.

Virus evolution, 4(2):vey033 pii:vey033.

Molecular phylogenetics is often used to estimate the time since the divergence of modern gene sequences. For highly diverged sequences, such phylogenetic techniques sometimes estimate surprisingly recent divergence times. In the case of viruses, independent evidence indicates that the estimates of deep divergence times from molecular phylogenetics are sometimes too recent. This discrepancy is caused in part by inadequate models of purifying selection leading to branch-length underestimation. Here we examine the effect on branch-length estimation of using models that incorporate experimental measurements of purifying selection. We find that models informed by experimentally measured site-specific amino-acid preferences estimate longer deep branches on phylogenies of influenza virus hemagglutinin. This lengthening of branches is due to more realistic stationary states of the models, and is mostly independent of the branch-length extension from modeling site-to-site variation in amino-acid substitution rate. The branch-length extension from experimentally informed site-specific models is similar to that achieved by other approaches that allow the stationary state to vary across sites. However, the improvements from all of these site-specific but time homogeneous and site independent models are limited by the fact that a protein's amino-acid preferences gradually shift as it evolves. Overall, our work underscores the importance of modeling site-specific amino-acid preferences when estimating deep divergence times-but also shows the inherent limitations of approaches that fail to account for how these preferences shift over time.

RevDate: 2018-11-14

Travis RC, Perez-Cornago A, Appleby PN, et al (2018)

A collaborative analysis of individual participant data from 19 prospective studies assesses circulating vitamin D and prostate cancer risk.

Cancer research pii:0008-5472.CAN-18-2318 [Epub ahead of print].

Previous prospective studies assessing the relationship between circulating concentrations of vitamin D and prostate cancer risk have shown inconclusive results, particularly for risk of aggressive disease. In this study, we examine the association between pre-diagnostic concentrations of 25-hydroxyvitamin D (25(OH)D) and 1,25(OH)2D and the risk of prostate cancer overall and by tumor characteristics. Principal investigators of 19 prospective studies provided individual participant data on circulating 25(OH)D and 1,25(OH)2D for up to 13,462 men with incident prostate cancer and 20,261 control participants. Odds ratios (OR) for prostate cancer by study-specific fifths of season-standardized vitamin D concentration were estimated using multivariable-adjusted conditional logistic regression. 25(OH)D concentration was positively associated with risk for total prostate cancer (multivariable-adjusted OR comparing highest versus lowest study-specific fifth was 1.22, 95% CI 1.13-1.31; P trend<0.001). However, this association varied by disease aggressiveness (Pheterogeneity=0.014); higher circulating 25(OH)D was associated with a higher risk of non-aggressive disease (OR per 80 percentile increase=1.24, 1.13-1.36) but not with aggressive disease (defined as stage 4, metastases, or prostate cancer death, 0.95, 0.78-1.15). 1,25(OH)2D concentration was not associated with risk for prostate cancer overall or by tumor characteristics. The absence of an association of vitamin D with aggressive disease does not support the hypothesis that vitamin D deficiency increases prostate cancer risk. Rather, the association of high circulating 25(OH)D concentration with a higher risk of non-aggressive prostate cancer may be influenced by detection bias.

RevDate: 2018-11-13

Brunstein CG, Pasquini MC, Kim S, et al (2018)

nThe Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(18)30699-2 [Epub ahead of print].

There are limited data on whether to adjust high-dose chemotherapy prior to autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) ≥ 30 kg/m2. Dose adjustment was defined as a reduction in standard dosing of ≥ 20%, based on ideal, reported dosing and actual weights. We included two groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n=1696) treated with high-dose melphalan; and we included patients with Hodgkin or non-Hodgkin lymphomas (n=781) who received carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning. Chemotherapy dose was adjusted in 1324 (78%) patients with MM and 608 (78%) patients with lymphoma. Age, sex, BMI, race, performance score, co-morbidity index, and disease features (stage at diagnosis, disease status and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (p=0.894) and treatment-related mortality (TRM) (p=0.62), progression (p=0.12), and progression-free survival (p=0.178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (p=0.176), TRM (p=0.802), relapse (p=0.633) or PFS (p=0.812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose prior to autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population.

RevDate: 2018-11-13

Pulsipher MA, Logan BR, Chitphakdithai P, et al (2018)

The Effect of Aging and Pre-Donation Comorbidities on the Related PBSC Donor Experience: A Report from the Related Donor Safety Study (RDSafe).

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(18)30698-0 [Epub ahead of print].

The development of reduced intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RD) of PBSC. The effects of age on donation efficacy, toxicity, and long-term recovery in RD are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms and recovery in 1211 related PBSC donors aged 18-79 enrolled in the Related Donor Safety Study (RDSafe). RD >60 had a lower median CD34+ level pre-apheresis compared to younger RD (age >60, 59 × 106/L; age 41-60, 81 × 106/L; age 18-40, 121 × 106/L; p<0.001). This resulted in older donors undergoing more apheresis procedures (49% vs. 30% ≥2 collections, p<0.001) and higher collection volumes (52% vs. 32% >24L, p<0.001), leading to high percentages of donors >60 with post-collection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3 days of collection, respectively). RD age 18-40 had a higher risk of grade 2-4 pain and symptoms peri-collection, but donors above age 40 had more persistent pain at 1, 6, and 12 months (OR1.7, p=0.02) and a higher rate of non-recovery to pre-donation levels (OR 1.7, p=0.01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by NMDP unrelated donor standards had an increased risk for persistent grade 2-4 pain (OR=2.41, p<0.001) and failure to recover to pre-donation baseline for other symptoms (OR=2.34, p=0.004). This information should be used in counseling RD regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

RevDate: 2018-11-13

Lastwika KJ, Kargl J, Zhang Y, et al (2018)

Tumor-Derived Autoantibodies Identify Malignant Pulmonary Nodules.

American journal of respiratory and critical care medicine [Epub ahead of print].

RATIONALE: Screening for non-small cell lung cancer is associated with earlier diagnosis and reduced mortality but also increased harm due to invasive follow up of benign pulmonary nodules. Lung tumorigenesis activates the immune system, components of which could serve as tumor specific biomarkers.

OBJECTIVES: To profile tumor-derived autoantibodies as peripheral biomarkers of malignant pulmonary nodules.

METHODS: High-density protein arrays were used to define the specificity of autoantibodies isolated from B cells of 10 resected lung tumors. These tumor-derived autoantibodies were also examined as free or complexed to antigen in the plasma of the same 10 patients and matched benign nodule controls. Promising autoantibodies were further analyzed in an independent cohort of 250 nodule positive patients.

MEASUREMENTS AND MAIN RESULTS: Thirteen tumor B cell-derived autoantibodies isolated ex vivo showed ≥50% sensitivity and ≥70% specificity for lung cancer. ‎In plasma, 11/13 autoantibodies were present both complexed to and free from antigen. In the larger validation cohort, 5/13 tumor-derived autoantibodies remained significantly elevated in cancers. A combination of 4 of these autoantibodies could detect malignant nodules with an AUC=0.74 and had an AUC=0.78 in a sub-cohort of indeterminate (8-20mm in the longest diameter) pulmonary nodules.

CONCLUSIONS: Our novel pipeline identifies tumor-derived autoantibodies that could effectively serve as blood biomarkers for malignant pulmonary nodule diagnosis. This approach has future implications for both a cost-effective and non-invasive approach to determine nodule malignancy for widespread LDCT screening.

RevDate: 2018-11-12

Gibson TM, Mostoufi-Moab S, Stratton KL, et al (2018)

Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: a report from the Childhood Cancer Survivor Study cohort.

The Lancet. Oncology pii:S1470-2045(18)30537-0 [Epub ahead of print].

BACKGROUND: Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment.

METHODS: We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk.

FINDINGS: Among 23 601 survivors with a median follow-up of 21 years (IQR 15-25), the 20-year cumulative incidence of at least one grade 3-5 chronic condition decreased significantly from 33·2% (95% CI 32·0-34·3) in those diagnosed 1970-79 to 29·3% (28·4-30·2; p<0·0001) in 1980-89, and 27·5% (26·4-28·6; p=0·012 vs 1980-89) in 1990-99. By comparison, the 20-year cumulative incidence of at least one grade 3-5 condition in 5051 siblings was 4·6% (95% CI 3·9-5·2). The 15-year cumulative incidence of at least one grade 3-5 condition was lower for survivors diagnosed 1990-99 compared with those diagnosed 1970-79 for Hodgkin lymphoma (17·7% [95% CI 15·0-20·5] vs 26·4% [23·8-29·1]; p<0·0001), non-Hodgkin lymphoma (16·9% [14·0-19·7] vs 23·8% [19·9-27·7]; p=0.0053), astrocytoma (30·5% [27·8-33·2] vs 47·3% [42·9-51·7]; p<0·0001), Wilms tumour (11·9% [9·5-14·3] vs 17·6% [14·3-20·8]; p=0·034), soft tissue sarcoma (28·3% [23·5-33·1] vs 36·5% [31·5-41·4]; p=0·021), and osteosarcoma (65·6% [60·6-70·6] vs 87·5% [84·1-91·0]; p<0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3-5 condition was higher (1990-99 vs 1970-79) for medulloblastoma or primitive neuroectodermal tumour (58·9% [54·4-63·3] vs 42·9% [34·9-50·9]; p=0·00060), and neuroblastoma (25·0% [21·8-28·2] vs 18·0% [14·5-21·6]; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3-5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64-0·92; HR with treatment in the model=0·89, 95% CI 0·72-1·11; pmediation=0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65-0·85; HR with treatment=0·91, 95% CI 0·73-1·12; pmediation=0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970-79 to survivors diagnosed 1990-99 were noted for endocrinopathies (5·9% [5·3-6·4] vs 2·8% [2·5-3·2]; p<0·0001), subsequent malignant neoplasms (2·7% [2·3-3·1] vs 1·9% [1·6-2·2]; p=0·0033), musculoskeletal conditions (5·8% [5·2-6·4] vs 3·3% [2·9-3·6]; p<0·0001), and gastrointestinal conditions (2·3% [2·0-2·7] vs 1·5% [1·3-1·8]; p=0·00037), while hearing loss increased (3·0% [2·6-3·5] vs 5·7% [5·2-6·1]; p<0·0001).

INTERPRETATION: Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population.

FUNDING: National Cancer Institute and the American Lebanese-Syrian Associated Charities.

RevDate: 2018-11-11

Welch LS, Dement JM, Cranford K, et al (2018)

Early detection of lung cancer in a population at high risk due to occupation and smoking.

Occupational and environmental medicine pii:oemed-2018-105431 [Epub ahead of print].

OBJECTIVE: The US National Comprehensive Cancer Network (NCCN) recommends two pathways for eligibility for Early Lung Cancer Detection (ELCD) programmes. Option 2 includes individuals with occupational exposures to lung carcinogens, in combination with a lesser requirement on smoking. Our objective was to determine if this algorithm resulted in a similar prevalence of lung cancer as has been found using smoking risk alone, and if so to present an approach for lung cancer screening in high-risk worker populations.

METHODS: We enrolled 1260 former workers meeting NCCN criteria, with modifications to account for occupational exposures in an ELCD programme.

RESULTS: At baseline, 1.6% had a lung cancer diagnosed, a rate similar to the National Lung Cancer Screening Trial (NLST). Among NLST participants, 59% were current smokers at the time of baseline scan or had quit smoking fewer than 15 years prior to baseline; all had a minimum of 30 pack-years of smoking. Among our population, only 24.5% were current smokers and 40.1% of our participants had smoked fewer than 30 pack-years; only 43.5% would meet entry criteria for the NLST. The most likely explanation for the high prevalence of screen-detected lung cancers in the face of a reduced risk from smoking is the addition of occupational risk factors for lung cancer.

CONCLUSION: Occupational exposures to lung carcinogens should be incorporated into criteria used for ELCD programmes, using the algorithm developed by NCCN or with an individualised risk assessment; current risk assessment tools can be modified to incorporate occupational risk.

RevDate: 2018-11-10

Iovino L, Taddei R, Bindi ML, et al (2018)

Clinical use of an immune monitoring panel in liver transplant recipients: A prospective, observational study.

Transplant immunology pii:S0966-3274(18)30095-9 [Epub ahead of print].

Immunosuppressive therapy greatly contributed to making liver transplantation the standard treatment for end-stage liver diseases. However, it remains difficult to predict and measure the efficacy of pharmacological immunosuppression. Therefore, we used a panel of standardized, commonly available, biomarkers with the aim to describe their changes in the first 3 weeks after the transplant procedure and assess if they may help therapeutic drug monitoring in better tailoring the dose of the immunosuppressive drugs. We prospectively studied 72 consecutive patients from the day of liver transplant (post-operative day #0) until the post-operative day #21. Leukocytes, neutrophils, lymphocytes (CD4+, CD8+), natural killer cells, monocytes, immunoglobulins and tacrolimus serum levels were measured on peripheral blood (at day 0, 3, 7, 14, 21 after surgery). Patients who developed infections showed significantly higher CD64+ monocytes on post operative day #7. IgG levels were lower on post operative day #3 among patients who later developed infections. We also found that a sharp decrease in IgA from post operative day #0 to 3 (-226 mg/dL in the ROC curve analysis) strongly correlates with the onset of infections among HCV- patients. No specific markers of rejection emerged from the tested panel of markers. Our results show that some early changes in peripheral blood white cells and immunoglobulins may predict the onset of infections and may be useful in modulating the immunosuppressive therapy. However, a panel of commonly available, standardized biomarkers do not support in improving therapeutic drug monitoring ability to individualize immunosuppressive drugs dosing.

RevDate: 2018-11-09

Elbing KL, R Brent (2018)

Recipes and Tools for Culture of Escherichia coli.

Current protocols in molecular biology [Epub ahead of print].

In this article, we provide information about culture media, including minimal liquid media, rich liquid media, solid media, top agar, and stab agar. We also provide descriptions and useful information about tools used with growth media such as inoculating loops, sterile toothpicks, and spreaders. © 2018 by John Wiley & Sons, Inc.

RevDate: 2018-11-09

Chang K, Willis JA, Reumers J, et al (2018)

Colorectal premalignancy is associated with consensus molecular subtypes 1 and 2.

Annals of oncology : official journal of the European Society for Medical Oncology, 29(10):2061-2067.

Background: Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown.

Patients and methods: We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier.

Results: Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-β activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations.

Conclusions: Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC.

RevDate: 2018-11-09

Pisarsky L, CM Ghajar (2018)

Anti-angiogenic Therapy-Mediated Endothelial Damage: A Driver of Breast Cancer Recurrence?.

Advances in experimental medicine and biology, 1100:19-45.

Anti-angiogenic therapy was conceived originally as a silver bullet able to maintain tumor dormancy indefinitely. By targeting new blood vessel formation, anti-angiogenic agents were expected to suppress the growth of any type of primary or metastatic tumor, independent of their subtype or genetic landscape. However, more that 20 years after the first anti-angiogenic preclinical trial, the astonishing inhibition of metastatic outgrowth originally observed in mouse models never translated into clinics. Indeed, whereas anti-angiogenic agents (sometimes) prolong progression-free survival, they fail to impact overall survival, particularly in breast cancer. This observation revealed to be true in early- and advanced-stage breast cancer patients treated either in adjuvant or neo-adjuvant settings, suggesting that the effect of anti-angiogenic therapy on repressing growth of overt metastases - and also on preventing outgrowth of disseminated tumor cells and micrometastases - is limited. What are the reasons underlying this failure? And, more importantly, is there still room for improvement?

RevDate: 2018-11-09

Halpern AB, Othus M, Huebner EM, et al (2018)

Phase 1/2 trial of cladribine, high-dose cytarabine, mitoxantrone, and G-CSF with dose-escalated mitoxantrone for relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms.

Haematologica pii:haematol.2018.204792 [Epub ahead of print].

RevDate: 2018-11-09

Smith SD, Gandhy S, Gopal AK, et al (2018)

Modified VR-CAP, Alternating With Rituximab and High-dose Cytarabine: An Effective Pre-transplant Induction Regimen for Mantle Cell Lymphoma.

Clinical lymphoma, myeloma & leukemia pii:S2152-2650(18)31203-5 [Epub ahead of print].

BACKGROUND: Initial treatment of mantle cell lymphoma (MCL) incorporating autologous stem cell transplantation affords long-term remissions, but relapses still occur. Optimal pretransplant therapy will afford high complete response rates and not impair stem cell collection. Incorporation of bortezomib represents a natural evolution of pretransplant therapy, given its proven first-line efficacy and minimal impact on stem cell collection.

PATIENTS AND METHODS: At the University of Washington/Seattle Cancer Care Alliance and the Cleveland Clinic Foundation, we developed modified VR-CAP/R+ara-C (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone, alternating with rituximab and high-dose cytarabine), for transplant-eligible patients with MCL. This regimen was administered as standard-of-care, pretransplant therapy to consecutive patients with MCL from April 2015 to the present.

RESULTS: A total of 37 patients were treated with this regimen, including 18 at the University of Washington/Seattle Cancer Care Alliance and 19 at the Cleveland Clinic Foundation. Most patients had intermediate- or high-risk disease by both (mantle-cell lymphoma international prognostic index (MIPI)-B and MIPI-C category. Complete response to induction was achieved in 32 (86%) of 37 evaluable patients; 2 achieved partial response, and 3 had primary refractory disease. Stem cell collection was successful in 1 attempt in 30 of 32 patients. The median follow-up of survivors measured from start of treatment is 17.4 months. Five patients have progressed, and 4 have died (2 owing to lymphoma, 2 from toxicity).

CONCLUSION: Modified VR-CAP/R+ara-C is feasible pretransplant therapy for patients with MCL and is associated with a high rate of complete response and eligibility for autologous stem cell transplantation.

RevDate: 2018-11-09

Cannon RB, Houlton JJ, Patel S, et al (2018)

Patterns of cervical node positivity, regional failure rates, and fistula rates for HPV+ oropharyngeal squamous cell carcinoma treated with transoral robotic surgery (TORS).

Oral oncology, 86:296-300.

OBJECTIVES: (1) Report the patterns of cervical node positivity for HPV + oropharyngeal squamous cell carcinoma (OPSCC) treated with transoral robotic surgery (TORS) and a unilateral level II-IV node dissection. (2) Investigate the regional failure rate following this operation. (3) Report the rate of pharyngocutaneous fistula (PCF) formation intraoperatively and postoperatively following TORS/neck dissection.

METHODS: Retrospective case series of 88 patients with HPV+ OPSCC treated with TORS and simultaneous neck dissection levels II-IV at the University of Washington from 2010 to 2016. Primary endpoints were PCF, regional recurrence, disease-free survival (DFS), and overall survival (OS).

RESULTS: The overall frequency of cervical node positivity was 93%, with 84% in level IIa, 7% in IIb, 23% in III, and 13% in IV. Two patients developed PCF intraoperatively, repaired with a local digastric flap, and no postoperative PCF occurred. Sixteen patients (18%) received surgery alone, 49 patients (56%) received adjuvant radiation, and 23 patients (26%) underwent adjuvant chemoradiation. DFS at 2 years was 95% and OS at 2 years was 100%. No concerning level Ib nodes were identified preoperatively or during surgery, and no regional failures occurred in this location.

CONCLUSION: Our data suggests, in TORS for HPV+ OPSCC, neck dissection of levels II-IV accurately stages the neck pathologically and prevents regional recurrences, with adjuvant therapy when indicated, and survival outcomes are excellent. Single-staged operations did not result in any postoperative PCF. Avoiding dissection of level Ib with TORS oropharyngectomy limits morbidity to the marginal mandibular nerve and salivary function, and resulted in no postoperative fistulas with minimal reconstruction interventions.

RevDate: 2018-11-08

Landovitz RJ, Li S, Grinsztejn B, et al (2018)

Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial.

PLoS medicine, 15(11):e1002690 pii:PMEDICINE-D-18-01723.

BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States.

METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population.

CONCLUSIONS: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress.

TRIAL REGISTRATION: Registry: Trial number: NCT02178800.

RevDate: 2018-11-08

Hay KA (2018)

Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy.

British journal of haematology [Epub ahead of print].

Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to B-cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR-T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes.

RevDate: 2018-11-08

Jones RL, Mo G, Baldwin JR, et al (2018)

Exposure-response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma.

Cancer chemotherapy and pharmacology pii:10.1007/s00280-018-3723-4 [Epub ahead of print].

PURPOSE: Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure-response relationship for progression-free survival (PFS), overall survival (OS), and safety.

METHODS: PFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (Cmin1) and the average concentration throughout treatment (Cavg). The rate of treatment-emergent adverse events (TEAEs) was compared across olaratumab exposure quartiles.

RESULTS: PFS and OS were described by models with an exponential hazard function and inhibitory EMAX functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (ECmin150 = 82.0 µg/mL, ECavg50 = 179 µg/mL) and OS (ECmin150 = 66.1 µg/mL, ECavg50 = 134 µg/mL) corresponded to the median and 25th percentile of Cmin1/Cavg in the study, respectively. Maximum predicted improvement in the hazard ratio for OS and PFS was approximately 75% and 60%, respectively. There was no change in the rate of TEAEs with increasing olaratumab serum levels.

CONCLUSIONS: PFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial.

RevDate: 2018-11-07

Borst AJ, Weidle CE, Gray MD, et al (2018)

Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core.

eLife, 7: pii:37688 [Epub ahead of print].

VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics. Our results show VRC01 germline antibodies interacted with a wild-type 426c core lacking variable loops 1-3 in the presence or absence of a glycan at position Asn276, with the latter form binding with higher affinity than the former. Interactions in the presence of an Asn276 oligosaccharide could be enhanced upon carbohydrate shortening, which should be considered for immunogen design.

RevDate: 2018-11-07

Morsink LM, Walter RB, GJ Ossenkoppele (2018)

Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia.

Blood reviews pii:S0268-960X(18)30072-9 [Epub ahead of print].

CLEC12A has recently been identified as an antigen, expressed on leukemic stem cells and leukemic blasts. Given the fact that this expression profile seems stable throughout diagnosis, treatment and relapse on leukemic blasts and leukemic stem cells, CLEC12A can be considered a highly potent and reliable marker for the detection of measurable residual disease and therefore applicable for risk stratification and prognostication in AML. Low CLEC12A expression on leukemic blasts seems to be independently associated with lower likelihood of achieving complete remission after 1 cycle of induction chemotherapy, shorter event free survival, as well as overall survival, indicating potential prognostic properties of CLEC12A expression itself. Lack of expression on the normal hematopoietic stem and progenitor cells, in contrast to CD123 and CD33, might result in less toxicity regarding cytopenias, making CLEC12A an interesting target for innovating immunotherapies, including monoclonal and bispecific antibodies, antibody-drug conjugates and CAR-T cells therapy.

RevDate: 2018-11-07

Hirsch A, Katz MA, Laufer Peretz A, et al (2018)

Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI): study protocol.

BMC infectious diseases, 18(1):550 pii:10.1186/s12879-018-3444-7.

BACKGROUND: The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospectively follows a cohort of healthcare personnel (HCP) in two hospitals in Israel. SHIRI will describe the frequency of influenza virus infections among HCP, identify predictors of vaccine acceptance, examine how repeated influenza vaccination may modify immunogenicity, and evaluate influenza vaccine effectiveness in preventing influenza illness and missed work.

METHODS: Cohort enrollment began in October, 2016; a second year of the study and a second wave of cohort enrollment began in June 2017. The study will run for at least 3 years and will follow approximately 2000 HCP (who are both employees and members of Clalit Health Services [CHS]) with routine direct patient contact. Eligible HCP are recruited using a stratified sampling strategy. After informed consent, participants complete a brief enrollment survey with questions about occupational responsibilities and knowledge, attitudes, and practices about influenza vaccines. Blood samples are collected at enrollment and at the end of influenza season; HCP who choose to be vaccinated contribute additional blood one month after vaccination. During the influenza season, participants receive twice-weekly short message service (SMS) messages asking them if they have acute respiratory illness or febrile illness (ARFI) symptoms. Ill participants receive follow-up SMS messages to confirm illness symptoms and duration and are asked to self-collect a nasal swab. Information on socio-economic characteristics, current and past medical conditions, medical care utilization and vaccination history is extracted from the CHS database. Information about missed work due to illness is obtained by self-report and from employee records. Respiratory specimens from self-collected nasal swabs are tested for influenza A and B viruses, respiratory syncytial virus, human metapneumovirus, and coronaviruses using validated multiplex quantitative real-time reverse transcription polymerase chain reaction assays. The hemagglutination inhibition assay will be used to detect the presence of neutralizing influenza antibodies in serum.

DISCUSSION: SHIRI will expand our knowledge of the burden of respiratory viral infections among HCP and the effectiveness of current and repeated annual influenza vaccination in preventing influenza illness, medical utilization, and missed workdays among HCP who are in direct contact with patients.

TRIAL REGISTRATION: NCT03331991 . Registered on November 6, 2017.

RevDate: 2018-11-06

Matejcic M, Saunders EJ, Dadaev T, et al (2018)

Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

Nature communications, 9(1):4616 pii:10.1038/s41467-018-06863-1.

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

RevDate: 2018-11-05

LaBranche CC, McGuire AT, Gray MD, et al (2018)

HIV-1 Envelope Glycan Modifications that Permit Neutralization by Germline-Reverted VRC01-Class Broadly Neutralizing Antibodies.

PLoS pathogens, 14(11):e1007431 pii:PPATHOGENS-D-18-01437 [Epub ahead of print].

Broadly neutralizing antibody (bnAb) induction is a high priority for effective HIV-1 vaccination. VRC01-class bnAbs that target the CD4 binding site (CD4bs) of trimeric HIV-1 envelope (Env) glycoprotein spikes are particularly attractive to elicit because of their extraordinary breadth and potency of neutralization in vitro and their ability to protect against infection in animal models. Glycans bordering the CD4bs impede the binding of germline-reverted forms of VRC01-class bnAbs and therefore constitute a barrier to early events in initiating the correct antibody lineages. Deleting a subset of these glycans permits Env antigen binding but not virus neutralization, suggesting that additional barriers impede germline-reverted VRC01-class antibody binding to functional Env trimers. We investigated the requirements for functional Env trimer engagement of VRC01-class naïve B cell receptors by using virus neutralization and germline-reverted antibodies as surrogates for the interaction. Targeted deletion of a subset of N-glycans bordering the CD4bs, combined with Man5 enrichment of remaining N-linked glycans that are otherwise processed into larger complex-type glycans, rendered HIV-1 426c Env-pseudotyped virus (subtype C, transmitted/founder) highly susceptible to neutralization by near germline forms of VRC01-class bnAbs. Neither glycan modification alone rendered the virus susceptible to neutralization. The potency of neutralization in some cases rivaled the potency of mature VRC01 against wildtype viruses. Neutralization by the germline-reverted antibodies was abrogated by the known VRC01 resistance mutation, D279K. These findings improve our understanding of the restrictions imposed by glycans in eliciting VRC01-class bnAbs and enable a neutralization-based strategy to monitor vaccine-elicited early precursors of this class of bnAbs.

RevDate: 2018-11-05

Shen BW, Doyle L, Bradley P, et al (2018)

Structure, subunit organization and behavior of the asymmetric Type IIT restriction endonuclease BbvCI.

Nucleic acids research pii:5160995 [Epub ahead of print].

BbvCI, a Type IIT restriction endonuclease, recognizes and cleaves the seven base pair sequence 5'-CCTCAGC-3', generating 3-base, 5'-overhangs. BbvCI is composed of two protein subunits, each containing one catalytic site. Either site can be inactivated by mutation resulting in enzyme variants that nick DNA in a strand-specific manner. Here we demonstrate that the holoenzyme is labile, with the R1 subunit dissociating at low pH. Crystallization of the R2 subunit under such conditions revealed an elongated dimer with the two catalytic sites located on opposite sides. Subsequent crystallization at physiological pH revealed a tetramer comprising two copies of each subunit, with a pair of deep clefts each containing two catalytic sites appropriately positioned and oriented for DNA cleavage. This domain organization was further validated with single-chain protein constructs in which the two enzyme subunits were tethered via peptide linkers of variable length. We were unable to crystallize a DNA-bound complex; however, structural similarity to previously crystallized restriction endonucleases facilitated creation of an energy-minimized model bound to DNA, and identification of candidate residues responsible for target recognition. Mutation of residues predicted to recognize the central C:G base pair resulted in an altered enzyme that recognizes and cleaves CCTNAGC (N = any base).

RevDate: 2018-11-05

Short NJ, Jabbour E, Albitar M, et al (2018)

Recommendations for the Assessment and Management of Measurable Residual Disease in Adults With Acute Lymphoblastic Leukemia: A Consensus of North American Experts.

American journal of hematology [Epub ahead of print].

Measurable residual disease (MRD) that persists after initial therapy is a powerful predictor of relapse and survival in acute lymphoblastic leukemia (ALL). However, the optimal use of this information to influence therapeutic decisions is controversial. Herein, we comprehensively review the role of MRD assessment in adults with ALL, including methods to quantify residual leukemia cells during remission, prognostic impact of MRD across ALL subtypes, and available therapeutic approaches to eradicate MRD. This review presents consensus statements and provides an evidence-based framework for practicing hematologists and oncologists to use MRD information to make rational treatment decisions in adult patients with ALL. This article is protected by copyright. All rights reserved.

RevDate: 2018-11-05

Pugh TJ, Fink JM, Lu X, et al (2018)

Assessing genome-wide copy number aberrations and copy-neutral loss-of-heterozygosity as best practice: An evidence-based review from the Cancer Genomics Consortium working group for plasma cell disorders.

Cancer genetics pii:S2210-7762(18)30076-0 [Epub ahead of print].

BACKGROUND: Plasma cell neoplasms (PCNs) encompass a spectrum of disorders including monoclonal gammopathy of undetermined significance, smoldering myeloma, plasma cell myeloma, and plasma cell leukemia. Molecular subtypes have been defined by recurrent cytogenetic abnormalities and somatic mutations that are prognostic and predictive. Karyotype and fluorescence in situ hybridization (FISH) have historically been used to guide management; however, new technologies and markers raise the need to reassess current testing algorithms.

METHODS: We convened a panel of representatives from international clinical laboratories to capture current state-of-the-art testing from published reports and to put forward recommendations for cytogenomic testing of plasma cell neoplasms. We reviewed 65 papers applying FISH, chromosomal microarray (CMA), next-generation sequencing, and gene expression profiling for plasma cell neoplasm diagnosis and prognosis. We also performed a survey of our peers to capture current laboratory practice employed outside our working group.

RESULTS: Plasma cell enrichment is widely used prior to FISH testing, most commonly by magnetic bead selection. A variety of strategies for direct, short- and long-term cell culture are employed to ensure clonal representation for karyotyping. Testing of clinically-informative 1p/1q, del(13q) and del(17p) are common using karyotype, FISH and, increasingly, CMA testing. FISH for a variety of clinically-informative balanced IGH rearrangements is prevalent. Literature review found that CMA analysis can detect abnormalities in 85-100% of patients with PCNs; more specifically, in 5-53% (median 14%) of cases otherwise normal by FISH and cytogenetics. CMA results in plasma cell neoplasms are usually complex, with alteration counts ranging from 1 to 74 (median 10-20), primarily affecting loci not covered by FISH testing. Emerging biomarkers include structural alterations of MYC as well as somatic mutations of KRAS, NRAS, BRAF, and TP53. Together, these may be measured in a comprehensive manner by a combination of newer technologies including CMA and next-generation sequencing (NGS). Our survey suggests most laboratories have, or are soon to have, clinical CMA platforms, with a desire to move to NGS assays in the future.

CONCLUSION: We present an overview of current practices in plasma cell neoplasm testing as well as an algorithm for integrated FISH and CMA testing to guide treatment of this disease.

RevDate: 2018-11-04

Kuhlmann AS, Haworth KG, Barber-Axthelm IM, et al (2018)

Long-Term Persistence of Anti-HIV Broadly Neutralizing Antibody-Secreting Hematopoietic Cells in Humanized Mice.

Molecular therapy : the journal of the American Society of Gene Therapy pii:S1525-0016(18)30458-1 [Epub ahead of print].

Broadly neutralizing antibodies (bNAbs) are among the most promising strategies to achieve long-term control of HIV-1 in the absence of combination antiretroviral therapy. Passive administration of such antibodies in patients efficiently decreases HIV-1 viremia, but is limited by the serum half-life of the protein. Here, we investigated whether antibody-secreting hematopoietic cells could overcome this problem. We genetically modified human CD34+ hematopoietic stem and progenitor cells (HSPCs) to secrete bNAbs and transplanted them into immunodeficient mice. We found that the gene-modified cells engraft and stably secrete antibodies in the peripheral blood of the animals for the 9 months of the study. Antibodies were predominantly expressed by human HSPC-derived T- and B cells. Importantly, we found that secreted PGT128 was able to delay HIV-1 viremia in vivo and also prevent a decline in CD4+ cells. Gene-modified cells were maintained in bone marrow and were also detected in spleen, thymus, lymph nodes, and gut-associated lymphoid tissue. These data indicate that the bNAb secretion from HSPC-derived cells in mice is functional and can affect viral infection and CD4+ cell maintenance. This study paves the way for potential applications to other diseases requiring long-lasting protein or antibody delivery.

RevDate: 2018-11-04

Zhen DB, Coveler A, Zanon S, et al (2018)

Biomarker-driven and molecularly targeted therapies for pancreatic adenocarcinoma.

Seminars in oncology pii:S0093-7754(18)30085-X [Epub ahead of print].

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with few effective treatment options. Our knowledge of molecular alterations in PDAC has significantly grown and helped identify new therapeutic targets. The success of immune checkpoint inhibition in mismatch repair deficient tumors, PARP inhibitors for tumors with DNA repair defects, and targeting hyaluronan with PEGPH20 in patients with high expressing (hyaluronan-high) tumors are examples of promising biomarker-driven therapies. We review the major biological mechanisms in PDAC and discuss current and future directions for molecularly targeted therapies in this disease.

RevDate: 2018-11-03

Iotchkova V, Huang J, Morris JA, et al (2018)

Author Correction: Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

In the version of the article published, the surname of author Aaron Isaacs is misspelled as Issacs.

RevDate: 2018-11-03

Riedel RF, Jones RL, Italiano A, et al (2018)

Systemic Anti-Cancer Therapy in Synovial Sarcoma: A Systematic Review.

Cancers, 10(11): pii:cancers10110417.

Synovial sarcoma (SS) is an aggressive malignancy which accounts for approximately 5⁻10% of all soft-tissue sarcomas. SS has pathologic and genomic characteristics that define it as a distinct subtype of soft tissue sarcoma (STS). STS subtypes continue to be recognized as distinct entities with specific characteristics, including differential chemo-sensitivity. The objective of this study was to conduct a descriptive review of current data on survival outcomes of systemic anti-cancer therapy specific to SS. A systematic literature review was conducted, using a custom search strategy to search EMBASE, Medline and CENTRAL for clinical trials and observational studies reporting overall survival (OS), progression-free survival (PFS) and/or response for cohorts of at least 50 SS patients. We identified 28 studies meeting these criteria, 25 of which were retrospective studies. Only three prospective studies were identified. Survival reports varied widely between studies based on the population, in particular on the disease stage, and reporting was heterogeneous in terms of the time points reported on. For patients with localized disease, reports of five-year PFS ranged from 26% to 80.7% and five-year OS from 40% to 90.7%, whereas five-year OS for patients with metastatic disease was very low at around 10%; and in one case, 0% was reported. Only four of the included publications reported outcomes by type of systemic anti-cancer therapy received. Our study draws attention to the fact that additional prospective studies to better define the most appropriate treatment for SS in all stages and lines of therapy are still needed.

RevDate: 2018-11-02

Blazquez L, Emmett W, Faraway R, et al (2018)

Exon Junction Complex Shapes the Transcriptome by Repressing Recursive Splicing.

Molecular cell, 72(3):496-509.e9.

Recursive splicing (RS) starts by defining an "RS-exon," which is then spliced to the preceding exon, thus creating a recursive 5' splice site (RS-5ss). Previous studies focused on cryptic RS-exons, and now we find that the exon junction complex (EJC) represses RS of hundreds of annotated, mainly constitutive RS-exons. The core EJC factors, and the peripheral factors PNN and RNPS1, maintain RS-exon inclusion by repressing spliceosomal assembly on RS-5ss. The EJC also blocks 5ss located near exon-exon junctions, thus repressing inclusion of cryptic microexons. The prevalence of annotated RS-exons is high in deuterostomes, while the cryptic RS-exons are more prevalent in Drosophila, where EJC appears less capable of repressing RS. Notably, incomplete repression of RS also contributes to physiological alternative splicing of several human RS-exons. Finally, haploinsufficiency of the EJC factor Magoh in mice is associated with skipping of RS-exons in the brain, with relevance to the microcephaly phenotype and human diseases.

RevDate: 2018-11-02

Ligthart S, Vaez A, Võsa U, et al (2018)

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

American journal of human genetics, 103(5):691-706.

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

RevDate: 2018-11-02

Liu Y, He Q, W Sun (2018)

Association analysis using somatic mutations.

PLoS genetics, 14(11):e1007746 pii:PGENETICS-D-18-00160 [Epub ahead of print].

Somatic mutations drive the growth of tumor cells and are pivotal biomarkers for many cancer treatments. Genetic association analysis using somatic mutations is an effective approach to study the functional impact of somatic mutations. However, standard regression methods are not appropriate for somatic mutation association studies because somatic mutation calls often have non-ignorable false positive rate and/or false negative rate. While large scale association analysis using somatic mutations becomes feasible recently-thanks for the improvement of sequencing techniques and the reduction of sequencing cost-there is an urgent need for a new statistical method designed for somatic mutation association analysis. We propose such a method with computationally efficient software implementation: Somatic mutation Association test with Measurement Errors (SAME). SAME accounts for somatic mutation calling uncertainty using a likelihood based approach. It can be used to assess the associations between continuous/dichotomous outcomes and individual mutations or gene-level mutations. Through simulation studies across a wide range of realistic scenarios, we show that SAME can significantly improve statistical power than the naive generalized linear model that ignores mutation calling uncertainty. Finally, using the data collected from The Cancer Genome Atlas (TCGA) project, we apply SAME to study the associations between somatic mutations and gene expression in 12 cancer types, as well as the associations between somatic mutations and colon cancer subtype defined by DNA methylation data. SAME recovered some interesting findings that were missed by the generalized linear model. In addition, we demonstrated that mutation-level and gene-level analyses are often more appropriate for oncogene and tumor-suppressor gene, respectively.

RevDate: 2018-11-02

Gust J, Taraseviciute A, CJ Turtle (2018)

Neurotoxicity Associated with CD19-Targeted CAR-T Cell Therapies.

CNS drugs pii:10.1007/s40263-018-0582-9 [Epub ahead of print].

Neurotoxicity is an important and common complication of chimeric antigen receptor-T cell therapies. Acute neurologic signs and/or symptoms occur in a significant proportion of patients treated with CD19-directed chimeric antigen receptor-T cells for B-cell malignancies. Clinical manifestations include headache, confusion, delirium, language disturbance, seizures and rarely, acute cerebral edema. Neurotoxicity is associated with cytokine release syndrome, which occurs in the setting of in-vivo chimeric antigen receptor-T cell activation and proliferation. The mechanisms that lead to neurotoxicity remain unknown, but data from patients and animal models suggest there is compromise of the blood-brain barrier, associated with high levels of cytokines in the blood and cerebrospinal fluid, as well as endothelial activation. Corticosteroids, interleukin-6-targeted therapies, and supportive care are frequently used to manage patients with neurotoxicity, but high-quality evidence of their efficacy is lacking.

RevDate: 2018-11-02

Jones GN, Rooney C, Griffin N, et al (2018)

pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry.

British journal of cancer pii:10.1038/s41416-018-0286-4 [Epub ahead of print].

BACKGROUND: AZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage.

METHODS: We used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue.

RESULTS: We found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers (n = 23), 99% colorectal cancers (n = 102), 95% triple-negative-breast cancers (TNBC) (n = 40) and 87.5% glioblastoma-multiformes (n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34-72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors.

CONCLUSION: Together these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.

RevDate: 2018-11-01

Wallmann T, Zhang XM, Wallerius M, et al (2018)

Microglia Induce PDGFRB Expression in Glioma Cells to Enhance Their Migratory Capacity.

iScience, 9:71-83 pii:S2589-0042(18)30170-6 [Epub ahead of print].

High-grade gliomas (HGGs) are the most aggressive and invasive primary brain tumors. The platelet-derived growth factor (PDGF) signaling pathway drives HGG progression, and enhanced expression of PDGF receptors (PDGFRs) is a well-established aberration in a subset of glioblastomas (GBMs). PDGFRA is expressed in glioma cells, whereas PDGFRB is mostly restricted to the glioma-associated stroma. Here we show that the spatial location of TAMMs correlates with the expansion of a subset of tumor cells that have acquired expression of PDGFRB in both mouse and human low-grade glioma and HCGs. Furthermore, M2-polarized microglia but not bone marrow (BM)-derived macrophages (BMDMs) induced PDGFRB expression in glioma cells and stimulated their migratory capacity. These findings illustrate a heterotypic cross-talk between microglia and glioma cells that may enhance the migratory and invasive capacity of the latter by inducing PDGFRB.

RevDate: 2018-11-01

Hagan KA, Harrington LB, Kim J, et al (2018)

Adiposity throughout the life course and risk of venous thromboembolism.

Thrombosis research, 172:67-73 pii:S0049-3848(18)30579-6 [Epub ahead of print].

OBJECTIVE: Adult body mass index (BMI) is strongly associated with venous thromboembolism (VTE), however whether earlier-life adiposity or other measures of adult adiposity are associated with VTE risk remains largely unknown.

MATERIALS AND METHODS: We evaluated associations of childhood somatotype, BMI in early adulthood, adult adiposity, and change in weight since early adulthood with incident VTE risk over ≥20 years of follow-up among 205,935 participants from Nurses' Health Studies (NHS/NHS II) and Health Professionals Follow-Up Study (HPFS), ages 29-76 at baseline. We estimated multivariable-adjusted hazard ratios for VTE using Cox proportional hazards models.

RESULTS AND CONCLUSIONS: Somatotype in childhood and young adulthood BMI were not significantly associated with VTE risk, after accounting for adult BMI. Adult BMI was strongly associated with VTE in all three cohorts (e.g., multivariable-adjusted HRs comparing ≥35 kg/m2 vs. <22.5 kg/m2: NHS:3.03[95% CI: 2.58, 3.56], NHS II:3.82[95% CI: 3.24, 4.51], HPFS:2.81 [95% CI: 2.08, 3.80]; all p-trends < 0.01). Adult waist circumference was associated with greater VTE risk, even after adjusting for adult BMI (all p-trends < 0.01). Increasing weight gain from young adulthood was significantly associated with VTE after adjusting for current BMI among women (HR comparing gain ≥20 kg vs. no change: NHS:1.36[95% CI: 1.13, 1.65], NHS II:1.48[95% CI: 1.17, 1.87]) and not men (HPFS:1.20[95% CI: 0.97, 1.50]). These results indicate that BMI and adiposity are likely more important acutely than cumulatively over time in the etiology and prevention of VTE. Clinically, encouraging weight loss in individuals who are overweight or obese could help reduce VTE risk.

RevDate: 2018-11-01

Makanani B, Balkus JE, Jiao Y, et al (2018)

Pregnancy and infant outcomes among women using the dapivirine vaginal ring in early pregnancy.

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

BACKGROUND: Monthly use of the dapivirine vaginal ring has been shown to be safe and effective for HIV-1 prevention in nonpregnant reproductive-aged women. The impact of dapivirine on pregnancy outcomes and infant is not known. We compared pregnancy incidence and outcomes by study arm among HIV-1 uninfected women who became pregnant while participating in MTN-020/ASPIRE.

METHODS: ASPIRE was a randomized, double-blind, placebo controlled phase III safety and effectiveness study of the dapivirine ring for HIV-1 prevention. Sexually active women aged 18-45 from Malawi, South Africa, Uganda, and Zimbabwe were enrolled. Urine pregnancy tests were performed monthly and, if positive, study product was withheld during pregnancy and breastfeeding. Pregnancy-related outcomes included: pregnancy incidence, pregnancy outcomes (live birth, preterm birth, pregnancy loss, congenital anomalies), and infant growth.

RESULTS: Of 2,629 women enrolled in ASPIRE, 169 became pregnant during follow-up, resulting in 179 incident pregnancies and 181 pregnancy outcomes. No difference in pregnancy incidence by study arm was observed (hazard ratio=0.93; 95% CI 0.68-1.26). The distribution of pregnancy outcomes was similar by study arm, and no difference was noted in the frequency or pattern of congenital anomalies or infant growth parameters by study arm.

CONCLUSION: Dapivirine use in the periconception period does not appear to be associated with adverse effects on pregnancy or infant outcomes. Our findings provide support for additional safety studies of the dapivirine ring throughout pregnancy.

RevDate: 2018-11-01

Andeen NK, Qu X, Antic T, et al (2018)

Clinical Utility of Chromosome Genomic Array Testing for Unclassified and Advanced-Stage Renal Cell Carcinomas.

Archives of pathology & laboratory medicine [Epub ahead of print].

CONTEXT.—: Cytogenomic analysis provides a useful adjunct to traditional pathology in the categorization of renal cell carcinomas (RCCs), particularly in morphologically ambiguous cases, but it has disadvantages, including cost.

OBJECTIVE.—: To define the clinical scenarios in which this technology has direct clinical applications.

DESIGN.—: DNA was isolated from paraffin-embedded tissue from 40 selected cases of RCC. Chromosome genomic array testing was performed using the OncoScan.

RESULTS.—: Of 23 cases of unclassified renal tumors, 19 (83%) were reclassified with incorporation of cytogenetic and histologic features, including 10 as clear cell RCC, 2 as collecting duct carcinoma, 2 as papillary RCC, and 1 as novel TFEB-amplified tumor lacking TFEB translocation. Of 5 tumors with "hybrid" oncocytic features, 3 were reclassified as an eosinophilic variant of chromophobe RCC and 1 as oncocytoma. Appropriate staging in 2 patients was determined by identifying distinct, nonshared cytogenetic profiles. Of 11 cases of metastatic clear cell RCC, 7 (63%) had cytogenetic features associated with a poor prognosis.

CONCLUSIONS.—: We identified 5 scenarios in which chromosome genomic array testing has direct clinical utility: (1) to investigate unclassified RCCs, (2) to understand tumors with "hybrid" features and "collision" tumors, (3) to determine appropriate staging in questions of bilateral tumors and/or metastases, (4) to identify chromosomal aberrations in metastatic clear cell RCCs associated with a worse prognosis, and (5) to identify new entities. This has practical value in our institution, where a molecular profile diagnostically separating morphologically difficult to classify clear cell, papillary, chromophobe, and unclassified RCC influences treatment recommendations and clinical trial eligibility.

RevDate: 2018-11-01

Ramchandani MS, Jing L, Russell RM, et al (2018)

Viral genetics modulate orolabial HSV-1 shedding in humans.

The Journal of infectious diseases pii:5154868 [Epub ahead of print].

Background: Orolabial herpes simplex virus type 1 (HSV-1) infection has wide severity spectrum in immunocompetent persons. To study the role of viral genotype and host immunity, we characterized oral HSV-1 shedding rates, host cellular response and genotyped viral strains in mono- (MZ) and dizygotic (DZ) twins.

Methods: 29 MZ and 22 DZ HSV-1 seropositive twin pairs were evaluated for oral HSV-1 shedding for 60 days. HSV-1 strains from twins were genotyped as identical or different. CD4 T-cell responses to HSV-1 proteins were studied.

Results: The median oral HSV shedding rate was 9% (mean 10.2%). A positive correlation between shedding rates within all twin pairs was observed, and in MZ and DZ twins. In twins with sufficient HSV-1 DNA to genotype, 15 had the same and 14 had different strains. Viral shedding rates were correlated for those with the same but not different strains. The median number of HSV-1 ORFs recognized per person was 16. The CD4 T-cell response agreement to different HSV-1 ORFs was greater between MZ twins, than between unrelated persons (p=0.002).

Conclusion: Viral strain characteristics likely contribute to oral HSV-1 shedding rates.

RevDate: 2018-11-01

Lupo PJ, Brown AL, Arroyo VM, et al (2018)

DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.

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

Because survivors of pediatric acute lymphoblastic leukemia (ALL) are more likely to be obese than unaffected contemporaries, we compared DNA methylation profiles between normal-weight and obese survivors at adiposity-associated CpG sites previously-reported by epigenome-wide association studies (EWAS) of body mass index (BMI) in the general population. We selected 96 ALL survivors from the Childhood Cancer Survivor Study (CCSS): 48 obese (BMI ≥30.0 kg/m2) and 48 normal weight (BMI = 18.5-24.9 kg/m2). The Illumina HumanMethylation450 BeadChip was used to compare DNA methylation at 211 loci identified in EWAS of BMI in the general population. The false discovery rate (FDR) was used to account for multiple testing. In exploratory analyses, we also tested for interaction between cranial radiotherapy (CRT) status and selected CpG sites to evaluate differences by CRT exposure. Thirty-nine loci were associated (FDR <0.05) with obesity among survivors who only received chemotherapy (n = 49), including ABCG1 cg06500161. No loci were significantly associated with obesity among CRT-exposed survivors (n = 47). There was evidence (P-value <0.05) of interaction between CRT and methylation at six of the 39 methylation sites. Our results suggest that previously identified BMI-DNA methylation loci are associated with obesity in pediatric ALL survivors who were spared CRT, while no loci were significantly associated with obesity in survivors who received CRT. Given the obesogenic characteristics of ALL therapy, this study adds to the growing evidence of that the mechanisms underlying obesity in ALL survivors differ based on treatment exposures and may inform future intervention strategies among these individuals. This article is protected by copyright. All rights reserved.

RevDate: 2018-11-01

Jia Y, Gu D, Wan J, et al (2018)

The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer.

Oncogene pii:10.1038/s41388-018-0553-0 [Epub ahead of print].

Pancreatic cancer, mostly pancreatic ductal adenocarcinomas (PDAC), is one of the most lethal cancers, with a dismal median survival around 8 months. PDAC is notoriously resistant to chemotherapy. Thus far, numerous attempts using novel targeted therapies and immunotherapies yielded limited clinical benefits for pancreatic cancer patients. It is hoped that delineating the molecular mechanisms underlying drug resistance in pancreatic cancer may provide novel therapeutic options. Using acquired gemcitabine resistant pancreatic cell lines, we revealed an important role of the GLI-SOX2 signaling axis for regulation of gemcitabine sensitivity in vitro and in animal models. Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC). Down-regulation of GLI transcription factors also decreased expression of TIC marker CD24. Similarly, high SOX2 expression is associated with gemcitabine resistance whereas down-regulation of SOX2 sensitizes pancreatic cancer cells to gemcitabine treatment. We further revealed that elevated SOX2 expression is associated with an increase in GLI1 or GLI2 expression. Our ChIP assay revealed that GLI proteins are associated with a putative Gli binding site within the SOX2 promoter, suggesting a more direct regulation of SOX2 by GLI transcription factors. The relevance of our findings to human disease was revealed in human cancer specimens. We found that high SOX2 protein expression is associated with frequent tumor relapse and poor survival in stage II PDAC patients (all of them underwent gemcitabine treatment), indicating that reduced SOX2 expression or down-regulation of GLI transcription factors may be effective in sensitizing pancreatic cancer cells to gemcitabine treatment.

RevDate: 2018-11-01

Sarhan J, Liu BC, Muendlein HI, et al (2018)

Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection.

Proceedings of the National Academy of Sciences of the United States of America pii:1809548115 [Epub ahead of print].

Cell death and inflammation are intimately linked during Yersinia infection. Pathogenic Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8-mediated cell death. Here, using Yersinia pseudotuberculosis in corroboration with costimulation of lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule inhibitor of TAK1, we show that caspase-8 activation during TAK1 inhibition results in cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME) in murine macrophages, resulting in pyroptosis. Loss of GsdmD delays membrane rupture, reverting the cell-death morphology to apoptosis. We found that the Yersinia-driven IL-1 response arises from asynchrony of macrophage death during bulk infections in which two cellular populations are required to provide signal 1 and signal 2 for IL-1α/β release. Furthermore, we found that human macrophages are resistant to YopJ-mediated pyroptosis, with dampened IL-1β production. Our results uncover a form of caspase-8-mediated pyroptosis and suggest a hypothesis for the increased sensitivity of humans to Yersinia infection compared with the rodent reservoir.

RevDate: 2018-11-01

Schiffer JT, CA Schiffer (2018)

To what extent can mathematical modeling inform the design of clinical trials? The example of safe dose reduction of tyrosine kinase inhibitors in responding patients with chronic myeloid leukemia.

Haematologica, 103(11):1756-1757.

RevDate: 2018-11-01

Tsai JJ, Velardi E, Shono Y, et al (2018)

Nrf2 regulates CD4+ T cell-induced acute graft-versus-host disease in mice.

Blood pii:blood-2017-10-812941 [Epub ahead of print].

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor well known for its role in regulating the cellular redox pathway. While there is mounting evidence suggesting a critical role of Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role of Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4+ donor T cells after allo-HCT. Allo-HCT recipients of Nrf2-/- donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios+ donor regulatory T cells in the allograft, as well as defective upregulation of the gut homing receptor LPAM-1 on alloreactive CD8+ T cells. Additionally, Nrf2-/- donor CD8+ T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2-/- donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings not only characterized a previously unrecognized role of Nrf2 in T-cell function, but also revealed a novel therapeutic target to improve the outcomes of allo-HCT.

RevDate: 2018-11-01

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

Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at 1-year compared to unrelated donors.

Haematologica pii:haematol.2018.200121 [Epub ahead of print].

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation related toxicities we conducted a prospective observational trial of 11,942 related and unrelated age 18-60. Bone marrow was collected at 37 transplant and 78 National Marrow Donor Program centers and peripheral blood stem cells were collected at 42 transplant and 87 unrelated donor centers in North America. Ascertainment of medical comorbidities occurred prior to donation and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for marrow collection in related and unrelated donors, however, related stem cell donors had increased risk of moderate (OR 1.42, p<0.001) and severe pain (OR 8.91, p<0.001) and toxicities (OR 1.84, p<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56 p=0.021) and non-recovery from pain (OR 1.42 p=0.001) at 1 year. RD with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43, p<0.001) and non-recovery from toxicities (OR 3.71, p<0.001) at 1 year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43, p<0.001) and non-recovery from toxicities (OR 3.71, p<0.001) at 1 year. Related donors reporting grade ≥2 pain had significant decreases in HR-QoL at 1 month and 1 year post-donation (p=0.004). Conclusion: related peripheral blood stem cell donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at 1 year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. NCT00948636.

RevDate: 2018-10-31

Choi YH, Lakhal-Chaieb L, Kröl A, et al (2018)

Risks of Colorectal Cancer and Cancer-Related Mortality in Familial Colorectal Cancer Type X and Lynch Syndrome Families.

Journal of the National Cancer Institute pii:5149368 [Epub ahead of print].

Background: The risk of cancers is well characterized in Lynch syndrome (LS) families but has been less studied in familial colorectal cancer type X (FCCTX) families.

Methods: In this article, we compare the risk estimates of first and second colorectal cancers (CRCs) in 168 FCTTX and 780 LS families recruited through the Colon Cancer Family Registry as well as the risk of cancer-related deaths and disease-free survival (DFS) after a first CRC. Our methodology is based on a survival analysis approach, developed specifically to model the occurrence of successive cancers (ie, first and second CRCs) in the presence of competing risk events (ie, death from any causes).

Results: We found an excess risk of first and second CRC in individuals with LS compared to FCCTX family members. However, for an average age at first CRC of 60 years in FCCTX families and 50 years in LS families, the DFS rates were comparable in men but lower in women from FCCTX vs LS families, eg , 75.1% (95% confidence interval [CI] = 69.0% to 80.9%) vs 78.9% (95% CI = 76.3% to 81.3%) for the 10-year DFS. The 10-year risk of cancer-related death was higher in FCCTX families vs LS families, eg, 15.4% in men (95% CI = 10.9% to 19.8%) and 19.3% in women (95% CI = 13.6% to 24.7%) vs 8.9% (95% CI = 7.5% to 11.4%) and 8.7% (95% CI = 7.1% to 10.8%), respectively.

Conclusions: Individuals with CRCs arising in the context of FCCTX do not experience the same improved DFS and overall survival of those with LS, and that difference may be relevant in management decisions.

RevDate: 2018-10-30

Dai JY, Wang X, Buas MF, et al (2018)

Whole-genome sequencing of esophageal adenocarcinoma in Chinese patients reveals distinct mutational signatures and genomic alterations.

Communications biology, 1:174 pii:182.

While the incidence of esophageal adenocarcinoma (EAC) has risen drastically in Western countries over the last 40 years, a similar trend has not been observed for EAC in China. Here, we analyzed mutational spectrum, copy number alterations, and structural variants from whole-genome sequencing of 10 Chinese EAC tumor samples and their matched normal samples, and compared them to previously reported EAC tumor specimens from Western countries. The mutational burden in Chinese EAC was significantly lower than that found in EAC from Western countries. The hallmark A>C mutational signature observed at high frequency in EAC from Western countries, which has been linked to acid reflux, is completely absent in Chinese samples. Furthermore, none of the Chinese samples showed evidence of chromothripsis and genome doubling that are often found in EAC from Western countries. In summary, Chinese EAC tumor samples had distinct genomic profiles and signatures, suggesting that EAC in Chinese individuals may arise from a different etiological pathway.

RevDate: 2018-10-29

Hlubocky FJ, Back AL, TD Shanafelt (2016)

Addressing Burnout in Oncology: Why Cancer Care Clinicians Are At Risk, What Individuals Can Do, and How Organizations Can Respond.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Despite their benevolent care of others, today, more than ever, the cancer care professional who experiences overwhelming feelings of exhaustion, cynicism, and inefficacy is in grave jeopardy of developing burnout. Clinicians are repeatedly physically and emotionally exposed to exceedingly long hours in direct care with seriously ill patients/families, limited autonomy over daily responsibilities, endless electronic documentation, and a shifting medical landscape. The physical and emotional well-being of the cancer care clinician is critical to the impact on quality care, patient satisfaction, and overall success of their organizations. The prevention of burnout as well as targeting established burnout need to be proactively addressed at the individual level and organizational level. In fact, confronting burnout and promoting wellness are the shared responsibility of both oncology clinicians and their organizations. From an individual perspective, oncology clinicians must be empowered to play a crucial role in enhancing their own wellness by identification of burnout symptoms in both themselves and their colleagues, learning resilience strategies (e.g., mindful self-compassion), and cultivating positive relationships with fellow clinician colleagues. At the organizational level, leadership must recognize the importance of oncology clinician well-being; engage leaders and physicians in collaborative action planning, improve overall practice environment, and provide institutional wellness resources to physicians. These effective individual and organizational interventions are crucial for the prevention and improvement of overall clinician wellness and must be widely and systematically integrated into oncology care.

RevDate: 2018-10-29

Coveler AL, Herman JM, Simeone DM, et al (2016)

Localized Pancreatic Cancer: Multidisciplinary Management.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Pancreatic cancer is an aggressive cancer that continues to have single-digit 5-year mortality rates despite advancements in the field. Surgery remains the only curative treatment; however, most patients present with late-stage disease deemed unresectable, either due to extensive local vascular involvement or the presence of distant metastasis. Resection guidelines that include a borderline resectable group, as well as advancements in neoadjuvant chemotherapy and radiation that improve resectability of locally advanced disease, may improve outcomes for patients with more invasive disease. Multi-agent chemotherapy regimens fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel with gemcitabine improved response rates and survival in metastatic pancreatic cancer and are now being used in earlier stages for patients with localized potentially resectable and unresectable disease, with goals of downstaging tumors to allow margin-negative resection and reducing systemic recurrence. Chemoradiotherapy, although still controversial for both resectable and unresectable pancreatic cancer, is being used in the context of contemporary chemotherapy backbone regimens, and novel radiation techniques such as stereotactic body frame radiation therapy (SBRT) are studied on the premise of maintaining or improving efficacy and reducing treatment duration. Patient selection for optimal treatment designation is currently provided by multidisciplinary tumor boards, but biomarker discovery, in blood, tumors, or through novel imaging, is an area of intense research. Results to date suggest that some patients with unresectable disease at the outset have survival rates as good as those with initially resectable disease if able to undergo surgical resection. Long-term follow-up and improved clinical trials options are needed to determine optimal treatment modalities for patients with localized pancreatic cancer.

RevDate: 2018-10-29

Unger JM, Cook E, Tai E, et al (2016)

The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Fewer than one in 20 adult patients with cancer enroll in cancer clinical trials. Although barriers to trial participation have been the subject of frequent study, the rate of trial participation has not changed substantially over time. Barriers to trial participation are structural, clinical, and attitudinal, and they differ according to demographic and socioeconomic factors. In this article, we characterize the nature of cancer clinical trial barriers, and we consider global and local strategies for reducing barriers. We also consider the specific case of adolescents with cancer and show that the low rate of trial enrollment in this age group strongly correlates with limited improvements in cancer population outcomes compared with other age groups. Our analysis suggests that a clinical trial system that enrolls patients at a higher rate produces treatment advances at a faster rate and corresponding improvements in cancer population outcomes. Viewed in this light, the issue of clinical trial enrollment is foundational, lying at the heart of the cancer clinical trial endeavor. Fewer barriers to trial participation would enable trials to be completed more quickly and would improve the generalizability of trial results. Moreover, increased accrual to trials is important for patients, because trials provide patients the opportunity to receive the newest treatments. In an era of increasing emphasis on a treatment decision-making process that incorporates the patient perspective, the opportunity for patients to choose trial participation for their care is vital.

RevDate: 2018-10-29

Lyman GH (2016)

Issues on the Use of White Blood Cell Growth Factors in Oncology Practice.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Appropriate use of myeloid growth factors may reduce the risk of neutropenic complications including febrile neutropenia (FN) in patients receiving cancer chemotherapy. The recently updated American Society of Clinical Oncology (ASCO) Guidelines on the Use of the White Blood Cell Growth Factors recommends routine prophylaxis with these agents starting in the first cycle when the risk of FN is 20% or greater. However, the risks for neutropenic complications and the risk of serious adverse consequences from FN vary considerably with different chemotherapy regimens as well as other disease-, treatment-, and patient-specific risk factors. Considerably more information is now available on the major risk factors for FN. Multivariable risk models combining factors look promising but require further validation. Most clinical studies of myeloid growth factor prophylaxis assessed relative risk (RR) of FN but were not powered to evaluate the effect of prophylaxis on disease-free or overall survival. Accumulating evidence suggests, however, that the appropriate use of these agents in selected patients may improve both short-term and long-term survival by reducing the immediate risk of mortality accompanying patients with high-risk disease developing FN as well as improving disease-free and overall survival by enabling the delivery of full dose intensity chemotherapy and reducing the risk of disease recurrence in patients treated with curative intent. Further studies to evaluate risk factors and models for FN are needed to guide clinical and shared decision making for the optimal personalized use of these agents and offer patients at increased risk the best chance of long-term disease control.

RevDate: 2018-10-29

Lee A, Huang P, DeMatteo RP, et al (2016)

Immunotherapy for Soft Tissue Sarcoma: Tomorrow Is Only a Day Away.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Despite the advances taking place for patients with many types of cancer, to date there has been little success in meeting the great need for novel treatments of advanced soft tissue sarcoma with effective immunologic therapies. Here, we review recent clinical and preclinical data that indicate immune responses against sarcomas occur spontaneously and can also be successfully provoked. Efforts to manipulate the sarcoma immune microenvironment have the potential to eradicate disease and may also sensitize tumors to other tumor-targeted immunotherapeutic approaches. Other approaches, including vaccines and genetic engineering of T cells, offer a promising opportunity to actively direct cytotoxic lymphocytes toward antigen-bearing sarcomas. Drawing parallels with recent advances made in other cancer types, we identify ways in which sarcomas can be included in the ongoing immunotherapy revolution.

RevDate: 2018-10-29

McCleary NJ, Benson AB, R Dienstmann (2017)

Personalizing Adjuvant Therapy for Stage II/III Colorectal Cancer.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

This review focuses on three areas of interest with respect to the treatment of stage II and III colon and rectal cancer, including (1) tailoring adjuvant therapy for the geriatric population, (2) the controversy as to the optimal adjuvant therapy strategy for patients with locoregional rectal cancer and for patients with colorectal resectable metastatic disease, and (3) discussion of the microenvironment, molecular profiling, and the future of adjuvant therapy. It has become evident that age is the strongest predictive factor for receipt of adjuvant chemotherapy, duration of treatment, and risk of treatment-related toxicity. Although incorporating adjuvant chemotherapy for patients who have received neoadjuvant chemoradiation and surgery would appear to be a reasonable strategy to improve survivorship as an extrapolation from stage III colon cancer adjuvant trials, attempts at defining the optimal rectal cancer population that would benefit from adjuvant therapy remain elusive. Similarly, the role of adjuvant chemotherapy for patients after resection of metastatic colorectal cancer has not been clearly defined because of very limited data to provide guidance. An understanding of the biologic hallmarks and drivers of metastatic spread as well as the micrometastatic environment is expected to translate into therapeutic strategies tailored to select patients. The identification of actionable targets in mesenchymal tumors is of major interest.

RevDate: 2018-10-29

Randolph TW, Ding J, Kundu MG, et al (2017)

Adaptive penalties for generalized Tikhonov regularization in statistical regression models with application to spectroscopy data.

Journal of chemometrics, 31(4):.

Tikhonov regularization was proposed for multivariate calibration by Andries and Kalivas [1]. We use this framework for modeling the statistical association between spectroscopy data and a scalar outcome. In both the calibration and regression settings this regularization process has advantages over methods of spectral pre-processing and dimension-reduction approaches such as feature extraction or principal component regression. We propose an extension of this penalized regression framework by adaptively refining the penalty term to optimally focus the regularization process. We illustrate the approach using simulated spectra and compare it with other penalized regression models and with a two-step method that first pre-processes the spectra then fits a dimension-reduced model using the processed data. The methods are also applied to magnetic resonance spectroscopy data to identify brain metabolites that are associated with cognitive function.

RevDate: 2018-10-29

Yu B, NE Davidson (2018)

Gonadotropin-Releasing Hormone (GnRH) Agonists for Fertility Preservation: Is POEMS the Final Verse?.

Journal of the National Cancer Institute pii:5145901 [Epub ahead of print].

RevDate: 2018-10-29

Graham JB, Swarts JL, Thomas S, et al (2018)

Immune correlates of protection from West Nile virus neuroinvasion and disease.

The Journal of infectious diseases pii:5145366 [Epub ahead of print].

Background: A challenge to the design of improved therapeutics and prevention strategies for neuroinvasive infection and associated disease is the lack of known natural immune correlates of protection. A relevant model to study such correlates is offered by the Collaborative Cross (CC), a panel of recombinant inbred mouse strains that exhibit a range of disease manifestations upon infection.

Methods: We performed an extensive screen of CC-F1 lines infected with West Nile virus (WNV), including comprehensive immunophenotyping, to identify groups of lines that exhibited viral neuroinvasion, neuroinvasion with disease, and lines that remained virus- and disease-free.

Results: Our data reveal that protection from neuroinvasion and disease is multifactorial, and that several immune outcomes can contribute. Immune correlates identified include decreased suppressive activity of regulatory T-cells at steady state, which correlates with peripheral restriction of the virus. Further, a rapid contraction of WNV-specific CD8 T-cells in the brain correlated with protection from disease.

Conclusions: These immune correlates of protection illustrate additional networks and pathways of the WNV immune response that cannot be observed in the C57BL/6 mouse model. Additionally, correlates of protection exhibited pre-infection at baseline provide insight into phenotypic differences in the human population that may predict clinical outcomes upon infection.

RevDate: 2018-10-29

Moore HCF, Unger JM, Phillips KA, et al (2018)

Final Analysis of the Prevention of Early Menopause Study (POEMS)/SWOG Intergroup S0230.

Journal of the National Cancer Institute pii:5145902 [Epub ahead of print].

Premature menopause is a serious long-term side effect of chemotherapy. We evaluated long-term pregnancy and disease-related outcomes for patients in S0230/POEMS, a study in premenopausal women with stage I-IIIA estrogen receptor-negative, progesterone receptor-negative breast cancer to be treated with cyclophosphamide-containing chemotherapy. Women were randomly assigned to standard chemotherapy with or without goserelin, a gonadotropin-releasing hormone agonist, and were stratified by age and chemotherapy regimen. All statistical tests were two-sided. Of 257 patients, 218 were eligible and evaluable (105 in the chemotherapy + goserelin arm and 113 in the chemotherapy arm). More patients in the chemotherapy + goserelin arm reported at least one pregnancy vs the chemotherapy arm (5-year cumulative incidence = 23.1%, 95% confidence interval [CI] = 15.3% to 31.9%; and 12.2%, 95% CI = 6.8% to 19.2%, respectively; odds ratio = 2.34; 95% CI = 1.07 to 5.11; P = .03). Randomization to goserelin + chemotherapy was associated with a nonstatistically significant improvement in disease-free survival (hazard ratio [HR] = 0.55; 95% CI = 0.27 to 1.10; P = .09) and overall survival (HR = 0.45; 95% CI = 0.19 to 1.04; P = .06). In this long-term analysis of POEMS/S0230, we found continued evidence that patients randomly assigned to receive goserelin + chemotherapy were not only more likely to avoid premature menopause, but were also more likely to become pregnant without adverse effect on disease-related outcomes.

RevDate: 2018-10-28

Grinde KE, Qi Q, Thornton TA, et al (2018)

Generalizing polygenic risk scores from Europeans to Hispanics/Latinos.

Genetic epidemiology [Epub ahead of print].

RevDate: 2018-10-28

Bhatt NS, Brazauskas R, Tecca HR, et al (2018)

Post-transplantation employment status of adult survivors of childhood allogeneic hematopoietic cell transplant: A report from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Cancer [Epub ahead of print].

BACKGROUND: Data are scarce regarding employment outcomes of survivors of childhood allogeneic hematopoietic cell transplantation (alloHCT) and the factors that affect their employment status.

METHODS: By using the Center for International Blood and Marrow Transplant Research database, the authors studied employment outcomes of ≥1-year survivors of childhood alloHCT who were age ≥18 years at their most recent assessment (year of transplantation, 1985-2010). Employment status was assessed at their attained ages (ages 18-22, 23-27, and 28-32 years) and according to transplantation center (TC) location (United States or International). A multivariable analysis assessing the factors that affected employed status (full-time/part-time work or student) was performed.

RESULTS: Unemployment rates among 2844 survivors were persistently high at all attained ages (United States TCs: ages 18-22 [14%], 23-27 [15%], and 28-32 [13%] years; International TCs: ages 18-22 [56%], 23-27 [53%], and 28-32 [68%] years). The factors associated a with higher likelihood of employment included: older age at alloHCT (ages 5-9-years: hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.65-2.6; ages 10-14 years: HR, 4.43; 95% CI, 3.58-5.47; ages 15-18-years: HR, 7.13; 95% CI, 5.72-8.88), myeloablative conditioning without total body irradiation (TBI) (HR, 1.56; 95% CI, 1.38-1.77), reduced-intensity conditioning with TBI (HR, 1.47; 95% CI, 1.19-1.8) or without TBI (HR, 2.51; 95% CI, 2.15-2.92), and US-based TC (HR, 1.84; 95% CI, 1.62-2.08).

CONCLUSIONS: Young adult survivors of childhood alloHCT have high unemployment rates at all studied attained ages after HCT. Future efforts should be directed toward understanding the causes of unemployment their and relation to quality of life using patient-reported outcome measures.

RevDate: 2018-10-27

Barkley AS, Kuo CH, Leary SES, et al (2018)

Unusual Radiographic Presentation of Intracranial Mature Teratoma and Resection via a Supraorbital Approach.

World neurosurgery pii:S1878-8750(18)32387-8 [Epub ahead of print].

BACKGROUND: Primary intracranial teratomas account for <1% of intracranial masses during childhood after infancy. When supratentorial, they commonly occur in the pineal and suprasellar regions demonstrating multilocularity, areas of fat as well as calcifications and increasing enhancement correlating with decreased maturity. However, the presence of a teratoma as a mobile fat lesion within a large unilocular suprasellar cyst is rarely documented in this patient population.

CASE DESCRIPTION: We present the first pediatric case of a suprasellar mature teratoma presenting as a mobile fat suppressing lesion within a large unilocular suprasellar cyst and describe a supraorbital approach with adjunctive use of the endoscope for resection. We also provide a literature review of other cases presenting with similar radiographic findings.

CONCLUSIONS: Mature teratomas may manifest atypically as unilocular cystic lesions with a central mobile fatty component and are treated by gross total surgical resection. The supraorbital approach with adjunctive use of an endoscope can provide adequate exposure for resection with optimal cosmetic outcome.

RevDate: 2018-10-27

Issaka RB, Avila P, Whitaker E, et al (2018)

Population health interventions to improve colorectal cancer screening by fecal immunochemical tests: A systematic review.

Preventive medicine pii:S0091-7435(18)30340-2 [Epub ahead of print].

Despite clear evidence that colorectal cancer (CRC) screening reduces mortality, screening, including fecal immunochemical tests (FIT), is underutilized. We conducted a systematic review to determine the evidence of efficacy of interventions to improve FIT completion that could be scaled and utilized in population health management. We systematically searched publication databases for studies evaluating provider- or system-level interventions to improve CRC screening by FIT between 1 January 1996 and 13 December 2017 without language restrictions. Twenty articles describing 25 studies were included, 23 were randomized controlled trials with 1 quasi-experimental and 1 observational study. Ten studies discussed mailed FIT outreach, 4 pre-FIT patient reminders, 3 tailored patient messages, 2 post-FIT reminders, 2 paired FIT with influenza vaccinations, 2 provider alerts and 1 study each described the use of high-quality small media and patient financial incentives. Mailed FIT outreach was consistently effective with median improvement in CRC screening of 21.5% (interquartile range (IQR) 13.6%-29.0%). FIT paired with vaccinations led to a median 15.9% (IQR 15.6%-16.3%) improvement, while pre-FIT and post-FIT reminders demonstrated modest efficacy with median 4.1% (IQR 3.6%-6.7%) and 3.1% (IQR 2.9%-3.3%) improvement in CRC screening, respectively. More than half the studies were at high or unclear risk of bias; heterogeneous study designs and characteristics precluded meta-analysis. FIT-based CRC screening programs utilizing multilevel interventions (e.g. mailed FIT outreach, FIT paired with other preventative services, and provider alerts) have the potential to significantly increase screening participation. However, such programs must also follow-up patients with abnormal FIT results.

RevDate: 2018-10-27

Chiyaka ET, Nghiem VT, Zhang L, et al (2018)

Cost-Effectiveness of Herpes Zoster Vaccination: A Systematic Review.

PharmacoEconomics pii:10.1007/s40273-018-0735-1 [Epub ahead of print].

BACKGROUND: Herpes zoster (HZ) is one of the most common diseases among adults. Its reactivation is characterized by a severe and painful complication. In addition to the existing herpes zoster vaccine (ZVL), the FDA approved a new adjuvanted subunit zoster vaccine (RZV) in 2017 for use in adults aged 50 years and older. Several studies have assessed the cost-effectiveness of ZVL, many of which were conducted before the long-term vaccine efficacy data was available in 2014.

OBJECTIVE: Our objectives were to (i) summarize and compare the cost-effectiveness analyses (CEAs) of ZVL conducted before and after 2014, (ii) summarize the CEAs of RZV, and (iii) critically assess the cost-effectiveness models and identify key parameters to consider for future CEAs of RZV.

METHODS: We searched PubMed and two other databases from inception to March 2018 for original cost-effectiveness, cost-utility, or cost-benefit analyses of HZ vaccines. Three investigators independently reviewed and assessed full-text articles after screening the titles and abstracts to determine eligibility. For all included studies, we assessed study quality using the Drummond and Jefferson's checklist and extracted study characteristics, model structure, vaccine characteristics, incidence of HZ and complications, incremental cost-effectiveness ratio, and sensitivity analyses. We summarized data by type of vaccine, year of publication, and funding sources.

RESULTS: Twenty-seven studies met eligibility criteria. All studies were from high-income countries and were of moderate-to-high or high quality. Twenty studies repeatedly used four cost-effectiveness models. The assumption on long-term efficacy of ZVL was not based on clinical trial data in > 50% of studies. Fifteen out of 25 studies concluded that ZVL was cost-effective compared with no vaccine at a vaccine price ranging between US$93 and US$236 per dose (2018 US$), 40% of which were published after 2014. All industry-funded studies favored the use of ZVL. The single study assessing RZV found it to be more effective and less costly than ZVL, and cost-effective compared with no vaccination. More studies conducted after 2014 included various efficacy endpoints for ZVL, adverse reactions, and productivity loss compared with those conducted before 2014.

CONCLUSIONS: A majority of studies of ZVL found it to be cost-effective compared with no vaccine using the authors' chosen willingness-to-pay thresholds. RZV was dominant in the single study comparing the two vaccines, but the finding needs to be confirmed with further studies in different settings. Future studies should assume vaccine efficacy in line with clinical data, account for more efficacy endpoints for ZVL, and include other HZ long-term complications, vaccine adverse reactions, and productivity loss.

RevDate: 2018-10-27

Moon JY, Zolnik CP, Wang Z, et al (2018)

Gut microbiota and plasma metabolites associated with diabetes in women with, or at high risk for, HIV infection.

EBioMedicine pii:S2352-3964(18)30455-9 [Epub ahead of print].

BACKGROUND: Gut microbiota alteration has been implicated in HIV infection and metabolic disorders. The relationship between gut microbiota and diabetes has rarely been studied in HIV-infected individuals, who have excess risk of metabolic disorders.

METHODS: Our study during 2015-2016 enrolled predominantly African Americans and Hispanics in the Women's Interagency HIV Study. We studied 28 women with long-standing HIV infection under antiretroviral therapy and 20 HIV-uninfected, but at high risk of infection, women (16 HIV+ and 6 HIV- with diabetes). Fecal samples were analyzed by sequencing prokaryotic16S rRNA gene. Plasma metabolomics profiling was performed by liquid chromatography-tandem mass spectrometry.

FINDINGS: No significant differences in bacterial α- or β-diversity were observed by diabetes or HIV serostatus (all P > .1). Relative abundances of four genera (Finegoldia, Anaerococcus, Sneathia, and Adlercreutzia) were lower in women with diabetes compared to those without diabetes (all P < .01). In women with diabetes, plasma levels of several metabolites in tryptophan catabolism (e,g., kynurenine/tryptophan ratio), branched-chain amino acid and proline metabolism pathways were higher, while glycerophospholipids were lower (all P < .05). Results were generally consistent between HIV-infected and HIV-uninfected women, and no significant modification effects by HIV serostatus were observed (all Pinteraction > 0.05). Anaerococcus, known to produce butyrate which is involved in anti-inflammation and glucose metabolism, showed an inverse correlation with kynurenine/tryptophan ratio (r = -0.38, P < .01).

INTERPRETATION: Among women with or at high risk for HIV infection, diabetes is associated with gut microbiota and plasma metabolite alteration, including depletion of butyrate-producing bacterial population along with higher tryptophan catabolism. FUND: NHLBI (K01HL129892, R01HL140976) and FMF.

RevDate: 2018-10-26

Langer SL, Romano JM, Todd M, et al (2018)

Links Between Communication and Relationship Satisfaction Among Patients With Cancer and Their Spouses: Results of a Fourteen-Day Smartphone-Based Ecological Momentary Assessment Study.

Frontiers in psychology, 9:1843.

Cancer treatment poses significant challenges not just for those diagnosed with the disease but also for their intimate partners. Evidence suggests that couples' communication plays a major role in the adjustment of both individuals and in the quality of their relationship. Most descriptive studies linking communication to adjustment have relied on traditional questionnaire methodologies and cross-sectional designs, limiting external validity and discernment of temporal patterns. Using the systemic-transactional model of dyadic coping as a framework, we examined intra- and inter-personal associations between communication (both enacted and perceived) and relationship satisfaction (RS) among patients with stage II-IV breast or colorectal cancer and their spouses (N = 107 couples). Participants (mean age = 51, 64.5% female patients, and 37.4% female spouses) independently completed twice-daily ecological momentary assessments (EMA) via smartphone for 14 consecutive days. Items assessed RS and communication (expression of feelings, holding back from expression, support and criticism of partner, and parallel ratings of partner behavior). Linear mixed models employing an Actor Partner Interdependence Model were used to examine concurrent, time-lagged, and cross-lagged associations between communication and RS. Expressing one's feelings was unassociated with RS. Holding back from doing so, in contrast, was associated with lower RS for both patients and spouses in concurrent models. These effects were both intrapersonal and interpersonal, meaning that when individuals held back from expressing their feelings, they reported lower RS and so too did their partner. Giving and receiving support were associated with one's own higher RS for both patients and spouses in concurrent models, and for patients in lagged models. Conversely, criticizing one's partner and feeling criticized were maladaptive, associated with lower RS (own and in some cases, partner's). Cross-lagged analyses (evening RS to next-day afternoon communication) yielded virtually no effects, suggesting that communication may have a stronger influence on short-term RS than the reverse. Findings underscore the importance of responsive communication, more so than expression per se, in explaining both concurrent and later relationship adjustment. In addition, a focus on holding back from expressing feelings may enhance the understanding of RS for couples coping with cancer.

RevDate: 2018-10-26

Zueger PM, Holmes HM, Qato DM, et al (2018)

Use of Nonpalliative Medications Following Burdensome Health Care Transitions in Hospice Patients: A Matched Cohort Analysis.

Medical care [Epub ahead of print].

BACKGROUND: Limited benefit medications (LBMs), those medications with questionable benefit at the end of life, are often recommended for discontinuation in hospice patients. Transitions in care are associated with inappropriate prescribing in older and terminally ill populations.

OBJECTIVES: To evaluate the association between burdensome health care transitions and subsequent receipt of LBMs in older hospice patients.

METHODS: We conducted a matched cohort analysis of patients admitted to hospice between 2008 and 2013 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. The prevalence of post-health care transition LBM use was assessed. Adjusted incidence rate ratios (IRRs) were estimated for the association between transitions and subsequent receipt of LBMs.

RESULTS: In total, 17.9% of 7064 hospice patients received at least 1 LBM following their first burdensome health care transition. Posttransition continuation of a medication class used before hospice admission was most common for antidementia medications (14.2%) and antihypertensives (11.2%). Transitions were associated with a 33% increase in the risk of receiving at least 1 LBM [IRR, 1.33; 95% confidence interval (CI), 1.25-1.42], increasing to 56% when evaluating only hospitalization transitions (IRR, 1.56; 95% CI, 1.39-1.76). Medication classes more likely to be dispensed after a transition included antihyperlipidemics (IRR, 1.38; 95% CI, 1.13-1.70), antihypertensives (IRR, 1.28; 95% CI, 1.16-1.40), and proton-pump inhibitors (IRR, 1.40; 95% CI, 1.20-1.63).

CONCLUSIONS: Burdensome health care transitions were associated with the receipt of nonpalliative medications in older hospice patients. Interventions aimed at improving provider communication and reducing fragmentation in care may help reduce unnecessary medication use in this vulnerable population.

RevDate: 2018-10-26

Mirzaei HR, Jamali A, Jafarzadeh L, et al (2018)

Construction and functional characterization of a fully human anti-CD19 chimeric antigen receptor (huCAR)-expressing primary human T cells.

Journal of cellular physiology [Epub ahead of print].

Although remarkable results have been attained by adoptively transferring T cells expressing fully murine and/or humanized anti-CD19 chimeric antigen receptors (CARs) to treat B cell malignancies, evidence of human anti-mouse immune responses against CARs provides a rationale for the development of less immunogenic CARs. By developing a fully human CAR (huCAR), these human anti-mouse immune responses are likely eliminated. This, perhaps, not only increases the persistence of anti-CD19 CAR T cells-thereby reducing the risk of tumor relapse-but also facilitates administration of multiple, temporally separated doses of CAR T cells to the same recipient. To these ends, we have designed and constructed a second-generation fully human anti-CD19 CAR (or huCAR19) containing a fully human single-chain variable fragment (ScFv) fused with a CD8a hinge, a 4-1BB transmembrane domain and intracellular T cell signaling domains of 4-1BB and CD3z. T cells expressing this CAR specifically recognized and lysed CD19+ target cells produced cytokines and proliferated in vitro. Moreover, cell volume data revealed that our huCAR construct cannot induce antigen-independent tonic signaling in the absence of cognate antigen. Considering our results, our anti-CD19 huCAR may overcome issues of transgene immunogenicity that plague trials utilizing CARs containing mouse-derived ScFvs. These results suggest that this huCAR19 be safely and effectively applied for adaptive T cell immunotherapy in clinical practice.

RevDate: 2018-10-26

Goddard ET, Bozic I, Riddell SR, et al (2018)

Dormant tumour cells, their niches and the influence of immunity.

Nature cell biology, 20(11):1240-1249.

Despite increased focus on the clinical relevance of dormant metastatic disease, our understanding of dormant niches, mechanisms underlying emergence from dormancy, and the immune system's role in this phenomenon, remains in its infancy. Here, we discuss key work that has shaped our current understanding of these topics. Because tumour dormancy provides a unique therapeutic window to prevent metastatic disease, we discuss on-going clinical trials and weigh the potential for immunotherapy to eradicate dormant disease.

RevDate: 2018-10-26

Ying Z, Sandoval M, S Beronja (2018)

Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth.

Nature cell biology, 20(11):1256-1266.

Oncogenic lesions are surprisingly common in morphologically and functionally normal human skin. However, the cellular and molecular mechanisms that suppress their cancer-driving potential to maintain tissue homeostasis are unknown. By employing assays for the direct and quantitative assessment of cell fate choices in vivo, we show that oncogenic activation of PI3K-AKT, the most commonly activated oncogenic pathway in cancer, promotes the differentiation and cell cycle exit of epidermal progenitors. As a result, oncogenic PI3K-AKT-activated epidermis exhibits a growth disadvantage even though its cells are more proliferative. We then sought to uncover the underlying mechanism behind oncogene-induced differentiation via a series of genetic screens in vivo. An AKT substrate, SH3RF1, is identified as a specific promoter of epidermal differentiation that has no effect on proliferation. Our study provides evidence for a direct, cell autonomous mechanism that can suppresses progenitor cell renewal and block clonal expansion of epidermal cells bearing a common and activating mutation in Pik3ca.

RevDate: 2018-10-26

Colonna L, Peterson CW, Schell JB, et al (2018)

Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation.

Nature communications, 9(1):4438 pii:10.1038/s41467-018-06736-7.

Allogeneic transplantation (allo-HCT) has led to the cure of HIV in one individual, raising the question of whether transplantation can eradicate the HIV reservoir. To test this, we here present a model of allo-HCT in SHIV-infected, cART-suppressed nonhuman primates. We infect rhesus macaques with SHIV-1157ipd3N4, suppress them with cART, then transplant them using MHC-haploidentical allogeneic donors during continuous cART. Transplant results in ~100% myeloid donor chimerism, and up to 100% T-cell chimerism. Between 9 and 47 days post-transplant, terminal analysis shows that while cell-associated SHIV DNA levels are reduced in the blood and in lymphoid organs post-transplant, the SHIV reservoir persists in multiple organs, including the brain. Sorting of donor-vs.-recipient cells reveals that this reservoir resides in recipient cells. Moreover, tetramer analysis indicates a lack of virus-specific donor immunity post-transplant during continuous cART. These results suggest that early post-transplant, allo-HCT is insufficient for recipient reservoir eradication despite high-level donor chimerism and GVHD.

RevDate: 2018-10-25

Soltys DT, Pereira CPM, Rowies FT, et al (2018)

Lower mitochondrial DNA content but not increased mutagenesis associates with decreased base excision repair activity in brains of AD subjects.

Neurobiology of aging, 73:161-170 pii:S0197-4580(18)30340-3 [Epub ahead of print].

Accumulation of oxidative mitochondrial DNA (mtDNA) damage and impaired base excision repair (BER) in brains have been associated with Alzheimer's disease (AD). However, it is still not clear how these affect mtDNA stability, as reported levels of mtDNA mutations in AD are conflicting. Thus, we investigated whether alterations in BER correlate with mtDNA instability in AD using postmortem brain samples from cognitively normal AD subjects and individuals who show neuropathological features of AD, but remained cognitively normal (high-pathology control). To date, no data on DNA repair and mtDNA stability are available for these individuals. BER activities, mtDNA mutations, and mtDNA copy number were measured in the nuclear and mitochondrial extracts. Significantly lower uracil DNA glycosylase activity was detected in nuclear and mitochondrial extracts from AD subjects, while apurinic/apyrimidinic endonuclease activity was similar in all groups. Although mtDNA mutation frequency was similar in all groups, mtDNA copy number was significantly decreased in the temporal cortex of AD brains but not of high-pathology control subjects. Our results show that lower mitochondrial uracil DNA glycosylase activity does not result in increased mutagenesis, but rather in depletion of mtDNA in early-affected brain regions during AD development.

RevDate: 2018-10-25

Chlebowski RT, Cirillo DJ, Eaton CB, et al (2018)

Estrogen alone and joint symptoms in the Women's Health Initiative randomized trial.

Menopause (New York, N.Y.), 25(11):1313-1320.

OBJECTIVE: Although joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen's influence on joint symptoms provide mixed results. Against this background, estrogen-alone effects on joint symptoms were examined in post hoc analyses in the Women's Health Initiative randomized, placebo-controlled, clinical trial.

METHODS: A total of 10,739 postmenopausal women who have had a hysterectomy were randomized to receive daily oral conjugated equine estrogens (0.625 mg/d) or a matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire in all participants at entry and on year 1, and in a 9.9% random subsample (n = 1,062) after years 3 and 6. Logistic regression models were used to compare the frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms.

RESULTS: At baseline, joint pain and joint swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After 1 year, joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group (76.3% vs 79.2%, P = 0.001), as was joint pain severity, and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen-alone group (42.1% vs 39.7%, P = 0.02). Adherence-adjusted analyses strengthen estrogen's association with reduced joint pain but attenuate estrogen's association with increased joint swelling.

CONCLUSIONS: The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.

RevDate: 2018-10-25

Brinton LA, Brogan DR, Coates RJ, et al (2018)

Breast cancer risk among women under 55 years of age by joint effects of usage of oral contraceptives and hormone replacement therapy.

Menopause (New York, N.Y.), 25(11):1195-1200.

OBJECTIVE: To assess effects on breast cancer risk of exposure to both oral contraceptives and menopausal hormones, an increasingly common exposure.

DESIGN: A case-control study of breast cancer among women under the age of 55 years in Atlanta, GA involving 1,031 cases and 919 population controls was conducted.

RESULTS: Ever use of oral contraceptives was associated with a relative risk of 1.1 (95% 0.9-1.4), whereas the relative risk for hormone replacement therapy was 0.9 (95% CI 0.7-1.2). Seventeen percent of the cases versus 19% of the population controls reported exposure to both agents, resulting in a relative risk of 1.0 (95% CI 0.7-1.4) relative to those unexposed to either preparation. Although there was little variation in risk associated with joint effects by either age or race, there were statistically nonsignificant elevations in risk for this exposure among women who had experienced a natural menopause (relative risk = 2.0, 95% CI 0.7-5.6), were relatively thin (relative risk = 1.5, 0.8-3.0), or who had a first degree relative with breast cancer (relative risk = 2.0, 0.6-7.0). When joint effects of longer term use of both agents were considered, subjects who reported use of oral contraceptives for 10 or more years and hormone replacement for 3 or more years had a relative risk of 3.2 (95% CI 1.4-7.4) compared with nonusers of either preparation.

CONCLUSIONS: Although our results must be cautiously interpreted given small numbers within subgroups, they raise concern and emphasize the need for further evaluation on breast cancer risk of the increasingly common exposure to both oral contraceptives and hormone replacement therapy.

RevDate: 2018-10-25

Andrews SS, Brent R, G Balázsi (2018)

Transferring information without distortion.

eLife, 7: pii:41894.

Despite employing diverse molecular mechanisms, many different cell signaling systems avoid losing information by transmitting it in a linear manner.

RevDate: 2018-10-25

Writing Group for the PReVENT Investigators, Simonis FD, Serpa Neto A, et al (2018)

Effect of a Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS: A Randomized Clinical Trial.

JAMA pii:2710774 [Epub ahead of print].

Importance: It remains uncertain whether invasive ventilation should use low tidal volumes in critically ill patients without acute respiratory distress syndrome (ARDS).

Objective: To determine whether a low tidal volume ventilation strategy is more effective than an intermediate tidal volume strategy.

A randomized clinical trial, conducted from September 1, 2014, through August 20, 2017, including patients without ARDS expected to not be extubated within 24 hours after start of ventilation from 6 intensive care units in the Netherlands.

Interventions: Invasive ventilation using low tidal volumes (n = 477) or intermediate tidal volumes (n = 484).

Main Outcomes and Measures: The primary outcome was the number of ventilator-free days and alive at day 28. Secondary outcomes included length of ICU and hospital stay; ICU, hospital, and 28- and 90-day mortality; and development of ARDS, pneumonia, severe atelectasis, or pneumothorax.

Results: In total, 961 patients (65% male), with a median age of 68 years (interquartile range [IQR], 59-76), were enrolled. At day 28, 475 patients in the low tidal volume group had a median of 21 ventilator-free days (IQR, 0-26), and 480 patients in the intermediate tidal volume group had a median of 21 ventilator-free days (IQR, 0-26) (mean difference, -0.27 [95% CI, -1.74 to 1.19] P = .71). There was no significant difference in ICU (median, 6 vs 6 days; 0.39 [-1.09 to 1.89] ; P = .58) and hospital (median, 14 vs 15 days; -0.60 [-3.52 to 2.31]; P = .68) length of stay or 28-day (34.9% vs 32.1%; hazard ratio [HR], 1.12 [0.90 to 1.40]; P = .30) and 90-day (39.1% vs 37.8%; HR, 1.07 [0.87 to 1.31]; P = .54) mortality. There was no significant difference in the percentage of patients developing the following adverse events: ARDS (3.8% vs 5.0%; risk ratio [RR], 0.86 [0.59 to 1.24]; P = .38), pneumonia (4.2% vs 3.7%; RR, 1.07 [0.78 to 1.47]; P = .67), severe atelectasis (11.4% vs 11.2%; RR, 1.00 [0.81 to 1.23]; P = .94), and pneumothorax (1.8% vs 1.3%; RR, 1.16 [0.73 to 1.84]; P = .55).

Conclusions and Relevance: In patients in the ICU without ARDS who were expected not to be extubated within 24 hours of randomization, a low tidal volume strategy did not result in a greater number of ventilator-free days than an intermediate tidal volume strategy.

Trial Registration: Identifier: NCT02153294.

RevDate: 2018-10-25

Cutler S, Lee LJ, T Tsukiyama (2018)

Chromatin Remodeling Factors Isw2 and Ino80 Regulate Chromatin, Replication, and Copy Number of the Saccharomyces cerevisiae Ribosomal DNA Locus.

Genetics pii:genetics.118.301579 [Epub ahead of print].

In the budding yeast Saccharomyces cerevisiae, ribosomal RNA genes are encoded in a highly repetitive tandem array referred to as the ribosomal DNA (rDNA) locus. The yeast rDNA is the site of a diverse set of DNA-dependent processes, including transcription of ribosomal RNAs by RNA Polymerases I and III, transcription of non-coding RNAs by RNA Polymerase II, DNA replication initiation, replication fork blocking, and recombination-mediated regulation of rDNA repeat copy number. All of this takes place in the context of chromatin, but little is known about the roles played by ATP-dependent chromatin remodeling factors at the yeast rDNA. In this work, we report that the Isw2 and Ino80 chromatin remodeling factors are targeted to this highly repetitive locus. We characterize for the first time their function in modifying local chromatin structure, finding that loss of these factors decreases the fraction of actively transcribed 35S ribosomal RNA genes and the positioning of nucleosomes flanking the ribosomal origin of replication. In addition, we report that Isw2 and Ino80 promote efficient firing of the ribosomal origin of replication and facilitate the regulated increase of rDNA repeat copy number. This work significantly expands our understanding of the importance of ATP-dependent chromatin remodeling for rDNA biology.

RevDate: 2018-10-25

Wagh K, Kreider EF, Li Y, et al (2018)

Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth.

Cell reports, 25(4):893-908.e7.

Densely arranged N-linked glycans shield the HIV-1 envelope (Env) trimer from antibody recognition. Strain-specific breaches in this shield (glycan holes) can be targets of vaccine-induced neutralizing antibodies that lack breadth. To understand the interplay between glycan holes and neutralization breadth in HIV-1 infection, we developed a sequence- and structure-based approach to identify glycan holes for individual Env sequences that are shielded in most M-group viruses. Applying this approach to 12 longitudinally followed individuals, we found that transmitted viruses with more intact glycan shields correlated with development of greater neutralization breadth. Within 2 years, glycan acquisition filled most glycan holes present at transmission, indicating escape from hole-targeting neutralizing antibodies. Glycan hole filling generally preceded the time to first detectable breadth, although time intervals varied across hosts. Thus, completely glycan-shielded viruses were associated with accelerated neutralization breadth development, suggesting that Env immunogens with intact glycan shields may be preferred components of AIDS vaccines.

RevDate: 2018-10-25

Shaik F, Uldrick TS, Esterhuizen T, et al (2018)

Health-Related Quality of Life in Patients Treated With Antiretroviral Therapy Only Versus Chemotherapy and Antiretroviral Therapy for HIV-Associated Kaposi Sarcoma: A Randomized Control Trial.

Journal of global oncology.

PURPOSE: In sub-Saharan Africa, Kaposi sarcoma (KS) is the most common HIV-associated cancer. KS causes substantial morbidity, and treatment goals should emphasize quality of life (QOL). Antiretroviral therapy (ART) is indicated, and early chemotherapy significantly improves tumor regression. The effect of ART alone or with chemotherapy on QOL in treatment-naïve South Africans with HIV-associated KS was assessed.

METHODS: KAART (Kaposi Sarcoma AIDS Anti-Retroviral Therapy) is a randomized, controlled, open-label trial of ART versus ART plus chemotherapy. Crossover between arms was allowed for patients with progressive disease. Eighty-nine percent of patients had advanced tumor burden. Within KAART, QOL measured by European Organization for Research and Treatment of Cancer-QLQ-C30 questionnaire evaluated functional and symptom domains and global QOL. Intragroup changes between baseline and month 12 (Wilcoxon rank sign test), changes between the arms (Mann-Whitney test), and the relationship between responses, determined by AIDS Clinical Trial Group criteria and QOL measures (Kruskal-Wallis test), were evaluated. P values < .01 were considered significant.

RESULTS: QOL information was available for 111 of 112 patients. Significant improvements over 12 months were seen in global health status and functional scales (emotional, cognitive, and social scales; not physical and role function). Most symptom scales (fatigue, pain, dyspnea, insomnia, appetite, diarrhea, and constipation) also showed significant improvement. There were no statistically significant changes between arms in intention-to-treat analysis. Patients showing a response to the tumor (complete or partial) reported significantly increased global QOL (P < .001), pain relief, and improved role functioning. Adherence, adverse events, HIV viral load, and CD4 count did not correlate with global QOL.

CONCLUSION: African patients with HIV-associated KS derive a significant benefit in QOL from ART and tumor regression.


ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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


Order from Amazon

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

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Papers in Classical Genetics

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

Digital Books

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


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


Biographical information about many key scientists.

Selected Bibliographies

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

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