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07 Dec 2019 at 01:37
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Bibliography on: Publications by FHCRC Researchers


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

RJR: Recommended Bibliography 07 Dec 2019 at 01:37 Created: 

Publications by FHCRC Researchers

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

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

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

Citations The Papers (from PubMed®)

RevDate: 2019-12-06

Loh KP, Xu H, Back A, et al (2019)

Patient-hematologist discordance in perceived chance of cure in hematologic malignancies: A multicenter study.

Cancer [Epub ahead of print].

BACKGROUND: Ensuring that patients with hematologic malignancies have an accurate understanding of their likelihood of cure is important for informed decision making. In a multicenter, longitudinal study, the authors examined discordance in patients' perception of their chance of cure versus that of their hematologists, whether patient-hematologist discordance changed after a consultation with a hematologist, and factors associated with persistent discordance.

METHODS: Before and after consultation with a hematologist, patients were asked about their perceived chance of cure (options were <10%, 10%-19%, and up to 90%-100% in 10% increments, and "do not wish to answer"). Hematologists were asked the same question after consultation. Discordance was defined as a difference in response by 2 levels. The McNemar test was used to compare changes in patient-hematologist prognostic discordance from before to after consultation. A generalized linear mixed model was used to examine associations between factors and postconsultation discordance, adjusting for clustering at the hematologist level.

RESULTS: A total of 209 patients and 46 hematologists from 4 sites were included in the current study. Before consultation, approximately 61% of dyads were discordant, which improved to 50% after consultation (P < .01). On multivariate analysis, lower educational level (
CONCLUSIONS: Patient-hematologist concordance in prognostic understanding appears to improve after a hematology consultation, but approximately one-half of patients' views of their prognoses were found to remain discordant with those of their hematologists. Interventions are needed to improve prognostic understanding among patients with hematologic malignancies.

RevDate: 2019-12-06

Mueller S, Kline CN, Buerki RA, et al (2019)

Stroke impact on mortality and psychologic morbidity within the Childhood Cancer Survivor Study.

Cancer [Epub ahead of print].

BACKGROUND: Poor socioeconomic and health-related quality of life (HRQOL) outcomes in survivors of childhood cancer can lead to distress and overall negatively impact the lives of these individuals. The current report has highlighted the impact of stroke and stroke recurrence on mortality, psychological HRQOL, and socioeconomic outcomes within the Childhood Cancer Survivor Study (CCSS).

METHODS: The CCSS is a retrospective cohort study with longitudinal follow-up concerning survivors of pediatric cancer who were diagnosed between 1970 and 1986. Mortality rates per 100 person-years were calculated across 3 periods: 1) prior to stroke; 2) after first stroke and before recurrent stroke; and 3) after recurrent stroke. Socioeconomic outcomes, the standardized Brief Symptoms Inventory-18, the Medical Outcomes Study 36-Item Short Form Health Survey, and the CCSS-Neurocognitive Questionnaire also were assessed.

RESULTS: Among 14,358 participants (median age, 39.7 years), 224 had a stroke after their cancer diagnosis (single stroke in 161 patients and recurrent stroke in 63 patients). Based on 2636 deaths, all-cause late mortality rates were 0.70 (95% CI, 0.68-0.73) prior to stroke, 1.03 (95% CI, 0.73-1.46) after the first stroke, and 2.42 (95% CI, 1.48-3.94) after the recurrent stroke. Among 7304 survivors, those with stroke were more likely to live with a caregiver (single stroke odds ratio [OR], 2.3 [95% CI, 1.4-3.8]; and recurrent stroke OR, 5.3 [95% CI, 1.7-16.8]) compared with stroke-free survivors. Stroke negatively impacted task efficiency (single stroke OR, 2.4 [95% CI, 1.4-4.1] and recurrent stroke OR, 3.3 [95% CI, 1.1-10.3]) and memory (single stroke OR, 2.1 [95% CI, 1.2-3.7]; and recurrent stroke OR, 3.5 [95% CI, 1.1-10.5]).

CONCLUSIONS: Stroke and stroke recurrence are associated with increased mortality and negatively impact HRQOL measures in survivors of pediatric cancer.

RevDate: 2019-12-06

Tseng YD, Mezheritsky I, Halasz LM, et al (2019)

Curative Intent Radiotherapy Delivered Within the Last Year of Life.

American journal of clinical oncology [Epub ahead of print].

OBJECTIVES: We studied a cohort of cancer patients that underwent curative-intent radiation within the last year of life (LYOL). Given the unexpectedly short survival, we evaluated the proportion with relapsed/refractory disease, determined causes of death, and explored whether treatment intent was associated with aggressiveness of care at the end of life.

MATERIALS AND METHODS: We extracted and linked claims data and radiotherapy records for patients seen at a single academic institution that died between October 1, 2014, and September 30, 2015.

RESULTS: Among 870 cancer patients, 290 were irradiated within the LYOL, of which 287 had treatment intent recorded (101 curative-intent, 186 palliative-intent). The majority of curative-intent patients had hematologic malignancies and/or underwent transplant (44.6%), followed by head and neck (9.9%) and gastrointestinal malignancies (9.9%). Half (n=49; 48.5%) had relapsed/refractory disease at the time of curative-intent radiation, including 13 with metastatic disease. Tumor progression (n=65; 64.4%) was the most common cause of death, followed by treatment-related mortality (n=27; 26.7%), of which transplant/hematologic malignancy patients (n=19) were the majority. Compared with palliative-intent patients, curative-intent patients had significantly higher rates of chemotherapy use within 14 days of death (P=0.04), intensive care unit stay within 30 days of death (P<0.00001), and death in the intensive care unit (P=0.001).

CONCLUSIONS: Cancer patients that receive curative-intent radiation in the LYOL appear to be heterogeneous and receive more aggressive care at the end of life compared with palliative-intent patients. Categorizing radiation as curative in patients with metastatic disease may reflect inappropriate decision-making among physicians. Additional studies are needed to understand how radiation oncologists categorize treatment as curative and whether prognostication models may help discriminate patients undergoing curative-intent radiation that have limited life expectancies.

RevDate: 2019-12-06

Peebles K, van der Straten A, Palanee-Phillips T, et al (2019)

Anal intercourse, HIV-1 risk, and efficacy in a trial of a dapivirine-containing vaginal ring for HIV-1 prevention.

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

OBJECTIVES: To describe receptive anal intercourse (RAI) behaviors and correlates in a cohort of sub-Saharan African women, evaluate the association of RAI with HIV-1 risk, and evaluate whether the HIV-1 prevention efficacy of a dapivirine-containing vaginal ring differs among women who reported RAI.

DESIGN: Secondary analysis of the MTN-020/ASPIRE trial, a randomized, double-blind, placebo-controlled trial evaluating a dapivirine-containing vaginal ring for HIV-1 prevention.

METHODS: At enrollment and month three, women reported RAI in the prior three months in audio computer-assisted self-interviews. We evaluated associations between RAI and participant characteristics with chi-square and t-tests adjusted for study site. Cox proportional hazards models stratified by study site tested the association of RAI with HIV-1 acquisition and effect modification by RAI.

RESULTS: Nineteen percent of women reported any RAI at enrollment and/or month 3, with a median of 2 (IQR: 1, 4) RAI acts in the prior three months, accounting for 1.5% of total sex acts. RAI prevalence was higher among women with lower educational attainment and those reporting transactional sex. In adjusted models, RAI was not associated with HIV-1 acquisition (aHR: 0.93, 95% CI: 0.57, 1.54). The ring reduced HIV-1 risk by 27% (95% CI: -5, 49) among women reporting no RAI and by 18% (95% CI: -57, 57) among women reporting any RAI (interaction p-value=0.77).

CONCLUSIONS: RAI was modestly infrequent and was not associated with reduced HIV-1 protection from the ring, suggesting that, in populations with rates of RAI similar to this cohort, RAI may not appreciably reduce the population-level impact of the dapivirine vaginal ring.

RevDate: 2019-12-06

Malhotra H, Radich J, P Garcia-Gonzalez (2019)

Meeting the needs of CML patients in resource-poor countries.

Hematology. American Society of Hematology. Education Program, 2019(1):433-442.

Subsequent to the development and global availability of BCR/ABL-targeted tyrosine kinase inhibitors (TKIs), the prognosis of patients with chronic myeloid leukemia (CML), at least those in the chronic phase, has markedly improved, and in the developed world, the average lifespan of these patients is now close to that of age- and sex-matched subjects without the disease. However, the situation in low- and middle-income countries (LMICs) may not be so rosy. Many important differences in hematological cancers, including CML, have been highlighted in various publications in LMICs vs developed countries. These include differences in incidence and prevalence rates, age and stage of disease at diagnosis, response rates, and survival. Some of the possible reasons proposed for these are varying socioeconomic milieu (impacting availability of effective drugs and essential monitoring), environmental factors (mainly exposure to viral infections and pesticides), nutritional factors with interplay of malnutrition and diet on drug absorption and blood levels, and possible unknown genetic factors. Although generic first-generation TKIs (imatinib) are available in many parts of the world, several challenges remain in providing optimal treatment to patients with CML in resource-poor countries. Some of these include availability of optimal and high-quality BCR/ABL testing, availability and expense related to use of second- and third-generation TKIs (nilotinib, dasatinib, bosutinib, and ponatinib) and hematopoietic stem cell transplantation, issues with compliance and toxicities of drugs, and ensuring a minimal standard-of-care treatment and monitoring for every patient diagnosed with CML. For the purpose of this article, the more objective country label-LMIC-coined by the World Bank will be used (gross national income per capita between $1026 and $3995; World Bank, June 2019). Some of these issues will be discussed in this article in greater detail by experts in the field in 3 different but interconnected sections.

RevDate: 2019-12-06

Chow VA, AK Gopal (2019)

Where does transplant fit in the age of targeted therapies?.

Hematology. American Society of Hematology. Education Program, 2019(1):287-293.

The role of hematopoietic cell transplantation (HCT) for indolent lymphoma has evolved over the last 5 years with the availability of novel low-toxicity therapies and a better understanding of the prognosis of these entities. However, despite numerous treatment options for patients with follicular lymphoma, none are thought to be curative, and many require ongoing therapy with chronic toxicity. Historical trials indicate that autologous HCT as initial consolidation leads to improved progression-free survival, but not overall survival (OS) and, thus, is not typically recommended. However, autologous HCT for chemosensitive relapse can be carried out with ∼1% early mortality risk, affording disease control lasting a median of 3 to 5 years and the potential to improve OS. These results may compare favorably in efficacy, toxicity, and cost vs multiple sequential novel therapies with shorter durations of benefit. Recent data indicate that autologous HCT in follicular lymphoma patients with early initial progression will result in more than one third being alive and without relapse at 5 years, leading to improved OS when used within a year of the first recurrence. Unlike other available therapies, allogeneic HCT has the potential to cure up to one half of those transplanted with indolent B-cell non-Hodgkin lymphoma, although the risks need to be recognized and appropriate patient and donor selection is critical to ensure the best outcomes. HCT continues to remain a viable option in the current era of multiple targeted agents.

RevDate: 2019-12-06

de Las Fuentes L, Sung YJ, Sitlani CM, et al (2019)

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

The pharmacogenomics journal pii:10.1038/s41397-019-0132-y [Epub ahead of print].

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

RevDate: 2019-12-06

Bakht MK, Lovnicki JM, Tubman J, et al (2019)

Differential expression of glucose transporters and hexokinases in prostate cancer with a neuroendocrine gene signature: a mechanistic perspective for FDG imaging of PSMA-suppressed tumors.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine pii:jnumed.119.231068 [Epub ahead of print].

Purpose: Although the incidence of de novo neuroendocrine prostate cancer (NEPC) is rare, recent data suggests that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine (NE) hallmarks and androgen receptor (AR)-suppression in prostate cancer (PC). Previous clinical reports indicate that PCs with a phenotype similar to NE tumors can be more amenable to imaging by 18F-Fluorodeoxyglucose (FDG) rather than PSMA-targeting radioligands. In this study, we evaluated the association between NE gene signature and FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported FDG-avidity of PSMA-suppressed tumors. Methods: Data mining approaches, cell lines and patient-derived xenograft (PDX) models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes: HK1 to 3 and GCK) and PSMA (FOLH1 gene) following AR-inhibition and in correlation with NE hallmarks. Also, we characterize a NE-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no NE histopathology. We measured glucose uptake in a NE-induced in vitro model and a zebrafish model by non-radioactive imaging of glucose uptake using fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrates that a NE gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR-inhibitors, high expression of GCK and low expression of SLC2A12 correlated with NE histopathology and PSMA gene suppression. GLUT12-suppression and amplification of glucokinase was observed in NE-induced PC cell lines and PDX models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: NE gene signature in NEPC and NELPC associates with a distinct transcriptional profile of GLUTs and HKs. PSMA-suppression correlates with GLUT12-suppression and glucokinase-amplification. Alteration of FDG uptake-associated genes correlated positively with higher glucose uptake in AR and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient pre-clinical method for monitoring non-radioactive glucose uptake.

RevDate: 2019-12-06

Corella AN, Cabiliza Ordonio MVA, Coleman I, et al (2019)

Identification of Therapeutic Vulnerabilities in Small Cell Neuroendocrine Prostate Cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-0775 [Epub ahead of print].

PURPOSE: Small-cell neuroendocrine prostate cancer (SCNPC) exhibits an aggressive clinical course and incidence rates appear to be increasing following resistance to potent androgen receptor (AR) antagonists. Currently, treatment options are limited and few model systems are available to identify new approaches for treatment. We sought to evaluate commonalities between SCNPC and other aggressive neuroendocrine carcinomas to identify therapeutic targets.

EXPERIMENTAL DESIGN: We generated whole transcriptome RNAseq data from AR-active prostate cancers (ARPC) and SCNPCs from tumors collected at rapid autopsy, and two other NE carcinomas, Merkel Cell Carcinoma (MCC) and small-cell lung cancer (SCLC). We performed cross-tumor comparisons to identify conserved patterns of expression of druggable targets. We tested inhibitors to highly upregulated drug targets in a panel of PC cell lines and in vivo patient-derived xenograft (PDX) models.

RESULTS: We identified BCL2 as highly upregulated in SCNPC compared to ARPC. Inhibitors targeting BCL2 induced apoptotic cell death in SCNPC cell lines at nanomolar concentrations while ARPC cell lines were resistant. Treatment with the BCL2 inhibitor Navitoclax lead to a reduction of growth of SCNPC PDX tumors in vivo, while ARPC PDX models were more resistant. We identified Wee1 as a second druggable target upregulated in SCNPC. Treatment with the combination of Navitoclax and the Wee1 inhibitor AZD-1775 repressed the growth of SCNPC PDX resistant to single agent BCL2 inhibitors.

CONCLUSIONS: The combination of BCL2 and Wee1 inhibition presents a novel therapeutic strategy for the treatment of SCNPC.

RevDate: 2019-12-06

Bekker LG, Tatoud R, Dabis F, et al (2019)

The complex challenges of HIV vaccine development require renewed and expanded global commitment.

Lancet (London, England) pii:S0140-6736(19)32682-0 [Epub ahead of print].

RevDate: 2019-12-05

Ramsey SD, SB Dusetzina (2019)

Weighing Costs and Benefits in the Economics of Cancer Care.

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

RevDate: 2019-12-05

Bender Ignacio R, Ddungu H, TS Uldrick (2019)

Untangling the Effects of Chemotherapy and HIV on CD4 Counts-Implications for Immunotherapy in HIV and Cancer.

JAMA oncology pii:2757075 [Epub ahead of print].

RevDate: 2019-12-05

Stankiewicz Karita HC, Magaret A, Huang ML, et al (2019)

Quantitative oral HPV16 and HPV18 detection in persons attending dental clinics.

Sexually transmitted diseases [Epub ahead of print].

OBJECTIVE: To assess quantitative HPV16 and HPV18 detection in oral rinses obtained in dental offices in Seattle, Washington.

METHODS: We evaluated oral rinses collected during dental visits from 2016-2018. Multiplex TaqMan qPCR was used to determine HPV16 and HPV18 viral load (VL).

RESULTS: Of 15313 persons, 152 (1%) had detectable oral HPV16/18. Men were at higher risk of oral HPV16/18 infection than women (1.6% vs 0.6%; OR 3.2, 95%CI 2.1-4.4). Compared to women, men with HPV16 were older (median 55 vs 48 years, P< 0.001) and had higher VL (39.7 vs 1.1 copies/mL, P< 0.001). Of 39 with HPV16 at baseline and a second oral rinse, 13 remained positive at subsequent rinse; of 8 with HPV18 at baseline, 2 remained positive at subsequent rinse. Persons with consecutive positive tests were all men and had higher baseline VL compared to those with first positive and second negative samples.

CONCLUSION: Oral rinse is an acceptable method of HPV testing and persons are interested in testing. Overall HPV16/18 prevalence was low, and detection was more frequent among men than women, especially at higher copy numbers. HPV16 persistence was more common in men with high VL at baseline test. Future studies are needed to evaluate the feasibility of an effective secondary prevention strategy for oropharyngeal cancer using quantitative oral HPV detection.

RevDate: 2019-12-05

Woodward Davis AS, Roozen HN, Dufort MJ, et al (2019)

The human tissue-resident CCR5+ T cell compartment maintains protective and functional properties during inflammation.

Science translational medicine, 11(521):.

CCR5 is thought to play a central role in orchestrating migration of cells in response to inflammation. CCR5 antagonists can reduce inflammatory disease processes, which has led to an increased interest in using CCR5 antagonists in a wide range of inflammation-driven diseases. Paradoxically, these antagonists appear to function without negatively affecting host immunity at barrier sites. We reasoned that the resolution to this paradox may lie in the CCR5+ T cell populations that permanently reside in tissues. We used a single-cell analysis approach to examine the human CCR5+ T cell compartment in the blood, healthy, and inflamed mucosal tissues to resolve these seemingly contradictory observations. We found that 65% of the CD4 tissue-resident memory T (TRM) cell compartment expressed CCR5. These CCR5+ TRM cells were enriched in and near the epithelial layer and not only limited to TH1-type cells but also contained a large TH17-producing and a stable regulatory T cell population. The CCR5+ TRM compartment was stably maintained even in inflamed tissues including the preservation of TH17 and regulatory T cell populations. Further, using tissues from the CHARM-03 clinical trial, we found that CCR5+ TRM are preserved in human mucosal tissue during treatment with the CCR5 antagonist Maraviroc. Our data suggest that the human CCR5+ TRM compartment is functionally and spatially equipped to maintain barrier immunity even in the absence of CCR5-mediated, de novo T cell recruitment from the periphery.

RevDate: 2019-12-04

Parks KR, MacCamy AJ, Trichka J, et al (2019)

Overcoming Steric Restrictions of VRC01 HIV-1 Neutralizing Antibodies through Immunization.

Cell reports, 29(10):3060-3072.e7.

Broadly HIV-1 neutralizing VRC01 class antibodies target the CD4-binding site of Env. They are derived from VH1-2∗02 antibody heavy chains paired with rare light chains expressing 5-amino acid-long CDRL3s. They have been isolated from infected subjects but have not yet been elicited by immunization. Env-derived immunogens capable of binding the germline forms of VRC01 B cell receptors on naive B cells have been designed and evaluated in knockin mice. However, the elicited antibodies cannot bypass glycans present on the conserved position N276 of Env, which restricts access to the CD4-binding site. Efforts to guide the appropriate maturation of these antibodies by sequential immunization have not yet been successful. Here, we report on a two-step immunization scheme that leads to the maturation of VRC01-like antibodies capable of accommodating the N276 glycan and displaying autologous tier 2 neutralizing activities. Our results are relevant to clinical trials aiming to elicit VRC01 antibodies.

RevDate: 2019-12-04

Weigl K, Hsu L, Knebel P, et al (2019)

Head-to-Head Comparison of Family History of Colorectal Cancer and a Genetic Risk Score for Colorectal Cancer Risk Stratification.

Clinical and translational gastroenterology [Epub ahead of print].

OBJECTIVES: Family history (FH) is associated with increased risk of colorectal cancer (CRC). We aimed to examine the potential for CRC risk stratification by known common genetic variants beyond FH in a large population-based case-control study from Germany.

METHODS: Four thousand four hundred forty-seven cases and 3,480 controls recruited in 2003-2016 were included for whom comprehensive interview, medical, and genomic data were available. Associations with CRC risk were estimated from multiple logistic regression models for FH and a genetic risk score (GRS) based on 90 previously identified risk variants.

RESULTS: CRC in a first-degree relative was associated with a 1.71-fold (95% confidence interval 1.47-2.00) increase in CRC risk. A higher risk increase (odds ratio 2.06, 95% confidence interval 1.78-2.39) was estimated for the GRS when it was dichotomized at a cutoff yielding the same positivity rate as FH among controls. Furthermore, the GRS provides substantial additional risk stratification in both people with and especially without FH. Equal or even slightly higher risks were observed for participants without FH with a GRS in the upper 20% compared with participants with FH with a GRS below median. The observed patterns were confirmed in a replication study.

DISCUSSION: In contrast to common perception, known genetic variants do not primarily reflect some minor share of the familial excess risk of CRC, but rather reflect a substantial share of risk independent of FH.

RevDate: 2019-12-04

Hayek S, Gibson TM, Leisenring WM, et al (2019)

Prevalence and Predictors of Frailty in Childhood Cancer Survivors and Siblings: A Report From the Childhood Cancer Survivor Study.

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

PURPOSE: To estimate the prevalence of frailty among childhood cancer survivors and to determine the direct and indirect effects of treatment exposures, lifestyle factors, and severe, disabling, and life-threatening chronic condition on frailty.

METHODS: Childhood cancer survivors (≥ 5 years since diagnosis), treated between 1970 and 1999 when < 21 years old (n = 10,899; mean age, 37.6 ± 9.4 years; 48% male, 86% white) and siblings were included (n = 2,097; mean age, 42.9 ± 9.4 years). Frailty was defined as ≥ 3 of the following: low lean mass, exhaustion, low energy expenditure, walking limitations, and weakness. Generalized linear models were used to evaluate direct and indirect associations between frailty and treatment exposures, sociodemographic characteristics, lifestyle factors, and chronic condition.

RESULTS: The overall prevalence of frailty among survivors was 3 times higher compared with siblings (6.4%; 95% CI, 4.1% to 8.7%; v 2.2%; 95% CI, 1.2% to 3.2%). Survivors of CNS tumors (9.5%; 95% CI, 5.2% to 13.8%) and bone tumors (8.1%; 95% CI, 5.1% to 11.1%) had the highest prevalence of frailty. Survivors exposed to cranial radiation, pelvic radiation ≥ 34 Gy, abdominal radiation > 40 Gy, cisplatin ≥ 600 mg/m2, amputation, or lung surgery had increased risk for frailty. These associations were partially but not completely attenuated when sociodemographic characteristics, lifestyle factors, and chronic conditions were added to multivariable models. Cranial radiation (prevalence ratio [PR], 1.47; 95% CI, 1.20 to 1.76), pelvic radiation ≥ 34 Gy (PR, 1.46; 95% CI, 1.01 to 2.11), and lung surgery (PR, 1.75; 95% CI, 1.28 to 2.38) remained significant after sociodemographic, lifestyle, and chronic conditions were accounted for.

CONCLUSION: Childhood cancer survivors reported a higher prevalence of frailty compared with siblings. Radiation and lung surgery exposures were associated with increased risk for frailty. Interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to decrease the prevalence of frailty and preserve function in this at-risk population.

RevDate: 2019-12-04

Duong A, Sweet A, Jain R, et al (2019)

Clinically significant drug interaction: letermovir and voriconazole.

The Journal of antimicrobial chemotherapy pii:5652247 [Epub ahead of print].

RevDate: 2019-12-04

Fisher LH, J Wakefield (2019)

Ecological inference for infectious disease data, with application to vaccination strategies.

Statistics in medicine [Epub ahead of print].

Disease surveillance systems provide a rich source of data regarding infectious diseases, aggregated across geographical regions. The analysis of such ecological data is fraught with difficulties, and, unless care and suitable data summaries are available, will lead to biased estimates of individual-level parameters. We consider using surveillance data to study the impacts of vaccination. To catalog the problems of ecological inference, we start with an individual-level model, which contains familiar parameters, and derive an ecologically consistent model for infectious diseases in partially vaccinated populations. We compare with other popular model classes and highlight deficiencies. We explore the properties of the new model through simulation and demonstrate that, under standard assumptions, the ecological model provides less biased estimates. We then fit the new model to data collected on measles outbreaks in Germany from 2005-2007.

RevDate: 2019-12-04

Morsink LM, Bezerra ED, Othus M, et al (2019)

Comparative analysis of total body irradiation (TBI)-based and non-TBI-based myeloablative conditioning for acute myeloid leukemia in remission with or without measurable residual disease.

RevDate: 2019-12-04

An J, Gharahkhani P, Law MH, et al (2019)

Author Correction: Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases.

Nature communications, 10(1):5617 pii:10.1038/s41467-019-13526-2.

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

RevDate: 2019-11-21

Black A, Moncla LH, Laiton-Donato K, et al (2019)

Genomic epidemiology supports multiple introductions and cryptic transmission of Zika virus in Colombia.

BMC infectious diseases, 19(1):963.

BACKGROUND: Colombia was the second most affected country during the American Zika virus (ZIKV) epidemic, with over 109,000 reported cases. Despite the scale of the outbreak, limited genomic sequence data were available from Colombia. We sought to sequence additional samples and use genomic epidemiology to describe ZIKV dynamics in Colombia.

METHODS: We sequenced ZIKV genomes directly from clinical diagnostic specimens and infected Aedes aegypti samples selected to cover the temporal and geographic breadth of the Colombian outbreak. We performed phylogeographic analysis of these genomes, along with other publicly-available ZIKV genomes from the Americas, to estimate the frequency and timing of ZIKV introductions to Colombia.

RESULTS: We attempted PCR amplification on 184 samples; 19 samples amplified sufficiently to perform sequencing. Of these, 8 samples yielded sequences with at least 50% coverage. Our phylogeographic reconstruction indicates two separate introductions of ZIKV to Colombia, one of which was previously unrecognized. We find that ZIKV was first introduced to Colombia in February 2015 (95%CI: Jan 2015 - Apr 2015), corresponding to 5 to 8 months of cryptic ZIKV transmission prior to confirmation in September 2015. Despite the presence of multiple introductions, we find that the majority of Colombian ZIKV diversity descends from a single introduction. We find evidence for movement of ZIKV from Colombia into bordering countries, including Peru, Ecuador, Panama, and Venezuela.

CONCLUSIONS: Similarly to genomic epidemiological studies of ZIKV dynamics in other countries, we find that ZIKV circulated cryptically in Colombia. More accurately dating when ZIKV was circulating refines our definition of the population at risk. Additionally, our finding that the majority of ZIKV transmission within Colombia was attributable to transmission between individuals, rather than repeated travel-related importations, indicates that improved detection and control might have succeeded in limiting the scale of the outbreak within Colombia.

RevDate: 2019-12-03

Schroeder CM, HS Malik (2019)

Meiosis: How Gambling Chromosomes Beat the Rules.

Current biology : CB, 29(23):R1247-R1248.

Selfish centromeres exploit asymmetric female meiosis to drive non-Mendelian segregation in their favor. Using inherent differences in drive propensity between mouse chromosomes, a new study reveals how proteins that modify chromatin states and microtubule stability enable this selfish behavior.

RevDate: 2019-12-03

Loughren MJ, Kharasch ED, Kelton-Rehkopf MC, et al (2019)

Influence of St. John's Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects: A Randomized Clinical Trial.

Anesthesiology [Epub ahead of print].

The popular herbal medicine, St. John's wort, is a potent inducer of several cytochrome P450 enzymes, including CYP3A4, which plays a role in the metabolism of fentanyl. St. John's wort may also influence the expression of P-glycoprotein, which can alter the movement of drugs across the blood-brain barrier.

The pharmacokinetics and pharmacodynamics (pupillary diameter over time) were examined in volunteers before and after treatment with St. John's wort. No differences were seen, suggesting that this herbal medication does not influence the clinical behavior of fentanyl.

BACKGROUND: Patients often use complementary and alternative herbal medicines, hence, potential exists for adverse herb-drug interactions. Fentanyl is metabolized by hepatic CYP3A4 and considered transported by blood-brain barrier P-glycoprotein. Both disposition processes could be upregulated by the herbal St. John's wort. This investigation evaluated effects of St. John's wort on fixed-dose and apparent steady-state IV fentanyl pharmacokinetics, pharmacodynamics, and clinical effects.

METHODS: Healthy volunteers received a fentanyl fixed-dose infusion and an individually tailored target controlled infusion on separate days, before and after 30-day St. John's wort (300 mg thrice daily; n = 8) or placebo control (n = 8) in a randomized parallel-group design. Fentanyl plasma concentrations, pupil diameter, analgesic response to experimental pain (cold pressor), subjective side effects, and cognitive effects were measured. Plasma fentanyl concentrations and changes in pupil diameter were subjected to pharmacokinetic-pharmacodynamic modeling.

RESULTS: St. John's wort did not alter fentanyl pharmacokinetics. Clearance (l/min) before and after St. John's wort (1.13 ± 0.29 and 1.24 ± 0.26, respectively) or placebo (0.96 ± 0.28 and 1.12 ± 0.27, respectively) were not different. St. John's wort also did not affect fentanyl pharmacodynamics as measured by pupil constriction after fixed-dose and tailored fentanyl infusions. EC50 (ng/ml) was 1.1 ± 0.7 and 1.4 ± 0.9 before and after St. John's wort versus 1.2 ± 0.8 and 1.4 ± 1.7 before and after placebo. Effect site equilibration time, T½,ke0 (min), was 12.8 ± 5.3 and 11.3 ± 6.4 before and after St. John's wort versus 11.4 ± 6.4 and 11.1 ± 5.6 before and after placebo. St. John's wort had no influence on analgesia, cognitive performance, or somatic cognitive-affective effects of fentanyl.

CONCLUSIONS: St. John's wort did not alter fentanyl pharmacokinetics, pharmacodynamics or clinical effects, suggesting no effect on hepatic clearance or blood-brain barrier efflux. Patients taking St. John's wort will likely not respond differently to IV fentanyl for anesthesia or analgesia.

RevDate: 2019-12-03

Schonfeld SJ, Howell RM, Smith SA, et al (2019)

Comparison of Radiation Dose Reconstruction Methods to Investigate Late Adverse Effects of Radiotherapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

Radiation research [Epub ahead of print].

Quantification of radiation dose to normal tissue during radiotherapy is critical for assessing risk for radiotherapy-related late effects, including subsequent neoplasms (SNs). Case-control studies of SNs typically reconstruct absorbed radiation dose to the specific SN location using individual treatment parameters. A simplified method estimates the maximum prescribed target dose to the body region in which the SN arises. We compared doses and risk estimates from these methods using data from case-control studies of subsequent brain tumors (64 cases, 244 controls) and breast cancer (94 cases, 358 controls) nested within the Childhood Cancer Survivor Study (≥5-year survivors of childhood cancer diagnosed 1970-1986). The weighted kappa statistic [95% confidence interval (CI)] evaluating agreement between categorical (>0-9.9/10-19.9/20-29.9/≥30 Gy) body-region and tumor location-specific doses was 0.95 (0.91-0.98) for brain and 0.76 (0.69-0.82) for breast. The body-region and location-specific doses were assigned to the same dose category for a smaller proportion of patients treated with fields delivering a heterogeneous dose across the tissue of interest (e.g., partial brain field = 57.1%; mantle field = 61.3%) than patients treated with fields delivering a more homogeneous dose (e.g., whole brain field = 100%). Excess odds ratios per Gy (95% CI) from conditional logistic regression were 1.25 (0.33-6.33) and 1.20 (0.31-6.14) for brain tumors and 0.21 (0.05-0.77) and 0.10 (0.02-0.44) for breast cancer, using location-specific and body-region doses, respectively. We observed that body-region doses can approximate location-specific doses when the tissue of interest is clearly in the radiation field or outside the treated body region. Agreement is lower when there is greater ambiguity of SN location relative to the treatment field.

RevDate: 2019-12-03

Sivay MV, Grabowski MK, Zhang Y, et al (2019)

Phylogenetic Analysis of Human Immunodeficiency Virus from People Who Inject Drugs in Indonesia, Ukraine, and Vietnam: HPTN 074.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5651189 [Epub ahead of print].

BACKGROUND: HIV Prevention Trials Network (HPTN) 074 evaluated human immunodeficiency virus (HIV) prevention interventions for people who inject drugs (PWID) in Indonesia, Ukraine, and Vietnam. Study interventions included support for HIV infection and substance use treatment. The study enrolled index participants living with HIV and injection partners who were not living with HIV. Seven partners acquired HIV infection during the study (seroconverters). We analyzed the phylogenetic relatedness between HIV strains in the cohort and the multiplicity of infection in seroconverters.

METHODS: Pol region consensus sequences were used for phylogenetic analysis. Data from next-generation sequencing (NGS, env region) were used to evaluate genetic linkage of HIV from the 7 seroconverters and the corresponding index participants (index-partner pairs), to analyze HIV from index participants in pol sequence clusters, and to analyze multiplicity of HIV infection.

RESULTS: Phylogenetic analysis of pol sequences from 445 index participants and 7 seroconverters identified 18 sequence clusters (2 index-partner pairs, 1 partner-partner pair, and 15 index-only groups with 2-7 indexes/cluster). Analysis of NGS data confirmed linkage for the 2 index-partner pairs, the partner-partner pair, and 11 of the 15 index-index clusters. The remaining 5 seroconverters had infections that were not linked to the corresponding enrolled index participant. Three (42.9%) of the 7 seroconverters were infected with more than 1 HIV strain (3-8 strains per person).

CONCLUSIONS: We identified complex patterns of HIV clustering and linkage among PWID in 3 communities. This should be considered when designing strategies for HIV prevention for PWID.


RevDate: 2019-12-03

Chemaly RF, Dadwal SS, Bergeron A, et al (2019)

A phase 2, randomized, double-blind, placebo-controlled trial of presatovir for the treatment of respiratory syncytial virus upper respiratory tract infection in hematopoietic-cell transplant recipients.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5651198 [Epub ahead of print].

BACKGROUND: Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind phase 2 trial in HCT recipients with RSV upper respiratory tract infection (URTI).

METHODS: Patients were randomized, stratified by lymphopenia (<200/µL) and ribavirin use, to receive oral presatovir 200 mg or placebo on days 1, 5, 9, 13, and 17, and followed through day 28. The coprimary efficacy endpoints were time-weighted average change in nasal RSV viral load between days 1 and 9, and proportion of patients developing lower respiratory tract complications (LRTC) through day 28.

RESULTS: From January 23, 2015, to June 16, 2017, 189 patients were randomized (96 presatovir, 93 placebo). Presatovir vs placebo treatment did not significantly affect (prespecified α = 0.01) time-weighted average decline in RSV viral load from day 1 to 9 (treatment difference: -0.33 log10 copies/mL; 95% CI: -0.64, -0.02 log10 copies/mL; p = 0.040) or progression to LRTC (11.2% vs 19.5%; odds ratio [95% CI], 0.50 [0.22, 1.18]; p = 0.11). In post hoc analysis among patients with lymphopenia, presatovir vs placebo treatment decreased LRTC development by day 28 (2/15 [13.3%] vs 9/14 [64.3%], p = 0.008). Adverse events were similar for patients receiving presatovir vs placebo.

CONCLUSIONS: Presatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia.

RevDate: 2019-12-03

Neufeld LM, García-Guerra A, Quezada AD, et al (2019)

A Fortified Food Can Be Replaced by Micronutrient Supplements for Distribution in a Mexican Social Protection Program Based on Results of a Cluster-Randomized Trial and Costing Analysis.

The Journal of nutrition, 149(Supplement_1):2302S-2309S.

BACKGROUND: Despite positive nutrition impacts, the prevalence of malnutrition among beneficiaries of Mexico's conditional cash transfer (CCT) program remains high. Greater nutrition impact may have been constrained by the type of nutritional supplements provided.

OBJECTIVE: The objective of this study was to inform a potential modification to the supplements distributed to pregnant and lactating women and children.

METHODS: Impact was assessed using 2 cluster-randomized trials (pregnant women, children) run simultaneously. Communities (n = 54) were randomly assigned to the fortified foods provided by the program (Nutrivida women, Nutrisano children) or alternatives: tablets (women), syrup (children), or micronutrient powders for women (MNP-W) and children (MNP-C). Each supplement for women/children contained the same micronutrients based on the formulations of Nutrivida and Nutrisano, respectively. Pregnant women (aged >18 y) were recruited before 25 weeks of gestation and followed to 3 mo postpartum. Children aged 6-12 mo were recruited and followed to age 24 mo. Primary outcomes were anemia for women and length growth for children. Statistical analyses appropriate for cluster-randomized designs were used, and structural equation modeling to estimate dose-response effects. Supplement costs per beneficiary (daily dose for 18 mo) were estimated for production and distribution.

RESULTS: There was no significant difference in change of anemia prevalence between supplement groups in women, or in length growth between groups in children. One daily dose of any supplement was associated with 0.8 cm greater length growth. From baseline to age 24 mo, the prevalence of anemia in the Nutrisano, syrup, and MNP-C groups decreased by 36.7, 40.8, and 37.9 percentage points, respectively (within-group, P < 0.05; between groups, P > 0.05). Costs per beneficiary ranged from $12.1 (MNP-C) to $94.8 (Nutrivida).

CONCLUSIONS: The CCT program could distribute alternative supplements at lower cost per beneficiary without compromising potential for impact. Acceptance among beneficiaries should also be considered in choice of alternatives. This trial was registered at www.clinicaltrials.gov as NCT00531674.

RevDate: 2019-12-03

Ene CI, Kreuser SA, Jung M, et al (2019)

Anti-PD-L1 antibody direct activation of macrophages contributes to a radiation-induced abscopal response in glioblastoma.

Neuro-oncology pii:5650878 [Epub ahead of print].

BACKGROUND: Most glioblastoma recurrences occur near prior radiation treatment sites. Future clinical success will require achieving and optimizing an 'abscopal effect', whereby un-irradiated neoplastic cells outside treatment sites are recognized and attacked by the immune system. Radiation combined with anti-PD-L1 demonstrated modest efficacy in phase II human glioblastoma clinical trials, but the mechanism and relevance of the abscopal effect during this response remains unknown.

METHODS: We modified an immune-competent, genetically-driven mouse glioma model (forced PDGF expression + PTEN loss) where a portion of the tumor burden is irradiated (PDGF) and another un-irradiated luciferase expressing tumor (PDGF+Luciferase) is used as a readout of the abscopal effect following systemic anti-PD-L1 immunotherapy. We assessed relevance of tumor neoepitope during the abscopal response by inducing expression of EGFRvIII (PDGF+EGFRvIII). Statistical tests were two-sided.

RESULTS: Following radiation of one lesion, anti-PD-L1 immunotherapy enhanced the abscopal response to the un-irradiated lesion. In PDGF-driven gliomas without tumor neoepitope (PDGF+Luciferase, n=8), the abscopal response occurred via anti-PD-L1-driven, ERK-mediated, bone marrow-derived macrophage phagocytosis of adjacent un-irradiated tumor cells, with modest survival implications (median survival 41 days vs. radiation alone 37.5 days, P=.03). In PDGF-driven gliomas with tumor neoepitope (PDGF+EGFRvIII, n=8), anti-PD-L1-enhanced abscopal response was associated with macrophage and T-cell infiltration and increased survival benefit (median survival 36 days vs. radiation alone 28 days, P=.001).

CONCLUSION: Our results indicate that anti-PD-L1 immunotherapy enhances a radiation induced abscopal response via canonical T-cell activation and direct macrophage activation in glioblastoma.

RevDate: 2019-12-03

Amezquita RA, Lun ATL, Becht E, et al (2019)

Orchestrating single-cell analysis with Bioconductor.

Nature methods pii:10.1038/s41592-019-0654-x [Epub ahead of print].

Recent technological advancements have enabled the profiling of a large number of genome-wide features in individual cells. However, single-cell data present unique challenges that require the development of specialized methods and software infrastructure to successfully derive biological insights. The Bioconductor project has rapidly grown to meet these demands, hosting community-developed open-source software distributed as R packages. Featuring state-of-the-art computational methods, standardized data infrastructure and interactive data visualization tools, we present an overview and online book (https://osca.bioconductor.org) of single-cell methods for prospective users.

RevDate: 2019-12-03

McLaughlin K, Hedden L, Pollock P, et al (2019)

Assessing the nutritional needs of men with prostate cancer.

Nutrition journal, 18(1):81 pii:10.1186/s12937-019-0506-7.

BACKGROUND: Nutrition is important for prostate cancer (PC) survivorship care to help achieve a healthy weight, reduce treatment side effects and reduce the risk of developing other chronic diseases. We aimed to advance the understanding of the nutritional needs of men with PC and services that could be potentially implemented to address them.

METHODS: We conducted a needs assessment of nutrition services for men with PC drawing on four perspectives; 1) patient evaluation of a nutrition education session in British Columbia (BC), 2) survey of BC health professionals, 3) an environmental scan of existing nutrition services across Canada and 4) a scoping literature review.

RESULTS: Patients expressed a need for more nutrition information and a desire for additional nutrition services. More than 60% of health professionals believed there is a need for more nutrition services for men with PC, and reported the focus should be on weight management or management of PC progression. The environmental scan revealed few existing services for men with PC across Canada, most were inclusive of multiple cancers and not tailored for men with PC. Eighteen completed studies were identified in the scoping literature review. The majority provided combined diet and exercise programs with various formats of delivery such as individual, group and home-based. Overall, 78% of studies reported improvements in one or more of the following measures: dietary intake/ diet quality, body composition, self-efficacy, quality of life, fatigue, practicing health behavior goals and physical function/ exercise. Four studies assessed feasibility, adherence or satisfaction with all reporting positive findings.

CONCLUSION: Despite the high prevalence of PC in Canada, and the perceived need for more support by patients and health professionals, there are limited nutrition services for men with PC. Evidence from the literature suggests nutrition services are effective and well-accepted by men with PC. Our findings define a need for standardized nutrition services for men with PC that assess and meet long term nutritional needs. Our findings also provide insight into the type and delivery of nutrition services that may help close the gap in care for men with PC.

RevDate: 2019-11-30

Lipira L, Rao D, Nevin PE, et al (2019)

Patterns of alcohol use and associated characteristics and HIV-related outcomes among a sample of African-American women living with HIV.

Drug and alcohol dependence, 206:107753 pii:S0376-8716(19)30530-7 [Epub ahead of print].

BACKGROUND: Alcohol use is common among people living with HIV and negatively impacts care and outcomes. African-American women living with HIV are subject to vulnerabilities that may increase risk for alcohol use and associated HIV-related outcomes.

METHODS: We used baseline data from a randomized controlled trial of an HIV-related stigma-reduction intervention among African-American women living with HIV in Chicago and Birmingham (2013-2015). Patterns of alcohol use [any use, unhealthy alcohol use (UAU), heavy episodic drinking (HED)] were measured using the AUDIT-C. We assessed demographic, social, and clinical characteristics which may influence alcohol use and HIV-related outcomes which may be influenced by patterns of alcohol use in bivariate and multivariable analyses.

RESULTS: Among 220 African-American women living with HIV, 54 % reported any alcohol use, 24 % reported UAU, and 27 % reported HED. In bivariate analysis, greater depressive symptoms, lower religiosity, lower social support, marijuana, and crack/cocaine use were associated with patterns of alcohol use (p < 0.05). Marijuana and cocaine/crack use were associated with patterns of alcohol use in adjusted analysis (p < 0.05). In adjusted analysis, any alcohol use and HED were associated with lower likelihood of ART adherence (ARR = 0.72, 95 % CI: 0.53-0.97 and ARR = 0.65, 95 % CI: 0.44-0.96, respectively), and UAU was associated with lack of viral suppression (ARR = 0.78, 95 % CI: 0.63-0.96).

CONCLUSIONS: Findings suggest any and unhealthy alcohol use is common and associated with poor HIV-related outcomes in this population. Regular alcohol screening and intervention should be offered, potentially targeted to subgroups (e.g., those with other substance use).

RevDate: 2019-11-30

Braun TP, Okhovat M, Coblentz C, et al (2019)

Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia.

Nature communications, 10(1):5455 pii:10.1038/s41467-019-13364-2.

Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of a subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.

RevDate: 2019-11-30

Chen H, Carrot-Zhang J, Zhao Y, et al (2019)

Genomic and immune profiling of pre-invasive lung adenocarcinoma.

Nature communications, 10(1):5472 pii:10.1038/s41467-019-13460-3.

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.

RevDate: 2019-11-29

Taguchi K, TW Kensler (2019)

Nrf2 in liver toxicology.

Archives of pharmacal research pii:10.1007/s12272-019-01192-3 [Epub ahead of print].

Liver plays essential roles in the metabolism of many endogenous chemicals and exogenous toxicants. Mechanistic studies in liver have been at the forefront of efforts to probe the roles of bioactivation and detoxication of environmental toxins and toxicants in hepatotoxicity. Moreover, idiosyncratic hepatoxicity remains a key barrier in the clinical development of drugs. The now vast Nrf2 field emerged in part from biochemical and molecular studies on chemical inducers of hepatic detoxication enzymes and subsequent characterization of the modulation of drug/toxicant induced hepatotoxicities in mice through disruption of either Nrf2 or Keap1 genes. In general, loss of Nrf2 increases the sensitivity to such toxic chemicals, highlighting a central role of this transcription factor and its downstream target genes as a modifier to chemical stress. In this review, we summarize the impact of Nrf2 on the toxicology of multiple hepatotoxicants, and discuss efforts to utilize the Nrf2 response in predictive toxicology.

RevDate: 2019-11-29

Lee YA, Al-Temimi M, Ying J, et al (2019)

Head and Neck Cancer Risk Prediction Models for the US Population from the INHANCE Consortium.

American journal of epidemiology pii:5628899 [Epub ahead of print].

Head and neck cancer (HNC) risk prediction models based on risk factor profiles have not yet been developed. We took advantage of the large database including 14 studies (1981-2010) in the US from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium to develop risk prediction models. Seventy percent of the data were used to develop HNC risk prediction models; the remaining 30% were used to validate the models. We used competing risk models to calculate absolute risks. The predictors included age, sex, education, race/ethnicity, alcohol drinking intensity, cigarette smoking duration and intensity or family history of HNC. The 20-year absolute HNC risk was 7.61% for a 60-year-old woman who smoked >20 cigarettes/day for >20 years, drank 3+ alcoholic drinks/day, was a high school graduate, with family history of HNC and was non-Hispanic White. The 20-year risk for men with a similar profile was 6.85%. The absolute risks of oropharyngeal and hypopharyngeal cancers were generally lower than those of oral cavity and laryngeal cancers. The AUC statistics were 0.70 or higher except for oropharyngeal cancer in men. The HNC risk prediction model may be useful in promoting healthier behaviors such as smoking cessation, or in aiding individuals with family history of HNC to evaluate their risks.

RevDate: 2019-11-29

Appelbaum FR (2019)

Maintenance therapy after allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

Best practice & research. Clinical haematology, 32(4):101109.

With improvements in the safety of allogeneic hematopoietic cell transplantation, disease recurrence following the procedure is now the most frequent reason for treatment failure. Administration of maintenance therapy after transplantation is one way to try and prevent recurrence. This paper provides a brief review of the topic.

RevDate: 2019-11-28

Ikuta K, Roychoudhury P, Xie H, et al (2019)

Trillions and Trillions: Herpes Simplex Virus-1 Hepatitis in an Immunocompetent Adult.

Open forum infectious diseases, 6(11):ofz465 pii:ofz465.

We describe a case of acute liver failure and myopericarditis due to herpes simplex virus-1 (HSV-1) in an immunocompetent adult. We estimate that, at the height of viremia, the patient contained a quantity of HSV-1 virions approaching that of human cells. The patient recovered with acyclovir that was dose-adjusted for neurotoxicity and developed a vigorous anti-HSV-1 T-cell response.

RevDate: 2019-11-28

DeLucia DC, JK Lee (2020)

Identification of Cell Surface Targets for CAR T Cell Immunotherapy.

Methods in molecular biology (Clifton, N.J.), 2097:45-54.

Immunotherapy has become a prominent approach for the treatment of cancer. Targeted killing of malignant cells by adoptive transfer of chimeric antigen receptor (CAR) T cells is a promising immunotherapy technique in oncology. However, the identification of cell surface antigens unique to tumor cells against which CAR T cells can be engineered has historically been challenging and not well documented in solid tumors. Here, we describe a generalized method to construct a cell subtype-specific surface antigen profile (i.e., surfaceome) from cell lines and identify high-confidence antigens as effective targets for CAR T cell therapy by integrating transcriptomics and cell surface proteomics. This method is widely applicable to all therapies utilizing CAR T cells, such as cancer, as well as infectious and autoimmune diseases.

RevDate: 2019-11-28

Harrington WE, Mató S, Burroughs L, et al (2019)

Vaccine Oka Varicella Meningitis in Two Adolescents.

Pediatrics pii:peds.2019-1522 [Epub ahead of print].

The live-attenuated varicella vaccine, a routine immunization in the United States since 1995, is both safe and effective. Like wild-type varicella-zoster virus, however, vaccine Oka (vOka) varicella can establish latency and reactivate as herpes zoster, rarely leading to serious disease, particularly among immunocompromised hosts. Previous cases of reactivated vOka resulting in meningitis have been described in young children who received a single dose of varicella vaccine; less is known about vOka reactivation in older children after the 2-dose vaccine series. We present 2 adolescents with reactivated vOka meningitis, 1 immunocompetent and 1 immunocompromised, both of whom received 2 doses of varicella vaccine many years before as children. Pediatricians should be aware of the potential of vOka varicella to reactivate and cause clinically significant central nervous system disease in vaccinated children and adolescents.

RevDate: 2019-11-28

Mason C, de Dieu Tapsoba J, Duggan C, et al (2019)

Eating behaviors and weight loss outcomes in a 12-month randomized trial of diet and/or exercise intervention in postmenopausal women.

The international journal of behavioral nutrition and physical activity, 16(1):113 pii:10.1186/s12966-019-0887-1.

BACKGROUND: Certain eating behaviors are common among women with obesity. Whether these behaviors influence outcomes in weight loss programs, and whether such programs affect eating behaviors, is unclear.

METHODS: Our aim was to examine the effect of baseline eating behaviors on intervention adherence and weight among postmenopausal women with overweight or obesity, and to assess intervention effects on eating behaviors. Four hundred and 39 women (BMI ≥25 kg/m2) were randomized to 12 months of: i) dietary weight loss with a 10% weight loss goal ('diet'; n = 118); ii) moderate-to-vigorous intensity aerobic exercise for 225 mins/week ('exercise'; n = 117); iii) combined dietary weight loss and exercise ('diet + exercise'; n = 117); or iv) no-lifestyle change control (n = 87). At baseline and 12 months, restrained eating, uncontrolled eating, emotional eating and binge eating were measured by questionnaire; weight and body composition were assessed. The mean change in eating behavior scores and weight between baseline and 12 months in the diet, exercise, and diet + exercise arms were each compared to controls using the generalized estimating equation (GEE) modification of linear regression adjusted for age, baseline BMI, and race/ethnicity.

RESULTS: Baseline restrained eating was positively associated with change in total calories and calories from fat during the dietary intervention but not with other measures of adherence. Higher baseline restrained eating was associated with greater 12-month reductions in weight, waist circumference, body fat and lean mass. Women randomized to dietary intervention had significant reductions in binge eating (- 23.7%, p = 0.005 vs. control), uncontrolled eating (- 24.3%, p < 0.001 vs. control), and emotional eating (- 31.7%, p < 0.001 vs. control) scores, and a significant increase in restrained eating (+ 60.6%, p < 0.001 vs. control); women randomized to diet + exercise reported less uncontrolled eating (- 26.0%, p < 0.001 vs. control) and emotional eating (- 22.0%, p = 0.004 vs. control), and increased restrained eating (+ 41.4%, p < 0.001 vs. control). Women randomized to exercise alone had no significant change in eating behavior scores compared to controls.

CONCLUSIONS: A dietary weight loss intervention helped women modify eating behaviors. Future research should investigate optimal behavioral weight loss interventions for women with both disordered eating and obesity.

TRIAL REGISTRATION: NCT00470119 (https://clinicaltrials.gov). Retrospectively registered May 7, 2007.

RevDate: 2019-11-27

Heffner JL, Watson NL, Serfozo E, et al (2019)

A Behavioral Activation Mobile Health App for Smokers With Depression: Development and Pilot Evaluation in a Single-Arm Trial.

JMIR formative research, 3(4):e13728 pii:v3i4e13728.

BACKGROUND: The integration of Behavioral Activation Treatment for Depression (BAT-D) into smoking cessation interventions is a promising approach to address depression as a barrier to quitting. However, this approach has only been tested as a face-to-face intervention, which has low reach.

OBJECTIVE: The aims of the study were to develop a BAT-D mobile health app with high potential reach and determine its feasibility, acceptability, and preliminary effects on theory-based behavioral processes of behavioral activation, reduced depressive symptoms, and smoking cessation.

METHODS: Following a user-centered design process consisting of competitive analysis, focus groups, and prototype testing, we conducted a single-arm pilot trial of Actify!, a BAT-D app for depressed smokers. Participants used SmokefreeTXT along with Actify! to provide cessation content that had not yet been built into the app for this initial phase of pilot testing. Participants in the trial were current, daily smokers with mild to moderate depressive symptoms. We examined use outcomes for all enrolled participants and process and cessation outcomes at 6 weeks postenrollment for study completers (16/17, 94% retention).

RESULTS: Regarding acceptability, average number of log-ins per participant was 16.6 (SD 13.7), and 63% (10/16) reported being satisfied overall with the app. Posttreatment interviews identified some usability challenges (eg, high perceived burden of planning and scheduling values-based activities). There was a significant decrease in depressive symptoms from baseline to follow-up (mean change in Patient Health Questionnaire-9 scores was -4.5, 95% CI -7.7 to -1.3; P=.01). Additionally, carbon monoxide (CO)-confirmed, 7-day point prevalence abstinence (PPA) at 6-week follow-up was 31% (5/16), and the 30-day PPA was 19% (3/16).

CONCLUSIONS: Results demonstrate promising engagement with Actify! and potential for impact on theory-based change processes and cessation outcomes. Preliminary quit rates compare favorably to previous trials of smoking cessation apps for the general population (ie, short-term, self-reported 30-day quit rates in the 8% to 18% range) and a previous trial of face-to-face BAT-D for depressed smokers (ie, CO-confirmed, 7-day PPA rate of 17% at end of treatment).

RevDate: 2019-11-27

Huang Y, XH Zhou (2019)

Identification of the optimal treatment regimen in the presence of missing covariates.

Statistics in medicine [Epub ahead of print].

Covariates associated with treatment-effect heterogeneity can potentially be used to make personalized treatment recommendations towards best clinical outcomes. Methods for treatment-selection rule development that directly maximize treatment-selection benefits have attracted much interest in recent years, due to the robustness of these methods to outcome modeling. In practice, the task of treatment-selection rule development can be further complicated by missingness in data. Here, we consider the identification of optimal treatment-selection rules for a binary disease outcome when measurements of an important covariate from study participants are partly missing. Under the missing at random assumption, we develop a robust estimator of treatment-selection rules under the direct-optimization paradigm. This estimator targets the maximum selection benefits to the population under correct specification of at least one mechanism from each of the two sets-missing data or conditional covariate distribution, and treatment assignment or disease outcome model. We evaluate and compare performance of the proposed estimator with alternative direct-optimization estimators through extensive simulation studies. We demonstrate the application of the proposed method through a real data example from an Alzheimer's disease study for developing covariate combinations to guide the treatment of Alzheimer's disease.

RevDate: 2019-11-27

Trebelcock WL, Lama JR, Duerr A, et al (2019)

HIV pretreatment drug resistance among cisgender MSM and transgender women from Lima, Peru.

Journal of the International AIDS Society, 22(11):e25411.

INTRODUCTION: Transmitted, or any pretreatment drug resistance (TDR, PDR) can compromise efficacy of first-line antiretroviral therapy (ART). In Peru, genotypic resistance testing is not routinely performed before ART initiation, and estimated PDR prevalence prior to 2012 ranged from 1.0% to 4.7%. We aimed to update estimates of PDR prevalence in men who have sex with men (cis-MSM) and transgender women (TW).

METHODS: We obtained HIV sequences from three studies of ART-naïve cisgender-MSM and TW (n = 470) in Lima, Peru from 2013 to 2017, almost two-thirds of whom had acute or recent infections. Sanger sequences of HIV pol were interrogated for surveillance drug resistance mutations (SDRM) using the Stanford Calibrated Population Resistance (CPR) tool and scored for resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) with the HIVdb programme. We calculated binomial proportions and 95% confidence intervals. χ2 and exact or trend tests were used to examine predictors of PDR.

RESULTS: Seventy-seven (16.4%) individuals had PDR (95% CI: 13.2 to 20.0); most resistance was likely TDR since 63% were incident infections. SDRM were present in 9.8% (7.3 to 12.9). Resistance to any NRTI was present in <1% of individuals, while efavirenz resistance was present in 10% (6.9% to 12.4%). TW were not statistically more likely than cis-MSM to have PDR (11.4% vs. 9.1%, p = 0.54). Age, incident versus prevalent infection, or residence district did not predict PDR. Prevalence of SDRM increased from 3% in 2013 to 21% 2017 within incident infections (p = 0.04), but not when including prevalent infections.

CONCLUSIONS: Prevalence of NNRTI resistance in three studies of ART-naïve MSM and TW in Lima, Peru reaches 10%. Because our study reports PDR in a population in which most acquired HIV recently, the overall prevalence of PDR, including previously treated persons, is likely underestimated. These results underscore the need for a nationally representative survey of PDR in Peru and consideration of non-NNRTI anchored first-line ART options. This study also represents the first evaluation of PDR in cis-MSM versus TW in South America, and demonstrates that, although TW are at higher risk of acquiring HIV, they are at similar risk of acquiring a virus with resistance mutations.

RevDate: 2019-11-27

Li A, Wu Q, Warnick G, et al (2019)

The incidence of thromboembolism for lenalidomide versus thalidomide in older patients with newly diagnosed multiple myeloma.

Annals of hematology pii:10.1007/s00277-019-03860-2 [Epub ahead of print].

It is uncertain if different immunomodulatory drugs (IMID) pose distinct thrombotic risk in patients with newly diagnosed multiple myeloma (MM). Among 2397 MM patients from the SEER-Medicare database from 2007 to 2013, 78% received lenalidomide, and 22% received thalidomide. After inverse probability weighting to balance confounders, the 12-month incidences of venous thromboembolism (VTE 10%) and arterial thromboembolism (ATE 5%) were similarly high in both groups. Lenalidomide versus thalidomide had a subdistribution hazard ratio of 1.11 (0.59-2.02) for VTE and a subdistribution hazard ratio of 0.96 (0.45-1.98) for ATE. Overall survival was not significantly different with a hazard ratio of 0.88 (0.60-1.18) for lenalidomide versus thalidomide. Concurrent anticoagulant prophylaxis was infrequently prescribed in < 20% of both groups. Our study demonstrates that despite improvement in myeloma-directed therapy and supportive care, thrombosis remains an important consideration for all IMID-treated MM patients. Appropriate risk stratification and vigilant thromboprophylaxis remain essential to prevent this complication.

RevDate: 2019-11-27

Rodriguez S, Abundis C, Boccalatte F, et al (2019)

Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL.

Leukemia pii:10.1038/s41375-019-0653-z [Epub ahead of print].

Timed degradation of the cyclin-dependent kinase inhibitor p27Kip1 by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27Kip1 pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).

RevDate: 2019-11-27

Rajawat YS, Humbert O, HP Kiem (2019)

In-Vivo Gene Therapy with Foamy Virus Vectors.

Viruses, 11(12): pii:v11121091.

Foamy viruses (FVs) are nonpathogenic retroviruses that infect various animals including bovines, felines, nonhuman primates (NHPs), and can be transmitted to humans through zoonotic infection. Due to their non-pathogenic nature, broad tissue tropism and relatively safe integration profile, FVs have been engineered as novel vectors (foamy virus vector, FVV) for stable gene transfer into different cells and tissues. FVVs have emerged as an alternative platform to contemporary viral vectors (e.g., adeno associated and lentiviral vectors) for experimental and therapeutic gene therapy of a variety of monogenetic diseases. Some of the important features of FVVs include the ability to efficiently transduce hematopoietic stem and progenitor cells (HSPCs) from humans, NHPs, canines and rodents. We have successfully used FVV for proof of concept studies to demonstrate safety and efficacy following in-vivo delivery in large animal models. In this review, we will comprehensively discuss FVV based in-vivo gene therapy approaches established in the X-linked severe combined immunodeficiency (SCID-X1) canine model.

RevDate: 2019-11-27

Navarro SL, Levy L, Curtis KR, et al (2019)

Modulation of Gut Microbiota by Glucosamine and Chondroitin in a Randomized, Double-Blind Pilot Trial in Humans.

Microorganisms, 7(12): pii:microorganisms7120610.

Glucosamine and chondroitin (G&C), typically taken for joint pain, are among the most frequently used specialty supplements by US adults. More recently, G&C have been associated with lower incidence of colorectal cancer in human observational studies and reduced severity of experimentally-induced ulcerative colitis in rodents. However, little is known about their effects on colon-related physiology. G&C are poorly absorbed and therefore metabolized by gut microbiota. G&C have been associated with changes in microbial structure, which may alter host response. We conducted a randomized, double-blind, placebo-controlled crossover trial in ten healthy adults to evaluate the effects of a common dose of G&C compared to placebo for 14 days on gut microbial community structure, measured by 16S rRNA gene sequencing. Linear mixed models were used to evaluate the effect of G&C compared to placebo on fecal microbial alpha and beta diversity, seven phyla, and 137 genera. Nine genera were significantly different between interventions (False Discovery Rate < 0.05). Abundances of four Lachnospiraceae genera, two Prevotellaceae genera, and Desulfovibrio were increased after G&C compared to placebo, while Bifidobacterium and a member of the Christensenellaceae family were decreased. Our results suggest that G&C affect the composition of the gut microbiome which may have implications for therapeutic efficacy.

RevDate: 2019-11-20

Bochner AF, Secor WE, Baeten JM, et al (2019)

Schistosomiasis was not associated with higher HIV-1 plasma or genital set point viral loads among HIV seroconverters from four cohort studies.

PLoS neglected tropical diseases, 13(11):e0007886 pii:PNTD-D-19-00579.

BACKGROUND: Many regions of sub-Saharan Africa experience a high prevalence of both schistosomiasis and HIV-1, leading to frequent coinfection. Higher plasma HIV-1 viral loads are associated with faster disease progression and genital HIV-1 loads are a primary determinant of HIV-1 transmission risk. We hypothesized that schistosome infection would be associated with higher HIV-1 viral loads in plasma and genital samples.

METHODS/PRINCIPAL FINDINGS: We utilized data from individuals who HIV-1 seroconverted while enrolled in one of four prospective cohort studies. Plasma and genital viral loads collected 4-24 months after the estimated date of HIV-1 acquisition, but prior to antiretroviral therapy initiation, were included. Detection of circulating anodic antigen in archived blood samples, collected prior to HIV-1 seroconversion, identified participants with active schistosomiasis; immunoblots determined the schistosome species causing infection. Our analysis included 370 HIV-1 seroconverters with plasma viral load results, of whom 82 (22%) had schistosomiasis. We did not find a statistically significant association between schistosomiasis and higher HIV-1 set point plasma viral loads (-0.17 log10 copies/ml, 95% CI -0.38 to 0.03); S. mansoni infection was associated with a lower set point (-0.34 log10 copies/ml, 95% CI -0.58 to -0.09). We found no association between schistosomiasis and cervical (+0.07 log10 copies/swab, 95% CI -0.20 to 0.34) or vaginal (+0.11 log10 copies/swab, 95% CI -0.17 to 0.39) set point viral loads; S. haematobium infection was associated with lower cervical viral loads (-0.59 log10 copies/swab, 95% CI -1.11 to -0.06).

CONCLUSIONS/SIGNIFICANCE: These results do not support the hypotheses that schistosome coinfection increases plasma or genital HIV-1 viral loads.

RevDate: 2019-11-26

Dean D (2020)

The first medications in my TMD toolbox.

Cranio : the journal of craniomandibular practice, 38(1):1-4.

RevDate: 2019-11-26

Lynch KL, Gooding LR, Garnett-Benson C, et al (2019)

Epigenetics and the dynamics of chromatin during adenovirus infections.

FEBS letters [Epub ahead of print].

The DNA genome of eukaryotic cells is compacted by histone proteins within the nucleus to form chromatin. Nuclear-replicating viruses such as adenovirus have evolved mechanisms of chromatin manipulation to promote infection and subvert host defenses. Epigenetic factors may also regulate persistent adenovirus infection and reactivation in lymphoid tissues. In this review we discuss the viral proteins E1A and protein VII that interact with and alter host chromatin, as well as E4orf3, which separates host chromatin from sites of viral replication. We also highlight recent advances in chromatin technologies that offer new insights into virus-directed chromatin manipulation. Beyond the role of chromatin in the viral replication cycle, we discuss the nature of persistent viral genomes in lymphoid tissue and cell lines, and the potential contribution of epigenetic signals in maintaining adenovirus in a quiescent state. By understanding the mechanisms through which adenovirus manipulates host chromatin, we will understand new aspects of this ubiquitous virus and shed light on previously unknown aspects of chromatin biology.

RevDate: 2019-11-26

Roger E, Martel S, Bertrand-Chapel A, et al (2019)

Schwann cells support oncogenic potential of pancreatic cancer cells through TGFβ signaling.

Cell death & disease, 10(12):886 pii:10.1038/s41419-019-2116-x.

Pancreatic ductal adenocarcinoma (PDAC) is one of the solid tumors with the poorest prognosis. The stroma of this tumor is abundant and composed of extracellular matrix and stromal cells (including cancer-associated fibroblasts and immune cells). Nerve fibers invading this stroma represent a hallmark of PDAC, involved in neural remodeling, which participates in neuropathic pain, cancer cell dissemination and tumor relapse after surgery. Pancreatic cancer-associated neural remodeling is regulated through functional interplays mediated by physical and molecular interactions between cancer cells, nerve cells and surrounding Schwann cells, and other stromal cells. In the present study, we show that Schwann cells (glial cells supporting peripheral neurons) can enhance aggressiveness (migration, invasion, tumorigenicity) of pancreatic cancer cells in a transforming growth factor beta (TGFβ)-dependent manner. Indeed, we reveal that conditioned medium from Schwann cells contains high amounts of TGFβ able to activate the TGFβ-SMAD signaling pathway in cancer cells. We also observed in human PDAC samples that high levels of TGFβ signaling activation were positively correlated with perineural invasion. Secretome analyses by mass spectrometry of Schwann cells and pancreatic cancer cells cultured alone or in combination highlighted the central role of TGFβ in neuro-epithelial interactions, as illustrated by proteomic signatures related to cell adhesion and motility. Altogether, these results demonstrate that Schwann cells are a meaningful source of TGFβ in PDAC, which plays a crucial role in the acquisition of aggressive properties by pancreatic cancer cells.

RevDate: 2019-11-26

Panpradist N, Beck IA, Vrana J, et al (2019)

OLA-Simple: A software-guided HIV-1 drug resistance test for low-resource laboratories.

EBioMedicine pii:S2352-3964(19)30743-1 [Epub ahead of print].

BACKGROUND: HIV drug resistance (HIVDR) testing can assist clinicians in selecting treatments. However, high complexity and cost of genotyping assays limit routine testing in settings where HIVDR prevalence has reached high levels.

METHODS: The oligonucleotide ligation assay (OLA)-Simple kit was developed for detection of HIVDR against first-line non-nucleoside/nucleoside reverse transcriptase inhibitors and validated on 672 codons (168 specimens) from subtypes A, B, C, D, and AE. The kit uses dry reagents to facilitate assay setup, lateral flow devices for visual HIVDR detections, and in-house software with an interface for guiding users and analyzing results.

FINDINGS: HIVDR analysis of specimens by OLA-Simple compared to Sanger sequencing revealed 99.6 ± 0.3% specificity and 98.2 ± 0.9% sensitivity, and compared to high-sensitivity assays, 99.6 ± 0.6% specificity and 86.2 ± 2.5% sensitivity, with 2.6 ± 0.9% indeterminate results. OLA-Simple was performed more rapidly compared to Sanger sequencing (<4 h vs. 35-72 h). Forty-one untrained volunteers blindly tested two specimens each with 96.8 ± 0.8% accuracy.

INTERPRETATION: OLA-Simple compares favorably with HIVDR genotyping by Sanger and sensitive comparators. Instructional software enabled inexperienced, first-time users to perform the assay with high accuracy. The reduced complexity, cost, and training requirements of OLA-Simple could improve access to HIVDR testing in low-resource settings and potentially allow same-day selection of appropriate antiretroviral therapy. FUND: USA National Institutes of Health R01; the Clinical and Retrovirology Research Core and the Molecular Profiling and Computational Biology Core of the UW CFAR; Seattle Children's Research Institute; UW Holloman Innovation Challenge Award; Pilcher Faculty Fellowship.

RevDate: 2019-11-25

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

Time Trends in First-Episode Genital Herpes Simplex Virus Infections in an Urban Sexually Transmitted Disease Clinic.

Sexually transmitted diseases, 46(12):795-800.

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

METHODS: Using an electronic database, we identified persons diagnosed as having first-episode genital herpes at Public Health - Seattle & King County STD Clinic from 1993 to 2014 and compared risk factors for genital HSV-1 versus herpes simplex virus type 2 (HSV-2) infection.

RESULTS: Of 52,030 patients with genital ulcers, 3065 (6.15%) had first-episode genital herpes infection: 1022 (33.3%) with HSV-1 and 2043 (67.7%) with HSV-2. Overall, 1154 (37.7%) were women, the median age was 28 years (interquartile range, 24-36 years), 1875 (61.2%) patients were white, and 353 (11.5%) were MSM. The number of patients diagnosed as having first-episode genital HSV-2 declined on average by 5.5 persons per year, from 208 in 1993 to 35 in 2014 (change of -5.6 per year; 95% confidence interval [CI], -6.9 to -4.1), whereas HSV-1 diagnoses remained stable at approximately 50 per year (change of 0.2; 95% CI, -0.4 to 0.9). In a multivariate model, persons diagnosed as having first-episode genital HSV-1 rather than genital HSV-2 infection were more likely to be younger (age <30 years [relative risk {RR}, 1.38; 95% CI, 1.22-1.55]), white (RR, 3.16; 95% CI, 2.57-3.88), and MSM (RR, 1.50; 95% CI, 1.31-1.71).

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

RevDate: 2019-11-25

Ujjani C, BD Cheson (2019)

Targeted Therapies in Chronic Lymphocytic Leukemia: Is 2 (or 3) Better Than 1?.

Cancer journal (Sudbury, Mass.), 25(6):449-454.

Small molecule inhibitors, including B-cell receptor antagonists and B-cell lymphoma - 2 inhibitors, have revolutionized the treatment of chronic lymphocytic leukemia (CLL). These agents have improved outcomes for patients of all prognostic backgrounds, thus securing their role in the frontline setting. Impressive activity has been demonstrated both with monotherapy and in combination with other targeted therapeutics. The most important remaining question is whether to administer small molecule inhibitors in a sequential fashion or in combination with each other and/or anti-CD20-directed therapy. Together, a number of retrospective and prospective clinical trials have provided insight into patient outcomes with different sequencing and combination strategies. While rituximab does not appear to provide significant additional benefit to ibrutinib, the incorporation of venetoclax appears to enable a deeper response and allow for a shorter duration of therapy. How durable of a response this produces and whether patients can be effectively retreated with venetoclax remain unclear. As various targeted therapy doublets and triplets are explored, it is important to investigate whether they produce significant long-term benefits over monotherapy and whether these approaches are appropriate for all patients.

RevDate: 2019-11-25

Eller MA, Hong T, Creegan M, et al (2019)

Activated PD-1+ CD4 T cells represent a short-lived part of the viral reservoir and predict poor immunologic recovery upon initiation of ART.

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

OBJECTIVE: Activated (CD38+HLA-DR+) PD-1+ CD4 T cells are strongly associated with virus replication and disease progression in untreated HIV-1 infection, and viral persistence in individuals on ART. Few studies have examined cell associated viral load (CAVL) in different activated CD4 T cell populations to measure relative contributions to viral reservoirs.

DESIGN: Longitudinal assessment of HIV-1 chronically infected Ugandans initiating ART, to investigate activated CD4 T cell populations and their contribution to viral reservoirs.

METHODS: We followed 32 HIV-1 chronically infected individuals from Kampala, Uganda, and determined their CD4 T cell counts and viral load at baseline, 6, and 12 months after the initiation of ART. T cell populations were sorted based on activation profiles and gag DNA was measured to determine CAVL within these populations. Soluble factors associated with inflammation were measured in plasma using a multiplexed platform.

RESULTS: Concomitant with viral load decline and CD4 T cell count rebound, the activated PD-1+ CD4 T cell population contracted upon initiation of ART. Baseline levels of activated PD-1+ CD4 T cells correlated with plasma levels of IP-10 and TNFRII. Interestingly, higher baseline level of activated PD-1+ CD4 T cells was associated with poorer CD4 T cell recovery after 12 months of ART. This population contributed significantly to the cell-associated HIV DNA load at baseline, whereas their contribution declined on ART, indicating high turnover.

CONCLUSION: Activated PD-1+ CD4 T cells are predictors of poor immunologic recovery on ART and may represent a short-lived component of HIV-1 reservoirs.

RevDate: 2019-11-25

Reddy K, Kelly C, Brown ER, et al (2019)

Use of the dapivirine vaginal ring and effect on cervical cytology abnormalities.

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

OBJECTIVE: We aimed to determine if the dapivirine vaginal ring and the ring device alone (flexible silicone matrix polymer) was associated with the development of cervical cytology abnormalities.

DESIGN: Secondary analysis comparing cervical cytology results between two randomized controlled microbicide trials (ASPIRE and VOICE) METHODS:: Data from the MTN-020/ASPIRE, a phase III, placebo-controlled trial of the dapivirine vaginal ring, were used in this analysis. Cervical cytology smears were evaluated at baseline and at the final visit with product use. We compared cytology results between women randomized to dapivirine versus placebo vaginal ring. We further assessed for the effect of the vaginal ring device on cervical cytology by comparing results with data from the oral placebo arm of MTN-003/VOICE, a prior HIV-1 prevention trial conducted in a similar population.

RESULTS: Cervical cytology results for 2394 women from ASPIRE (1197 per study arm) were used in this analysis; median time between baseline and final visit with product use was 22.1 months. Cytology smear findings were comparable between dapivirine and placebo vaginal ring arms: at final visit, normal: 90.6% vs. 91.5%, ASC-US//LSIL: 7.8% vs. 7.4%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 1.7% vs. 1.1%, p = 0.44. Cytology data from VOICE had findings (normal: 87.8%, ASC-US/LSIL: 9.8%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 2.4%) comparable to that of both dapivirine (p = 0.93) and placebo vaginal ring arms (p = 0.24).

CONCLUSIONS: These findings indicate that neither use of the dapivirine vaginal ring nor the vaginal ring device alone, over a period of two years, is associated with development of cervical cytology abnormalities that could lead to pre-cancerous or cancerous lesions.

RevDate: 2019-11-25

Synold TW, Plets M, Tangen CM, et al (2019)

Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).

Kidney cancer, 3(2):111-118 pii:KCA180049.

Background: S0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.

Methods: Patients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.

Results: A total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0-12.9, 12.9-22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p < 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p = 0.02 and OR = 2.63; p = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p = 0.01 and OR = 2.90; p = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p = 0.05).

Conclusions: We identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity.

RevDate: 2019-11-25

Di Meo A, Batruch I, Brown MD, et al (2019)

Identification of Prognostic Biomarkers in the Urinary Peptidome of the Small Renal Mass.

The American journal of pathology, 189(12):2366-2376.

Renal cell carcinoma (RCC) is often diagnosed incidentally as a small renal mass (SRM; pT1a, ≤4 cm). Increasing concerns surrounding the overtreatment of patients with benign or clinically silent SRMs has resulted in a recent shift in treatment recommendations, especially in elderly and infirm patients. There are currently no biomarkers that can predict progression. We used a quantitative label-free liquid chromatography-tandem mass spectrometry peptidomics approach and targeted parallel-reaction monitoring to identify early, noninvasive diagnostic and prognostic biomarkers for early-stage RCC-SRMs. In total, 115 urine samples, including 33 renal oncocytoma (≤4 cm) cases, 30 progressive and 26 nonprogressive clear cell RCC-SRM cases, and 26 healthy controls were evaluated. Nine endogenous peptides that displayed significantly elevated expression in clear cell RCC-SRMs relative to healthy controls were identified. Peptides NVINGGSHAGNKLAMQEF, VNVDEVGGEALGRL, and VVAGVANALAHKYH showed significantly elevated expression in clear cell RCC-SRMs relative to renal oncocytoma. Additionally, peptides SHTSDSDVPSGVTEVVVKL and IVDNNILFLGKVNRP displayed significantly elevated expression in progressive relative to nonprogressive clear cell RCC-SRMs. Peptide SHTSDSDVPSGVTEVVVKL showed the most significant discriminatory utility (area under the curve, 0.76; 95% CI, 0.62-0.90; P = 0.0027). Patients with elevated SHTSDSDVPSGVTEVVVKL expression had significantly shorter overall survival (hazard ratio, 4.13; 95% CI, 1.09-15.65; P = 0.024) compared to patients with low expression. Pretreatment characterization of urinary peptides can provide insight into early RCC progression and may aid clinical decision-making and improve disease management.

RevDate: 2019-11-24

Langer S, Yi J, Chi NC, et al (2019)

Psychological impacts and ways of coping reported by spousal caregivers of hematopoietic cell transplant recipients: a qualitative analysis.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30816-X [Epub ahead of print].

Allogeneic hematopoietic cell transplantation (HCT) is a demanding treatment with well-established medical and psychosocial sequelae. Impacts on significant others are tremendous. Using an unfiltered qualitative approach, we asked spouses (N=15) of HCT recipients to talk about their thoughts and feelings regarding the transplant and their role as caregiver. Recordings were transcribed and independently coded to identify recurrent patterns. Caregivers mentioned both negative and positive psychological impacts of HCT, but the number of negative impacts was greater: 164 versus 34 instances. The most frequently mentioned negative psychological impacts were anxiety/ worry (30 instances), fear (20 instances), feeling overloaded/ overwhelmed (19 instances), and uncertainty (17 instances). Other emergent categories were roles/ responsibilities (49 instances) such as parenting, work, and treatment-related tasks; and coping strategies (55 instances). The latter included both adaptive and maladaptive strategies (75% and 25%, respectively). Despite the preponderance of negatively toned thoughts and feelings, signs of adjustment emerged given mention of positive psychological states such as optimism and gratitude, and adaptive coping strategies such as active coping, use of emotional support, and self-care. Interventions intended to facilitate adaptation to the HCT experience should employ strategies to help caregivers manage symptoms of distress and promote adaptive coping.

RevDate: 2019-11-24

González HM, Tarraf W, Fornage M, et al (2019)

A research framework for cognitive aging and Alzheimer's disease among diverse US Latinos: Design and implementation of the Hispanic Community Health Study/Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA).

Alzheimer's & dementia : the journal of the Alzheimer's Association pii:S1552-5260(19)35362-2 [Epub ahead of print].

Hispanics/Latinos are the largest ethnic/racial group in the United States and at high risk for Alzheimer's disease and related dementia (ADRD). Yet, ADRD among diverse Latinos is poorly understood and disparately understudied or unstudied compared to other ethnic/racial groups that leave the nation ill-prepared for major demographic shifts that lay ahead in coming decades. The primary purpose of this Perspectives article was to provide a new research framework for advancing Latino ADRD knowledge, encompassing the unique sociocultural, cardiometabolic, and genomic aspects of Latino health, aging, and ADRD. In addition, we describe some of the research challenges to progress in Latino ADRD research. Finally, we present the Study of Latinos - Investigation of Neurocognitive Aging (SOL-INCA) as an example of implementing this new framework for advancing Latino ADRD research.

RevDate: 2019-11-23

Teh C, Onstad L, SJ Lee (2019)

Reliability and validity of the modified 7-day Lee Chronic-versus-Host Disease Symptom Scale: Modified Lee chronic GVHD symptom scale.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30787-6 [Epub ahead of print].

Chronic graft-versus-host disease (cGVHD) adversely affects patients' quality of life, functional status and survival following allogenic hematopoietic cell transplantation. The Lee Symptom Scale is a 30 item scale that was developed to measure the symptoms of cGVHD. Although the original 30-item scale uses a one month recall period, we tested the reliability and validity of a 28 item scale (deleting two items based on supportive care needs rather than symptoms) with a 7-day recall period, a format that is more appropriate for use in clinical trials. Results show the modified 7-day scale is reliable and valid in the modern era and may be used to assess the symptom burden of cGVHD in clinical trials. Using the distribution method, a 5-6 point difference (half a standard deviation) is considered clinically meaningful.

RevDate: 2019-11-23

Chng MHY, Lim MQ, Rouers A, et al (2019)

Large-Scale HLA Tetramer Tracking of T Cells during Dengue Infection Reveals Broad Acute Activation and Differentiation into Two Memory Cell Fates.

Immunity pii:S1074-7613(19)30451-0 [Epub ahead of print].

T cells play important multifaceted roles during dengue infection, and understanding their responses is important for defining correlates of protective immunity and identifying effective vaccine antigens. Using mass cytometry and a highly multiplexed peptide-HLA (human leukocyte antigen) tetramer staining strategy, we probed T cells from dengue patients-a total of 430 dengue and control candidate epitopes-together with key markers of activation, trafficking, and differentiation. During acute disease, dengue-specific CD8+ T cells expressed a distinct profile of activation and trafficking receptors that distinguished them from non-dengue-specific T cells. During convalescence, dengue-specific T cells differentiated into two major cell fates, CD57+ CD127--resembling terminally differentiated senescent memory cells and CD127+ CD57--resembling proliferation-capable memory cells. Validation in an independent cohort showed that these subsets remained at elevated frequencies up to one year after infection. These analyses aid our understanding of the generation of T cell memory in dengue infection or vaccination.

RevDate: 2019-11-22

Ballen K, Logan BR, Chitphakdithai P, et al (2019)

Unlicensed umbilical cord blood units provide a safe and effective graft source for a diverse population: A study of 2456 umbilical cord blood recipients.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30783-9 [Epub ahead of print].

Umbilical Cord Blood (UCB) transplant (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the Food and Drug Administration (FDA) required that unrelated UCBT use either licensed UCB or unlicensed UCB via an Investigational New Drug (IND). The National Marrow Donor Program® (NMDP) manages an IND under which 2456 patients (1499 adults and 957 children (564 malignant disease and 393 non-malignant disease) received single or double UCBT between October 2011 and December, 2016. Median age was 31 years (<1 to 81); 50% of children and 36% of adults were non-Caucasian. Median days to neutrophil engraftment (absolute neutrophil count ≥ 500/mm3) were 22, 20 and 19 days and the incidence of engraftment at 42 days was 89%, 88%, and 90% for adult, pediatric malignant, and pediatric non-malignant, respectively. Acute GVHD Grades II-IV was 35%, 32%, and 24%, chronic GVHD was 24%, 26%, and 24% and one year overall survival (OS) was 57%, 71%, and 79% for adults, pediatric malignant, and pediatric non-malignant.. In multivariate analysis, younger age, lower HCT-CI, early stage chemotherapy sensitive disease, and higher performance score predicted improved OS for adults. In a subset analysis of children with malignancies receiving single UCBT, use of either licensed (n=48) or unlicensed UCB (n=382) was associated with similar engraftment and survival. Use of unlicensed UCB units is safe, effective and provides an important graft source for a diverse population.

RevDate: 2019-11-22

Giralt S, Costa LJ, Maloney D, et al (2019)

Tandem Autologous-Autologous versus Autologous-Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Multiple Myeloma: Long-term Follow-Up Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30785-2 [Epub ahead of print].

Allogeneic hematopoietic cell transplantation (HCT) may improve long-term multiple myeloma (MM) control through graft vs myeloma (GVM) effect. The BMT CTN 0102 was a biological assignment trial comparing tandem autologous transplant (auto-auto) vs. autologous followed by reduced intensity allogeneic (auto-allo) transplantation in patients with newly diagnosed MM with standard (N=625) or high-risk (beta 2 microglobulin at diagnosis ≥ 4 mg/dl or deletion of chromosome 13 by conventional karyotyping) disease (N=85). While the initial 3-year analysis showed no difference in progression-free survival (PFS) between arms in either risk group, we hypothesized that long-term follow-up may better capture the impact of GVM. Median follow-up of survivors is over 10 years. Among standard risk patients there was no difference in PFS (HR 1.11, 95% C.I. 0.93- 1.35, P=0.25) or OS (HR 1.03, 95% C.I. 0.82-1.28, P=0.82). The 6-year PFS was 25% in the auto-auto vs. 22% in auto-allo arm(P=0.32), and 6-year overall survival (OS) was 60% and 59% respectively (P=0.85). In the high-risk group, while there was no statistically significant difference in PFS (HR 0.66, 95% C.I. 0.41-1.07, P=0.07) and OS (HR 1.01, 95% C.I. 0.60-1.71, P=0.96), a reduction in 6-year risk of relapse, 77% vs. 47% (P= 0.005), was reflected in better PFS, 13% vs. 31% (P=0.05), but similar OS, 47% vs. 51% (P=0.69). Allogeneic HCT can lead to long-term disease control in patients with high risk MM and needs to be explored in the context of modern therapy.

RevDate: 2019-11-22

Xie SH, Fang R, Huang M, et al (2019)

Association Between Levels of Hormones and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus.

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association pii:S1542-3565(19)31317-5 [Epub ahead of print].

BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones associated with risk of EAC or Barrett's esophagus (BE).

METHODS: We conducted a Mendelian randomization analysis using data from patients with EAC (n=2488) or BE (n=3247) and control participants (n=2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs.

RESULTS: Higher genetically predicted levels of follicle stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per standard deviation increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulphate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index.

CONCLUSIONS: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle stimulating and luteinizing hormones and risk of BE and EAC.

RevDate: 2019-11-22

Qin A, Rengan R, Lee S, et al (2019)

A Pilot Study of Atezolizumab plus Hypofractionated Image-guided Radiotherapy for the Treatment of Advanced Non-Small Cell Lung Cancer.

International journal of radiation oncology, biology, physics pii:S0360-3016(19)34007-6 [Epub ahead of print].

INTRODUCTION: Preclinical data and subset analyses from immunotherapy clinical trials indicate that prior radiotherapy was associated with better progression-free survival (PFS) and overall survival (OS) when combined with immune checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC). We present a prospective study of hypofractionated, image-guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic NSCLC.

METHODS: Patients meeting eligibility criteria received atezolizumab 1200mg IV every 3 weeks with concurrent 3- or 5-fraction HIGRT starting no later than the second cycle. The 3-fraction regimen employed a minimum of 8 Gy per fraction compared to 6 Gy for the 5-fraction regimen. Imaging was obtained every 12 weeks to assess response.

RESULTS: From October 2015 to February 2017, 12 patients enrolled in the study (median age 64, range 55-77). The best response by RECIST criteria was partial response in 3 and stable disease in 3, for a disease control rate (DCR) of 50%. Five patients had a grade 3 immune-related adverse event (irAE), including choreoretinitis (n =1), pneumonitis (n=1), transaminitis (n=1), fatigue (n =1) and peripheral neuropathy (n=1). The median PFS was 2.3 months and the median OS was 6.9 months (range: 0.4-not reached). There was no clear association between peripheral blood T-cell repertoire characteristics at baseline, PD-L1, or tumor mutations and response or outcome. One long-term survivor exhibited oligoclonal T cell populations in a baseline tumor biopsy that were consistently detected in peripheral blood over the entire course of the study.

CONCLUSIONS: HIGRT plus atezolizumab resulted in ORR of 25% and DCR of 50% in this pilot study. The incidence of grade 3 AEs was similar to that of atezolizumab alone. Though a pilot study with limited sample size, the results generated hypotheses worthy of further investigation.

RevDate: 2019-11-22

Watts GS, Thornton JE, Youens-Clark K, et al (2019)

Identification and quantitation of clinically relevant microbes in patient samples: Comparison of three k-mer based classifiers for speed, accuracy, and sensitivity.

PLoS computational biology, 15(11):e1006863 pii:PCOMPBIOL-D-19-00012 [Epub ahead of print].

Infections are a serious health concern worldwide, particularly in vulnerable populations such as the immunocompromised, elderly, and young. Advances in metagenomic sequencing availability, speed, and decreased cost offer the opportunity to supplement or even replace culture-based identification of pathogens with DNA sequence-based diagnostics. Adopting metagenomic analysis for clinical use requires that all aspects of the workflow are optimized and tested, including data analysis and computational time and resources. We tested the accuracy, sensitivity, and resource requirements of three top metagenomic taxonomic classifiers that use fast k-mer based algorithms: Centrifuge, CLARK, and KrakenUniq. Binary mixtures of bacteria showed all three reliably identified organisms down to 1% relative abundance, while only the relative abundance estimates of Centrifuge and CLARK were accurate. All three classifiers identified the organisms present in their default databases from a mock bacterial community of 20 organisms, but only Centrifuge had no false positives. In addition, Centrifuge required far less computational resources and time for analysis. Centrifuge analysis of metagenomes obtained from samples of VAP, infected DFUs, and FN showed Centrifuge identified pathogenic bacteria and one virus that were corroborated by culture or a clinical PCR assay. Importantly, in both diabetic foot ulcer patients, metagenomic sequencing identified pathogens 4-6 weeks before culture. Finally, we show that Centrifuge results were minimally affected by elimination of time-consuming read quality control and host screening steps.

RevDate: 2019-11-22

Ho LST, Dinh V, Matsen FA, et al (2019)

On the convergence of the maximum likelihood estimator for the transition rate under a 2-state symmetric model.

Journal of mathematical biology pii:10.1007/s00285-019-01453-1 [Epub ahead of print].

Maximum likelihood estimators are used extensively to estimate unknown parameters of stochastic trait evolution models on phylogenetic trees. Although the MLE has been proven to converge to the true value in the independent-sample case, we cannot appeal to this result because trait values of different species are correlated due to shared evolutionary history. In this paper, we consider a 2-state symmetric model for a single binary trait and investigate the theoretical properties of the MLE for the transition rate in the large-tree limit. Here, the large-tree limit is a theoretical scenario where the number of taxa increases to infinity and we can observe the trait values for all species. Specifically, we prove that the MLE converges to the true value under some regularity conditions. These conditions ensure that the tree shape is not too irregular, and holds for many practical scenarios such as trees with bounded edges, trees generated from the Yule (pure birth) process, and trees generated from the coalescent point process. Our result also provides an upper bound for the distance between the MLE and the true value.

RevDate: 2019-11-22

González HM, Tarraf W, Schneiderman N, et al (2019)

Prevalence and correlates of mild cognitive impairment among diverse Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging results.

Alzheimer's & dementia : the journal of the Alzheimer's Association pii:S1552-5260(19)35376-2 [Epub ahead of print].

INTRODUCTION: We estimated the prevalence and correlates of mild cognitive impairment (MCI) among middle-aged and older diverse Hispanics/Latinos.

METHODS: Middle-aged and older diverse Hispanics/Latinos enrolled (n = 6377; 50-86 years) in this multisite prospective cohort study were evaluated for MCI using the National Institute on Aging-Alzheimer's Association diagnostic criteria.

RESULTS: The overall MCI prevalence was 9.8%, which varied between Hispanic/Latino groups. Older age, high cardiovascular disease (CVD) risk, and elevated depressive symptoms were significant correlates of MCI prevalence. Apolipoprotein E4 (APOE) and APOE2 were not significantly associated with MCI.

DISCUSSION: MCI prevalence varied among Hispanic/Latino backgrounds, but not as widely as reported in the previous studies. CVD risk and depressive symptoms were associated with increased MCI, whereas APOE4 was not, suggesting alternative etiologies for MCI among diverse Hispanics/Latinos. Our findings suggest that mitigating CVD risk factors may offer important pathways to understanding and reducing MCI and possibly dementia among diverse Hispanics/Latinos.

RevDate: 2019-11-21

Wang Z, Usyk M, Sollecito CC, et al (2019)

Altered Gut Microbiota and Host Metabolite Profiles in HIV-infected Women.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5636878 [Epub ahead of print].

BACKGROUND: Alterations in gut microbiota (GMB) and host metabolites have been noted in HIV-infected individuals. However, it remains unclear whether alterations in GMB and related functional groups may contribute to disrupted host metabolite profiles in HIV-infected individuals.

METHODS: This study included 185 women (128 with long-standing HIV infection, 88% under antiretroviral therapy; and 57 HIV-uninfected from the same geographic location with comparable characteristics). Stool samples were analyzed by 16S rRNA V4 region sequencing, and GMB function was inferred by PICRUSt. Plasma metabolomic profiling was performed using liquid chromatography tandem mass spectrometry, and133 metabolites (amino acids, biogenic amines, acylcarnitines and lipids) were analyzed.

RESULTS: Four predominant bacterial genera were identified to be associated with HIV infection, with higher abundances of Ruminococcus and Oscillospira and lower abundances of Bifidobacterium and Collinsella in HIV-infected women compared to HIV-uninfected women. HIV-infected women showed a distinct plasma metabolite profile, featured with elevated glycerophospholipid levels, compared to HIV-uninfected women. Functional analyses also indicated that GMB lipid metabolism was enriched in HIV-infected women. Ruminococcus and Oscillospira were among the top bacterial genera that contribute to the GMB glycerophospholipid metabolism pathway and showed positive correlations with host plasma glycerophospholipid levels. One bacterial functional capacity in the acetate and propionate biosynthesis pathway was identified to be mainly contributed by Bifidobacterium, and this functional capacity was lower in HIV-infected women than that in HIV-uninfected women.

CONCLUSION: Our integrative analyses identified altered gut microbiota with related functional capacities that might be associated with disrupted plasma metabolite profiles in HIV-infected women.

RevDate: 2019-11-21

Shen JC, Kamath-Loeb AS, Kohrn BF, et al (2019)

A high-resolution landscape of mutations in the BCL6 super-enhancer in normal human B cells.

Proceedings of the National Academy of Sciences of the United States of America pii:1914163116 [Epub ahead of print].

The super-enhancers (SEs) of lineage-specific genes in B cells are off-target sites of somatic hypermutation. However, the inability to detect sufficient numbers of mutations in normal human B cells has precluded the generation of a high-resolution mutational landscape of SEs. Here we captured and sequenced 12 B cell SEs at single-nucleotide resolution from 10 healthy individuals across diverse ethnicities. We detected a total of approximately 9,000 subclonal mutations (allele frequencies <0.1%); of these, approximately 8,000 are present in the BCL6 SE alone. Within the BCL6 SE, we identified 3 regions of clustered mutations in which the mutation frequency is ∼7 × 10-4 Mutational spectra show a predominance of C > T/G > A and A > G/T > C substitutions, consistent with the activities of activation-induced-cytidine deaminase (AID) and the A-T mutator, DNA polymerase η, respectively, in mutagenesis in normal B cells. Analyses of mutational signatures further corroborate the participation of these factors in this process. Single base substitution signatures SBS85, SBS37, and SBS39 were found in the BCL6 SE. While SBS85 is a denoted signature of AID in lymphoid cells, the etiologies of SBS37 and SBS39 are unknown. Our analysis suggests the contribution of error-prone DNA polymerases to the latter signatures. The high-resolution mutation landscape has enabled accurate profiling of subclonal mutations in B cell SEs in normal individuals. By virtue of the fact that subclonal SE mutations are clonally expanded in B cell lymphomas, our studies also offer the potential for early detection of neoplastic alterations.

RevDate: 2019-11-21

Böhmer AC, Hecker J, Schröder J, et al (2019)

Shared genetic etiology of obesity-related traits and Barrett's esophagus/adenocarcinoma: Insights from genome-wide association studies.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-19-0374 [Epub ahead of print].

BACKGROUND: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits.

METHODS: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association meta-analyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses.

RESULTS: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA (rg=0.13, P=2×10-04) and a rg of 0.12 between WHR and BE/EA (P=1×10-02). Sex-specific analyses revealed a pronounced genetic correlation between BMI and EA in females (rg=0.17, P=1.2×10-03); and WHR and EA in males (rg=0.18, P=1.51×10-02). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P=8.45×10-03) and WHR and BE/EA risk variants (P=2×10-02).

CONCLUSIONS: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mechanisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA.

IMPACT: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.

RevDate: 2019-11-21

Kallas EG, Grunenberg NA, Yu C, et al (2019)

Antigenic competition in CD4+ T cell responses in a randomized, multicenter, double-blind clinical HIV vaccine trial.

Science translational medicine, 11(519):.

T cell responses have been implicated in reduced risk of HIV acquisition in uninfected persons and control of viral replication in HIV-infected individuals. HIV Gag-specific T cells have been predominantly associated with post-infection control, whereas Env antigens are the target for protective antibodies; therefore, inclusion of both antigens is common in HIV vaccine design. However, inclusion of multiple antigens may provoke antigenic competition, reducing the potential effectiveness of the vaccine. HVTN 084 was a randomized, multicenter, double-blind phase 1 trial to investigate whether adding Env to a Gag/Pol vaccine decreases the magnitude or breadth of Gag/Pol-specific T cell responses. Fifty volunteers each received one intramuscular injection of 1 × 1010 particle units (PU) of rAd5 Gag/Pol and EnvA/B/C (3:1:1:1 mixture) or 5 × 109 PU of rAd5 Gag/Pol. CD4+ T cell responses to Gag/Pol measured 4 weeks after vaccination by cytokine expression were significantly higher in the group vaccinated without Env, whereas CD8+ T cell responses did not differ significantly between the two groups. Mapping of individual epitopes revealed greater breadth of the Gag/Pol-specific T cell response in the absence of Env compared to Env coimmunization. Addition of an Env component to a Gag/Pol vaccine led to reduced Gag/Pol CD4+ T cell response rate and magnitude as well as reduced epitope breadth, confirming the presence of antigenic competition. Therefore, T cell-based vaccine strategies should aim at choosing a minimalist set of antigens to reduce interference of individual vaccine components with the induction of the maximally achievable immune response.

RevDate: 2019-11-19

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

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

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

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

RevDate: 2019-11-19

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

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

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

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

RevDate: 2019-11-19

Neuhouser ML (2019)

Red and processed meat: more with less?.

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

RevDate: 2019-11-19

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

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

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

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

RevDate: 2019-11-18

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

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

Blood pii:428815 [Epub ahead of print].

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

RevDate: 2019-11-18

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

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

Frontiers in immunology, 10:2533.

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

RevDate: 2019-11-17

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

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

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

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

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

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

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

RevDate: 2019-11-17

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

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

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

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

RevDate: 2019-11-16

Marsh TL, Janes H, MS Pepe (2019)

Statistical inference for net benefit measures in biomarker validation studies.

Biometrics [Epub ahead of print].

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

RevDate: 2019-11-16

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

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

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

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

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

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

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

RevDate: 2019-11-16

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

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

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

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

RevDate: 2019-11-15

Richter DJ, TC Levin (2019)

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

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

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

RevDate: 2019-11-15

Kopmar NE, EH Estey (2019)

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

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

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

RevDate: 2019-11-15

Montgomery B (2019)

Prostate cancer in military veterans.

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

RevDate: 2019-11-15

Lyman GH (2019)

How biosimilars will impact costs and care in oncology.

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

RevDate: 2019-11-15

Baker KS (2019)

Insights into survivorship care for cancer patients.

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

RevDate: 2019-11-15

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

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

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

RevDate: 2019-11-15

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

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

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

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

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

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

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

RevDate: 2019-11-15

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

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

HIV medicine [Epub ahead of print].

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

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

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

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

RevDate: 2019-11-15

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

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

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

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

RevDate: 2019-11-14

Hanash SM, Feng Z, A Taguchi (2019)

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

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

RevDate: 2019-11-14

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

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

Medicine, 98(46):e17960.

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

RevDate: 2019-11-14

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

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

Blood, 134(Supplement_1):40.

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

RevDate: 2019-11-14

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

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

Blood, 134(Supplement_1):6.

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

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

RevDate: 2019-11-13

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

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

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

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

RevDate: 2019-11-13

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

Misregulation of Drosophila Myc Disrupts Circadian Behavior and Metabolism.

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

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


RJR Experience and Expertise


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


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


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


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


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


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


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


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

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

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Collection of publications by R J Robbins

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

Research Gate page for R J Robbins

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

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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RJR Picks from Around the Web (updated 11 MAY 2018 )