tbuckley/cabot-search huggingface dataset:
Clinical characteristics of men with prostate cancer and evaluation of NCCN prostate cancer guidelines on germline genetic testing outcomes.
Authors: Samantha Greenberg, Brock O'Neil, Kathleen A. Cooney, Lisa M. Pappas, Jonathan David Tward
Journal: Journal of Clinical Oncology (2019)

252 Background: Growing evidence suggests up to 12% of men with metastatic prostate cancer (PC) harbor a pathogenic variant (PV) in genes associated with hereditary cancer risk. Updated NCCN PC guidelines include consideration for germline testing (GT) in men with high risk, very high risk, regional, or metastatic PC. As a result, we expanded our criteria for GT in men with PC to include these groups and men with a strong family history for PC beginning in January 2018. This study reports the clinical characteristics and germline findings before and after this expansion. Methods: Men with PC underwent multi-gene genetic testing (GT) for PVs from June 2016-June 2018 with genetic counselors. Clinical information and germline GT results were analyzed. Results: Of 285 eligible men who met with a genetic counselor, there were 201 evaluable GT results. One PV was excluded for suspicion of clonal hematopoiesis of indeterminate potential. Twenty-seven PVs were identified in 24 men (12.4%). Three men had two PVs identified (1.5%), at least one PV of which was in ATM or BRCA2. The most common PVs were ATM (n = 6, 3.0%), BRCA2 (n = 7, 3.5%), MYH (n = 4, 2.0%), and HOXB13 (n = 4, 2.0%). Rate of PVs were not statistically different across the two timeframes of GT, (2016-17, 14%; 2018, 11.2%; p = 0.60). PVs were not statistically associated with a higher ISUP group (1-3: 10.1%, 4-5: 13.6%; p = 0.49) and were distributed across multiple NCCN risk groups. Almost all men tested reported a family history of cancer, with the most frequent cancers reported including PC (n = 79, 39.3%), breast (n = 55, 27.4%), and colon cancer (n = 23, 11.4%). Family history of PC was not statistically associated with genetic test results (PV: 54%, no PV: 37%; p = 0.11). Conclusions: Expanding germline GT criteria will substantially increase patient volume without significant changes to the PV rate. Higher PC risk defined by ISUP or NCCN was not associated with the rate of PVs. Given this finding, further broadening the criteria for GT in PC may be warranted.
Abstract 21: Lipid Metabolites Are Associated With Epigenetic Aging Acceleration in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Tao Gao, Yinan Zheng, Brian Joyce, John Wilkins, Philip Greenland, Donald Lloyd-Jones, Lifang Hou
Journal: Circulation (2019)

Background: Epigenetic aging measures including phenotypic aging (PA) and extrinsic epigenetic age acceleration (EEAA) have been associated with age-related diseases and conditions that include cardiovascular diseases, diabetes, and cancer. However, associations between epigenetic aging and lipids have not been widely investigated. Hypothesis: We hypothesized that adverse lipid metabolite profiles are associated with epigenetic age acceleration. Methods: We estimated measures of epigenetic age acceleration in 957 white and black participants from the CARDIA Study with whole-genome blood DNA methylation profiling by the Illumina EPIC array at Year 20 (Y20; ages 38-52). We used separate linear regression models to examine cross-sectional associations of PA and EEAA estimates with fasting triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels after adjusting for race, sex, education, alcohol intake, smoking status and physical activity. Results: Participants were 51% female (n=490) and 39% black (n=393) with mean chronological age 45±4 years. Compared with participants in the 1st tertile of TG, those in the 2nd tertile had 1.32 years older PA (95%CI 0.33-2.30) and 1.04 years older EEAA (95%CI 0.22-1.87); those in the 3rd tertile had 1.78 years older PA (95%CI 0.75-2.81) and 1.09 years older EEAA (95%CI 0.23-1.95). Compared to participants in the 1st tertile of HDL-C, those in the 3rd tertile had decreased EEAA by 1.21 years (95%CI -2.16--0.27). There were no significant differences of PA or EEAA among participants of LDL-C tertiles. (Figure 1.) Conclusions: Adverse lipid metabolites (TG and HDL-C) are associated cross-sectionally with accelerated epigenetic aging. Further studies are needed to understand the longitudinal associations between epigenetic aging and adverse lipid profiles as well as the potential mechanisms that underlie these associations.
Most unambiguous loss-of-function <i>CPA1</i> mutations are unlikely to predispose to chronic pancreatitis
Authors: Jin-Huan Lin, Arnaud Boulling, Emmanuelle Masson, David N Cooper, Zhao-Shen Li, Claude Férec, Zhuan Liao, Jian-Min Chen
Journal: Gut (2019)

ti tis.G u t 6 9 (4) , p p. 7 8 5-7 8 6 .
Abstract P406: Trajectories of Engagement in Leisure-time Physical Activity and Risk of Incident Ischemic Stroke: the Atherosclerosis Risk in Communities Study
Authors: Logan Cowan, Yelena Tarasenko, Kelly Evenson, Priya Palta, Kamakshi Lakshminarayan
Journal: Circulation (2019)

Introduction: Engagement in leisure-time physical activity (PA) levels recommended by the American Heart Association (AHA) is inversely associated with ischemic stroke risk. PA level can fluctuate over time but the association between PA fluctuations and ischemic stroke risk is unknown. The extent that ischemic stroke risk could be attenuated by increasing PA among those who are inactive could inform stroke prevention. Hypothesis: We hypothesize that participants who remained active or increased their PA levels will have lower ischemic stroke risk relative to those who were persistently inactive. Methods: We included 12,611participants of the Atherosclerosis Risk in Communities (ARIC) cohort study ages 45-64 at visit 1 (1987-1989) who did not have a history of stroke at visit 3 (1993-1995). Leisure-time PA was assessed using the modified Baecke questionnaire at visits 1 and 3 and categorized according to the AHA guidelines for PA (ideal, intermediate, or poor). All adjudicated definite and probable incident ischemic strokes between visit 3 and end of year 2013 were included. Cox-proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ischemic stroke by cross-categories of PA at visits 1 and 3 using those with poor PA at both visits as the referent group. We adjusted for age, sex, race/center, smoking status, and alcohol intake at visit 3. Results: During a median of 18.6 years of follow-up, 777 incident ischemic stroke events occurred. Compared with those with poor PA at visits 1 and 3, participants with ideal PA at both visits had the lowest ischemic stroke risk (HR=0.64, 0.51, 0.80). Those whose PA increased from poor to ideal also had significantly lower ischemic stroke risk (HR = 0.70, 0.53, 0.94). Conclusion: Sustained ideal PA was associated with the lowest ischemic stroke risk. Increasing PA between visit 1 and visit 3 was also associated with significantly lower ischemic stroke risk. Increasing PA may be an important component of stroke prevention.
Immunological predictors of fatigue outcomes in prostate cancer patients receiving radiation therapy.
Authors: Li Rebekah Feng, Brian S Wolff, Nada Lukkahatai, Leorey N Saligan
Journal: Journal of Clinical Oncology (2015)

e16130 Background: Fatigue is one of the most debilitating side effects of cancer therapy, and it persists long after treatment completion. In this study, we aimed to examine correlations between levels of immunological markers and fatigue in men receiving external beam radiation therapy (EBRT) for non-metastatic prostate cancer (NM-PC). Methods: Thirty-four men with NM-PC scheduled to receive EBRT were followed at baseline (prior to EBRT initiation), midpoint of EBRT, and one year following EBRT completion. Demographic and clinical data were obtained by chart review. The Functional Assessment of Cancer Therapy-Fatigue (FACT-F) was administered to measure fatigue levels over time. Blood was drawn at each time point and plasma cytokine levels were determined using the Bio-rad Bio-plex cytokine assay kits. T-tests and correlations were used to determine associations between fatigue scores and cytokine concentrations. Correlation plots were created with MATLAB (MathWorks) and pathway analysis was performed using Ingenuity Pathway Analysis (Qiagen). Results: Significant correlations were observed between fatigue score changes from baseline to one year-post EBRT and plasma concentrations of IL-3, IL-8, IL-9, IL-10, IL-16, IP10, IFNa2, IFNg, and SDF1a measured at midpoint of EBRT. Pathway analysis revealed a highly interconnected network with IFNg being a central player. Conclusions: Immunological changes in our study precede development of fatigue, suggesting these cytokines may be contributors to the development of persistent fatigue one year after treatment completion. Further, these cytokines may serve as markers and predictors of chronic fatigue in prostate cancer patients receiving EBRT. Acknowledgements:This study is fully supported by the Intramural Research Program of the National Institute of Nursing Research of the NIH, Bethesda, Maryland.
Intervention to reduce racial treatment disparities in early stage non-small cell lung cancer (NSCLC).
Authors: Paul R. Walker, Sam Cykert, Peggye Dilworth-Anderson, Maria Cirino-Marcano, Lloyd Edwards
Journal: Journal of Clinical Oncology (2015)

e17597 Background: Racial differences in the treatment of non-small lung cancer (NSCLC) continue to exist leading to poorer outcomes in African-Americans (AA) compared to Caucasians (C). Our previous multi-institutional prospective cohort study of 386 patients identified a surgical rate of 66% C but only 55% AA (p = 0.05; OR 0.75; 95% CI 0.57-0.99). Surgical rates for AA patients were particularly low when 2 or more co-morbidities were present compared to C, 13% vs 62% (OR 0.04; 95% CI 0.01-0.25) but also with a negative perception of 1-year prognosis (OR 0.27; 95% CI 0.14-0.50). (Cykert et al JAMA 2010) Methods: To further strengthen our data, a 3 year retrospective chart review for all patients with early stage NSCLC at the 3 academic institutions involved in this current intervention study was undertaken to establish baseline surgical rates according to demographic features. 714 patients with early stage NSCLC were reviewed. Controlling for comorbidities, COPD, age and other demographic data, the OR for surgery for AA compared to C was 0.64 (95% CI 0.43-0.96). 157 patients, 54 (34%) AA, have been recruited to this intervention study utilizing a trained navigator to enhance patient communication and treatment understanding. Results: Surgical rate current patient cohort 82% C vs 78% AA (p = 0.5). In multivariate analysis, using demographic variables, comorbid illness, pulmonary function, and patient perceptions of communication as independent variables, age > 70 (OR 0.18; 95% CI 0.38-0.83) and a forced expiratory volume < 40% of predicted (OR 0.04; 95% CI .001-0.19) were associated with lower surgical rates. Notably, AA race and medical comorbidity scores had no impact on surgical rates. Conclusions: Early results from a multifaceted intervention designed to enhance patient communication and treatment understanding narrowed the surgical gap between AA and C in early stage NSCLC.
Chaperonin-containing T Complex (CCT) is a novel target for treatment of metastatic breast cancer.
Authors: Priya Vishnubhotla, Amr Khaled, Rania Bassiouni, Orielyz Flores, J.Manuel Perez, Annette R Khaled
Journal: Journal of Clinical Oncology (2015)

e13530 Background: Metastatic breast cancer is uniformly fatal with median survival of 1-2 years. Progressive and refractory disease is the cause. Our group developed a novel cytotoxic peptide, CT20p, and a nanotechnology-based platform to deliver and concentrate CT20p in breast tumors. Using murine xenografts, we found that treatment with nanomolar amounts of CT20p resulted in significant regression of breast cancer tumors. Tumors cells treated with CT20p lost the capacity to rearrange their cytoskeleton and maintain substrate attachment, causing cell death. Methods: To identify the intracellular target of CT20p, we used biotinylated-CT20p to “pull-down” interacting proteins from the cellular lysates of breast cancer cells and normal epithelial cells. Interacting proteins, specific to breast cancer cells, were identified by mass spectrometry. Tissue microarrays (TMAs) for breast cancer were examined by immunohistochemistry for the expression of the interacting proteins. Results were scored and correlated to breast cancer stage, grade and hormone receptor status. Results: We discovered that the intracellular target of CT20p is a protein called chaperonin-containing T-complex (CCT). CCT is a large macromolecular complex composed of 8 subunits that is essential for the folding of actin and tubulin into their native forms. Inhibition of CCT causes the accumulation of unfolded proteins, producing a cell death response such as was observed upon CT20p treatment. CCT expression in cells correlated to susceptibility to killing by CT20p. Using breast cancer TMAs, we observed increased CCT expression in tumor tissues that were stage 2 or higher as compared to cancer adjacent tissues. Increased CCT expression did not correlate with estrogen receptor (ER) levels but did correlate with increased progesterone receptor (PR) levels and Her2/Neu. Tissues from triple negative breast cancer (TNBC) showed a range of CCT expression. Conclusions: These studies suggest that CCT could be novel indicator of breast cancer progression that may be independent of known biomarkers and could be a promising new target for therapeutic intervention, especially in advanced stage breast cancers.
Abstract 12566: Novel Genes Associated With Platelet Function Discovered Through Whole Genome Sequencing
Authors: Lisa R Yanek, Margaret A Taub, Kruthika R Iyer, Ingo Ruczinski, Dhananjay Vaidya, Brian G Kral, Nauder Faraday, Diane M Becker, Lewis C Becker, Rasika A Mathias
Journal: Circulation (2015)

Platelet aggregation on ruptured or eroded atherosclerotic plaques can initiate arterial thromboses. GWAS have identified common loci associated with platelet aggregation, but cumulatively they account for only a small portion of the variability in platelet aggregation. We used whole genome sequencing (WGS) in 286 healthy subjects from families with early onset coronary artery disease (GeneSTAR Study) to identify additional genes harboring rare/novel functional variants that determine platelet aggregation at baseline and post-aspirin therapy (ASA, 81mg/day for 14 days). Deep (&gt;30X) WGS was performed on the Illumina Hiseq platform with an average of ~3.7M variants per individual and analyses presented here were limited to coding functional (i.e., missense, stop-gained and stop-lost) variants that were either rare (MAF &lt; 5%) or novel (not observed in public catalogs of variation). Using a 2-Step process, we: (1) tested for perfect co-segregation between these variants in each gene and a variety of dichotomized platelet aggregation phenotypes in n=34 subjects from 5 African American (AA) families and n=38 subjects from 7 European American (EA) families; (2) any gene with evidence across multiple families was then replicated in a set of independent samples (n=95 AA, n=119 EA) using Skat-O. To dichotomize phenotypes, ‘hyper-aggregators’ were defined as subjects in the upper 10th percentile while ‘normals’ were those between the 25th-75th percentile for each trait. We identified three novel genes harboring coding functional variants not previously reported to be associated with platelet aggregation in both races: (1) HMG20B, associated with baseline aggregation to ADP; (2) PGA5, associated with baseline aggregation to collagen; and (3) PLAC4, associated with post-ASA aggregation to collagen. HMG20B is involved in megakaryocyte development and platelet production and interacts with KIF4, a microtubule based motor protein, while the role of PGA5 and PLAC4 is less clear. Follow-up studies may identify new platelet biological pathways that can be targeted for clinical purposes.
Abstract P262: Parity and Ideal Cardiovascular Health: The Multi-Ethnic Study of Atherosclerosis
Authors: Oluseye Ogunmoroti, Olatokunbo Osibogun, Olamide Kolade, Wendy Ying, Garima Sharma, Dhananjay Vaidya, Erin D Michos
Journal: Circulation (2019)

Background: Parity (null or grand multiparity) is associated with an increased cardiovascular disease (CVD) risk through several biological pathways. The American Heart Association’s Life’s Simple 7 (LS7) metrics are a useful framework for the promotion of ideal cardiovascular health (CVH). However, the effects of parity on CVH are uncertain. We examined the association between parity and ideal CVH among an ethnically diverse group of middle to older aged women free of CVD at baseline. Methods: We analyzed cross-sectional data of 3,430 women aged 45 to 84 years enrolled in the Multi-Ethnic Study of Atherosclerosis. Parity was self-reported, defined as the total number of live births, and categorized as 0, 1-2, 3, 4 and ≥5. The LS7 metrics (smoking, physical activity, body mass index, diet, blood pressure, total cholesterol and blood glucose) were each categorized into ideal (2 points), intermediate (1 point) and poor (0 points). A total score of 0-8 was considered inadequate; 9-10, average and 11-14, optimal for CVH. The number of metrics in the ideal category was also counted. Multinomial logistic regression was used to examine the association between parity and CVH measured by the score and number of ideal metrics. Results: Mean age (SD) was 62 (10) years. Using women with 1-2 live births as reference, for nulliparous women, the odds of having an average CVH score were 38% higher, while for women with a history of 3 and ≥5 live births, the odds of having optimal CVH were 26% and 54% lower, respectively (Table) . Additionally, women with ≥5 live births were less likely to achieve 5 ideal metrics [OR 0.39 (0.21-0.69)], with a similar trend for 6-7 ideal metrics [0.41 (0.16-1.07)]. Test for interaction by race/ethnicity was not significant (p=0.3). Conclusion: While there was not a strong graded association of parity and CVH scores, our data suggest that women with ≥5 live births are less likely to achieve optimal CVH and greater numbers of ideal metrics. More research will be required to explore the mechanisms by which parity improves or worsens CVH.
Single-Cell Omics Analyses Enabled by Microchip Technologies
Authors: Yanxiang Deng, Amanda Finck, Rong Fan
Journal: Annual Review of Biomedical Engineering (2019)

Single-cell omics studies provide unique information regarding cellular heterogeneity at various levels of the molecular biology central dogma. This knowledge facilitates a deeper understanding of how underlying molecular and architectural changes alter cell behavior, development, and disease processes. The emerging microchip-based tools for single-cell omics analysis are enabling the evaluation of cellular omics with high throughput, improved sensitivity, and reduced cost. We review state-of-the-art microchip platforms for profiling genomics, epigenomics, transcriptomics, proteomics, metabolomics, and multi-omics at single-cell resolution. We also discuss the background of and challenges in the analysis of each molecular layer and integration of multiple levels of omics data, as well as how microchip-based methodologies benefit these fields. Additionally, we examine the advantages and limitations of these approaches. Looking forward, we describe additional challenges and future opportunities that will facilitate the improvement and broad adoption of single-cell omics in life science and medicine.
Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-Risk Patients
Authors: Jeffrey J. Popma, G. Michael Deeb, Steven J. Yakubov, Mubashir Mumtaz, Hemal Gada, Daniel O’Hair, Tanvir Bajwa, John C. Heiser, William Merhi, Neal S. Kleiman, Judah Askew, Paul Sorajja, Joshua Rovin, Stanley J. Chetcuti, David H. Adams, Paul S. Teirstein, George L. Zorn, John K. Forrest, Didier Tchétché, Jon Resar, Antony Walton, Nicolo Piazza, Basel Ramlawi, Newell Robinson, George Petrossian, Thomas G. Gleason, Jae K. Oh, Michael J. Boulware, Hongyan Qiao, Andrew S. Mugglin, Michael J. Reardon
Journal: New England Journal of Medicine (2019)

Transcatheter aortic-valve replacement (TAVR) is an alternative to surgery in patients with severe aortic stenosis who are at increased risk for death from surgery; less is known about TAVR in low-risk patients.
Clinical Characteristics and Survival in Patients with EBV Positive Diffuse Large B- Cell Lymphoma, Not Otherwise Specified: Report of 60 Cases
Authors: Brady E. Beltrán, Denisse A. Castro, Yesenia M. Huerta- Collado, Jose Manuel Malaga, Mauricio Postigo, Eduardo Sotomayor, Jorge J. Castillo
Journal: Blood (2018)
Elucidation of the IMiDs-Resistant Mechanism and Development of the Overcoming Drugs Inducing CRBN Independent G2/M Cell Cycle Arrest in Myeloma Cells
Authors: Ryo Uozaki, Shuji Aida, Takasi Yamagughi, Tomofumi Yamamoto, Sho Kashiwazaki, Hiroshi Yanagawa, Daiju Ichikawa, Maiko Matsushita, Yutaka Hattori
Journal: Blood (2018)
S100A8/A9 as a potent serological marker in monitoring the activity of chemotherapy in pancreatic cancer.
Authors: Shuichi Mitsunaga, Masafumi Ikeda, Satoshi Shimizu, Izumi Ohno, Hideaki Takahashi, Hiroyuki Okuyama, Yusuke Hashimoto, Kazuo Watanabe, Kumiko Umemoto, Atsushi Ochiai
Journal: Journal of Clinical Oncology (2015)

e15265 Background: The serum tumor-marker during chemotherapy is insufficient in advanced pancreatic cancer (PC). S100A8/A9 is one of inflammatory markers, contributes proliferation and survival of cancer cell, and is upregulated in PC. It was hypothesized that serum S100A8/A9 level served as an early marker to activity of chemotherapy for PC. The aim of this study was to analyze the correlation between the efficacies of chemotherapy and the changes of carbohydrate antigen 19-9 (CA19-9) and inflammatory markers including S100A8/A9 in prospective cohort of advanced PC. Methods: Treatment-naïve patients with PC and liver metastasis were eligible. Serum levels of CA19-9, S100A8/A9, and C-reactive protein (CRP) were measured on the morning before chemotherapy and one month later. A decrease of at least 25% in CA19-9, S100A8/A9, or CRP level was tested in association with overall survival (OS) using multivariate Cox proportional analysis. The prognostic values of pretreatment serological markers were also evaluated. Results: Eighty patients were analyzed in this study (male: 65%, median age: 66 years, Eastern Cooperative Oncology Group performance status [PS] 0: 52.5%). All patients received chemotherapy (gemcitabine [GEM]: 20 pts, GEM doublets: 44 pts, 5FU-based regimen: 16 pts). The median of serum S100A8/A9 at baseline was 3.51μg/ml. Patients with low S100A8/A9 at baseline showed better OS, compared to high S100A8/A9 group (P = 0.01). Patients with a decrease of at least 25% in S100A8/A9 (69.4%) or CA19-9 (37.5%) showed better OS to be compared to patients without a decrease of at least 25% in S100A8/A9 (P < 0.01) or CA19-9 (P = 0.02). A decrease of at least 25% in CRP (40.3%) was not associated with better OS (P = 0.54). Multivariate analysis revealed that a decrease of at least 25% in S100A8/A9 was an independent predictor to longer OS (hazard ratio [HR]: 0.44, P = 0.02). A decrease of at least 25% in CA19-9 showed the tendency of relation to longer OS (HR: 0.55, P = 0.07). Conclusions: Early decrease of S100A8/A9 was associated with lengthened survival in this study. Serum S100A8/A9 might be a useful marker in monitoring the activity of chemotherapy for advanced PC.
Sixty seconds on . . . reversing type 2 diabetes
Authors: Gareth Iacobucci
Journal: BMJ (2019)

It sure was. “Soup and shake diet offers hope of reversing diabetes for millions,” “Proof new diet can reverse diabetes,” and “Weight loss can reverse type 2 diabetes” were some of the feverish headlines.

A cluster randomised controlled study1 in Lancet Diabetes and Endocrinology that looked at a structured weight management programme for reversing type 2 diabetes. The two year update …