tbuckley/cabot-search huggingface dataset:
Identification of ERCC2 as novel susceptibility gene for hereditary breast and ovarian cancer.
Authors: Pauline Wimberger, Anna Benet-Pages, Steffen Schubert, Ramunas Janavicius, Jan Dominik Kuhlmann, Andreas Tzschach, Karin Kast, Alfons Meindl, Elke Holinski-Feder, Steffen Emmert, Evelin Schrock, Andreas Rump
Journal: Journal of Clinical Oncology (2015)

1512 Background: Breast and ovarian cancer (BC/OC) predisposition has been associated with several high-, moderate-, and low-penetrance susceptibility genes. Despite comprehensive testing by next-generation sequencing (NGS), there is still a large portion of high risk cases with absence of mutations in any of the known susceptibility loci. Therefore, it is essential to extend the diagnostic spectrum by screening novel candidate genes. Methods: Inclusion criteria for study patients (n = 717, German and Lithuanian) were defined by the German Consortium for Breast and Ovarian Cancer. NGS was performed on the Illumina MiSeq sequencer and with the TruSight cancer panel including 94 genes cancer associated genes. Results: In 19.7 % of the patients, BRCA1 or BRCA2 variations were found. These were either pathogenic loss-of-function mutations (43%) or rare unclassified missense variations with high probability of a deleterious effect (57%). In 17.9% of the patients we found null-mutations and rare unclassified missense variants in the acknowledged BC/OC susceptibility genes ATM, CDH1, CHEK2, NBN, PALB2, RAD51C/D and TP53. Analysis of the non-BC/OC genes on the NGS panel identified the
Abstract MP30: Gaps in Provider Lifestyle Counseling and Its Adherence Among Obese Adults With Diabetes in the United States
Authors: Ehimen Aneni, Javier Valero-Elizondo, Chukwuemeka U Osondu, Eric J Brandt, Khurram Nasir
Journal: Circulation (2019)

Introduction: The 2013 ACC/AHA guidelines on the management of obesity in adults strongly recommend lifestyle counseling on calorie restriction, improved physical activity and referral to a weight loss program for obese adults who are likely to benefit from them. This study assessed clinician adherence to these guidelines and the compliance with this advice among obese adults with diabetes in the United States. Methods: We utilized the National Health Interview Survey (2016 -2017) for this study. Individuals were asked if in the last 12 months, they had been told to reduce caloric intake, increase physical activity, or if they had been referred to a weight loss program by their health provider. For those who said yes, they were asked if they had taken the advice of the provider. We analyzed the frequencies of these questions and the compliance with this advice among obese individuals with diabetes. Results: Among those who were mildly obese (BMI 30 - 34.9kg/m 2 , N=1,502), approximately 37% and 40% were not counseled on caloric restriction and increasing physical activity respectively. Among the morbid obese with diabetes (BMI ≥35 kg/m 2 , N=1,670), this number was approximately 28% for both caloric restriction and increasing physical activity. Referral for a weight loss program was very low: 21% and 32% in mild and morbidly obese with diabetes. Among those referred, only approximately 30% enrolled in a weight loss program. In subgroup analyses, females, persons with public insurance or who lacked insurance, low-income earners and those with 10+ years from their diabetes diagnosis were less likely to be counseled about any 2 of these lifestyle changes. Conclusions: Lifestyle counseling and its compliance among obese adults with diabetes in the United States is still suboptimal and shows disparities by gender and socioeconomic status. This study highlights the gaps in the implementation of the AHA/ACC 2013 guidelines on management of obesity among adults particularly among those with diabetes who will derive the greatest benefit.
Travellers as sentinels of chikungunya epidemics: a family cluster among Finnish travellers to Koh Lanta, Thailand, January 2019
Authors: Anu Kantele
Journal: Eurosurveillance (2019)

In January 2019, five of 11 travellers to Koh Lanta, Thailand, contracted chikungunya, symptoms starting 4 days after presumed transmission. Four cases were hospitalised, one child treated in intensive care; 6 weeks after disease onset, all three adults have persistent arthralgias/arthritis, incapacitating for two. Together with a recent report of eight chikungunya cases among travellers to various destinations in Thailand, the high attack rate in our cluster points to an ongoing outbreak in the country.
Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells
Authors: Shaojun Xing, Kexin Gai, Xiang Li, Peng Shao, Zhouhao Zeng, Xudong Zhao, Xin Zhao, Xia Chen, William J. Paradee, David K. Meyerholz, Weiqun Peng, Hai-Hui Xue
Journal: The Journal of Experimental Medicine (2019)

Tcf1 and Lef1 have versatile functions in regulating T cell development and differentiation, but intrinsic requirements for these factors in regulatory T (T reg) cells remain to be unequivocally defined. Specific ablation of Tcf1 and Lef1 in T reg cells resulted in spontaneous multi-organ autoimmunity that became more evident with age. Tcf1/Lef1-deficient T regs showed reduced protection against experimentally induced colitis, indicative of diminished immuno-suppressive capacity. Transcriptomic analysis revealed that Tcf1 and Lef1 were responsible for positive regulation of a subset of T reg-overrepresented signature genes such as Ikzf4 and Izumo1r Unexpectedly, Tcf1 and Lef1 were necessary for restraining expression of cytotoxic CD8+ effector T cell-associated genes in T reg cells, including Prdm1 and Ifng Tcf1 ChIP-seq revealed substantial overlap between Tcf1 and Foxp3 binding peaks in the T reg cell genome, with Tcf1-Foxp3 cooccupancy observed at key T reg signature and cytotoxic effector genes. Our data collectively indicate that Tcf1 and Lef1 are critical for sustaining T reg suppressive functions and preventing loss of self-tolerance.
Liver X receptor (LXR) as a target for ovarian cancer
Authors: Daniel Scoles, Hisae Karahashi, Haimei Wang, Beth Karlan
Journal: Cancer Research (2008)

3433  Serum oxidized LDL (oxLDL) is associated with increased ovarian cancer risk. OxLDL may also be elevated in the serum of obese individuals and we recently reported outcomes data from 216 ovarian cancer patients demonstrating that obesity was associated with reduced survival. To define the underlying mechanism for these observations, this study investigates targeting of liver X receptor (LXR) as a means to reverse proliferation of ovarian cancer cells mediated by ox-LDL. Serum oxLDL is regulated upon its binding scavenger receptors (CD36 & SRA), mediating oxLDL cell entry by receptor mediated endocytosis. Upon entering the cell oxLDL activates LXR nuclear receptors resulting in expression of ATP binding cassette transporter (ABCA1) leading to cholesterol efflux to HDL and subsequent reduction of LDL synthesis by the liver. Activation of LXR by synthetic nonsteroidal LXR ligands elicits the same response in mouse models, reducing atherosclerosis and other oxLDL-related disorders. We hypothesized that oxLDL is directly mitogenic to ovarian carcinoma cells and that LXR agonist can inhibit oxLDL mediated proliferation. Ovarian carcinoma cell lines CAOV3, OVCAR3 and SKOV3 were cultured as indicated and MTT proliferation assays were conducted. Expression of cell surface receptors was assessed by immunoblotting. Proliferation of each of the cell lines was significantly increased by oxLDL, but LDL had no mitogenic effect. A dose-dependent increase in cellular proliferation was seen with increasing oxLDL concentration. LXR synthetic ligand TO901317 doses between 10-50 ng/ml significantly inhibited the proliferation of all three cell lines. Growth stimulated by 25 μg/ml oxLDL was also reversed with the addition of 50 ng/ml TO901317. OxLDL also reduced the inhibitory effect of cisplatin for CAOV3 cells. We confirmed that each of the cell lines expressed CD36. We also showed that media conditioned on adipose cells was mitogenic to ovarian carcinoma cells. We conclude that LXR agonists may be effective for treating ovarian cancer based on dual roles of lowering LDL synthesis by the liver and directly effecting the inhibition of ovarian cancer cell proliferation.
Race/Ethnicity and Geographic Access to Urban Trauma Care
Authors: Elizabeth L. Tung, David A. Hampton, Marynia Kolak, Selwyn O. Rogers, Joyce P. Yang, Monica E. Peek
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Little is known about the distribution of life-saving trauma resources by racial/ethnic composition in US cities, and if racial/ethnic minority populations disproportionately live in US urban trauma deserts. <h3>Objective</h3> To examine racial/ethnic differences in geographic access to trauma care in the 3 largest US cities, considering the role of residential segregation and neighborhood poverty. <h3>Design, Setting, and Participants</h3> A cross-sectional, multiple-methods study evaluated census tract data from the 2015 American Community Survey in Chicago, Illinois; Los Angeles (LA), California; and New York City (NYC), New York (N = 3932). These data were paired to geographic coordinates of all adult level I and II trauma centers within an 8.0-km buffer of each city. Between February and September 2018, small-area analyses were conducted to assess trauma desert status as a function of neighborhood racial/ethnic composition, and geospatial analyses were conducted to examine statistically significant trauma desert hot spots. <h3>Main Outcomes and Measures</h3> In small-area analyses, a trauma desert was defined as travel distance greater than 8.0 km to the nearest adult level I or level II trauma center. In geospatial analyses, relative trauma deserts were identified using travel distance as a continuous measure. Census tracts were classified into (1) racial/ethnic composition categories, based on patterns of residential segregation, including white majority, black majority, Hispanic/Latino majority, and other or integrated; and (2) poverty categories, including nonpoor and poor. <h3>Results</h3> Chicago, LA, and NYC contained 798, 1006, and 2128 census tracts, respectively. A large proportion comprised a black majority population in Chicago (35.1%) and NYC (21.4%), compared with LA (2.7%). In primary analyses, black majority census tracts were more likely than white majority census tracts to be located in a trauma desert in Chicago (odds ratio [OR], 8.48; 95% CI, 5.71-12.59) and LA (OR, 5.11; 95% CI, 1.50-17.39). In NYC, racial/ethnic disparities were not significant in unadjusted models, but were significant in models adjusting for poverty and race-poverty interaction effects (adjusted OR, 1.87; 95% CI, 1.27-2.74). In comparison, Hispanic/Latino majority census tracts were less likely to be located in a trauma desert in NYC (OR, 0.03; 95% CI, 0.01-0.11) and LA (OR, 0.30; 95% CI, 0.22-0.40), but slightly more likely in Chicago (OR, 2.38; 95% CI, 1.56-3.64). <h3>Conclusions and Relevance</h3> In this study, black majority census tracts were the only racial/ethnic group that appeared to be associated with disparities in geographic access to trauma centers.
Alkylating agents as first line chemotherapy in castration resistant prostate cancer: Is survival compromised? An analysis using an updater prognostic model in castration-resistant prostate cancer.
Authors: Matthew Mee, Peter Wilson, Wendy Ansell, Jonathan Shamash
Journal: Journal of Clinical Oncology (2015)

e16082 Background: Docetaxel is the standard first line therapy for castration-resistant prostate cancer (CRPC). We reviewed the outcome to patients treated with alkylating drugs (normally low dose oral chlorambucil and lomustine). Many patients received dexamethasone and diethylstilbestrol prior to chemotherapy and received chemotherapy on PSA progression. We wished to see how such an approach compared to docetaxel . Until recently it has been difficult to compare different approaches due to the lack of validated prognostic factors. We used the model described by Halabi et al (JCO 2014) Methods: The outcome of 252 consecutive patients with CRPC treated between 1999 and 2014 at St Bartholomew’s Hospital who required chemotherapy and had enough data for a prognostic group to be ascribed were reviewed . Results: Twenty- four had low, 57 intermediate and 171 high risk disease according to the model.The overall survival from start of definitive treatment for CRPC – either corticosteroids +/- estrogens followed by chemotherapy or chemotherapy alone was 22.4 months (20.0-25.8). The median time from CRPC hormonal therapy to chemotherapy in the low, intermediate and high risk groups was 15.9 (1.2 -48.7),11.1 (1.1-81.6) and 7.0 (0.9-93.2) months respectively. The survival from first chemotherapy was 10.7 months ( 8.6-11.8). For the low, intermediate and high risk group it was 30.6 (22.8-41.2), 19.4 (15.3-26.3),7.2(6.0-8.5). For the respective groups the numbers receiving alkylators vs docetaxel were 19 vs 5, 47 vs 10, and 108 vs 63. The survivals were similar -32.6 (22.2-49.9) vs 22.8 (20.3-non evaluable), 19.4 (14.8-26.3) vs 26.1 (6.0-NE) and 7.2 (5.9-8.9) vs 7.3 (5.0-8.9) Chi2 3.32 (p = 0.07), 0.01(p = 0.98) and 0.04 (p = 0.851) respectively Conclusions: The results confirm the utility of this prognostic classification in the alkylator treated population.Although retrospective the data suggests that an approach using alkylating agents produces similar survival to docetaxel as initial chemotherapy .Further research in to whether certain subgroups are particularly likely to benefit from one or other approach is warranted.
Targeting the Epichaperome As an Effective Precision Medicine Approach in a Novel PML-SYK Fusion Acute Myeloid Leukemia
Authors: Gail J. Roboz, Mayumi Sugita, Juan Miguel Mosquera, David C Wilkes, Sarah Nataraj, Reyna A Jimenez-Flores, Rohan Bareja, LunBiao Yan, Kenneth W Eng, Jaclyn A Croyle, Theresa Y MacDonald, Zohal Noorzad, Danielle Pancirer, Shuhua Cheng, Jenny Z Xiang, Luke Olson, David Rickman, Wayne Tam, Mark A. Rubin, Himisha Beltran, Andrea Sboner, Koen Van Besien, Bob Morgan, Duane C. Hassane, Olivier Elemento, Gabriela Chiosis, Monica L. Guzman
Journal: Blood (2018)
Global liver disease burdens and research trends: Analysis from a Chinese perspective
Authors: Jia Xiao, Fei Wang, Nai-Kei Wong, Jinhan He, Rui Zhang, Ruijuan Sun, Yanying Xu, Yingxia Liu, Wei Li, Kazuo Koike, Weiling He, Hong You, Yinglei Miao, Xiaowei Liu, Mingming Meng, Bin Gao, Hua Wang, Cui Li
Journal: Journal of Hepatology (2019)
CD4 T cell sphingosine 1-phosphate receptor (S1PR)1 and S1PR4 and endothelial S1PR2 regulate afferent lymphatic migration
Authors: Yanbao Xiong, Wenji Piao, C. Colin Brinkman, Lushen Li, Joseph M. Kulinski, Ana Olivera, Andreane Cartier, Timothy Hla, Keli L. Hippen, Bruce R. Blazar, Susan R. Schwab, Jonathan S. Bromberg
Journal: Science Immunology (2019)

Sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) regulate migration of lymphocytes out of thymus to blood and lymph nodes (LNs) to efferent lymph, whereas their role in other tissue sites is not known. Here, we investigated the question of how these molecules regulate leukocyte migration from tissues through afferent lymphatics to draining LNs (dLNs). S1P, but not other chemokines, selectively enhanced human and murine CD4 T cell migration across lymphatic endothelial cells (LECs). T cell S1PR1 and S1PR4, and LEC S1PR2, were required for migration across LECs and into lymphatic vessels and dLNs. S1PR1 and S1PR4 differentially regulated T cell motility and vascular cell adhesion molecule-1 (VCAM-1) binding. S1PR2 regulated LEC layer structure, permeability, and expression of the junction molecules VE-cadherin, occludin, and zonulin-1 through the ERK pathway. S1PR2 facilitated T cell transcellular migration through VCAM-1 expression and recruitment of T cells to LEC migration sites. These results demonstrated distinct roles for S1PRs in comodulating T cell and LEC functions in migration and suggest previously unknown levels of regulation of leukocytes and endothelial cells during homeostasis and immunity.
Avelumab treatment in metastatic urothelial carcinoma: Post-hoc analysis of high-risk populations in the phase Ib JAVELIN Solid Tumor Study.
Authors: Andrea B. Apolo, Manish R. Patel, John Allan Ellerton, Luc Dirix, Juliane Manitz, Vijay Kasturi, John Warth, Galit Rosen, James L. Gulley
Journal: Journal of Clinical Oncology (2019)

428 Background: Avelumab is a human anti‒PD-L1 IgG1 antibody approved in the US, Canada, and Israel for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) progressed after platinum chemotherapy. In the JAVELIN Solid Tumor study, patients (pts) in various subgroups had a favorable objective response rate (ORR) with avelumab. Here, we report further post hoc analyses of safety and efficacy outcomes with avelumab in high-risk mUC subgroups. Methods: Pts with mUC that had progressed after platinum-based therapy in the JAVELIN Solid Tumor study were analyzed. Best overall response (per RECIST 1.1) was adjudicated by an independent review committee. ORR, disease control rate (DCR), progression-free survival (PFS), and adverse event (AE) profiles for pre-specified subgroups of high-risk pts were compared. Results: 242 pts with mUC received avelumab and were followed up for ≥2 years (data cutoff, Apr 2018). No difference was found in ORR between pts with renal insufficiency (creatine clearance [CrCl], &lt;60 mL/min; n=107) and pts with CrCl ≥60 mL/min (n=131; 17.8% [95% CI: 11.0-26.3] vs 15.3% [95% CI: 9.6-22.6]) or between pts with upper (n=56) vs lower tract tumors (n=186; 14.3% [95% CI: 6.4-26.2] vs 17.2% [95% CI: 12.1-23.4]). ORR in pts with baseline liver metastases (n=83) was 6.0% (95% CI: 2.0-13.5) vs 22.0% (95% CI: 15.8-29.3) in pts without (n=159). ORR in elderly pts (≥75 years; n=68) was 25.0% (95% CI: 15.3-37.0) vs 13.2% (95% CI: 8.6-19.2) in younger pts (n=174). ORR in pts with albumin ≥35 g/L (n=197) was 19.8% (95% CI: 14.5-26.1) vs 2.2% (95% CI: 0.1-11.8) in pts with &lt;35 g/L (n=45). Except for the albumin levels and age subgroups (where the trend in ORR was not confirmed), subgroups showed DCR and PFS that were consistent with ORR trends. AE profiles did not exhibit any higher risk of adverse effects in these subgroups. Conclusions: Responses to avelumab occurred in select assessed subgroups previously defined as poor prognostic or high risk, suggesting that immunotherapy may achieve comparable efficacy irrespective of factors such as site of disease and renal status; no difference in safety profiles was identified. Clinical trial information: NCT01772004.
Abstract P310: Erectile Dysfunction and Venous Thromboembolism Risk in the Health Professionals Follow-up Study
Authors: Laura B Harrington, Kaitlin Hagan, Jae H Kang, Jihye Kim, Edward Giovannucci, Murray A Mittleman, Eric B Rimm, Christopher Kabrhel, Majken K Jensen, Kenneth J Mukamal
Journal: Circulation (2019)

Introduction: Erectile function requires both intact arterial inflow and venous occlusion, and it has thus been posited that erectile dysfunction (ED) could be a marker of cardiovascular risk. Although a positive association between ED and arterial thrombotic risk has been well-characterized, whether ED is associated with venous thromboembolic event risk is unknown. Hypothesis: ED is positively associated with risk of incident venous thromboembolism (VTE) events, including both deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods: Eligible men were Health Professionals Follow-up Study (HPFS) participants without VTE and prostate cancer prior to baseline in 2000 (n=27,771). As part of biennial mailed questionnaires, men reported their current erectile function in 2000, 2004, and 2008, which was categorized as ED presence (“very poor” or “poor” erectile function) or ED absence (“fair”, “good”, or “very good”). Self-reported incident VTE included the first occurrence of either PE or DVT. We used Cox Proportional Hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE associated with time-varying ED presence versus absence, with participants censored at death, warfarin use, loss to follow-up, or incident prostate cancer. Multivariable analyses adjusted for age, smoking, body mass index, physical activity, caloric intake, race, alcohol consumption, aspirin use, diabetes, hypertension, hypercholesterolemia, myocardial infarction/angina, and cancer. Results: Over 256,678 person-years of follow-up, men self-reported 665 VTE events. At baseline, men were on average 65 years of age and 31% reported presence of ED. In multivariable-adjusted analyses, ED presence was associated with a 30% greater risk of incident VTE (HRadj=1.3; 95% CI: 1.1, 1.6; erectile function linear p-trend=0.003). Estimates were similar in sensitivity analyses of the smaller subgroup of confirmed PE (n=196 PEs confirmed by medical record review/participant reconfirmation or self-reported among persons with prior cancer) (HRadj=1.3; 95% CI: 0.9, 1.8). Conclusions: Presence of ED was positively associated with VTE risk in this study of U.S. men, even after multivariable adjustment for traditional cardiovascular risk factors, suggesting that ED has potential as a marker of VTE risk.
The Efficacy and Safety of Anti-CD19 CAR T-Cell Therapy in Young Adults with Relapsed and Refractory Aggressive B-Cell Malignancies—the Experience of a Single Center in Israel
Authors: Abraham Avigdor, Michal Besser, Arnon Nagler, Orit Itzhaki, Jacob Schachter, Avichai Shimoni, Ronit Yerushalmi, Amos Toren, Elad Jacobi
Journal: Blood (2017)
Quality of life differences for LHRH-antagonist versus LHRH-agonist in special patient groups with cardiovascular comorbidities and higher tumor burden in patients with hormone-sensitive prostate cancer (hsPCa).
Authors: Jan Lehmann, Markus Flesch, Michael Gedamke
Journal: Journal of Clinical Oncology (2019)

153 Background: ADT with LHRH-agonists or LHRH-antagonists (degarelix, D) is the standard of care in advanced hsPCa. An analysis of ProComD from 2018 showed that D was more frequently used in patients with cardiac and peripheral arterial disease. Methods: In the ProComD, a two-arm, prospective non-interventional study, potential differences in comorbidity and other parameters such as baseline PSA and metastatic status on patient reported outcome between D and LHRH-agonists treatment were investigated. Results: Data on patients with a minimum follow-up period of one year (n = 285, D = 179, LHRH-agonist = 106) up to three years (n = 62, D = 40, LHRH-agonist = 22) were documented. Baseline criteria were generally similar except for disease T-stage (p = 0.0238), metastatic status (p = 0.0419) and PSA (p = 0.0041). The average age of patients was 74.1 years. Stage distribution: D vs LHRH-agonists, pT2 25.7/24.5%, pT3 24.1/34.9%, pT4 6.1/2.8%, unknown. 44.1/37.7%, cNX 49.7/44.3%, cN0 32.4/42.5%, cN+ 17.9/12.3%, cMX 27.4/25.5%, cM0 34.1/49.1%, cM1 38.6/25.5%. Global health status (EORTC) did not change over 12 months neither for D nor for LHRH-agonists. Differences in subscales between D and LHRH-agonists were observed for role functioning, cognitive functioning and, while QoL was unchanged under D, LHRH-agonists sig. reduced QoL (p = 0.073, p = 0.0368). Pain (marginal sig.) p = 0.0621) as well as analgesics (17.3% vs 1.1% at 3 months vs baseline) were reduced by D. Since baseline PSA differed sig., we specifically evaluated the subgroup of patients with a PSA &gt; 50 ng/ml, where Global Health Status was found to be different between D and LHRH-agonists already at month 6 and at month 12 (p = 0.0331, p = 0.0232), favoring D. Conclusions: Our results indicate that Degarelix, with a different mode of action, is used in a different patient group (CVD and higher tumor stage as well as metastatic patients) compared to LHRH-agonists treatment. EORTC Global Health is similar to LHRH-agonists, but differences occur in subscales (role and cognitive functioning) as well as in subgroups (PSA &gt; 50 ng/ml) in favour of the LHRH-antagonist. Clinical trial information: NCT02234089.