tbuckley/cabot-search huggingface dataset:
Analysis of DNA damage response (DDR) genes and tumor mutational burden (TMB) across 17,486 carcinomas of the tubular GI tract: Implications for therapy.
Authors: Aparna Raj Parikh, Yuting He, Theodore S. Hong, Ryan Bruce Corcoran, Jeffrey W. Clark, David P. Ryan, Daniel V.T. Catenacci, Joseph Chao, Marwan Fakih, Jeffrey S. Ross, Philip J. Stephens, Vincent A. Miller, Siraj Mahamed Ali, Alexa Betzig Schrock
Journal: Journal of Clinical Oncology (2018)

43 Background: The DDR pathway is important in tumor biology, allowing cancer cells a mechanism to resist damage by chemotherapy and radiotherapy. BRCA1/2 are the most well described genes in the pathway, but several others ( ATM, ATR, PALB2, etc.) are involved with DDR and are mutated in many cancers. Tumors with a DDR defect are susceptible to PARP inhibition (PARPi) in some cases, but also potentially to immune checkpoint inhibitors (ICPIs), given immunomodulatory effects of PARPi and the hypermutated phenotype commonly associated with these genomic alterations (GA). We looked at the prevalence of select DDR defects in tubular GI cancers and the correlation between DDR and TMB. Methods: We prospectively analyzed samples from 17,486 unique patients with advanced colorectal (CRC), esophageal, gastric, or small bowel carcinomas using hybrid-capture based comprehensive genomic profiling. TMB (mutations/Mb) was calculated from 1.11 Mb of sequenced DNA. We looked at GA in 8 genes- ARID1A, ATM, ATR, BRCA1, BRCA2, CDK12, PALB2, RAD51 across these tumors types. Results: DDR GA were found in 16% of cases: gastric 464/1,750 (27%), small bowel 141/666 (21%), esophageal 441/2,501 (18%), and CRC 1,824/12,569 (15%). ARID1A (9.0%) and ATM (5%) were the most commonly altered DDR genes in this series, followed by BRCA2 (2.3%), BRCA1 (1.1%), ATR (0.8%), CDK12 (0.7%), PALB2 (0.6%), and RAD51 (0.1%), with 24% (675/2,870) of DDR-altered cases having GA in more than one DDR gene. Among DDR-altered cases, 21% had high TMB (≥20 mut/Mb) compared to just 1.4% high TMB in DDR-wild-type cases (p &lt; 0.001). Microsatellite instability (MSI) status was available for a subset of cases and 19% (419/2,154) of those with a DDR GA were MSI high. CDK12 and ATR altered cases had the highest proportion of high TMB: CDK12 (55%, median TMB 31.5 mut/Mb) and ATR (55%, median TMB 35.1 mut/Mb), followed by cases with GA in BRCA2 (40%), BRCA1 (28%), ARID1A (27%), ATM (22%), and RAD51 (20%). Conclusions: DDR defects are relatively common across tubular GI tumor types and are associated with a hypermutated phenotype in over 20% of cases. This may be important to identify likely responders to both PARPi and ICPIs.
EXTENDED CARDIAC MONITORING IN PATIENTS WITH SEVERE SLEEP APNEA AND NO HISTORY OF ATRIAL FIBRILLATION (THE REVEAL XT-SA STUDY)
Authors: Cynthia Yeung, Doran Drew, Sharlene Hammond, Gwen Ewart, Damian Redfearn, Christopher Simpson, Hoshiar Abdollah, Benedict Glover, Adrian Baranchuk
Journal: Journal of the American College of Cardiology (2018)
TAILORED PREDIABETES PROGRAM IMPROVES CARDIOVASCULAR RISK
Authors: Mariam Kashani, Arn Eliasson, Claire Fuller, Elaine Walizer, Ellen Turner, Nancy Tschiltz, Marilyn Grunewald, Joy Halsey, Renata Engler, Todd Villines, Marina Vernalis
Journal: Journal of the American College of Cardiology (2018)
Dietary Patterns to Reduce Weight and Optimize Cardiovascular Health
Authors: Cheryl A.M. Anderson
Journal: Circulation (2018)

ealthful dietary patterns have a major role in healthy lifestyles and are necessary for cardiovascular health promotion. 1Over the past decade, dietary patterns have been a focus of human nutrition research studies.This is largely because of the well-recognized fact that we do not eat nutrients, we eat foods, and that we do not eat foods in isolation, we eat them in patterns.6][7] The specific components of these patterns, including the types of foods they include, macronutrient balance, and amount of energy deficit created (if weight loss is desired), can impact adherence and effectiveness.In this issue of Circulation, Sofi et al 8 report findings from the CARDIVEG trial (Prevention of Cardiovascular Disease With the Vegetarian Diet) conducted in Florence, Italy, from 2014 to 2015.Participants in the trial were overweight (body mass index ≥25 kg/m 2 ) and met one of the following criteria: total cholesterol >190 mg/dL, low-density lipoprotein cholesterol >115 mg/dL, triglyceride levels >150 mg/dL, and glucose levels >110 but <126 mg/dL.Individuals were randomly assigned to 1 of 2 interventions: (1) a low-calorie vegetarian diet, or (2) a low-calorie Mediterranean-style diet.The low-calorie vegetarian diet excluded meat, meat products, poultry, fish, seafood, and flesh from any other animals.It included eggs and dairy products and all other nonmeat food groups.The low-calorie Mediterranean diet comprised all food groups, including meat, meat products, poultry, and fish.To facilitate compliance with the intervention, participants were given a 1-week detailed menu plan and instructions containing tips and details about food groups that could be included and those that should be excluded.To my knowledge, this represents the first randomized trial comparing the effectiveness of a low-calorie vegetarian diet with a low-calorie Mediterranean diet on cardiovascular risk parameters in individuals considered to be clinically healthy and exhibiting a low-risk profile for cardiovascular disease.Study participants (n=118) were followed for 3 months and, over this time, had measurements of body weight, body composition, and cardiovascular disease risk factors such as lipids, markers of glycemia, oxidative stress, and inflammation.Eighty-five percent of study participants provided measurements at baseline and at the 3-month follow-up.Those who did not complete the study were younger, had a higher body mass index, had a higher percentage of fat mass, and consumed a lower percentage of total calories from carbohydrates.At the end of the first dietary intervention period, participants reported significant dietary changes relative to baseline, including fewer calories, less total fat,
Late thrombectomy reduced disability in acute stroke with mismatched clinical deficit and infarction volume
Authors: Lauren M. Mai, Wes Oczkowski
Journal: Annals of Internal Medicine (2018)

Source Citation Nogueira RG, Jadhav AP, Haussen DC, et al; DAWN Trial Investigators. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018:378:11-21.29129157
STAT-3–independent production of IL-17 by mouse innate-like αβ T cells controls ocular infection
Authors: Anthony J. St. Leger, Anna M. Hansen, Hatice Karauzum, Reiko Horai, Cheng-Rong Yu, Arian Laurence, Katrin D. Mayer-Barber, Phyllis Silver, Rafael Villasmil, Charles Egwuagu, Sandip K. Datta, Rachel R. Caspi
Journal: The Journal of Experimental Medicine (2018)

Appropriate regulation of IL-17 production in the host can mean the difference between effective control of pathogens and uncontrolled inflammation that causes tissue damage. Investigation of conventional CD4+ T cells (Th17 cells) has yielded invaluable insights into IL-17 function and its regulation. More recently, we and others reported production of IL-17 from innate αβ+ T cell populations, which was shown to occur primarily via IL-23R signaling through the transcription factor STAT-3. In our current study, we identify promyelocytic leukemia zinc finger (PLZF)–expressing iNKT, CD4−/CD8+, and CD4−/CD8− (DN) αβ+T cells, which produce IL-17 in response to TCR and IL-1 receptor ligation independently of STAT-3 signaling. Notably, this noncanonical pathway of IL-17 production may be important in mucosal defense and is by itself sufficient to control pathogenic Staphylococcus aureus infection at the ocular surface.
Health inequity in the post-conflict ethnic regions of northeastern Myanmar: a cross-sectional survey
Authors: Yingxi Zhao, Kun Tang, Bolun Li, Siqiao Zhang
Journal: The Lancet Global Health (2018)

BackgroundThe health system in the Myanmar–China border regions has undergone complex changes and the population has experienced ongoing political turbulence. Limited service points, poor financial protection mechanisms, and gender-based inequity restrain the population's access to health-care services. This study aims to analyse health inequity in the ethnic regions of northeastern Myanmar from three perspectives: geographical barriers, gender-based disparities, and financial consequences of receiving health services.MethodsA multistage-stratified random cluster survey was conducted in Shan State Special Region 2 and Eastern Shan State Special Region 4 of northeastern Myanmar between January and March, 2016. 4235 participants with complete information were recruited into the survey, including Wa, Dai, Aini, and other ethnicities. Data were collected on demographics, health status, household economic status, and service use. Interviews were conducted by a trained interviewers from a non-governmental service-providing organisation. Linear and logistic regressions were performed to understand the association between geographic distance, gender, and household income and inpatient/outpatient service use as well as the subsequent financial burdens.FindingsResidents living within 5 km of any health-care facility paid more outpatient visits (90·06 visits per 1000 population) in the past 2 weeks, than did those living 5–20 km and over 20 km away (54·84 and 54·02 per 1000 population, respectively). A similar but less significant difference was found for inpatient service use. Average costs for outpatient visits were US$46 in rural health centres, $40 in private clinics, $205 in township hospitals, and $449 in health facilities, whereas average costs for inpatient visits were $201, $223, $411, and $1415, respectively. Adults with a household income of above $720 per year were more likely to seek outpatient services than those with an annual income of less than $360 (odds ratio 1·43, 95% CI 0·98–2·10). After adjusting for other covariates, women were less likely to seek inpatient treatment (0·55, 0·35–0·84) and outpatient services (0·86, 0·64–1·15) than men.InterpretationGeographical barriers, gender-based disparities, and financial burdens significantly restrict the ethnic people's access to health-care facilities. Tackling health inequity in the Myanmar border areas requires a better primary health-care system, proper financial protection mechanisms, and a special focus on women. Although the study is exposed to several limitations, including potential interviewer bias and respondents' recall bias, the present study is the largest and one of the few studies of health inequity in the Myanmar–China border area.FundingNone.
Long-term outcomes of intensity-modulated radiation therapy combined with neoadjuvant hormonal therapy for Japanese patients with non-metastatic prostate cancer.
Authors: Rihito Aizawa, Kenji Takayama, Kiyonao Nakamura, Takahiro Inoue, Takashi Kobayashi, Shusuke Akamatsu, Toshinari Yamasaki, Osamu Ogawa, Takashi Mizowaki
Journal: Journal of Clinical Oncology (2018)

49 Background: This study aimed to evaluate long-term outcomes of intensity-modulated radiation therapy (IMRT) combined with neoadjuvant (NA) hormonal therapy (HT) in Japanese patients with non-metastatic prostate cancer (NMPC). Methods: We retrospectively analyzed the data of 485 patients with T1-T4N0M0 adenocarcinoma of the prostate treated with IMRT combined with NA-HT. Of these patients, 32, 113, 250, and 90 patients were categorized into the low-, intermediate-, high-, and very high-risk groups, respectively, according to the NCCN risk classification. NA-HT was administered over a median duration of 6 months. In principle, 74 or 78 Gy in 2 Gy per-fraction were delivered to the prostate and seminal vesicles according to the risk. We did not administer adjuvant HT (A-HT) for any patient following the completion of IMRT. Salvage HT (S-HT) commenced when prostate-specific antigen (PSA) values exceeded 4 ng/mL. Results: The median follow-up period was 103.4 months, and the median PSA value at the initiation of S-HT was 5.1 ng/mL. In the low-risk group, the 8-year biochemical relapse-free survival, prostate cancer-specific survival, overall survival, and S-HT-free (SHTF) rates were 89.7%, 100.0%, 100.0%, and 96.7%, respectively. Those were 83.7%, 100.0%, 96.0%, and 94.3% for the intermediate-risk group, 64.5%, 97.8%, 87.0%, and 79.4% for the high-risk group, and 47.7%, 96.6%, 89.7%, and 53.3% for the very high-risk group, respectively. The estimated 8-year cumulative incidence rates of late gastrointestinal and genitourinary (grades 2–3) toxicity were 7.2% and 21.8%, respectively. We observed no grade 4 or higher toxicity. Conclusions: High-dose IMRT, combined with NA-HT and without A-HT under the early S-HT policy, achieved excellent survival outcomes with acceptable morbidities for a Japanese cohort with NMPC. Moreover, especially for high, and very high-risk patients, this approach could be a viable alternative to the uniform provision of long-term A-HT because more than the half of the patients maintained SHTF status over a period of 8-year after IMRT. Prospective trials are warranted to validate the findings of this study.
MAJOR BLEEDING IN PATIENTS WITH PERIPHERAL ARTERY DISEASE: INSIGHTS FROM THE EUCLID TRIAL
Authors: William Schuyler Jones, Rachael Ward, Zhen Huang, Frank Rockhold, Iris Baumgartner, Jeffrey Berger, Juuso Blomster, F. Gerry Fowkes, Brian Katona, Kenneth Mahaffey, Lars Norgren, Rajendra Mehta, Thomas Povsic, Sreekanth Vemulapalli, William Hiatt, Manesh R. Patel
Journal: Journal of the American College of Cardiology (2018)
Inhibin Is a Novel Paracrine Factor for Tumor Angiogenesis and Metastasis
Authors: Priyanka Singh, Laura M. Jenkins, Ben Horst, Victoria Alers, Shrikant Pradhan, Prabhjot Kaur, Tapasya Srivastava, Nadine Hempel, Balázs Győrffy, Eugenia V. Broude, Nam Y. Lee, Karthikeyan Mythreye
Journal: Cancer Research (2018)

Abstract Inhibin is a heterodimeric TGFβ family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers; however, its tumor-specific functions remain unknown. Here, we demonstrate that the α subunit of inhibin (INHA), which is critical for the functionality of dimeric inhibin A/B, correlates with microvessel density in human ovarian tissues and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that inhibin-regulated angiogenesis is necessary for metastasis. Although inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis in vitro and in vivo. Inhibin-induced angiogenesis was abrogated via anti-inhibin α antibodies. The endothelial-specific TGFβ receptor complex comprising ALK1 and endoglin was a crucial mediator of inhibin signaling, offering a molecular mechanism for inhibin-mediated angiogenesis. These results are the first to define a role for inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting inhibin therapeutically. Significance: Inhibin is a predictor of poor patient survival in multiple cancers and is a potential target for antiangiogenic therapies. Cancer Res; 78(11); 2978–89. ©2018 AACR.
Differential <i>in Vitro</i> Biological Action, Coregulator Interactions, and Molecular Dynamic Analysis of Bisphenol A (BPA), BPAF, and BPS Ligand–ERα Complexes
Authors: Yin Li, Lalith Perera, Laurel A. Coons, Katherine A. Burns, J. Tyler Ramsey, Katherine E. Pelch, René Houtman, Rinie van Beuningen, Christina T. Teng, Kenneth S. Korach
Journal: Environmental Health Perspectives (2018)

Background: Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that might be harmful to human health. Recently, there has been widespread usage of bisphenol chemicals (BPs), such as bisphenol AF (BPAF) and bisphenol S (BPS), as replacements for BPA. However, the potential biological actions, toxicity, and the molecular mechanism of these compounds are still poorly understood. Objectives: Our objective was to examine the estrogenic effects of BPA, BPAF, and BPS and the molecular mechanisms of action in the estrogen receptor alpha (ERα) complex. Methods: In vitro cell models were used to compare the estrogenic effects of BPA, BPAF, and BPS to estrogen. Microarray Assay for Real-Time Coregulator-Nuclear receptor Interaction (MARCoNI) analysis was used to identify coregulators of BPA, BPAF, and BPS, and molecular dynamic (MD) simulations were used to determine the compounds binding in the ERα complex. Results: We demonstrated that BPA and BPAF have agonistic activity for both ERα and ERβ, but BPS has ERα-selective specificity. We concluded that coregulators were differentially recruited in the presence of BPA, BPAF, or BPS. Interestingly, BPS recruited more corepressors when compared to BPA and BPAF. From a series of MD analysis, we concluded that BPA, BPAF, and BPS can bind to the ER–ligand-binding domain with differing energetics and conformations. In addition, the binding surface of coregulator interactions on ERα was characterized for the BPA, BPAF, and BPS complexes. Conclusion: These findings further our understanding of the molecular mechanisms of EDCs, such as BPs, in ER-mediated transcriptional activation, biological activity, and their effects on physiological functions in human health. https://doi.org/10.1289/EHP2505
P015 Autophagy controls TREGS to TH17 conversion and shapes the severity of arthritis
Authors: J Niven, N Madelon, A Caruso, S Hugues, M Gannage
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Macroautophagy is an important contributor of cellular homeostasis, and therefore is active and up regulated in various conditions of cellular stress and inflammation. The pathway has been implicated in shaping the innate and adaptive immune responses by acting at multiple and diverse levels including cytokine secretion and antigen presentation. <h3>Objectives</h3> Our aim is to analyse the contribution of macroautophagy in antigen presenting cells to the adaptive immune response in the context of arthritis. We analysed the antigen induced arthritis model in mice that are deficient in autophagy in their dendritic cells. <h3>Methods</h3> CD11c-Cre mice (C57BL/6), (Jackson Laboratory) were crossed with Atg5<sup>flox/flox</sup> mice (C57BL/6) provided by Dr. Noboru Mizushima (Japan). ATG5 is an essential autophagy gene, its targeted deletion in dendritic cells completely abolished a functional autophagy pathway in these cells (DC/ATG5<sup>-/-</sup>).For the antigen induced arthritis mice model (AIA), mice were immunised with methylated BSA (mBSA) and CFA. Monoarthritis was induced at day 21 by injection of mBSA into the knee joint and animals sacrificed at day 28. Sections from knees were stained with hematoxylin and eosin for macroscopic scoring of the cellular infiltrate. In parallel, toluidine blue staining was used for cartilage damage. T cell function was monitored by cytokine production by ELISA, after <i>in vitro</i> re-stimulation with mBSA or CD3/CD28 for 72 hour, using single cell suspensions from lymph nodes. <h3>Results</h3> Mice lacking autophagy in their dendritic cells (DC/ATG5<sup>-/-</sup>) showed enhanced cartilage destruction and bone erosion. Interestingly, the Th1/Th17 response in DC/ATG5<sup>-/-</sup> mice was significantly increased. In parallel this phenotype was linked to a decreased Foxp3 expression in the regulatory T cell (Treg) population. Using Treg transfer upon AIA we could demonstrate that regulatory T cells switch to Th17 cells in the context of inflammation. <h3>Conclusions</h3> Autophagy deficiency in dendritic cells exacerbates the Th1/Th17 inflammatory response in the AIA model, resulting in increased cartilage destruction and bone erosion. This phenotype is linked to Tregs instability upon inflammation. <h3>Disclosure of interest</h3> None declared
Randomized phase III study of gemcitabine and cisplatin (GC) versus dose dense methotrexate, vinblastine, doxorubicin and cisplatin (DD-MVAC) in the perioperative setting for patients with locally advanced transitional cell cancer of the bladder: The French GETUG/AFU V05 VESPER trial.
Authors: Christian Pfister, Gwenaelle Gravis, Geraldine Pignot, Aude Flechon, Michel Soulie, Christine Chevreau, Laurent Guy, Brigitte Laguerre, Nicolas Mottet, Florence Joly, Michel Henry-Amar, Francois Radvanyi, Yves Allory, Stephane Culine
Journal: Journal of Clinical Oncology (2018)

TPS530 Background: Radical cystectomy remains the gold standard treatment for invasive non metastatic transitional cell cancer of the bladder. Perioperative chemotherapy (adjuvant ou neoadjuvant) has been developed to increase overall survival. However, the chemotherapy administration time and optimal chemotherapy regimen are not yet determined. As DD-MVAC has been shown to be associated with higher response rates in bladder metastatic disease, also a better efficacy can be suspected in the perioperative setting. Methods: We designed a randomized phase III study to compare the efficacy of GC and DD-MVAC in term of progression-free survival in patients for whom chemotherapy has been decided, before or after radical cystectomy (disease defined by a T2, T3 or T4a N0 M0 stadification for patients receiving neoadjuvant chemotherapy or pT3 or pT4 or pN+ and M0 for patients receiving adjuvant chemotherapy). Secondary endpoints include overall survival, side effects, response rate in the neoadjuvant setting. Main exclusion criteria were histological variants (pure adenocarcinoma or pure epidermoid carcinoma or pure or mixed small-cell neuro-endocrine carcinoma) and ventricular ejection fraction under 50%. The total number of patients projected was 500 based on the median progression-free survival rate of 50% at 3 years observed in patients treated with GC (standard arm A) in the perioperative setting. An absolute improvement of 10% (HR = 0.74) was expected with DD-MVAC (experimental arm B) with a = 0.05 and b = 0.20. In October 2017, 460 patients have been included. An interim analysis is planned after the occurrence of 174 events. With an estimated uniform accrual rate of 140 patients per year for 3.5 years and exponential survival, the final analysis is expected to occur 8 years after the start of the trial. Concomitant ancillary study has also started, focusing on the identification of subgroups for muscle invasive bladder tumors sensitivity to neoadjuvant chemotherapy, as suggested by the recent MDA classification. Clinical trial information: NCT 018 12369.
Reactive Oxygen Species in Metabolic and Inflammatory Signaling
Authors: Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling
Journal: Circulation Research (2018)

Reactive oxygen species (ROS) are well known for their role in mediating both physiological and pathophysiological signal transduction. Enzymes and subcellular compartments that typically produce ROS are associated with metabolic regulation, and diseases associated with metabolic dysfunction may be influenced by changes in redox balance. In this review, we summarize the current literature surrounding ROS and their role in metabolic and inflammatory regulation, focusing on ROS signal transduction and its relationship to disease progression. In particular, we examine ROS production in compartments such as the cytoplasm, mitochondria, peroxisome, and endoplasmic reticulum and discuss how ROS influence metabolic processes such as proteasome function, autophagy, and general inflammatory signaling. We also summarize and highlight the role of ROS in the regulation metabolic/inflammatory diseases including atherosclerosis, diabetes mellitus, and stroke. In order to develop therapies that target oxidative signaling, it is vital to understand the balance ROS signaling plays in both physiology and pathophysiology, and how manipulation of this balance and the identity of the ROS may influence cellular and tissue homeostasis. An increased understanding of specific sources of ROS production and an appreciation for how ROS influence cellular metabolism may help guide us in the effort to treat cardiovascular diseases.