tbuckley/cabot-search huggingface dataset:
Genetic Inactivation of <scp>ZCCHC</scp>6 Suppresses Interleukin‐6 Expression and Reduces the Severity of Experimental Osteoarthritis in Mice
Authors: Mohammad Y. Ansari, Nazir M. Khan, Nashrah Ahmad, Jonathan Green, Kimberly Novak, Tariq M. Haqqi
Journal: Arthritis & Rheumatology (2018)

Objective Cytokine expression is tightly regulated posttranscriptionally, but high levels of interleukin‐6 ( IL ‐6) in patients with osteoarthritis ( OA ) indicate that regulatory mechanisms are disrupted in this disorder. The enzyme ZCCHC 6 (zinc‐finger CCHC domain–containing protein 6; TUT ‐7) has been implicated in posttranscriptional regulation of inflammatory cytokine expression, but its role in OA pathogenesis is unknown. The present study was undertaken to investigate whether ZCCHC 6 directs the expression of IL ‐6 and influences OA pathogenesis in vivo. Methods Human and mouse chondrocytes were stimulated with recombinant IL ‐1β. Expression of ZCCHC 6 in human chondrocytes was knocked down using small interfering RNA s. IL ‐6 transcript stability was determined by actinomycin D chase, and 3′‐uridylation of micro RNA s was determined by deep sequencing. Zcchc6 −/− mice were produced by gene targeting. OA was surgically induced in the knee joints of mice, and disease severity was scored using a semiquantitative grading system. Results ZCCHC 6 was markedly up‐regulated in damaged cartilage from human OA patients and from wild‐type mice with surgically induced OA . Overexpression of ZCCHC 6 induced the expression of IL ‐6, and its knockdown reduced IL ‐6 transcript stability and IL ‐1β–induced IL ‐6 expression in chondrocytes. Reintroduction of Zcchc6 in Zcchc6 −/− mouse chondrocytes rescued the IL ‐1β–induced IL ‐6 expression. Knockdown of ZCCHC 6 reduced the population of micro‐ RNA 26b (miR‐26b) with 3′‐uridylation by 60%. Zcchc6 −/− mice with surgically induced OA produced low levels of IL ‐6 and exhibited reduced cartilage damage and synovitis in the joints. Conclusion These findings indicate that ZCCHC 6 enhances IL ‐6 expression in chondrocytes through transcript stabilization and by uridylating miR‐26b, which abrogates repression of IL ‐6. Inhibition of IL ‐6 expression and significantly reduced OA severity in Zcchc6 −/− mice identify ZCCHC 6 as a novel therapeutic target to inhibit disease pathogenesis.
GW29-e1347 Enhanced β1/2 adrenergic receptor antibodies levels are associated with atrial arrhythmia
Authors: Mengjiao Shao, Ling Zhang, Jia Shi, Yaodong Li, Jianghua Zhang, Qiang Xing, Yanmei Lu, Baopeng Tang, Xianhui Zhou
Journal: Journal of the American College of Cardiology (2018)
Abstract 258: Progressive Diastolic Dysfunction, Perivascular Fibrosis and Left Ventricular Hypertrophy in LDL-Receptor Deficient Mice
Authors: Walid Nachar, Candace Lee, Foued Maafi, Yanfen Shi, Téodora Mihalache-Avram, Éric Rhéaume, Jean-Claude Tardif
Journal: Circulation Research (2016)

Background and Aim: Left ventricular diastolic dysfunction (LVDD) refers to abnormal filling of the left ventricle (LV) due to its impaired relaxation or increased stiffness. Animal models of LVDD are limited and underlying mechanisms remain largely unknown. We aimed to assess LVDD in Ldlr -/- mice using imaging and gene expression measurements. Methods: Sixty-nine Ldlr -/- mice were fed with a western-type diet supplemented with vitamin D 2 (30 U/g/day) for 20 weeks to induce LVDD. Eight normal mice were fed with a normal diet and used as control group. Serial echocardiograms were used to assess cardiac structure and function, histological analyses were done on LV sections, and RT-PCR was performed on LV samples. Results: Echocardiographic results show the development of LVDD over time (P values &lt;0.05), with a modest increase in LV mass/BW and preserved systolic function. There was an increase of perivascular fibrosis (14.9%±1.0% (14.9 to 100) vs 9.0%±1.6%; (9 to 100), respectively, P&lt;0.01) in Ldlr -/- mice compared to controls as detected by Masson’s trichrome staining, which was correlated with increased mRNA expression for TGFß1 and Smad2 and 3 (P&lt;0.05 for all). This was accompanied by numerical increases in Type I and III collagen mRNAs ( Col I : 1.33 (1.03; 1.97) vs 1.03 (0.90; 1.11), P=0.06; Col III : 1.49±0.30 vs 1.00±0.10, P=0.14). The angiotensin II precursor Agt mRNA level was also higher (1.07±0.08 vs 0.72±0.05; P&lt;0.01) in Ldlr -/- mice compared to controls. Conclusion: Taken together, Ldlr -/- mice fed with a western diet supplemented with vitamin D 2 develop progressive LVDD, perivascular fibrosis and mild left ventricular hypertrophy, which represents a new model of lipid-mediated diastolic dysfunction that may be used in future studies for the evaluation of novel treatments.
Modeling double strand break susceptibility to interrogate structural variation in cancer
Authors: Tracy J. Ballinger, Britta A. M. Bouwman, Reza Mirzazadeh, Silvano Garnerone, Nicola Crosetto, Colin A. Semple
Journal: Genome biology (2019)

Structural variants (SVs) are known to play important roles in a variety of cancers, but their origins and functional consequences are still poorly understood. Many SVs are thought to emerge from errors in the repair processes following DNA double strand breaks (DSBs).
BMA secures government commitments on junior doctor contract
Authors: Abi Rimmer
Journal: BMJ (2018)

Since August the BMA has been working with NHS Employers and the Department of Health and Social Care for England to review the 2016 junior doctor contract.1 As part of the ongoing process the BMA says it has secured commitments from the government in several areas

The pay linked to evening and weekend working will be reconsidered, and the …
Second cycle remission achievement with 7+3 and survival in adults with newly diagnosed acute myeloid leukemia: analysis of recent SWOG trials
Authors: Megan Othus, Elihu H. Estey, Guillermo Garcia-Manero, Brent L. Wood, Derek L. Stirewalt, John E. Godwin, James K. Weick, Jeanne E. Anderson, Frederick R. Appelbaum, Harry P. Erba, Roland B. Walter
Journal: Leukemia (2018)
FRI0675 Rabiopred, an innovative theranostic tool to assist clinicians select an optimal anti-tnf alpha biological therapy for rheumatoid arthritis patients
Authors: E. Schordan, M. Coq, S. AIT ABBI NAZI, M. Mehdi, H. Firat, N. Arber, V. Breuil, L. A.-Demoux, A. Gül, E. J.-Gottenberg, G. Hatemi, T. Huizinga, N. Inanç, J. Vencovský, C. Jorgensen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> TNF alpha blockers form 2nd line treatment choice for Rheumatoid Arthritis (RA) patients. Up to 30% of RA patients do not respond to TNF alpha blockers for unknown reasons, causing a significant impact on patients’ outcome and healthcare industry. Therefore, there is an unmet need for a tool to predict treatment response that could help clinicians to choose an optimal treatment for RA patients. <h3>Objectives:</h3> By using Immuno-Detect, an innovative targeted gene sequencing panel of 2155 mRNA targets associated with immune-inflammatory pathways, we aimed to develop an algorithm, RABIOPRED, that predicts non-response to TNF alpha blockers. <h3>Methods:</h3> Paxgene samples obtained at baseline from 68 patients naïve to TNF alpha blockers were directly profiled without extraction with Immuno-Detect panel on HTG EdgeSeq platform, a combination of a nuclease protection assay &amp; next generation sequencing (NGS). Patients were treated with Infliximab, Etanercept or Adalimumab and disease activity score was measured based on DAS28 score at 3 months. Response to treatment was assessed by categorizing the patients according to EULAR response criteria. Gene combinations were selected using variable importance score (VIS). Predictive modeling performance was evaluated using the area under the curve (AUC) and confusion matrix. <h3>Results:</h3> Analytical validation of Immuno-Detect panel shows a very high reproducibility on Paxgene and extracted RNA samples with correlation factor of 0.975 and 0.96 respectively. In paxgene samples, among 2155 genes, 1172 mRNAs are significantly expressed with a mean CV of 9.77% (976 mRNAs and mean CV of 11.98% for RNA). Most expressed target represent only 5% of the total reads and only 20 targets are reaching 1% of total reads showing a very well balanced panel. Performance of our predictive model shows an AUC of 0.905 with 0.88 accuracy. Our algorithm predicts non-responders to TNF alpha blockers with the sensitivity of 0.78 and positive predictive value of 0.91. This algorithm will be further validated within the ongoing RABIOPRED Proof-of-Performance study (ClinicalTrials.gov Identifier: NCT03016260) based on 720 patients treated by anti-TNF alpha drugs (5 originators &amp; 3 biosimilars) launched in December 2016. <h3>Conclusions:</h3> We are showing that Immuno-Detect panel accurately measures mRNA expression using HTG-EdgeSeq NGS platform. This panel can be further used to build signatures to predict TNF alpha blocker’s non-response. The algorithm obtained in the current study will be later on validated in a multi-centric proof-of-performance clinical study. <h3>Disclosure of Interest:</h3> None declared
Initial cohort expansion results of sustained arginine depletion with pegzilarginase in melanoma patients in a phase I advanced solid tumor trial
Authors: B. Chmielowski, M. Gordon, E.I. Buchbinder, R.J. Sullivan, J.V. Cohen, B.D. Curti, D. Davar, J. Homsi, K.M. Komatsubara, H. Lara-Guerra, S.E. Alters, S. Ferrati, S. Eckert, S.W. Rowlinson, J.E. Wooldridge, A. Ribas, R.D. Carvajal
Journal: Annals of Oncology (2018)
Vulvar cancer association with groin hidradenitis suppurativa: A large, urban, midwestern US patient population study
Authors: Supriya Rastogi, Kevin R. Patel, Vivek Singam, Yasmeen Ali, Jing Gao, Ahmad Amin, Bethanee J. Schlosser, Dennis P. West, Beatrice Nardone
Journal: Journal of the American Academy of Dermatology (2018)
Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma
Authors: François Audenet, Sumit Isharwal, Eugene K. Cha, Mark T.A. Donoghue, Esther N. Drill, Irina Ostrovnaya, Eugene J. Pietzak, John P. Sfakianos, Aditya Bagrodia, Paari Murugan, Guido Dalbagni, Timothy F. Donahue, Jonathan E. Rosenberg, Dean F. Bajorin, Maria E. Arcila, Jaclyn F. Hechtman, Michael F. Berger, Barry S. Taylor, Hikmat Al-Ahmadie, Gopa Iyer, Bernard H. Bochner, Jonathan A. Coleman, David B. Solit
Journal: Clinical Cancer Research (2018)

Abstract Purpose: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors. Experimental Design: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness. Results: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q &amp;lt; 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q &amp;lt; 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness. Conclusions: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.
A Routine Laboratory Data–Based Model for Predicting Recurrence After Curative Resection of Stage II Colorectal Cancer
Authors: Zhong Ye, Chun Wang, Limin Guo, Juan P. Palazzo, Zhixing Han, Yinzhi Lai, Jing Jiang, James A. Posey, Atrayee Basu Mallick, Bingshan Li, Li Jiang, Hushan Yang
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Use of chemotherapy in stage II colorectal cancer (CRC) is controversial because it improves survival only in some patients. We aimed to develop a statistical model using routine and readily available blood tests to predict the prognosis of patients with stage II CRC and to identify which patients are likely to benefit from chemotherapy. Methods: We divided 422 patients with stage II CRC into a training and a testing set. The association of routine laboratory variables and disease-free survival (DFS) was analyzed. A prognostic model was developed incorporating clinically relevant laboratory variables with demographic and tumor characteristics. A prognostic score was derived by calculating the sum of each variable weighted by its regression coefficient in the model. Model performance was evaluated by constructing receiver operating characteristic curves and calculating the area under the curve (AUC). Results: Significant associations were seen between 5 laboratory variables and patient DFS in univariate analyses. After stepwise selection, 3 variables (carcinoembryonic antigen, hemoglobin, creatinine) were retained in the multivariate model with an AUC of 0.75. Compared with patients with a low prognostic score, those with a medium and high prognostic score had a 1.99- and 4.78-fold increased risk of recurrence, respectively. The results from the training set were validated in the testing set. Moreover, chemotherapy significantly improved DFS in high-risk patients, but not in low- and medium-risk patients. Conclusions: A routine laboratory variable–based model may help predict DFS of patients with stage II CRC and identify high-risk patients more likely to benefit from chemotherapy.
Abstract 18394: Predicting Value of Platelet Reactivity on Bleeding and Major Adverse Cardiac Events in Eastern Asian PCI Patients
Authors: Wenyao Wang, Kuo Zhang, Yuejin Yang, Yi-Da Tang
Journal: Circulation (2015)

Introduction: Previous studies have shown that high and low platelet reactivity (HPR and LPR respectively) are associated with adverse events following percutaneous coronary intervention (PCI), however, therapy windows were not consistent in different studies. We aimed to determine the optimal cutoff value of platelet reactivity to prevent major adverse cardiac events (MACE) and bleeding in eastern Asian PCI patients. Methods: Consecutive 6266 non-emergent PCI patients with aspirin and clopidogrel therapy were enrolled prospectively in the single-center, large-volume investigation from January to December 2013. Platelet reactivity (ADP-induced platelet-fibrin clot strength [MAADP]) was determined by thrombelastography. MACE and Bleeding Academic Research Consortium (BARC) classification≥2 bleeding were assessed between different categories of platelet reactivity and Syntax Score (SS). Results: Overall, 475 MACE and 152 major bleeding (BARC grade≥2) events were recorded during one year follow-up. With receiver operating characteristic (ROC) curve, we determined the cutoff values of MAADP for MACE and major bleeding (45 mm and 34mm, respectively). Then, patients were classified according to MAADP (&gt;45 mm, 34-45 mm, and &lt;34 mm) and we evaluated the impact of platelet reactivity on MACE and major bleeding in different Syntax Score subgroups (SS45 mm was the predictor of MACE (HR: 2.3; 95%CI: 1.6-5.9), but MAADP45 mm was still the predictor of MACE (HR: 2.6; 95%CI: 1.3-6.3), while MAADP&lt;34 mm show significant impact on major bleeding (HR: 1.8; 95%CI: 1.2-4.7). Conclusions: Platelet reactivity measured by thrombelastography could predict MACE and major bleeding in elective PCI patients, especially in those with high SS. Therapy window of anti-platelet drugs is narrow in eastern Asian population and further studies on tailored treatment of high-risk patients are needed.
Preoperative hypofractionated radiotherapy (RT) in patients with locally advanced myxoid liposarcomas: Interim analysis of prospective phase II clinical trial
Authors: H.M. Kosela Paterczyk, M. Spalek, M. Wagrodzki, A. Borkowska, A. Szumera-Cieckiewicz, A. Cieszanowski, T. Morysinski, J. Palucki, P.L. Rutkowski
Journal: Annals of Oncology (2018)
Noninvasive and ultrasensitive quantitation of circulating tumor DNA by hybrid capture and deep sequencing.
Authors: Scott Victor Bratman, Aaron M Newman, Jacqueline To, Jacob F Wynne, Joel W. Neal, Heather A. Wakelee, Joseph B Shrager, Billy W. Loo, Maximilian Diehn, Ash A. Alizadeh
Journal: Journal of Clinical Oncology (2014)

11016 Background: No validated biomarkers exist for minimal residual disease (MRD) detection in non-small cell lung cancer (NSCLC). We aimed to design a next-generation sequencing-based method for quantifying circulating tumor-derived DNA in NSCLC and other cancers. Methods: We developed CAPP-Seq (Cancer Personalized Profiling by deep Sequencing), a novel method for noninvasive cancer burden measurement. Our strategy leverages affinity capture to enrich recurrently mutated genomic regions from tumor DNA and plasma cfDNA. After benchmarking sensitivity, we analyzed a set of NSCLC tumors and corresponding serial plasma samples collected before and after radiation therapy, chemotherapy, and/or surgery. Results: We show that CAPP-Seq detects multiple cancer-specific somatic mutation types within NSCLC DNA, including single nucleotide variants, insertions/deletions, and rearrangements. Benchmarking analyses demonstrate that CAPP-Seq accurately enumerates mutations within cfDNA at a fractional abundance of ≥0.02%. Applying CAPP-Seq to tumor/normal genomic DNA pairs from 17 NSCLC patients uncovered a median of 6 mutations per patient (range, 1-28). Plasma samples (35) from 13 patients were profiled by CAPP-Seq. The abundance of patient-specific cancer markers within plasma cfDNA was readily measured by CAPP-Seq in both early- and late-stage NSCLC. Importantly, circulating tumor DNA responded appropriately to diverse therapies, becoming undetectable in 7 patients (including after surgery, chemoradiation, and targeted therapy) and declining but remaining detectable in others. CAPP-Seq measurements correlated with tumor volume (R2 = 0.97) and allowed for detection of resistance mutations in patients being treated with targeted therapies. Conclusions: We describe a novel NGS-based approach to MRD testing in cancer patients. CAPP-Seq could have utility for monitoring disease burden and response to therapy, early detection of relapse, and risk stratification in early-stage NSCLC following surgery or stereotactic body radiation therapy. Ultimately, we envision CAPP-Seq becoming a routine clinical assay for measuring tumor burden in diverse cancers from plasma and other body fluids.
Abstract 13569: Identification of Eight Genetic Variants as Novel Determinants of Dyslipidemia in Japanese by Exome-wide Association Studies
Authors: Mitsutoshi Oguri, Kimihiko Kato, Tetsuo Fujimaki, H Horibe, Jun Sakuma, Ichiro Takeuchi, Toyoaki Murohara, Yoshiki Yasukochi, Yoshiji Yamada
Journal: Circulation (2017)

Introduction: Genome-wide association studies (GWASs) have implicated various genes and loci as determinants of blood lipid levels or in predisposition to dyslipidemia in European-ancestry populations. Although several polymorphisms have been shown to be related to blood lipid profiles in Japanese, genetic variants that influence circulating lipid levels in Japanese remain to be identified definitively. Hypothesis: Low-frequency or rare variants might influence circulating lipid levels or confer susceptibility to dyslipidemia in Japanese. We performed exome-wide association studies (EWASs) to identify single nucleotide polymorphisms (SNPs) that influence serum concentrations of triglycerides, HDL-cholesterol, or LDL-cholesterol or confer susceptibility to hypertriglyceridemia, hypo-HDL-cholesterolemia, or hyper-LDL-cholesterolemia in Japanese. Methods: EWASs for serum triglycerides (13,414 subjects), HDL-cholesterol (14,119 subjects), LDL-cholesterol (13,577 subjects), hypertriglyceridemia (4742 cases, 86...
Changing the cancer label: beware the euphemistic treadmill
Authors: George R Huntington
Journal: BMJ (2018)

No discussion on medical etymology1 is complete without mentioning Steven Pinker’s concept of the “euphemistic treadmill.” Coined in his 2002 work The Blank Slate , the euphemistic treadmill describes the gradual creep by which labels and categories become pejorative.2 Pinker uses a handful of former psychiatric diagnoses …
A phase II study on the efficacy of Nivolumab in Japanese patients with cancer of unknown primary (CUP) (NivoCUP)
Authors: Junko Tanizaki, Hidetoshi Hayashi, Hironobu Minami, Makoto Arai, Shin Takahashi, Yoshihiko Segawa, Yukinori Ozaki, Hiroki Ueda, Kohei Akiyoshi, Yasuo Iwamoto, Kan Yonemori, Yasuhiro Kidera, Kazuya Fukuoka, Kazuto Nishio, Kazuhiko Nakagawa
Journal: Annals of Oncology (2018)
Abstract 20555: Association of Diabetes and Baseline Ankle-Brachial Index With Functional Decline in Peripheral Arterial Disease
Authors: Tamar S Polonsky, Yihua Liao, Lu Tian, Mary M McDermott
Journal: Circulation (2016)

Introduction: Lower ankle brachial index (ABI) values are associated with greater decline in some measures of functioning among people with and without peripheral artery disease (PAD). Little is kn...
Tight junction proteins in gastrointestinal and liver disease
Authors: Mirjam B Zeisel, Punita Dhawan, Thomas F Baumert
Journal: Gut (2018)

Over the past two decades a growing body of evidence has demonstrated an important role of tight junction (TJ) proteins in the physiology and disease biology of GI and liver disease. On one side, TJ proteins exert their functional role as integral proteins of TJs in forming barriers in the gut and the liver. Furthermore, TJ proteins can also be expressed outside TJs where they play important functional roles in signalling, trafficking and regulation of gene expression. A hallmark of TJ proteins in disease biology is their functional role in epithelial-to-mesenchymal transition. A causative role of TJ proteins has been established in the pathogenesis of colorectal cancer and gastric cancer. Among the best characterised roles of TJ proteins in liver disease biology is their function as cell entry receptors for HCV-one of the most common causes of hepatocellular carcinoma. At the same time TJ proteins are emerging as targets for novel therapeutic approaches for GI and liver disease. Here we review our current knowledge of the role of TJ proteins in the pathogenesis of GI and liver disease biology and discuss their potential as therapeutic targets.