tbuckley/cabot-search huggingface dataset:
P105An iPSC-derived drug screening platform to identify therapeutic compounds for marfan syndrome
Authors: M Mcnamara, A Granata, F Serrano, W Bernard, D Smith, S Sanjay
Journal: Cardiovascular Research (2018)

were used.Washed RBCs from WT or db/db mice treated with vehicle or nitrate were administered to WT hearts at the onset of ischemia.In both protocols post-ischemic recovery of cardiac function was evaluated by determination of left ventricular developed pressure (LVDP).Results: Post-ischemic recovery of LVDP was impaired in hearts from db/db mice in comparison with hearts from WT mice in Protocol 1 (Fig. A).Dietary nitrate restored the ischemic tolerance of hearts from db/db mice but did not affect post-ischemic recovery of hearts from WT mice (Fig. A).In Protocol 2, administration of RBCs collected from vehicle-treated db/db mice significantly impaired post-ischemic recovery of hearts from WT mice (Fig. B).Notably, administration of RBCs from nitrate-treated db/db mice completely reversed the impairment of post-ischemic cardiac function induced by diabetic RBCs (Fig. B).Interestingly, post-ischemic cardiac function did not differ between hearts given RBCs from nitrate-treated db/db and WT mice (Fig. B).Conclusion: Dietary nitrate restores cardiac ischemic tolerance in db/db mice and protects the heart against ischemia-reperfusion injury via an effect mediated through RBCs.
Abstract 18773: Lipoprotein(a) Level is a Predictor of Clinical Outcome After Endovascular Intervention for Atherosclerotic Lesions in Superficial Femoral Artery
Authors: Shun Nakagama, Keiichi Hishikari, Shun Nakamura, Masafumi Mizusawa, Toru Misawa, Kazuto Hayasaka, Tasuku Yamamoto, Junichi Doi, Yuya Utsugi, Takamitsu Takagi, Jun Nakajima, Yasuaki Tanaka, Kenji Okubo, Katsumasa Takagi, Taishi Kuwahara, Hiroyuki Hikita, Atushi Takahashi, Mitsuaki Isobe
Journal: Circulation (2016)

Introduction:  Peripheral arterial disease (PAD) is the third leading cause of cardiovascular morbidity after myocardial infarction and stroke. Among PAD patients, superficial femoral artery (SFA) is a major target lesion for endovascular therapy (EVT). On the other hand, high lipoprotein(a) level is a major risk factor for cardiovascular disease. There are, however, few reports investigating the association between the lipoprotein(a) level and the clinical course of PAD patients.   Hypothesis:  We assessed the hypothesis that the serum lipoprotein(a) level could be a predictive biomarker for clinical outcome of PAD patients who underwent EVT for SFA lesions.   Methods:  We measured the serum lipoprotein(a) concentrations in the consecutive 233 PAD patients on admission, who underwent successful EVT for SFA lesions. Patients were divided into two groups, based on the serum lipoprotein(a) level. Median follow-up period was 18 months and major adverse limb events (MALE) were followed, including amputation, target lesion revascularization and EVT for another new de novo lesion.   Results:  Patients were divided into two groups as follows: LOW lipoprotein(a) group with the level 2 =15.7; p   Conclusions:  In conclusion, high lipoprotein(a) level (≧40 mg/dl) was associated with the higher incidence of major adverse limb events after EVT for PAD patients with SFA lesions.
Hepatitis B Virus Evasion From Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase Sensing in Human Hepatocytes
Authors: Eloi R. Verrier, Seung‐Ae Yim, Laura Heydmann, Houssein El Saghire, Charlotte Bach, Vincent Turon‐Lagot, Laurent Mailly, Sarah C. Durand, Julie Lucifora, David Durantel, Patrick Pessaux, Nicolas Manel, Ivan Hirsch, Mirjam B. Zeisel, Nathalie Pochet, Catherine Schuster, Thomas F. Baumert
Journal: Hepatology (2018)

Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mechanisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood. Recently, the cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) was identified as a DNA sensor. In this study, we investigated the functional role of cGAS in sensing HBV infection and elucidate the mechanisms of viral evasion. We performed functional studies including loss‐of‐function and gain‐of‐function experiments combined with cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes, and HBV‐infected human liver chimeric mice. Here, we show that cGAS is expressed in the human liver, primary human hepatocytes, and human liver chimeric mice. While naked relaxed‐circular HBV DNA is sensed in a cGAS‐dependent manner in hepatoma cell lines and primary human hepatocytes, host cell recognition of viral nucleic acids is abolished during HBV infection, suggesting escape from sensing, likely during packaging of the genome into the viral capsid. While the hepatocyte cGAS pathway is functionally active, as shown by reduction of viral covalently closed circular DNA levels in gain‐of‐function studies, HBV infection suppressed cGAS expression and function in cell culture models and humanized mice. Conclusion : HBV exploits multiple strategies to evade sensing and antiviral activity of cGAS and its effector pathways.
Efficacy of a program based on on-site dried blood spot testing for hepatitis C to improve linkage to care and treatment uptake for people who injected drugs
Authors: D.M. Arraez, F. Gutierrez, E. Quintero, V. Casañas-Sanchez, A. De Vera, L.G.S. Gutierrez, E. Cuisido, Z.R. Marrero, V.P. Perez, A.R. Perez, M.J.M. Alonso, E.M. Carballo, F. Diaz-Flores, J.N. Casariego, M. Hernandez-Guerra
Journal: Journal of Hepatology (2018)
Effectiveness and Safety of Rivaroxaban in Patients With Cancer-Associated Venous Thrombosis
Authors: Christine G. Kohn, Gary H. Lyman, Jan Beyer-Westendorf, Alex C. Spyropoulos, Thomas J. Bunz, William L. Baker, Daniel Eriksson, Anna-Katharina Meinecke, Craig I. Coleman
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Although not designated as guideline-recommended first-line anticoagulation therapy, patients are receiving rivaroxaban for the treatment and secondary prevention of cancer-associated venous thrombosis (CAT). We sought to estimate the cumulative incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality/hospice care in patients with CAT treated with outpatient rivaroxaban in routine practice. Methods: Using US MarketScan claims data from January 2012 through June 2015, we identified adults with active cancer (using SEER program coding) who had ≥1 primary hospitalization or emergency department discharge diagnosis code for VTE (index event) and received rivaroxaban as their first outpatient anticoagulant within 30 days of the index VTE. Patients were required to have ≥180 days of continuous medical/prescription benefits prior to the index VTE. Patients with a previous claim for VTE, atrial fibrillation, or valvular disease or receiving anticoagulation during the baseline period were excluded. We estimated the cumulative incidence with 95% CIs of recurrent VTE, major bleeding, and mortality or need for hospice care at 180 days, assuming competing risks. Results: A total of 949 patients with active cancer were initiated on rivaroxaban following their index VTE. Time from active cancer diagnosis to index CAT was ≤90 days for 27% of patients, 91 to 180 days for 19%, and >180 days for 54%. The mean [SD] age of patients was 62.5 [12.8] years, 43.6% had pulmonary embolism, and metastatic disease was present in 42.6%. During follow-up, there were 37 cases of recurrent VTE, 22 cases of major bleeding (17 gastrointestinal, 3 intracranial, 1 genitourinary, and 1 other bleed), and 105 deaths/hospice claims. The cumulative incidence estimate was 4.0% (95% CI, 2.8%–5.4%) for recurrent VTE, 2.7% (95% CI, 1.7%–4.0%) for major bleeding, and 11.3% (95% CI, 9.2%–13.6%) for mortality/hospice care. Conclusions: Event rates observed in this rivaroxaban-treated cohort were overall consistent with previous studies of patients with rivaroxaban- and warfarin-managed CAT.
Abstract 11359: Relationship of Incident Atrial Fibrillation to the Electrocardiographic Strain Pattern in Hypertensive Patients With Electrocardiographic Left Ventricular Hypertrophy
Authors: Peter M Okin, Kristian Wachtell, Sverre E Kjeldsen, Richard B Devereux
Journal: Circulation (2016)

Background: Atrial fibrillation (AF) is strongly related to hypertension and to left ventricular hypertrophy (LVH) and both regression of ECG LVH and achievement of lower systolic blood pressure (SBP) are associated with lower incidence of AF. The ECG strain pattern of lateral ST depression and T-wave inversion has been associated with more severe LVH, decreased LV systolic function and an increased risk of cardiovascular mortality and morbidity, including new heart failure (HF). However, whether ECG strain is associated with an increased risk of new AF is unclear. Methods: Risk of new-onset AF was examined in relation to the presence of the strain pattern on baseline ECG in 7921 hypertensive patients with ECG LVH with no history of AF, who were in sinus rhythm on their baseline ECG, had baseline strain determination and were randomized to losartan- vs atenolol-based treatment. Results: During 4.7±1.1 years follow-up, new-onset AF was diagnosed in 621 patients (7.8%). Baseline ECG strain was present in 882 patients (11.1%) and was associated with a significantly higher 5-year incidence of AF in Kaplan-Meier estimates (12.2 vs 7.4%, p&lt;0.001) and with a 66% greater risk of new AF in a univariate Cox model (HR 1.66, 95% CI 1.34-2.06, p&lt;0.001), compared with the absence of ECG strain. After adjusting for other univariate predictors of new AF in this population, including age, sex, race, prior anti-hypertensive treatment, randomized treatment allocation, prevalent diabetes, history of ischemic heart disease, prior myocardial infarction, stroke or HF, baseline serum cholesterol and urine albumin/creatinine ratio entered as standard covariates and incident HF and on-treatment diastolic BP, SBP, heart rate and Cornell product LVH entered as time-varying covariates, ECG strain remained associated with a 39% greater risk of new-onset AF (HR 1.39, 95% CI 1.09-1.76, p=0.008). Conclusions: The presence of strain on a baseline ECG is strongly associated with an increased risk of developing new-onset AF in hypertensive patients with ECG LVH, independent of other AF risk factors and the effects of incident HF, LVH regression and SBP reduction. These findings suggest that hypertensive patients with ECG strain should be followed closely for development of new AF.
Associations of Time-Related Deployment Variables With Risk of Suicide Attempt Among Soldiers
Authors: Robert J. Ursano, Ronald C. Kessler, James A. Naifeh, Holly Herberman Mash, Carol S. Fullerton, Pablo A. Aliaga, Gary H. Wynn, Tsz Hin H. Ng, Hieu M. Dinh, Nancy A. Sampson, Tzu-Cheg Kao, Paul D. Bliese, Murray B. Stein
Journal: JAMA Psychiatry (2018)

There has been limited systematic examination of whether risk of suicide attempt (SA) among US Army soldiers is associated with time-related deployment variables, such as time in service before first deployment, duration of first deployment, and dwell time (DT) (ie, length of time between deployments).
Clinical benefit of entrectinib for patients with metastatic pancreatic cancer who harbor NTRK and ROS1 fusions.
Authors: Michael J. Pishvaian, Christian Diego Rolfo, Stephen V. Liu, Pratik S. Multani, Edna Chow Maneval, Ignacio Garrido-Laguna
Journal: Journal of Clinical Oncology (2018)

521 Background: Despite recent improvements in chemotherapy for pancreatic cancer that have demonstrated improvements in survival, response rates remain at less than 50%. Distinct molecular subgroups of pancreatic cancer that harbor specific actionable molecular alterations have recently been identified. These include gene fusions of the receptor tyrosine kinases NTRK and ROS1. Entrectinib is a CNS-active, potent, and selective TRK and ROS1 inhibitor that has shown substantial clinical activity in patients with locally advanced or metastatic solid tumors that have NTRK or ROS1 fusions (Drilon A, et al. Cancer Discov. 2017;7[4]:400-409). Methods: We examined 3 cases of pancreatic cancer where an actionable gene rearrangement was identified: 2 with a TPR-NTRK gene fusion, and 1 with an SCL4-ROS1 gene fusion. All 3 patients were treated with entrectinib 600 mg daily in a phase 2 trial (NCT02568267). Results: Entrectinib was well tolerated with mostly grade 1-2 adverse events consisting primarily of arthralgias, myalgias, and fatigue. All 3 patients showed evidence of clinical improvement, with normalization of the tumor biomarker CA19-9 and confirmed partial responses as per RECIST v1.1 in the 2 patients with a TPR-NTRK fusion, 1 of which was associated with a significant decrease in metabolic activity as assessed by PET/CT scan. The patient with the SCL4-ROS1 fusion had stable disease for at least 6 months. All 3 patients had an improvement to, or maintenance of, a high quality of life while on study. At the time of data cutoff, 1 of the patients with a TPR-NTRK fusion remained on treatment &gt; 1 year. Conclusions: Entrectinib treatment was associated with response and prolonged disease control in these 3 patients with NTRK or ROS1 fusion-positive pancreatic cancer. NTRK and ROS1 gene fusions are rare in pancreatic cancer. The true incidence is unknown, as routine testing for gene fusions in pancreatic cancer is not yet standard practice. Given the benefit seen here with entrectinib and the clinical need for improved therapeutics, there may be value in broader and earlier molecular testing of patients with pancreatic cancer for these actionable fusions. Clinical trial information: NCT02568267.
Target cell killing effects of CD20 targeting chimeric antigen receptor T cells derived from the type II anti-CD20 antibody.
Authors: Yihong Yao, Xin Yao, Shigui Zhu, Wei Zhu, Zhiyuan Li, Qingxia Wang, Lin Zhu, Anyun Ma, Yanfeng Li, Yutian Wei, Chengxiang Dai, Li Zhang, Jiaqi Huang, Bizuo Liu
Journal: Journal of Clinical Oncology (2017)

e14548 Background: Chimeric Antigen Receptor T cells (CAR-Ts) targeting CD19 have shown very promising clinical outcomes in treatment of B-cell linage hematological malignancies. However, many patients with relapsed diseases were found to have down-regulated/loss of CD19 surface expression after CD19 CAR-T therapy. To solve this issue of CD19 single-targeting escape, we explored the application of another B-cell antigen, CD20, for targeted CAR-T therapy. Methods: We constructed four CD20 targeting CARs (all with 4-1BB co-stimulatory signaling) base on single-chain variable fragments (scFV) derived from four well-studied CD20 specific antibodies: Leu16, Rituximab, Obinutuzumab, and Ofatumumab. Leu16, Rituximab, and Obinutuzumab belong to the type I anti-CD20 antibody family and appear to bind to different epitopes located on the large loop of CD20, whereas Ofatumumab is the type II anti-CD20 antibody which has been shown to interact with the hydrophobic residues on the small loop surrounding a deep binding cleft. Results: All four CAR-T cells can specifically recognized CD20 positive target cells in our pre-clinical studies. They all showed up-regulated antigen-specific cell activation and high level of IFN-g release upon CD20 stimulation, and CAR-T20-Ofatumumab cells appeared to have significantly higher cell activation and more than 2-fold increase in IFN-g release compared to the other three CAR-T20 cells with their scFVs deriving from type I anti-CD20 antibodies. CAR-T20-Ofatumumab cells also showed higher degranulation upon stimulation, and it displayed ~50% of increase in ability to kill CD20 positive cells in cytotoxicity assays. Conclusions: Our data suggested that CAR-T20-Ofatumumab has better in vitro function and appears to be a CAR superior to those derived from other three antibodies. A possible explanation for this observation is that Ofatumumab interacts with the hydrophobic residues on the small loop, which is very close to cell membrane and confers more extensive binding to the small loop with striking slow off-rate. Our results suggest that CAR-Ts targeting CD20 with the scFVs from the type II anti-CD20 antibody may have superior cell killing effects.
Clinical Inertia in Type 2 Diabetes Management: Evidence From a Large, Real-World Data Set
Authors: Kevin M. Pantalone, Anita D. Misra-Hebert, Todd M. Hobbs, Xinge Ji, Sheldon X. Kong, Alex Milinovich, Wayne Weng, Janine Bauman, Rahul Ganguly, Bartolome Burguera, Michael W. Kattan, Robert S. Zimmerman
Journal: Diabetes Care (2018)

Despite clinical practice guidelines that recommend frequent monitoring of HbA1c (every 3 months) and aggressive escalation of antihyperglycemic therapies until glycemic targets are reached (1,2), the intensification of therapy in patients with uncontrolled type 2 diabetes (T2D) is often inappropriately delayed. The failure of clinicians to intensify therapy when clinically indicated has been termed “clinical inertia.” A recently published systematic review found that the median time to treatment intensification after an HbA1c measurement above target was longer than 1 year (range 0.3 to >7.2 years) (3). We have previously reported a rather high rate of clinical inertia in patients uncontrolled on metformin monotherapy (4). Treatment was not intensified early (within 6 months of metformin monotherapy failure) in 38%, 31%, and 28% of patients when poor glycemic control was defined as an HbA1c >7% (>53 mmol/mol), >7.5% (>58 mmol/mol), and >8% (>64 mmol/mol), respectively.

Using the electronic health record system at Cleveland Clinic (2005–2016), we identified a cohort of 7,389 patients with T2D who had an HbA1c value ≥7% (≥53 mmol/mol) (“index HbA1c”) despite having been on a stable regimen of two oral antihyperglycemic drugs (OADs) for at least 6 months prior to the …
Re: Michael B. Atkins, Elizabeth R. Plimack, Igor Puzanov, et al. Axitinib in Combination with Pembrolizumab in Patients with Advanced Renal Cell Cancer: A Non-randomised, Open-label, Dose-finding, and Dose-expansion Phase 1b Trial. Lancet Oncol 2018;19:405–15
Authors: Vincenzo Di Nunno, Matteo Santoni, Francesco Massari
Journal: European Urology (2018)
Age distribution of tumor gene expression in patients with stage II/III colon cancer.
Authors: Howard S. Hochster, Anna Lau, Michelle Turner, Christy Ann Russell
Journal: Journal of Clinical Oncology (2018)

552 Background: Colorectal cancer (CRC) incidence and mortality have been rising in the US among adults &lt;55 y. Younger patients with CRC are more likely than older patients to receive postoperative systemic chemotherapy, despite lack of consensus on the prognostic value of age in this disease. CRC diagnosed in younger patients may be biologically different from that in older patients, but characteristics are unknown. Thus, we examined whether age-specific differences were measurable by tumor gene expression using the 12-gene Oncotype DX Colon Recurrence Score (RS) test (Genomic Health, Inc. [GHI]; Redwood City, CA). The Colon RS test is validated to predict risk of recurrence in patients with stage II/III colon cancer. Methods: We analyzed Colon RS test results and single-gene results for the 12 genes by age group (age &lt;40, 40-54, 55-64, and ≥65) using data from the GHI clinical laboratory dated 1/2010 to 7/2017. Results: As of 7/2017, 21,925 Colon RS reports have been delivered. Median age was 63 y; 50% were male. About 23% of patients were &lt;55 y (Table). Mean (SD) RS result was 25 (11). Colon RS result distributions were similar by age group (Table). Expression of individual tumor genes measured in the Colon RS test were also similar by age group (data to be presented). Conclusions: The etiology of the increase in both incidence and mortality from CRC in adults &lt;55 y is poorly understood. Our findings suggest that colon cancer in younger patients is not biologically different from that in older patients, as measured by the Colon RS test in a large cohort referred for testing. As shown by this test in the GHI clinical laboratory experience, most patients with stage II/III colon cancer have low-risk disease, including patients &lt;55 years. Our findings support a biology-driven approach to disease management of patients with stage II/III colon cancer regardless of age. This well-validated genomic assay may identify a group of younger patients for whom adjuvant chemotherapy might represent overtreatment. [Table: see text]
CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis
Authors: Lei Zhao, Chang Zhang, Xiaoxiao Luo, Pei Wang, Wei Zhou, Shan Zhong, Yunxia Xie, Yibo Jiang, Ping Yang, Renkuang Tang, Qin Pan, Andrew R. Hall, Tu Vinh Luong, Jiangao Fan, Zac Varghese, John F. Moorhead, Massimo Pinzani, Yaxi Chen, Xiong Z. Ruan
Journal: Journal of Hepatology (2018)
Resolution of clinically significant portal hypertension after sustained virologic response to interferon-free regimens prevents hepatic decompensation
Authors: M. Mandorfer, K. Kozbial, P. Schwabl, D. Chromy, B. Scheiner, R. Paternostro, A. Stättermayer, P. Munda, A. Ferlitsch, M. Trauner, M. Peck-Radosavljevic, P. Ferenci, T. Reiberger
Journal: Journal of Hepatology (2018)
Manipulation of the gut–liver axis by interruption of bile acid recirculation: an option for the treatment of sclerosing cholangitis?
Authors: Daniel Jahn, Marco Marzioni, Andreas Geier
Journal: Gut (2018)

Patients affected by primary sclerosing cholangitis (PSC) have a dramatically increased risk to develop end-stage liver disease and cholangiocarcinoma. Medical treatment options for PSC are currently limited and often liver transplantation remains inevitable. This demonstrates the urgent need for novel pharmacological treatment strategies that are safe and efficient.

Bile acid (BA) sequestrants are resins that bind to BAs in the intestinal lumen, thereby decreasing their intestinal re-uptake and interrupting their enterohepatic circulation. Resins have a longstanding use in the treatment of BA-induced diarrhoea and cholestatic pruritus. However, only a very limited number of studies have so far investigated the therapeutic impact of BA sequestrants on the underlying cholestatic liver disease.

In Gut , Fuchs et al present an experimental study investigating the effects of the BA sequestrant colesevelam on cholestatic liver disease in the Mdr2− /− mouse model of sclerosing cholangitis.1 Using this model, the authors convincingly show that colesevelam efficiently treats the clinically relevant liver phenotype including inflammation, tissue damage, fibrosis and efficiently normalised serum liver enzymes. With regard to the underlying mechanisms, the study clearly shows that colesevelam profoundly alters BA homeostasis. This is demonstrated by a marked increase of the total faecal BA output together with a nearly complete loss of the intestinal fibroblast growth factor (FGF) 15 expression and a concomitant increase of hepatic de novo BA synthesis. Interestingly, the increased synthesis apparently even overcompensates the faecal BA loss, since colesevelam-treated Mdr2− /− animals had an increased hepatic and biliary BA pool size compared with untreated controls. However, there is also a profound impact of colesevelam on BA pool …