tbuckley/cabot-search huggingface dataset:
Folfirinox versus gemcitabine/nab-paclitaxel for neoadjuvant treatment of resectable and borderline resectable pancreatic adenocarcinoma: A propensity matched analysis.
Authors: Mashaal Dhir, Mazen S Zenati, Ahmad Hamad, Aatur D. Singhi, Nathan Bahary, Melissa Ellen Hogg, Herbert Zeh, Amer H. Zureikat
Journal: Journal of Clinical Oncology (2018)

402 Background: Comparative effectiveness of FOLFIRINOX and Gemcitabine/nab-paclitaxel (G-nP) in the neoadjuvant treatment (NAT) of pancreatic ductal adenocarcinoma (PDA), remains unknown. The aim of this study was to perform a propensity matched analysis of neoadjuvant FOLFRINOX vs G-nP for resectable(R) and borderline resectable (BR) PDA. Methods: A single institution retrospective review of all R and BR PDA patients who underwent resection after NAT with FOLFIRINOX or G-nP was performed. Comparative effectiveness analysis was conducted using inverse-probability-weighted estimators. Primary endpoint was overall survival (OS) from the time of diagnosis. Results: A total of 193 patients (FOLFIRINOX=73, G-nP=120) who underwent resection from 01/11-03/17 were included. Median OS was 28.9 months (95% CI 26.1-39.7). Patients treated with FOLFIRINOX were younger (median age 63 vs. 69 y), had less comorbidities (median CCI 4 vs. 5), more frequent BR disease (79 vs. 59%), and larger tumors (median CT size 2.9 v 2.7 cm) compared to G-nP (all p &lt; 0.05). Duration of NAT was similar and both regimens were equally effective in achieving a 50% or 80% decline in CA19-9 (logistic regression, P 0.9). Rates of R0 resection were also similar (80%), but folfirnox was associated with a reduction in pN1 disease (56% vs. 72%, p =0.028). Receipt of adjuvant therapy was similar in both groups (74 vs. 75%, p =0.79). In a multivariable cox regression analysis utilizing only preoperative variables (FOLFIRINOX v G-nP, age, gender, CT tumor size, BR vs. R, pre NAT CA19-9 and number of NAT cycles), only the number of neoadjuvant cycles was an independent predictor of survival (HR 0.49, 95% CI 0.34-0.71, p &lt; 0.001). In a propensity matched analysis of 166 patients using the same preoperative variables, the average treatment effect of FOLFIRINOX was to increase OS by 4.9 months above G-nP (p=0.012). Conclusions: FOLFIRINOX and Gem Abraxane are viable options for neoadjuvant treatment of PDA. In this study, FOLFIRINOX was associated with a 4.9 month improvement in OS when compared to G-nP in the neoadjuvant setting after adjusting for covariates.
Survival outcome in <i>HER2-</i>amplified metastatic colorectal cancer (mCRC).
Authors: Kentaro Sawada, Wataru Okamoto, Yoshiaki Nakamura, Takeharu Yamanaka, Satoshi Yuki, Takayuki Yoshino, Yoshito Komatsu, Naoya Sakamoto, Satoshi Fujii
Journal: Journal of Clinical Oncology (2018)

642 Background: HER2 amplifications have been observed in approximately 3% of patients (pts) with metastatic colorectal cancer (mCRC). Early clinical trials with combined HER2-targeted therapies showed promising activities. However, it remains unclear whether HER2 amplification in mCRC is as prognostic as RAS or BRAF V600E mutant (mt). We aimed to evaluate survival outcome for mCRC pts with HER2 amplification compared to those with RAS or BRAF mt. Methods: mCRC pts who received a palliative resection of the primary tumor with metastatic diseases at presentation, or recurred after curative resection of the primary tumor between 2005 and 2015, were analyzed. HER2 immunohistochemistry (IHC) was performed using formalin-fixed and paraffin-embedded (FFPE) sections obtained from the primary tumor, and HER2 amplification was confirmed by fluorescence in situ hybridization (FISH) in case of IHC 2+ or 3+. Criteria for HER2 amplification were a HER2- to CEP17- signal ratio of 2.0 or higher. RAS / BRAF status was centrally assessed by a PCR-based method. The pts were classified into four subgroups based on RAS, BRAF and HER2 status: Group R , RAS mt; Group B, BRAF V600E mt; Group H, HER2 amplification with RAS / BRAF wild-type (wt); and Group W, RAS / BRAF wt. Results: Among 370 pts, 359 pts (97%) were successfully analyzed. A total of 15 pts (4%) had HER2 amplifications, out of which four pts had overlapped RAS mt (subclassified as Group R). RAS or BRAF mutations are mutually exclusive. The number in Group R, B, H and W was 204 (57%), 13 (4%), 11 (3%) and 131 (36%), respectively. There was no remarkable difference in baseline characteristics among groups. With a median follow-up time of 63 months (mos), the median overall survival of the 359 pts was 27 mos (95%CI 24 - 29 mos); Group R, 24 mos; Group B, 14 mos; Group H, 20 mos; and Group W, 39 mos. The HR of R vs. H is 0.83 (95%CI 0.41-1.70, p= 0.618), B vs. H is 1.16 (95%CI 0.47-2.84, p= 0.748), and W vs. H is 0.52 (95%CI 0.25-1.08, p= 0.080), respectively. Conclusions: This study suggests that the prognosis of mCRC pts with HER2 amplification tends to be worse as compared to those with RAS / BRAF wt, similar to those with RAS mt, and better than those with BRAF mt, although these comparisons were not statistical significant.
Persistence of decompensation despite long-term abstinence in alcoholic cirrhosis is associated with poor outcomes and lower survival
Authors: A. Clemente, D. Rincón, C. Martínez, C. Villaseca, E. Cervilla, M. Romero, A.M. Matilla, R. García, G. Clemente, R. Bañares
Journal: Journal of Hepatology (2018)
Cerium oxide nanoparticles protect against oxidant mediated injury and recover kinase activity of multiple pathways in human-derived hepatocellular carcinoma cells
Authors: M.P. Corominas, S.C. Restoy, G. Casals, D. Oró, J. Ribera, E. Casals, P. Casado-Izquierdo, G.F. Varo, P. Cutillas, V. Puntes, W. Jiménez
Journal: Journal of Hepatology (2018)
Abstract 15933: Scn5a Gating Pore Current Causes Cardiac Arrhythmias Associated With Dilated Cardiomyopathy
Authors: Adrien Moreau, Aurélie Mercier, Pascal Gosselin-Badaroudine, Bettina Burger, Dagmar I Keller, Mohamed Chahine
Journal: Circulation (2015)

Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers, impairs cardiac contractility and systolic function leading to heart failure. SCN5A gene encodes the cardiac sodium channel (Nav1.5) in which mutations have been identified in patients with arrhythmic disorders associated with DCM. However, it is not understood how a dysfunction in SCN5A may cause very atypical cardiac arrhythmias associated with dilatation remodeling of the heart. We generated control and patient specific human induced pluripotent cells (hiPS) carrying the Nav1.5/R219H mutation. hiPS were differentiated to obtain cardiomyocytes derived from hiPS (hiPS-CM). Molecular dynamic simulations experiments revealed that the R219H mutation opens up a pathway directly through the voltage sensitive domain (VSD) of Nav1.5 channels. We hypothesized that such a proton leak through the VSD caused by the R219H mutation may be responsible for the clinical phenotypes observed in our index patient. We unraveled the underlying mechanism responsible for the association of SCN5A and DCM. Indeed, the data shows the presence of a gating pore or omega current that is responsible of the observed abnormal ionic homeostasis, absent in control hiPS-CM. Action potential recordings showed abnormal electrical activities in both atrial and ventricular hiPS-CM. Myocytes stemmed from the index patient exhibited dilatation. Single cardiomyocytes contractility probed using atomic force microscopy revealed a higher frequency of contractility with reduced force compared to control myocytes. This could be attributed to the observed contractile protein dysfunction uncovered using immunofluorescence. Overall, the results support the hypothesis that the Nav1.5/R219H mutation creates a proton leak. This leak then causes electrical, structural and contractile disturbances that may explain the related cardiac arrhythmias associated with myocytes dilatation. We concluded that gating pore current, a novel cardiac channelopathy is directly related to the association of SCN5A and DCM. We suggest that this aberrant leak current should be investigated to characterize similar SCN5A mutations with similar clinical phenotypes.
Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients
Authors: María-Carlota Londoño, Lara Neves Souza, Juan-José Lozano, Rosa Miquel, Juan G. Abraldes, Laura-Patricia Llovet, Alberto Quaglia, Antoni Rimola, Miquel Navasa, Alberto Sánchez-Fueyo
Journal: Journal of Hepatology (2018)
LJN452 (tropifexor) attenuates steatohepatitis, inflammation, and fibrosis in dietary mouse models of nonalcoholic steatohepatitis
Authors: B. Laffitte, E. Hernandez, Y. Kim, B. Liu, P. Rucker, D. Chianelli, D. Bao, J. Zoll, J. Xu, V. Molteni, P. Mcnamara, M. Badman
Journal: Journal of Hepatology (2018)
RASSF1A Deficiency Enhances RAS-Driven Lung Tumorigenesis
Authors: M. Lee Schmidt, Katharine R. Hobbing, Howard Donninger, Geoffrey J. Clark
Journal: Cancer Research (2018)

Abstract Mutant K-RAS has been shown to have both tumor-promoting and -suppressing functions, and growing evidence suggests that the RASSF family of tumor suppressors can act as RAS apoptosis and senescence effectors. It has been hypothesized that inactivation of the RASSF1A tumor suppressor facilitates K-RAS–mediated transformation by uncoupling it from apoptotic pathways such as the Hippo pathway. In human lung tumors, combined activation of K-RAS and inactivation of RASSF1A is closely associated with the development of the most aggressive and worst prognosis tumors. Here, we describe the first transgenic mouse model for activation of K-RAS in the lung in a RASSF1A-defective background. RASSF1A deficiency profoundly enhanced the development of K-RAS–driven lung tumors in vivo. Analysis of these tumors showed loss of RASSF1A-uncoupled RAS from the proapoptotic Hippo pathway as expected. We also observed an upregulation of AKT and RALGEF signaling in the RASSF1A− tumors. Heterozygosity of RASSF1A alone mimicked many of the effects of RAS activation on mitogenic signaling in lung tissue, yet no tumors developed, indicating that nonstandard Ras signaling pathways may be playing a key role in tumor formation in vivo. In addition, we observed a marked increase in inflammation and IL6 production in RASSF1A-deficient tumors. Thus, RASSF1A loss profoundly affects RAS-driven lung tumorigenesis and mitogenic signaling in vivo. Deregulation of inflammatory pathways due to loss of RASSF1A may be essential for RAS-mediated tumorigenesis. These results may have considerable ramifications for future targeted therapy against RAS+/RASSF1A− tumors. Significance: A transgenic mouse model shows that suppression of RASSF1A dramatically enhances Ras-driven tumorigenesis and alters Ras signaling pathway activity. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/10/2614/F1.large.jpg. Cancer Res; 78(10); 2614–23. ©2018 AACR.
Age and sex of surgeons and mortality of older surgical patients: observational study
Authors: Yusuke Tsugawa, Anupam B Jena, E John Orav, Daniel M Blumenthal, Thomas C Tsai, Winta T Mehtsun, Ashish K Jha
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To investigate whether patients’ mortality differs according to the age and sex of surgeons. <h3>Design</h3> Observational study. <h3>Setting</h3> US acute care hospitals. <h3>Participants</h3> 100% of Medicare fee-for-service beneficiaries aged 65-99 years who underwent one of 20 major non-elective surgeries between 2011 and 2014. <h3>Main outcome measure</h3> Operative mortality rate of patients, defined as death during hospital admission or within 30 days of the operative procedure, after adjustment for patients’ and surgeons’ characteristics and indicator variables for hospitals. <h3>Results</h3> 892 187 patients who were treated by 45 826 surgeons were included. Patients’ mortality was lower for older surgeons than for younger surgeons: the adjusted operative mortality rates were 6.6% (95% confidence interval 6.5% to 6.7%), 6.5% (6.4% to 6.6%), 6.4% (6.3% to 6.5%), and 6.3% (6.2% to 6.5%) for surgeons aged under 40 years, 40-49 years, 50-59 years, and 60 years or over, respectively (P for trend=0.001). There was no evidence that adjusted operative mortality differed between patients treated by female versus male surgeons (adjusted mortality 6.3% for female surgeons versus 6.5% for male surgeons; adjusted odds ratio 0.97, 95% confidence interval 0.93 to 1.01). After stratification by sex of surgeon, patients’ mortality declined with age of surgeon for both male and female surgeons (except for female surgeons aged 60 or older); female surgeons in their 50s had the lowest operative mortality. <h3>Conclusion</h3> Using national data on Medicare beneficiaries in the US, this study found that patients treated by older surgeons had lower mortality than patients treated by younger surgeons. There was no evidence that operative mortality differed between male and female surgeons.
TCTAP A-025 Transradial Percutaneous Coronary Intervention in Very Elderly Patients (Age 80 Years or above) with Acute Coronary Syndrome: Immediate and Short-term Outcome, Single Center Experience
Authors: Vipin Mughilassery Thomachan, Abdullah M.A. Shehab, Ahmed Siddiqui
Journal: Journal of the American College of Cardiology (2018)
238Protective actions of substance p in diabetes induced cardiac fibrosis
Authors: A Widiapradja, E J Manteufel, L L Kolb, J D Imig, C Yu, K J Bubb, G A Figtree, S P Levick
Journal: Cardiovascular Research (2018)

Introduction: Diabetes is an independent risk factor for cardiovascular disease, with 50% of diabetic patients developing cardiomyopathy, including fibrosis.Substance P (SP) is a neuropeptide located in sensory nerves, and diabetic rat hearts have reduced levels of SP.This reduced SP appears to contribute to the loss of cardioprotection in response to ischaemic post conditioning, indicating that SP may play a protective role in diabetic hearts.Purpose: Our aim was to further examine the cardio-protective role of SP in diabetes.We hypothesised that a loss of SP leads to fibrosis in diabetic hearts and that this adverse remodelling is reversible by restoring SP levels.Methods: 10 week old Leprdb obese diabetic mice received a daily subcutaneous injection of either saline or SP (1mg/kg) for four weeks.Wild type C57B/6 mice were included as controls.For in vitro studies, cardiac fibroblasts were isolated and treated with SP (10, 30, 100, 300 and 1000 nM) in high glucose media (DMEM þ 9 g/L of glucose) for 24 hours to mimic diabetes.SP levels were also measured in plasma samples from diabetic patients.
Determinants of clinical efficacy of empirical antibiotic treatment in patients with cirrhosis and bacterial infections: Results from the ICA global study
Authors: R. Maiwall, S. Piano, V. Singh, P. Caraceni, C. Alessandria, J. Fernandez, E. Soares, D.J. Kim, S.E. Kim, M. Marino, J. Vorobioff, R. de Cassia Ribeiro Barea, M. Merli, L. Elkrief, V.M.V. Blasco, A. Krag, S. Singh, L.A. Lesmana, C. Toledo, S. Marciano, V. Xavier, F. Wong, N. Intagliata, L. Rabinowich, L.A. Colombato, S.G. Kim, A. Gerbes, F. Durand, J.P. Roblero, J.H. Kim, R.D. Man, D.S. Song, C.E. Brodersen, A. Gadano, S.K. Sarin, P. Angeli
Journal: Journal of Hepatology (2018)
Abstract 18806: Integrated Proteomic Analysis of Cardiovascular Disease Reveals Novel Protein Quantitative Trait Loci
Authors: George Chen, Chen Yao, Shih-Jen Hwang, Chunyu Liu, Ci Song, Tianxiao Huan, Michael M Mendelson, Paul Courchesne, Asya Lyass, Martin Larson, Andrew D Johnson, Daniel Levy
Journal: Circulation (2016)

Introduction:  Recent genome-wide association studies (GWAS) have examined associations between genetic variants and gene expression to help understand the molecular underpinnings of complex diseases. Few large-scale studies have analyzed genetic variants that modify protein levels. Studying protein quantitative trait loci (pQTLs) may provide novel insights into the role of the proteome in the pathogenesis of disease.   Methods and Results:  We assayed 71 plasma proteins in 7242 Framingham Heart Study participants (mean age 50 years, 53% women) using bead-based multiplex immunoassays. Proteins were selected using evidence of association with CVD or its risk factors based on: a) comprehensive literature search, b) proteomics discovery via mass spectrometry, and c) proteins coded by genes identified by gene expression profiling or published GWAS of CVD and its risk factors. We tested the associations of plasma concentrations of the 71 proteins with 25 million SNPs, adjusting for age, age 2 , sex, and family structure. We identified 18,549 genome-wide significant SNPs (P -8 ) for 57 proteins of which 36 had at least one  cis -pQTL and 41 had at least one  trans -pQTL. To explore how pQTLs may affect CVD phenotypes by altering protein levels, we examined the overlap of pQTLs with SNPs (P -8 ) from published GWAS results. Our analysis revealed that 210 pQTLs for 12 proteins coincided with SNPs for coronary artery disease (CAD) or myocardial infarction (MI). The top pQTLs for each protein often explained a substantial proportion of inter-individual variation in protein abundance. For example, rs12740374 at the  CELSR2/SORT1  locus, reported in previous GWAS to be associated with lipids and CAD/MI, explained 15% of inter-individual variation in plasma granulin levels. Of note, progranulin binds to SORT1; Sort1 knockout mice have markedly elevated levels of progranulin. Granulin levels and CVD phenotypes share common genetic origins, suggesting that granulin may be a candidate for functional studies to develop novel ways to predict, prevent, or treat CVD.   Conclusions:  We conducted GWAS for high-value plasma proteins, identified novel pQTLs, and elucidated integrated networks of genetic variants, circulating protein levels, and CVD traits.
TCTAP C-047 Delayed Stenting and RePOT Technic in Acute Thrombotic Distal Left Main Stenosis Involving the Left Anterior Descending Artery
Authors: Nazim Megherbi, Wathik Takdemt, Said Benghezel, Mohamed Abed Bouraghda, Mohamed Chettibi, Mohamed Tahar Chafik Bouafia
Journal: Journal of the American College of Cardiology (2018)
High agreement with HCV RNA in screening and DAA treatment monitoring indicates that cost-effective HCV core Ag test can also be enlisted in the fight to eliminate hepatitis C
Authors: N. Chitadze, M. Alkhazashvili, G. Chanturia, A. Gamkrelidze, B. Skaggs, J. Drobeniuc, G. Cloherty, G. Kamkamidze, R. Sukhiashvili, F. Averhoff
Journal: Journal of Hepatology (2018)
S100a11 is part of a whole network of tumor suppressors and oncogenes deregulatedearly with hepatic steatosis and contributing to hepatocellular carcinoma development
Authors: C. Sobolewski, A. Daniel, F. Berthou, N. Calo, C. Sempoux, A.-S. Ay, P. Clavien, H. Bostjan, J.-F. Dufour, A. Alexander, M. Foti
Journal: Journal of Hepatology (2018)
NHS accountable care organisations would be unlawful, campaigners tell High Court
Authors: Clare Dyer
Journal: BMJ (2018)

The NHS would be exceeding its legal powers by going ahead with its plans for accountable care organisations (ACOs), campaigners have told a High Court judge in the first of two legal challenges to the proposals.1

ACOs are intended to help deliver integrated care, where hospital and ambulance trusts, GPs, local authorities, social care providers, and health commissioning groups would work more closely together. But campaigners, who see them as vehicles for NHS privatisation and cuts to services, have applied for judicial review of the plans.

At …
State of Behavioral Health Integration in U.S. Diabetes Care: How Close Are We to ADA Recommendations?
Authors: Samantha A. Barry, David M. Harlan, Nicole L. Johnson, Kristin L. MacGregor
Journal: Diabetes Care (2018)

In December 2016, the American Diabetes Association (ADA) published a position statement on psychosocial care in diabetes, with evidence-based guidelines for psychosocial assessment and care of individuals with diabetes (1). As a part of this position statement, it is recommended that diabetes practitioners identify and coordinate with qualified behavioral/mental health providers who are ideally embedded in the diabetes care setting and knowledgeable about diabetes treatment and psychosocial aspects of diabetes. These comprehensive recommendations were reiterated in the ADA Standards of Medical Care in Diabetes—2018 (2).

Despite the documented benefit of psychosocial intervention and the ADA recommendation, we believe that behavioral health integration is not yet standard care. Moreover, little is known about the prevalence of behavioral health integration. Here, we targeted U.S. academic adult diabetes practices in order to understand the current state of behavioral health integration in diabetes care across the U.S. We identified diabetes practices by their membership to one of two well-known diabetes groups and administered surveys to clinic leadership. Respondents identified as …
P382Factors related to cardiovascular event after two years of follow-up of stage 3 chronic kidney disease patient's
Authors: Y Rivero Viera, N Esparza Martin, S Suria Gonzalez, E Bosch Benitez-Parodi, R Guerra Rodriguez, A Ramirez Puga, A C Rodenas Galvez, S Fernandez, G Perez Suarez, C Garcia-Canton
Journal: Cardiovascular Research (2018)
Screening for Wiskott-Aldrich syndrome by flow cytometry
Authors: Samuel C.C. Chiang, Sue M. Vergamini, Ammar Husami, Lisa Neumeier, Kathryn Quinn, Teresa Ellerhorst, Linda Sheppard, Carrie Gifford, David Buchbinder, Avni Joshi, Marianne Ifversen, Gary I. Kleiner, James B. Bussel, Shanmuganathan Chandrakasan, Robert D. Pesek, Tamara C. Pozos, Melissa J. Rose, Amy M. Scurlock, Kejian Zhang, Yenan T. Bryceson, Jack Bleesing, Rebecca A. Marsh
Journal: Journal of Allergy and Clinical Immunology (2018)
Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance
Authors: Taka-aki Koshimizu, Kenji Honda, Sachi Nagaoka-Uozumi, Atsuhiko Ichimura, Ikuo Kimura, Michio Nakaya, Nobuya Sakai, Katsushi Shibata, Kentarou Ushijima, Akio Fujimura, Akira Hirasawa, Hitoshi Kurose, Gozoh Tsujimoto, Akito Tanoue, Yukio Takano
Journal: Nature Neuroscience (2018)
Infection-related ventilator-associated complications in ICU patients colonised with extended-spectrum β-lactamase-producing Enterobacteriaceae
Authors: François Barbier, Sébastien Bailly, Carole Schwebel, Laurent Papazian, Élie Azoulay, Hatem Kallel, Shidasp Siami, Laurent Argaud, Guillaume Marcotte, Benoît Misset, Jean Reignier, Michaël Darmon, Jean-Ralph Zahar, Dany Goldgran-Toledano, Étienne de Montmollin, Bertrand Souweine, Bruno Mourvillier, Jean-François Timsit
Journal: Intensive Care Medicine (2018)
Early HCV viral kinetics in the setting of transplantation of kidneys from HCV-infected deceased donors into HCV-negative recipients
Authors: D. Goldberg, R. Reddy, E. Blumberg, G. Cloherty, V. Holzmayer, M. Kuhns, R. Bloom, P. Abt, D. Sawinski, A. Sicili, M. Levine, A. Naji, P. Porrett, S. Nazarian, M. Kaminski, V.V. Deerlin, J. Smith, C. Gentile, P. Reese
Journal: Journal of Hepatology (2018)