tbuckley/cabot-search huggingface dataset:
P65Lack of heme oxygenase-1 affects electrophysiological properties of cardiomyocytes derived from human induced pluripotent stem cells
Authors: M Jez, J Stepniewski, K Andrysiak, A Kania, L Chrobok, K Palus-Chramiec, M H Lewandowski, A Jozkowicz, J Dulak
Journal: Cardiovascular Research (2018)

too low to efficiently compensate for the loss of functional myocardium in heart disease.We hypothesize that cardiomyocyte proliferation is tightly controlled by regulatory mechanisms that can be reactivated to promote endogenous repair after heart injuries.Unequivocal identification of cycling cardiomyocytes is a fundamental requirement for the investigation of these mechanisms.Methods: We used a preexisting transgenic mouse model based on the FUCCI (Fluorescent Ubiquitination-based Cell Cycle Indicator) system to discriminate cycling cardiomyocytes (S/G2/M phases, green fluorescent nuclei) from non-cycling ones (G0/G1 phases, red fluorescent nuclei).In mice ubiquitously expressing FUCCI constructs, we used the myocyte-specific perinuclear marker Pericentriolar Material 1 (PCM-1) to distinguish cardiomyocyte from non-myocyte cells in the heart tissue.Single cardiomyocyte isolations from FUCCI mice neonatal hearts followed by FACS sorting into 96-well plates were performed to obtain single cell transcriptome of cycling and non-cycling cardiomyocytes at different post-natal stages.Results: The presented transgenic strategy proved to be efficient for the identification of cycling cardiomyocytes in neonate, juvenile and adult mouse hearts in vitro and in vivo.The validity of transgenes expression was verified in both systems with immunohistochemistry by co-localization of cardiomyocytes and cell cycle markers with FUCCI fluorescence.The FUCCI system allowed us to confirm previous observations of a gradual decrease in the number of cycling cardiomyocyte during the neonatal period.P0 and P7 cardiomyocyte transcriptome were generated using single cell RNA-sequencing.The cell cycle stage of cardiomyocytes as indicated by their FUCCI fluorescence was highly correlated by their transcriptome profile.Conclusion: Strategies that allow to unambiguously identify cycling cardiomyocytes in vitro and in vivo provide important tools to study the regulation of cardiomyocyte proliferation.With the FUCCI system we seek to identify novel molecular targets that could promote cardiomyocyte proliferation, by using transcriptome profiling (RNA-seq) of isolated cycling cardiomyocytes.
Specific IgG 4 antibodies to cow's milk proteins in pediatric patients with eosinophilic esophagitis
Authors: Alexander J. Schuyler, Jeffrey M. Wilson, Anubha Tripathi, Scott P. Commins, Princess U. Ogbogu, Patrice G. Kruzsewski, Barrett H. Barnes, Emily C. McGowan, Lisa J. Workman, Jonas Lidholm, Sheryl L. Rifas-Shiman, Emily Oken, Diane R. Gold, Thomas A.E. Platts-Mills, Elizabeth A. Erwin
Journal: Journal of Allergy and Clinical Immunology (2018)
Preemptive Activation of the Integrated Stress Response Protects Mice From Diet‐Induced Obesity and Insulin Resistance by Fibroblast Growth Factor 21 Induction
Authors: Xu Xu, Christopher Krumm, Jae‐Seon So, Curtis J. Bare, Corey Holman, Jesper Gromada, David E. Cohen, Ann‐Hwee Lee
Journal: Hepatology (2018)

Integrated stress response (ISR) is a signaling system in which phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by stress‐specific kinases and subsequent activation of activation transcription factor (ATF) 4 help restore cellular homeostasis following exposure to environmental stresses. ISR activation has been observed in metabolic diseases, including hepatic steatosis (HS), steatohepatitis (SH), and insulin resistance (IR), but it remains unclear whether ISR contributes to disease pathogenesis or represents an innate defense mechanism against metabolic stresses. Constitutive repressor of eIF2α phosphorylation (CReP) is a critical regulatory subunit of the eIF2α phosphatase complex. Here, we show that CReP ablation causes constitutive eIF2α phosphorylation in the liver, which leads to activation of the ATF4 transcriptional program including increased fibroblast growth factor 21 (FGF21) production. Liver‐specific CReP knockout (CReP LKO ) mice exhibited marked browning of white adipose tissue (WAT) and increased energy expenditure and insulin sensitivity in an FGF21‐dependent manner. Furthermore, CReP LKO mice were protected from high‐fat diet (HFD)‐induced obesity, HS, and IR. Acute CReP ablation in liver of HFD‐induced obese mice also reduced adiposity and improved glucose homeostasis. Conclusion: These data suggest that CReP abundance is a critical determinant for eIF2α phosphorylation and ensuing ISR activation in the liver. Constitutive ISR activation in the liver induces FGF21 and confers protection from HFD‐induced adiposity, IR, and HS in mice. Augmenting hepatic ISR may represent a therapeutic approach to treat metabolic disorders.
P173Effect of vitamin e and tempol on low density lipoprotein oxidation at lysosomal pH
Authors: HADEEL Alboaklah
Journal: Cardiovascular Research (2018)

During atherosclerosis, smooth muscle cells (SMCs) accumulate into the intima and switch from a contractile to a synthetic phenotype.We have previously isolated two distinct SMC populations from the porcine coronary artery, spindle-shaped (S) and rhomboid (R) SMCs.R-SMCs display the features of synthetic SMCs.S100A4, a calcium-binding protein, was identified as being a marker of R-SMCs in vitro and of intimal SMCs, in both pig and man.Recently, we have shown that the extracellular form of S100A4 is essential for the establishment of the R-phenotype.By treating S-SMCs with S100A4-rich conditioned medium, we observed the phenotypic transition towards Rphenotype that was associated with acquisition of pro-inflammatory properties.To further study the pivotal role of extracellular S100A4 on SMC phenotypic transition, S-SMCs were treated with dimeric and multimeric form of recombinant S100A4.Dimeric S100A4 had no effect on SMC phenotypic transition nor activation.Treatment with multimeric S100A4 was associated with a partial transition from S-to R-phenotype, NFjB translocation into the nucleus, increased expression of S100A4 and decreased expression of a-smooth muscle actin (a-SMA).Remarkably, treatment of S-SMCs with multimeric S100A4 and platelet-derived growth factor-BB (PDGF-BB) together induced a complete SMC transition toward a R-phenotype, associated with enhanced proliferation, increased S100A4 expression, decreased expression of a-SMA and NFjB activation compared with multimeric S100A4 or PDGF-BB alone (Figure).Multimeric S100A4 and PDGF-BB together induced a pro-inflammatory profile as shown by real-time PCR of matrix metalloproteinase-3 (fold change versus control 100.8610.1)and granulocyte-macrophage colonystimulating factor (fold change versus control 184.5615.1).Moreover RNA sequencing showed that 67 genes were strongly upregulated exclusively when cells were treated with multimeric S100A4 and PDGF-BB together compared to treatments with multimeric S100A4 or PDGF-BB alone.High majority of these genes are involved in pathways related to inflammation.Furthermore, multimeric S100A4 and PDGF-BB-induced SMC phenotypic transition as well as activation were prevented by silencing of toll-like receptor 4 (TLR4).Our results indicate that extracellular multimeric S100A4 and PDGF-BB act in synergy to promote a pro-inflammatory-like SMC phenotype likely through TLR4.Pro-inflammatory-like SMCs could be involved in plaque rupture and monocyte activation.Further studies will be focused on signaling pathways activated by extracellular multimeric S100A4 and/or PDGF-BB and on in vivo studies.We have preliminary shown that intimal SMCs in this mouse model co-expressed S100A4 and a-SMA while in the media S100A4 was absent, thereby confirming that S100A4 is a marker of intimal SMCs.The effect of S100A4 neutralization in balloon catheter-induced intimal thickening in mice will be further examined.
Drug-eluting stents versus bare-metal stents in saphenous vein grafts: a double-blind, randomised trial
Authors: Emmanouil S Brilakis, Robert Edson, Deepak L Bhatt, Steven Goldman, David R Holmes, Sunil V Rao, Kendrick Shunk, Bavana V Rangan, Kreton Mavromatis, Kodangudi Ramanathan, Anthony A Bavry, Santiago Garcia, Faisal Latif, Ehrin Armstrong, Hani Jneid, Todd A Conner, Todd Wagner, Judit Karacsonyi, Lauren Uyeda, Beverly Ventura, Aaron Alsleben, Ying Lu, Mei-Chiung Shih, Subhash Banerjee, Bina Ahmed, D Michelle Ratliff, Mark Ricciardi, Mark Sheldon, Milton Icenogle, Richard Snider, Amer Ardati, Brahmajee Nallamothu, Claire Duvernoy, Daniel S Menees, Hitinder Gurm, Michael P Thomas, Paul Grossman, Kristine Owen, On Topaz, Gautam Kumar, Kreton Mavromatis, Peter Block, David A Zidar, Hiram Bezerra, Jonathan Goldberg, Jose Ortiz, Joseph Jozic, Mohammed Osman, Noah Rosenthal, Sahil A Parikh, Tom A Lassar, Albert Chan, Arun Kumar, Kul Aggarwal, Tillmann Cyrus, Emmanouil S Brilakis, Jerrold Grodin, Subhash Banerjee, Brack Hattler, Ehrin Armstrong, Ivan Casserly, John Messenger, Michael Kim, R Kevin Rogers, Stephen Waldo, Thomas Tsai, Kenneth Morris, Mitchell Krucoff, Sunil Rao, Thomas J Povsic, William S Jones, Anthony Bavry, Calvin Choi, Ki Park, Jayson Liu, MD, Biswajit Kar, David Paniagua, Hani Jneid, Jeffrey Breall, Islam Bolad, Rita Mukerji, Roopa Subbarao, Ahmed Abdel-Latif, David C Booth, Khaled M Ziada, Lawrence Rajan, Abdul Hakeem, Barry F Uretsky, Mayank Agrawal, Rajesh Sachdeva, Zubair Ahmed, Jesse McGee, Kodangudi Ramanathan, Rahman Shah, Alok Sharma, Edward McFalls, Rizwan Siddiqui, Santiago Garcia, Selcuk Adabag, Stefan Bertog, Anand Irimpen, Drew Baldwin, Nidal Abi Rafeh, Owen Mogabgab, Patrice Delafontaine, Jeffrey Lorin, Steven Sedlis, Eliot Schechter, Faisal Latif, Mazen Abu-Fadel, Talla Rousan, Udho Thadani, Fady Malik, Jeffrey Zimmet, Kendrick Shunk, Tony Chou, Alexis Beatty, Kenneth Lehmann, Michael Stadius, Andrew Klein, Caroline Rowe, Megumi Taniuchi, Andrew J Klein, Michael Forsberg, Divya Kapoor, Elizabeth Juneman, Huu Tam Truong, Kapildeo Lotun, Ryan Tsuda, Sergio Thai, Steven Goldman, Hoang Thai, David Lu, Vasilios Papademetriou, David Faxon, Deepak L Bhatt, Kevin Croce, Sammy Elmariah, Scott Kinlay
Journal: The Lancet (2018)
Emerging Role of Precision Medicine in Cardiovascular Disease
Authors: Jane A. Leopold, Joseph Loscalzo
Journal: Circulation Research (2018)

Precision medicine is an integrative approach to cardiovascular disease prevention and treatment that considers an individual’s genetics, lifestyle, and exposures as determinants of their cardiovascular health and disease phenotypes. This focus overcomes the limitations of reductionism in medicine, which presumes that all patients with the same signs of disease share a common pathophenotype and, therefore, should be treated similarly. Precision medicine incorporates standard clinical and health record data with advanced panomics (ie, transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics) for deep phenotyping. These phenotypic data can then be analyzed within the framework of molecular interaction (interactome) networks to uncover previously unrecognized disease phenotypes and relationships between diseases, and to select pharmacotherapeutics or identify potential protein–drug or drug–drug interactions. In this review, we discuss the current spectrum of cardiovascular health and disease, population averages and the response of extreme phenotypes to interventions, and population-based versus high-risk treatment strategies as a pretext to understanding a precision medicine approach to cardiovascular disease prevention and therapeutic interventions. We also consider the search for resilience and Mendelian disease genes and argue against the theory of a single causal gene/gene product as a mediator of the cardiovascular disease phenotype, as well as an Erlichian magic bullet to solve cardiovascular disease. Finally, we detail the importance of deep phenotyping and interactome networks and the use of this information for rational polypharmacy. These topics highlight the urgent need for precise phenotyping to advance precision medicine as a strategy to improve cardiovascular health and prevent disease.
Results of a placebo-controlled double blind randomised trial to investigate the efficacy of rifaximin-alpha versus placebo in improving systemic inflammation in patients with cirrhosis and chronic hepatic encephalopathy (RIFSYS Trial)
Authors: V. Patel, M.J.W. Mcphail, A. Zamalloa, S. Støy, G.M. Vijay, X. Huang, G. Rogers, J. Choo, L. Edwards, E. Gray, C. Woodhouse, S. Gencer, M. Coen, J. Wendon, K. Bruce, D. Shawcross
Journal: Journal of Hepatology (2018)
Association Between Hospice Length of Stay, Health Care Utilization, and Medicare Costs at the End of Life Among Patients Who Received Maintenance Hemodialysis
Authors: Melissa W. Wachterman, Susan M. Hailpern, Nancy L. Keating, Manjula Kurella Tamura, Ann M. O’Hare
Journal: JAMA Internal Medicine (2018)

Patients with end-stage renal disease are less likely to use hospice services than other patients with advanced chronic illness. Little is known about the timing of hospice referral in this population and its association with health care utilization and costs.To examine the association between hospice length of stay and health care utilization and costs at the end of life among Medicare beneficiaries who had received maintenance hemodialysis.This cross-sectional observational study was conducted via the United States Renal Data System registry. Participants were all 770 191 hemodialysis patients in the registry who were enrolled in fee-for-service Medicare and died between January 1, 2000, and December 31, 2014. The dates of analysis were April 2016 to December 2017.Hospital admission, intensive care unit (ICU) admission, and receipt of an intensive procedure during the last month of life; death in the hospital; and costs to the Medicare program in the last week of life.Among 770 191 patients, the mean (SD) age was 74.8 (11.0) years, and 53.7% were male. Twenty percent of cohort members were receiving hospice services when they died. Of these, 41.5% received hospice for 3 days or fewer. In adjusted analyses, compared with patients who did not receive hospice, those enrolled in hospice for 3 days or fewer were less likely to die in the hospital (13.5% vs 55.1%; P < .001) or to undergo an intensive procedure in the last month of life (17.7% vs 31.6%; P < .001) but had higher rates of hospitalization (83.6% vs 74.4%; P < .001) and ICU admission (54.0% vs 51.0%; P < .001) and similar Medicare costs in the last week of life ($10 756 vs $10 871; P = .08). Longer lengths of stay in hospice beyond 3 days were associated with progressively lower rates of utilization and costs, especially for those referred more than 15 days before death (35.1% hospitalized and 16.7% admitted to an ICU in the last month of life; the mean Medicare costs in the last week of life were $3221).Overall, 41.5% of hospice enrollees who had been treated with hemodialysis for their end-stage renal disease entered hospice within 3 days of death. Although less likely to die in the hospital and to receive an intensive procedure, these patients were more likely than those not enrolled in hospice to be hospitalized and admitted to the ICU, and they had similar Medicare costs. Without addressing barriers to more timely referral, greater use of hospice may not translate into meaningful changes in patterns of health care utilization, costs, and quality of care at the end of life in this population.
The gut-liver axis is essential for disease progression in the Mdr2–/– mouse model of primary sclerosing cholangitis
Authors: L. Liao, K.M. Schneider, M. Frissen, T. Strowig, H.-U. Marschall, A. Wahlström, G. Eric, A. Mohs, P. Jin, J. Jung, J. Reissing, H. Sun, C. Elfers, V. Bieghs, F.J. Cubero, C. Trautwein
Journal: Journal of Hepatology (2018)
Palmitoylation determines the subcellular localization of the hepatitis E virus ORF3 protein
Authors: J. Gouttenoire, P. Angela, A. Laurence, M. Maxime, D.T.V. Loan, S. Dagmara, O. Joël, M. Johann, G. van der Goot, D. Moradpour
Journal: Journal of Hepatology (2018)
Multicenter study on outcome of HCV elimination using LDV/SOF combination in Mongolians
Authors: L. Nemekhbaatar, B. Oidov, D. Radnaa, S. Ulziibayar, M. Sarandavaa, J. Palam, T. Davaadorj, E. Damba, B. Dorjgotov, N. Dulmaa, A. Jenskhan, C. Nagir, S. Batmunkh, G. Uugantsetseg, M. Batmunkh, A. Jazag
Journal: Journal of Hepatology (2018)
Phase 2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: Interim analysis.
Authors: Nathan Bahary, Ignacio Garrido-Laguna, Pelin Cinar, Mark Allen O'Rourke, Bradley G. Somer, Asha Nyak-Kapoor, Jin S. Lee, David Munn, Eugene Paul Kennedy, Nicholas N. Vahanian, Charles J. Link, Andrea Wang-Gillam
Journal: Journal of Clinical Oncology (2016)

3020 Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that plays a key role in the normal regulation of peripheral immune tolerance. Tumors also employ this mechanism. In cancer, IDO can either be expressed by the tumor cells themselves, or induced indirectly in host antigen presenting cells. In these settings, IDO mediates an acquired immune tolerance, allowing evasion of immune mediated destruction. Indoximod is a broad IDO pathway inhibitor, shown to potentially interfere with multiple targets. The combination of gemcitabine and nab-paclitaxel is a current SOC for metastatic pancreas cancer. Pre-clinical models have demonstrated synergy between IDO inhibition with indoximod and chemotherapy. The Phase 1 results demonstrated safety of the combination and a promising preliminary objective response rate. Additionally, a delay in the occurrence of the observed responses and the durability of the observed responses suggested an immune mediated mechanism. Methods: Patients are treated with indoximod (1200mg BID continuous dosing) in combination with gemcitabine / nab-paclitaxel (1000mg/m2 / 125mg/m2 q week x3 per 4 week cycle) in continuous 4 weeks cycles. Eligible patients have treatment naïve metastatic pancreatic cancer or 1st line salvage therapy after previous resection and adjuvant therapy. Treatment continues until disease progression or toxicity. Primary endpoint is overall survival. Secondary endpoints include response rate and progression free survival. Target enrollment is 80 patients in Phase 2. Results: At this interim analysis, 30 patients to date have been enrolled in Phase 1 / 2 and completed protocol treatment at least through imaging at the end of cycle 2. Of these, 11 (37%) have demonstrated an objective response by RECIST criteria including one patient with a confirmed complete response. One adverse event of immunological significance (colitis) was observed and required study withdrawl. Conclusions: The combination of indoximod and gemcitabine / nab-paclitaxel continues to demonstrate a promising objective response rate. Updated results will be presented. Clinical trial information: NCT02077881.
Serum bile acids alteration is associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD
Authors: C. Caussy, C. Hsu, S. Seema, B. Shirin, K. James, C. Faulkner, R. Bettencourt, M. Valasek, L. Richards, B. David, R. Loomba
Journal: Journal of Hepatology (2018)
Risk assessment of hepatocellular carcinoma in chronic liver disease patients with a combination of liver stiffness measurement and controlled attenuation parameter by FibroScan
Authors: K. Morikawa, T. Izumi, T. Sho, K. Suzuki, A. Nakamura, M. Ohara, N. Kawagishi, M. Umemura, M. Nakai, G. Suda, K. Ogawa, Y. Kudo, M. Nishida, M. Baba, K. Furuya, N. Sakamoto
Journal: Journal of Hepatology (2018)
In Blunt Traumatic Cardiac Arrest, Does It Really Matter Who Performs Prehospital Advanced Life Support?
Authors: Sandra DiBrito, Elliott R. Haut
Journal: JAMA Surgery (2018)

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Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies
Authors: Justin I. Odegaard, John J. Vincent, Stefanie Mortimer, James V. Vowles, Bryan C. Ulrich, Kimberly C. Banks, Stephen R. Fairclough, Oliver A. Zill, Marcin Sikora, Reza Mokhtari, Diana Abdueva, Rebecca J. Nagy, Christine E. Lee, Lesli A. Kiedrowski, Cloud P. Paweletz, Helmy Eltoukhy, Richard B. Lanman, Darya I. Chudova, AmirAli Talasaz
Journal: Clinical Cancer Research (2018)

Abstract Purpose: To analytically and clinically validate a circulating cell-free tumor DNA sequencing test for comprehensive tumor genotyping and demonstrate its clinical feasibility. Experimental Design: Analytic validation was conducted according to established principles and guidelines. Blood-to-blood clinical validation comprised blinded external comparison with clinical droplet digital PCR across 222 consecutive biomarker-positive clinical samples. Blood-to-tissue clinical validation comprised comparison of digital sequencing calls to those documented in the medical record of 543 consecutive lung cancer patients. Clinical experience was reported from 10,593 consecutive clinical samples. Results: Digital sequencing technology enabled variant detection down to 0.02% to 0.04% allelic fraction/2.12 copies with ≤0.3%/2.24–2.76 copies 95% limits of detection while maintaining high specificity [prevalence-adjusted positive predictive values (PPV) &amp;gt;98%]. Clinical validation using orthogonal plasma- and tissue-based clinical genotyping across &amp;gt;750 patients demonstrated high accuracy and specificity [positive percent agreement (PPAs) and negative percent agreement (NPAs) &amp;gt;99% and PPVs 92%–100%]. Clinical use in 10,593 advanced adult solid tumor patients demonstrated high feasibility (&amp;gt;99.6% technical success rate) and clinical sensitivity (85.9%), with high potential actionability (16.7% with FDA-approved on-label treatment options; 72.0% with treatment or trial recommendations), particularly in non–small cell lung cancer, where 34.5% of patient samples comprised a directly targetable standard-of-care biomarker. Conclusions: High concordance with orthogonal clinical plasma- and tissue-based genotyping methods supports the clinical accuracy of digital sequencing across all four types of targetable genomic alterations. Digital sequencing's clinical applicability is further supported by high rates of technical success and biomarker target discovery. Clin Cancer Res; 24(15); 3539–49. ©2018 AACR.