tbuckley/cabot-search huggingface dataset:
Multi-Omics Profiling Reveals Distinct Microenvironment Characterization and Suggests Immune Escape Mechanisms of Triple-Negative Breast Cancer
Authors: Yi Xiao, Ding Ma, Shen Zhao, Chen Suo, Jinxiu Shi, Meng-Zhu Xue, Miao Ruan, Hai Wang, Jingjing Zhao, Qin Li, Peng Wang, Leming Shi, Wen-Tao Yang, Wei Huang, Xin Hu, Ke-Da Yu, Shenglin Huang, François Bertucci, Yi-Zhou Jiang, Zhi-Ming Shao
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The tumor microenvironment has a profound impact on prognosis and immunotherapy. However, the landscape of the triple-negative breast cancer (TNBC) microenvironment has not been fully understood. Experimental Design: Using the largest original multi-omics dataset of TNBC (n = 386), we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TNBC microenvironment. We further analyzed the potential immune escape mechanisms of TNBC. Results: The TNBC microenvironment phenotypes were classified into three heterogeneous clusters: cluster 1, the “immune-desert” cluster, with low microenvironment cell infiltration; cluster 2, the “innate immune-inactivated” cluster, with resting innate immune cells and nonimmune stromal cells infiltration; and cluster 3, the “immune-inflamed” cluster, with abundant adaptive and innate immune cells infiltration. The clustering result was validated internally with pathologic sections and externally with The Cancer Genome Atlas and METABRIC cohorts. The microenvironment clusters had significant prognostic efficacy. In terms of potential immune escape mechanisms, cluster 1 was characterized by an incapability to attract immune cells, and MYC amplification was correlated with low immune infiltration. In cluster 2, chemotaxis but inactivation of innate immunity and low tumor antigen burden might contribute to immune escape, and mutations in the PI3K-AKT pathway might be correlated with this effect. Cluster 3 featured high expression of immune checkpoint molecules. Conclusions: Our study represents a step toward personalized immunotherapy for patients with TNBC. Immune checkpoint inhibitors might be effective for “immune-inflamed” cluster, and the transformation of “cold tumors” into “hot tumors” should be considered for “immune-desert” and “innate immune-inactivated” clusters.
Abstract 19469: PBI-4050 Reduces Cardiovascular Biomarkers in Type II Diabetic Patients With Metabolic Syndrome
Authors: Pierre Laurin, Brigitte Grouix, Alexandre Laverdure, Boulos Zacharie, Lyne Gagnon
Journal: Circulation (2016)

Introduction: Patients suffering of metabolic syndrome and type II diabetes with elevated blood levels of pentraxine-3 and resistin have been shown to have a significantly increased incidence of ca...
Predicting Early Mortality in Multiple Myeloma Patients Treated with Novel Agents
Authors: Catarina Geraldes, Adriana Roque, Ana Bela Sarmento-Ribeiro, Maria Leticia Ribeiro, Rui Bergantim, Fernanda Trigo, Sérgio Chacim, Ana Macedo, Carolina Viveiros, Cristina Joao, Manuel Neves, Paulo Lucio
Journal: Blood (2018)
LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION IN A PATIENT WITH LONG-TERM NON-PROGRESSIVE HUMAN IMMUNODEFICIENCY VIRUS
Authors: Andrew S. Brown, Jeremiah Lee, Harveen Lamba, Adeel A. Butt, Oscar Frazier, Jeffrey Morgan, Andrew Civitello, Faisal H. Cheema
Journal: Journal of the American College of Cardiology (2019)
VENOUS THROMBOEMBOLISM IN PATIENTS WITH LIVER CIRRHOSIS: FINDINGS FROM THE RIETE REGISTRY
Authors: Behnood Bikdeli, David Jimenez, Guadelupe Garcia-Tsao, Raquel Barba, Carme Font, María del Carmen Díaz-Pedroche, Lucia Mazzolai, Derek Henry Wallace Little, Antonello Tufano, Deborah Siegal, Gregory Lip, Manuel Monreal
Journal: Journal of the American College of Cardiology (2019)
Chlorhexidine versus routine bathing to prevent multidrug-resistant organisms and all-cause bloodstream infections in general medical and surgical units (ABATE Infection trial): a cluster-randomised trial
Authors: Susan S Huang, Edward Septimus, Ken Kleinman, Julia Moody, Jason Hickok, Lauren Heim, Adrijana Gombosev, Taliser R Avery, Katherine Haffenreffer, Lauren Shimelman, Mary K Hayden, Robert A Weinstein, Caren Spencer-Smith, Rebecca E Kaganov, Michael V Murphy, Tyler Forehand, Julie Lankiewicz, Micaela H Coady, Lena Portillo, Jalpa Sarup-Patel, John A Jernigan, Jonathan B Perlin, Richard Platt
Journal: The Lancet (2019)
DETERMINANTS OF DISCORDANCE BETWEEN FRACTIONAL FLOW RESERVE AND DIASTOLIC PRESSURE RATIO IN ANGIOGRAPHICALLY INTERMEDIATE CORONARY STENOSIS
Authors: Yohei Sumino, Masahiro Hoshino, Tomoki Horie, Haruhito Yuki, Hidenori Hirano, Yoshinori Kanno, Hiroaki Ohya, Masahiro Hada, Masao Yamaguchi, Yoshihisa Kanaji, Akinori Sugano, Taishi Yonetsu, Tsunekazu Kakuta
Journal: Journal of the American College of Cardiology (2019)
ROLE OF CIRCULATING MIR-497 IN ACUTE MYOCARDIAL INFARCTION PATIENTS AND HYPOXIA/REOXYGENATION H9C2 CELLS
Authors: Md Sayed Ali Sheikh, A. Alduraywish, U. Salma, Wu Zhichao, Ke Xia, T.L. Yang, J. Peng
Journal: Journal of the American College of Cardiology (2019)
Abstract 344: Proteomic Analysis Revealing Association of hiPSC-exosomal Proteins in Epigenetic Inheritance
Authors: Yan Tang, Yujia Yue, Venkata N Garikipati, Suresh Verma, Zhongjian Cheng, Maria Cimini, David Goukassian, Chunlin Wang, May Cao, Raj Kishore
Journal: Circulation Research (2018)

Background: Exosomes, as a mediator of cell-to-cell communication has regulatory effects on the genetic and epigenetic processes in the recipient cells. Although the ability of human induced pluripotent stem cells (hiPSCs) derived exosomes to participate in tissue repair is being increasingly recognized, the information inside the hiPSC-exosomes especially protein content is not completely identified yet. Method: Exosomes derived from human fibroblast cell line IMR90 and IMR90 derived hiPSC cell line iPS (IMR90)-4 were collected using differential ultracentrifugation, then the exosomal proteins were identified by mass spectrometry analysis. The proteomics results were confirmed by western blot. To validate the role hiPSC-exosome in epigenetic processes, the H9C2 cells were treated with both types of exosomes and the histone epigenetic state were analyzed. Results: Gene ontology (GO) analysis of the exosome proteome showed that the hiPSC-exosome protein content had statistically significant enrichment in epigenetic modification such as acetylation, phosphorylation and methylation. The proteomic analysis indentified 6 epigenetic enzymes (UBE2N, DNMT3B, AURKB, CARM1, HDAC2 and HAT1) which only expressed in hiPSC-exosomes whereas 2 enzymes (PRMT5 and PRMT1) showed increased level in hiPSC-exosomes. The differential expressions of HDAC2 and PRMT5 were validated by western blot. Furthermore, H9C2 cell treated with hiPSC-exosomes showed a significant decrease in pan-acetylation level of H4 compared with IMR90-exosomes. Conclusion: In a global analysis presented here, hiPSC-exosomal proteins have been found to be associated with mammalian epigenetic inheritance, which provide important information for the exosome-based therapy.
THE SGLT2 INHIBITOR EMPAGLIFLOZIN IMPROVES DIASTOLIC FUNCTION IN A HEART FAILURE MODEL MEDIATED VIA ENHANCED MYOCARDIAL KETONE METABOLISM
Authors: Carlos G. Santos-Gallego, Alvaro Garcia-Ropero, Rodolfo San Antonio, Juan Antonio Requena-Ibanez, Belén Picatoste, Rebecca Smoller, Shin Watanabe, Angel Sanz Salvo, Roger Hajjar, Kiyotake Ishikawa, Valentin Fuster, Juan Badimon
Journal: Journal of the American College of Cardiology (2019)
Abstract 241: In Vitro Disease Modeling and Discovery of Small Molecules for the Treatment of Duchenne Muscular Dystrophy Utilizing Patient iPSC-derived Cardiomyocytes
Authors: Chicheng Sun, Deena Qadir, Anthony Accorsi, Natalie Moore, Ling Lin, Angela Cacace, John Graef
Journal: Circulation Research (2018)

Duchenne Muscular Dystrophy (DMD) is a fatal disease of skeletal and cardiac muscle characterized by progressive muscle weakness and atrophy. Current average life expectancy is in the mid-20s and mortality is often linked to end stage cardiomyopathy. DMD is a monogenic disease caused by loss-of-function mutations in the dystrophin gene. While dystrophin is critical for muscle function by connecting the cytoskeleton to the sarcolemma and extracellular matrix, its absence can be largely compensated for by up-regulation of utrophin (UTRN), the fetal orthologue of dystrophin. Because of the importance of UTRN expression in the heart in both DMD patients and preclinical models, we utilized DMD patient iPSC-derived cardiomyocytes as a relevant cellular model to perform in vitro pharmacology as well as functional assessment. Human iPSC-derived cardiomyocytes recapitulate key properties of bona fide cardiomyocytes, such as expression of cardiac genes, spontaneous contractility, and response to chronotropic drugs (eg. isoproterenol and hERG channel blockers). We have created an isogenic pair of healthy control and DMD iPSC lines with exon 51 deletion using CRISPR/Cas9 technology. Functional measurements of cardiomyocyte electrophysiology were performed by multielectrode array (MEA) and fluorometric imaging plate reader (FLIPR) platforms. High-throughput assays were developed to measure UTRN expression in cardiomyocyte culture in 384-well plates. Importantly, we have identified small molecules that increased UTRN expression in both patient and isogenic DMD iPSC-derived cardiomyocytes. Our study represents a valuable strategy for small molecule drug discovery for the treatment of DMD cardiomyopathy based on iPSC technology.
Long-Term Stability of the Adult Sickle Cell Quality of Life Measure (ASCQ-Me)​
Authors: Keesha L. Roach, Yingwei Yao, Marie L. Suarez, Veronica Angulo, David Shuey, Miriam O. Ezenwa, Judith M. Schlaeger, Roger B. Fillingim, Zaijie J. Wang, Robert E. Molokie, Diana J. Wilkie
Journal: Blood (2018)
Abstract 21538: Tetrahydrobiopterin Enhances Hydrogen Peroxide Production by Nitric Oxide Synthase While Suppressing Superoxide Generation: Implications for Cardiovascular Disease
Authors: Lawrence Druhan, Xiaoping Liu, Jay L Zweier
Journal: Circulation (2010)

Research into the involvement of NOS in cardiovascular disease has focused on two products of the enzyme, nitric oxide (NO•) and superoxide (•O2-). Some therapeutic regiments have endeavored to reg...
POINT-OF-CARE CYP2C19 GENOTYPE GUIDED ANTIPLATELET THERAPY IN CARDIAC CATHETERIZATION LABORATORY AND CLINICAL OUTCOMES AFTER PCI
Authors: Paul A. Gurbel, Kevin Bliden, Matthew Sherwood, Shahram Yazdani, Hamid Taheri, Alexander Truesdell, Marjaneh Akbari, Kelly Epps, Udaya Tantry
Journal: Journal of the American College of Cardiology (2019)
A COMPARISON OF CHARACTERISTICS OF US MEDICAL GRADUATES VERSUS INTERNATIONAL MEDICAL GRADUATES WHO SUCCESSFULLY MATCHED TO CARDIOVASCULAR FELLOWSHIP DURING THE 2017 INTERVIEW CYCLE
Authors: Arnav Kumar, Amir Kazerouninia, Kyoko Miki, Kristin West, Ada Stefanescu Schmidt, Poonam Velagapudi, Chittur A. Sivaram
Journal: Journal of the American College of Cardiology (2019)
A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring
Authors: Ayelet Alpert, Yishai Pickman, Michael Leipold, Yael Rosenberg-Hasson, Xuhuai Ji, Renaud Gaujoux, Hadas Rabani, Elina Starosvetsky, Ksenya Kveler, Steven Schaffert, David Furman, Oren Caspi, Uri Rosenschein, Purvesh Khatri, Cornelia L. Dekker, Holden T. Maecker, Mark M. Davis, Shai S. Shen-Orr
Journal: Nature Medicine (2019)
HIGH-FAT HIGH-CARBOHYDRATE DIET ACCELERATES LEFT-VENTRICULAR DYSFUNCTION FASTER THAN HIGH-FAT DIET ALONE VIA INCREASING MITOCHONDRIAL DYSFUNCTION IN OBESE-INSULIN RESISTANT RATS
Authors: Nattayaporn Apaijai, Apiwan Arinno, Siripong Palee, Wasana Pratchayasakul, Sasiwan Kerdphoo, Thidarat Jaiwongkam, Titikorn Chunchai, Siriporn Chattipakorn, Nipon Chattipakorn
Journal: Journal of the American College of Cardiology (2019)
Abstract 578: β-arrestin-Biased β2-Adrenergic Receptor Signaling Enhances Cardiomyocyte Contractility via ROCK-Dependent Signaling
Authors: Ama Dedo Okyere, Claudio de Lucia, Jianliang Song, Rhonda L Carter, Jeffrey L Benovic, Walter J Koch, Joseph Y Cheung, Douglas G Tilley
Journal: Circulation Research (2018)

During heart failure, chronically decreased cardiac output can be treated with positive inotropes, but classic inotropes such as β-adrenergic receptor (βAR) agonists that increase cAMP-dependent Ca 2+ mobilization and contractility ultimately enhance patient mortality. Thus, an alternate approach would be to enhance cardiomyocyte contractility without alterations in cAMP and Ca 2+ levels, such as regulation of sarcomeric proteins. Recently, we demonstrated that a small lipidated pepducin designed from the 1 st intracellular loop of β2AR (ICL1-9) enhanced cardiomyocyte contractility in a Ca 2+ -independent, β-arrestin-dependent manner. We also showed that β2AR stimulation in hearts in vivo or neonatal rat ventricular myocytes (NRVM) in vitro activates RhoA in a βarr-dependent manner, therefore we sought to determine whether ICL1-9-dependent cardiomyocyte contractility is mediated downstream of RhoA. Using adult murine cardiomyocytes isolated from wild-type C57Bl/6J mice, we measured basal, ICL1-9- and isoproterenol (ISO, as a positive control)-promoted contractility either alone or in the presence of inhibitors of myosin light chain kinase (ML7), ROCK1 (Y-27632) and MEK (PD181452). Consistent with RhoA activation by ICL1-9, ROCK1 inhibition was able to attenuate ICL1-9-mediated contractility, as was inhibition of MLCK, though inhibition of MEK/ERK signaling had no effect. Through the use of GPCR kinase 5 knockout (GRK5KO) cardiomyocytes, we observed that ICL1-9 was unable to enhance contractility in the absence of GRK5 expression. Further, treatment of isolated cardiomyocytes with ICL1-9 increased phoshphorylation of the myosin light chain regulatory subunit (RLC). Therefore, ICL1-9 acts proximally via β2AR/GRK5/βarr-dependent engagement of RhoA/ROCK1 signaling to distally increase RLC phosphorylation, representing a new signaling paradigm for the enhancement of cardiomyocyte contractility.
Image Gallery: Polymorphic lesions in a haematological patient
Authors: F.E. Rojas Farias, C. Martínez‐Morán, R. Khedaoui, E. Esteban‐Garrido, J. Company‐Quiroga, S. Alique‐Garcia, A. Hernández‐Núñez, J. Borbujo‐Martínez
Journal: British Journal of Dermatology (2019)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, A 74‐year‐old man with a 3‐year history of chronic lymphocytic leukaemia presented pruritic lesions (papules, vesicles and bullae) on his trunk and extremities, which coincided with the progression of his disease to Richter syndrome (a, b). A deep‐skin biopsy revealed a superficial and deep perivascular eosinophil‐rich lymphohistiocytic infiltrate and negative direct immunofluorescence (c). The common causes were excluded and the definitive diagnosis was eosinophilic dermatosis of haematological malignancy. This is a rare, nonspecific cutaneous manifestation of lymphoproliferative disorders, characterized by polymorphous, pruritic and recurrent lesions that can simulate drug reaction, insect bites and bullous pemphigoid. The patient received prednisone and was steroid‐responsive but demonstrated clinical relapses off treatment.
CLINICAL SIGNIFICANCE OF THE PRESENCE OF PUFF-CHANDELIER RUPTURES DETECTED BY NON-OBSTRUCTIVE AORTIC ANGIOSCOPY: A RETROSPECTIVE MULTICENTER COHORT STUDY
Authors: Masao Yamaguchi, Masahiro Hoshino, Tomoki Horie, Haruhito Yuki, Hidenori Hirano, Yoshinori Kanno, Yohei Sumino, Hiroaki Ohya, Masahiro Hada, Yoshihisa Kanaji, Taishi Yonetsu, Tsunekazu Kakuta
Journal: Journal of the American College of Cardiology (2019)
BURDEN OF MORTALITY AND DISEASE ATTRIBUTABLE TO HOSPITALIZED ATRIAL FIBRILLATION IN CIRRHOTIC PATIENTS IN THE UNITED STATES: A NATIONWIDE, PROPENSITY SCORE MATCHED ANALYSIS
Authors: Tarun Jacob Bathini, Wisit Cheungpasitporn, Charat Thongprayoon, Ronpichai Chokesuwattanaskul, Patompong Ungprasert, Karn Wijarnpreecha, Paul T. Kröner
Journal: Journal of the American College of Cardiology (2019)
Low-Dose Amitriptyline for Chronic Low Back Pain
Authors: Jayantee Kalita, Usha K. Misra
Journal: JAMA Internal Medicine (2019)

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ARNT2 Tunes Activity-Dependent Gene Expression through NCoR2-Mediated Repression and NPAS4-Mediated Activation
Authors: Nikhil Sharma, Elizabeth A. Pollina, M. Aurel Nagy, Ee-Lynn Yap, Florence A. DiBiase, Sinisa Hrvatin, Linda Hu, Cindy Lin, Michael E. Greenberg
Journal: Neuron (2019)

Neuronal activity-dependent transcription is tuned to ensure precise gene induction during periods of heightened synaptic activity, allowing for appropriate responses of activated neurons within neural circuits. The consequences of aberrant induction of activity-dependent genes on neuronal physiology are not yet clear. Here, we demonstrate that, in the absence of synaptic excitation, the basic-helix-loop-helix (bHLH)-PAS family transcription factor ARNT2 recruits the NCoR2 co-repressor complex to suppress neuronal activity-dependent regulatory elements and maintain low basal levels of inducible genes. This restricts inhibition of excitatory neurons, maintaining them in a state that is receptive to future sensory stimuli. By contrast, in response to heightened neuronal activity, ARNT2 recruits the neuronal-specific bHLH-PAS factor NPAS4 to activity-dependent regulatory elements to induce transcription and thereby increase somatic inhibitory input. Thus, the interplay of bHLH-PAS complexes at activity-dependent regulatory elements maintains temporal control of activity-dependent gene expression and scales somatic inhibition with circuit activity.
OUTCOMES OF ISOLATED TRICUSPID VALVE SURGERY HAVE IMPROVED IN THE MODERN ERA
Authors: Robert Smith, Mohanad Hamandi, William Ryan, Laith Batarseh, Anupama Vasudevan, Paul Grayburn, Timothy George, Katherine Harrington, J. Michael DiMaio, Kelly Hutcheson, William Brinkman, Molly Szerlip, David Moore, Michael Mack
Journal: Journal of the American College of Cardiology (2019)
CARDIOGENIC SHOCK COMPLICATING HYPERTROPHIC CARDIOMYOPATHY: INSIGHTS FROM THE NATIONAL INPATIENT SAMPLE DATABASE FROM 2010 TO 2015
Authors: Sagar Ranka, Mohit Pahuja, Pablo Michel, Udit Joshi, Harsh Rawal, Pedro Villablanca, Wilbert Aronow, Srihari Naidu
Journal: Journal of the American College of Cardiology (2019)
CHOOSING THE BEST MORTALITY PREDICTOR FOR ISOLATED CABG IN COMPLEX CORONARY ARTERY DISEASE PATIENTS: PERFORMANCE COMPARISON OF STS, EUROSCORE II, AND SYNTAX SCORE II
Authors: Luis Gonzales-Tamayo, Carlos M. Campos, Luiz Augusto Ferreira Lisboa, Luis Alberto Oliveira Dallan, Fábio Biscegli Jatene, Omar A.V. Mejia
Journal: Journal of the American College of Cardiology (2019)
Phase II multicenter study of gene mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma.
Authors: Laura K. Aguilar, Lee A. Wheeler, Andrea G. Manzanera, Susan D. Bell, Robert Cavaliere, John M. McGregor, Simon Lo, John C. Grecula, Herbert B. Newton, Behnam Badie, Todd W. Trask, David S. Baskin, Jana Portnow, Pamela Z. New, Estuardo Aguilar-Cordova, E. Antonio Chiocca
Journal: Journal of Clinical Oncology (2015)

2010 Background: New therapies are desperately needed for malignant gliomas since aggressive standard of care (SOC) treatment with surgery, radiation, and temozolomide leads to median survival of less than 15 months. Gene Mediated Cytotoxic Immunotherapy (GMCI) generates a polyvalent anti-tumor immune response through local delivery of aglatimagene besadenovec (AdV-tk) plus prodrug, synergizing with SOC to improve patient outcomes. Methods: A Phase II open-label multicenter trial was designed to assess safety and overall survival (OS) after GMCI+SOC compared to a concurrent matched control group meeting protocol criteria and SOC at an institution not active in the treatment trial. AdV-tk was injected into the resection bed followed by oral valacyclovir for 14 days. Primary efficacy analysis was planned on the null hypothesis of no improvement in the 2-year survival over the SOC group with planned subset analysis of significant disease prognostic factors. Results: From 2006 to 2010, 48 patients completed SOC+GMCI and 134 SOC in the matched cohort. There were no dose-limiting toxicities. Fever, fatigue, and headache were the most common GMCI-related symptoms. Median OS increased by 3.6 months, from 13.5 for SOC to 17.1 months for GMCI+SOC (p = 0.0417). Survival at 1- 2- and 3-years increased from 57%, 22%, and 8% to 67%, 35%, and 19%, respectively. The improvement was mostly in patients that underwent gross total resection: median OS increased from 16.9 to 25 months (p = 0.0492); 1- 2- and 3-year survival rates from 64%, 28% and 6% to 90%, 53% and 32%. Conclusions: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival rates compared favorably to historical reports and a matched control group. Survival outcomes were significantly improved in patients with minimal residual disease after total resection. The 2-year survival rate met the planned statistical threshold for significance. No significant differences were observed for subtotal resections. This is the first study to demonstrate a correlation between maximum debulking and a survival advantage using immunotherapy. These data strongly support further evaluation of GMCI for malignant gliomas. Clinical trial information: NCT00589875.