tbuckley/cabot-search huggingface dataset:
COMBINED VASCULAR BRACHYTHERAPY AND STENTING FOR TREATMENT OF IN-STENT RESTENOSIS
Authors: Yuefeng Chen, Kyle Buchanan, Nauman Khalid, Evan Shlofmitz, Micaela Iantorno, Deepakraj Gajanana, Jiaxiang Gai, Rebecca Torguson, Toby Rogers, Itsik Ben-Dor, Lowell Satler, Ron Waksman
Journal: Journal of the American College of Cardiology (2019)
Abstract 408: Defective Mitochondrial Dynamics Contribute to Cardiac Contractile Dysfunction in Desminopathy
Authors: Shafiul Alam, Chowdhury S Abdullah, Richa Aishwarya, Sumitra Miriyala, Manikandan Panchatcharam, Jonette P Green, A. W Orr, Jeanne James, Jeffrey Robbins, Md. S Bhuiyan
Journal: Circulation Research (2018)

Rational: Desmin plays a critical role in the maintenance of the structural and mechanical integrity of the sarcomere. Mutation in desmin causes disorganization of contractile apparatus leading to cardiomyopathy. Cardiomyocyte-specific expression of mutated desmin (a seven amino acid deletion R172-E178, D7-Des Tg) causes accumulations of toxic protein aggregates leading to cardiac contractile dysfunction. Whether these alterations result in maladaptive changes in mitochondrial dynamics and contribute to mitochondrial respiratory defects resulting in cardiomyopathies remains obscure. Objective: In this study, we investigated whether altered mitochondrial dynamics play a causative role in the development of cardiac contractile dysfunction and cardiomyocyte death in D7-Des Tg mouse model of desminopathy. Methods and results: D7-Des Tg hearts showed accumulation of desmin aggregates resulting in disruption of the desmin network, development of cardiomyocyte hypertrophy, and contractile dysfunction. Ultrastructural analysis by electron microscopy showed highly perturbed mitochondrial spatial organization and mitochondrial fragmentation in D7-Des Tg mice. D7-Des Tg mice hearts showed increased mtDNA copy number, increased expression of mitochondrial fission regulatory proteins, defects in mitochondrial respiration and activation of apoptotic cell death. Adenoviral-mediated expression of D7-Des in cardiomyocytes also showed increased mitochondrial fission, expression dependent inhibition of mitochondrial respiration and activation of cellular toxicity. Inhibition of mitochondrial fission by mitochondrial division inhibitor mdivi-1 significantly improved mitochondrial respiration and inhibited cellular toxicity associated with D7-Des expression in cardiomyocytes. Conclusion: Aberrant mitochondrial fission results in mitochondrial respiratory defects and apoptotic cell death in a D7-Des Tg hearts. Inhibition of aberrant mitochondrial fission using mitochondrial division inhibitor significantly preserved mitochondrial function and decreased apoptotic cell death. Therefore, our study shows that maladaptive aberrant mitochondrial fission causes desminopathy-associated cellular dysfunction.
Abstract 412: The Role of ETC Complexes I and II in the Respirasome Assembly in Heart Mitochondria
Authors: Sehwan Jang, Sabzali Javadov
Journal: Circulation Research (2018)

Mitochondrial electron transport chain (ETC) plays an important role in ATP synthesis and its dysfunction is associated with human diseases. Recent cryo-electron microscopy studies revealed that individual ETC complexes are assembled into supercomplexes (SCs). Structural organization and physiological role as well as mechanisms of assembling and maintenance of the SCs are yet not completely understood. ETC complexes contribute unequally to structural organization of SCs, particularly the respirasome, the main SC which contains complexes I, III, and IV in various stoichiometries. However, many questions related to structural organization of the respirasome, particularly, a possible role of complexes I and II in respirasome formation remain unclear. Here, we focus on the role of complexes I and II in structural organization of SCs using both genetic and chemical inhibition of complex I and complex II in H9c2 cardiac myoblast cells and isolated cardiac mitochondria. Respiratory SCs were analyzed by blue native polyacrylamide gel electrophoresis. Pharmacological inhibition of complex I by rotenone and complex II by malonate stimulated dissociation of respirasome. Rotenone inhibited whereas malonate had no effect on calcium-induced mitochondrial swelling, a marker of permeability transition. On the other hand, the rate of mitochondrial ROS production was remarkably (&gt;5 fold) stimulated by rotenone but not by malonate. Knockdown of the complex I subunit NDUFA11, which according to cryo-electron microscopy studies interacts with complex III in respirasome formation, stimulated dissociation of respirasome and reduced the activity of complexes I, III, and IV but not complex II. Downregulation of the SDHC subunit of complex II had no effect on the respirasome assembly but reduced the activity of complexes II and IV. In addition, knockdown of NDUFA11 or SDHC significantly reduced ATP levels in the cells. Overall, these studies for the first time provide biochemical evidence that NDUFA11 subunit of complex I is important for structural integrity of respirasome whereas complex II is less likely contribute to the integrity of respirasome.
Abstract P302: Energy Expenditure Responses to Exercise Training in Older Women: The Influence of Baseline Physical Activity
Authors: Xuewen Wang, Kimberly Bowyer, Ryan Porter, Charity Breneman, Sabra Custer
Journal: Circulation (2017)

Introduction: Components of energy expenditure are not static. There is debate over whether there is a reduction in non-exercise activity thermogenesis (NEAT) that compensates for energy cost of exercise training. The purpose of this study was to determine the changes in components of energy expenditure following exercise training, and whether any of the changes differ by dose of exercise. Methods: Older inactive women (60-75 years, less than 20 minutes of structured exercise for 3 times/week, n=72) participated in 4 months of exercise training of lower- or higher-dose (8 and 14 kcal/kg body weight weekly, respectively). The exercise was treadmill walking, 3 to 4 times per week, at 50-55% of heart rate reserve. Total daily energy expenditure (TDEE) by the doubly labeled water method, resting metabolic rate (RMR) via indirect calorimetry, and total physical activity by ActiGraph accelerometers (counts per minute), were measured at baseline and in the last two weeks of exercise training. Exercise energy cost was determined by speed, slope, and duration of walking according to the American College of Sports Medicine guideline. NEAT was calculated as (TDEE x 0.9 – RMR – exercise energy cost). Results: There were no group differences in the changes in energy expenditure measures (p for time x group interaction &gt; 0.10 for all). TDEE, RMR, NEAT and total physical activity did not change at the end of exercise training (p &gt; 0.05 for all). However, a significant baseline physical activity x time interaction was found for several energy expenditure measures. Data were therefore stratified into tertiles based on baseline physical activity. In the highest tertile, TDEE remained unchanged but NEAT and total physical activity decreased (p &lt; 0.05 for all). In contrast, in the mid- and lowest tertiles, NEAT remained unchanged, total physical activity increased, and TDEE was unchanged or increased (p &lt; 0.05 for all). Conclusions: In this group of older women, 4 months of aerobic exercise training did not change any of the energy expenditure measures in the overall sample. However, baseline physical activity levels influenced the energy expenditure responses, indicating reductions in NEAT and total physical activity despite participation in exercise training in those who had higher physical activity level at baseline.
Abstract 512: Regulation of Neutrophil Extracellular Traps (NETs) by Mesenchymal Stromal Cell Derived Adenosine
Authors: Rebecca Levit, Eric Shin, Kai Xu, Lanfang Wang
Journal: Circulation Research (2018)

Introduction: Mesenchymal stromal cells (MSCs) reduce the infiltration of leukocytes into the heart after ischemia reperfusion injury (MI/R). Inhibition of the surface ectonucleotidase CD73 prevents this anti-inflammatory effect. CD73 is a key step in a pathway that converts adenine nucleotides (ATP, ADP, AMP) into adenosine, which in turn exerts vasodilatory and immunosuppressive effects. Neutrophil extracellular trap (NET) formation is a thrombotic and inflammatory process involved in coronary occlusion and myocardial damage. We hypothesized that adenosine may be a key regulator of NET formation and that CD73-dependant adenosine production by MSCs reduces NETs after MI/R. Methods: Neutrophils isolated from venous blood of healthy donors by percoll gradient density centrifugation were cultured with MSCs for in vitro studies. MSCs were encapsulated in aliginate by electrostatic encapsulation and secured to the epicardium with PEG-maleimide hydrogel at the time of reperfusion. This biomaterial strategy supports and maintains viable cells in the vicinity of injury for 1 week. 24 hours after injury, hearts were perfused, excised, and digested and NETs quantified by flow cytometry. Results: Treatment of neutrophils with adenosine or the adenosine receptor agonist NECA reduces NET formation in vitro . Co-culture of MSCs with neutrophils also prevents NET formation. Inhibition of CD73 activity on MSCs with the antagonist APCP prevents the anti-NET activities of MSCs. In vivo , encapsulation and placement of MSCs on the epicardial surface at the time of MI/R reduces myocardial NETs 24 hours after MI/R. Treatment of MSCs with APCP prior to implantation reduces the anti-NET effects of MSCs, as well as functional benefits. Conclusions: There is growing evidence of the importance of NETs in cardiac ischemia-reperfusion injury but little is known of the regulation of NETs in vivo . Our data suggests that adenosine exerts a strong anti-NET effect and that CD73-generated adenosine from MSCs may be capable of in vivo anti-inflammatory and anti-NET regulation. Future studies are focused on genetic techniques to knock down CD73 activity on MSCs, direct implication of NETs on cardiovascular pathophysiology, and non-cellular methods to deliver CD73 in MI/R.
Metformintreatment Overcomes ATRA-Resistance in Acute Promyelocytic Leukemia and Increases FOXO3A Expression
Authors: Diego Antonio Pereira-Martins, Cesar Ortiz, Pedro Luis Franca-Neto, Isabel Weinhäuser, Josiane Lilian Schiavinato, Patrícia Vianna Bonini Palma, Camila Bonaldo, Luisa C A Koury, Mariane Cristina Do Nascimento, Raul Antônio Morais Melo, Rosane Bittencourt, Katia B B Pagnano, Ricardo Pasquini, Evandro Maranhão Fagundes, Ana Beatriz F. Gloria, Fabio R. Kerbauy, Maria de Lourdes Chauffaille, Armand Keating, Martin S. Tallman, Raul Ribeiro, Richard Dillon, Arnold Ganser, Bob Lowenberg, Peter Valk, Francesco Lo-Coco, Miguel A. Sanz, Nancy Berliner, Antonio R. Lucena-Araujo, Eduardo Magalhães Rego
Journal: Blood (2018)
COMPARISON OF THE INCIDENCE, CLINICAL CHARACTERISTICS, AND PROCEDURAL OUTCOMES OF CHRONIC TOTAL OCCLUSION INTERVENTIONS AMONG DIFFERENT TARGET VESSELS: INSIGHTS FROM A CONTEMPORARY MULTICENTER-REGISTRY
Authors: Iosif Xenogiannis, Dimitrios Karmpaliotis, Khaldoon Alaswad, Farouc Jaffer, Mitul Patel, Ioannis Tsiafoutis, Barry Uretsky, M. Nicholas Burke, A.J. Conrad Smith, Habib Samady, Brian Jefferson, Taral Patel, Elizabeth Holper, Jeffrey Moses, Nicholas Lembo, Manish Parikh, Ajay Kirtane, Ziad Ali, Fotis Gargoulas, Peter Tajti, Allison B. Hall, Rangan Bavana, Shuaib Abdullah, Subhash Banerjee, Emmanouil S. Brilakis
Journal: Journal of the American College of Cardiology (2019)
Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma
Authors: Akshay V. Bhat, Monica Palanichamy Kala, Vinay Kumar Rao, Luca Pignata, Huey Jin Lim, Sudha Suriyamurthy, Kenneth T. Chang, Victor K. Lee, Ernesto Guccione, Reshma Taneja
Journal: Cancer Research (2019)

Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer with poor prognosis. As transient and stable modifications to chromatin have emerged as critical mechanisms in oncogenic signaling, efforts to target epigenetic modifiers as a therapeutic strategy have accelerated in recent years. To identify chromatin modifiers that sustain tumor growth, we performed an epigenetic screen and found that inhibition of lysine methyltransferase G9a significantly affected the viability of ARMS cell lines. Targeting expression or activity of G9a reduced cellular proliferation and motility in vitro and tumor growth in vivo. Transcriptome and chromatin immunoprecipitation-sequencing analysis provided mechanistic evidence that the tumor-suppressor PTEN was a direct target gene of G9a. G9a repressed PTEN expression in a methyltransferase activity-dependent manner, resulting in increased AKT and RAC1 activity. Re-expression of constitutively active RAC1 in G9a-deficient tumor cells restored oncogenic phenotypes, demonstrating its critical functions downstream of G9a. Collectively, our study provides evidence for a G9a-dependent epigenetic program that regulates tumor growth and suggests targeting G9a as a therapeutic strategy in ARMS. SIGNIFICANCE: These findings demonstrate that RAC1 is an effector of G9a oncogenic functions and highlight the potential of G9a inhibitors in the treatment of ARMS.
Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination
Authors: Eléna Gonçalves, Olivia Bonduelle, Angèle Soria, Pierre Loulergue, Alexandra Rousseau, Marine Cachanado, Henri Bonnabau, Rodolphe Thiebaut, Nicolas Tchitchek, Sylvie Behillil, Sylvie van der Werf, Annika Vogt, Tabassome Simon, Odile Launay, Behazine Combadière
Journal: Journal of Clinical Investigation (2019)

Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We have been exploring novel strategies to shape the adaptive immune response, by targeting innate immune cells through novel immunization routes.This randomized phase I/II clinical study (n=60 healthy subjects aged 18-45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV season 2012-2013) (1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition (HI), microneutralization (MN) antibodies and CD4, CD8 effector T cells) were measured at baseline Day (D)0 and at D21. Blood transcriptome was analyzed at D0 and D1.TIV-specific CD8+GranzymeB+(GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, while immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating two clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy confirmed by nine genes and serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T-cell or antibody responses. A logistic regression analysis demonstrated that these nine genes and serum levels of CXCL10 (D1/D0) best foreseen TIV-specific CD8+GRZ+ T-cell and antibody responses at D21.This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses.
Abstract 494: Comparing Cardiac Dynamics Between Neonatal and Adult Rats
Authors: Luther M Swift, James Hiebert, Morgan Burke, Manelle Ramadan, Rafael Jaimes, Nikki Posnack
Journal: Circulation Research (2018)

Background: In the broad field of cardiology, pediatric research has lagged behind in establishing appropriate models to study the developing heart. Human cardiomyocytes exhibit a limited life span and immortalized cell lines lack physiologically relevant automaticity. Pediatric animal models include caveats related to action potential morphology, ion channel expression, and excitation-contraction coupling. Changes that occur in these parameters as the animal transition from neonate to adult are relatively unknown, especially as it may be translated to a human model. In quantifying the toxicological effect of plasticizer exposure in a pediatric population, we first sought to establish the limits of using hearts from developing neonatal rats as a viable model. Objective: This study aimed to quantify the advantages and limitations associated with using neonatal rat hearts as a model for toxicological screening. Methods/Design: The heart from rats ranging in age from 2 days old, up to adult were excised, and the aorta was cannulated. It was placed on a Langendorff system and retrograde perfused. Calcium and voltage sensitive dyes were used to stain the heart for imaging. It was mechanically uncoupled with blebbistatin to eliminate motion artifacts and an ECG was recorded continuously. Results/Discussion: Preliminary results showed that compared to adult cohorts, neonatal rats displayed a longer action potential duration (APD80: adult= 85.9ms, neonatal=95.5ms, p=0.026), likely associated with delayed Ito expression. Likewise, calcium handling was also slower in the neonatal hearts as shown by the calcium imaging. (Cad80: Adults: 128.9ms, neonatal=138.8, p=.004) Without autonomic modulation, we observed an increase in heart rate from 320 to 350bpm between neonatal and adult populations which has been shown in vivo . The developing excitation contraction coupling machinery will be further probed for the mechanism behind these phenomena.
ADVANCED GLYCATION END PRODUCTS IMPAIRED VOLTAGE-GATED K+ CHANNEL ON RAT CORONARY SMOOTH MUSCLE CELLS BY ACTIVATING NF-KB SIGNALING PATHWAY
Authors: Bing Hua, Qingbo Liu, Side Gao, Beibing Di, Shandong Yu, Wen Su, Weiping Li, Hongwei Li
Journal: Journal of the American College of Cardiology (2019)
Abstract 11995: Extreme Endogenous Testosterone and Estrogen Concentrations and Risk of Ischemic Stroke in Men and Women: A Prospective Cohort Study and Meta-Analyses
Authors: Haya N Holmegard, Børge G Nordestgaard, Gorm B Jensen, Anne Tybjærg-Hansen, Marianne Benn
Journal: Circulation (2014)

Introduction: Sex hormone concentrations are associated with stroke risk factors and the incidence of ischemic stroke (IS) depends on gender. Whether sex hormones per se associate with IS is unclea...
Abstract 19646: Impacting the Quality of Care in Severe Aortic Stenosis - The Effect of Facilitated Data Transfer in a European Cohort of 2,151 Patients (impulse Registry)
Authors: Richard P Steeds, Antonio Serra, Eberhard Schulz, Matthias Lutz, Marco Aiello, Tanja Rudolph, Jana Kurucova, Peter Bramlage, Norbert Frey, David Messika-Zeitoun
Journal: Circulation (2017)

Introduction: Many patients with severe AS are inappropriately denied intervention and continue to present late with advanced symptoms. Hypothesis: We aimed to assess the efficacy of facilitated data transfer (FDT) intervention in improving time to intervention in severe AS. Methods: Prospective, multicentre registry in 23 centres with all treatment options (sAVR, TAVI, BAV) on site in 9 European countries. The registry started with a 3 months observational phase A, followed by a 6 months interventional phase (FDT), and a 3 months observational phase B to investigate a legacy effect. Results: A total of 2,151 pts with severe AS with or without symptoms were enrolled (observation A: 759, intervention: 905, observational B: 487) with comparable demographic and disease characteristics between phases. During observational phase A, 44% patients were scheduled to undergo TAVI (preference in GER & ITA), 23% SAVR (in FRA & UK as frequent as TAVI), 20% watchful waiting (strong preference in the UK), 9% active deci...
Abstract 570: Activin A Regulates SERCA2a Expression in Cardiomyocytes Through Ubiquitin-proteasome Mediated Degradation
Authors: Ryan Hobson, Vinita Chaudhari, Anthony Rosenzweig, Jason D Roh
Journal: Circulation Research (2018)

Sarco/endoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) is a critical regulator of cardiac function whose expression is decreased in aging and heart failure (HF). Activin-A, a member of the TGFβ superfamily, has been shown to be a potent paracrine inhibitor of SERCA2a expression in cardiomyocytes (CM). However, the mechanism by which this occurs remains unclear. Here, we confirm that Activin-A decreases SERCA2a protein expression in isolated CMs (reductions in SERCA2a expression at 25ng/ml: 35±5%, p=0.02; 50ng/ml: 55±14%, p= 0.003; 100ng/ml: 56±8%, p.= 0.001; n=2-3/group, three replicates). Moreover, we show that increasing circulating Activin-A levels in vivo also decreases cardiac SERCA2a protein (reductions in SERCA2a expression at 1-25ng/ml: 22±12%, p=0.27; 25-50ng/ml: 63±14%, p=0.0015; &gt;50ng/ml: 79±2%, p= 0.0002; n=4 per group). Using systematic gene set enrichment analysis of RNAseq data from hearts and CMs exposed to increased Activin-A, we identify the ubiquitin-proteasome system (UPS) as one of the most highly up-regulated pathways induced by Activin-A. With ubiquitination prediction modeling revealing multiple ubiquitin binding sites on SERCA2a, we hypothesized that Activin-A regulates SERCA2a expression through modulation of its UPS-mediated degradation. Indeed, inhibiting the proteasome with MG132 attenuated the inhibitory effects of Activin-A on CM SERCA2a expression. Although Activin-A did not directly affect proteasome activity in CMs, we found that it increased ubiquitination of SERCA2a, resulting in increased proteasome-mediated degradation. Additionally, targeted inhibition of the Activin type II receptors (ActRII) with a monoclonal ActRII blocking antibody reversed the effects of Activin-A on SERCA2a protein expression in isolated CMs in a dose-dependent fashion. Importantly, these effects of Activin-A/ActRII blockade on SERCA2a expression were recapitulated in vivo in a transverse aortic constriction model of HF, and further led to improvements in cardiac function. Collectively, these data identify a novel UPS-mediated mechanism by which Activin-A regulates CM SERCA2a expression, which warrants further investigation as a potential therapeutic approach to augmenting SERCA2a in HF.