tbuckley/cabot-search huggingface dataset:
Abstract 446: Transcription Factor EB, Not mTOR is a Therapeutic Target for Rag GTPase Protein C S75Y-based Cardiomyopathy
Authors: Maengjo Kim, Qiu Qi, Xiao Ma, Xiaolei Xu
Journal: Circulation Research (2018)

Rationale: We recently reported the association of S75Y, a point mutation in the Rag GTPase protein C ( RRAGC ) gene, with pediatric DCM. Because RRAGC directly binds and regulates mTOR and the S75Y mutation results in abnormally activated mTOR, these in vitro data prompts that the mTOR pathway could be harnessed for therapeutic benefits. Methods: We aimed to integrate in vitro neonatal rat ventricle cardiomyocytes (NRVCM) and in vivo zebrafish system to elucidate underling mechanism of RRAGC -S75Y-based cardiomyopathy, and to seek targeted therapeutic strategies. Results: Overexpression of RRAGC with S75Y mutation, but not RRAGC WT, significantly increased cell size of NRVCM, suggesting the establishment of a cellular model of RRAGC - S75Y-based cardiomyopathy. At the molecular level, overexpression of RRAGC S75Y mutant increased activity of mammalian target of rapamycin (mTOR) and decreased activity of transcription factor EB (tfeb), a direct downstream target of mTOR. Intriguingly, treatment with rapamycin, a mTOR inhibitor, did not affect cellular hypertrophy, whereas adenovirus-mediated overexpression of TFEB was able to rescue cellular hypertrophy induced by RRAGC S75Y mutation. Consistently, treatment with trehalose, an mTOR-independent tfeb activator, rescued cellular hypertrophy induced by RRAGC -S75Y. To confirm the in vitro results, we generated a knock-in (KI) zebrafish line harboring the S75Y corresponding point mutation in rragc via the TALEN (Transcription Activator-Like Effector Nucleases) technology. The cardiac function of rragc KI fish was determined by high frequency echocardiography, and the KI fish showed a significant decrease in fractional shortening compared with control littermates. Conclusion: Both cellular and in vivo models of RRAGC -S75Y-based cardiomyopathy have been generated. Studies in the cellular model suggested that tfeb, but not mTOR, is a therapeutic target for this particular type of cardiomyopathy. We will report our progress in validating this conclusion in our in vivo model, and will discuss potential mechanisms.
SEX-BASED DIFFERENCES IN OUTCOMES AFTER TRANSCATHETER REPAIR OF MITRAL REGURGITATION WITH THE MITRALCLIP SYSTEM
Authors: Pedro Arturo Villablanca, Sreekanth Vemulapalli, Dadi (David) Dai, Mathew Williams, Marvin Eng, Cezar Staniloae, Dee Dee Wang, Prakriti Gaba, Matthew Finn, Martin Leon, William O'Neill, Binita Shah
Journal: Journal of the American College of Cardiology (2019)
Associations Among School Absenteeism, Gastrointestinal and Respiratory Illness, and Income — United States, 2010–2016
Authors: David Berendes, Ashley Andujar, Lisa C. Barrios, Vincent Hill
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Control of communicable diseases in children, including respiratory and diarrheal illnesses that affect U.S. school-aged children, might require public health preventive efforts both in the home and at school, a primary setting for transmission. National Health Interview Survey (NHIS) data on school absenteeism and gastrointestinal illness in the United States during 2010-2016 were analyzed to identify associations among income, illness, and absenteeism. Prevalence of gastrointestinal and respiratory illnesses in the 2 weeks preceding the survey increased as income decreased. Although the likelihood of missing any school days during the past year decreased with reduced income, among children missing school, those from low-income households missed more days of school than did children from higher income households. Although the reason for absenteeism cannot be ascertained from this analysis, these data underscore the importance of preventive measures, such as hand hygiene promotion and education, and the opportunity for both homes and schools to serve as an important point for implementation of public health preventive measures, including hand hygiene practice and education.
Abstract 20254: Pediatric Heart Transplant Waitlist Outcomes Stratified by Diagnosis
Authors: Raheel Rizwan, Farhan Zafar, Chet R Villa, Roosevelt Bryant, David L Morales, Angela Lorts
Journal: Circulation (2017)

Introduction: Adult candidates with restrictive cardiomyopathy (RCM), congenital heart disease (CHD) & re-transplant (Re-Tx) have a higher risk of mortality on heart transplant (HTx) waitlist (WL). This study aims to characterize the effect of diagnosis on WL outcomes for pediatric HTx candidates. Methods: The United Network of Organ Sharing (UNOS) database was used to identify all pediatric (≤17y) HTx candidates from 2001- 2016. Patients were grouped by diagnosis. WL outcomes at 1 year were compared between the diagnosis groups. Results: Of 8201 HTx candidates, 2998 (36%) had dilated cardiomyopathy (DCM), 437 (5.3%) had RCM, 201 (2.5%) had hypertrophic cardiomyopathy (HCM), 3805 (46%) had CHD, 538 (6.6%) had prior-HTx & 232 (2.8%) had “other” diagnosis. CHD, Re-Tx and “other” candidates had worse WL outcomes compared to all cardiomyopathies (p<0.05) (Figure). After adjusting for age, renal function, inotropic use, mechanical circulatory support & ventilator use, multivariate analysis revealed CHD had the...
EVOLUTION AND STRUCTURAL CORRELATION OF SUBACUTE CORONARY MICROCIRCULATORY CHANGES AFTER ADMINISTRATION OF ALLOGENEIC CARDIAC STEM CELLS FOR TREATING MYOCARDIAL INFARCTION
Authors: Enrique Gutierrez, Maria Jesus Piña, Itziar Palacios, Claudia Baez-Diaz, Ricardo Sanz-Ruiz, Lombardo Eleuterio, Esther Perez-David, Francisco Miguel Sanchez Margallo, Francisco Fernandez-Aviles, Javier Bermejo
Journal: Journal of the American College of Cardiology (2019)
EFFECT OF TRANSCATHETER MITRAL VALVE REPAIR ON HEART FAILURE MANAGEMENT AND PULMONARY ARTERY PRESSURES AS ASSESSED BY CARDIOMEMS
Authors: Christopher Vanichsarn, Amitabh Pandey, Matthew Price, Rajeev Mohan, J. Thomas Heywood, Ajay Srivastava
Journal: Journal of the American College of Cardiology (2019)
Abstract 274: Regulation of Myocardial Ketone Body Oxidation Capacity by Increased Protein O-GlcNAcylation in Diabetic Heart
Authors: Manoja K Brahma, Chae-Myeong Ha, Andrew K Paterson, Martin E Young, Adam R Wende
Journal: Circulation Research (2018)

Diabetes increases the risk of heart failure independently of underlying coronary artery disease. Perturbations in myocardial substrate utilization have been proposed to contribute to the pathogenesis of cardiac dysfunction. However, the exact mechanisms linking impaired substrate utilization to disease progression remain elusive. Compared to the well-established roles of glucose and fatty acids metabolism in cardiac physiology and pathology, the importance of ketone body (KB) metabolism is less well understood. Several findings suggest the importance of KB in the cardiac health and disease. More recently, two independent studies have simultaneously demonstrated increased reliance on KB utilization by the failing heart in the absence of diabetes. Despite these observations, our understanding of the importance of KB metabolism in a diabetic heart is incomplete. Interestingly, our findings from the hearts of streptozotocin-induced diabetic mice confirmed elevated cardiac β-hydroxybutyrate (a major KB) levels and transcriptional suppression of Oxct1 gene expression that encodes for SCOT (succinyl-CoA:3-oxoacid CoA transferase; a rate limiting enzyme of KB oxidation), consistent with a mismatch between KB availability and utilization. To determine a specific role for glucose delivery in this regulation we used an inducible transgenic mouse model with cardiac-restricted expression of the glucose transporter 4 (GLUT4; mG4H). Interestingly, mG4H mice had reduced cardiac SCOT protein levels and oxidation of KB in isolated working heart suggesting that glucose is sufficient to regulate the ketone metabolic pathway. Hyperglycemia associated with diabetes alter protein function via post-translational O -GlcNAcylation. Interestingly, we found that myocardial SCOT expression was also reduced in a third mouse model with increased cardiac O -GlcNAc levels (overexpression of a dominant negative form of O -GlcNAcase, which normally removes O -GlcNAc; dnOGAh) suggesting that increased protein O -GlcNAcylation is directly involved. Collectively, these studies establish a novel role of glucose and its downstream regulator, O -GlcNAc, in attenuation of KB metabolism in the diabetic heart.
Abstract 574: An Amino-Terminal Peptide of GRK5 Prevents Pathological Cardiac Hypertrophy in Response to Pharmacological and Surgical Stress
Authors: Ryan Coleman
Journal: Circulation Research (2018)

Introduction: The pathogenesis and progression of heart failure (HF) encompasses maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. A gene expression maladaptation in HF is an increase in expression of G protein-coupled receptor kinase (GRK5). Recently, non-canonical roles for GRK5 have been uncovered that are crucial for the development of maladaptive hypertrophy and these are due to its nuclear translocation. We have shown that nuclear targeting of GRK5 is mediated by an amino-terminal (NT) domain that can bind calmodulin. Hypothesis: We hypothesize that expression of a peptide encoding the NT of GRK5 that includes this calmodulin binding domain will act as a calmodulin inhibitor preventing the nuclear accumulation of GRK5 and inhibit its non-canonical pathological activities. Methods: To further study this, neonatal rat ventricular cardiomyocytes overexpressing GRK5-NT or a negative control virus were treated with 50μM phenylephrine (PE) or vehicle for 48 hours to induce a hypertrophic response. Cell areas and transcript levels of fetal genes were measured after treatment. Novel transgenic GRK5-NT and non-transgenic littermate control (NLC) mice were characterized before and 4 weeks after transverse aortic constriction (TAC) or sham surgery. Echocardiography, myocyte cross-sectional area, and heart weight to tibia length metrics were used to evaluate TAC response. Results: In vitro, expression of the GRK5-NT peptide abrogated the hypertrophic effects of PE, both in terms of fetal gene re-activation and myocyte size. In vivo, transgenic GRK5-NT mice did not demonstrate any hypertrophy after 4 weeks of TAC and cardiac dysfunction seen in NLC mice at this time point was absent in GRK5-NT mice. Further, GRK5-NT TAC mice showed no increase in cell surface area compared to their respective sham controls post-TAC. Conclusion: In this study, we show that the GRK5-NT peptide prevents the pathological response to pharmacological and surgical models of cardiac hypertrophy. Further studies in vivo will reveal whether GRK5-NT can preserve function in the long-term, and further in vitro characterization will reveal whether the mechanism is GRK5-dependent.
IMPACT OF DIABETES MELLITUS ON LONG-TERM OUTCOMES AFTER PERCUTANEOUS CORONARY INTERVENTION WITH DRUG-ELUTING STENT IN A HIGH-BLEEDING RISK POPULATION: OUTCOMES FROM THE POOLED XIENCE REGISTRY
Authors: Ridhima Goel, Paul Guedeney, Bimmer Claessen, Mortiz Blum, Roxana Mehran, Marco Valgimigli
Journal: Journal of the American College of Cardiology (2019)
Criminalisation of unintentional error in healthcare in the UK: a perspective from New Zealand
Authors: Rohan Ameratunga, Hilary Klonin, Jenny Vaughan, Alan Merry, Jonathan Cusack
Journal: BMJ (2019)

Legal reform in New Zealand that saw changes to the prosecution of health professionals for gross negligence manslaughter may have important lessons for the UK in light of the recent case of Hadiza Bawa-Garba, say Rohan Ameratunga and colleagues
Abstract 17806: Clinical Outcomes of Patients Treated With First Generation vs. Second Generation Drug-eluting Stents for Left Main Coronary Artery Disease: A Meta-analysis
Authors: Carlos A Gongora, Abel Casso Dominguez, Chirag Bavishi, Jacobo Pena, Patricia Chavez, Shilpkumar Arora, Pedro Moreno, Jacqueline Tamis-Holland
Journal: Circulation (2015)

Introduction: The second generation drug-eluting stents Everolimus and/or Zotarolimus (S-DES) have been proven to be superior to the first generation drug-eluting stents Sirolimus and/or Paclitaxel (F-DES) when treating non-left main coronary artery lesions. Previous studies have come to inconsistent results regarding the efficacy of these two stent types in patients treated for left main coronary artery disease (LMCAD). Hypothesis: We hypothesized that the use of S-DES would results in better outcomes than F-DES in patients with LMCAD. Methods: We performed a meta-analysis to summarize the up-to-date evidence on this subject. We included studies comparing clinical outcomes for S-DES vs F-DES in patients with LMCAD. We examined the following end-points: Mortality, myocardial infarction (MI), and target-vessel revascularization (TVR). In addition we examined the rates of stent thrombosis and major adverse cardiac events (MACE). MACE was defined according to the definition used by each of the included studies. Pooled risk ratios (RR) and their 95% confidence intervals (CI) were calculated for all the clinical outcomes using a random-effect model. Results: A total of 4 studies met our search criteria and were included in the analysis. Among these studies 701 patients were treated with F-DES and 753 patients were treated with S-DES. There was no significant difference in all-cause mortality or MI in the group of patients treated with S-DES as compared with those treated with F-DES. TVR was lower with S-DES. (Figure 1). In addition, S-DES was associated with lower MACE rates (RR: 0.63; 95% CI: 0.48 to 0.82; p &lt;0.05) and there was a trend toward a lower rate of stent thrombosis (RR: 0.40; 95% CI: 0.13 to 1.20; p 0.10) with S-DES. Conclusions: The use of S-DES for the treatment of LMCAD is associated with improved clinical outcomes as compared with F-DES. S-DES should be the stents of choice when treating patients with LMCAD.
ECONOMIC IMPACT OF ANEMIA ON HEART FAILURE HOSPITALIZATIONS: A NATIONAL INPATIENT SAMPLE ANALYSIS
Authors: Aravdeep Jhand, Aiza Ahmad, Raviteja Guddeti, Abhishek Thandra, Ryan Walters, Venkata Andukuri, Venkata Alla, Aiman Smer
Journal: Journal of the American College of Cardiology (2019)
Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion
Authors: Christopher R. McEvoy, Huiling Xu, Kortnye Smith, Dariush Etemadmoghadam, Huei San Leong, David Y. Choong, David J. Byrne, Amir Iravani, Sophie Beck, Linda Mileshkin, Richard W. Tothill, David D. Bowtell, Bindi M. Bates, Violeta Nastevski, Judy Browning, Anthony H. Bell, Chloe Khoo, Jayesh Desai, Andrew P. Fellowes, Stephen B. Fox, Owen W.J. Prall
Journal: Journal of Clinical Investigation (2019)

BRAF and CRAF are critical components of the MAPK signaling pathway which is activated in many cancer types. In approximately 1% of melanomas, BRAF or CRAF are activated through structural arrangements. We describe here a metastatic melanoma with a GOLGA4-RAF1 fusion and pathogenic variants in CTNNB1 and CDKN2A. Anti-CTLA4/anti-PD1 combination immunotherapy failed to control tumor progression. In the absence of other actionable variants the patient was administered MEK inhibitor therapy on the basis of its potential action against RAF1 fusions. This resulted in a profound and clinically significant response. We demonstrated that GOLGA4-RAF1 expression was associated with ERK activation, elevated expression of the RAS/RAF downstream co-effector ETV5, and a high Ki67 index. These findings provide a rationale for the dramatic response to targeted therapy. This study shows that thorough molecular characterization of treatment-resistant cancers can identify therapeutic targets and personalize management, leading to improved patient outcomes.
Assessment of Quality of Life and Treatment Outcomes of Patients With Persistent Postchemotherapy Alopecia
Authors: Azael Freites-Martinez, Donald Chan, Vincent Sibaud, Jerry Shapiro, Gabriella Fabbrocini, Antonella Tosti, Juhee Cho, Shari Goldfarb, Shanu Modi, Devika Gajria, Larry Norton, Ralf Paus, Tessa Cigler, Mario E. Lacouture
Journal: JAMA Dermatology (2019)

Persistent alopecia occurs in a subset of patients undergoing chemotherapy, yet the quality of life (QOL) of these patients and their response to therapy have not been described in a large patient cohort.To characterize the clinical presentation of patients with persistent chemotherapy-induced alopecia (pCIA) or endocrine therapy-induced alopecia after chemotherapy (EIAC) and their QOL and treatment outcomes.A retrospective multicenter cohort of 192 women with cancer treated with cytotoxic agents who received a clinical diagnosis of persistent alopecia (98 with pCIA and 94 with EIAC) between January 1, 2009, and July 31, 2017, was analyzed. All patients were from the dermatology service in 2 comprehensive cancer centers and 1 tertiary-care hospital. Data on demographics, chemotherapy regimens, severity, clinical patterns, and response to hair-growth promoting agents were assessed. Data from the Hairdex questionnaire were used to assess the QOL of patients with alopecia.The clinical presentation, response to dermatologic therapy, and QOL of patients with pCIA were assessed and compared with those of patients with EIAC.A total of 98 women with pCIA (median age, 56.5 years [range, 18-83 years]) and 94 women with EIAC (median age, 56 years [range, 29-84 years]) were included. The most common agents associated with pCIA were taxanes for 80 patients (82%); the most common agents associated with EIAC were aromatase inhibitors for 58 patients (62%). Diffuse alopecia was predominant in patients with pCIA compared with patients with EIAC (31 of 75 [41%] vs 23 of 92 [25%]; P = .04), with greater severity (Common Terminology Criteria for Adverse Events, version 4.0, grade 2) among patients with pCIA (29 of 75 [39%] vs 12 of 92 [13%]; P < .001). A negative emotional effect was reported by both groups. After treatment with topical minoxidil or spironolactone, moderate to significant improvement was observed for 36 of 54 patients with pCIA (67%) and for 32 of 42 patients with EIAC (76%).Persistent chemotherapy-induced alopecia is frequently more severe and diffuse when compared with EIAC, and both groups of patients experienced a negative effect. A modest benefit was observed with dermatologic therapy. Additional studies are warranted to develop effective strategies for prevention and effective therapy for pCIA and EIAC.
LEADLESS HEMODYNAMIC MONITORING TO IMPROVE CARDIAC RESYNCHRONIZATION THERAPY
Authors: Sarah Baalman, Reinoud Knops, Anne-Floor Quast, Tom Brouwer, Robin Wesselink, Kirsten Kooiman, Antonia Veelenturf, Wouter Kok, Vokko van Halm
Journal: Journal of the American College of Cardiology (2019)
Do multi-ingredient protein supplements augment resistance training-induced gains in skeletal muscle mass and strength? A systematic review and meta-analysis of 35 trials
Authors: Kerry R O’Bryan, Thomas M Doering, Robert W Morton, Vernon G Coffey, Stuart M Phillips, Gregory R Cox
Journal: British Journal of Sports Medicine (2019)

To determine the effects of multi-ingredient protein (MIP) supplements on resistance exercise training (RT)-induced gains in muscle mass and strength compared with protein-only (PRO) or placebo supplementation.Systematic search of MEDLINE, Embase, CINAHL and SPORTDiscus.Randomised controlled trials with interventions including RT ≥6 weeks in duration and a MIP supplement.Random effects meta-analyses were conducted to determine the effect of supplementation on fat-free mass (FFM), fat mass, one-repetition maximum (1RM) upper body and 1RM lower body muscular strength. Subgroup analyses compared the efficacy of MIP supplementation relative to training status and chronological age.The most common MIP supplements included protein with creatine (n=17) or vitamin D (n=10). Data from 35 trials with 1387 participants showed significant (p<0.05) increases in FFM (0.80 kg (95% CI 0.44 to 1.15)), 1RM lower body (4.22 kg (95% CI 0.79 to 7.64)) and 1RM upper body (2.56 kg (95% CI 0.79 to 4.33)) where a supplement was compared with all non-MIP supplemented conditions (means (95% CI)). Subgroup analyses indicated a greater effect of MIP supplements compared with all non-MIP supplements on FFM in untrained (0.95 kg (95% CI 0.51 to 1.39), p<0.0001) and older participants (0.77 kg (95% CI 0.11 to 1.43), p=0.02); taking MIP supplements was also associated with gains in 1RM upper body (1.56 kg (95% CI 0.80 to 2.33), p=0.01) in older adults.When MIP supplements were combined with resistance exercise training, there were greater gains in FFM and strength in healthy adults than in counterparts who were supplemented with non-MIP. MIP supplements were not superior when directly compared with PRO supplements. The magnitude of effect of MIP supplements was greater (in absolute values) in untrained and elderly individuals undertaking RT than it was in trained individuals and in younger people.CRD42017081970.
APPLICATION OF MACHINE LEARNING TO DETERMINE TOP PREDICTORS OF NON-CALCIFIED CORONARY PLAQUE BURDEN IN PSORIASIS
Authors: Harry Choi, Eric Munger, Amit Dey, Youssef Elnabawi, Jacob Groenendyk, Noor Khalil, Justin Rodante, Milena Aksentijevich, Aarthi Reddy, Jenis Argueta-Amaya, Martin Playford, Ahmed Hasan, Mohsin Saleet Jafri, Veit Sandfort, Marcus Chen, David Bluemke, Joel Gelfand, Nehal Mehta
Journal: Journal of the American College of Cardiology (2019)
Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial
Authors: Michael E J Lean, Wilma S Leslie, Alison C Barnes, Naomi Brosnahan, George Thom, Louise McCombie, Carl Peters, Sviatlana Zhyzhneuskaya, Ahmad Al-Mrabeh, Kieren G Hollingsworth, Angela M Rodrigues, Lucia Rehackova, Ashley J Adamson, Falko F Sniehotta, John C Mathers, Hazel M Ross, Yvonne McIlvenna, Paul Welsh, Sharon Kean, Ian Ford, Alex McConnachie, Claudia-Martina Messow, Naveed Sattar, Roy Taylor
Journal: The Lancet Diabetes & Endocrinology (2019)
IMPACT OF CLINICAL PRESENTATION, LESION COMPLEXITY, AND TREATMENT STRATEGIES ON MID-TERM OUTCOMES AFTER PERCUTANEOUS INTERVENTIONS IN CORONARY BIFURCATIONS: A RETROSPECTIVE ANALYSIS FROM THE EURO BIFURCATION CLUB REGISTRY
Authors: Alaide Chieffo, Francesco Radico, Ricardo Costa, Marco Zimarino, Carlo Briguori, Ignacio Amat-Santos, Emanuele Barbato, Plinio Cirillo, Andrejs Erglis, Habib Gamra, Robert Gill, Vojko Kanic, Sasko Kedev, Nicola Maddestra, Sunao Nakamura, Mariano Pellicano, Ivo Petrov, Maja Strozzi, Tullio Tesorio, Vukcevic Vladan, Goran Stankovic
Journal: Journal of the American College of Cardiology (2019)