tbuckley/cabot-search huggingface dataset:
Abstract 121: Interleukin 11 Mediates Wnt/β-catenin-dependent Fibrotic Response Of Human Cardiac Fibroblasts
Authors: Edyta Dzialo, Marcin Czepiel, Maciej Siedlar, Gabriela Kania, Przemyslaw Blyszczuk
Journal: Circulation Research (2021)

Wnt proteins family represents secreted glycoproteins implicated in the number of fibrotic cardiac pathologies. The transcriptional activity of Wnts is broad and involves β-catenin-dependent or β-catenin-independent responses. In this study, we examined the effect of exogenous Wnt3a (β-catenin-dependent) and Wnt5a (β-catenin-independent) in TGF-β-activated human cardiac fibroblasts. Furthermore, we assessed the hypothesis that Wnt3a could regulate IL-11 production and analyzed its contribution to profibrotic response in cardiac fibroblasts.By employing a full genome transcriptomics, we analyzed transformation of human cardiac fibroblasts induced by TGF-β in the presence of Wnt3a or Wnt5a produced by cell culture supernatant of L-Wnt3a, L-Wnt5a or control L-cells. Stimulation with Wnt3a of TGF-β-activated fibroblasts resulted in induction of 66 genes, specifically involved in myofibroblast differentiation including ACTA2 (encoding alpha smooth muscle actin; αSMA) ACTG2 (encoding gamma smooth muscle actin; γSMA) and VCL (encoding vinculin). In contrast to Wnt3a, treatment with Wnt5a upregulated expression of only 2 genes in TGF-β-activated cells. Additionally, in the presence of TGF-β, Wnt3a enhanced phosphorylation of TAK1 and production and secretion of IL-11. Importantly, in the absence of TGF-β, Wnt3a did not promote fibroblast-to-myofibroblast transition, TAK1 phosphorylation and IL-11 production. To determine, if Wnt3a-dependent production of IL-11 could contribute to profibrotic response we blocked IL-11 activity with anti-IL-11 neutralizing antibody in cardiac fibroblasts activated with TGF-β and Wnt3a. We found that neutralizing anti-IL11 antibody effectively suppressed production of αSMA, γSMA, fibronectin and pro-collagen I alpha 1, both on mRNA and protein levels. In line with these findings, blockade of IL-11 suppressed contractile properties of TGF-β/Wnt3a-activated cardiac fibroblasts. In conclusion, Wnt3a and Wnt5a differentially regulate gene expression of TGF-β-activated cardiac. Activation of the Wnt/β-catenin pathway promotes fibroblast-to-myofibroblast transition by enhancing production of profibrotic IL-11. It seems that identifying the profibrotic Wnt/β-catenin-IL11 mechanism in cardiac fibroblasts might represent a promising strategy in development of new therapies against cardiac fibrosis.
Abstract 10414: Audit of Percutaneous Coronary Intervention Use in St-Elevation Myocardial Infarction Under the Indian National Health Insurance Program Ayushman Bharat
Authors: Bhanu Duggal, Mithlesh Chourase, Nupur Sharma, Mona Duggal, Praveen Gedam, Sujata Saunik, Ajai Agrawal, Brahmajee K Nallamothu
Journal: Circulation (2021)

Introduction: National health insurance programs like Ayushman Bharat (AB) have increased access to treatments like PCI to poor patients in low-to-middle income countries (LMICs). Evaluating such systems for STEMI care through electronic health records (e-HR) data can provide a unique opportunity to assess quality of PCI. Methods: We evaluated PCI cases within AB across 5 Indian states, selecting 4 hospitals from each state (2 public &amp; 2 private facilities). Each week from January to May 2020, we selected 5 random cases from each hospital for detailed review. We accessed e-HR data of these patients. To ensure data quality, data was double abstracted at two different time points. We report descriptive statistics focused on the timing of PCI relative to their symptom onset and first medical contact (FMC). Results: Of 300 PCIs reviewed within AB, 196 patients were managed for STEMI. A total of 47 from Uttar Pradesh, 53 from Chhattisgarh, 43 from Maharashtra, 28 from Madhya Pradesh, and 25 from Haryana. Of these, 59.7% (117/196) patients reached FMC within 3 hours of symptom onset; 17.9% (35/196) within 3-12 hours, 5.1% (10/196) within 12-48 hours, 3.1% (6/196) within 48-72 hours, and 12.8% (25/196) after 72 hours. From FMC, PCI was done in only 4.6 % (9/196) patients within 3 hours and 8.7 % (17/196) within 12 hours. Over half (107/196 or 54.6%) received PCI after 72 hours (Figure). Of these, only 3/107 (2.8%) received fibrinolytic therapy and 35/107 (32.7%) had complete occlusion of the culprit vessel, nullifying the benefit of PCI based on randomized trial evidence. Conclusion: Many poor Indian patients undergoing PCI for STEMI under AB are receiving PCI after long delays with underuse of fibrinolytic therapy. Opportunities to improve reperfusion therapy in India exist for socioeconomically disadvantaged patients.
Abstract 12176: Oral Anticoagulant Therapy Following Single-Lead ECG Screening Among Older Patients With Atrial Fibrillation: The VITAL-AF Trial
Authors: Jeffrey M Ashburner, Daniel Singer, Yuchiao Chang, Shaan Khurshid, Ana Lipsanopoulos, Leila H Borowsky, Patrick T Ellinor, David D McManus, Steven A Lubitz, Steven Atlas
Journal: Circulation (2021)

Introduction: A substantial proportion of patients with atrial fibrillation do not take oral anticoagulants (OAC). Point of care ECG testing at primary care visits may prompt reassessment of OAC eligibility in patients with AF. Methods: VITAL-AF (NCT035115057) was a cluster-randomized trial of AF screening using single-lead handheld electrocardiograms within 16 primary care practices affiliated with Massachusetts General Hospital. The goal of VITAL-AF was to screen for undiagnosed AF. For pragmatic reasons the trial included all individuals aged ≥ 65 years, including those with an established diagnosis of AF. We evaluated screening uptake among prevalent AF patients in the screening arm, OAC initiation among both screening and control patients with prevalent AF, and OAC initiation by screening result (adjusted for stroke/bleed risk factors compared to all patients not screened). OAC use was identified using electronic health record medication lists during the 1-year prior to and following a patient’s study index visit. Results: Prevalent AF was present in 2,250 patients (75% on OAC) in the screening arm and 2,343 patients (76% on OAC) in the control arm. 90% of patients in the screening arm were screened at least once during the study period (mean 2.4 times screened). 31.5% had a “Possible AF” and 17.2% had an “Unclassified” automated algorithm screening result during their first screening encounter (40.1% “Possible AF” and 27.4% “Unclassified” during any encounter). Overall, OAC initiation was similar among prevalent AF patients from the screening arm and control arm ( Table ). OAC initiation was higher among screened patients who had a “Possible AF” automated result (Adjusted Odds Ratio 1.14, 95% CI: 1.05-1.24). Conclusions: Point of care cardiac rhythm assessment was not associated with significant changes in the use of OAC in patients with a history of AF. However, screened patients not on OAC who had a positive single-lead ECG were more likely to initiate OAC.
CTNI-39. IDENTIFICATION OF AN AUTOPHAGY-RELATED GENE SIGNATURE AND ESTABLISHMENT OF A NOMOGRAM PREDICTING SURVIVAL OF LOWER-GRADE GLIOMA
Authors: Lei Wen, hui Wang, Mingyao Lai, Changguo Shan, Linbo Cai
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE The aim of our study was to establish an autophagy-related signature for individualized risk stratification and prognosis prediction in LGG. METHODS RNA-sequencing data from The Cancer Genome Atlas (TCGA), Genome Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) were used. The 232 ARGs were obtained from the Human Autophagy Database (HADb). Univariate and Lasso regression were employed to identify differentially expressed autophagy-related genes (ARGs) and establish a prognostic signature whose performance was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell’s concordance index (C-index) and calibration curve. RESULTS Fifty-three autophagy-related DEGs were identified. Four autophagy-related genes (DIRAS3, GNAI3, PTK6, and BIRC5) were selected to establish the prognostic signature and verified in the CGGA validation cohorts. Univariate and multivariate Cox regression indicated that the autophagy signature (HR, 95%CI, P) was an independent predictor of prognosis in LGG. Finally, a prognostic nomogram incorporating age, grade, targeted therapy, new event, tumor status and autophagy signature achieved excellent predicative performance (AUC 0.907, 0.865 and 0.858 for 1-year, 3-year and 5-year survival, respectively) verified by Time-dependent ROC, C-index (0.844, 95% CI, 0.799 to 0.889; P = 1.01e-12) and calibration plots. CONCLUSION The present study constructed a robust four autophagy-related gene signature. A prognostic nomogram in risk stratification and prediction of overall survival in LGG was established. The findings may be beneficial to individualized survival prediction and medical decision-making for LGG.
Abstract P426: Inactivating Grk5 Impairs Basal Cardiac Function And Survival Via P53 Modulation
Authors: Federica Marzano, Antonio Rapacciuolo, Walter J Koch, Alessandro Cannavo
Journal: Circulation Research (2021)

Introduction: G protein-coupled receptor (GPCR) kinase 5 (GRK5) is a multifunctional protein and depending on its localization within the cell, it has been shown to elicit either protective or deleterious effects. For instance in the heart, when anchored to the plasma membrane, this kinase can regulate specific GPCRs via canonical phosphorylation that can confer cardioprotection. However, when it accumulates in the nucleus its non-canonical activity can drive pathological hypertrophic gene transcription. Interestingly, the latter effects may not be kinase-dependent. Hypothesis: The role played by GRK5’s catalytic activity in the heart has not been fully elucidated and for that reason we sought to assess the in vivo consequences of inactivating the catalytic site of GRK5 with an initial focus at examining the basal cardiac phenotype and response to stress. Methods: We used CRISPR/Cas9 technology to generate a novel knock-in mouse model, with the ATP binding lysine (K) 215 in the catalytic cleft replaced by arginine (R) (GRK5-K215R) resulting in mice devoid of any GRK5 catalytic activity. We studies baseline cardiac function in these mutant mice compared to wild-type (WT) littermates and then stressed them via transverse aortic constriction (TAC). In vitro, we used H9c2 cardiomyocytes and various GRK5 mutants for mechanistic studies. Results: Compared to age-matched WT littermates, GRK5-K215R mice revealed marked and early (9 weeks) deterioration of cardiac function, with augmented apoptosis and fibrosis basally. Importantly, mutant knock-in mice displayed increased p53 gene expression (both at mRNA and protein levels). Moreover, TAC induced increased dysfunction and fibrosis in GRK5-K215R mice compared to WT. Mechanistically, we transduced H9c2 cells with adenoviruses (Ad), encoding for WT GRK5 (Ad-GRK5) or a mutant GRK5 lacking its nuclear localization signal (Ad-NLS) and when GRK5 was localized only outside the nucleus, there was a significant protection against apoptosis, with reduced p53 protein and mRNA levels. Conversely, when we overexpressed a mutant GRK5 without nuclear export signal (GRK5-ΔNES) to trap GRK5 within the nucleus, we found a significant increase in apoptosis, with high p53 protein expression levels. Conclusions: Inactivating GRK5’s catalytic activity impairs its nuclear regulation of p53. This can result in higher levels of p53 mRNA and protein resulting in higher rates of apoptosis in the heart leading to significant cardiac dysfunction and an intolerance to stress.
Abstract 12756: Long-Term Efficacy and Safety of Evinacumab in Adult and Adolescent Patients With Homozygous Familial Hypercholesterolemia
Authors: Daniel Gaudet, samir saheb, Gabriella Iannuzzo, Claudia STEFANUTTI, Erik S Stroes, Robert S Rosenson, Traci Turner, shazia ali, Poulabi Banerjee, Tiera Drewery, robert pordy, Jian Zhao, Frederick J Raal
Journal: Circulation (2021)

Introduction: Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare genetic lipid disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease, underscoring the need for early and aggressive treatment. Evinacumab, an angiopoietin-like 3 inhibitor, significantly reduced LDL-C in patients with HoFH in a pivotal Phase 3 trial (NCT03399786). The current study assesses long-term safety and efficacy of evinacumab in patients with HoFH. Methods: This is an interim analysis of an evinacumab open-label Phase 3 trial (NCT03409744) in adult and adolescent(12-&lt;18 years) patients with HoFH. Patients who previously received evinacumab or who were evinacumab-naïve both received intravenous evinacumab 15 mg/kg every 4 weeks. Results: A total of 115 patients (50.4% male; mean [range] age 39 [12-75] years; 11.3% adolescent) were enrolled and treated for a mean (range) duration of 53 (4-132) weeks. At baseline, mean (standard deviation [SD]) LDL-C was 261.8 (160.5) mg/dL; 44 (38.3%) patients were receiving concomitant lipoprotein apheresis. At Week 24, data were available for 81 patients. From baseline to Week 24, evinacumab reduced mean LDL-C for all patients by 43.7% (mean [SD], 133.0 [125.9] mg/dL); mean LDL-C reduction for adult (n=72) and adolescent (n=9) subgroups was 42.6% (mean [SD], 126.7 [127.9] mg/dL) and 52.4% (mean [SD], 183.4 [101.6] mg/dL), respectively. Treatment-emergent adverse events (TEAEs) occurred in 76 (66.1%) patients; one patient reported pregnancy which led to discontinuation of study treatment per protocol. Serious TEAEs were reported by 16 (13.9%) patients; two (1.7%) patients experienced a TEAE resulting in death, none of which were considered related to study treatment. Conclusions: In this large cohort of patients with HoFH, evinacumab markedly reduced LDL-C irrespective of age. Evinacumab was generally well tolerated, and the efficacy and safety of evinacumab was sustained over the long term.
Abstract 12118: Patterns of Anticoagulation Use in Atrial Fibrillation and Active Cancer: Observations From Medicare
Authors: Sean Chen, Anne Hellkamp, Brooke Alhanti, Chiara Melloni, Jonathan P Piccini, Michel G Khouri, Christopher Granger, Sean Pokorney
Journal: Circulation (2021)

Introduction: Use of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) and cancer is challenging due to increased thrombotic and bleeding risks, and data on prescription patterns are lacking. Hypothesis: Underutilization of OAC among patients with AF and cancer is associated with cancer specific factors. Methods: This study examined OAC use and factors associated with discontinuation of OAC among Medicare patients with AF and a new diagnosis of cancer from 2011-2016. We described OAC use patterns prior to and after a diagnosis of cancer. Logistic regression was used to evaluate clinical variables associated with discontinuation of OAC at time of cancer diagnosis and cox proportional hazards model was used to evaluate variables associated with discontinuation after diagnosis. Results: Among 44,769 patients with established AF and newly diagnosed cancer, 30.2% (n=13,508) were taking OAC at the time of cancer diagnosis. A total of 15,228 patients (34%) had an OAC prescription fill after index cancer diagnosis. Warfarin was the most commonly used OAC, but direct oral anticoagulant use increased over the study period. A total of 29.5% of patients had their OAC discontinued at the time of cancer diagnosis. Patients with gastric (OR 2.75, CI 2.12-3.57), pancreatic (OR 2.71, CI 2.15-3.41), and colorectal (OR 1.97, CI 1.70-2.28) cancer were most likely to have their OAC discontinued at diagnosis (Figure). Bleeding (HR1.37, CI 1.28-1.48) and chemotherapy (HR 1.38, CI 1.06-1.80) were associated with subsequent discontinuation in those who remained on OAC after diagnosis. Conclusions: Nearly 2 in 3 patients with established AF were not treated with OAC after cancer diagnosis despite an elevated stroke risk. Significant heterogeneity in OAC use exists depending on cancer type, baseline comorbidities, and chemotherapy use. Studies are needed to characterize the thrombotic and bleeding risks in this population to establish management guidelines.
Abstract 14276: Bridging The Gap To Optimal Dosing For Guideline-directed Medical Therapy For Patients With Heart Failure And Reduced Ejection Fraction
Authors: Franck H Azobou Tonleu, Martin L Campbell, Stephanie C Miller, Nathan R Steele, Ryon L Arrington, ZhenChao Chen, Yetunde A Fatade, Modele O Ogunniyi
Journal: Circulation (2021)

Introduction: The key to improving heart failure (HF) outcomes and its ultimate impact on reducing health care costs include the initiation, optimization, and maintenance of guideline-directed medical therapy (GDMT) in patients with Heart Failure and Reduced Ejection Fraction (HFrEF). The ACC/AHA/HFSA guidelines recommend maximum tolerated doses for these patients unless contraindicated. Despite widespread knowledge, there is underutilization of GDMT at recommended target doses in eligible patients. Hypothesis: Majority of eligible patients (&gt;50%) in our safety-net HF Clinic are on optimal doses of GDMT. Methods: We conducted a retrospective analysis of GDMT use in patients who were diagnosed with HFrEF between January 1 to March 31, 2019, and completed at least two HF clinic visits in 2019. The primary outcomes were the percent of patients on optimal doses of: (1) beta blockers, (2) renin-angiotensin-aldosterone system (RAAS) inhibitors, and (3) mineralocorticoid antagonists (MRAs). Optimal dose was defined &gt;/= 50% of target dose or maximum tolerated dose. Results: Our cohort of 227 patients was predominantly male (70%), African American (94%) with mean age of 59 +/- 11 years. Most patients were on beta blockers (96%) and RASS inhibitors (88%). Only 11% were on Angiotensin Receptor-Neprilysin Inhibitors(ARNI), and 30% on MRAs. Only 52%, 43%, and 20% of patients were prescribed target doses of beta blockers, ACEI/ARBs, and MRAs respectively. Conclusions: GDMT dosing in our safety-net HF Clinic was suboptimal. Based on these findings, we are implementing a quality improvement process to facilitate early initiation and up-titration of GDMT with the overall goal of reducing the morbidity and mortality in our patient population.
A Phase 2a Study Evaluating the Safety and Pharmacokinetics (PK) of Luspatercept in Pediatric Patients with Transfusion-Dependent β-Thalassemia (TDT)
Authors: Vip Viprakasit, Thomas D. Coates, Khaled M. Musallam, Julie Vienne Buerki, Meera Patturajan, Natalia Holot, Yesim Aydinok
Journal: Blood (2021)
Abstract 13846: Prognostic Value of Echocardiographic Markers of Diastolic Dysfunction for Heart Failure in Overweight and Obese Patients in CAMELLIA-TIMI 61
Authors: Jingyi Gong, Benjamin M Scirica, Neil J Weissman, Minao Tang, Silvio E Inzucchi, Darren K McGuire, Anthony C Keech, Stephen D Wiviott, Marc S Sabatine, Erin Bohula
Journal: Circulation (2021)

Background: Recent guidelines have outlined echo markers of diastolic dysfunction (DD); evidence is limited for their prognostic value for hospitalization for heart failure (HHF) in overweight and obese pts. Methods: CAMELLIA-TIMI 61 was a randomized placebo-controlled trial of the weight loss agent lorcaserin in 12,000 pts with BMI ≥27 with or at risk for CV disease (median follow-up, 3.3 yrs). Echo with core lab interpretation was performed on a subset of pts. Established DD parameters were measured, including the ratio of the peak early transmitral diastolic flow velocity over the early diastolic mitral annulus velocity (average E/e’), left atrium volume index (LAVi), and tricuspid regurgitation jet velocity (TRV). These were analyzed continuously, using the standard cutpoints of &gt;14, &gt;34 mL/m 2 , and &gt;2.8 m/s, respectively, and separately to determine the optimal cutpoints. The primary outcome for this analysis was HHF. Results: In 3,972 pts with baseline ejection fraction ≥50%, all 3 variables on a continuous scale predicted increased risk of HHF; using standard cutpoints, only E/e’&gt;14 remained independently associated with HHF after adjustment for the other 2 echo parameters and clinical variables ( Panel A ). In an analysis of optimal cutpoints in these overweight and obese pts, &gt;13 was optimal for E/e’, &gt;2.5 m/s for TRV, and &gt;58 mL/m 2 for LAVi. In a model with all 3 echo parameters, all remained significant predictors of HHF. After incorporation of clinical variables, E/e’ (HR 2.15, 95%CI 1.24-3.72) and LAVi (HR 2.41, 1.33-4.36) remained independent predictors of HHF ( Panel A ). Rates of HHF were 0.6, 3.3, and 10.1% (p-trend&lt;0.0001) in pts with none, one, or both measures of DD ( Panel B ). Conclusions: Several echocardiographic markers of diastolic dysfunction used in current guidelines predict increased risk of HHF events in the understudied obese and overweight population. A higher LAVi (&gt; 58 ml/m 2 ) cutpoint should be considered in these pts to prognosticate risk of HHF.
EPID-19. CONDUCTING A NATIONWIDE BRAIN TUMOR EPIDEMIOLOGY STUDY IN AN LMIC: A MULTI-INSTITUTIONAL EXPERIENCE
Authors: Erum Baig, Mashal Shah, Mohammad Hamza Bajwa, Altaf Ali Laghari, Naveed Zaman Akhunzada, Saad Bin-Anis, Usman Khalid, Namra Qadeer, Areeb Lutfi, Izza Tahir, Rameen Bajwa, Huzaifa Rashid, Haleema Sadia, Kinzah Ghazi, Mishal Gillani, Sameen Siddiqi, Syed Ather Enam
Journal: Neuro-Oncology (2021)

Abstract Very little research has been conducted on brain tumor epidemiology in Pakistan and a few studies that do exist provide regional data only. Conducting population based epidemiological studies in low-and-middle income countries (LMICs) like Pakistan can be particularly challenging due to limited resources, poor clinical and research infrastructure, unreliable or incomplete hospital records and a lack of standardization across the health care system. Population-wide studies and registries play an important role in cancer epidemiology and can help identify the current magnitude of cancer burden and its likely future evolution, allowing for better planning of prevention, diagnosis, management, and rehabilitation. This paper describes our experience in designing and conducting Pakistan Brain Tumor Epidemiology Study (PBTES), a first-ever nationwide study carried out to assess the distribution of brain tumors in Pakistan. In addition to the aforementioned obstacles, we were also faced with the global health crisis caused by the COVID-19 pandemic and had to promptly adjust our study accordingly. Other investigators conducting epidemiological studies in LMICs with similarly challenging and constricting settings could benefit from our experiences.