tbuckley/cabot-search huggingface dataset:
Abstract 12064: Accurate Detection of Severe Aortic Stenosis Using Wavelet Analysis and Machine Learning for Heart Murmur
Authors: Hirotada Masuda, Shigeru Miyagawa, Yuji Sakashita, Kazuo Shimamura, Toru Kuratani, Yoshiki Sawa
Journal: Circulation (2021)

Introduction: Auscultation is a well-accepted screening method for valvular disease. However, it is not adequate for the screening because the detecting rate of valvular disease by non-cardiologist is about 43% only. Hypothesis: Artificial intelligence (AI)-assisted heart murmur analysis could detect valvular disease following a heart murmur record using a digital stethoscope. Methods: The current study included 71 patients admitted to our hospital to undergo transcatheter aortic valve replacement due to aortic stenosis (AS). We recorded preoperative and postoperative heart murmur using digital stethoscope Eko. Three of 71 cases were diagnosed with severe AS due to prosthetic valve dysfunction. After denoise processing, an acoustic analysis was done to set objective parameters of the murmur. Machine learning was performed to detect severe AS by utilizing the characteristic parameters of severe AS as essential features. A total of 142 sound sources were acquired, 100 cases were used as training data, and the remaining were used as test data to verify the detection accuracy of severe AS. Results: The prolonged duration of the first sound and the peak frequency of systolic murmur with 300 Hz or higher were important for detecting severe AS. The detection accuracy of severe AS was 98% in the support vector machine model. All were detected in PVD cases, but not in the low flow &amp; low gradient cases. Conclusions: It was suggested that severe AS could be detected by AI-assisted heart murmur analysis. We are developing the auscultation device, which is designed to be easy for elderly outpatients, to detect severe AS and to classify the severity of AS with differences in the peak frequency of the murmur.
Abstract 10213: Acute Protein Kinase C Beta Inhibition Preserves Coronary Endothelial Function After Cardioplegic Hypoxia/Reoxygenation
Authors: Shawn Kant, Hang Xing, Yuhong Liu, Frank W Sellke, Jun Feng
Journal: Circulation (2021)

Introduction: Cardioplegic ischemia and reperfusion (CP-I/R) or CP-hypoxia and reoxygenation (CP-H/R) are associated with protein kinase C (PKC) overexpression/activation and coronary endothelial dysfunction. Hypothesis: This study aimed to determine whether acute inhibition of PKC could protect against CP-H/R-induced coronary endothelial dysfunction. Methods: Isolated small coronary arteries from mice (n = 6/group, male and female) were subjected to hyperkalemic, cardioplegic hypoxia (1 hour) and reoxygenation (1 hour) with Krebs buffer. The vessels undergoing CP-H/R were divided into 2 groups: those treated with the selective PKCβ inhibitor Ruboxistaurin (RBX, 50 nM, CP-H/R + RBX group) 5 minutes before and during CP-H/R, and those that received no treatment. Sham control vessels were continuously perfused with oxygenated Krebs buffer without CP-H/R and drug treatment. Vascular reactivity was measured by vessel myography. At the end of 1-hour re-oxygenation, all vessels were pretreated with endothelin-1; then, responses to the endothelium-dependent, NO-mediated vasodilator adenosine-diphosphate (ADP) and the endothelium-dependent/SK channel activator NS309 were examined. Results: CP-H/R caused a significant decrease in the coronary relaxation response to the endothelium-dependent, NO-mediated vasodilator ADP (10 - 4 M, * P =0.006) and the SK channel activator NS309 (10 -5 M, * P =0.0001) as compared with the Sham control group. Treatment with the selective PKCβ inhibitor RBX significantly increased the recovery of coronary relaxation responses to ADP ( # P = 0.031) and NS309 ( # P =0.004) compared with the untreated CP-H/R group (Figure). Conclusion: Acute inhibition of PKCβ significantly improved the recovery of coronary endothelial function after a period of CP-H/R injury in the mouse coronary microvasculature, suggesting that acute PKCβ inhibition may be a novel approach for protecting coronary endothelial function during CP-H/R.
Abstract 11725: Low Left Ventricular Mass and Cardiomyopathy in Muscular Dystrophies: A Different Perspective on Potential Cardiac Mechanisms
Authors: Rahul Sheth, Daniel Galvan, Hannah Lehrenbaum, Daniel Cheeran, Faris Araj, Alpesh Amin, Mark H Drazner, Vlad G Zaha, Ronald M Peshock, Pradeep P Mammen
Journal: Circulation (2021)

Introduction: Cardiomyopathy is a common complication in muscular dystrophy (MD) patients, though the mechanism is not clear. Retrospective data from adults with Duchenne muscular dystrophy suggest they have reduced LV mass compared to adults with other forms of non-ischemic cardiomyopathy. This raises the question whether pathologic hypertrophy contributes to the development of neuromuscular-associated cardiomyopathies. In this study, we hypothesized that MD patients have lower LV mass and associated changes in cardiac function as compared to healthy individuals. Methods: Utilizing cardiac magnetic resonance imaging (cMRI) data, a retrospective study was undertaken to compare LV mass, structure, and function between adults with MD and healthy age-, sex-, weight-matched controls from the Dallas Heart Study (DHS). Types of MD included dystrophinopathies, facioscapulohumeral MD, Freidreich ataxia, limb-girdle MD, myotonic dystrophy, and other rare MD. Approximately 50% of the MD patients were able to ambulate. MD patients were stratified into normal and reduced LVEF, defined as &lt; 62% on cMRI, for further comparison. Statistical analysis was done using a two-sample, two-tailed t-test. Results: There were 339 MD patients (221 male) of mean age 40 and 417 DHS patients (187 male) of mean age 42. MD patients had a significantly lower LV mass, LV mass index, and LVEF than DHS adults. They also had significantly higher absolute and indexed volumes. In those with normal LVEF, all variables except LVESVi were significantly different from DHS. In those with reduced LVEF, all variables were significantly different from DHS. The results are summarized in Table 1. Conclusions: Collectively, MD patients have a reduced LV mass compared to healthy adults. In addition, MD patients with normal LVEF have lower LV mass than those patients with reduced LV function. Whether this observed decrease in LV mass represents cardiac hypoplasia or atrophy warrants further investigation.
Clinical Pharmacology of Oral Antidiabetic Agents
Authors: Jan Koch-Weser, Shiao-Wei Shen, Rubin Bressler
Journal: New England Journal of Medicine (1977)

Treatment with Oral Hypoglycemic AgentsThe main justifications for clinical use of oral hypoglycemic agents are that they are taken by mouth once or twice a day, making them more convenient and acceptable to the patient than insulin, that they are effective in lowering the blood glucose, and that they are safe. The first is self-evident, but the other two reasons for use deserve close examination.Efficacy in Lowering Blood GlucoseBoth the sulfonylureas and the biguanides acutely lower blood glucose. The more important consideration is whether or not the glucose-lowering effect is maintained during prolonged use. In other words, . . .
Abstract 10910: The Role of Extracellular Matrix Biomarkers in Phenotypes of Subclinical Heart Failure
Authors: Amera Halabi, Elizabeth Potter, Hong Hilda Yang, Bing Wang, Leah Wright, Thomas Marwick
Journal: Circulation (2021)

Introduction: The extracellular matrix (ECM) plays a pivotal role in the development of heart failure (HF). Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) are key regulators of collagen turnover; several MMP and TIMP enzymes are associated with fibrosis and clinical HF. Hypothesis: This study compared ECM biomarkers with clinical biomarkers of cardiac function (N-terminal pro-brain natriuretic peptide [NTpBNP] and troponin-T [tropT]) in subclinical HF. Methods: 316 asymptomatic patients (71±5 years; 58% female) with at least one HF risk factor (hypertension, obesity, type 2 diabetes mellitus) from two community-based populations underwent a comprehensive echo, including global longitudinal strain (GLS), diastolic function (annular velocity [e’]) and LV geometry (LV mass index [LVMi], relative wall thickness [RWT]). ECM was assessed with MMP-2 and -9, and TIMP-1 and -2. Results: In the cohort, systolic function was preserved (GLS -18.4±3%), myocardial relaxation was slightly reduced (7.8±2cm/s) and LVMi was within normal limits (78.7±19g/m 2 ). Abnormal GLS (&gt;-16%) was associated with elevated TropT ( p =0.007) and NTpBNP ( p =0.008; Table), but no association was found with ECM biomarkers. However, elevated RWT and LVMi were associated with lower MMP-2, MMP-9 and TIMP-1, but not TropT or NTpBNP (Table). In multivariable regression analyses, there were weak negative associations observed between LVMi and MMP-2 (β=-0.05 [95% CI -0.09, -0.02], p =0.003), MMP-9 (β=-0.017 [-0.028, -0.007], p =0.001) and TIMP-1 (β=-0.03 [-0.05, -0.01], p =0.001). However, all ECM biomarkers had poor diagnostic utility in detecting elevated LVMi (AUC MMP-2 61%; MMP-9 58%; TIMP-1 61%). Similar trends were observed with RWT (AUC MMP-2 58%; MMP-9 64%; TIMP-1 61%). Conclusions: Although ECM biomarkers are associated mechanistically with cardiac remodelling, they lack clinical utility in recognition of subclinical HF.
FLGS-05. Maximal safe glioma resection using high resolution exoscope with 5-ALA-induced fluorescence
Authors: Kuniaki Saito, Nobuyoshi Sasaki, Keiichi Kobayashi, Hirofumi Nakatomi, Yoshiaki Shiokawa, Motoo Nagane
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION 5-aminolevulinic acid (5-ALA) guided surgery has been reported to prolong progression-free survival of patients with high grade glioma. Although blue-light capable microscope enables us to detect fluorescence intraoperatively, visualization of anatomy is difficult under blue-light microscope. On the other hand, exoscope permits to visualize both fluorescence and anatomy under blue-light conditions. We introduce our glioma surgery using an exoscope equipped with a 5-ALA fluorescence visual system. METHODS We attempted maximal safe resection for the patients with high grade glioma using 3D/4K exoscope with 5-ALA-induced fluorescence, neuronavigation, and electrophysiological monitoring or awake mapping. Visualization of fluorescence and anatomy under blue light, extent of resection, morbidity, and postoperative infarction were retrospectively reviewed. RESULTS Twenty patients (age 26–79, male 10/female 10, glioblastoma 11/lower grade glioma 9) underwent exoscopic tumor removal. Intraoperative fluorescence was observed in 100% of the tumor with gadolinium enhancement. Surrounding structures such as white matter, vessels and nerves were clearly visualized under blue light. Even perforators were visible and could be preserved. Supra-total resection and gross total resection of gadolinium-enhancing tumor was achieved in 6 (30%) and 10 (50%) patients, respectively. Surgical morbidity included hemianopsia in 1 patient and transient hemiparesis in 1 patient. Postoperative infarction was observed in 2 (10%) patients, which tended to be lower compared to 23 of 77 (29.9%) patients with glioblastoma who underwent tumor resection with fluorescence-equipped microscope(p=0.05). CONCLUSION Clear visualization of 5-ALA-indced tumor fluorescence and anatomical structures with use of high resolution exoscope help maximal safe tumor resection. Longer progression-free survival is expected as a result of greater extent of tumor resection.
Abstract 12153: Gender Differences in Patients with Val122ile Hereditary Transthyretin Cardiac Amyloidosis
Authors: Sreeram Yalamanchili, Austin Rim, Thomas Bigham, Matthew T Brown, Kunal Bhatt
Journal: Circulation (2021)

Introduction: Hereditary Transthyretin Cardiac Amyloidosis (hATTR-CA) of the Valine 122 Isoleucine (Val122Ile) variant is prevalent among 3.4% African Americans. More commonly diagnosed in men, there is limited data on sex differences in clinical characteristics and outcomes in patients with Val122Ile hATTR-CA. Methods: Retrospective chart review identified a total of 90 patients with a genetic confirmation of Val122Ile hATTR-CA and either positive technetium pyrophosphate (PYP) scanning or endomyocardial biopsy. Cohorts were divided based on sex and clinical and demographic data was collected from time of diagnosis. Results: Among our cohort, 64 (71%) were males and 26 (28%) were females. All were African Americans. Women were significantly older at the time of diagnosis compared to men, 76 ± 6 vs 71 ± 7, p=0.001. New York Heart Association (NYHA) Functional Classification scores were similar between sexes with the majority presenting with NYHA class II and III symptoms. Men had significantly higher rates of coronary artery disease compared to women, 17 (26.6%) vs 2 (7.7%), p=0.047, but all other comorbidities and extra-cardiac manifestations were similar. Troponin I, BNP, eGFR, and prealbumin did not differ significantly between sexes. Electrocardiographic variables, arrhythmia rates, and cardiac implantable electronic distribution were also similar between gender. However, several echocardiographic variables at diagnosis significantly differed: left ventricular ejection fraction (LVEF, %) was lower in men compared to women (41 ±17 vs 33 ± 15, p=0.024) whereas left ventricular end-diastolic diameter (LVeDd, mm) and mass index (LVMI, g/m2) were both higher in men (44.3 ± 6.7 vs 38.4 7.6, p = 0.001 and 168 ± 63 vs 131 ± 38, p = 0.009 respectively). There was no difference in time to diagnosis or survival between men and women in our cohort. Conclusions: Consistent with prior data, women with Va1122Ile hATTR-CA were significantly older with higher LVEF at diagnosis when compared to men. Despite this, women were found to have similar NYHA classification, extra-cardiac manifestation rates, biomarkers, and survival. These findings support a delayed, but equally infiltrative phenotype that should be considered in women with preserved heart failure.
Abstract 12491: Use of a Self-Care Mobile Phone Application Can Improve Patient Education and Medication Adherence in Patients With Acute Decompensated Heart Failure
Authors: Hani essa, mohee kevin, ashwin balu, sophia brousas, Isobel Whybrow-huppatz, sanjana kochhar, carolyn jackson, naomi murphy, annmarie kelly, homeyra douglas, rajiv sankaranarayanan
Journal: Circulation (2021)

Introduction: The use of digital health technologies using mobile phone health applications has increased over the last few years. We developed a mobile phone application (APP) (Aintree Heart Failure Passport APP) for heart failure (HF) patient self-education and improved medication adherence. The APP consisted of a Traffic Light System for education self-care advice, prompt for medications, reminder of appointments, educational videos as well as a mood check questionnaire. Methods: This was a pilot feasibility study in a British university hospital conducted in 2019 and 2020. We assessed self-care behaviour following the use of the Aintree Heart Failure Passport Mobile APP in a cohort of patients with acute decompensated HF. We employed the use of European Heart Failure Self-care Behaviour scale (EHFSBs), medication adherence using the Medication Adherence Report Scale (MARS-5) at 2 weeks and compared 30-day HF readmissions with annual hospital HF data. Descriptive statistics were represented as continuous variables as means with standard deviations. Categorical variables were represented with percentages and analysed using Chi-squared test. Results: 102 patients with acute decompensated HF were recruited to this pilot feasibility study. 57% were men and mean age 56 years±5.1. 55% patients had HF with reduced ejection fraction (HFrEF), 34% had HF with preserved EF (HFpEF) and 11% had HF with mid-range EF. Mean EHFSBs was 19.7±6.1and mean MARS-5 score was 23.5±1. 10/102 (10%) patients were re-hospitalised with HF compared to the annual hospital HF rehospitalisation incidence which was 19% (95/393); p=0.04. Conclusions: Results from our pilot feasibility study suggest that use of a HF self care mobile phone APP (Aintree Heart Failure Passport App) in patients with acute decompensated HF, leads to high quality self care behaviour, high levels of medication adherence and lower levels of 30-day HF re-hospitalisation. These results will need to be validated in a randomised controlled trial.
Abstract P366: The Impact Of Estrogen Signaling On Gut Epithelial Cells
Authors: Alice E Solomon, Christina Hoyer-Kimura, Archana Kangath, Frank Duca, John P Konhilas
Journal: Circulation Research (2021)

Cardiovascular disease (CVD) is the leading cause of death in women worldwide. Menopause is associated with increased susceptibility to CVD, but the mechanism is currently unknown. Studies have suggested that loss of estrogen signaling in the intestine during menopause may lead to worse myocardial infarction (MI) outcomes in female mice. Our lab has shown that suppressing inflammation in the gut using pre- and pro-biotics protects the heart from ischemic heart disease caused by MI through unknown means. We propose that alterations in gut microbiota are due to destruction of intestinal pattern recognition receptors (PRRs) such as toll-like receptor 4 (TLR4) and TLR5. Studies show that estrogen signaling modulates PRRs in other tissues, but this has yet to be investigated in gut epithelial cells. To elucidate the mechanisms of estrogen receptor function in the gut as a direct mediator of vascular health, we are utilizing an immortalized human cell line of colorectal adenocarcinoma brush border expressing (Caco2 BBE) cells. We hypothesized that estrogen treatment in gut epithelial cells will lead to increased expression of PRRs and decreased inflammation in Caco2 BBE cell lines. To investigate expression and localization of estrogen receptors (ERs), Caco2 BBE cells at different confluency were treated with estradiol (E2) or DMSO control for 24hrs, then either RNA or protein were harvested for use in qPCR and western blot, or cells were formalin fixed for use in immunohistochemistry. In each case, ERα was not detected, but ERβ was present at varying concentrations. Data also showed increased expression of TLR5 and TLR7 in E2 treated cells, while TNF-α and IL-1 were decreased. In conclusion, data show potential confluency dependent ERβ expression and suggest that ERα may not be present in our Caco2 BBE cell line. Our hypothesis is also supported by data for PPRs and inflammatory markers. Though these results are revealing, future studies are needed to further characterize Caco2 BBE cells in the context of ER signaling.
Pan-Stakeholder Core Outcome Set (COS) Definition for Selected Hematological Malignancies - Results of the Harmony Alliance
Authors: Katharina M Lang, Tamás Bereczky, Natacha Bolanos, Ana Vallejo, Ananda Plate, Kathryn E. Morgan, Sophie Wintrich, Nick York, Gert J. Ossenkoppele, Brian J.P Huntly, Hartmut Döhner, Gilles Salles, Martin H. Dreyling, Silvia Montoto, Pieter Sonneveld, Jesus San-Miguel, Mario Boccadoro, Pierre Fenaux, Andrea Kündgen, Valeria Santini, Paolo Ghia, Sarka Pospisilova, Francesc Bosch, Katy Harrison, Jan Geissler, Yann Guillevic, Frederico Calado, Guillermo Sanz, Jesus Maria Hernández-Rivas, Paula Williamson, Ellen De Waal, Martje Barbus, Renate Schulze-Rath, Lars Bullinger
Journal: Blood (2021)
STEM-19. NON-REDUNDANT, ISOFORM-SPECIFIC ROLES OF HDAC1 IN THE REGULATION OF THE GLIOMA STEM CELL PHENOTYPE
Authors: Costanza Lo Cascio, James McNamara, Ernesto Luna Melendez, Erika Lewis, Matthew Dufault, Nader Sanai, Christopher Plaisier, Shwetal Mehta
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the Histone Deacetylases (HDACs), are considered promising therapeutic targets for GBM due to their repressive influences on transcription. Although HDACs share redundant functions and common substrates, the unique isoform-specific roles of different HDACs in GBM remain unclear. There is a temporal and cell-type specific requirement of HDAC1 and 2 during normal brain development, with HDAC2 being indispensable in neural stem cells. Here, we specifically investigated the functional importance of HDAC1 in glioma stem cells, an HDAC isoform whose expression increases with brain tumor grade and is correlated with decreased survival. Using cell-based and biochemical assays, transcriptomic analyses and patient-derived xenograft models, we report that knockdown of HDAC1 alone has profound effects on the glioma stem cell (GSC) phenotype and survival in a p53-dependent manner. HDAC1 is the essential class I deacetylase in glioma stem cells, and its loss is not compensated for by its paralogue HDAC2 or other HDACs. Loss of HDAC1 expression significantly suppresses viability of GSCs harboring functional p53, and that HDAC2 expression is completely dispensable in GSCs. In addition, HDAC1 silencing but not HDAC2, stabilizes and acetylates p53 in GSCs, resulting in upregulation of key p53 target genes and induction of programmed cell death. Furthermore, ablation of HDAC1 function alone results in histone hyperacetylation and a collapse of the stemness state in GSCs. We demonstrate significant suppression in tumor growth upon targeting of HDAC1 and identify compensatory pathways that provide insights into combination therapies for GBM. Our study highlights the importance of HDAC1 in GBM and the need to develop isoform-specific HDAC inhibitor drugs.
CBIO-05. SOX2 CHROMATIN ARCHITECTURE AND ENHANCER ACTIVITY IN THE MAINTENANCE AND DEVELOPMENT OF NEURAL STEM CELLS
Authors: Devin Bready, Aram Modrek, Joshua Frenster, Jane Skok, Dimitris Placantonakis
Journal: Neuro-Oncology (2021)

Abstract Gain of function mutations in isocitrate dehydrogenase I (IDH1) result in the formation of the oncometabolite 2-hydroxyglutarate (2HG) in adult lower grade gliomas. To gain insight into mechanisms of gliomagenesis, our lab previously created a tractable human cellular model of low grade astrocytoma (LGA) using the putative cell-of-origin, human neural stem cells (NSCs), engineered to express mutant IDH1 and knockdown constructs against TP53 and ATRX, the two other genetic changes that accompany the IDH mutation in these tumors. We found that transcription factor (sex determining region Y)-box 2 SOX2, which is essential to NSC multipotency, the ability to differentiate to neuroglial lineages, behaves as a tumor suppressor during glioma initiation. In this context, we showed SOX2 is transcriptionally downregulated to impair NSC multipotency, thus locking NSCs in an undifferentiated state to initiate gliomagenesis. This downregulation occurs secondary to dynamic reorganization of the topologically associating domain (TAD) of SOX2 and the loss of contact with several genomic loci with histone modifications and chromatin accessibility suggestive of being enhancers. Here we show that those putative enhancers acquire enhancer-like features simultaneous to tje TAD organizing in a way that facilitates interaction with the SOX2 promoter during the process of pluripotent stem cell differentiation into neuroectodermal lineages, suggesting a developmental role. Preliminary data suggests that disruption of the SOX2 TAD by preventing binding of the genome organizer CTCF downregulates SOX2 expression in NSCs. Targeted silencing of several regions of a putative enhancer with CRISPRi also downregulates SOX2. In human embryonic stem cells (hESCs), interfering with these CTCF binding sites biases their differentiation away from the neuroectoderm. We are currently performing CRISPRi screen against all putative enhancer loci, teratoma formation assays on hESCs lacking relevant CTCF binding, and CRISPR mediated deletion of putative enhancers. Understanding this developmental process may reveal underlying vulnerabilities in LGA.