tbuckley/cabot-search huggingface dataset:
Abstract 12156: Loss of Thiol on C674 SERCA2 Leads to Ca2 <sup>+</sup> Mishandling With Hypertrophy in Right Ventricular Exposed to Hypoxia
Authors: Kazuki Kagami, Kei Ito, Hirotaka Yada, Yusuke Yumita, Midori Iwashita, Ishinoda Yuki, Takumi Toya, Takayuki Namba, Yukinori Ikegami, Risako Yasuda, Nobuyuki Masaki, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
Journal: Circulation (2021)

Introduction: Right ventricular (RV) dysfunction is the strongest predictor of mortality in pulmonary artery hypertension (PAH). Reactive oxygen species in heart failure cause irreversible oxidation of sarcoplasmic reticulum (SR) Ca 2+ -ATPase2 (SERCA2) C674, which results in SERCA2 dysfunction and intracellular Ca 2+ overload. However, the contribution of the loss of the thiol on C674 SERCA2 and RV failure in PAH remains unclear. Hypothesis: The loss of the thiol on C674 SERCA2 contributes to the RV dysfunction in PAH. Methods &amp; Results: We employed the SERCA2 C674S heterozygote knock-in (SKI) mice, in which C674 is replaced by serine, mimics oxidative modification of SERCA2 by loss of the specific thiol. Wild-type mice (WT) and SKI were exposed to either normoxia (Nx) or chronic hypoxia (Hx) for four weeks. Hypoxia elevated RV systolic pressure (WT-Nx: 21.4mmHg vs. WT-Hx: 37.0mmHg, P&lt;0.0001) and represented pulmonary vascular remodeling similarly both in WT and SKI. In histology, SKI-Hx showed the markedly increased Fulton's Index with higher levels of the mRNA expression of atrial natriuretic peptide and B-type natriuretic peptide than WT-Hx. In the exercise test, exercise duration was shorter and peak oxygen consumption was decreased in SKI-Hx than WT Hx. The mRNA levels of SERCA2 were not changed among the four groups. In Ca 2+ transient measurement of isolated myocytes with Fluo-4, SKI prolonged the time to 50% of cytosolic Ca 2+ extrusion (T50) and lower the peak Ca 2+ transient amplitude (F/F0) than WT under Nx. Prolonged T50 and lowered peak F/F0 were observed in WT-Hx, both of which additionally progressed in SKI-Hx. Conclusions: Hypoxia impaired SR Ca 2+ homeostasis in RV. SKI additionally impaired SR Ca 2+ homeostasis with the progression of RV hypertrophy. The loss of the thiol on C674 SERCA2 contributed to the pathogenesis of RV failure in PAH.
CSIG-01. EPIGENETIC REPROGRAMMING DRIVES MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MPNST) DE-DIFFERENTIATION AND TREATMENT RESISTANCE
Authors: Harish Vasudevan, Sydney Lastella, Matthew Sale, Timothy Casey-Clyde, Benjamin Demaree, Cyrille Delley, Calixto Lucas, Stephen Magill, John Liu, William Chen, Steve Braunstein, Alyssa Reddy, Arie Perry, Line Jacques, Melike Pekmezci, Adam Abate, Frank McCormick, David Raleigh
Journal: Neuro-Oncology (2021)

Abstract Schwann cell derived tumors comprising schwannomas, neurofibromas, and malignant peripheral nerve sheath tumors are the most common malignancies of the peripheral nervous system. While schwannomas and neurofibromas are benign, MPNSTs are malignant, metastasize, and respond poorly to treatment. Neurofibromas and MPNSTs are associated with loss of NF1, a tumor suppressor that inhibits Ras/MEK signaling, and MPNSTs alone are distinguished by loss of the Polycomb Repressive Complex 2 (PRC2), an epigenetic regulator of methylation. To understand the genomic mechanisms of Schwann cell tumorigenesis and treatment resistance, we performed DNA methylation profiling, RNA-sequencing, and whole exome sequencing of primary Schwann cell tumor resection specimens (n=119 total: n=66 schwannoma, n=13 neurofibroma, n=40 MPNSTs). Hierarchical clustering identified three epigenetic Schwann cell tumor groups with transcriptional differences in PRC2 target genes associated with Schwann cell differentiation. Integrating biochemical and genomic approaches in primary human tumor cell lines from NF1 intact peripheral nerve, NF1 mutant neurofibromas, and MPNSTs, we found MPNST and neurofibroma cell lines with CRISPR knockout SUZ12 or EZH1/2 neurofibroma cell lines demonstrated repression of Schwann cell differentiation genes and induction of Ras signaling target genes. Further, MPNST cells deficient in PRC2 and NF1 exhibited increased basal active Ras-GTP levels, and therapeutically, PRC2 deficient MPNST cell lines were more resistant to the MEK inhibitor selumetinib and radiotherapy when compared to NF1-deficient neurofibroma cells. Single cell RNA sequencing analysis suggested distinct mechanisms of selumetinib resistance in PRC2 intact neurofibroma cells compared to PRC2-deficient MPNST cells. Taken together, our data demonstrate the importance of epigenetic dysregulation in malignant Schwann cell transformation and suggest differentiation status underlies a novel mechanism of MEK inhibitor resistance.
Abstract 12050: Dapagliflozin Therapy is Associated With Improved Left and Right Ventricular Function in Chronic Heart Failure Patients With Reduced Ejection Fraction
Authors: Gregor Poglajen, Neža orž, Sabina Frljak, Andraž Cerar, Renata Okrajek, Miran ebetjen, Gregor Zemljic, Bojan Vrtovec
Journal: Circulation (2021)

Introduction: Although sodium-glucose transporter 2 inhibitors (SGLT2i) were shown to improve clinical outcomes of patients with heart failure with reduced ejection fraction (HFrEF), data on the effects of SGLT2i on myocardial function are scarce. Hypothesis: We evaluated the effects of dapagliflozin on left and right ventricular function in HFrEF patients. Methods: In a prospective sequential pilot clinical study we enrolled 14 HFrEF patients with NYHA II or III heart failure symptoms and LVEF&lt;40%. In Phase I, all patients were treated with optimized heart failure therapy including sacubitril/valsartan, beta blockers and spironolacton. After 3 months, dapagliflozin (10 mg qd) was added to the regimen and the patients were followed for another 3 months (Phase II). At baseline, 3- and 6- month follow-up we collected clinical, biochemical and echocardiographic data. Renal dysfuntion was defined as eGFR&lt;90 ml/min/1,73m 2 . Results: Of 14 patients, 10 (71%) were male; the average age was 57±16 years. Ishemic and non-ischemic heart failure was present in 3 (21%) and 11 (79%) of patients, respectively; 7 (50%) had renal dysfunction, 3 (21%) had diabetes and 6 (43%) had a history of hypertension. In Phase I we found no significant changes in LVEF (from 28±9% to 28±8%, P=0.91), left ventricular outflow tract VTI (LVOT VTI: from 12.8±3.6 cm to 13.3±5.3, P=0.80), or TAPSE (1.8±0.3 cm vs. 1.7±0.4 cm, P=0.62). Also, there were no significant changes in NYHA functional class (from 2.5±0.5 to 2.4±0.6, P=0.66), and NT-proBNP levels (from 1557±1745 pg/mL to 1677±1467 pg/mL, P=0.86). In contrast, in Phase II, we found a significant increase in LVEF (from 28±8% to 35±9%, P=0.02) and TAPSE (from 1.7±0.4 cm to 2.1±0.3 cm, P=0.04), and a trend of increase in LVOT VTI (from 13.3±5.3 cm to 16.7±3.4, P=0.07). In addition, after dapagliflozin therapy, we found a significant decrease in NYHA functional class (from 2.4±0.6 to 1.7±0.5, P=0.01) and NT-proBNP levels (from 1677±1467 pg/mL to 773±523, P=0.03). Conclusions: Dapagliflozin appears to improve echocardiographic parameters of left and right ventricular function in patients with HFrEF. Changes in heart function after dapagliflozin therapy occur in parallel with impovements in heart failure symptoms and levels of NTproBNP.
Abstract 10083: Deaths in Acute Myocardial Infarction; Us Location Trends
Authors: Abdul Minhas, Robert Ariss, Waqas Ullah, Hassaan Arshad, Muhammmad Khan, Marat Fudim, Khurram Nasir
Journal: Circulation (2021)

Introduction: The need for increased utilization of hospice in the dying patients has been recognized in multiple fields including cardiology recently. The aim of this study to examine the trends in location of deaths in acute myocardial infarction (AMI) related deaths in the United States from 2003 to 2019. Methods: The CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) was used to access the National Vital Statistics System data from 2003 to 2019. AMI related deaths in patients ≥ 25 years of age were identified from multiple causes of death. Joinpoint regression was used to examine changes in trend, annual percentage change (APC), and average annual percentage change (AAPC). Location of death was categorized as home, medical facility, hospice facility, nursing home/long term care (NH/LTC) and other/unknown. Results: Of AMI related deaths, 23.62% occurred at home, 0.94% at hospice facility, 39.64% at medical facility and 13.30% at NH/LTC. From 2003-2019, the number of deaths has increased at hospice facility (AAPC 24.7[95% CI, 18.1 to 31.6]) and decreased at both medical facilities (AAPC -3.1[95% CI, -3.5 to -2.8]) and NH/LTC (AAPC -4.3[95% CI, -4.6 to -3.9]). The number of deaths initially decreased at home till 2009 (APC -1.9[95% CI, -2.5 to -1.3]) followed by increase till 2019 (APC 1.5[95% CI, 1.2 to 1.8]). Conclusion: Although there was an increasing trend in AMI related mortality at hospice and home locations, rates of utilization of hospice facility remain very low.
DDRE-22. DISRUPTING REDOX BALANCE VIA THE TETRAHYDROBIOPTERIN PATHWAY IN GLIOBLASTOMA
Authors: Kaysaw Tuy, Sajina GC, Wei Chen, David Harrison, John Aleman, Anita Hjelmeland
Journal: Neuro-Oncology (2021)

Abstract Aberrant redox statuses are observed in glioblastoma (GBM), and we previously identified GTP cyclohydrolase I (GCH1) to be a redox regulator upregulated in brain tumor initiating cells (BTICs). GCH1 is a rate-limiting enzyme in the de novo synthesis of tetrahydrobiopterin (BH4), a cofactor that produces catecholamine precursors and nitric oxide (NO) and, once used, becomes 7,8-dihydrobiopterin (BH2). Regeneration of BH2 into BH4 by dihydrofolate reductase (DHFR) helps to maintain proper BH4/BH2 ratios for redox balance. Although the BH4 pathway has traditionally been studied in the vasculature system for its regulation of NO, our previous work and that of others suggests the GCH1/BH4 pathway plays a critical redox role including in neoplastic cells. In silico analysis of primary and recurrent gliomas indicate high expression of BH4 related enzymes that correlated with worse patient survival in both primary and recurrent gliomas. The observed elevation of the BH4 pathway not only emphasizes its importance, but a therapeutic opportunity for improving survival in glioma patients. By repurposing FDA approved drugs known to cross the blood brain barrier and previously suggested as anti-glioma therapies, combining inhibitors for the de novo synthesis (sulfasalazine) and regeneration (pyrimethamine) of BH4 could prove to be an effective strategy for targeting the GCH1/BH4 through redox disruption. Preliminary data BTICs isolated from patient derived xenografts (PDXs) indicated reduced viability when treated with sulfasalazine (SASP) and pyrimethamine (PYR). Furthermore, we observed lower/depleted levels of BH4 relative to BH2 when BTICs were treated with SASP and PYR. Lastly, there is an increase in mitochondrial ROS upon SASP and PYR treatment, suggesting dysregulated redox states. Importantly, temozolomide resistant GBM cells remained sensitive to SASP and PYR. Taken together, our preliminary data suggests the plausibility of targeting the GCH1/BH4 pathway with SASP and PYR to disrupt redox balance in glioma through the depletion of BH4.
Abstract 14109: Ischemic and Bleeding Outcomes of Potent P2y12 Inhibitor Antiplatelet Agents versus Clopidogrel in Elderly Patients With Acute Coronary Syndrome: A Meta-Analysis of Randomized Trials
Authors: Waiel Abusnina, Ahmad Al-abdouh, Anas Bizanti, Gauravpal S Gill, Abdelrazeg Abdelrazeg Houssien, Yazeid Alshebani, Arun K Kanmanthareddy, Khagendra B Dahal
Journal: Circulation (2021)

Introduction: Potent oral P2Y12 inhibitors (prasugrel or ticagrelor) are recommended in patients who present with acute coronary syndrome (ACS) compared to clopidogrel on the basis of landmark trials. However, there is no clear recommendation for such agents in elderly patients (&gt;65 years) with ACS. Methods: We queried the electronic databases of PubMed, Cochrane Central Register of Clinical Trials, EMBASE and ClinicalTrial.gov since inception through February 25, 2021 for randomized studies evaluating potent oral P2Y12 inhibitors vs. clopidogrel in elderly patients who present with ACS. Hazard ratios (HR) with 95% confidence interval (CI) were computed and p&lt;0.05 was considered statistically significant. Results: Eight randomized studies including a total of 10,081 patients were included in this analysis. At mean follow-up of 26 months, there was no significant difference between potent oral P2Y12 inhibitors and clopidogrel in terms of MACE [HR 0.97, 95% CI 0.82-1.15; P 0.73] (Figure), all-cause mortality [HR 0.91, 95% CI; 0.75-1.10: P 1.00], myocardial infarction [HR 0.95, 95% CI; 0.78-1.17: P 0.64], and stroke [HR 1.24, 95% CI; 0.82-1.86: P 0.31]. There was significant increase in major bleeding with potent oral P2Y12 inhibitors in elderly compared to clopidogrel [HR 1.32, 95% CI; 1.09-1.59: P 0.004](Figure) while the cardiovascular mortality was significantly decreased in the elderly treated with potent oral P2Y12 inhibitors compared to clopidogrel [HR 0.82, 95% CI; 0.68-0.98: P 0.03]. Conclusions: This meta-analysis suggests that using potent oral P2Y12 inhibitors in elderly patients with ACS is associated with a reduction in the risk of cardiovascular mortality with increased risk of bleeding compared to clopidogrel with no significant change in terms of MACE.
EPID-16. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN PEDIATRIC PATIENTS: A QUANTITATIVE EXPLORATION
Authors: Victor Lu, Long Di, David Daniels, Ossama Maher, Toba Niazi
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Diffuse leptomeningeal glioneuronal tumor (DLGNT), also known as oligodendrogliomatosis, is a rare neuro-oncologic condition along the neuraxis that remains poorly understood in children. We sought to describe our institutional experience and quantitively summarize the clinical survival and prognostic features of DLGNT in the pediatric population across the contemporary literature. METHODS We report four institutional cases of pediatric DLGNT diagnosed between 2000-2020 based on retrospective review of our records, and performed a comprehensive literature search for published cases from 2000 onwards to create an integrated cohort for analysis. Kaplan-Meier estimations, Fisher’s exact test, and logistic regression were utilized to interrogate the data. RESULTS Our overall integrated cohort consisted of 54 pediatric DLGNT patients, with 19 (35%) female and 35 (65%) male patients diagnosed at an average age of 6.4 years (range, 1.3-17 years) by means of surgical biopsy. Chemotherapy was used in 45 cases (83%), and mean follow-up time of 54 months (range, 3-204). Across the entire cohort, overall survival 1 month after diagnosis was 96% (95% CI 86-99%), and by 10 years was 69% (95% CI 49-82%). On multivariate analysis of complete data, chemotherapy treatment (HR=0.23, P=0.04) was statistically predictive of longer overall survival. When including limited data, longer duration of symptoms by presentation (HR=1.03, P=0.03) was statistically predictive of shorter overall survival. CONCLUSIONS This is the first quantitative study of pediatric DLGNT clinical course. More than 2-out-of-3 pediatric DLGNT patients survive beyond one decade. Chemotherapy is statistically associated with longer survival in DLGNT pediatric patients and should form the core of any treatment regimen in this setting. Early detection by means of judicious imaging and surgical biopsy for tissue diagnosis can lead to earlier treatment and likely superior outcomes.
The Promise and Peril of the Patient Portal
Authors: Kristen M. Coppola
Journal: JAMA Neurology (2021)

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Abstract 14096: Heart Rate Variability in Post-COVID-19 Recovered Subjects Using Machine Learning
Authors: Shekhar Kunal, Manu K Shetty, Bhushan Shah, MP Girish, ANKIT BANSAL, Vishal Batra, Saibal Mukhopadhyay, Jamal Yusuf, Anubha Gupta, Mohit Gupta
Journal: Circulation (2021)

Introduction: A significant proportion of patients recovering from COVID-19 infection experience symptoms attributable to autonomic cardiovascular dysregulation. Heart rate variability (HRV) is a non-invasive marker of cardiovascular dysautonomia. Machine learning (ML) models based on HRV can be used to identify post COVID-19 patients with autonomic dysfunction. Methods: We evaluated HRV and blood pressure (BP) responses to orthostatic stress (3-min active standing) in 92 patients within 30-45 days of recovery from COVID-19 infection and 120 healthy controls. HRV was evaluated based on 12-lead electrocardiogram over a 60 second period during supine paced breathing. Lead II was used to extract ECG features including (a) average RR interval, (b) R wave height, (c) Heart Rate (HR) standard deviation and (d) HRV root mean square [HRV-RMS]. We also assed for (1) orthostatic hypotension (OH; &gt;20/10 mmHg fall in BP) and (2) postural orthostatic tachycardia syndrome (POTS; HR increase &gt;30 bpm without OH). Using ML, eleven candidate features were tested with eight algorithms (logistic regression, RandomForests, CatBoost, XGBoost, Extra-tree classifier, Multiple Perceptron (ANN), Support Vector Machines and AdaBoost Classifier) to distinguish between COVID-19 recovered and healthy controls. Results: HRV was significantly lower in post COVID-19 recovered subjects as compared to healthy controls (6.25+4.9 ms vs 9.8+8.9 ms; P&lt;0.001). OH was reported in 12 patients (13.1%) while two patients (2.2%) had POTS. Patients with OH had a significantly lower HRV as compared to those without OH (3.29+3.16 ms vs 6.69+5.01 ms; P=0.025). Accuracy of various ML models varied between 67-80% with multiple perceptron being top model [80% weighted accuracy, AUC: 79.8%, Matthews’s correlation coefficient: 0.59]. Permutation importance feature ranking showed HRV, Average RR and HR to be top feature that distinguish between COVID-19 recovered and healthy controls. Conclusions: A significant proportion of COVID-19 recovered patients experienced autonomic dysfunction as evident by lower HRV and presence of OH and POTS. ML model can help in early identification of autonomic dysfunction thereby leading to proper management in these patients
Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C
Authors: Mikko T. Huuskonen, Yaoming Wang, Angeliki Maria Nikolakopoulou, Axel Montagne, Zhonghua Dai, Divna Lazic, Abhay P. Sagare, Zhen Zhao, Jose A. Fernandez, John H. Griffin, Berislav V. Zlokovic
Journal: The Journal of Experimental Medicine (2021)

Subcortical white matter (WM) stroke accounts for 25% of all strokes and is the second leading cause of dementia. Despite such clinical importance, we still do not have an effective treatment for ischemic WM stroke, and the mechanisms of WM postischemic neuroprotection remain elusive. 3K3A-activated protein C (APC) is a signaling-selective analogue of endogenous blood protease APC that is currently in development as a neuroprotectant for ischemic stroke patients. Here, we show that 3K3A-APC protects WM tracts and oligodendrocytes from ischemic injury in the corpus callosum in middle-aged mice by activating protease-activated receptor 1 (PAR1) and PAR3. We show that PAR1 and PAR3 were also required for 3K3A-APC’s suppression of post–WM stroke microglia and astrocyte responses and overall improvement in neuropathologic and functional outcomes. Our data provide new insights into the neuroprotective APC pathway in the WM and illustrate 3K3A-APC’s potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.
Abstract 11606: Mature Ipsc-Derived Atrial Cardiomyocytes Show That Saturated Fatty Acids Differentially Modulate Ion Channel and Structural Remodeling in Obesity-Induced Atrial Fibrillation
Authors: Arvind Sridhar, Olivia T Ly, Mahmud Arif Pavel, Hanna Chen, Francisco Gonzalez, Srikanth Perike, Liang HONG, Mark McCauley, Jalees Rehman, Dawood Darbar
Journal: Circulation (2021)

Background: Obesity-induced atrial fibrillation (AF) is modulated in part by increased serum free fatty acids (FFA) and FA infiltration of the heart. Mass spectrometry data on obese mice have shown increased saturated FAs (SFA), monounsaturated FAs (MUFA), and polyunsaturated FAs (PUFA) compared to lean controls with the largest increase in the PUFA, linoleic acid (LA). Although reports suggest that some FAs induce ventricular arrhythmias in mice, the differential electrophysiological (EP) effects of SFAs, MUFAs, and PUFAs on the atria remain unclear. Objective: To determine if SFAs, MUFAs, and PUFAs differentially modulate atrial remodeling using mature human induced pluripotent stem-derived atrial cardiomyocytes (iPSC-aCMs) and HL1 cells. . Methods: We compared iPSC-aCMs and HL-1 cells treated with bovine serum albumin (BSA) with palmitic acid (PA), oleic acid (OA) and LA (600 uM each) for 1 week. Ion channel function was assessed using whole-cell patch clamping and we assessed β-oxidation and atrial remodeling with using ELISA, qPCR, and Western blotting. Results: iPSC-aCMs treated with PA, OA, and LA displayed higher expression of FABP3 , ANGPTL4 , and CPT1A suggesting increased FA metabolism and β-oxidation (Figure A-C). In HL1 cells, protein expression of Cpt1a was increased in all groups after FA treatment (Figure D). PA differentially modulated expression of Kv7.1 and NCX1 in HL1 cells (Figure E-F) and ion channel mRNA expression in iPSC-aCMs (Figure G-L). After 1 week PA and LA treatment β-adrenergic signaling was significantly increased in iPSC-aCMs while OA decreased it compared to controls (Figure M-O). Conclusions: Using mature iPSC-aCMs, we showed for the first time that SFA, MUFA, and PUFA not only increased FA metabolism but also differentially modulated ion channel and structural remodeling and β-adrenergic signaling in the atria. Our findings may have important implications for the management of obesity-induced AF in patients.