tbuckley/cabot-search huggingface dataset:
Abstract 11169: The HVCN1 Voltage-Gated Proton Channel Contributes to Ph Regulation in Canine Ventricular Myocytes
Authors: Jianyong Ma, Xiaoqian Gao, Yutian Li, Thomas DeCoursey, Gary E. Shull, Hong-sheng Wang
Journal: Circulation (2021)

Regulation of intracellular pH (pH i ) in cardiomyocytes is crucial for cardiac function; however, currently known mechanisms for direct or indirect extrusion of acid from cardiomyocytes seem insufficient for energetically-efficient extrusion of the massive H + loads generated under in vivo conditions. In cardiomyocytes, voltage-sensitive H + channel activity mediated by the HVCN1 proton channel would be a highly efficient means of disposing of H + , while avoiding Na + -loading, as occurs during direct acid extrusion via Na + /H + exchange or indirect acid extrusion via Na + -HCO 3 - cotransport. PCR and immunoblotting demonstrated expression of HVCN1 mRNA and protein in canine heart. Patch clamp analysis of canine ventricular myocytes revealed a voltage-gated H + current that was highly H + -selective. The current was blocked by external Zn 2+ and the HVCN1 blocker 5-chloro-2-guanidinobenzimidazole (ClGBI). Both the gating and Zn 2+ blockade of the current were strongly influenced by the pH gradient across the membrane. All characteristics of the observed current were consistent with the known hallmarks of HVCN1-mediated H + current. Inhibition of HVCN1 and the NHE1 Na + /H + exchanger, singly and in combination, showed that either mechanism was largely sufficient to maintain pH i in beating cardiomyocytes, but that inhibition of both activities caused rapid acidification. These results show that HVCN1 is expressed in canine ventricular myocytes and provides a major H + -extrusion activity, with a capacity similar to that of NHE1. In the beating heart in vivo , this activity would allow Na + -independent extrusion of H + during each action potential and, when functionally coupled with anion transport mechanisms, could facilitate transport-mediated CO 2 disposal.
Abstract 11287: Trends in Pulmonary Embolism Mortality Rates by Age Group in the United States, 1999-2019
Authors: Ayla Cash, Abdul Minhas, SALIK NAZIR, Robert W Ariss, Rajesh Gupta
Journal: Circulation (2021)

Introduction: Acute pulmonary embolism (PE) is a major cause of mortality in the United States. Recent reports indicate that PE-related mortality rates have increased among individuals 25-64 and 65-79 years old and plateaued among individuals ≥80 years old. A narrowly focused and clinically meaningful age group analysis is necessary. Methods: Death certificate data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database were examined to determine all-cause PE mortality trends from 1999 to 2019 among adults 25-39, 40-54, 55-69, 70-84, and ≥85 years old. The crude death rates for individual years were calculated by dividing the number of PE-related deaths by the corresponding population. Annual percentage change (APC) was calculated to determine trends. Results: Among individuals 25-39 years old, the death rate increased from 1.76 to 2.01 (APC 0.7 [95% confidence interval (CI) 0.2 to 1.1]) between 1999 and 2014 and continued to increase from 2.01 to 2.42 (APC 4.1 [95% CI 1.8 to 6.5]) between 2014 and 2019. Among those 40-54 years old, the death rate increased from 5.7 to 7.46 (APC 2.0 [95% CI 1.6 to 2.5]) between 2007 and 2019. Among those 55-69 years old the death rate increased from 15.64 to 18.53 (APC 2.2 [95% CI 1.9 to 2.5]) between 2010 and 2019. Among those 70-84 years old the death rate decreased from 49.46 to 43.96 (APC -0.7 [95% CI -0.8 to -0.5]) between 1999 and 2019. While death rate among those older than 85 decreased from 112.31 to 100.53 (APC -1.3 [95% CI -1.9 to -0.7]) between 2007 and 2016, the death rate among this cohort increased non-significantly between 2016 and 2019. Conclusions: Despite significant improvements in PE risk stratification and clinical management, recent PE related mortality rates increased significantly among those younger than 69 years old. The APC in mortality was highest among those 25-39 years old. Among individuals older than 70 years old, recent death rates decreased or plateaued.
Development of a patient-reported outcome questionnaire to assess signs and symptoms of hidradenitis suppurativa: The Hidradenitis Suppurativa Symptom Diary
Authors: Afsaneh Alavi, Sarah Baradaran, Susan D. Mathias, Hilary H. Colwell, Michael Song, Iltefat H. Hamzavi, Chenglong Han
Journal: Journal of the American Academy of Dermatology (2021)
BIOM-40. TARGETED GENE EXPRESSION PROFILING PREDICTS MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES
Authors: William Chen, Abrar Choudhury, Harish Vasudevan, Calixto Lucas, Minh Nguyen, Jacob Young, Theresa Yu, Tai-Chung Lam, Jenny Pu, Lai-Fung Li, Gilberto Leung, Jason Chan, Nancy Ann Oberheim-Bush, Javier Villanueva-Meyer, Jessica Schulte, Steve Braunstein, Nicholas Butowski, Penny Sneed, Mitchel Berger, Arie Perry, David Solomon, Michael McDermott, Stephen Magill, David Raleigh
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Surgery is the mainstay of meningioma treatment, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. DNA methylation profiling, copy number variants (CNVs), exome sequencing, and RNA sequencing have improved understanding of meningioma biology, but have not superseded histologic grading, or revealed biomarkers for radiotherapy responses. To address these unmet needs, we optimized and validated a targeted gene expression biomarker predicting meningioma outcomes and responses to radiotherapy. METHODS Targeted gene expression profiling was performed on a discovery cohort of 173 meningiomas (median follow-up 8.1 years) and a validation cohort of 331 meningiomas (median follow-up 6.1 years) treated with surgery (n=504) and postoperative radiotherapy (n=73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). Optimized targeted gene expression models predicting clinical outcomes (34 genes) or radiotherapy responses (12 genes) were developed from the discovery cohort, and compared to histologic and molecular classification systems by performing DNA methylation profiling, CNV analysis, exome sequencing, and RNA sequencing on the same meningiomas. RESULTS Targeted gene expression profiling achieved a concordance-index of 0.75 ± 0.03 (SEM) for local freedom from recurrence (LFFR) and 0.72 ± 0.03 for overall survival (OS) in the validation cohort, outperforming WHO grade (5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p=0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p=0.01) for LFFR, disease-specific survival, and OS. The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and identified meningiomas benefiting from radiotherapy (interaction p-value=0.0008), suggesting postoperative radiotherapy could be refined in 30.2% of cases. CONCLUSIONS Targeted gene expression profiling of 504 meningiomas improves discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and predicts radiotherapy responses.
Adverse Events Following CAR T-Cell Therapy: A Single Institution Retrospective Analysis of Toxicities Following CAR T-Cell Therapy for Children and Young Adults with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia
Authors: Sara K. Silbert, Elizabeth M. Holland, Seth M. Steinberg, Lauren Little, Toni Foley, Haneen Shalabi, Bonnie Yates, Nirali N. Shah
Journal: Blood (2021)
Do PROs Tell the Whole Story? Differential Outcomes Based on Patient-Reported Outcomes (PROs) Versus Performance-Based Metrics (PBM) on Cognition for Patients Receiving Chimeric Antigen Receptor (CAR)-T Cell Therapy
Authors: Irena Tan, Rachel Cusatis, Emma Crawford, Aline Thiengmany, Claire Piehowski, Idayat Akinola, Juliana Craig, Sheila Lahijani, Matthew J. Frank, Nirav N. Shah, Anita D'Souza, David B. Miklos, Lori Muffly, Kathryn E Flynn, Surbhi Sidana
Journal: Blood (2021)
Abstract 12804: Knowledge of Cardiovascular Disease Risk in Young Women of Reproductive Age: A Cross-Sectional Survey-Based Study
Authors: Lauren Nelson, Abigail S Baldridge, Elizabeth Hibler, Natalie Bello, Kelly C Epps, Kenzie Cameron, Holly Gooding, Janet Catov, Janet Rich-edwards, Lynn Yee, Paloma Toledo, Jennifer Banayan, Sadiya Khan
Journal: Circulation (2021)

Introduction: Knowledge of cardiovascular disease (CVD) as the leading cause of death (LCOD) among women in the United States is declining. Young women who experience an adverse pregnancy outcome (APO) are at increased risk for CVD, but knowledge of CVD risk has not been well characterized in this population in the perinatal period. Our objective was to examine knowledge of CVD risk in postpartum women and to determine whether risk perception differs based on experience of APO. Methods: A cross-sectional study was conducted among postpartum individuals who had a live birth at a single high-volume quaternary care center between 1/1/20 and 7/1/20. Knowledge of CVD risk was assessed through a self-administered online survey adapted from the American Heart Association Survey of Women’s CVD Awareness. Survey data were collected between 3/1/21 and 4/18/21. We examined differences in knowledge of CVD risk factors based upon self-reported APO status. Results: Of the 5,612 eligible individuals contacted, 13% completed the survey. Among respondents, the majority identified as White (70%) with a mean age of 34 + 4.2 years, and 25% reported an APO. Similar proportions of women with (62%) and without (62%) an APO identified CVD as the LCOD in women. There was no significant difference in knowledge of traditional or pregnancy-specific CVD risk factors by APO status ( TABLE ). Women who experienced an APO were more likely to report intention to contact a healthcare professional regarding personal CVD risk compared with women who did not. Conclusions: Gaps remain in knowledge of CVD risk factors among young women, in whom primary prevention of CVD may be most beneficial over the lifespan. Heterogeneity in knowledge deficits related to APO subtypes as CVD risk factors present a unique opportunity for targeted education at a time when healthcare engagement is high. Given the modest response rate to this survey, awareness may be even lower in the general population.
NCOG-24. REAL-WORLD ANALYSIS OF OUTCOMES OF PATIENTS RECEIVING BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA IN BRITISH COLUMBIA
Authors: Manik Chahal, Brian Thiessen
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Bevacizumab (Bev) has been publicly funded in British Columbia (BC) since 2011 for treatment of recurrent glioblastoma (rGBM). We performed a retrospective outcomes assessment of patients with rGBM treated with Bev. METHODS Patients with rGBM treated at BC Cancer centers with Bev between January 2011 and December 2016 were reviewed. Patient demographics, tumor characteristics, treatment regimens, and dates of radiographic progression and death were collected. Kaplan-Meier method was used to assess survival, and comparisons were made using the log-rank test. RESULTS 138 patients were reviewed. There were 136 reported deaths with median PFS 3 months (CI95 = 2.5 - 3.5) and OS 7 months (CI95 = 6.1-8.0) from Bev initiation. 64% of patients on corticosteroids prior to Bev reduced their dose shortly after initiation. The majority of patients (72%) were treated with multiple lines of therapy prior to Bev, with a median time from chemoradiation to Bev initiation of 8 months (range 1-67). Patients started on Bev &amp;lt; 6 months from chemoradiation (prior to completion of adjuvant temozolomide) had improved OS compared to those who started Bev later (p = 0.05), but there was no association between extent of treatment prior to Bev and outcomes (p = 0.182). Addition of chemotherapy to Bev did not improve survival over Bev monotherapy (p = 0.175). CONCLUSIONS Despite limited benefits to overall survival, Bev is associated with reduction in corticosteroid use and likely improvement in quality of life. Bev combinations with chemotherapy did not confer survival advantage over Bev monotherapy. Furthermore, our results show that patients receiving Bev before completion of adjuvant chemotherapy have better outcomes, suggesting pseudoprogression may have prompted the therapeutic switch. Further research is required to optimize patient selection for and administration of Bev. Additional analysis of rGBM patients prescribed Bev until 2020 in BC is currently underway.
Abstract 11303: Reduced Level of ErbB Receptors in Non-Myocyte Left Ventricular Cells in Patients with Diabetes Mellitus Undergoing Coronary Artery Bypass Grafting Surgery Contributes to Vascular Dysfunction
Authors: Michael P Robich, Angela Kosta, Joshua Carver, Teaka Jackson, Bailey Shevenell, Joanne T deKay, Douglas Sawyer, Sergey V Ryzhov
Journal: Circulation (2021)

Introduction: ErbB signaling contributes to the regulation of vascular function through endothelial cell differentiation, proliferation, survival, and regulation of barrier integrity. Patients with diabetes (DM) are at an increased risk for endothelial dysfunction and worse outcomes after CABG. We investigated the level of ErbB expression on CD31 endothelial cells and CD105+ cells in DM and non-DM patients undergoing CABG. Methods: With IRB approval, left ventricular (LV) epicardial biopsies and blood samples from 25 patients (non-DM=9, DM=16), were obtained during surgery. Flow cytometry was used to determine the cell surface expression of ErbB receptors on cardiac endothelial and CD105+ cells isolated from the LV. Subpopulations of white blood cells were determined in blood samples. Plasma levels of IL-6, IL-8, and TNFα were measured. Results: Lower levels of ErbB1 and ErbB2 receptors expression on endothelial cells isolated from LV biopsies were found in patients with DM compared to non-DM control, and the expression of ErbB receptors negatively correlated with HgbA1c level. There were fewer CD105+ cells in DM patients (122 vs 153 cell/mg tissue, P=.021). Trends toward a negative association were found between the expression of ErbB2 in CD105+ cells and the number of neutrophils, as well as, HgbA1c level. No differences were found between DM and non-DM patients in the number of white blood cell subsets or plasma levels of IL-6, IL-8 and TNFα. Conclusions: We demonstrated that DM and high glucose blood levels are associated with reduced expression of ErbB1 and ErbB2 on endothelial cells and decreased number of CD105+ cells in the LV. Cardiac CD105+ are endothelial progenitor cells that differentiate in response to ErbB ligands. A decreased pool of CD105 endothelial progenitors in combination with down-regulation of ErbB1 and ErbB2 receptors in endothelial cells represent a novel mechanism for vascular dysfunction and adverse remodeling seen in diabetic patients.
Abstract 14377: The Role of Allometric Scaling in the Association Between Professional Playing Career and Aortic Root Diameter Among Retired NFL Players
Authors: Genevieve E Smith, Camilo Fernandez, Gregory W Stewart
Journal: Circulation (2021)

Introduction: While there is concern that participation in certain elite-level sports may increase risk for aortic dilation, clinical assessment of aortic root diameter (ARD) in professional athletes remains difficult owing to the lack of available normative data proportionate to anthropomorphic variables, which further complicates proper assessment of aortic disease during the post-professional life when risk factors may be greater. Thus, we examined the effect of allometric scaling on the association between ARD and professional football career length (NFLYrs) or playing position in retired National Football League (NFL) players. Methods: This cross-sectional study included 1,328 retired NFL players (mean age 53.1 ± 12.7 yrs; 54.6% Black) that participated in NFL Player Care Foundation health screenings. Two-dimensional echocardiogram was used to determine ARD at the sinus of Valsalva and indexed to body surface area (BSA) 0.6 (aortic root index; ARI). Multivariable-adjusted linear regression models were utilized to examine the association of playing position group and NFLYrs with ARD or ARI, after adjusting for traditional cardiometabolic risk factors. Results: The mean ARD and ARI of this study cohort were 33.0 ± 6.4 mm and 19.5 ± 3.8 mm, respectively. In regression models, NFLYrs was not associated with either ARD (B: -0.04, standard error [SE]: 0.04, p = 0.3496) or ARI (B: -0.03, SE: 0.03, p = 0.3177). Conversely, increasing ARD was associated with both Big (B: 1.12, SE: 0.53, p = 0.0340) and Big Skill (B:1.10, SE: 0.45, p = 0.0144) position groups, although this was attenuated to non-significance by allometric scaling of ARD (Big, B: -0.25, SE: 0.32, p = 0.4303; Big Skill, B: 0.22, SE: 0.26, p = 0.3978). Conclusions: NFLYrs was not associated with increasing ARD or AIH, suggesting that a longer professional football career did not potentiate larger aortic root size later in life. While football playing position was associated with increasing ARD, this association became non-significant upon indexing of ARD to BSA 0.6 , suggesting that allometric scaling may be necessary to appropriately assess aortic root diameter in these individuals. This underlines the need for further studies examining optimal allometric scaling methodologies in this population.
Abstract 12972: Acute Left Main Coronary Artery Thrombosis During Exercise Testing
Authors: Tudor Sturzoiu, Jamshid Shirani
Journal: Circulation (2021)

Background: Exercise stress testing (EST) is safe and effective in evaluating suspected coronary artery disease (CAD). Serious complications are rare. We present a unique case of acute left main coronary artery (LMCA) thrombosis during EST. Case presentation: A 58-year old man with hypertension and hyperlipidemia presented with two episodes of substernal chest pressure within 2 weeks. He had no known CAD, led an active lifestyle and did not smoke, drink, or use drugs. Initial vital signs, routine labs, troponin, ECG, and echocardiogram (TTE) were normal. EST (Bruce Protocol) was terminated at 3’ 54” due to chest pain, hypotension and down-sloping ST segment depressions in inferolateral leads followed by ST segment elevation in leads V1, V2, aVL and aVR. TTE showed severe hypokinesis of apex and anterior, anteroseptal, and anterolateral walls. Emergent coronary angiography (Figure) revealed complete thrombotic occlusion of LMCA. LMCA was wired and ballooned restoring antegrade flow and resolving ST segment elevation. Minutes later, recurrent ST elevations were noted due to LMCA reocclusion. Flow was restored and patient underwent emergent coronary artery bypass surgery. TTE two days later showed preserved LV systolic function with mild hypokinesis of the LV apex and apical septal wall. Conclusions: Pathophysiology of AMI triggered by exercise is only partially understood. Vigorous exercise is shown to increase relative risk of AMI particularly within first hour following exertion. In such a scenario, exercise likely acts as a trigger for plaque rupture in presence of an underlying vulnerable atherosclerotic lesion. Compared to other forms of AMI, those triggered by exercise occur more commonly in men and are more often characterized by total thrombotic occlusion of culprit coronary artery. To our knowledge, acute thrombosis of LMCA has not previously been reported as a complication of EST.
Can repurposing drugs play a role in malaria control?
Authors: Roland A. Cooper, Laura Kirkman
Journal: The Journal of Experimental Medicine (2021)

Innovative drug treatments for malaria, optimally with novel targets, are needed to combat the threat of parasite drug resistance. As drug development efforts continue, there may be a role for a host-targeting, repurposed cancer drug administered together with an artemisinin combination therapy that was shown to improve the speed of recovery from a malaria infection.
Degeneration and Regeneration of the Nervous System.
Journal: JAMA (1929)

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Abstract 12522: Semaphorin-3F Suppresses Vascular Permeability and Inflammation
Authors: Yao Gao, David Li, Dakshnapriya Balasubbramanian, Asma Almazyad, Hong Chen, David Briscoe, Rosalyn Adam, Diane Bielenberg
Journal: Circulation (2021)

The endothelium mediates microvascular fluid exchange between the blood and the interstitial tissue compartments. Vascular endothelial growth factor (VEGF-A) mediates vascular permeability via its tyrosine kinase receptor VEGFR2. However, the role of Neuropilin-2 (Nrp2), a co-receptor for both VEGF-A and Semaphorin-3F (SEMA3F), in vascular leakage is less understood. Nrp2 -deficient mice show enhanced and prolonged swelling in acute inflammation models. We hypothesize that endogenous Sema3F acts as a competitive ligand with VEGF-A for Nrp2 and that Sema3F/Nrp2 signaling reduces edema by inhibiting vascular permeability and promoting a quickened resolution of inflammation. To test our hypothesis we compared tissue thickness and vascular permeability in constitutive or tissue-specific, inducible Sema3F -deficient mice and control littermates under basal conditions or following cutaneous, acute delayed-type hypersensitivity reactions in the ear. Our results demonstrate that depletion of SEMA3F protein, either genetically using knockout mice or pharmacologically using systemic administration of SEMA3F neutralizing antibodies, significantly prolonged tissue swelling and increased vascular permeability compared to control mice during acute inflammation. Conversely, intravenous injection of SEMA3F adenovirus decreased ear swelling and edema during acute inflammation compared to control virus. Using proximity ligation assays, VEGFA/Nrp2 binding was found to be dramatically increased in Sema3F -knockout mice compared to wildtype mice. Taken together, our results demonstrate that the NRP2 signaling cascade mediates fluid homeostasis via its stimulatory (VEGFA) and inhibitory (SEMA3F) ligands during inflammatory reactions. SEMA3F acts as a competitive ligand with VEGFA binding to Nrp2 and promotes resolution by attenuating vascular permeability leading to reduced inflammation and edema. Our research suggests that the NRP2 axis may be a potential therapeutic target for inflammation-mediated diseases.