tbuckley/cabot-search huggingface dataset:
TAMI-28. IDENTIFICATION OF A NEUROLIGIN-3 BINDING PARTNER IN HIGH-GRADE GLIOMAS AND NORMAL PROGENITORS
Authors: Shawn Gillespie, Yoon Seok Kim, Anna Geraghty, Michael Quezada, James Reed, Pamelyn Woo, Michelle Monje
Journal: Neuro-Oncology (2021)

Abstract High-grade gliomas, including diffuse intrinsic pontine glioma, are lethal cancers whose progression is strongly regulated by neuronal activity. One way in which gliomas detect neuronal activity is via interaction with the ectodomain of post-synaptic adhesion protein neuroligin-3 (NLGN3), which is shed from neurons and oligodendrocyte precursors (OPCs) by the ADAM10 sheddase in an activity dependent manner. NLGN3 signaling drives glioma growth, but the cognate binding partner of shed NLGN3 (sNLGN3) on glioma cells is unknown. Here, we employed a proximity labeling technique to identify chondroitin sulfate proteoglycan 4 (CSPG4) as a putative binding partner of sNLGN3 in gliomas. We then confirmed complexing between recombinant proteins with size exclusion chromatography and are determining kinetics and affinity by surface plasmon resonance. When looking for evidence of binding in cells, we were surprised to find that sNLGN3 triggers regulated intramembrane proteolysis (RIP) of CSPG4, leaving no trace of the interaction at the membrane. sNLGN3 binding first induces ADAM10-mediated cleavage and release of the CSPG4 ectodomain, followed by gamma secretase-mediated release of the intracellular domain and downstream signaling in OPCs and gliomas. Pre-treatment of glioma cells or OPCs with an ADAM10 inhibitor entirely blocks sNLGN3-induced CSPG4 shedding. Acute depletion of CSPG4 via CRISPR gene editing renders glioma cells insensitive to the growth-promoting effects of sNLGN3 in vitro. Furthermore, we find that tamoxifen-induced deletion of NLGN3 from murine OPCs reduces the total number of OPCs, suggesting that this signaling axis promotes maintenance of OPC stemness in an autocrine fashion. Indeed, gamma secretase inhibition accelerates OPC differentiation in vitro, pointing towards a fundamental role for sNLGN3-CSPG4 signaling in OPCs and high-grade gliomas. Altogether, our results form a critical missing link in understanding how glioma cells detect a key neuronal activity-regulated signal, suggest intriguing links to OPC biology and identify a therapeutic target to disrupt neuron-glioma interactions.
Abstract 14272: Whole Exome Sequence Analysis of Pulmonary Hypertension in the UK Biobank
Authors: Katharine Clapham, Akhil Pampana, Seung H Choi, Michael Honigberg, Gina Peloso, Patrick T Ellinor, Pradeep Natarajan
Journal: Circulation (2021)

Introduction: Pulmonary hypertension (PH) is a progressive disease characterized by adverse remodeling of the lung vasculature and right ventricular failure. While BMPR2 mutations account for the majority of familial pulmonary arterial hypertension (PAH), the predisposing genetic factors in non-familial PH are not well understood. Whole exome sequencing (WES) data from individuals in the UK Biobank (UKB) provides a unique opportunity to interrogate the genetic factors underlying this rare disease. Hypothesis: Rare disruptive coding variants associated with sporadic PH will provide novel mechanistic insights. Methods: Exome sequences were aligned to the GRCh38 reference genome and variants annotated using Variant Effect Predictor. We identified rare (minor allele frequency &lt;1%) high confidence loss-of-function variants using LOFTEE and deleterious missense variants using MetaSVM. We then performed a rare variant burden association study using logistic regression in REGENIE adjusting for age, sex, array, smoking status, and principal components 1-10. These analyses were performed on unrelated individuals identified based on kinship (kinship &gt; 0.0884). We secondarily curated a list of 58 candidate PAH genes based on recent publications of rare variants identified in PAH, as well as the ClinVar database. PH was defined utilizing ICD codes 416.0 (ICD-9), I27.0, I27.2 (ICD-10). Results: 185,586 UKB participants were included; 665 with PH (age 62 years (+/-6), 46% female) and 184,921 controls (age 56 years (+/-8), 55% female). Rare variant association testing did not identify exome-significantly associated genes (p&lt;2.5x10 -7 ), nor nominal associations in candidate PAH genes. Four novel genes with p&lt;0.01 were identified, which included genes important in mitochondrial function ( ACADM ), nicotinic acetylcholine receptor signaling ( MYO18A ), pulmonary surfactant metabolism ( SFTPA1 ) and smooth muscle function ( BEST2 ). Conclusions: We identified putative genes associated with PH in the population which have not been previously implicated in familial PAH. If additional evidence supports the roles of these genes in PH, these findings may provide new therapeutic insights.
Abstract 13069: Baseline QRS Duration ≫ for >140 msec is Associated With Poor In-Hospital Prognosis of Patients With Acute Myocarditis
Authors: Ayano Yoshida, Takuma Takada, Kentaro Jujo, Eiji Shibahashi, Takanori Kawamoto, Motoko Kametani, Natsuko Satomi, Kazuho Kamishima, Takashi Saito, Erina Tomari, Atsushi Honda, Atsushi Takagi, Kyomi Ashihara, Nobuhisa Hagiwara
Journal: Circulation (2021)

Introduction: The clinical manifestation of acute myocarditis (AM) is highly variable, and the mechanisms of this diversity have not been fully elucidated. Hence, it is hard to precisely predict th...
Abstract 11746: Prior Heart Failure Hospitalization and Effects of a Nurse-Led Disease Management Program to Reduce Readmission in Heart Failure
Authors: Quan Huynh, Georgios Zisis, Thomas Marwick
Journal: Circulation (2021)

Background: Hospitalization due to heart failure (HF) is a strong predictor of adverse outcomes. This study sought to what extent previous HF admissions impacted on the success of a disease management program (DMP) to reduce readmission. Methods: We prospectively enrolled 1363 consecutive HF pts, who were followed for 3 months after discharge. Of these, 431 (31%) received a DMP (1-month duration, including post-discharge home visits, medication reconciliation, exercise guidance and early clinical review). Study outcomes were all-cause readmission or death at 30- and 90-day post-discharge. Previous HF admissions were collected from medical records. Results: Of the 1363 HF patients, death or readmission occurred in 386 (28%) at 30 days and 556 (41%) at 90-days post-discharge. Compared to 765 patients without any previous HF admission ever, the 143 patients with a previous HF admission &gt;12 months before the current admission had no higher risks of readmission or death at 30 days (relative risk) and 23% higher risks of readmission or death at 90 days. The 420 patients who had a previous HF admission ≤12 months from the current admission had higher risks of the composite outcome at both 30 and 90 days (Table). DMP was not associated with any reductions in risks of adverse outcomes at both 30 and 90 days among patients with a previous HF admission in ≤12 months, but was significantly associated with a reduction in risks at 30 and 90 days (Table) among those without any previous HF admission in ≤12 months. These findings were independent of HF severity, systolic and diastolic function, comorbidities, cognitive function and any demographic or socioeconomic factors. Conclusion: Higher levels of attention should be focused on HF patients with a recent prior HF admission who have higher risks of post-discharge adverse outcomes and appear to be non-responsive to a DMP to reduce readmission.
Abstract 11106: Unanticipated Interstage Readmissions in Infants with Hypoplastic Left Heart Syndrome: Association of Home Monitoring and Identification of Patient Risk Factors
Authors: Rachel J Shustak, Laura Mercer-rosa, Jennifer Faerber, Alyson Stagg, David A Hehir, Shobha S Natarajan, Tamar J Preminger, Anita Szwast, Jonathan J Rome, Therese M Giglia, Chitra Ravishankar, Monique M Gardner
Journal: Circulation (2021)

Introduction: Home monitoring in the interstage (IS) period has resulted in a significant decline in mortality in infants with hypoplastic left heart syndrome (HLHS). We hypothesize that this may in part be attributed to an increase in IS readmissions preventing out-of-hospital adverse events. We sought to examine the impact of our Infant Single Ventricle Monitoring Program (ISVMP) on the frequency and severity of unanticipated IS readmissions and to identify risk factors for readmission. Methods: This retrospective single-center cohort study compared infants with HLHS enrolled in ISVMP to historical controls. Readmission rate was defined as the number of unanticipated readmissions per interstage days. Severe readmission was defined by mortality, extracorporeal support, cardiopulmonary resuscitation, mechanical ventilation, or initiation of vasoactive medication. The relationship between ISVMP and number of interstage readmissions was modeled using inverse probability weighted (IPW) Poisson regression. The effect of ISVMP on the probability of severe readmission was modeled using IPW logistic regression. Multivariable Poisson regression models were used to identify risk factors for readmission. Results: We compared 198 ISVMP infants from 12/2010 to 12/2019 to 128 historical controls from 1/2007 to 11/2010. Readmissions were more frequent in the ISVMP group vs. controls (median 1.09 vs. 0.68 readmissions/100 days, p &lt; 0.0001) with more than double the rate of readmissions in ISVMP infants (adjusted IRR 2.13; 95% CI 1.61-2.82; p &lt; 0.0001). Despite a greater readmission rate, ISVMP infants were less likely to have severe readmissions (adjusted OR 0.25; 95% CI 0.11-0.60; p = 0.018). Independent risk factors for readmission were residing closer to our center, younger gestational age, postnatal diagnosis, genetic syndrome, and discharge with exclusive enteral tube feeds. Conclusions: In this single-center study, ISVMP infants had more frequent but less severe unanticipated readmissions. These findings suggest that the prevention of IS morbidity and mortality may have resulted in greater resource utilization. Future efforts should focus on strategies to decrease unanticipated readmissions without increasing adverse events.
EPID-01. THE EPIDEMIOLOGY OF BRAIN METASTASES IN ADOLESCENT AND YOUNG ADULT (AYA) PATIENTS DISTINCTLY DIFFERS FROM THE ADULT POPULATION
Authors: Nayan Lamba, Bryan Iorgulescu
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Few data exist regarding the epidemiology of brain metastases (BMs) in adolescent and young adult (AYA) patients. Herein we use national cancer registry data to dissect their epidemiology and compare to the adult population. METHODS AYA patients (15 ≤ age ≤ 39) who newly presented with a BM between 2010 and 2017 were identified in the National Cancer Database (comprising &amp;gt;70% of all newly-diagnosed cancers in the U.S.). The epidemiology of BMs was analyzed by primary cancer of origin, and compared between AYA and adult patients. Overall survival was analyzed with multivariable Cox regression. RESULTS 2,773 AYA patients presenting with BMs were identified (98% with histopathological diagnosis), compared to 156,103 adult patients (94% with histopathological diagnosis). Whereas 39.6% of newly-diagnosed brain tumors with histopathological confirmation were BMs in adults, BMs represented only 5.8% of such tumors in AYA patients. Additionally, the distributions of primary cancer types differed substantially between adults and AYA patients: notably, NSCLC dominated in adults (64.2%) vs representing only 31.6% of BMs in AYA patients. AYA patients were more likely to present with BMs from melanoma (13.0% of AYA BMs vs 3.7% in adult), soft tissue (4.5% vs 0.3%), testicular (in males 26.2% vs 0.1%), and breast (in females 29.5% vs 7.8%) primaries. Among breast BMs in females, AYA patients were less likely to have HR+/HER2- primaries (40.2% vs 47.8%) and more likely to have HER2+ (25.2% vs 20.1%) and triple positive (11.1% vs. 9.8%) primaries than adults. Overall survival was significantly longer for AYA patients with BMs (HR=0.61 compared to adult patients, 95%CI:0.58-0.64, p&amp;lt; 0.001) even after adjusting for primary cancer type, patient sex. CONCLUSIONS The epidemiology and cancer types of BMs in AYA patients differ substantially from adult patients. Future research aimed at understanding the unique differences in pathophysiology and outcomes of BMs in AYA patients is warranted.
Abstract 11121: Outcomes in Left Ventricular Thrombi Treated with Direct Oral Anticoagulants at a Safety Net Hospital
Authors: Anne Kerchberger, Rina Mauricio, Chris Mathew, Sandeep R Das
Journal: Circulation (2021)

Introduction: Direct oral anticoagulants (DoACs) are increasingly used off-label for the treatment of left ventricular (LV) thrombus due to ease of use. Current efficacy and safety data are mixed. DoACs offer advantages in low resource populations and have not been studied in this context. This study aimed to assess the efficacy of DOACs for the treatment of LV thrombus in a medically underserved population. Methods: A retrospective chart review was performed of patients treated with DoACs for LV thrombus from January 2017 to February 2020 in a medically underserved, multi-ethnic population receiving care at a large county hospital. Baseline demographic, clinical, and echocardiographic data were collected. Adverse events were obtained via chart review. AE were categorized into fatal bleeding, intracerebral hemorrhage and non-hemorrhagic stroke documented on CT or MRI, bleeding event requiring transfusion, myocardial infarction, and death. Results: Forty patients were identified. Average age was 52 ± 11 years, 19 (48%) were African American and 12 (30%) were women. At thrombus diagnosis, 19 (48%) initiated rivaroxaban. 21 started warfarin then transitioned to rivaroxaban (17, 43%) or apixaban (4, 10%). Average LV ejection fraction at diagnosis was 23 ± 13 % and average treatment length was 16 ± 10 months. Twenty-two (76%) of 29 follow up echoes showed thrombus resolution. Four patients were lost to follow up. Adverse events included 2 non-hemorrhagic strokes and 3 deaths. Conclusion: This is the largest single center retrospective study of LV thrombi at a publicly funded, county hospital caring for a diverse, medically underserved patient population. For this patient population treated with DoACs, successful resolution of LV thrombi occurred in most patients with few adverse events. These results underscore the need for randomized trials to understand the efficacy and safety of DOACs for the treatment of LV thrombus, particularly in underserved communities.
Clinical and Subclinical Cardiotoxicity after Hematopoietic Stem Cell Transplantation
Authors: Ana Carolina Oliver, Federico Superchi, Roberto Superchi, Matilde Canabal, Jubin Silvana, Carolina Errecarte, Ricardo Fabian Mosquera, Caneiro Ada, Silvia Pierri, Eloisa Riva, Sebastian Galeano, Bello Laura, Regis Gai, Miller Andrew, Pablo J. Muxi
Journal: Blood (2021)
Optimizing First-Line Therapy for Advanced-Stage Classic Hodgkin Lymphoma
Authors: Ranjana H. Advani
Journal: Journal of the National Comprehensive Cancer Network (2021)

Goals of first-line therapy in classic Hodgkin lymphoma (cHL) should focus on balancing risk versus benefit to the individual while increasing efficacy and decreasing toxicity. Overall, the ABVD regimen is well tolerated but slightly less effective, with a better safety profile compared with escalated BEACOPP. BV-AVD is somewhere in between ABVD and escalated BEACOPP on the cure/morbidity scale. Interim PET is predictive, but new prognostic biomarkers are emerging that may better identify patients at high risk for treatment failure. In patients with interim PET-negative cHL, de-escalating therapy does not impact overall survival along 1) with no proven role for radiotherapy. cHL is largely a disease of young people, and the choice of treatment should always take into account the potential for both short- and long-term toxicity with the goal of optimizing survivorship.
Abstract 13123: Global Knockout of LDLRAP1 Regulates Atherosclerosis, Adipose Metabolism, and Insulin Resistance
Authors: Tani Leigh, Tatsuo Kawai, Sheri E Kelemen, Rachael Okune, Cali Corbett, Amanda St Paul, Jun Yu, Rosario G Scalia, Michael Autieri
Journal: Circulation (2021)

Introduction: Atherosclerotic vascular syndromes account for 50% of all deaths in the United States, and are a considerable medical and socioeconomic problem contributing to mortality of several conditions, including myocardial infarction and stroke. It is accepted that atherosclerosis and symptoms of metabolic syndrome, such as obesity, insulin resistance, and hypercholesterolemia often coincide with and exacerbate one another, however the molecular events in common with these conditions are not yet fully understood. One event that may link these two disorders is lipid receptor trafficking and signaling of the LDL receptor (LDLR), which plays a key role in LDL uptake and regulation of plasma LDL concentration. Low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) is a cytosolic adaptor protein which interacts with the cytoplasmic tail of the LDLR, mediating internalization of the LDL-LDLR complex and connecting it to the cell’s endocytic machinery. The purpose of this study was to characterize the effects of LDLRAP1 global knockout on atherogenesis and metabolic function in order to gain a better understanding of the molecular mechanisms that interconnect atherosclerosis and metabolic syndrome. Results: LDLRAP1 global knockout mice fed a high-fat western diet (HFD) for 16 weeks displayed increased atherosclerotic plaque burden (p&lt;0.0001), serum cholesterol (p&lt;0.0001) and triglyceride levels (p&lt;0.01), and expression of lipid receptors SR-A1 and CD36 (p&lt;0.05), and gained significantly more weight compared to controls (p&lt;0.0001). LDLRAP1 -/- adipose also displayed decreased glucose uptake (p&lt;0.01) and pAKT and AKT protein levels (p&lt;0.05). Both before and after a HFD, LDLRAP1 -/- mice were also significantly insulin resistant (p&lt;0.01) with concomitant dysregulated insulin signaling in adipose tissue, and displayed metabolic differences as quantified by metabolic cage analysis (p&lt;0.05). Conclusions: These data suggest that in addition to a function in cholesterol internalization, LDLRAP1 participates in regulating adipose metabolism and insulin sensitivity. This implicates LDLRAP1 as a key molecule and potential therapeutic target in treatment of diseases which constitute metabolic syndrome.
Implementation of a High-Dose Cytarabine Outpatient Program for Acute Myeloid Leukemia Patients in a Limited-Source Setting
Authors: Juan C Haro, Evelyn Espinoza-Morales, Johan Espino, Fátima Jiménez-Mozo, Nathaly Poma, Jhoisy Casas, Melanie Castro-Mollo, Gustavo Sandival, Emperatriz Ortega, Katia Roque, Lourdes Lopez, Cindy Alcarraz, Sophia Lozano, Elizabeth Cervantes, Shirley Quintana, Tatiana Vidaurre, Daniel J Enriquez
Journal: Blood (2021)
Abstract 13528: Interventional Hepatic ApoC-III Knockdown Improves Atherosclerotic Plaque Stability and Remodeling via Lowering Remnant Lipoproteins
Authors: Philip Gordts, Bastian Ramms, Ariane Pessentheiner, Xiaoli Sun, Gloria M Ducasa, Sam Tsimikas, Joseph L Witztum
Journal: Circulation (2021)

Introduction: Apolipoprotein C-III (apoC-III) is a key regulator in triglyceride (TG) metabolism and correlates positively with hypertriglyceridemia and incidences of CVD. Recent studies also identified apoC-III as an inducer of sterile inflammation by activating the inflammasome, another CVD risk factor. It remains unclear if therapeutic apoC-III lowering can reduce CVD risk, nor is it clear if this is dependent on lipid-lowering or anti-inflammatory properties or both. Hypothesis: We set out to test the concept that interventional apoC-III lowering reduces atherosclerosis development only when TG-lowering is achieved. Methods: We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotides (ASOs) in hypertriglyceridemic mouse models where the intervention results in TG-lowering ( Apoe -/- Ndst1 f/f Alb-Cre + , Ldlr -/- Ndst1 f/f Alb-Cre + ) or not ( Ldlr -/- Lrp1 f/f Alb-Cre + ). Results: ApoC-III ASO treatment did not alter atherosclerotic lesion volume in the murine models mice simultaneously fed a Western diet. However, when TG-lowering was obtained, apoC-III ASO treatment significantly attenuated advanced and unstable plaque development. In contrast, no improvement in lesion composition and hyperlipidemia was observed in apoC-III ASO-treated Ldlr -/- Lrp1 f/f Alb-Cre + mice lacking hepatic receptors responsible for apoC-III inhibition of TRL clearance. To mimic an interventional setting, we tested the impact of therapeutic apoC-III lowering in combination with a switch to a lipid-poor chow diet intervention after 12-week Western diet feeding. We observed that apoC-III ASO treatment significantly reduced atherosclerotic lesion size progression when an additive TG-lowering was achieved. No differences in lesion development were observed in similarly treated Ldlr -/- Lrp1 f/f Alb-Cre + mice wherein no additive TG-lowering was achieved by apoC-III ASO intervention. Conclusions: Our data highlight that the impact of apoC-III on atherogenesis depends on its lipid-modifying properties and suggest that interventional apoC-III lowering in hypertriglyceridemia patients can prevent plaque rupture and reduce CVD-associated mortality.
Abstract 13909: Multi-Marker Risk Assessment in Patients Hospitalized With Coronavirus Disease-2019: Results From the American Heart Association COVID-19 Cardiovascular Disease Registry
Authors: Ankeet Bhatt, Erin Bohula, Lori Daniels, James A De Lemos, Erica Goodrich, David A Morrow
Journal: Circulation (2021)

Introduction: The pathobiology of inflammation, thrombosis, and myocardial injury associated with SARS-CoV2 may be assessed by circulating biomarkers. However, their relative prognostic importance ...
Abstract 12168: Long-Term Effects of Pulmonary Endarterectomy on Pulmonary Hemodynamics and RV Function in Chronic Thromboembolic Pulmonary Hypertension
Authors: Azar Kianzad, Natalia J Braams, Jessie Van Wezenbeek, Frank P Oosterveer, Petr Symersky, Esther J Nossent, Anco Boonstra, Anton Vonk Noordegraaf, Frances S De Man, Lilian J Meijboom, Harm Bogaard
Journal: Circulation (2021)

Background: Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to improvement in right ventricular (RV) function in the majority of chronic thromboembolic pulmonary hypertension (CTEPH) patients. However, little is known about the long-term effects of PEA on RV function. We aimed to describe long-term changes in RV function in PEA treated CTEPH-patients. Methods: In this prospective study we included patients diagnosed with CTEPH who underwent PEA. Structured follow-up measurements were performed using right heart catheterization (RHC) and cardiac magnetic resonance (CMR) imaging before PEA and 6 and 18 months after treatment. Single beat pressure-volume loop analysis was used to determine load-independent RV contractility (Ees) and RV afterload (Ea). RV volume, mass and function were derived from CMR. Results: The study protocol was completed in 25 CTEPH-patients. PEA led to a significant decline in mean pulmonary arterial pressure (mPAP 45±11 to 24±9 mmHg; p&lt;0.0001), pulmonary vascular resistance (PVR 561 [427-711] to 132 [112-194] dynes/s/cm 5 ; p&lt;0.0001) and RV afterload (Ea 0.6 [0.49-0.81] to 0.2 [0.2-0.3] mmHg/ml; p&lt;0.0001) 6 months after treatment. In addition, RV dimensions improved 6 months after PEA as demonstrated by a decrease in indexed RV end-diastolic volume (RVEDVi 91±28 to 71±13 ml/m 2 ; p=0.0009), indexed RV mass (43±15 to 27±11 g/m 2 ; p &lt;0.0001) and increase in RV ejection fraction (RVEF 41±14 to 52±9%; p=0.0003) and Ees (0.7 [0.5-1.1] to 0.3 [0.2-0.4] mmHg/ml; p&lt;0.0001). No further changes were seen in pulmonary hemodynamics and RV dimensions between 6 and 18 months after PEA. Conclusion: Restoration in pulmonary hemodynamics and RV dimensions occurs within 6 months after PEA. No further improvements are observed between 6 and 18 months after PEA.