tbuckley/cabot-search huggingface dataset:
TAMI-56. TARGETING AMINO ACID METABOLIC VULNERABILITIES IN IDH-MUTANT AND IDH-WILDTYPE GLIOMAS
Authors: Shigeo Ohba, Akiyoshi Hirayama, Keisuke Hitachi, Hisateru Yamaguchi, Joydeep Mukherjee, Russell Pieper, Yuichi Hirose
Journal: Neuro-Oncology (2021)

Abstract IDH-wildtype glioma and IDH-mutant glioma have different genetical and metabolic background although their histological appearances are similar. The aim of the study is to reveal the difference in metabolites between IDH-wildtype glioma and IDH-mutant glioma, and to find the effective treatment targeting cancer metabolism according to the status of IDH in gliomas. Two artificial cell lines made from normal human astrocyte were used: NHAE6E7hTERTRas (IDH-wildtype) and NHAE6E7hTERTIDHmut (IDH-mutant). Capillary electrophoresis time-of-flight-mass spectrometry (CE-TOFMS) revealed that the amount of asparagine was lower in NHAE6E7hTERTRas cells compared with NHAE6E7hTERTIDHmut cells. L-asparaginase, which converts asparagine into aspartate, was more effective in the former cells than the latter cells. L-asparaginase induced autophagy and inhibition of autophagy by 3-MA suppressed L-asparaginase-induced antitumor effect. Adding asparagine into the culture medium rescued the antitumor effect of L-asparaginase. L-asparaginase increased the expression of asparagine synthetase (ASNS) and genetical or pharmacological inhibition of ASNS enhanced the antitumor effect of L-asparaginase. CE-TOFMS showed the lower amount of glutamine, glutamate and 2-oxoglutarate in NHAE6E7hTERTIDHmut cells than NHAE6E7hTERTRas cells. GLUD1 inhibitor inhibited proliferation by inducing higher ROS level and apoptosis in NHAE6E7hTERTIDHmut cells than NHAE6E7hTERTRas cells. ROS inhibitor, NAC suppressed GLUD1 inhibitor-induced ROS, apoptosis, and cytotoxicity in NHAE6E7hTERTIDHmut cells. Exogeneous dimethyl 2-oxoglutarate rescued the cytotoxicity induced by GLUD1 inhibitor. L-asparaginase and GLUD1 inhibitor will be new therapeutic option for IDH-wildtype glioma and IDH-mutant glioma, respectively.
Abstract 9882: Cannabis Use Poses Alarming Risk of Atrial Tachyarrhythmia and Stroke in Young Patients with Obesity Associated Obstructive Sleep Apnea: A Propensity-Score Matched Analysis
Authors: Rupak Desai, Zainab J Gandhi, Terry R Went, Dwayne Wiltshire, Theresa Allagoa, Vibhor Garg, Arashpreet Chhina, Abhishek Deshmukh, Gautam Kumar, Rajesh Sachdeva
Journal: Circulation (2021)

Introduction: Obesity is a known risk factor and causes worse cardiovascular outcomes in obstructive sleep apnea. With the growing use of cannabis in the US, so we aimed to assess the impact of cannabis use disorder (CUD) on risk of atrial tachyarrhythmias (atrial fibrillation, AF; atrial fibrillation, AFL) and stroke in young patients with obesity-associated obstructive sleep apnea (OOSA). Methods: The National Inpatient Sample (2015Oct-2017) with relevant ICD-10 codes were used to identify admissions among young adults (18-44 years) with OOSA. We then matched (1:1) two cohorts of cannabis use disorder (CUD+) vs. without (CUD-) with controlling potential sociodemographic confounders. Primary outcomes of interest were frequency and risk of atrial tachyarrhythmias and stroke assessed by multivariable analysis. Results: Of 7470 demographically-matched OOSA admissions, CUD+ and CUD- cohorts had 3735 hospitalizations in each cohort. Both cohorts were comparable mean age of 38 years and CUD+ cohort more frequently included male (66.6% vs. 53.5%), African American (40.0% vs. 30.1%) patients admitted non-electively (92.3% vs. 84.5%). Rates of drug abuse, hypertension, smoking and chronic pulmonary disease were higher but diabetes mellitus, hyperlipidemia, and renal failure were lower in CUD+ cohort vs. CUD- cohort (p&lt;0.001). The frequency of AF/AFL (5.7% vs 7.4%) related admissions were lower; however, the risk of AF/AFL (OR:1.64, 95%CI:1.17-2.30, p=0.004) and stroke (OR:4.41, 95%CI:1.41-13.77, p&lt;0.011) admissions were significantly higher in the OOSA-CUD+ cohort vs. CUD- cohort in the multivariable analysis controlled for relevant cardiovascular/extracardiac comorbidities and concomitant alcohol/drug abuse and smoking. Conclusions: This propensity-matched analysis highlights that recreational cannabis use in young patients with OOSA may alarmingly increase emergency hospitalizations and independently increase the risk of AF/AFL and stroke.
Abstract 14230: Effects of Oral Carbon Monoxide on Doxorubicin-Induced Cardiotoxicity
Authors: Rodrigo W Alves De Souza, David Gallo, Howard Levy, Edward Gomperts, Mark Young, Andrew Gomperts, Leo E Otterbein
Journal: Circulation (2021)

Introduction: Doxorubicin (DOX) and other anthracyclines comprise important anticancer drugs. However, anthracycline treatment-related cardiotoxicity is a major clinical problem for which there are currently no effective treatments. Low-dose carbon monoxide (CO) presents an exciting and promising approach to preventing anthracycline cardiotoxicity. Endogenous CO is generated in the body by heme oxygenase enzymes during the degradation of heme. There is a literature precedent that supports low-dose CO in providing cardioprotection without reducing DOX efficacy. Hypothesis: the present study aimed to test an oral formulation of CO (HBI-002) to attenuate DOX-induced cardiotoxicity. Methods: Male C57BL/6, 10 to 12-week-old mice were subjected to acute (single dose, 20mg/kg, i.p.), and chronic (ten doses, 2mg/kg, i.p., every other day) DOX regimens in combination with HBI-002 (10ml/kg) or vehicle (10ml/kg). Animals were sacrificed after one hour of single DOX injection to evaluate serum tissue damage markers, such as creatine kinase (CK), lactate dehydrogenase (LDH), and heme. Moreover, cardiac function was evaluated after seven days of single DOX injection and after a chronic DOX regimen by echocardiography. Results: Here, we show that after DOX injection, HBI-002 can prevent a rapid and early release of excess serum CK (Vehicle: 2547 ± 260 U/L vs. HBI-002: 1122 ± 168 U/L; p&lt;0.05 ), LDH (Vehicle: 1390 ± 103 U/L vs. HBI-002: 1122 ± 168 U/L; p&lt;0.05 ), and heme (Vehicle: 47.5 ± 6.7 uM vs. HBI-002: 5.3 ± 2.7 uM; p&lt;0.05 ) levels. Moreover, we observed that HBI-002 prevented a decrease in the ejection fraction after seven days of a single dose of DOX (Vehicle: 54.3 ± 1.3% vs. HBI-002: 64.7 ± 7.5%; p&lt;0.05 ), as well as after DOX chronic regimen (Vehicle: 44.5 ± 3.6% vs. HBI-002: 61.6 ± 5.4%; p&lt;0.05 ). Finally, HBI-002 attenuated DOX-induced mortality compared to the vehicle-treated group. Conclusions: Collectively, these findings support HBI-002 as a promising cardioprotective agent against DOX toxicity and warrant further development as a therapeutic.
Abstract 10196: A History of Dengue Infection is Associated with Lower Global Longitudinal Strain by Speckle Tracking Echocardiography in Men from the Amazon Basin
Authors: Molly D Kaagaard, Alma Wegener, Laura C Gomes, Anna Engell Holm, Karine O Lima, Luan O Matos, Isabelle Vieira, Rodrigo Souza, C Marinho, T B-S, o ms, Philip Brainin
Journal: Circulation (2021)

Background: Studies have shown that infection with dengue virus may affect the heart in the acute phase, and that men possibly have a higher risk of severe dengue complications. No studies have investigated if dengue infection also may affect long-term cardiovascular function. Hypothesis: We hypothesized that adults from the general population with a self-reported history of dengue infection had lower myocardial strain compared to controls. Furthermore, that strain could be even lower in men with a history of dengue. Methods: We enrolled individuals from the general population in the Amazon Basin. History of self-reported dengue infection and cardiovascular risk factors were collected by questionnaires. All persons underwent physical examination and bedside echocardiography. We analyzed global longitudinal strain (GLS) and circumferential strain (GCS). Results: We included 529 individuals (mean age 39±15 years, 39% men) of which 49% (n=259) had a history of dengue infection. A history of dengue infection was not associated with lower GLS (Figure A). However, when stratifying the population by sex, dengue infection in men was significantly associated with lower GLS (OR 1.13 per 1% decrease [95%CI 1.02 to 1.24], P=0.014) and GCS (OR 1.06 per 1% decrease [95%CI 1.01 to 1.12], P=0.030), whereas no relationship was found for women (Figure A). In multivariable models adjusted for age, blood pressure, heart rate, creatinine, smoking habits, diabetes and income, the association with GLS (OR 1.13 [95%CI 1.02 to 1.25], P=0.016) and GCS (OR 1.07 [95%CI 1.01 to 1.14], P=0.015) remained significant in men (Figure B and C). We found no significant relationship with left ventricular ejection fraction. Conclusion: Dengue may potentially have long term effects on left ventricular systolic function as measured by strain in men. This calls for further studies to assess long-term cardiac sequelae and subclinical myocardial impairment in individuals with a history of dengue.
Abstract 12077: Reduced Potency of Blood Pressure Lowering Drugs in the Presence of Diabetes Mellitus - Results from the Triumph Randomized Controlled Trial
Authors: Sonali Gnanenthiran, Ruth Webster, Abdul Salam, Asita de Silva, Alta Schutte, Anushka Patel, Anthony Rodgers
Journal: Circulation (2021)

Introduction: Whether the presence of diabetes mellitus (DM) affects the ability of antihypertensive therapies to lower blood pressure (BP) is uncertain. We investigated whether DM affects the efficacy of a low dose triple combination pill or usual care among people with hypertension. Methods: TRIUMPH (TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension) was a randomized controlled open-label trial of patients requiring initiation or escalation of antihypertensive therapy. Patients from urban hospital clinics in Sri Lanka were randomised to a once-daily low-dose triple combination polypill (telmisartan 20mg, amlodipine 2.5mg, chlorthalidone 12.5mg) or standard care. This analysis compared BP reduction and percentage of time below 140/90mmHg (time at target) in the intervention and usual care groups over 24 week follow-up, stratified by the presence of DM. Predicted potency of therapy was calculated according to estimation methods of Law et al. Results: The trial comprised 700 patients (56±11yrs, 58% women, 31% DM). Patients on the triple pill achieved greater BP reduction compared to standard care at week 24 in both diabetic and non-diabetic groups (Table 1, p&gt;0.05 for heterogeneity). DM was a negative predictor of time at target BP (OR 0.18, 95%CI 0.10-0.31, p&lt;0.001). Observed BP reduction from baseline to week 24 was lower in diabetics compared to non-diabetics on the triple pill (25/11 vs 31/15 mmHg, p≤0.01) and on usual care (17/7 vs 22/11, p≤0.01). Diabetics also achieved lower time at target BP than non-diabetics in the triple pill group (44% vs 73%, p&lt;0.001) and in usual care (27% vs 51%, p&lt;0.001). This was despite no difference between diabetics and non-diabetics in number of drugs prescribed or predicted potency of therapy. Conclusion: While both drug regimens were associated with reduced potency in the presence of DM, the triple pill achieved greater BP reduction compared to usual care in mild-moderate hypertension.
Abstract 13326: Racial Differences in Non-Elective Implantable Cardioverter-Defibrillator Placement in Older (≥ 66) Medicare Patients With Heart Failure
Authors: Nathaniel Kuhrt, Ehimare Akhabue, Uri Shalmon, Benjamin Bates, Melanie Rua, Aayush Visaria, Eileen Lee, Chintan Dave, Poonam Gandhi, Soko Setoguchi
Journal: Circulation (2021)

Introduction: Racial and ethnic disparities in ICD use for primary prevention among HF patients have dissipated in recent years. While HF patients who received ICDs non-electively during unplanned or shortly after acute hospitalization were shown to have worse outcomes, racial and ethnic disparities in such non-elective ICD placement have not been described. Methods: We identified older (age≥66) HF patients with ICD placements in 20% random sample Medicare data (2008-2018) and defined ICD placement as: 1) non-elective - during unplanned or after recent (&lt;3 month) hospitalization or 2) elective - during planned hospitalization or as ambulatory procedure. We described the temporal trends in elective vs non-elective ICD placement over time and by racial and ethnic subgroups. Adjusted rate ratios (RRs) for non-elective ICD placement were estimated using multivariable modified Poisson regression. Results: Among 97,925 ICD patients (mean age 76, 67% male, 85% White), Black and Hispanic patients had more comorbidities and were more often dual eligible for Medicaid ( Table ). The rate of non-elective placement for all patients has decreased over time (56% in 2008 to 34% in 2018). Black and Hispanic patients had a higher rate of non-elective placement compared to White patients ( Figure ) which persisted after multivariable adjustment [RR = 1.10 (95% CI: 1.07 - 1.13) for Black and RR = 1.09 (95% CI: 1.04 - 1.14) for Hispanic vs. White patients]. Conclusions: Racial and ethnic disparities in non-elective ICD use persist after adjustment. Future work is needed to understand how these disparities may impact outcomes after ICD placement in racial and ethnic minorities.
Abstract 11723: Depression and Obesity Are Associated with Chest Pain in Patients with Non-Obstructive Coronary Artery Disease
Authors: Nishant Vatsa, Puja K Mehta, Laura P Kimble, Melinda Higgins, Arshed A Quyyumi
Journal: Circulation (2021)

Introduction: Chest pain in patients with non-obstructive coronary artery disease (NO-CAD) is a major clinical problem impacting the quality of life and can present a therapeutic challenge for providers. The objective of this study was to identify clinical factors associated with chest pain frequency in NO-CAD patients. Mainly, we investigated the hypothesis that increased body mass index (BMI) and depression are associated with increased chest pain frequency in NO-CAD patients. Methods: We identified a sample of 439 patients with NO-CAD (mean age 55.3 years, 50% women, 72% white) in the Emory Cardiovascular Biobank, a database of patients who underwent coronary angiography for suspected myocardial ischemia. Sociodemographic variables, clinical risk factors like BMI, and Patient Health Questionnaire 9 (PHQ9) results - a depression screening tool - were collected. We measured chest pain frequency through a questionnaire that asked patients how many times they had chest pain, chest tightness, or angina over the preceding four weeks. Within the sample, 180 patients (41%) reported no chest pain, chest tightness, or angina, and 259 patients (69%) reported one or more instances of chest pain, chest tightness, or angina in the preceding four weeks. We compared these two groups using t-test, Mann-Whitney U test, and multivariate logistic regression analyses. Results: The sample mean BMI was 30.6 ± 6.6 kg/m 2 . The median PHQ9 score was 3.0, with scores ranging from 0 to 27 and 34% having minimal to major depressive symptoms. Compared to those with no chest pain, patients with chest pain had higher BMI (31.5 ± 7.1 vs 29.4 ± 5.6 kg/m 2 , p=0.001) and higher PHQ9 scores (median [interquartile range]: 4 [1,8] vs 1 [0,3], p&lt;0.001). Furthermore, higher BMI and PHQ9 scores were associated with higher odds of chest pain (odds ratio [95% confidence interval]: 1.041 [1.004-1.079] and 1.104 [1.044-1.168], respectively). Conclusions: In patients with NO-CAD, higher BMI and PHQ9 scores were associated with higher chest pain frequency. Thus, weight and depression optimization could reduce symptoms and improve quality of life in NO-CAD patients; however, this needs further study.
Abstract 12620: Myeloid Cell-Specific Arginase-1 is Essential for Cardiosphere-Derived Cell Extracellular Vesicle Mediated Angiogenesis Following Acute MI
Authors: Kyle I Mentkowski, Cody A Manzanero, Lisa A Eagler, Jennifer K Lang
Journal: Circulation (2021)

Introduction: Following a myocardial infarction (MI), macrophages play a pivotal role in initiating and resolving inflammation. Extracellular vesicles (EVs) released by cardiosphere-derived cells (CDCs) have been shown to improve cardiac function in animal models of ischemia in part via effects on immunomodulation. We have recently shown that CDC-EVs polarize macrophages toward a unique pro-angiogenic phenotype, characterized by increased expression of Arginase-1 (Arg1) and enhanced release of pro-angiogenic factors. We hypothesized that CDC-EV dependent activation of Arg1 could underlie their therapeutic benefit in vivo . Methods: LysMCre mice were crossed with Arg1 fl/fl mice to generate a myeloid cell-specific Arg1 knockout model (Arg1-KO) according to institutional approved protocols. To assess the importance of myeloid-specific Arg1 in the therapeutic efficacy of CDC-EVs in vivo , Arg1-KO mice and their fl/fl littermates (wt) were subjected to permanent LAD ligation and randomized to receive 1) CDC-EVs or 2) vehicle control. Prior to euthanasia, mice were injected with BSL-1 Lectin to measure capillary density. Ejection fraction was measured by echocardiography at 5 days post-MI and tissue samples processed for western blot, PCR, flow cytometry, and histological analyses. Results: Arg1 protein expression was significantly repressed in splenic monocytes isolated from Arg1-KO mice compared with WT mice (fold change: 0.3 ± 0.1, p&lt;0.05, t-test, n=3). CDC-EV therapy enhanced ejection fraction in both Arg1-KO mice and WT mice following MI (Arg1-KO: 49.0 ± 3.2% vs. 40.3 ± 1.9%, WT: 51.2 ± 2.9% vs. 39.0 ± 3.8%, p&lt;0.05, t-test, n=6-7 mice/group). CDC-EV therapy significantly increased capillary density in WT mice compared with PBS control (3642 ± 632 vs. 2125 ± 290 capillaries/mm 2 , p&lt;0.05, t-test, n=4-5), but was unable to increase capillary density in Arg1-KO mice above the level seen with PBS treatment (2979 ± 341 vs. 3033 ± 469 capillaries/mm 2 , ns, t-test, n=4-5). Conclusions: Myeloid-specific Arg1 expression is required for CDC-EV mediated angiogenesis but occurs independently of CDC-EV beneficial effects on LVEF following acute MI.
EXTH-37. PAK4 INHIBITION REPROGRAMS VASCULAR MICROENVIRONMENT AND IMPROVES CAR T IMMUNOTHERAPY IN GLIOBLASTOMA
Authors: Fan Yang, Zev Binder, Donald M O’Rourke, Yi Fan
Journal: Neuro-Oncology (2021)

Abstract Malignant solid tumors are characterized by aberrant vascularity that inhibits T cell adhesion to vasculature and impedes T cell delivery into the tumors, contributing to glioblastoma (GBM) resistance to T cell-based immunotherapy such as adoptive chimeric antigen receptor (CAR)–T transfer. Vascular abnormality is driven by pro-angiogenic pathway activation and genetic reprogramming in tumor endothelial cells (ECs). Here, our kinome-wide functional screening of mesenchymal-like transcriptional activation in human GBM-derived ECs identifies p21-activated kinase 4 (PAK4) as a selective regulator of genetic programming and aberrant vascularization in tumor. Genetic ablation of PAK4 reprograms EC transcriptome and inhibits mesenchymal-like transformation. Interestingly, deficiency of PAK4 induces adhesion protein re-expression in tumor ECs, reduces vascular abnormalities in tumors, improves T cell infiltration into the tumors, and inhibits GBM growth in mice. Moreover, pharmacological PAK4 inhibition normalizes the tumor vascular microenvironment and sensitizes GBM to Egfrviii CAR–T cell immunotherapy. Finally, we reveal a MEF2D/ZEB1- and SLUG-mediated mechanism by which PAK4 reprograms the EC transcriptome and downregulates claudin-14 and VCAM-1 expression, enhancing vessel permeability and reducing T cell adhesion to the endothelium. Thus, targeting PAK4-mediated EC plasticity may offer exciting opportunities to recondition the vascular microenvironment and strengthen cancer immunotherapy.
Abstract 13155: Validation of a Decision Aid for Familial Hypercholesterolemia
Authors: Hana Bangash, Alexandra Miller, Ian Hargraves, Sandra Hartasanchez, Justin Gundelach, Victor M Montori, Iftikhar J Kullo
Journal: Circulation (2021)

Introduction: We validated the “Familial Hypercholesterolemia (FH) Decision Aid” to promote shared decision making (SDM) about lipid lowering therapy, based on patient-clinician encounters. Methods: Validation of the DA included an assessment of whether the content and design of the tool facilitated SDM and patient engagement and to determine how well the tool integrated with clinical workflow. Validation was conducted during patient-clinician encounters in the Mayo preventive cardiology clinic. As inclusion criteria we considered an upcoming appointment in the clinic, an LDL-C level ≥ ~160 mg/dL, and no prior diagnosis of FH. Prior to the encounters, each clinician viewed a demonstration of the online, interactive DA. During the encounters, the DA was shared with patients using the clinic room computer screen, either in-person or virtually. Patient-clinician encounters were video recorded for further analysis by two design researchers and experts in SDM. Results: Ten patients were enrolled in the study (7 male; average age 51 years). The average patient LDL-C level was 207 mg/dL, range 157 - 248 mg/dL. Review and qualitative analysis of the encounter recordings yielded 4 key findings: i) clinicians primarily used the cardiovascular risk estimate in the DA to guide conversation with patients; ii) highly trained specialists needed to change their usual approach to care and conversation to integrate the DA with their clinical workflows; iii) as clinicians became more familiar with the DA, they moved through the tool at a more efficient pace; and iv) each clinician developed his/her own style of navigating the DA, either moving through it one screen at a time or focusing on one specific section for the duration of the conversation. The DA effectively guided conversation and facilitated active patient engagement in 6 of 10 encounters. Social distancing and use of telemedicine encounters, due to the COVID-19 pandemic, limited patient engagement in 2 of 10 encounters. Overall, the DA promoted SDM regarding FH management in 9 of 10 encounters. Conclusion: Using patient-clinician encounters, we found the FH DA to facilitate SDM regarding lipid-lowering therapy. The tool has potential to improve care of FH patients and increase patient engagement and knowledge.