tbuckley/cabot-search huggingface dataset:
Abstract 11767: Mechanisms of Nighttime Sudden Death: Arrhythmogenic Potential of Central Nervous System-Affecting Medications
Authors: Parth Visrodia, Archana Ramireddy, Harpriya Chugh, Kyndaron Reinier, Audrey Uy-Evanado, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2021)

Introduction: We have previously reported an independent association between central nervous system-affecting medications (CNS-Meds) and nighttime sudden cardiac death (N-SCD). Hypoxia remains a possible trigger due to somnolence and respiratory depression but direct myocardial effects resulting in lethal arrhythmia have not been explored. Hypothesis: Heart rate is significantly lower during sleep, and this increases vulnerability to lethal arrhythmias mediated by prolongation of the QTc interval. Methods: From the population-based Oregon Sudden Unexpected Death Study, we evaluated SCD cases that occurred in the community (2002-2016) between 10 pm and 6 am (nighttime) and compared them with daytime cases. Analysis was restricted to subjects with available pre-arrest information regarding prescribed medications. We identified QT prolonging drugs from the comprehensive list at crediblemeds.com. Time of SCA was determined by the 911 call and review of circumstances provided by the emergency medical services. Univariate comparisons were evaluated using Pearson’s chi-square tests and independent samples t-tests. Results: A total of 3328 SCD cases (65% male, mean age 67y) met criteria for analysis, and 22% (n=739) were N-SCD. Women were more likely to suffer N-SCD compared to men (25% vs 21%, p=0.002). Anti-depressants (36%) were the most frequently used CNS-Meds among N-SCD cases, followed by pain medications (34%) and anti-epilepsy drugs (26%). Specifically, opioids and serotonin modulators were more likely to be used during N-SCD vs. daytime SCD (34% vs 27%, p&lt;0.01, and 11% vs 8%, p&lt;0.01). Importantly, CNS-Meds that prolong QTc interval were more likely to be used during N-SCD than daytime SCD (48% vs 42%, p&lt;0.01). Conclusion: Nighttime SCD was associated with high usage of CNS-Meds especially anti-depressants, pain medications and anti-epileptic drugs. These findings suggest that CNS-Meds may be contributing to nighttime SCD via occurrence of bradycardia-dependent prolonged QTc-associated ventricular arrhythmias. Further investigation is needed to optimize use of CNS-Meds in order to minimize risk of nighttime SCD.
Clinical Impact of Copy Number Variation Revealed By Next Generation Sequencing in Acute Myeloid Leukemia
Authors: Kamila Janusz, Ruth Stuckey, Clara Aparicio Pérez, Cristina Bilbao, Inmaculada Fernández Camacho, Manuel Yébenes, Josefina Serrano, Jesús M Hernández Rivas, María Teresa Gómez-Casares, Joaquín Sánchez
Journal: Blood (2021)
Abstract 12969: Community-Level Socioeconomic Distress, Race, and Risk of Adverse Outcomes Following Heart Failure Hospitalization Among Medicare Beneficiaries
Authors: Amgad Mentias, Mary S Vaughan Sarrazin, Shreya Rao, Milind Y Desai, Alanna A Morris, Jennifer Hall, Venu Menon, Clyde Yancy, Mario Sims, Alana A Lewis, Gregg C Fonarow, Saket Girotra, Ambarish Pandey
Journal: Circulation (2021)

Background: Socioeconomic (SE) disadvantage is a strong determinant of adverse outcomes in patients with HF. The contribution of SE disparities to adverse outcomes in HF may differ among Black vs. White patients and has not been well studied. Methods: Using the 100% CMS MedPAR data, Black and White patients hospitalized with HF between 2014 and 2017 were identified and stratified based on the distressed community index (DCI)—a measure of the SE disadvantage of residential ZIP codes on a continuous scale (range 0-100, see Fig. legend)—into two groups: SE distressed (Q5) vs. non-distressed (Q1-4). The rates of 30-day and 1-year mortality and readmission were compared across the distressed vs. non-distressed race groups. The adjusted association between DCI and risk of adverse outcomes was assessed separately across the race groups using adjusted hierarchical logistic regression models with restricted cubic splines. Results: The study included 1,238,537 White (14.8% distressed) and 190,721 Black (44.4% distressed) patients. White patients living in SE distressed communities had a significantly higher risk of adverse outcomes at 30-days and 1-year f/u (Fig. A). In contrast, among Black patients, the risk of adverse outcomes among those living in distressed vs. non-distressed communities were not meaningfully different at 30-days and became more prominent by 1-year f/u. Similar results were noted in the restricted cubic spline analysis with stronger and more graded association between DCI score and risk of adverse outcomes in White (vs. Black) patients (Fig. B). Conclusion: SE distress is strongly associated with risk of adverse outcomes in White patients with HF. Among Black patients, SE distress is more common, but its adverse effects are less evident during short-term f/u and are better highlighted in the long-term. Other societal factors such as structural racism and poor access to care may be important prognostic determinants in Black patients with HF.
TAMI-80. CELLULAR METABOLISM IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Omkar Ijare, Jeanne Manalo, Martyn Sharpe, David Baskin, Kumar Pichumani
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive form of brain tumor in children, comprising &amp;gt;10% of all pediatric brain tumors. The median survival after diagnosis is &amp;lt; 1 year. Since DIPG tumors infiltrate brainstem and pons, they are inoperable. Currently radiotherapy is the mainstay of treatment, and there is a great need for novel therapies for the treatment of DIPG. Cellular metabolism plays a key role in carcinogenesis, unravelling active metabolic pathways in DIPG would help in developing targeted therapies. Glucose and glutamine are the two major nutrients necessary for the growth and proliferation of cancer cells. In this study, we have investigated the glucose and glutamine metabolism in SF8628 DIPG cells using 1H/13C NMR and GC-MS based metabolic flux analysis. SF8628 cells were grown in DMEM containing 11.0 mM glucose, supplemented with 10% FBS, and 2.0 mM glutamine at 37 °C under humidified air and 5% CO2. When cells reached confluency (replicates = 4), treated with 11.0 mM [U-13C]glucose or 4.0 mM glutamine in DMEM (supplemented with 10% FBS). After 24 h, cells were harvested for NMR/GC-MS analysis. The 13C-isotopomer analysis revealed that SF8628 cells produced 25.26 ± 10.63% acetyl-CoA from [U-13C]glucose which is ~3.7 times higher than that produced from GBM cells (6.83 ± 0.76%; our previous work), suggesting that DIPGs are metabolically very active. [U-13C]glutamine metabolism showed that DIPG cells also have an active TCA cycle metabolism (citrate M+4; 40.07 ± 1.06%) and moderately active reductive carboxylation pathway (citrate M+5; 10.59 ± 1.13%). Inhibition of both glycolytic and glutaminolysis pathways will be valuable in developing treatment strategies for DIPGs and these studies are in progress.
Abstract 11280: Effect of Homelessness on Incidence of Autopsy-Defined Causes of Presumed Sudden Cardiac Death: Insights from the San Francisco Postmortem Systematic Investigation of Sudden Cardiac Death (POST SCD) Study
Authors: Satvik Ramakrishna, James W Salazar, Emily Siegel, Jeffrey E Olgin, Ellen Moffatt, Zian H Tseng
Journal: Circulation (2021)

Introduction: Prior studies report higher cardiovascular mortality in persons experiencing homelessness (PEH), but presume cardiac cause of death (COD) from EMS records or death certificates. The effect of homelessness on autopsy-defined SCD is unknown. In this prospective postmortem study of all SCDs in San Francisco (SF) County, we hypothesized a greater incidence of presumed SCD in PEH, but more non-cardiac COD on autopsy. Methods: Between 2/2011 - 3/2014, all incident World Health Organization-defined (presumed) SCDs ages 18-90 were autopsied via active surveillance of out of hospital deaths in the POST SCD Study. A multidisciplinary committee adjudicated COD. Autopsy-defined SCDs had no extra-cardiac COD (e.g., overdose, pulmonary embolism, stroke). Homeless status was determined from medical records; rates of presumed and autopsy-defined SCD were compared to those for housed individuals. The countywide homeless population was determined from the 2013 SF Homeless Count and Survey. Results: We identified 525 presumed SCDs over 37 months: 36 (7%) were PEH and 489 (93%) were housed. Presumed SCDs in PEH were younger than housed subjects (56.5 ± 9.9 v. 63.2 ± 14.6 years), more often male (97% v. 67%), less likely to be Asian (0% v. 22%) or have dyslipidemia (3% v. 32%), but more likely to have alcohol (58% v. 21%) and substance use disorder (44% v. 13%, p&lt;0.01 for all). The presence of psychiatric disorders was similar between groups. Among presumed SCDs, PEH had a lower proportion of autopsy-defined SCDs than housed individuals (9/36 [25%] v. 306/489 [63%]), with more non-cardiac COD including aspiration, aortic dissection, occult overdose, and infection (p&lt;0.05 for all). Observed incidence rates for presumed SCD were 181.4 v. 22.7 per 100,000 person-years (IRR 8.01, p&lt;0.01) in PEH v. housed individuals, and 45.4 v. 14.2 per 100,000 person-years (IRR 3.20, p&lt;0.01) for autopsy-defined SCD. Conclusion: In this 3-year comprehensive postmortem study of all incident SCDs in a diverse urban setting, homelessness was associated with &gt;3-fold higher risk of autopsy-confirmed SCD and 8-fold higher risk of sudden mortality overall. Only one-fourth of presumed SCDs in PEH were autopsy-confirmed SCDs, while one-third of non-cardiac causes were due to occult drug overdose.
Abstract 9501: Duration of Ideal Cardiovascular Health With Risk of Chronic Kidney Disease and Cardiovascular Disease
Authors: So Mi J Cho, Justin Y Jeon, Tae-Hyun Yoo, Hae-young Lee, Yong-ho Lee, Hyeon Chang Kim
Journal: Circulation (2021)

Introduction: Increasing number of clinical guidelines are adopting comprehensive cardiovascular risk assessment tools for treatment decision and disease management in the context of primary and secondary prevention. Yet, little is known regarding the exact cardiovascular risks associated with length of favorable cardiometabolic health sustenance in midlife. Methods: From the Korean Genome and Epidemiology Study Ansung-Ansan cohort, we included 7,854 middle-aged adults without chronic kidney disease and 7,796 without cardiovascular disease at baseline. Duration of ideal cardiovascular health was the sum of time spent with ideal body mass index, blood pressure, fasting glucose, total cholesterol, non-smoking, alcohol drinking, and physical activity levels. We employed Cox proportional hazards model to assess chronic kidney disease and cardiovascular events risks. Results: The median age of the participants was 50.0 years and 47.9% were male. Over a median follow-up of 15.0 years, 1,401 new chronic kidney disease and 493 new cardiovascular disease occurred. With &lt;5 years group as the reference, multivariable-adjusted hazard ratios [95% confidence intervals] for chronic kidney disease were 0.63 [0.39-0.93] with 5 to 10 years and 0.33 [0.15-0.74] with ≥10 years of ideal cardiovascular health ( P trend, 0.0057). Similarly, participants lived with longer ideal cardiovascular health had significantly lower cardiovascular disease (5 to 10 years, 0.83 [0.54-1.27]; ≥10 years, 0.22 [0.08-0.60]). Subtype-specific analyses indicated negatively graded risks for coronary artery disease ( P trend, 0.0239) and cerebrovascular disease ( P trend, 0.0514). Conclusions: Our findings confer that maintaining favorable health behaviors and clinical cardiometabolic profile in midlife will improve later-life cardiovascular outcomes.
Abstract 12931: The Association of Depression With Cardiac Rehabilitation Attendance by Age and Sex Among Patients With Myocardial Infarction: Results From the Behavioral Risk Factor Surveillance System
Authors: Cenjing Zhu, Phoebe Tran, Rachel P Dreyer, Judith H Lichtman
Journal: Circulation (2021)

Background: Cardiac rehabilitation (CR) is a core component of secondary prevention shown to improve quality of life and reduce all-cause mortality after myocardial infarction (MI). Depression is twice as prevalent among young women (18-44y) versus men with MI and is linked with worse post-MI outcomes, yet information on sex-specific associations of depression and CR attendance is limited, particularly among younger MI patients. Methods: Using data from the 2011, 2013, 2015, and 2017 self-reported US Behavioral Risk Factor Surveillance System (BRFSS) surveys, we assessed the association between depression and CR attendance in adults with MI using logistic regression adjusting for sociodemographic factors. We calculated CR rates by sex and age subgroups for MI patients with and without depression. BRFSS survey weighting was applied to all analyses. Results: The study included 12,252 MI patients (44.2% women). CR attendance was comparable between MI patients with and without depression (36.1% vs 37.4%, p=0.440) ( Figure 1a ), and the association between depression and CR remained nonsignificant after adjusting for age, sex, race, education, and household income (OR=1.16, 95% CI: 1.00-1.35). CR attendance ranged from 19.0% to 51.0% across age and sex subgroups, with the lowest rate seen among women 18-44y with depression ( Figure 1b ). Women who were 45-64y and 65+y were less likely to attend CR than similarly aged men, regardless of depression status. Conclusions: Overall, just over one-third of patients with MI participated in CR, and depression was not associated with CR attendance. We found marked heterogeneity by subgroups, with lower CR rates observed for women across age groups, potentially putting them at higher risk for subsequent adverse cardiac events. Further research is needed to identify barriers leading to sex- and age-specific CR disparities to optimize attendance of post-acute care among subgroups, especially among younger women with depression.
CTNI-32. CASE SERIES OF BRAF INHIBITORS FOR THE TREATMENT OF BRAFV600E GLIOBLASTOMA
Authors: Naveed Wagle, Jose Carrillo, Akanksha Sharma, Minhdan Nguyen, Judy Truong, Jared Chow, Evie Landa, Annie Heng, Jaya Gill, Garni Barkhoudarian, Daniel Kelly, Santosh Kesari
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is the most common and aggressive primary brain tumor. Beyond upfront therapy with radiation and temozolomide chemotherapy there is no standard therapy that has been effective. Inhibitors of BRAF and MEK, a downstream protein immediately following BRAF, have been shown to have survival benefit for patients with other BRAF V600E mutant neoplasm including advanced melanoma. We describe our experience using this combined target therapy for two patients with BRAF V600E mutant glioblastoma. Two adult patients with pathologically diagnosed glioblastoma presented with radiographic evidence of tumor progression after prior treatment with chemotherapy or immunotherapy. Neither had received radiation therapy within 3 months of starting treatment. Molecular characterization was performed though Caris which showed evidence of BRAF V600E mutation. BRAF inhibitors were initiated in combination with standard therapy options. MRI imaging was obtained to monitor for disease progression. BRAF inhibitors were tolerated well without any side effects not previously reported. Partial objective response was seen in both patients on subsequent MRI imaging within 8 weeks of starting treatment. Progression free survival and overall survival have not been reached in either case. BRAF inhibition may have therapeutic benefit in BRAF mutated glioblastoma. Partial response was seen in this case series. The molecular profile of glioblastoma may suggest treatment options beyond standard chemotherapy options. This series supports the use of BRAF inhibitors for the treatment of BRAFV600E glioblastoma A controlled trial should be supported.
Abstract 10753: Exercise-Induced ECG Changes Predict Adverse Outcomes in Pulmonary Hypertension
Authors: Maya Kailas, Aimee Layton, Meredith Pesce, Robert Garofano, Thomas Starc, Erika Berman-Rosenzweig, Leonardo Liberman, Usha Krishnan
Journal: Circulation (2021)

Introduction: Cardiopulmonary exercise testing (CPET) is an important tool in assessing the functional status of patients with pulmonary hypertension (PH). During CPET, ECG is used as marker of exercise induced ischemia. We hypothesize that ECG changes with exercise may be an early indicator of clinical worsening in PH and could predict adverse outcomes. Methods: Clinical, hemodynamic, and CPET data of 101 PH patients who underwent CPET between 2013 and 2019 were included. ECGs were analyzed for ST depressions and T wave inversions during the earliest CPET in this time frame, along with coincident hemodynamic data. These data were correlated to adverse outcomes, including shunt creation (atrial septostomy or POTTs shunt), lung transplantation, and death. Results: Median age was 19 y (7-40 y, IQR 12-26), 68% were female, and median follow up time was 3 y (1-8 y, IQR 1-5). Sixteen patients had an adverse outcome (8 shunt creation, 4 lung transplant, 7 death). Twenty-two patients demonstrated significant ST/T wave changes with exercise, 18 ST depressions and 9 T wave inversions. Multivariate regression, including pulmonary arterial pressure, revealed exercise induced ST/T wave changes to be an independent predictor of procedure-free survival (without lung transplantation or shunt creation) (hazard ratio 11.10, p=.006). Only 21% with ST/T wave changes demonstrated procedure-free survival vs 85% without. Conclusions: ST/T wave changes on exercise ECG are significantly associated with adverse outcomes in PH on a medium term follow up study. These ECG changes with exercise can be used as early indicators of clinical worsening in PH and predictors of adverse outcomes.
Abstract 12566: Aortic Smooth Muscle Cell Focal Adhesion Kinase (FAK) Activation is Prominently Associated With Acute Aortic Dissections in Patients and Mouse Models and Loss of FAK Signaling Augments Dissections in Mice
Authors: Zhen Zhou, Yanming Li, Chen Zhang, Hernan G Vasquez, Yuki Kawamura, Tomas Vaisar, David A Dichek, Yvan Saeys, Alan Daugherty, Jay D Humphrey, Ying H Shen, Scott A Lemaire, Dianna M Milewicz
Journal: Circulation (2021)

Introduction: Genetic variants predisposing to thoracic aortic disease disrupt proteins either in the extracellular matrix (ECM) or the smooth muscle cell (SMC) contractile unit, and focal adhesions (FAs) are molecular bridges between these aortic wall components. We sought to identify molecular triggers for acute aortic dissection (AAD) in a mouse model with AAD induced by β-aminopropionitrile (BAPN) and patients with type A AAD. Methods: At postnatal day 21 (P21), C57BL/6J mice were exposed to BAPN in drinking water (0.5%) and proximal aortas were harvested for single-cell RNA sequencing (scRNA-seq), proteomics assays and transmission electron microscopic (TEM) analysis at P35. Ascending aortic scRNA-seq assays were performed on AAD patients (n=3) and age-matched, cardiac transplantation donors (n=3). Results: In the BAPN mice, ruptured AAD-deaths started at P36, and 54% of mice died by P49, despite a significant decrease of BP (111/79 to 95/66 mmHg, p&lt;0.0001). ScRNA-seq and KEGG pathway analysis identified increased FA signaling as the top altered pathway in the BAPN-treated SMC clusters. Similarly, FA signaling was identified as a top upregulated pathway in SMCs from patients’ aortas. Western blots confirmed increased level of FAK phosphorylation in BAPN-treated aortas. Proteomics analysis revealed a FAK-interacting protein, cortactin, and apoptotic proteins, annexin A1, A3 and A5 (p&lt;0.01), as the top proteins increased with BAPN treatment, which was consistent with increased TUNEL signal in BAPN-treated aortas (p&lt;0.01). TEM analysis identified collagen deposition between SMCs and elastic fibers and loss of elastic extensions in BAPN-treated aortic media. Importantly, administration of a FAK inhibitor, PF-573228, starting at P30 in BAPN-treated mice significantly increased AAD-deaths (starting at P35 and all mice died by P48) when compared to BAPN-only treated mice (p&lt;0.0001). Conclusions: FA signaling is the major pathway activated in SMCs in mouse pre-dissection aortas and human dissected aortas, thus implicating disruption of SMC-ECM interactions in AADs. Disruption of FAK signaling augments AADs, suggesting that maintenance of FA signaling delays AADs in the ECM-compromised, BAPN-treated aortas.
IMMU-15. INVESTIGATING CD8 T CELL EXHAUSTION STATES GLIOBLASTOMA
Authors: Jessica Waibl Polania, William Tomaszweski, Alexandra Hoyt-Miggelbrink, Karolina Woroniecka, Peter Fecci
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioblastoma (GBM) is the most common primary brain cancer in adults and remains universally lethal. Median survival remains a bleak 15-17 months from time of diagnosis, and current immunotherapeutic efficacy continues to be hindered by the robust immunosuppression present in the GBM microenvironment. T cells, critical for tumor clearance, are particularly affected, and many take on a functionally exhausted phenotype within the tumor. Importantly, two exhaustion states, progenitor and terminal, have been identified in models of chronic infection and cancer. This distinction is particularly relevant, as progenitor exhausted T cells can respond favorably to immune checkpoint blockade, while terminally exhausted T cells are resistant. To date, the dynamics and characteristics of these exhausted populations in GBM remain unclear. RESULTS In an orthotopic murine model of GBM, progenitor and terminal exhausted CD8 T cells were identified by flow cytometry as PD1+SLAMF6+ and PD1+TIM3+, respectively. Using a time-course approach, we detected progenitor exhaustion by day 8 in the tumor, but not in draining lymph nodes. Additionally, we show that the frequency of progenitor exhaustion is highest during early tumor progression, while terminal exhaustion is the most abundant in more advanced tumors ( &amp;gt;14 days). Functional differences between subsets were evaluated via intracellular staining of IFNγ, TNFα, granzyme B, and Ki67. Terminally exhausted T cells displayed higher cytotoxic molecule expression than progenitor exhausted T cells, similar to what has been documented in melanoma models. CONCLUSIONS Our findings identify T cell exhaustion subsets within GBM that require further investigation and may be relevant to overcome current barriers to immunotherapeutic efficacy.