tbuckley/cabot-search huggingface dataset:
Abstract 11553: Sudden Cardiac Death in Type 1 and Type 2 Diabetes
Authors: Faye L Norby, Kyndaron Reinier, Audrey Uy-Evanado, Gregory A Nichols, Eric Stecker, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2021)

Introduction: Diabetes is a known risk factor for sudden cardiac death (SCD). Whether type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D) confer a similar risk of SCD remains unclear. Our aim was to determine and compare the association of T1D and T2D with SCD. Hypothesis: Given the differences in the pathophysiology, clinical presentation, and management, the likelihood of having SCD in T1D and T2D is different. Methods: Using data collected from 2002-19, we performed a case-control study of 2,771 cases of SCD (age ≥18 years) from the Oregon Sudden Unexpected Death Study and 8,313 control patients from Kaiser Permanente Northwest (matched for age, sex, and race/ethnicity) who did not have SCD or prior cardiac arrest. We used medical records to determine diabetes status and used logistic regression to evaluate the independent association between diabetes and SCD. Results: Our cases and matched controls had a mean age of 65 ± 16 years, were 33% female and 24% non-White race. In total, 37% (n=1,016) of cases and 24% (n=1,981) of controls had diabetes. In those with diabetes, the proportion of T1D was 6% (n=66) among cases and 2% among controls (n=40; P&lt;0.001). The presence of diabetes was associated with a 1.5- times higher odds of SCD. Compared to those without diabetes, the odds ratio (OR) and 95% confidence interval (CI) for SCD was 4.36 (2.81–6.75; P&lt;0.001) in T1D and 1.45 (95% CI, 1.30–1.63; P&lt;0.001) in T2D after adjustment for age, sex, race/ethnicity, body mass index, and relevant comorbidities. Within the diabetic population (n=2,997), the odds of having SCD were 2.4 times higher in T1D than in T2D (adjusted OR: 2.41; 95% CI, 1.53–3.80; P&lt;0.001). Conclusions: Individuals with T1D and T2D have a higher risk of SCD than those without diabetes. In the diabetic population, T1D is more strongly associated with SCD compared to T2D. These findings have implications for sudden death risk stratification in diabetics.
Can you do what I’m asking you to do?
Authors: Tessa Richards
Journal: BMJ (2021)

Advance care planning (ACP), in its most sophisticated form, is a comprehensive, ongoing, and holistic communication between a physician and his or her patient (or the patient9s designated proxy) about their values, treatment preferences, and goals of care. However, treatment decisions at the end-of-life are very complex, making comprehensive ACP extremely challenging: everyone is reluctant to talk about death; clinicians find it easier to offer hope and another treatment or technology rather than comfort and support; and families find it hard to believe that treatment will not restore health. A number of ACP programs have learned how to successfully meet these challenges, many using the process of 'rapid-cycle' Quality Improvement (QI) to achieve 'breakthrough' change and improvements in practice. This presentation provides guidance and real-life examples for implementing ACP practices in local settings, summarizing over 10 years of successful ACP and related clinical QI work in the US with hundreds of health care professionals and social service providers across the gamut of service delivery silos. Key points covered in the presentation are ways to: target appropriate patients; embed ACP practices in busy healthcare settings; conduct rapid-cycle QI activities and test 'front-line' ideas and successful practices in daily practice; and change the 'usual' healthcare delivery setting culture by making QI and patient safety a top priority. Ensuring the centrality of the patient and family9s voice in treatment decision-making is one of the most important goals for achieving patient/family-centred care. This presentation demonstrates how QI can help improve ACP.
Abstract 12223: Prognostic Significance of Hyperkalemia in Chronic Heart Failure Patients With Implantable Cardioverter-Defibrillator
Authors: Makoto Kishihara, Hidetoshi Hattori, Atsushi Suzuki, Noriko Kikuchi, Yuichiro Minami, Morio Shoda, Nobuhisa Hagiwara
Journal: Circulation (2021)

Introduction: Hyperkalemia is a common morbidity in heart failure (HF) patients and potentially leads to the lethal arrhythmia. However, whether hyperkalemia is associated with worse outcome in chronic HF patients with Implantable Cardioverter-Defibrillator (ICD) is unknown. Methods: This was a retrospective review of all HF patients (n=532) who had been implanted with ICD from 2008 to 2017 at our institution. We examined the association of hyperkalemia with all-cause mortality, hospitalization for HF and appropriate ICD therapy for ventricular tachycardia or ventricular fibrillation. Results: Hyperkalemia (≥5.0 mmol/L) were present in 48 patients (9%) and normokalemia (3.5 to 4.9 mmol/L) in 476 patients (89%). The median potassium levels were 5.2 mmol/L [interquartile range (IQR) 5.0-5.3] in the hyperkalemia group and 4.2 mmol/L (IQR 4.0-4.5) in the normokalemia group. Mean follow-up was 1,602 days. The Kaplan-Meier analysis showed there were no significant between-group differences in all-cause mortality and appropriate ICD therapy for ventricular tachycardia or ventricular fibrillation (log-rank P = 0.10 and P = 0.97, respectively). However, in hyperkalemia group there was a significant higher rate of hospitalization for HF (log-rank P = 0.0002). Cox regression analysis after adjustment for significant predictors demonstrated that hyperkalemia was independently associated with hospitalization for HF compared with normokalemia. Conclusion: In chronic HF patients with ICD, hyperkalemia is an independent predictor of hospitalization for HF, but hyperkalemia is not associated with increased risk of ventricular tachycardia or ventricular fibrillation.
Abstract 12797: Mitochondrial Dysfunction in a Large-Animal Model of Peripheral Artery Disease
Authors: Ahmed Ismaeel, Evlampia Papoutsi, Feifei Li, Carson Hoffman, Maiko Sasaki, Joseph Zarge, Luke P Brewster, Panagiotis Koutakis
Journal: Circulation (2021)

Introduction: Our group recently developed an endovascular porcine model of ischemic myopathy from peripheral artery disease (PAD). We previously demonstrated that this model results in persistent ischemia that is accompanied by a severe myopathy. Herein, we attempted to study the effect of this model on mitochondrial function. Methods: A total of 9 Yorkshire swine were exposed to acute right hindlimb ischemia (HLI) by endovascular occlusion of the external iliac artery. The left hindlimbs served as control, non-ischemic limbs, and 2 pigs were used as absolute controls with no ischemia induction. Animals were terminated between 4 to 6 weeks. Mitochondrial respiration and reactive oxygen species (ROS) production in permeabilized gastrocnemius fiber bundles were simultaneously measured by high-resolution respirometry. Relative mRNA expression was measured using PCR Arrays and protein expression was measured by western blot. Results: The oxygen consumption rate was significantly reduced in ischemic muscle during Complex I, Complex III, and Complex IV respiration compared to control hindlimb muscles. ROS production was significantly elevated during the respiration of all complexes. The mRNA and protein expression of several mitochondrial energy metabolism components, including NDUFB8, SDHB, UQCRC2, MTCO1, and ATP5A were significantly reduced in ischemic muscle. Oxidative stress markers NOX2 and NOX4 were significantly upregulated in ischemic muscle as well. Conclusions: These data suggest that this porcine model may be a suitable preclinical model to study the pathophysiology of mitochondrial dysfunction associated with PAD. We demonstrate that this model also results in a mitochondrial metabolic myopathy similar to that seen in PAD patients. This model may be useful for testing novel therapeutics targeting mitochondrial dysfunction.
Abstract 11137: Caveolin 1 Ameliorated Coronary Flow Responsible for Cardiac Function Improvement After Cardiac Ischemia Reperfusion
Authors: Jumpei Tsukuda, Jonathan Koa, Zhijun Meng, Zhen Zhang, Yajing Wang, Xinliang Ma
Journal: Circulation (2021)

Introduction: Caveolin-1 (Cav-1) is the main structural protein of caveolae, which is dominantly expressed in vascular tissue. It associates with vascular homeostasis by regulating vascular signals. However, Cav-1 KO aggravated the cardiac dysfunction of systolic and diastolic function after cardiac ischemia reperfusion. Injection of Cav-1 peptides successfully preserved left ventricular function post-ischemic reperfusion through the increase in nitric oxide (NO). Hypothesis and Methods: To evaluate the role of Cav-1 in cardiac function, we assessed cardiac function, heart rate and coronary artery blood flow through global ischemia and reperfusion using Langendorff-perfused mouse heart model. Results: In the final analysis of 15 mice, 7 were wild type (WT) and 8 were Cav-1 KO at the age of 12-23 weeks. There are significantly differences in baseline of Left ventricular pressure (LVP), heart rate (HR), max and minimum dp/dp before and after ischemia in each mouse group. We further concluded that the markedly decrease of Coronary artery flow (CF) is the reason for the inhibition of cardiac diastolic function, while heart rate (HR) did not show obvious difference in WT and Cav-1 KO mice. Cav-1 deficiency inhibited the coronary artery flow after ischemia reperfusion and led to aggravation of cardiac dysfunction. Conclusions: As further experiments are needed, both cardiac functions and coronary flow in Cav-1 KO could be impaired. More experiments will be performed and results will be updated.
Abstract 10334: The Association of Trimethylamine N-oxide (TMAO) with Findings of Vascular Brain Injury on Magnetic Resonance Imaging in the Cardiovascular Health Study (CHS)
Authors: Suraj Dahal, Peilin Shi, Meng Wang, Will Longstreth, Heidi Lai, Rozenn Lemaitre, David S Siscovick, Barbara McKnight, Amanda M Fretts, Marcia D Otto, Nona Sotoodehnia, W. H. Wilson Tang, Stanley L Hazen, Dariush Mozaffarian, Matthew J Budoff
Journal: Circulation (2021)

Introduction: Findings on MRI of vascular brain injury, such as brain infarcts and white matter hyperintensities, are chronic manifestation of atherosclerosis. A gut-microbiome-generated metabolite, trimethylamine N-oxide (TMAO), is an independent predictor of clinical cardiovascular events. However, no study has examined associations between TMAO and subclinical vascular brain injury in the general population. Hypothesis: TMAO levels are positively associated with evidence of progressive subclinical vascular brain injury on serial MRI scans with incident brain infarcts and white matter worsening. Methods: The Cardiovascular Health Study (CHS) is a community-based prospective cohort study in adults aged &gt;65 years. Plasma TMAO was measured using mass spectrometry from samples collected in 1992-1993 and 1996-1997. Brain MRI was performed at 1991-1994 and again at 1997-1999. White matter was graded on a 10-point scale, higher being worse, and white matter worsening (WMW) was defined by an increase of least one point comparing initial and follow up scans. In these analyses, participants with prior TIA or stroke were excluded. Those with serum TMAO and both MRI scans were included: n=1196 for incident brain infarct and n=1553 for white matter worsening. Logistic regression was used for the association of baseline TMAO levels and incident brain infarcts, and Poisson regression, for the change in TMAO levels and WMW. Models were adjusted for age, sex, race, alcohol use, intake of meat and vegetable, and vascular risk factors. Results: Between the two MRI scans, 191(15.9%) participants had subclinical incident brain infarcts, and 423 (27.2%) participants had WMW. Comparing the highest vs. lowest quartile, the first TMAO were not significantly associated with incident brain infarcts: odds ratio 0.78 (95% CI: 0.49 to 1.25). Again comparing the highest vs. lowest quartile, changes in TMAO were not associated with WMW: 1.08 (0.77 to 1.51). Conclusions: Baseline and changes in plasma TMAO levels were not associated with findings of subclinical vascular brain injury on MRI in older US adults. The associations of TMAO with the adverse clinical events seen in prior clinical samples of patients were not seen at the subclinical level in our population-based study.
Abstract 10198: Association Between Admission Low-Density Lipoprotein Cholesterol and In-Hospital Mortality Among Inpatients with Acute Myocardial Infarction in China: Findings from CCC-ACS Project
Authors: Tianxiao Liu, Jing Liu, Yongchen Hao, Jun Liu, Na Yang, Yong Huo, Sidney C Smith, Junbo Ge, Gregg C Fonarow, Louise Morgan, Chang-Sheng Ma, Han Yaling, Dong Zhao, Yue Qi
Journal: Circulation (2021)

Introduction: Lowering low-density lipoprotein cholesterol (LDL-C) to &lt;1.4 mmol/L is an important strategy for most patients with acute myocardial infarction (AMI) in secondary prevention of cardiovascular diseases. The association between admission LDL-C levels and all-cause mortality during acute period of AMI is not well established. This study aims to examine the relation between admission LDL-C levels and the risk of in-hospital all-cause mortality among patients with AMI. Methods: The Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome Project is a nationwide registry study. Admission LDL-C level associated with in-hospital all-cause mortality were evaluated on a continuous scale with restricted cubic splines and by categories with multivariate Cox regression models among 94623 inpatients with AMI in 159 tertiary hospitals and 82 secondary hospitals in 30 provinces from November 2014 to December 2019. Results: Among total inpatients, 1852 cases (2.0%) died, 5434 patients (5.7%) have LDL-C level&lt;1.4 mmol/L. The association between LDL-C levels and the risk of all-cause mortality was U shaped, with low and high LDL-C levels associated with an increased risk. Compared with inpatients with LDL-C level of 1.4-1.8 mmol/L, the adjusted hazard ratio was 1.48 (95% confidence interval: 1.18 to 1.87) for patients with LDL-C&lt; 1.4 mmol/L, and 1.50 (95%CI: 1.19 to 1.90) for patients with LDL-C≥ 4.1 mmol/L. Propensity score matched analysis confirmed these associations. Similar results were seen in both gender, in patients with and without diabetes, across age groups and triglycerides groups, across ST-segment elevation AMI and non-ST-segment elevation AMI patients, and after excluding patients who died within 24 hours after admission. However, such association was not observed in patients received lipid-lowering treatment before hospitalization and those treated with percutaneous coronary intervention during hospitalization. Conclusions: Lower LDL-C is associated with increased risk of in hospital all-cause mortality among patients hospitalized for AMI. Lower LDL-C levels may help identify patients at higher risk for in-hospital mortality, who could potentially benefit from intensification of treatment strategies.
BIOM-12. DEVELOPMENT OF 5-ALA BASED LIQUID BIOPSY FOR THE NON-INVASIVE DIAGNOSIS OF GLIOBLASTOMA
Authors: Anudeep Yekula, Tiffaney Hsia, Leonora Balaj, Bob Carter
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Tumor specificity of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is widely applied for fluorescence-guided surgery (FGS) in gliomas. We recently showed the feasibility of detecting tumour-specific fluorescent PpIX extracellular vesicles (EVs) derived from the plasma of glioblastoma (GBM) patients undergoing 5-ALA based fluorescence-guided surgery. Here, we further develop methods to characterize, sort and study fluorescent PpIX EVs in plasma of patients with glioma. METHODS We used imaging flow cytometry and Astrios EQ nanoFACS to characterize and sort PpIX EVs, respectively. Downstream RNA analysis utilized transcriptome sequencing analysis and droplet digital PCR (EGFRvIII mRNA). RESULTS All GBM cell lines (Gli36vIII, U87, Gli36 WT) dosed with 5-ALA demonstrated PpIX fluorescence, and released PpIX positive EVs. There was a high correlation between fluorescence in cells and the number of PpIX EVs released (r2=0.9). We sorted 100,000 PpIX EVs from Gli36vIII cells dosed with 5-ALA and detected 65 copies and 24 copies of mutant EGFRvIII mRNA and wildtype EGFR mRNA per 100,000 EVs, respectively. RNAseq analysis of the sorted PpIX EVs showed expression patterns reflective of parent cells. Furthermore, 100,000 sorted PpIX EVs from the plasma of a patient with EGFRvIII glioma yielded 22 copies of EGFRvIII mRNA while &amp;lt; 5 copies were detected in 1ml of plasma and healthy control plasma, demonstrating the tumor-specific nature of PpIX EVs. Finally, we performed transcriptome analysis on 250,000 PpIX EVs each from 8 patients undergoing 5-ALA based FGS. We identified several mRNAs including Gli3, STAG2, ELF3, PHLPP1 which play an important role in cancer. CONCLUSION The ability to sort and characterize tumor specific PpIX EVs following 5-ALA administration opens new avenues for liquid biopsy-based glioma diagnosis.
Socioeconomic Position and Risk of Disease Progression and Death in Patients with Myelodysplastic Syndromes: A Danish Nation-Wide Population-Based Cohort Study
Authors: Tine Bichel Lauritsen, Lene Sofie Granfeldt Oestgaard, Kirsten Groenbaek, Susanne Oksbjerg Dalton, Jan M. Norgaard
Journal: Blood (2021)
IMMU-31. TUMOR-SPECIFIC ALTERNATIVE SPLICING GENERATES SPATIALLY-CONSERVED HLA-BINDING NEOANTIGEN TARGETS DETECTED THROUGH INTEGRATIVE TRANSCRIPTOMIC AND PROTEOMIC ANALYSES
Authors: Darwin Kwok, Takahide Nejo, Joseph Costello, Hideho Okada
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND While immunotherapy is profoundly efficacious in certain cancers, its success is limited in cancers with lower mutational burden, such as gliomas. Therefore, investigating neoantigens beyond those from somatic mutations can expand the repertoire of immunotherapy targets. Recent studies detected alternative-splicing (AS) events in various cancer types that could potentially translate into tumor-specific proteins. Our study investigates AS within glioma to identify novel MHC-I-presented neoantigen targets through an integrative transcriptomic and proteomic computational pipeline, complemented by an extensive spatiotemporal analysis of the AS candidates. METHODS Bulk RNA-seq of high tumor purity TCGA-GBM/LGG (n=429) were analyzed through a novel systematic pipeline, and tumor-specific splicing junctions (neojunctions) were identified in silico by cross-referencing with bulk RNA-seq of GTEx normal tissue (n=9,166). Two HLA-binding prediction algorithms were subsequently incorporated to predict peptide sequences with high likelihood for HLA-presentation. Investigation of the tumor-wide clonality and temporal stability of the candidates was performed on extensive RNA-seq data from our spatially mapped intratumoral samples and longitudinally collected tumor tissue RNA-seq. Proteomic validation was conducted through mass-spec analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC)-GBM repository (n=99). RESULTS Our analysis of TCGA-GBM/LGG bulk RNA-seq identified 249 putative neojunctions that translate into 222 cancer-specific peptide sequences which confer 21,489 tumor-specific n-mers (8-11 amino acids in length). Both prediction algorithms concurrently identified 271 n-mers likely to bind and be presented by HLA*A0101, HLA*A0201, HLA*A0301, HLA*A1101, or HLA*A2402. We confirmed the expression of 15 out of 58 HLA*A0201-binding candidates in HLA*A0201+ patient-derived glioma cell line RNA-seq with a subset of candidates conserved spatially. Analysis of CPTAC-GBM mass-spec data detected 23 tumor-specific peptides with 5 containing detected n-mers highly predicted to be HLA-presented. CONCLUSION Tumor-specific neojunctions identified in our unique integrative pipeline present novel candidate immunotherapy targets for gliomas and offer a new avenue in neoantigen discovery across cancer types.
TAMI-76. INTEGRATED MULTI-OMICS REVEAL INTRATUMOUR HETEROGENEITY AND NOVEL THERAPEUTIC TARGETS IN PAEDIATRIC EPENDYMOMA
Authors: Alina Pandele, Alison Woodward, Sophie Lankford, Donald Macarthur, Ian Kamaly-Asl, David Barrett, Richard Grundy, Dong-Hyun Kim, Ruman Rahman
Journal: Neuro-Oncology (2021)

Abstract Ependymoma (EPN) is the second most common malignant paediatric brain tumour with a five-year survival rate of only 25% following relapse. While molecular heterogeneity between EPN tumours is well understood, little is known concerning spatially-distinct intratumour heterogeneity within patients. In this context, we present a multi-omics integration of expression data at transcriptomic and metabolomic levels revealing intratumour heterogeneity and novel therapeutic targets. Surgically resected ependymoma tissue from two epigenetic subgroups, posterior fossa-A (PF-A) and supratentorial RELA, were first homogenised and polar metabolites, lipids and RNA simultaneously extracted from the same cellular population. Using liquid chromatography-mass spectrometry (LC-MS) and RNAseq 115 metabolites and 1580 upregulated genes were identified between the two subgroups, therefore validating previously reported genetic clustering of these two subtypes. Sampling of anatomically distinct regions was performed between eight PF-A EPN patients and multi-omic data was compared across 28 intratumour regions, with at least 3 different regions per patient. Integration of genes and metabolites revealed 124 dysregulated metabolic pathways, encompassing 156 genes and 49 metabolites. A large number of interactions occur in the gluconeogenesis and glycine pathways in 6 out of 8 patients, putatively representing therapeutically relevant ubiquitous metabolic pathways critical for EPN survival. Each anatomical region also presented at least one unique gene-metabolite interaction demonstrating heterogeneity within and across PF-A EPN tumours. A subset of the eight most prevalent genes across patients (GAD1, NT5C, FBP1, FMO3, HK3, TALDO1, NT5E, ALDH3A1) were selected for in vitro metabolic assays using 10 repurposed cytotoxic agents against PF-A EPN cell lines derived from intratumour regions of the same patient. 5/8 genes map within the gluconeogenesis metabolic pathway, further highlighting its significance within PF-A EPN. This is the first instance where multi-omic data integration and intratumour heterogeneity has been investigated for paediatric EPN revealing novel potential targets in the context of gene-metabolite correlations.