tbuckley/cabot-search huggingface dataset:
Abstract P409: GSK-3β Deficiency In Cardiomyocyte Induces Cardiac Progenitor Cell Proliferation In The Ischemic Heart
Authors: Ayesha Yusuf, Rizwan Qaisar, James R Woodgett, Firdos Ahmad
Journal: Circulation Research (2021)

The cardiomyocytes are terminally differentiated cells and ischemia-induced cardiomyopathy is an irreparable loss. Novel strategies are needed to induce resident cardiac progenitor cells (CPCs) proliferation in situ to enhance the possibility of cardiac regeneration. Here we sought to identify a potential role for glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPCs proliferation in the ischemic heart. Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were recruited and challenged with myocardial infarction (MI). The cardiac function was assessed using trans-thoracic M-mode echocardiography. The level of CPC proliferation in the ischemic cKO hearts was determined at 2, 4 and 8 weeks post-MI through immunofluorescence labeling of stem cell marker c-Kit. To confirm the lineage of identified c-Kit -positive cells (KPCs) in the heart, a hematopoietic lineage marker was stained along with c-Kit. The cardiac left ventricular chamber dimension (LVID) and contractile functions were comparable until 2 weeks post-MI. The cKO mice displayed significantly preserved LV chamber [LVIDd(mm); 5.01±0.67 vs.6.09±0.65, p =0.01] and contractile function [LVEF(%); 31.98±8.52 vs. 18.06±7.11., p =0.01] in comparison to control mice at 4 week post-MI. Consistent with protective phenotypes, an increased percentage of KPC was observed in the cKO hearts at 4 and 6-weeks post-MI which was accompanied by an increased level of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts were mostly from a cardiac lineage as the majority of identified KPCs were negative for the hematopoietic marker, CD45. In conclusion, our findings strongly suggest that GSK-3β inhibits CPCc proliferation post-ischemia, and loss of GSK-3β in cardiomyocytes promotes resident CPCc proliferation potentially through paracrine mechanisms.
Abstract 11905: Implications of Periprocedural Myocardial Injury and Reinfarction After Left Main PCI in Patients With Acute Myocardial Infarction
Authors: Haoyu Wang, Bo Xu, Kefei Dou
Journal: Circulation (2021)

Objectives: We aimed to investigate 1) the association between biomarker elevation with CK-MB or cTn following PCI and mortality in patients undergoing LM PCI for acute myocardial infarction (AMI), and 2) the prognostic impact of periprocedural myocardial reinfarction rates according to various PMI definitions on long-term mortality. Methods: The study enrolled 313 consecutive AMI patients undergoing LM PCI at a single center from January 2009 to December 2016. CK-MB and cTn were routinely collected at baseline and at frequent intervals between 8 and 48 hours after PCI. Periprocedural myocardial reinfarction was adjudicated occurring within 48 h of PCI according to definitions of the SCAI, ARC-2, and 4th UDMI. The primary and secondary outcomes were the covariate-adjusted 3-year rates of cardiovascular (CV) mortality. Results: 28.2% and 51.2% of patients had a new absolute increase (≥1хURL) in CK-MB and cTnI values, respectively. Compared with patients with absolute post-procedural &lt;1х URL, the risk of 3-year CV death was higher in those with absolute post-procedural CK-MB levels of ≥1хURL (HR: 2.67, 95% CI: 1.11-6.41), ≥3хURL (HR: 4.95 [2.05-11.95]), ≥5х URL (HR: 4.50 [1.73-11.27]), ≥10х URL (HR: 8.36 [3.21-21.78]), ≥35х URL (HR: 77.12 [14.13-421.07]), respectively. We did not observe an incremental CV mortality rate using a higher isolated cTnI cutoff (≥1хURL, HR: 3.02 [0.61-14.95]; ≥3хURL, HR: 4.03 [0.81-20.00]; ≥5хURL, HR: 2.93 [0.70-12.26]; ≥10хURL, HR: 2.19 [0.55-8.77]; ≥35хURL, HR: 0.73 [0.09-5.93]). Periprocedural myocardial reinfarction rates (SCAI, ARC-2, and 4th UDMI) were 8.0%, 12.5%, and 20.4%, respectively. SCAI-defined periprocedural myocardial reinfarction was associated with a 7-fold increase in adjusted hazards of 3-year CV mortality (adjusted HR: 6.88; 95% CI: 2.66-17.77), which had greater prognostic relevance than ARC-2 and 4th UDMI (ARC-2, adjusted HR: 3.07 [1.15-8.20]; 4th UDMI, adjusted HR: 2.60 [1.04-6.50]). Conclusions: In a large cohort of consecutive patients with AMI undergoing LM PCI, periprocedural myocardial reinfarction according to the SCAI, ARC-2, and 4th UDMI definitions were both associated with significant risk for 3- year CV mortality, with the patients with SCAI definition having a higher risk for CV death.
IMMU-01. CHARACTERIZATION OF TUMOR-INFILTRATING CD8+ T CELLS IN BRAIN METASTASES
Authors: Lisa Sudmeier, William Hudson, Kimberly Hoang, Edjah Nduom, Stewart Neill, Matthew Schniederjan, Jeffrey Olson, Rafi Ahmed
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Use of immune checkpoint blockade (ICB) therapy has prolonged overall survival in patients with metastatic cancer. One potential strategy to improve the effectiveness of ICB is to target additional inhibitory receptors on exhausted CD8+ T cells, which may promote rescue of CD8+ T cells that do not respond to PD-1 pathway blockade alone. This therapeutic strategy requires knowledge of the inhibitory molecules expressed on tumor-specific CD8+ T cells. Toward achieving this goal, we characterized the phenotype of CD8+ T cells infiltrating brain metastases. METHODS We performed flow cytometry on 45 brain metastases samples, single cell RNA sequencing with T cell receptor (TCR) sequencing on 5 samples, and spatially-resolved transcriptomics on 8 samples. RESULTS Analysis of our scRNA-seq data revealed 4 populations of PD-1+ CD8+ T cells infiltrating brain metastases. One of these populations (cluster A) has a terminal effector exhausted phenotype suggesting that this population contains tumor-specific CD8+ T cells. Two of the other populations (clusters B and C) have a transcriptional profile that suggests they may contain stem-like CD8+ T cells. TCR sequencing shows that cells in cluster A do not express the same TCRs as cells in clusters B and C, suggesting that stem-like cells in clusters B and C are not the progenitors of the terminal effector cells in cluster A. Bystander cells expressing TCRs specific for viral antigens are found predominantly in clusters B and C, further supporting the hypothesis that cluster A contains tumor-specific cells. Spatial transcriptomics reveals that cluster A cells are infiltrating the tumor parenchyma while cluster B and C cells are predominantly in peri-tumoral inflammatory tissue. CONCLUSIONS Brain metastases are infiltrated by a population of terminally-differentiated effector CD8+ T cells which express co-inhibitory molecules that may be potential therapeutic targets to improve control of metastatic disease in the brain.
Abstract 9580: Impact of Clopidogrel Metabolizer Status on Incidence of Gastrointestinal Bleed
Authors: Aditya singh, Kevin Coy, Daniel Schmidtman, Adam Stys, Tom Stys
Journal: Circulation (2021)

Introduction: Clopidogrel is used for secondary prevention of coronary artery disease, stroke, and peripheral vascular disease. Increased doses has been associated with increased odds of gastrointestinal (GI) complications (gastritis, gastric ulcer and bleeding). Effectiveness of clopidogrel is dependent on its conversion to active metabolite by liver enzyme CY2C19. Hypothesis: Clopidogrel metabolizer status impacts the incidence of GI bleed. Methods: Patients aged &gt;18 years, on clopidogrel and known CYP2C19 status were included in the study. Based on functional copies of CYP2C19 they were divided into two groups slow (poor or intermediate) and adequate metabolizers (normal, rapid, ultra-rapid) and were retrospectively analyzed for documented diagnosis of GI bleed after initiation of clopidogrel. Results: A total of 3778 patients were included in the study who were on clopidogrel and had known CYP2C19 status. Of these patients, 74.2% were adequate and 25.8% were slow metabolizers. Overall, there were 332 patients (8.8%) with a documented diagnosis of GI bleed following initiation of clopidogrel. There was no significant difference observed in incidence of GI bleed among slow and adequate metabolizers (8% vs 9.1%, p=0.313). Conclusions: Our study demonstrates that the clopidogrel metabolizer status does not appear to have any significant impact on incidence of GI bleeding, which further strengthens the fact that GI bleed is a multi-factorial pathology.
A Phase 1/2 Dose-Escalation and Dose-Expansion Study of the Safety and Efficacy of Anti-CD7 Allogeneic CAR-T Cells (WU-CART-007) in Patients with Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL)/ Lymphoblastic Lymphoma (LBL)
Authors: Armin Ghobadi, Ibrahim Aldoss, Frederick L. Locke, Ryan J. Mattison, Deepa Bhojwani, Shannon L. Maude, Preeta Dasgupta, Karen Gheesling Mullis, Ayman Kabakibi, Alexander S. Hamil, Tom Leedom, Kenneth Chrobak, Eileen McNulty, Jan K Davidson-Moncada, Matthew L Cooper, John F. DiPersio
Journal: Blood (2021)
EPCO-21. CORE REGULATORY CIRCUIT TRANSCRIPTION FACTORS DRIVE EXPRESSION FROM HIGH LEVEL AMPLICONS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Davy Deng, Frank Dubois, Alexander Crane, Ashot Harutyunyan, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Pediatric High-Grade Gliomas (pHGGs) show recurrent high-level amplifications around the oncogenes MET, MYCN and EGFR. However what drives expression of the oncogenes from these amplicons remains unclear. We aim to discover enhancers on these amplicons that are responsible for oncogene expressions and the core regulatory transcription factors (TFs) they bind. METHOD Using RNA-seq from 12 pHGG cell lines, we identified groups of high and low-expressing pHGG lines for MET, MYCN and EGFR. We then compared the H3K27Ac ChIP-seq between the two groups using diffbind. This allowed us to identify statistically significant peaks that are differentially activated in the oncogene-high v.s. oncogene-low expressing groups. Additionally, we overlapped the positions of these candidate oncogene enhancers with the regions that are recurrently incorporated into high-level amplicons based on published whole genome sequencing data. Using a previously defined set of core regulatory TFs we determined which TF binds the amplified oncogene enhancers and could be driving oncogenic expressions of MET, MYCN and EGFR in pHGGs. RESULTS We identify 3 cell lines for both the high- and low-expressing groups for each oncogene. Cell lines with high expression of the oncogene showed distinct enhancers with significant enrichment in H3K27Ac compared to the cell lines with low expression for each oncogene. Of all enhancers with enrichment high oncogene expression groups those with binding sites for known pHGG core regulatory circuit TF were preferentially incorporated into the high-level amplicons of the oncogene. We also identified core TFs that bind enhancers for MYCN, EGFR and MET as well as core TFs that are unique to a single oncogene. CONCLUSION We identified candidate core transcription factor that drives expression of multiple oncogenes in pHGG. These could serve as a potential novel therapeutic target for pHGGs with addiction to MYCN or RTK signaling.
Dexamethasone in hospitalised COVID-19 patients not on intensive respiratory support
Authors: Kristina Crothers, Rian DeFaccio, Janet Tate, Patrick R. Alba, Matthew Bidwell Goetz, Barbara Jones, Joseph T. King, Vincent Marconi, Michael E. Ohl, Christopher T. Rentsch, Maria C. Rodriguez-Barradas, Shahida Shahrir, Amy C. Justice, Kathleen M. Akgün
Journal: European Respiratory Journal (2021)

Dexamethasone decreases mortality in coronavirus disease 2019 (COVID-19) patients on intensive respiratory support (IRS) but is of uncertain benefit if less severely ill. We determined whether early (within 48 h) dexamethasone was associated with mortality in patients hospitalised with COVID-19 not on IRS.We included patients admitted to US Veterans Affairs hospitals between 7 June 2020 and 31 May 2021 within 14 days after a positive test for severe acute respiratory syndrome coronavirus 2. Exclusions included recent prior corticosteroids and IRS within 48 h. We used inverse probability of treatment weighting (IPTW) to balance exposed and unexposed groups, and Cox proportional hazards models to determine 90-day all-cause mortality.Of 19 973 total patients (95% men, median age 71 years, 27% black), 15 404 (77%) were without IRS within 48 h. Of these, 3514 out of 9450 (34%) patients on no oxygen received dexamethasone and 1042 (11%) died; 4472 out of 5954 (75%) patients on low-flow nasal cannula (NC) only received dexamethasone and 857 (14%) died. In IPTW stratified models, patients on no oxygen who received dexamethasone experienced 76% increased risk for 90-day mortality (hazard ratio (HR) 1.76, 95% CI 1.47-2.12); there was no association with mortality among patients on NC only (HR 1.08, 95% CI 0.86-1.36).In patients hospitalised with COVID-19, early initiation of dexamethasone was common and was associated with no mortality benefit among those on no oxygen or NC only in the first 48 h; instead, we found evidence of potential harm. These real-world findings do not support the use of early dexamethasone in hospitalised COVID-19 patients without IRS.
NIMG-41. PH-WEIGHTED MOLECULAR MRI AS AN EARLY BIOMARKER OF METABOLIC RESPONSE TO IDH INHIBITION IN IDH MUTANT GLIOMAS
Authors: Benjamin Ellingson, Yao Jingwen, Akifumi Hagiwara, David Nathanson, Talia Oughourlian, Chencai Wang, Catalina Raymond, Whitney Pope, Noriko Salamon, Albert Lai, Phioanh Nghiemphu, Richard Everson, Won Kim, Linda Liau, Susan Pandya, Lori Steelman, Islam Hassan, Timothy Cloughesy
Journal: Neuro-Oncology (2021)

Abstract The current study tested the hypotheses that (1) pH-weighted MRI measurements of tumor acidity reflect glycolytic activity in human gliomas, (2) that tumor acidity, and thus glycolytic activity, differs between human IDH mutant (mIDH) and wild type gliomas, and (3) that an increase in tumor acidity, suggestive of increased glycolytic activity, occurs after inhibition of mutant IDH enzyme activity and reduction in 2HG, an oncometabolite. To test these hypotheses, we employed a custom pH-weighted amine chemical exchange saturation transfer echoplanar (CEST-EPI) technique in 152 patients with IDH mutant or wildtype glioma prior to surgery and 11 patients before and after treatment with AG120 or AG881 enrolled at our institution in a phase 1 perioperative study in patients with recurrent, non-enhancing, IDH mutant low-grade gliomas (NCT03343197). Results from image-guided biopsies in more than 100 patients demonstrated a significant correlation between MTRasym at 3ppm, a measure of tumor acidity from pH-weighted amine CEST-EPI, and expression of key glycolytic proteins including GLUT3 (R2=0.2188,P=0.0105), HK2 (R2=0.1788,P=0.0314), LDHA (R2=0.1111,P=0.0071), and MCT1 (R2=0.1228,P=0.0039) as well as ex vivo extracellular flux analysis estimates of ATP consumption from glycolysis (R2=0.6684,P=0.0021). Data suggests a significantly lower acidity (MTRasym@3ppm) within non-enhancing tumor in IDH mutant gliomas when compared to IDH wild type gliomas (P&amp;lt; 0.0001). Patients in a phase 1 perioperative study showed a shift toward higher tumor acidity (i.e. higher glycolytic activity) following inhibition of IDH based on 2HG suppression in resected tumors, but at levels below that of IDH wild type gliomas. Levels of 2HG within the tumor after IDH inhibition were inversely correlated with post-treatment tumor acidity (R2=0.6342, P=0.0180). Overall, results suggest mIDH gliomas have low levels of glycolytic activity, and successful inhibition of the mutant IDH enzyme results in reduction in 2HG and a measurable metabolic shift toward elevated glycolysis as evidenced using pH-weighted molecular MRI.
Abstract 9712: Impact of Heart Failure on Prognosis in Cancer Patients (Kurume-CREO Study)
Authors: Nagisa Morikawa, Tatsuhiro Shibata, Shoichiro Nohara, Yoshihiro Fukumoto
Journal: Circulation (2021)

Introduction: With recent progress in treatment of cancers, cancer survivors have an increased risk of cardiovascular diseases (CVDs) due to aging or toxicities of anti-cancer drugs. However, more evidence regarding CVD risk in cancer survivors is required. Hypothesis: CVD as comorbidity has a big impact on prognosis in cancer patients. Methods: We enrolled 400 patients with hematological malignancy and breast cancer visiting Kurume University Hospital between October in 2016 and December in 2019 in Kurume-CREO study, a prospective observational study. We evaluated blood test and chest X-ray, electrocardiogram and echocardiography at baseline and follow up every 6 months after baseline. Outcomes were defined as all-cause deaths and CVD mortality due to myocardial infarction, heart failure (HF) and pulmonary thromboembolism. HF was defined as either N-terminal prohormone of brain natriuretic peptide elevation or findings in chest X-ray or diagnosed HF by cardiologists. We followed up until September 23th in 2019. Results: Mean age (± standard deviation) of participants was 64.1 (± 12.9) years old, and 280 of 400 patients (70%) were enrolled before chemotherapy. Among hematological malignancies, non-Hodgkin’s lymphoma (n=223, 68.2%) and multiple myeloma (n=55, 16.8%) were most frequently observed. During the follow-up period, 85 patients (21.3%) died, 2 patients (0.5%) died from CVD and 50 patients (12.5%) had HF. Survival curves showed a significantly worse survival rate in patients with hematological malignancy compared to those with breast cancer (Log-rank p = 0.002)(Fig 1). All cancer patients with HF during the period had significantly worse prognosis than those without HF (Log-rank p = 0.003)(Fig 2). Conclusions: Mortality in cancer patients with HF comorbidities was significantly higher than in those without HF. CVD death was very rare in the present study, but HF comorbidity was a significant prognostic factor in cancer.
Abstract 12133: Association Between Polyvascular Disease and Adverse Outcomes Among Patients Undergoing Coronary Artery Bypass Grafting in a Regional Registry
Authors: Niveditta Ramkumar, Benjamin M Westbrook, Fuyuki Hirashima, David J Malenka, Cathy S Ross, Alexander Iribarne, Michael Young, Stanislav Henkin
Journal: Circulation (2021)

Introduction: Polyvascular disease is defined as the simultaneous presence of coronary artery disease (CAD) and peripheral artery disease (PAD) or cerebrovascular disease (CVD). Hypothesis: We hypothesized that polyvascular disease may be associated with worse short- and long-term outcomes in patients undergoing coronary artery bypass grafting (CABG). Methods: We performed a retrospective, multi-center analysis of patients undergoing isolated CABG from 2005-2018 among 7 medical centers in Northern New England. Patients were stratified by number of vascular beds affected: CAD only, CAD+PAD or CVD, and CAD+PAD+CVD. The primary outcomes of 30-day and long-term mortality were assessed using multivariable logistic and Cox regression, respectively. Results: Of 18,984 patients, 18% had either PAD or CVD, while 4.8% had PAD and CVD. Compared to those with CAD alone, patients with polyvascular disease were older, more likely to be female, and had a higher prevalence of comorbidities including diabetes, smoking, and renal failure (all p&lt;0.001). The risk-adjusted odds of 30-day mortality was higher for patients with either CVD or PAD (OR=1.57, 95% CI: 1.2-2.07) and combination of CVD and PAD (OR=1.56, 95% CI: 1.00-2.42) versus CAD alone. Polyvascular disease patients had higher risk of long-term all-cause mortality compared to CAD only patients (Figure). Conclusions: Among patients undergoing CABG in Northern New England, those with polyvascular disease had a higher risk of short- and long-term adverse outcomes compared to CAD alone, with incremental increase in risk dependent on number of vascular beds affected. Aggressive secondary prevention measures, prior to and after CABG, should be routinely employed for these patients.
Abstract 10919: Prevalence, Awareness, Treatment, and Control of Hypertension in Hospitalized Patients with Atrial Fibrillation in China: Findings from the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation Project
Authors: Zhaoqing Sun, 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, Jing Liu
Journal: Circulation (2021)

Introduction: Reports on the current status of hypertension control in patients with atrial fibrillation (AF) remain lacking in China. We aimed to provide the latest estimates on the prevalence, awareness, treatment, and control rates of hypertension and factors associated with uncontrolled hypertension in hospitalized patients with AF in China. Methods: Based on the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation (CCC-AF) Project, hospitalized patients with AF collected from 236 hospitals in 30 provinces of China between February 2015 and December 2019 were included in current analysis. The prevalence, awareness, treatment, and control rates of hypertension were estimated according to the Chinese Hypertension Guideline. Hypertension was defined as SBP ≥140mmHg or DBP ≥90mmHg measured at the time of admission, or a documented history of hypertension. Multivariable logistic regression was used to analyze the factors associated with uncontrolled hypertension (SBP ≥140 mmHg or DBP≥90mmHg). Results: A total of 61,136 hospitalized patients with AF were included, and the prevalence of hypertension was 66.1%. The awareness, treatment, and control rates of hypertension were 80.1%, 55.8%, and 39.9%, respectively. Among patients treated for hypertension, only 46% had their blood pressure controlled. The rates varied by patient characteristics and geographic regions (Table). Younger age (18-45 years of age), rural insurance, alcohol drinking, history of heart failure, mitral stenosis, pre-hospital use of antiplatelet drugs, valvular AF, new-onset AF, and Northeast China were associated with uncontrolled hypertension in patients with AF. Conclusions: Hypertension is common in hospitalized patients with AF. Although most patients are aware of this comorbidity, the treatment and control rates of hypertension are still low. The management of hypertension in patients with AF needs to be further strengthened.