tbuckley/cabot-search huggingface dataset:
PATH-06. DNA METHYLATION PATTERNS AND IMMUNE MICROENVIRONMENT IN CYSTICGBM
Authors: Zhihua Chen, Denis O’Meally, David Frankhouser, Mari Shahmanyan, Biao Tang, Shu Yao, Russell C Rockne
Journal: Neuro-Oncology (2021)

Abstract As a rare subtype of glioblastomas (GBM), genetic features in cystic GBM (cGBM) are still largely unknown. We have previously identified a series of active T cell subsets and positive cytokines/chemocytokines in the cystic fluid of cGBMs, including IFN-gamma, IL-2, IL-6, IL-8, TNF-alpha, and MIP-1alpha/beta. This study aimed to evaluate the prognosis of cGBM through DNA methylation patterns and immune microenvironment transcriptional signatures. IvyGAP, EGA and fresh samples from a prospective Chinese cohort were collected to investigate genomic signatures, immune microenvironment and survival outcomes in patients with cGBMs. Gd T1-weighted, T2-weighted, T2-Flair, DWI or ADC images were used to classify cGBM. 143 cases with MGMT/IDH record were used to compare survival time and genomic analysis. Among the three cohorts, Kaplan-Meier analysis showed cystic features have benefit to overall survival (OS). Moreover, cyst feature is the forth factor (HR=0.65, [95% CI 0.42, 1.01]) of survival after IDH, MGMT and Stupp therapeutic regimen. Interestingly, in IDH-wild/MGMT-unmethyled subtype, cGBM patients have longer OS vs noncystic GBM (noncGBM) patients (HR = 0.57, [95% CI 0.33, 0.99]). Compared to noncGBM, cGBM patients have hypomethylation state both in whole gene region and cpG islands. Ivygap database showed between cystic and noncystic group, in sub-structures such as CT (cellular tumor region), CTpan (pseudopalisading cells around necrosis) and CTpnz (perinecrotic zone) there are differential gene expressions and different enrichment pathways. GSEA analysis showed within cGBM group, many gene sets associated with immune function activation such as TRL1/2/3/7 and IFN pathways. These results suggest that cysts of GBM may be associated with hypomethylation status an activated immune microenvironment which is associated with longer survival and may define a unique subgroup of GBM with intrinsically different biology and prognosis.
Abstract 12039: Assessing the Applicability of Three Heart Failure Randomised Controlled Trials by Calibration to Scottish Registry
Authors: LILI WEI, Anoop Shah, John G Cleland, Jim Lewsey, David McAllister
Journal: Circulation (2021)

Intro: Randomised controlled trials are the gold standard method for assessing treatment effects. However, those who participate in trials of heart failure (HF) are usually highly selected (by the protocol, investigators and patient-choice) and, on average, younger and with fewer comorbidities than those encountered in clinical practice. Trials can be calibrated to better reflect routine clinical practice by re-estimating treatment effects after adjusting for differences in characteristics between trial and target populations, whilst maintaining the principle of randomisation. Methods: Using individual-level participant data, we calibrated 2 trials of HF with predominantly reduced left ventricular ejection fraction (HFrEF) - COMET (100% HFrEF) and DIG (87% HFrEF) and 1 trial of HF with preserved left ventricular ejection fraction TOPCAT - to 8,012 HF patients from a Scottish HF register using two methods - one regression-based and one using inverse propensity score weighting (IPSW). Results: Compared to register patients, trial participants had lower furosemide doses and were younger (mean (standard deviation) age 73 (12) years vs 62 (11), 64 (11) and 69 (10) years) with higher eGFR (59 (23) vs 67 (21), 62 (21) and 68 (18) ml/min/1.73m 2 for register vs COMET, DIG and TOPCAT respectively). For each trial, effect estimates from uncalibrated and calibrated analyses were similar (Figure 1; e.g. odds ratios in COMET for all-cause mortality were 0.83 (0.74, 0.93), 0.71 (0.58, 0.88) and 0.97 (0.72, 1.27) in the uncalibrated, IPSW and regression-based analyses). The calibrated estimates for all three trials were at most 1.5-fold less precise (i.e., 1.5-fold wider 95% confidence intervals) than the standard estimates. Conclusions: Calibration may be used to estimate the applicability of trial findings to populations typically encountered in clinical settings, with only small reductions in the precision of the effect estimates, and without breaking randomisation.
Abstract 9992: Homelessness and Heart Failure
Authors: Abdul Minhas, Husam Salah, Izza Shahid, Haider J Warraich, Marat Fudim, Khurram Nasir, Safi U Khan
Journal: Circulation (2021)

Background: Homelessness is an important social determinant of health. Since heart failure (HF) contributes to significant morbidity and mortality, we sought to investigate the association of homelessness with clinical outcomes in the patients hospitalized with HF. Methods: We analyzed the National Inpatient Sample (NIS) database between 2016 and 2018. Primary HF hospitalizations and homeless adults were identified through ICD codes. Multivariable adjusted logistic regression was used to assess the association of homelessness and clinical outcomes. Results: Of 3522459 weighted primary HF hospitalizations identified, only minority of patients were identified as homeless (n=28555; 0.81%). Homeless adults were younger (mean age: 56 vs. 72 years) and had lower prevalence of clinical comorbidities (diabetes, hypertension, obesity, dyslipidemia, renal failure, peripheral vascular disease, stroke) compared with non-homeless adults. However, homeless adults had higher prevalence of drug, tobacco, and alcohol abuse than non-homeless adults. Adjusted models showed lower odds of inpatient mortality and clinical complications among homeless adults. Conclusion: Homeless adults were younger and had higher prevalence of drug abuse, but lower burden of clinical comorbidities than non-homeless adults. While homeless adults had lower inpatient mortality and clinical complications, the interpretation of these results is limited by lower hospitalization rates among homeless. Majority of homeless adults may not seek medical attention due to poor social support. .
Abstract 10768: Use of Cellular Indices to Predict All-Cause Mortality Outcomes in Patients with Pulmonary Embolism
Authors: Andrew Sagalov, Amir Darki, Brett Slajus, Trent Reed, Omer Iqbal, Jawed Fareed
Journal: Circulation (2021)

Introduction: Pulmonary embolism (PE) is a life-threatening condition with variable severity that results from dysregulation of complex inflammatory and hematologic processes. Current risk stratifications suffer from a low positive predictive variable. Complete blood count data offers a relatively low cost and easily accessible opportunity to supplement current risk models. We aim to identify trends in blood indices in patients with pulmonary embolism to stratify all-cause mortality. Materials and Methods: Patients with acute PE (n=231) confirmed on diagnostic imaging were followed during a three-year period for all-cause mortality. Complete blood count with differential was obtained within 24 hours of PE diagnosis through the electronic medical records system. SPSS Statistics was used to conduct bivariate analysis to identify correlations and interquartile ranges of selected indices against mortality. Results: Platelet count (PCC=-0.241, p &amp;It0.001) and platelets/mean platelet volumes (PCC=-0.229, p &amp;It0.001) were found to be negatively correlated with all-cause mortality, while platelets/neutrophils (PCC=0.160, p &amp;It0.021) and neutrophils/lymphocytes (PCC=.244, p &amp;It0.001) had a positive correlation. Values with a p value &amp;It0.05 were declared statistically significant. Patients with active infection, malignancy, or undergoing immunosuppressive therapy were excluded from analysis due to potential confounding. Conclusion: Our study concludes lower levels of platelets are associated with increased mortality in patients with pulmonary embolism. We hypothesize the large clot burden in PE consumes platelets, which results in thrombocytopenia. By leveraging these findings in a clinical setting, we can supplement scoring criteria for pulmonary embolisms to create a more comprehensive model to predict all-cause mortality.
Abstract 11189: Obesity is Associated with Better Intra-Hospital Outcome in Diabetes Patients Hospitalized for Stemi: Findings from the National Inpatient Sample
Authors: Ramez Bodair, SOHA DARGHAM, Jassim M Al suwaidi, Hani Jneid, Charbel Abi Khalil
Journal: Circulation (2021)

Introduction: An obesity paradox is observed in patients with diabetes. Hypothesis: We hypothesized that obese patients with diabetes hospitalized for STEMI have a better intra-hospital outcome. Methods: We used data from the National Inpatient Sample (NIS) from 2008 to 2014. Patients with STEMI and diabetes were classified according to their BMI: Underweight (BMI &lt;19), Normal (BMI 19-24.9), Class I Obesity (BMI 25.0-29.9), Class II Obesity (BMI 30.0-39.9), and Class III Obesity (BMI &gt;40). We compared different classes and assessed in-hospital events. Results: 1.7% patients were underweight, 3.0% had normal weight, 10.4% had Obesity Class I, 54.8% had Obesity Class II, and 30.2% had Obesity Class III. Mean age (SD) was higher in underweight patients (73 ±13) but decreases progressively to reach 58 ± 11 in class III obesity (p&lt;0.001). There were more females in underweight patients and more males in normal weight and obese patients (p&lt;0.001). Obese patients had a significantly lower risk compared to normal weight patients, but not underweight (Figure 1). In cardiogenic shock, underweight and class I obese patients had a similar risk compared to normal weight, but class II (a OR= 0.53 [0.40-0.70]) and class III (OR=0.62 [0.46 - 0.82] had a lower risk. The risk of ventricular fibrillation was not different according to groups. Interestingly, the risk of atrial fibrillation was lower in class I (OR= 0.72 [0.52-0.98]) and class II (OR= 0.7 [0.53-0.93]) patients without being higher in underweight patients. Increasing age was a strong predictor of cardiovascular events (OR of mortality is 7.99 [5.83 - 10.83] for patients &gt;84 years old). Multivariable adjustments did not affect the significance of the results. Conclusions: An obesity paradox is observed in patients with diabetes hospitalized for STEMI. Higher BMI is correlated with lower risk of mortality, cardiogenic shock, and atrial fibrillation. Underweight patients did not have a higher risk of cardiovascular events.
Clinical Profile and Long-Term Outcomes of Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Eculizumab in a Real-World Setting: High Frequency of Anemia Despite Decreased Intravascular Hemolysis
Authors: Katharina Versmold, Ferras Alashkar, Carina Raiser, Richard Ofori-Asenso, Tao Xu, Yutong Liu, Pablo Katz, Aijing Shang, Alexander Roeth
Journal: Blood (2021)
Abstract 12287: Clonal Hematopoiesis is Associated With Higher Risk of Stroke
Authors: Romit Bhattacharya, Seyedeh Zekavat, Jeffrey Haessler, Md Mesbah Uddin, Alexander G Bick, Abhishek Niroula, Christopher Gibson, Siddhartha Jaiswal, Peter Libby, Charles Kooperberg, Eric A Whitsel, Joann Manson, Benjamin Ebert, Pradeep Natarajan, Alex Reiner
Journal: Circulation (2021)

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is a newly recognized aging-related condition due to clonal expansion of mutated hematopoietic stem cells (HSC) that results in increased risk for coronary artery disease (CAD). The extent to which CHIP is associated with stroke risk is not well understood. Methods: CHIP genotypes were obtained from 6 cohort studies [the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), the Women’s Health Initiative (WHI)] and two electronic health record-based biobanks [UK Biobank (UKBB) and Massachusetts General Brigham Biobank (MGBB)]. Incident stroke was ascertained by physician adjudicators in the cohort studies, and by ICD codes in the biobanks. Cox proportional hazards models were fitted with adjustment for age, sex, diabetes mellitus, smoking status (never, past, current) and race. Fixed-effects meta-analysis was used to estimate pooled effect sizes. Results: A total of 74,306 participants from 8 studies were included. In the fixed-effects meta-analysis, CHIP mutations were associated with an increased risk of total stroke (HR= 1.17, 95% CI 1.05-1.28) ( Figure 1 ). In analysis of stroke subgroups, the risk was greater for hemorrhagic (HR= 1.37, 95% CI 1.15-1.59) than ischemic stroke (HR= 1.13, 95% CI 1.00-1.26). Individuals with particularly expanded CHIP mutations (i.e. variant allele fraction &gt;10%), showed similar effect estimates of association for total stroke, ischemic stroke, or hemorrhagic stroke were observed (HR any stroke = 1.21, 95% CI 1.09-1.34; HR ischemic stroke = 1.15, 95% CI 1.01-1.30; HR hemorrhagic stroke = 1.43, 95% CI 1.20-1.67) . Conclusions: CHIP is associated with incident ischemic and hemorrhagic stroke.
Abstract P466: Sqstm1/p62 Regulates Hypoxia Inducible Factor 1 Alpha Stabilization And Protects The Heart From Hypoxic Injury
Authors: Rajeshwary Ghosh, Nima Fatahian, Vinod Vishaka, J D Symons, Sihem Boudina
Journal: Circulation Research (2021)

Ischemic heart disease (IHD) is characterized by cardiac tissue hypoxia, dysregulatedmetabolism, and cell death. Hypoxia inducible factor 1a (HIF1α) is a major component of thehypoxia pathway that regulates metabolic and angiogenic genes. Under normoxia, HIF1α getshydroxylated by the prolyl hydroxylases (PHDs), followed by its ubiquitination, and degradationby the Ubiquitin Proteasome System (UPS). Given the short half-life of HIF1α (&gt;5mins), PHDinhibitors are employed to stabilize HIF1α and improve cardiac function in animal models ofischemia/infarction. Because PHD inhibitors exert off-target effects, alternative strategies tostabilize HIF1α are needed. In cancer cells, p62 stabilizes HIF1α by binding PHD3. Wehypothesized that p62 would stabilize HIF1α and provides cardioprotection from hypoxia. Wegenerated mice with tamoxifen-inducible cardiomyocyte-specific p62 deletion (cip62KO mice)and exposed them to 7% O2 for 6h. Compared to wild-type (WT) littermates, cip62KO micedisplayed increased oxidative stress and enhanced cell death. Hypoxia caused contractiledysfunction in cip62KO vs. WT mice. To gain mechanistic insights as to how lack of p62exacerbated hypoxic injury, cultured H9c2 cardiac myoblasts were exposed to 21% (normoxia)or 1% (hypoxia) O2 for 24h. Hypoxia increased HIF1α and p62 protein expression in H9c2 cells(p&lt;0.05). To determine whether hypoxia-induced p62 accumulation is required for HIF1αstabilization, H9c2 cells were transfected with p62 or scrambled (ctrl) siRNA for 48h, andexposed to hypoxia. Compared to ctrl siRNA cells, hypoxia-induced HIF1α protein accumulationwas reduced (p&lt;0.05) after p62 knockdown. Additionally, hypoxia increased expression ofHIF1α downstream targets: Egln1 , Vegfa , Bnip3 and Hmox1 mRNA, in ctrl siRNA cells, but theresponse was blunted (p&lt;0.05) after p62 knockdown. These data indicate that p62 contributes tohypoxia-induced HIF1α stabilization and transcriptional activation. Defining how p62contributes to HIF1α stabilization and hypoxia tolerance is relevant clinically and could identifyp62 as a therapeutic target for treating IHD.
Abstract 14338: Mitochondria-Targeted ROS Scavenger JP4-039 Induces Coronary Angiogenesis in Ischemic Myocardium Resulting in the Improvement of Cardiac Function in Post-MI Animals
Authors: Rayane Brinck Teixeira, Catherine Karbasiafshar, Aja Tucker, Sidharth Raj, Mohamed Sabra, Frank W Sellke, Peter Wipf, Ruhul Abid
Journal: Circulation (2021)

Introduction: A reduction of mitochondrial reactive oxygen species (mito-ROS) has been sought as a potential approach for recovering energy supply and improving cardiac function in cardiovascular disease. Here, we evaluated JP4-039, a mito-ROS scavenger, for post-myocardial infarction (MI) recovery. Hypothesis: We hypothesized that mitochondrial antioxidant JP4-039 will induce coronary angiogenesis and improve post-MI cardiac function in mice. Methods: FVB mice (n=8/group) underwent MI surgery and were assigned to either vehicle (sunflower seed oil) or JP4-039 group (1mg/kg, i.p., 3x/week for 4 weeks). A SHAM surgery group received vehicle only. Left ventricle (LV) ejection fraction (EF), fractional shortening (FS), and fractional area change (FAC) were assessed by echocardiography 28 days post-MI. Capillary (CD31 antibody) and arteriole density (α-SMA antibody) were quantified by immunofluorescence of ischemic heart sections 28 days post-MI. Western blot of myocardial homogenates was conducted to evaluate activation of Akt, ERK1/2, and AMPKα. Data were analyzed by One-way ANOVA and Tukey’s post-hoc, and a p value &lt;0.05 was taken as significant. Results: Mice treated with JP4-039 presented with a 35% decrease in infarction size, and a 57% increase in EF compared to the vehicle group (43.6±5.1 vs. 27.8±5.3). FS and FAC of JP4-039-treated mice increased by 65% (21.9±2.9 vs. 13.3±2.6) and 90% (38.0±5.6 vs. 20.0±4.0), respectively. In ischemic myocardium, the JP4-039 group showed an increase in capillary density of 39% in comparison to vehicle (208.6±21.7 vs 149.9±18.0). Interestingly, arteriogenesis was decreased in ischemic myocardium by 31% in JP4-039-treated mice compared to vehicle group (9.0±1.1 vs. 13.1±1.5). Although activation of Akt or ERK1/2 signaling were unchanged, p-AMPKα was decreased by 67% in JP4-039 vs. vehicle (0.39±0.07 vs. 0.65±0.03) in myocardium. Conclusions: The findings suggest that mitochondrial antioxidant JP4-039 improves capillary angiogenesis in ischemic myocardium, resulting in improved cardiac function in post-MI mice. Mechanisms involved in differential levels of capillary and arteriole densities in ischemic myocardium are being examined in human coronary ECs and will be presented at the meeting.
Abstract 10369: Artificial Intelligence-Assisted Prediction of Blood Cells Regenerative Capacity in Patients with Diabetes Mellitus
Authors: Amankeldi A Salybekov, Zholdas Buribayev, Sakai Katsuaki, Ainur Yerkos, Makoto Natsumeda, Yuji Ikari, Shuzo Kobayashi, Takayuki Asahara
Journal: Circulation (2021)

Introduction: Peripheral blood mononuclear cell (PBMC) regenerative capacity is impaired in pre/diabetes mellitus patients (DMPs). In vitro evaluation of PBMCs pre/post vasculogenic conditioning (VC) and integrative assessment of classical clinical risk factors using complex machine learning-based (ML) methods may help to distinguish patients' immune cell regenerative potential. Methods: Eighteen DMPs diagnosed with myocardial infarction and sixteen controls were enrolled. Isolated PBMC regenerative capability was evaluated pre/post-VC using endothelial progenitor cell colony formation assay/unit (EPC-CFA/U) and flow cytometry analysis. The following classification ML algorithms were used for data analysis: support vector machine (SVM), logistic regression (LR), random forest (RF), decision tree (DT), and adaptive boosting (AB). Results: An in vitro EPC-CFA assay revealed that DMPs showed decreased fresh PBMC-derived definitive EPCs (DEPCs) compared with controls. Decreased colony formation was observed in patients with a reduced number of circulating EPCs and they did not appropriately respond to VC according to ML findings. Furthermore, proinflammatory M1 macrophages significantly increased (P = 0.03) in the majority of DMPs (non-responders) compared to that in controls, whereas VC shifted the phenotype toward M2 along with CD4 + T and Treg cell expansion. Clinical, pre/post culture cell phenotype, and EPC-CFU data integration and comprehensive ML analyses distinguished “non-responder”-associated distinct biomarkers, clinical parameters, such as elevated proinflammatory cells and systemic inflammation, and elderly patients from those of responders. Notably, SVM prediction accuracy was 100%; both LR and RF were 86%; and those of AB and DT were 71% and 43%, respectively. Conclusions: Applying comprehensive ML methods, as well as integrative analysis of the findings of in vitro assays, such as EPC-CFA; such as EPCs, M1/M2 macrophages, and T cells pre/post-VC; and clinical-laboratory parameters, enabling us to precisely evaluate regeneration capacity of impaired PBMNC functions. Moreover, this cell culture methodology can be used before cell therapy to define optimal dose and cell ratio for transplantation.
Abstract 12766: Treatment of Patients With Atrial Fibrillation and Heart Failure in the AIM-AF (Antiarrhythmic Medication for Atrial Fibrillation) Study: A Physician Survey on the Prescription of Antiarrhythmic Drugs in the US and Europe
Authors: Jonathan P Piccini, Carina Blomstrom-Lundqvist, Giuseppe Boriani, Andreas L Goette, Peter R Kowey, Jose Merino, James A Reiffel, Sanjeev Saksena, Alan J Camm
Journal: Circulation (2021)

Introduction: ACC/AHA/HRS guidelines recommend dofetilide or amiodarone in patients with atrial fibrillation (AF) and symptomatic heart failure (HF). ESC 2020 guidelines added dronedarone (IA) and sotalol (IIbA) as antiarrhythmic drug (AAD) options for patients with AF and HF with preserved ejection fraction (HFpEF), retaining only amiodarone (IA) for AF and HF with reduced ejection fraction (HFrEF). Dronedarone was also added for patients with normal or mildly impaired (but stable) left ventricular function (IA). In both guidelines, catheter ablation (ABL) may be considered in AF and HFrEF to improve outcomes. Methods: An online survey to understand treatment practice in patients with AF and HF was conducted in the US, Germany, Italy, Sweden, and the UK. Respondents were cardiologists or cardiac electrophysiologists (N=629) actively treating ≥10 patients with AF who received AAD therapy and/or had received or were referred for ABL. The survey comprised 96 questions on physician demographics, AF types, and treatment practices. Results: After AF type and symptom status, presence of HF was the third most cited reason to select rhythm control over rate control (13% of respondents). Overall, 39% preferred first-line ABL over AADs in patients with AF and comorbidities such as HF; yet HFrEF was the top-ranked factor for favoring AADs over ABL by 20%. Amiodarone was the AAD selected most often in HFrEF (81%), and HFpEF (60%), and used less in the US than Europe (particularly in HFrEF: 71% vs 91%). Sotalol was selected by 18% as a typical choice for AF with HFrEF (US 25%, Europe 12%), not in accordance with guideline recommendations; class Ic drugs were also selected in HFrEF (US 8%, Europe 4%) contrary to recommendations. Use of dronedarone (18% vs 27%) and sotalol (26% vs 42%) was less common in the US than Europe in patients with HFpEF; use of class Ic agents, against recommendations, was the same in both regions (18%). Conclusions: Presence of HF is frequently considered by physicians in AF treatment decisions, but treatment patterns indicate divergence from guideline recommendations with several specific AADs. However, the guidelines do not clearly define HF and, in clinical practice, use of non-recommended agents appear acceptable to some in individual circumstances.