tbuckley/cabot-search huggingface dataset:
Abstract 11563: Frailty Predicts Hospital Outcomes in Patients With LVAD: A Nationwide Inpatient Analysis
Authors: Francisco J ROMEO, Jose S Aguilar-Gallardo, Ashish A Correa, Johanna P Contreras
Journal: Circulation (2021)

Introduction: Frailty is recognized as a major prognostic indicator in heart failure and is linked to perioperative morbidity and mortality. We sought to evaluate the prognostic value of frailty on hospital outcomes in patients with Left Ventricular Assist Device (LVAD) therapy. Hypothesis: Frailty portends a worse prognosis in patients with LVAD. Methods: This population-based, retrospective observational study extracted data of hospitalized adult patients with current LVAD therapy from the US Nationwide Inpatient Sample (NIS) database (2018). Participants were stratified into frail and non-frail using the Johns Hopkins (ACG) frailty-defining diagnosis indicator. Study endpoints were in-hospital mortality, sepsis, length of hospital stay, and total charges (u$$). Univariate and multivariate analyses were performed to determine associations between the endpoints and frailty. Results: A total of 23,210 weighted adult patients had the presence of LVAD therapy during index hospital admission. The mean age was 60 years old, 86% were men and a total of 13% of the patients with LVAD were considered frail. Of note, frail patients with current LVAD had an overall higher burden of comorbidities than those without frailty status. In addition, the prevalence of frailty steadily increased in groups with higher Charlson Comorbidity Index (CCI) scores (p-value &lt;0.001). Hospital outcomes including mortality, sepsis, and LOS were higher among the frail populations as well as hospital costs (Table 1). Finally, after multivariate analysis for clinical variables, frailty at admission had a nearly 2-fold increase in mortality (OR 1.67, CI 95% 1.19-2.34, p-value 0.002). Conclusions: Frailty is a prevalent condition among patients with current LVAD therapy and portends a worse prognosis as well as higher hospital costs. Table 1. In-Hospital outcomes
Abstract 12370: Prognostic Value of Inflammatory Markers in Recurrent Pericarditis
Authors: Ashwin K Kumar, Abdullah Yesilyaprak, Muhammad M Furqan, Beni Verma, vardhmaan jain, Mohamed Gad, Ankit Agrawal, Bryce Montane, Christine Jellis, Paul Cremer, Allan L Klein
Journal: Circulation (2021)

Background: Expert guidelines recommended the use of inflammatory markers for the confirmatory diagnosis of recurrent pericarditis (RP), however the prognostic role in management is unknown. Inflammatory marker levels in RP fluctuate, therefore measurement during flare is paramount. We attempt to assess the prognostic value of inflammatory markers (ESR, hs-CRP) taken during active flare in idiopathic/viral RP. Methods: We retrospectively reviewed 130 patients with established RP from 2015 to 2019 with inflammatory markers during flare. RP was diagnosed if two of these features were present; pleuritic chest pain, EKG changes, rub, and effusion. Active flare was defined as pleuritic chest pain with raised inflammatory markers. Clinical improvement (CI) and remission (CR) were assessed. CI was defined as symptom improvement on dual anti-inflammatory therapy. CR was established with symptom resolution and cessation of therapy. Results: Mean age was 46 ± 16, 57% were female, and a median number of recurrences was 3. The median follow-up time was 633 days, and median time to first recurrence was 263 days. Patients with lower hs-CRP &lt;10 mg/L were more likely to have CI as compared to the higher hs-CRP ≥10 mg/L group (79% vs 42%, p=0.012). Also, patients in the lower hs-CRP group showed a higher tendency to achieve CR (43% vs 20%, p = 0.081). ESR was statistically insignificant for the outcomes. The median time to CI in the low hs-CRP group was less compared to the high hs-CRP group (11 vs. 32 months). Majority of high hs-CRP patients did not achieve CR. The probability of CI and CR among low hs-CRP is higher as compared to high hs-CRP (log-rank p=0.001; log-rank p=0.034) [Figure 1]. Conclusion: Patients who had higher hs-CRP were less likely and required more time to achieve CI and CR as compared to patients with lower hs-CRP. This highlights the prognostic significance of hs-CRP that may assist management of RP even without a concurrent ESR level. Figure 1: Kaplan-Meier Analysis of CI and CR
Abstract 468: TAB2 is Molecular Switch That Critically Regulates Myocardial Survival and Necroptosis
Authors: Haifeng Yin, Xiaoyun Guo, Yi Chen, Rachel Steinmetz, Qinghang Liu
Journal: Circulation Research (2017)

Our recent study identified a key role for TAK1 (transforming growth factor β activated kinase-1) in regulating myocardial remodeling and heart failure propensity by antagonizing necroptosis, also termed programmed necrosis ( Circulation 2014;130:2162-2172). TAB2 (TAK1 binding protein-2) is an adaptor protein that regulates TAK1 activation and downstream signaling. Here we tested the hypothesis that TAB2 functions as a critical regulator of myocardial necroptosis and pathological remodeling. We found that both TAB2 and TAK1 were up-regulated during compensatory cardiac hypertrophy but down-regulated in end-stage heart failure. Genetic ablation of TAB2 in cardiomyocytes, but not other TAK1 binding proteins TAB1 or TAB2, markedly increased necroptosis in response to TNFα stimulation. Genetic deletion of RIP3 (receptor interacting protein-3), a key regulator of necroptosis, also largely blocked cell death in TAB2-deficent cells, further confirming the role of TAB2 in regulating necroptotic cell death. Mechanistically, our data showed that TAB2 functions as a molecular switch that tightly regulates TAK1-RIP1 interaction (pro-survival) and the RIP1-RIP3 necrosome formation (pro-necroptosis). We further showed that loss of TAB2 promotes necroptosis in cardiomyocytes via two independent mechanisms: acutely through the induction of RIP1-RIP3 necrosome and later through inhibition of the NFκB pathway. Importantly, cardiac-specific ablation of TAB2 in mice showed enhanced pathological remodeling with massive fibrosis and necroptosis, and the TAB2-deficient mice gradually developed dilated cardiomyopathy and heart failure starting 2 months old. Moreover, the TAB2-deficient mice are also predisposed to heart failure after pathological stress by pressure overload or myocardial infarction, suggesting a protective role of TAB2 in cardiac stress response. These results strongly indicate that TAB2 functions as a molecular switch that critically regulates the pro-survival TAK1 signaling and the necroptosis machinery, thus playing a critical role in myocardial survival and stress response. The TAB2-TAK1 signaling network may serve as a novel therapeutic target in heart disease and other pathological conditions driven by necroptosis.
Why Exceptional Public Investment in the Development of Vaccines Is Justified for COVID-19, But Not for Other Unmet Medical Needs
Authors: Eline M. Bunnik, Jilles Smids
Journal: The American Journal of Bioethics (2021)

If we don't make it by 2025, what will we tell Congress and the American people?Alzheimer's disease, cancer, COVID-19 and diabetes are not engineering problems to be solved.They're diseases embodied in humans who must be cared for and who, out of great desperation, can demand we do terrible things, like the accelerated approval of aducanumab for the treatment of Alzheimer's disease.Let us rally our nation to solve the problems of Alzheimer's, cancer, COVID-19 and diabetes, but don't fly us to the moon, especially on a deadline.
Abstract 14416: The Redox Effect of Stem-Cell Derived Extracellular Vesicles on Normal and Diabetic Human Coronary Artery Endothelial Cells
Authors: Catherine Karbasiafshar, Nagib Ahsan, Giana Blume Corssac, Rayane Teixeira, Frank W Sellke, Ruhul Abid
Journal: Circulation (2021)

Introduction: Cardiovascular disease continues to be the leading cause of death globally, necessitating the study of novel therapeutic modalities. Following the lack of success with stem-cell based therapies, their extracellular vesicles (EVs) have emerged as a promising strategy. Hypothesis: We hypothesized that EVs will reduce oxidative stress in normal and diabetic human coronary artery endothelial cells (HCAEC). Methods: Human bone marrow-derived stem cells (HBMSC) were grown to passage 7 and subject to 24 hours of preconditioning by serum starvation media. EVs were then isolated via ultracentrifugation and submitted for LC-MS/MS for proteomics. Normal HCAEC and diabetic HCAEC (DM-HCAEC) were starved for 12 hours then treated with vehicle (1% DMSO in PBS) or EVs (1x108 particles/ml) for 6 hours. Following treatment, mitochondrial (mito) ROS using mitosox, total ROS using DCF-DA, and protein expression using Western blots were analyzed by 2-way ANOVA with Bonferroni multiple-comparisons correction. Results: A total of 473 EV proteins were identified, among which were antioxidants catalase, thioredoxin, peroxiredoxins, SOD1, and ferritin. EV-treatment reduced mito-ROS levels significantly in HCAEC, but not in DM-HCAEC. Basal (ambient) levels of total ROS in DM-HCAEC were significantly higher compared to HCAEC (p=0.0393), however, EV treatment reduced total ROS in both cell types significantly (p=0.002). Western blot analysis revealed that EV increased mitochondrial antioxidant MnSOD (SOD2) levels in HCAEC but not in DM-HCAEC. Catalase expression was unaffected by EV treatment in both cell types. Conclusions: EVs displayed differential effects on the mito-ROS, but reduced total ROS in both HCAEC and DM-HCAEC. EV-induced reduction in mito-ROS in non-diabetic HCAEC plausibly resulted from corresponding increase in MnSOD expression. Data from our ongoing studies will be presented at the meeting demonstrating whether the above changes in redox states by EVs correspond to differential proliferation, migration and angiogenesis in HCAEC vs. DM-HCAEC.
Abstract 9889: Novel Mechanisms of Cardiac Macrophage-Mast Cell Interactions in Radiation-Induced Myocardial Fibrosis
Authors: Swati D Sonkawade, Arezoo Momeni, Shirley Xu, Saraswati Pokharel, Umesh C Sharma
Journal: Circulation (2021)

Introduction: Both galectin-3 (gal3) and macrophages are implicated in myocardial fibrotic remodeling. Macrophages express gal3 on their surface, whereas mast cells express a high-affinity gal3 receptor, FcεRI. Understanding the mechanisms of their interactions will lead to highly targeted therapeutic approaches. Hypothesis: We hypothesize that a macrophage-expressed pro-fibrotic molecule, gal3, is a mediator of macrophage-mast cell interactions in a pre-clinical model of radiation-induced myocardial fibrosis. Methods: We studied myocardial fibrosis, cardiac macrophage-mast cell infiltration, and gal3 expression in a rodent model of thoracic radiation. We performed long-term culture of the bone-marrow cells isolated from gal3 KO (gal3 -/- ) and gal3 overexpression (gal3 +/+ ) mice. Recombinant M-CSF co-cultured cells transformed to macrophages (F4/80 + /CD11B + ), whereas IL-3-treated cells transformed to mast cells (FCεR1 + /c-kit + ). Then, we used microfluidic and transwell systems to examine the gal3-dependent macrophage-mast cell interactions in the live cell culture. Results: Thoracic radiation exposure induced myocardial fibrosis (% fibrosis, radiation: 5±2, controls: 2±0.6; p=0.01, N=5-8), which was also associated with macrophage (cells/cm 3 , radiation: 114±28, controls: 81±0.3; p=0.05, N=8) and mast cell (cells/cm 3 , radiation: 14±5, controls: 9±0.3; p=0.05, N=5-8) infiltration, and cardiac gal3 expression (pg/ng, radiation: 85±15, controls: 14±8; p=0.001, N=7). Exogenous gal3 treatment led to increased mast cell tryptase activity confirming their activation [tryptase (ng/ml), untreated: 291±46, gal3: 494±191; p&lt;0.01, N=3-8]. Quantitative macrophage-mast cell activity in a microfluidic system showed 7.5-fold increased macrophage-mast cell adhesion in gal3 +/+ cells suggesting increased interactions with gal3 overexpression [cell adhesion (cells/mm 2 ), WT: 23±5.8, Gal3 +/+ :175±38; p&lt;0.01, N=4]. Conclusion: In a pre-clinical model of radiation-induced myocardial fibrosis, gal3 can mediate crucial macrophage-mast cell interactions. Our data provide possible mechanistic evidence of gal3 involvement in macrophage-mast cell interactions en route to myocardial fibrosis after radiation exposure.
CTNI-14. EVALUATING METABOLIC ALTERATIONS IN PATIENTS WITH EGFR ACTIVATED RECURRENT GLIOBLASTOMA (RGBM) BY INHIBITING EGFR WITH OSIMERTINIB
Authors: Timothy Cloughesy, Benjamin Ellingson, Andrei Gafita, Saewon Chun, Emese Filka, Phioanh Nghiemphu, Albert Lai, Stacey Green, Jonathan Tsang, Yao Jingwen, Jeremie Calais, Ida Sonni, Gang Li, David Nathanson
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND EGFR activated GBM is highly metabolically active and effective targeting with EGFR TKis in human-tumor models rapidly attenuates glucose metabolism engaging apoptotic machinery. Rapid changes in glucose uptake using 18F-FDG-PET is an effective predictive biomarker of therapeutic response in these models. Clinical 18F-FDG-PET may allow investigators to obtain early readout on EGFR TKi in this patient population. We explore this approach using osimertinib in EGFRamp/p53wt rGBM. METHODS EGFRamp/p53wt rGBM patients were treated with oral osimertinib 240mg for three days followed by 160mg/day until progression. F18-FDG-PET scan was obtained as a double baseline, 24 hours apart, prior to dosing with osimertinib. Third scan was obtained after 3 doses of 240mg. Primary objective defines test-retest variance of tumor FDG uptake before osimertinib and to evaluate if osimertinib significantly decreases glucose utilization after three doses. Study-drug and funding provided by AstraZeneca. RESULTS 12 pts were evaluated, 10 female, median age 57.5 years (44-61). Volumetric mRANO showed no responses, 6 SD, 5 PD, and one NE. Median PFS was 31 days, no patient achieved 6-month-PFS and median OS was 5.5 months. No new adverse event signal appeared. Double baseline PET SUV mean was 0.97 (normalized to whole cerebellum) with upward trend from first to second scan with mean percent change of 2.8 and 95% CI(0.7,5.1). Change in PET from 2nd to 3rd showed mean percent change -3.2 with 95% CI (-11.1,4.8). Preclinical models suggest 15-20% attenuation is needed to predict improved outcomes in patients treated with EGFR-TKi. CONCLUSION F18-FDG-PET has little variance with test-retest showing upward trend with second scan. Post osimertinib F18-FDG-PET shows limited attenuation of tumor FDG uptake. No clinical signal was seen in study. Deeper attenuation of FDG uptake may be needed to show clinical effect from EGFR inhibitors. F18-FDG-PET can be used to evaluate change in tumor glucose utilization.
Safety and Efficacy of Daratumumab with Ixazomib and Dexamethasone in Patients with One Prior Lenalidomide-Based Regimen: Outcomes of the Phase 2 Daria Study
Authors: Evangelos Terpos, Maria Gavriatopoulou, Eirini Katodritou, Evdoxia Hatjiharissi, Ioanna Dialoupi, Evgenia Verrou, Alexandros Leonidakis, Magdalini Migkou, Sosana Delimpasi, Argiris Symeonidis, Efstathios Kastritis, Meletios A. Dimopoulos
Journal: Blood (2021)
Abstract 13710: Long-Term Survival After Stroke Hospitalisations in Australia and New Zealand, 2008-2017: A Population-Based Cohort Study
Authors: Yang Peng, Linh Ngo, Isuru Ranasinghe
Journal: Circulation (2021)

Introduction: There is a paucity of national data on the long-term survival after stroke in Australia and New Zealand. We assessed survival up to 10 years, and factors associated with survival, following a stroke hospitalisation. Methods: We included all adults with the first stroke hospitalisation in the study period at all public and most private hospitals in Australia and New Zealand during 2008-2017. All-cause mortality up to December 31, 2017 were assessed by linking to regional death registries. Incidence rates of mortality and hazard ratios (HRs) were calculated. Results: 313,162 patients were included (mean ± SD age 73.0 ± 14.6 y, 52.0% were male) with ischemic stroke (175,547, 56.1%) is the most prevalent type, followed by haemorrhagic stroke (77,940, 24.9%) and unspecified stroke (59,675, 19.1%). Of these patients, 140,751 (44.9%) died in the follow-up period. The overall survival probability was 79.5% at 3 months, 73.0% at 1 year, 52.8% at 5 years and 38.8% at 9 years. The incidence rate of all-cause mortality declined with time post-stroke, from 986.6 per 1,000 person-years within 3 months to 76.7 per 1,000 person-years in 5-10 years. In the multivariable analysis, a haemorrhagic stroke (HR, 2.00; 95% confidence interval (CI), 1.97-2.03) and older age (85 years or older vs 18-54 years: aHR, 7.21; 95% CI, 7.00-7.42) was associated with a poorer prognosis. A history of congestive heart failure (aHR, 1.49; 95% CI, 1.46-1.52), acute coronary syndrome (aHR, 1.04; 95% CI, 1.01-1.07), vascular disease (aHR, 1.20; 95% CI, 1.17-1.24), and several non-cardiac conditions could also increase the mortality risk. Conclusions: Only 38.8% of stroke patients in Australia and New Zealand could survive over 9 years since their first stroke hospitalisations. Risk of death is especially high for the first few months after stroke. Further efforts are needed for those with increased risk of deaths.
Inherited TP53 Variants and Risk of Prostate Cancer
Authors: Kara N. Maxwell, Heather H. Cheng, Jacquelyn Powers, Roman Gulati, Elisa M. Ledet, Casey Morrison, Anh Le, Ryan Hausler, Jill Stopfer, Sophie Hyman, Wendy Kohlmann, Anne Naumer, Jennie Vagher, Samantha E. Greenberg, Lorraine Naylor, Mercy Laurino, Eric Q. Konnick, Brian H. Shirts, Saud H. AlDubayan, Eliezer M. Van Allen, Bastien Nguyen, Joseph Vijai, Wassim Abida, Maria I. Carlo, Marianne Dubard-Gault, Daniel J. Lee, Luke D. Maese, Diana Mandelker, Bruce Montgomery, Michael J. Morris, Piper Nicolosi, Robert L. Nussbaum, Lauren E. Schwartz, Zsofia Stadler, Judy E. Garber, Kenneth Offit, Joshua D. Schiffman, Peter S. Nelson, Oliver Sartor, Michael F. Walsh, Colin C. Pritchard
Journal: European Urology (2021)

Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53.To determine whether gTP53 predisposes to prostate cancer.This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort.We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer.We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis.Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing.Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.
Abstract 13232: Prokineticin as a Biomarker of Cardiotoxicity in Cancer Patients
Authors: Canan G Nebigil, Anaïs AUDEBRAND, Daniela Cardinale
Journal: Circulation (2021)

Many anticancer drugs are highly effective for cancer treatments. However, they triggerclinically significant cardiovascular morbidity and in some case mortality. Recently,experimental data support an important protective role of prokineticin-2, a cytokine, againstanthracycline-mediated cardiovascular toxicity. The aim of this study was to examine thelevels of plasma prokineticins (PROK1 and PROK2), and clinically used cardiac biomarkers(Troponin-T, Brain Natriuretic peptide) to assess possible correlations of these cytokines withrisk and severity of cardiotoxicity of cancer treatments. 200 patients with different type oftumor (mostly breast cancer, and ovarian cancer, urinarybladder cancer or other types oftumors), were enrolled. They were scheduled for cancer treatments including anthracyclinesalone, monoclonal antibody-based tyrosine kinase inhibitors TKI alone, a combination ofanthracyclines and TKI, and a combination of both anticancer agents and taxanes. Theexclusion criteria were previous anticancer treatments and cardiovascular pathologies suchashypertension, cardiomyopathy, coronary artery disease, life threatening arrhythmias, andongoing cardiovascular treatments. High-sensitive troponin I (TNI), BNP, PROK1 and PROK2were assessed in the plasma and cardiac systolic function (left ventricular ejection fraction,LVEF) were assessed by ECHO atbaseline and at 3, 6, 12 months after the completion of theoncology treatments. 42/142 patients (33%) showed an increase in TNI during or soon afterthe completion of cancer therapy. All patients (except for2) with an elevated TNI received acardioprotective therapy with enalapril. LVEF gradually and significantly decreased frombaseline during the observational period (P&lt;0.001). This was associated with increased levelsof TNI levels during and soon after cancer treatments. BNP levels remained unaltered. PROK1levels (N=63) had slightly, but not significant increased. PROK2 levels significantly increased(N=63) from baseline. This pilot study confirmed the role of TNI in predicting chemotherapy-mediated cardiotoxicity, and identified for the first time PROK2 as potential biomarker thatmay help to identify patients more prone to develop cardiotoxicity.