tbuckley/cabot-search huggingface dataset:
Abstract 12803: Human IPSC-Derived Committed Cardiac Progenitor Cells Engraft and Differentiate Following Transendocardial Injections in a Swine Ischemic Heart Failure Model
Authors: Amish N Raval, Eric G Schmuck, Sushmita Roy, Yukihiro Saito, Tianhua Zhou, Timothy A Hacker, Chad Koonce, Meghan Boyer, Kristin Stack, Ellen Hebron, Scott Nagle, Patrick Hsieh, Timothy J Kamp
Journal: Circulation (2021)

Introduction: A hallmark of human myocardium is the inability to regenerate functional myocardium following myocardial infarction (MI) which can result in heart failure. In an effort to remuscularize infarcted myocardium, we tested a novel human iPSC-derived committed cardiac progenitor (CCP) cell population. Whether CCPs survive and differentiate to form grafts following transcatheter delivery in a clinically representative large animal model is unknown. Hypothesis: We hypothesized that transendocardial injection (TEI) of CCPs, combined with a cardiac fibroblast-derived matrix (CFM) particles as a cell retention agent leads to functional cardiac tissue grafts. Methods: Large MI following coronary artery balloon-occlusion reperfusion was induced in mini-swine that received a 4-drug immunosuppression regimen. 28 days later, TEI targeting the peri-infarct region was performed using combinations of 200 million CCPs with or without 50 mg CFM particles and Flexbumin control. 14 injections/pig were performed, and animals were followed for 4-8 weeks. Histopathology, continuous ECG recording and cardiac MRI were performed. Results: Human cell grafts were identified using Ku80+ human cell specific antibody in the initial n=11 evaluable CCP treated swine after 1 month (see representative image, Ku80+ human cells=green). The CCPs largely differentiate into TnI positive cardiomyocytes (red) in grafts observed at one month. Immunolabeling for a panel of cardiomyocyte markers confirmed the presence of human cardiomyocytes. Of n=29 initial pigs, no treatment-related safety issues were identified, such as post TEI pericardial effusion, ventricular tachyarrhythmias or tumors. Conclusions: TEI of CCPs, with and without CFM, resulted in grafts of human cardiomyocytes in the myocardium of immunosuppressed pigs, after 1 month post MI. Ongoing cardiac MRI analyses will determine the impact of CCP therapy on cardiac structure and function.
EXTH-41. IMPROVING THE RADIOSENSITIVITY OF DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG) BY TARGETING HYPOXIA AND MITOCHONDRIAL METABOLISM
Authors: Han Shen, Cecilia Chang, Prunella Ing, Kristina Cook, Kelly McKelvey, Joey Lai, Brian Gloss, Victoria Prior, Geraldine O'Neill, Anneke Blackburn, Harriet Gee, Eric Hau
Journal: Neuro-Oncology (2021)

Abstract DIPG is the leading cause of brain tumor-related death in children. Radiotherapy is the only treatment that offers transient benefit and provides palliative care. DIPGs are hypo-perfused with tumor cells being exposed to hypoxia, a potent barrier to effective radiotherapy. Reducing the oxygen consumption rate (OCR) is therefore a potential strategy to reduce tumor hypoxia. We therefore performed a high-throughput screening with 1963 FDA-approved drugs that could reduce tumor hypoxia and OCR, thereby improving radiosensitivity of DIPGs. A subset of anti-diabetic drugs was identified, with phenformin amongst the most potent. It significantly reduced OCR in a panel of DIPG cultures and subsequently suppressed hypoxia in 3-dimensional DIPG neurosphere models that mimic the hypoxic microenvironment. In addition, phenformin demonstrated greater anti-tumor activity and radiosensitizing effect with much lower doses compared with metformin, a less potent biguanide that improved radiosensitivity of DIPG in a patient-derived xenograft (PDX) model in our previous study. The effect of phenformin was further enhanced by combining a second drug dichloroacetate that simultaneously attenuated phenformin-induced acidification rate. Specifically, the combination of phenformin and dichloroacetate induced higher levels of hypoxia inhibition, reactive oxygen species, DNA damage and apoptosis. RNA sequencing demonstrated significant changes induced by the combination treatment in cell-cycle, DNA repair, unfolded protein response and alternative energetic pathways. These changes were further validated by PCR array and western blotting at mRNA and protein levels. In addition, two master regulators that enhance the metabolic capacity of tumor cells through increased glycolysis thus contributing to radioresistance, HIF-1α and c-Myc, were also significantly suppressed by combination treatment. Ultimately, the triple combination of phenformin, DCA and irradiation demonstrated the most potent efficacy in inducing DNA damage, apoptosis and clonogenic inhibition in DIPG cultures. This promising triple combination therapy is currently being tested in our PDX cohort in vivo.
Abstract MP256: CCCTC-binding Factor Site Mutation In <i>Sirt1</i> Promoter Reduces Systolic Cardiac Function In Mice
Authors: Tobias Wagner, Rudi Micheletti, Havilah Taylor, Yousin Suh, Michael G Rosenfeld, Alice E Zemljic-Harpf
Journal: Circulation Research (2021)

Regulation of the geroprotective histone-deacetylase SIRT1 is an important physiological strategy to protect against cardiovascular disease. SIRT1 activity regulates the oxidative stress response, DNA damage pathways, cell death, and cardioprotective SIRT1 levels decreases with age. Based on this and GWAS studies implicating misregulation linked to myocardial infarction risk, we hypothesized that disrupting proximal promoter regulation of SIRT1 causes cardiac stress. Focusing on Single Nucleotide Polymorphisms (SNPs) in the SIRT1 promoter, we used reporter gene assays to test if the transcriptional regulation of SIRT1 after oxidative stress is altered by the SNPs. Identifying a candidate A/G polymorphism at the -92 position in the promoter of SIRT1 , we show that the presence of the minority allele causes a disrupted epigenetic activation of SIRT1 . In model cell systems, binding of CCCTC-binding factor (CTCF) in the promoter of SIRT1 is reduced after oxidative stress in cells carrying the minority allele, correlating with a lack of activation of stress-protective SIRT1 expression in iPSC-derived cardiomyocytes. To investigate the physiological consequences of this mutation, we used Crispr/Cas9 to generate global Sirt1 promoter CTCF site mutant (Sirt1-mut) mice. Echocardiography in 7-month-old male mice shows reduced FS% (control 31.1±1.5%, Sirt1-mut 20.9±0.8%, mean±sem, p&lt;0.0001, n=10-12 each), as well as increased LVIDs and decreased LVPWd wall dimensions in Sirt1-mut mice. RNA-seq on left ventricular cardiac tissue of 8-month-old control and Sirt1-mut mice identified 130 genes that are differentially regulated. Gene Ontology term enrichment analysis finds the differentially expressed genes are in pathways linked to regulation in response to reactive oxygen species and oxidative stress. In conclusion, we show that a mutation in the Sirt1 promoter critical for oxidative stress responses leads to systolic cardiac dysfunction. The transcriptional regulation of cardioprotective SIRT1 is an important and hitherto overlooked factor in the pathophysiology of heart failure.
Trends in Receipt of Help at Home After Hospital Discharge Among Older Adults in the US
Authors: Eric Bressman, Norma B. Coe, Xinwei Chen, R. Tamara Konetzka, Rachel M. Werner
Journal: JAMA Network Open (2021)

<h3>Importance</h3> With declining use of institutional postacute care, more patients are going directly home after hospital discharge. The consequences on the amount of help needed at home after discharge are unknown. <h3>Objective</h3> To estimate trends in the frequency and duration of receipt of help with activities of daily living (ADLs) among older adults discharged home. <h3>Design, Setting, and Participants</h3> Repeated cross-sectional study of a national sample of community-dwelling older adults who returned home after hospital discharge from 2011 to 2017. Participants included respondents to National Health and Aging Trends Study (NHATS), an annual population-based, nationally representative survey of Medicare beneficiaries, who were 69 years or older and were discharged from an acute care hospital to home during the years of the study. A nationally representative sample was estimated using NHATS' analytic weights. Unweighted frequencies and weighted and unweighted percentages are reported. The analysis was conducted from September 2020 to October 2021. <h3>Exposures</h3> Discharge from an acute care hospitalization. <h3>Main Outcomes and Measures</h3> Receipt of help with ADLs during the 3 months after hospital discharge. <h3>Results</h3> Of the 3591 survey participants who were discharged home from an acute care hospital during the study period, 53.3% were female, 54.8% were married or living with a partner, and the mean (SD) age was 78.5 (7.0) years. Of these, 1710 (44.1%) reported receiving help within 3 months of discharge. Compared with people not receiving help, those receiving help were older (mean [SD] years, 79.7 [7.5] years vs 77.6 [6.3] years), had worse self-rated health at baseline (47.1% with fair or poor health vs 26.5%) and were more likely to have dementia (21.8% vs 5.5%). The percentage of respondents who reported receiving help increased during the study period from 38.1% of hospital discharges in 2011 to 51.5% in 2017. For those who were independent in their ADLs before hospitalization, the percentage receiving help after discharge more than doubled over the study period increasing from 9.3% receiving help in 2011 to 31.8% in 2017. Among patients who did not receive Medicare-reimbursed home health, the percentage receiving help also increased from 22.1% to 28.1%. Among those who received help after discharge, the need for help slowly declined to prehospitalization levels over the ensuing 9 months. <h3>Conclusions and Relevance</h3> In this cross-sectional study, older adults' receipt of help at home after hospital discharge increased from 2011 to 2017, including patients relying on non-Medicare funded sources of care. As payers steer patients away from inpatient postacute care facilities, policymakers will need to pay attention to this shifting burden of care.
112P Immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in cancer patients receiving immunotherapy agents
Authors: F. Longo Muñoz, A. Cortés Salgado, J.J. Serrano Domingo, J.L. Casado, A. Vallejo, C. Saavedra Serrano, J. Chamorro Pérez, D.I. Rosero Rodríguez, H. Velasco, A. Martin, A. Soria, M.E. Olmedo Garcia, A. Gomez Rueda, Y. Lage, T. Alonso Gordoa, J. Molina Cerrillo, P. Gajate Borau, Í. Martínez del Frade, P. Garrido Lopez, A. Carrato-Mena
Journal: Annals of Oncology (2021)
Abstract 11285: Non-Vitamin K Antagonist Oral Anticoagulant Drug-Drug Interactions in Patients with Atrial Fibrillation Using Dronedarone and Non-Dronedarone Antiarrhythmic Drugs
Authors: Victor Chien-Chia Wu, Chun-Li Wang, Yu-Chang Huang, Hui-Tzu Tu, Yu-Tung Huang, Chang-Fu Kuo, Shao-Wei Chen, Kuo-Chun Hung, Ming-Shien Wen, Shang-hung Chang
Journal: Circulation (2021)

Introduction: Non-vitamin K antagonist oral anticoagulant (NOAC) do not normally require INR-monitoring. We aimed to investigate drug-drug interactions of NOACs in patients with atrial fibrillation (AF) using antiarrhythmic drugs. Hypothesis: Dronedarone may have less drug-drug interaction compared to non-dronedarone antiarrhythmic drugs. Methods: National Health Insurance Research Database were retrieved between 2012 and 2017 for patients with AF. We excluded patients not taking antiarrhythmic drugs, bradycardia, heart block, history of heart failure, mitral stenosis, prosthetic valve, incomplete demographic data, and follow-up &lt;3 months. Primary outcomes were major bleeding, intracranial hemorrhage, and gastrointestinal bleeding. Results: In total, 84,933 patients used NOAC in patients with AF were enrolled. After exclusion criteria, there were 26,773 patients with 204,937 person-quarters remained for analysis after the exclusion criteria were applied In terms of major bleeding, there was no increased major bleeding due to DDI between NOAC and dronedarone (adjusted rate ratio [aRR]: 0.77, 99% confidence interval [CI]: 0.54-1.12, p = 0.074). In terms of intracranial hemorrhage, there was no increased major bleeding due to DDI between NOAC and dronedarone (aRR: 0.64, 99% CI: 0.34-1.20, p = 0.0668). In terms of gastrointestinal bleeding, there was no increased major bleeding due to DDI between NOAC and dronedarone (aRR: 0.86, 99% CI: 0.55-1.35, p = 0.3819). Conclusions: In this study, NOACs and dronedarone coprescription is not associated with an increased risk of major bleeding, intracranial hemorrhage, nor gastrointestinal bleeding. The results suggest that such NOAC with dronedarone coprescription should be practiced in place of NOAC with amiodarone when the clinical criteria are appropriate.
Abstract 14113: Age-Related Demographic Trends in Mortality Due to Ischemic Heart Disease in the United States From 1999 to 2019
Authors: Mohammed Essa, Alireza Ghajar, Augustin DeLago, Matthew Hammond-Haley, Joseph Shalhoub, Dominic Marshall, Justin Salciccioli, Lissa Sugeng, Binu Philips, Kamil Faridi
Journal: Circulation (2021)

Introduction: United States Ischemic heart disease (IHD) mortality has decreased recently. mortality trends for demographic groups across different ages have not been well described. Hypothesis: Different age groups have different IHD mortality trends Methods: WWe performed a nationwide analysis using the CDC WONDER database to evaluate IHD mortality trends from 1999 to 2019. Crude mortality rates per 100,000 were evaluated by sex, race, ethnicity and ten-year age groups. We used Joinpoint linear regression to assess average annual percentage change (AAPC) in IHD-related mortality. Results: From 1999 to 2019, IHD mortality decreased from 189.8 to 110.0/100,000 (AAPC -2.9%, 95% CI -3.3 to -2.6%) nationally. Compared to the 65-74 year age group (AAPC -1.7%, 95% CI -1.9 to -1.4%), decline in IHD-related mortality was lower for 35-44 year (-0.4%, 95% CI -0.4 - 0.0%; p &lt; 0.001), 45-54 year (-0.4%, 95% CI -0.5 to -0.3%; p &lt; 0.001), and 55-64 year (-0.5%, 95% CI -0.8% to -0.2%; p &lt; 0.001) age groups but similar for the 75-84 year group and higher for ≥85 year age group. Black populations had the highest mortality rates among men and women across all age groups except men ≥85 years old. All the studied groups had significant decreases in mortality between 2002 and 2010. From 2010 to 2019, all groups had significant decreases in mortality except for 35-44 year-old minority groups (black women AAPC -0.7%, 95% CI -2.3% to 1.0%; black men -0.6%, 95% CI -1.7% to 0.6%; Hispanic women 0.9, 95% CI -1.7% to 3.6%; Hispanic men 0.3%, 95% CI -0.9% to 1.5%) (Figure). Conclusions: U.S. populations &lt;65 years old have had slower declines in IHD-related mortality than those ≥65 years, and black populations continue to have the highest IHD-related mortality across almost all age groups. Since 2010, black and Hispanic populations between 35 and 44 years old have not had significant decreases in IHD-related mortality. Greater focus on prevention and treatment of IHD in younger and minority populations is needed.
Treatment Updates in Acute Myeloid Leukemia
Authors: Alexander E. Perl
Journal: Journal of the National Comprehensive Cancer Network (2021)

The NCCN Guidelines for the management of acute myeloid leukemia (AML) have, for the most part, remained unchanged from 2020, with some shifts in emphasis, fine-tuning, and several important updates in the 2021 version. The guidelines now emphasize physiologic age rather than chronologic age, and recommend that fit patients should receive intensive chemotherapy. Actionable genetics are being used to guide selection of therapy. Minimal residual disease assessment after induction therapy is now incorporated in the guidelines. New therapeutic options include oral azacitidine and combination venetoclax + azacitidine, and preliminary evidence suggests that IDH inhibitors will come to the fore in the treatment of AML.
Abstract 12556: The Matrikine Proline-Glycine-Proline is a Novel Biomarker of Coronary Artery Disease Amongst Patients With Chronic Obstructive Pulmonary Disease
Authors: Jean Paul O Osula, Vivian Lin, Chunyan Song, Xin Xu, Dongqi Xing, James M Wells, Gregory A Payne
Journal: Circulation (2021)

Introduction: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of coronary artery disease (CAD). Proline-glycine-proline (PGP) is an extracellular matrix-derived chemokine ( matrikine ) that is increased in COPD and known to promote neutrophil chemotaxis, endothelial dysfunction, and vascular inflammation through activation of the CXC Chemokine Receptor 2 (CXCR2). Despite these observations, no study has examined PGP as a marker of CAD within COPD patients. Hypothesis: We hypothesized that circulating PGP is associated with comorbid CAD amongst COPD patients. Methods: Current and former smokers with COPD enrolled in the UAB P rospective R epository for coupling EVE nts to N ovel pa T hways in COPD (PREVENT COPD) cohort underwent phlebotomy and spirometry. Cardiovascular diagnoses were adjudicated by two physician reviewers with access to medical records. CAD was defined as a composite of prior myocardial infarction, coronary revascularization, or by physician diagnosis of CAD. Plasma PGP was measured using a solid-phase extraction method coupled with tandem mass spectrometry. Other known CXCR2 ligands (e.g. GRO alpha, IL-8) were measured by multiplex protein assay. SPSSv27 was used for logistic regression models to measure associations between plasma biomarkers and the presence of CAD. Results: The 104 participants were 60±9 years old, 50% male, and 50% Black race. CAD was prevalent in 21 (21%) of the cohort. Plasma PGP was detectable for all participants (0.05 - 15.1 ng/mL). Participants with CAD had higher PGP concentrations compared to participants without CAD (1.26 vs. 0.52 ng/mL, p=0.042). Similarly, PGP was increased among participants with prior coronary revascularization (p&lt;0.01). Associations between plasma PGP and CAD remained significant after adjustment for FEV1 % predicted and smoking status (OR 1.62, 95%CI 1.02-2.56). Concentrations of other CXCR2 ligands were low and not associated with CAD. Conclusions: Our results highlight PGP as a potentially novel biomarker of CAD among individuals with COPD. Future studies are needed to assess whether plasma PGP is predictive of CAD outcomes in COPD, as well as determine the significance of endothelial CXCR2 activation on the development of atherosclerosis.
DDRE-04. EFFECTIVENESS AND SAFETY OF OSIMERTINIB FOR PATIENTS WITH LEPTOMENINGEAL METASTASES FORM NON-SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Lei Wen, Changguo Shan, hui Wang, yanying Yang, Minting Ye, Weiping Hong, Linbo Cai
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND the FLAURA study established Osimertinib to be the priority choice for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring mutated epidermal growth factor receptor (EGFR). However, like many previous studies, the FLAURA study excluded patients with symptomatic CNS metastases. Hence, we performed a systematic review and meta-analyses of studies to assess the efficiency and safety of Osimertinib for the treatment of NSCLC with leptomeningeal metastases (LM). METHODS We included studies published between 2010 and 2021 that evaluated the efficacy and toxicity of Osimertinib in NSCLC patients with LM. We searched PubMed, Embase, and oncology meeting abstracts (ASCO, ESMO and WCLC). Primary outcomes were objective response rate (ORR), disease control rate (DCR), any grade 3/4 toxicity rate. We used the random-effects model to generate pooled estimates for proportions. Newcastle-Ottawa Scale (NOS) was used to assess the certainty in the evidence. RESULTS Twelve studies reporting on 367 patients were included in the meta-analysis. Most patients (≥90%) received Osimertinib as at least second line of treatment. The objective response rate was 42% (95% CI, 24%-59%; n = 184), and CNS disease control rate was 90% (95% CI, 85%-94%; n = 154). Intracranial progression free survival and overall survival ranged from 3.7 to 15.6 months, and 11.0 to 18.8 months, respectively. Adverse events were similar with previous studies and Common Terminology Criteria for Adverse Events (version 3.0) grade 3 or higher adverse event rates was acceptable. CONCLUSION This meta-analysis confirmed that for advanced NSCLC with LM harboring EGFR-TKI-sensitizing mutations, Osimertinib showed impressive antitumor activity and acceptable toxicity.
EPID-15. AGE AND DOSIMETRIC IMPACTS ON RADIOTHERAPY ASSOCIATED GROWTH IMPAIRMENT FOR PATIENTS WITH INTRACRANIAL GERM CELL TUMORS (GCTs)
Authors: Guanhua Deng, Zhaoming Zhou, Juan Li, Mingyao Lai, Qingjun Hu, Cheng Zhou, Linbo Cai
Journal: Neuro-Oncology (2021)

Abstract PURPOSE Intracranial germ cell tumors (GCTs) are rare pediatric central nervous system (CNS) tumors. Growth impairment induced by radiation treatments was rarely evaluated. We aimed to study the impacts of radiotherapy on height development and identify the dosimetric constraints. MATERIALS AND METHODS A total of 148 pediatric patients diagnosed with GCTs were retrospectively analyzed. Sex, age at irradiation, physical doses and biologically effective dose (BED), height, and endocrine status were obtained from patient records. The cumulative change in height was assessed using age-matched normalized height (ANH). Variables were assessed for correlations and statistical significance. RESULTS Cumulative physical doses and BEDs for the whole brain and pituitary were derived via DVHs and BEDVHs. In contrast to patients &amp;gt;11.5 yr, linear correlations between ANH and cumulative physical doses as well as BEDs to the whole brain and pituitary were identified in patients≤11.5 yr. Dosimetric constrains to the pituitary was 36 Gy for physical dose (AUC=0.70 [95% CI, 0.54-0.86], P&amp;lt; 0.05) and 63 Gy2 BED (AUC=0.69 [95% CI, 0.53-0.86], P&amp;lt; 0.05). Intriguingly, no significant differences in ANH were found among different CSI dose groups in patients ≤11.5 yr. (all P&amp;gt;0.05). Impaired hormone secretions in terms of GH and TSH were identified following cranial irradiation (both P&amp;lt; 0.001), particularly for those with tumors at the suprasellar region (GH: P&amp;lt; 0.01, TSH: P&amp;lt; 0.001). CONCLUSION Our study revealed the impacts of age, dosimetrics and tumor locations for growth impairment. This study will contribute to the optimization of radiation treatment planning and facilitate more individualized therapeutic strategies in pediatric patient with GCTs.