tbuckley/cabot-search huggingface dataset:
Abstract 11561: Pharmacological Inhibition of Rage/diaph1 Axis Enhances Weight Loss in Diet Induced Obese Mice and Improves Glucose Homeostasis
Authors: Robin Wilson, Lakshmi Arivazhagan, Henry Ruiz, Michaele Manigrasso, Ravichandran Ramasamy, Ann Marie Schmidt
Journal: Circulation (2021)

Introduction: The incidence of obesity and its comorbidities has soared at an alarming rate in US and around the world. Our previous studies have shown that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and insulin resistance. Both global and adipocyte-specific Ager (gene encoding RAGE) deleted mice fed a high fat diet (HFD) showed protection from weight gain and insulin resistance. However, if RAGE deletion/inhibition affects weight loss in mice with established obesity is under investigation. We have discovered novel small molecule antagonists of the interaction between the cytoplasmic domain of RAGE with its intracellular effector Diaphanous 1(DIAPH1). We tested the hypothesis that these chow containing small molecule antagonists vs. vehicle might enhance weight loss and improve metabolic function in obese mice undergoing weight loss. Methods: Male mice (C57BL/6, N=78) were fed HFD (60% kcal/fat) for 20 weeks starting at 8 weeks of age to establish obesity; mice were then switched to either low fat RAGE/DIAPH1 inhibitor diet (N=40) or vehicle diet (N=38). Body mass was serially monitored and after six weeks of medicated chow vs. vehicle, glucose and insulin tolerance, body composition, plasma insulin and lipids were measured. Adipocyte size was monitored by histology. Results: Six weeks administration of RAGE/DIAPH1 antagonist in mice with established obesity resulted in significantly greater weight loss and fat mass vs. vehicle treatment. Further, metabolic recovery was enhanced, as evidenced by greater improvement in glucose tolerance and reduced plasma insulin and cholesterol levels. Histology revealed that epididymal and subcutaneous adipose tissues displayed smaller mean adipocyte size in mice receiving the RAGE/DIAPH1 antagonists vs. vehicle. Conclusion: Pharmacological inhibition of RAGE/DIAPH1 axis in mice with established obesity enhances weight loss, and improves metabolic recovery.
A novel Iowa–Mayo validated composite risk assessment tool for allogeneic stem cell transplantation survival outcome prediction
Authors: Kalyan Nadiminti, Kimberly Langer, Ehsan Shabbir, Mehrdad Hefazi, Lindsay Dozeman, Yogesh Jethava, Bradley Loeffler, Hassan B. AlKhateeb, Mark Litzow, Mrinal Patnaik, Mithun Shah, William Hogan, Umar Farooq, Margarida Silverman, Sarah L. Mott
Journal: Blood Cancer Journal (2021)

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematologic conditions and is associated with considerable morbidity and mortality. Therefore, prognostic tools are essential to navigate the complex patient, disease, donor, and transplant characteristics that differentially influence outcomes. We developed a novel, comprehensive composite prognostic tool. Using a lasso-penalized Cox regression model (n = 273), performance status, HCT-CI, refined disease-risk index (rDRI), donor and recipient CMV status, and donor age were identified as predictors of disease-free survival (DFS). The results for overall survival (OS) were similar except for recipient CMV status not being included in the model. Models were validated in an external dataset (n = 378) and resulted in a c-statistic of 0.61 and 0.62 for DFS and OS, respectively. Importantly, this tool incorporates donor age as a variable, which has an important role in HSCT outcomes. This needs to be further studied in prospective models. An easy-to-use and a web-based nomogram can be accessed here: https://allohsctsurvivalcalc.iowa.uiowa.edu/ .
Abstract 10253: Sin3a Gene Delivery Restores Bmpr2 Expression Through Foxk2 in Pulmonary Arterial Endothelial Cells and Inhibits Sugen/Hypoxia-Induced Pah
Authors: Malik Bisserier, shihong zhang, Peter Dorfmuller, Marc Humbert, Thomas Weber, Frederic Perros, Yassine Sassi, Sebastien Bonnet, Lahouaria Hadri
Journal: Circulation (2021)

Background: Pulmonary arterial hypertension (PAH) is a fatal lung disease of multifactorial etiology, with no curative treatment. Several studies have previously suggested that the loss of BMPR2 expression is associated with a severe hemodynamic profile and poor outcomes in PAH patients. Furthermore, preclinical studies showed that the loss of BMPR2 function is sufficient to induce a PAH-like phenotype. Recently, our group showed that SIN3a (Switch-Independent 3) plays a critical role in the epigenetic regulation of BMPR2 expression in human pulmonary arterial smooth muscle cells (hPASMC). However, our preliminary data suggested that SIN3a regulates BMPR2 expression through a different pathway independently of DNA-methylation in human pulmonary arterial endothelial cells (hPAEC). Methods/Results: We found a significant downregulation of SIN3a expression in the PAEC isolated from PAH patients. In hPAEC, our results showed that SIN3a inhibits cell proliferation, migration and upregulates BMPR2 independently of the methylation status by upregulating the FOXK2 transcription factor. Using a loss-of-function approach using a specific shRNA against FOXK2, we found that the loss of FOXK2 expression using a specific shRNA decreased the expression of BMPR2 in hPAECs. Interestingly, we found that SIN3a overexpression in FOXK2-depleted hPAEC restored the expression of BMPR2. Our results also showed that SIN3a regulates hPAEC proliferation in a FOXK2-dependant manner. Mechanistically, we found that SIN3a interacts physically with FOXK2 to promote its nuclear localization. As a result, we also found enrichment in FOXK2 abundance within the BMPR2 promoter by ChIP-qPCR in PAEC. In vivo , our results showed that restoring SIN3a expression by lentivirus-mediated gene transfer significantly decreased SuHx-induced PAH in mice, as illustrated by decreased vascular remodeling, RV hypertrophy (Fulton index, hypertrophic markers, cardiomyocyte size), and RV systolic pressure. Conclusions: Altogether, our study revealed that SIN3a plays a critical role in the regulation of BMPR2 expression through FOXK2. Additionally, our study identifies lung-targeted SIN3a gene therapy as a new promising therapeutic strategy for treating PAH patients.
Abstract 10879: Risk of Cardiac-Specific Mortality Among Ovarian Cancer Survivors: A Population-Based Study
Authors: Joseph Heaton, Motisola Mutema, Christina W Malouf, Sherlene Trotman
Journal: Circulation (2021)

Background: Ovarian cancer ranks as the fifth deadliest cancer among women and the top cause of female reproductive cancers. Studies identifying the consequences of treatment modalities are not well defined in the literature. We aim to compare the cardio-oncologic effect of therapy amongst ovarian cancer survivors. Methods: Data on patients diagnosed with ovarian cancer between 2000 and 2016 was extracted from the Surveillance, Epidemiology and End Results (SEER) registry. Patients were included when greater than 18 years of age at diagnosis and survival was 60 months or greater. Results: A total of 27,003 cancer patients were identified from the SEER registry. At diagnosis, the mean age was 55.6 ± 14.1 years; approximately 29.6% presented with localized cancer, 29.2% with regional cancer, and 37.3% with distant cancer. Overall, the median cardiac-specific survival time was 100 months compared to 80 months due to the primary cancer (log rank P &lt; 0.001). Survival estimates are plotted in Figure 1. Ten-, and fifteen-year cardiac-specific survival for ovarian cancer was 82%, and 24%, respectively. Adjusted Cox proportional hazard models revealed an increased cardiac-specific mortality when using chemotherapy alone [HR 2.210, 95% CI 1.851 to 2.640, P &lt; 0.001] and with any chemotherapy use [HR 1.937, 95% CI 1.841 to 2.037, P &lt; 0.001]. Decreased cardiac-specific mortality was noted with surgery alone [HR 0.526, 95% CI 0.459 to 0.603, P &lt; 0.001] and with combination surgery and radiation [HR 0.612, 95% CI 0.408 to 0.918, P = 0.18]. Conclusion: Survivors of ovarian cancer are burdened by cardiac sequelae. The median survival time was twenty months greater for cardiac-specific mortality than the primary cancer. Death risk from diseases of the heart was significantly increased for patients receiving chemotherapy. Figure 1. Kaplan-Meier Survival EstimatesEstimated survival times by diseases of heart, primary cancer, and all other causes of death.
EPID-26. ALIGNING THE CBTRUS HISTOLOGY GROUPS WITH 2016 WHO CLASSIFICATION OF TUMORS OF THE CENTRAL NERVOUS SYSTEM
Authors: Carol Kruchko, Nirav Patil, Gino Cioffi, Daniel Brat, Janet Bruner, Roger McLendon, Tarik Tihan, Jill Barnholtz-Sloan, Quinn Ostrom
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The Central Brain Tumor Registry of the United States (CBTRUS) uses a histology grouping scheme modeled after the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) to classify cancer registry records for clinically relevant statistical reporting. Molecular studies have identified genetic features which precisely stratify tumor types, resulting in the 2016 update to the WHO Classification incorporating these markers. To continue providing clinically relevant statistics, the histology groupings have been aligned with the 2016 update. Resulting changes to groupings were assessed. METHODS In collaboration with four consulting neuropathologists the scheme was reviewed and realigned to the 2016 update. Obsolete histology nomenclature and ICD-O-3 codes were identified. Evaluation of the frequency of affected codes in the 2013-2017 data was conducted. RESULTS 417,767 total cases of primary brain and CNS tumors were diagnosed during 2013-2017 in the US. After review of the CBTRUS grouping scheme, 67 codes were noted to be obsolete, 51 codes were re-classified and 12 new codes were incorporated. This reorganization could result in grouping assignment or reporting changes for 2,588 cases (0.6%). The histology groups most significantly affected were mesenchymal tumors and neuronal and mixed neuronal glial tumors. CONCLUSIONS The 2016 revision to WHO Classification has affected collection and reporting of CNS tumors. The CBTRUS data edits program is now undergoing revision, which will become the basis of reporting. Some histology-specific molecular markers require additional data to distinguish between cases. In collaboration with CBTRUS, the NAACCR SSDI Committee developed a new variable for collection of molecular information. This variable was included in Uniform Data Standards beginning on January 1, 2018 and will be available for reporting in 2021. A 2021 update to the WHO Classification is scheduled for release later this year, requiring further classification updates.
Abstract P484: Defining Disease Specific Cardiac Regulatory Networks
Authors: Sonja Lazarevic, Zhezhen Wang, Kaitlyn Shen, Margaret Gadek, Carlos Perez-Cervantes, David Park, Ivan Moskowitz
Journal: Circulation Research (2021)

The transcriptional basis of homeostasis and disease is implied by the non-coding nature of genetic variation identified by GWAS. Functional genomic approaches to unveil the gene regulatory networks (GRNs) relevant to disease are therefore a high priority. Most models for transcriptional dysregulation presume that perturbation of a wild-type gene regulatory network causes disease risk. For example, the T-box transcription factor (TF) TBX5, is essential for atrial rhythm homeostasis and directly drives a physiologically relevant GRN composed of cardiac channel genes. Alternatively, the expression of many genes pertinent to cardiac pathology are upregulated after the removal of Tbx5, implicating a disease-specific GRN absent from the wild-type atrium. We applied TF-dependent noncoding RNA (ncRNA) profiling, using differential deep ncRNA sequencing from atria of wild-type and Tbx5 mutant mice, to identify TBX5-dependent enhancers and ncRNAs that were only activated following TBX5 removal. We hypothesized that these regulatory elements would reveal disease-response enhancers, essential for coping with atrial dysfunction. To identify the cell-specific regulatory elements, we generated cell-type specific Assay from Transposase-Accessible Chromatin (ATAC) datasets for left atrial tissue, cardiac fibroblasts, and cardiomyocytes. Overlap with the Tbx5 -repressed ncRNAs defined candidate cell-type specific regulatory elements. Candidate regulatory elements were identified upstream of Sox9, a known modulator of cardiac fibrosis, along with other cardiac stress-response pathways, including mediators of TGF-β signaling. Activation of the enhancer at Sox9 was confirmed in isolated cardiac fibroblasts treated with TGF-β. We hypothesized that the disease-acquired GRN in TBX5 mutant atria may be generalizable to other cardiac insults. We therefore examined the transcriptional and genomic changes in the left atria of the heart failure Transverse Aortic Constriction (TAC) mouse model. This analysis revealed remarkable correlation between differentially expressed genes and ncRNAs between TAC and TBX5 mutant disease models. The conservation of the coding and non-coding transcriptional response between arrhythmia and heart failure models supports a paradigm of a common disease-specific GRN that mediates the physiologic consequences of distinct cardiac diseases.
In vivo genome-wide CRISPR screens identify SOCS1 as intrinsic checkpoint of CD4 <sup>+</sup> T <sub>H</sub> 1 cell response
Authors: Aurélien Sutra Del Galy, Silvia Menegatti, Jaime Fuentealba, Francesca Lucibello, Laetitia Perrin, Julie Helft, Aurélie Darbois, Michael Saitakis, Jimena Tosello, Derek Rookhuizen, Marc Deloger, Pierre Gestraud, Gérard Socié, Sebastian Amigorena, Olivier Lantz, Laurie Menger
Journal: Science Immunology (2021)

Although CD8+ T cells undergo autonomous clonal proliferation after antigen stimulation in vivo, the expansion of activated CD4+ T cells is limited by intrinsic factors that are poorly characterized. Using genome-wide CRISPR-Cas9 screens and an in vivo system modeling of antigen-experienced CD4+ T cell recruitment and proliferation during a localized immune response, we identified suppressor of cytokine signaling 1 (SOCS1) as a major nonredundant checkpoint imposing a brake on CD4+ T cell proliferation. Using anti–interleukin-2 receptor (IL-2R) blocking antibodies, interferon-γ receptor (IFN-γR) knockout mice, and transcriptomic analysis, we show that SOCS1 is a critical node integrating both IL-2 and IFN-γ signals to block multiple downstream signaling pathways abrogating CD4+ T helper 1 (TH1) cell response. Inactivation of SOCS1 in both murine and human CD4+ T cell antitumor adoptive therapies restored intratumor accumulation, proliferation/survival, persistence, and polyfunctionality and promoted rejection of established tumors. However, in CD8+ T cells, SOCS1 deletion did not affect the proliferation but rather improved survival and effector functions, which allowed for optimal therapeutic outcome when associated with SOCS1 inactivation in CD4+ T cells. Together, these findings identify SOCS1 as a major intracellular negative checkpoint of adoptive T cell response, opening new possibilities to optimize CAR-T cell therapy composition and efficacy.
The Impact of Hypomethylating Agents and BCL-2 Inhibitor on HLA Expression on THP-1 Cells
Authors: Benjamin Peton, Melissa Valerio, Michiko Taniguchi, Ivan Rodriguez, Ebtsesam Nafie, Guido Marcucci, Monzr M. Al Malki, Lucy Ghoda, Ketevan Gendzekhadze
Journal: Blood (2021)
Abstract 10326: Do Veterans Having Superficial Femoral Artery Revascularization Have Worse Disease and Poorer Long-Term Outcomes Than Non-Veterans?
Authors: Scott Kinlay, Thomas Todoran, Simon Ostrowski, Rebecca Sherrod, Eisenhauer Andrew, Piotr Sobieszczyk
Journal: Circulation (2021)

Introduction: Veteran Affairs (VA) patients may have higher risk factors and worse outcomes after peripheral revascularization compared to patients treated in non-VA facilities. Hypothesis: Compared to non-VA patients, VA patients have higher rates of risk factors and poorer outcomes after superficial femoral artery (SFA) endovascular revascularization. Methods: We assessed long-term outcomes in all patients having SFA endovascular revascularization between 2003-2010 in 2 regional referral institutions in Boston, one a VA hospital (VA Boston) and the other a non-VA hospital (Brigham and Women’s Hospital). Atherosclerosis risk factors, lesion characteristics, and outcomes of death, repeat revascularization, and limb amputation were assessed by review of the chart and national death indices. The hazard ratio and 95% confidence interval (HR, 95%CI) of death and adverse limb events for VA versus non-VA patients were assessed by Cox proportional hazard models. Results: Of the 203 subjects, 88 were VA patients and 115 were non-VA patients and 254 limbs were revascularized. VA and non-VA patients had a similar mean age (68 vs 68 years, p=0.74), and aspirin and statin use were over 90% in both groups. VA patients had a higher prevalence of diabetes (59% vs 41%, p=0.011) and current smoking (36% vs 18%, p=0.006). The prevalence of limbs with critical limb ischemia was similar (VA: 20% vs Non-VA: 17%, p=0.51), but limbs in VA patients were more likely to have TASC C or D lesions (57% vs 43%, p=0.028), and lesions &gt; 200mm in length (44% vs 31%, p=0.044). Over an average 5.1 years follow-up, 96 patients died and 82 limbs required repeat revascularization. Compared to non-VA patients, VA patients had similar risks of death (HR=0.91, 95%CI=0.55, 1.49) and repeat revascularization (HR=1.1, 95%CI=0.67, 1.75). 17 limbs required subsequent surgical revascularization and 16 limbs had minor or major amputation with similar rates in both groups. Multivariable models showed similar results. Conclusion: In this comparison, VA patients having SFA endovascular revascularization had a higher prevalence of some atherosclerosis risk factors and more complex lesion characteristics, but similar long-term outcomes over an average 5 years.
Abstract 13966: Chronic ICD Lead Removal From the Substernal Space is Feasible Without Complication
Authors: Haris Haqqani, Russell Denman, Anil Prabhu, Amy Thompson, Mark Marshall, Bridget Portway, Ian G Crozier
Journal: Circulation (2021)

Introduction: The transvenous ICD is the device standard for treatment of ventricular arrhythmias, but ICD lead extraction from the heart and vasculature has morbidity and mortality concerns. The extravascular ICD (EV ICD) with lead placement in the anterior mediastinum (substernal space) is in development as an alternative to transvenous ICD. Described is the first reported substernal lead removal experience from humans. Hypothesis: The anterior mediastinum, a soft tissue space absent major vascular elements, provides a suitable environment for chronic lead removal without complication. Methods: The first-in-human EV ICD pilot study was a prospective study conducted at 4 sites in Australia and New Zealand. Subjects with a class I or IIa indication for single-chamber ICD were implanted via minimally invasive technique, with the distal end of the lead placed substernally via an incision near the xiphoid, and the proximal end tunneled subcutaneously to a left midaxillary device. Results: A total of 21 patients underwent the EV ICD procedure, and 17 entered chronic follow-up after successful implant and testing. Among these 17 patients, 3 were electively explanted at 85, 114 and 310 days post-implant. Respectively, the first patient experienced a lead tip displacement resulting in P-wave oversensing and inappropriate shock; the second underwent elective chronic defibrillation testing 3 months post-implant, where a 10-Joule safety margin was not established; and the third experienced recurrent VT and intolerance to ATP due to high pacing threshold. Lead removals were conducted per HRS guidelines. The proximal end of the lead was removed from the device pocket to the xiphoid incision, with minor resistance noted in pulling the lead connector through the subcutaneous tunnel. Light traction was sufficient to remove the distal end of the lead from the substernal space, with minor tissue adhesions observed near the lead incision site. All leads were removed intact, and there were no adverse events associated with system removal. Conclusions: ICD lead removal from the substernal space is feasible through 310 days without adverse events. Further understanding from a larger patient population with greater implant duration will help verify these early results.
Effects of Low-intensity Resistance Exercise with Restricting Muscle Blood Flow on Intracellular PTX3 and MPO in Neutrophils
Authors: Nakajima Toshiaki, Kurano Miwa, Iida Haruko, Fukuda Taira, Fukumura Kazuya, Takano Haruhito, Morita Toshihiro
Journal: Circulation (2011)
Abstract 10417: Parity and Progression of Coronary Artery Calcium: The Multi-Ethnic Study of Atherosclerosis
Authors: Kimberly Vu, Erin Michos, WENJUN FAN, Jonathan Evans, Morgana Mongraw-chaffin, Matthew Budoff, Nathan D Wong
Journal: Circulation (2021)

Introduction: Coronary artery calcium (CAC) is a measure of subclinical atherosclerosis and predicts cardiovascular disease (CVD) events. Higher parity, the number of live births, has been shown to relate to CVD. We examined whether parity is associated with progression of CAC as one pathway to CVD. Methods: We studied 2772 women aged 44 to 84 years free of CVD at baseline in the prospective Multi-Ethnic Study of Atherosclerosis. Parity was examined continuously as number of live births as well as by categories: 0-1 (reference), 2-3, and ≥4 in relation to change in CAC score from baseline to follow-up from repeat exams up to 11 years later. We used linear mixed effect models to account for repeated measures when assessing whether progression of CAC was associated with parity, adjusted for baseline CAC and other risk factors. Results: Women with higher parity had greater annualized progression of CAC scores (unadjusted p&lt;0.01) (figure). Using linear mixed effects modeling adjusted for age, ethnicity, baseline CAC scores, and other risk factors, parity was associated with progression of CAC (parity-CAC progression interaction terms): continuous parity (&lt;0.0001), parity 2-3 vs 0-1 (p=0.06), &gt; 4 vs. 0-1 (p&lt;0.0001). Conclusion: We show parity to be associated with the progression of CAC; this may help explain the increased CVD risk observed with higher parity and lends support to adding parity as a risk enhancing factor in women.