tbuckley/cabot-search huggingface dataset:
Abstract 11832: Activated Cardiomyocytes in the Cell Cycle Promote Cardiac Engraftment
Authors: Manabu Kasamoto, Yoshinori Yoshida, Shunsuke Funakoshi, Takeshi Hatani, Takeshi Kimura, Chikako Okubo
Journal: Circulation (2021)

Rationale: The only treatment for drug-resistant heart failure is heart transplantation, however, it has problems such as donor shortages and rejection. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-cardiomyocytes) are promising sources of regenerative medicine that can solve these problems. The engraftment potential of hiPSC-cardiomyocytes following the transplantation into the host heart should be improved to realize this therapy. Objective: We aim to discover a compound to enhance the engraftment of hiPSC-cardiomyocytes following the cell transplantation into the damaged heart. We also aim to realize a larger graft size and recover cardiac function. Methods and Results: We established an iPSC line constitutively expressing Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI), which can show the cell cycle phase in real-time. We compared the engraftment capacity of hiPSC-cardiomyocytes in between the S/G2/M (activation) phase and G0/G1 (inactivation) phase for three months after transplantation, finding cell cycle activated hiPSC-cardiomyocytes showed significantly higher engraftment efficiency than those in inactivated. We, thus, conducted the screening to find cell-cycle activating compounds in the hiPSC-cardiomyocytes. The screening identified some candidates from more than 4000 compounds, and we focused on the most effective compound (CCA-1). An EdU assay and cell number count demonstrated the activation of proliferative capacity by CCA-1. Moreover, genetic analysis revealed a group of genes related to CCA-1-induced cell cycle activation. Finally, using in vivo bioluminescent imaging, we confirmed that CCA-1 treated hiPSC-cardiomyocytes showed enhanced graft size after transplantation into mice ischemic heart. Conclusions: This study highlights the effectiveness of the FUCCI system to analyze the cell cycle status in hiPSC-cardiomyocytes, and the cell cycle activation by CCA-1 is the efficient strategy to increase the graft size following the cell transplantation into the damaged heart.
Abstract 13873: Ischemic Time and Interleukin 6 Levels in Acute Myocardial Infarction
Authors: Hilde E Groot, Irene V van Blokland, Jacco C Karper, Pim van der Harst, Erik Lipsic
Journal: Circulation (2021)

Introduction: Increased levels of the inflammatory cytokine interleukin 6 (IL-6) after percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) are associated with larger infarct size and decreased cardiac function. Early treatment with the IL-6 receptor inhibitor tocilizumab in STEMI patients resulted in less myocardial damage, especially in patients treated &gt;3 hours after symptom onset. However, the specific window of opportunity for IL-6 inhibition in STEMI patients remains to be investigated. Therefore, we studied IL-6 levels in STEMI patients varying in ischemic time (i.e. time from symptom onset to PCI), and its association with infarct size. Methods: In 369 STEMI patients IL-6 levels were measured at 24 hours post-PCI. Patients were categorized according to ischemic time (&lt;2 hours, 2-3 hours, 3-4 hours, 4-5 hours, &gt;5 hours). At 4 months, infarct size was assessed by magnetic resonance imaging. IL-6 levels were log transformed for statistical analysis. Results: IL-6 levels at 24 hours post-PCI increased from 9.2 ng/ml (IQR 5.2-16.7 ng/ml) in patients with symptom onset &lt;2 hours to 13.2 ng/ml (IQR 9.0-20.2 ng/ml) in patients with symptom onset between 4-5 hours (P trend =0.036), stabilizing in patients with symptom onset &gt;5 hours ( Figure 1A ). Higher IL-6 levels at 24 hours post-PCI were associated with larger infarct size in patients with symptom onset &lt;4 hours (&lt;2 hours: β 1.9, 95% CI 0.6-3.1, P=0.004; 2-3 hours: β 1.9, 95% CI 0.3-3.4, P=0.019; 3-4 hours: β 3.0, 95% CI 1.6-4.5, P&lt;0.001) ( Figure 1B ). Conclusions: IL-6 levels at 24 hours post-PCI are related to ischemic time. Moreover, higher IL-6 levels are associated with larger infarct size in patients with ischemic time shorter than 4 hours, suggesting a time dependent role of IL-6. This suggests that the window of opportunity for IL-6 inhibition in STEMI patients is within 4 hours of symptom onset. Randomized controlled trials are necessary to further establish this relationship.
CSIG-04. UNCOUPLING OF ETS1 FROM MAPK PATHWAY SIGNALS AS RESISTANCE MECHANISM TOWARDS BRAF INHIBITORS IN BRAF-MUTATED CHILDHOOD GLIOMA
Authors: Lisa Gabler, Daniela Lötsch-Gojo, Dominik Kirchhofer, Anna Laemmerer, Lisa Mayr, Christine Pirker, Carola Jaunecker, Lucia Kastler, Amedeo A Azizi, Christian Dorfer, Thomas Czech, Christine Haberler, Andreas Peyrl, Irene Slavc, Sabine Spiegl-Kreinecker, Karl Roessler, Johannes Gojo, Walter Berger
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND High-grade gliomas are among the most aggressive brain tumors across all age groups. BRAF is within the most frequently altered genes in pediatric glioma, sometimes connected with telomerase reverse transcriptase (TERT) promoter mutations, predicting a particularly aggressive course of disease. Precision medicine approaches targeting the MAPK pathway have shown promising results in patients with BRAF-mutated glioma. Although acquired insensitivity to BRAF inhibitors appears as major issue for therapy failure, underlying molecular mechanisms are still poorly understood. METHODS Cell models from an anaplastic pleomorphic xanthoastrocytoma with BRAF V600E and TERT promoter mutations and the recurrent tumor, operated following MAPK pathway-targeting therapy, were established. Furthermore, a dabrafenib-resistant subline of the recurrent tumor was generated. The patient-derived cell models were genetically characterized using array-based genomic hybridization (aCGH). Sensitivity of the cells towards different MAPK pathway inhibitors was tested. Basal expression and activation of MAPK pathway and downstream signals were analyzed by qRT-PCR and Western blots. RESULTS Screening a panel of both primary and immortalized glioma cell models with different BRAF and TERT promoter status revealed significantly induced MAPK pathway activation and enhanced TERT levels in BRAF V600E and TERT promoter double-mutant gliomas. Furthermore, cells with both mutations were hyper-sensitive towards BRAF-targeting agents and BRAF inhibition resulted in reduced TERT levels. ETS1 expression was strongly increased in the recurrent tumor and identified as important player in telomerase re-activation. aCGH revealed gains of chromosomal regions encoding for different ETS-factors in the dabrafenib-resistant subline. Western blot analyses suggested a BRAF/ERK-independent survival mechanism in the dabrafenib-resistant subline. Accordingly, dabrafenib insensitivity triggered cross-resistance towards the MEK inhibitor trametinib. Uncoupled from the MAPK pathway, ETS1 expression was further upregulated in the dabrafenib-resistant subline. CONSLUSION: Taken together, our data demonstrate that MAPK-independent ETS transcription factor upregulation is a central mechanism of BRAF inhibitor therapy failure in BRAF-mutated pediatric glioma patients.
RADT-09. ROLE OF RADIOTHERAPY IN MANAGEMENT OF PRIMARY SPINAL HIGH GRADE GLIOMA: A SINGLE INSTITUTION RETROSPECTIVE ANALYSIS
Authors: Rituraj Upadhyay, Swapnil Khose, Halyna Pokhylevych, Arnold dela Cruz Paulino, Mary Frances McAleer, Amol Ghia, Jing Li, Debra Nana Yeboa, Monica Loghin, Rebecca Harrison, Barbara O'Brien, Carlos Kamiya-Matsuoka, John DeGroot, Vinay Puduvalli, Claudio Tatsui, Sujit Prabhu, Wafik Zaky, Frank Lin, Jeffrey Weinberg, Laurence Rhines, Greg Fuller, David Sandberg, Jason Michael Johnson, Susan McGovern
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Primary spinal high-grade gliomas(S-HGG) are rare, aggressive tumors and radiation therapy(RT) plays a dominant role in the management given their infiltrative nature. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs. METHODS Patients with biopsy-proven S-HGG who received RT from 2001-2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan-Meier estimate and Cox proportional hazard regression method were used for survival analyses. RESULTS Twenty-nine patients were identified with a median age of 25.9 years (range 1-74y). Four patients had gross total resection(GTR) while 25 underwent subtotal resection or biopsy. Nineteen patients had WHO grade 4 tumor. IDH1 mutation and MGMT promoter methylation were analyzed in 14 and four patients respectively; all were IDH wildtype and MGMT-promoter unmethylated. H3K27M mutation was present in five out of 10 patients tested. Twenty-two patients received photon-based radiation and 7 received proton therapy. Median RT dose was 50.4 Gy (range 39.6-54Gy) with 79% receiving &amp;gt;45Gy. 65% patients received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8(35%) had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS after RT was 9.7 months. On univariate analysis, age, sex, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer median PFS after RT compared to those without the mutation but the difference did not reach statistical significance (p = 0.26). CONCLUSIONS Although 86% of patients had gross disease at RT and received a lower median RT dose than typically used in cerebral high-grade gliomas, only 55% of patients failed locally. H3K27M mutation may portend worse survival; future studies to improve the therapeutic approach in these patients are warranted.
Abstract 13389: Critical Role of Electron Leak From Mitochondrial Electron Transport Chain Complex I in Oxygen Sensing in the Rabbit Ductus Arteriosus
Authors: Austin Read, Rachel Bentley, Ashley Martin, Kimberly J Dunham-Snary, Jeffrey Mewburn, Bernard Thebaud, Willard W Sharp, Stephen L Archer
Journal: Circulation (2021)

Introduction: The ductus arteriosus (DA) allows placentally oxygenated blood to bypass the non-ventilated fetal lungs and enter the systemic circulation. The fetus’ systemic pO 2 is ~40 mmHg, maintaining the DA in a state of hypoxic vasodilation. As pO 2 rises, with the first breath, the DA constricts and achieves functional closure within minutes. We have identified a mitochondrial O 2 -sensor controlling functional closure within DA smooth muscle cells (DASMC). Increased pO 2 leads to increased reactive oxygen species (ROS) production by complexes I and III of the electron transport chain (ETC). These ROS are diffusible signaling molecules and inhibit redox sensitive potassium channels causing DASMC depolarization and vasoconstriction. We propose this reflects electron leak from ETC complexes. Using the term rabbit model, we investigated the differential function of ETC I vs III complex-specific electron leak suppressors (S1QEL vs S3QEL) on vascular tone in DA rings. Methods: DA’s from term rabbits (n=11 rabbits, n=29 individual DA rings) were mounted on a force transducer at ~800 mg in Krebs at a PO 2 of ~40mmHg. DA’s were subject to varying pO 2 levels (from 35-155 mmHg) and at peak O 2 constriction were treated with ETC leak suppressors, ETC complex inhibitors or vehicle controls (DMSO). Results: Exposure to normoxia caused an average 1100±62 mg increase in DA tension. S1QEL (50 μM) caused an average 20.9±6.2% reduction in DA tension (n=8) whereas S3QEL (100 μM) only reduced DA tension by 4.4±2.2% (n=4). Rotenone (complex I inhibitor) and antimycin A (complex III inhibitor) also relaxed the DA while vehicle had minimal effect (-2.6±1.5%). Conclusions: Electron leak from complex 1, but not complex 3, is implicated in DA O 2 -sensing.
Abstract 9521: Improvement of Left Ventricular Ejection Fraction After Surgical Revascularization in Patients Eligible for Implantable Cardioverter Defibrillator
Authors: Niyada Naksuk, Selma Carlson, Amy Gravely, Melissa Buelt-Gebhardt, Mohammad Madjid, Selcuk Adabag
Journal: Circulation (2021)

Introduction: Left ventricular ejection fraction (LVEF) ≤35% is the cornerstone criterion for implantable cardioverter-defibrillator (ICD) eligibility. But improvement in LVEF may occur in ICD-eligible patients after coronary artery bypass graft surgery (CABG). Methods: We studied the incidence, predictors, and outcomes of LVEF improvement among patients with LVEF ≤35% who underwent CABG as part of the Surgical Treatment for Ischemic Heart Failure (STICH) trial and had pre- and post-operative (4 months) LVEF assessment using the same cardiac imaging modality. Improvement in LVEF was defined as post-operative EF &gt;35% and &gt;5% absolute improvement from baseline. Results: Of the 427 patients (mean age 62±10 and 50 women), 125 (29.2%) had LVEF improvement from 26.8%±5.8% to 43.3%±6.5%; p&lt;0.001. Improvement in LVEF occurred in 20% and 38% of patients with pre-operative LVEF &lt;25% and 30-35%, respectively (Figure). Post-operative improvement in LVEF was 2.20 times more likely in patients with pre-operative LVEF ≥25% (95% CI 1.41-3.43; p&lt;0.001) than those with pre-operative EF &lt;25%. The odds of post-operative LVEF improvement were 1.96 times higher (95% CI 0.91-4.23, p=0.09) in patients with myocardial viability. After adjusting for age, sex, and pre-operative LVEF, improvement in LVEF was associated with a 42% lower risk of all-cause mortality (HR 0.58, 95% CI 0.35-0.96; p=0.03) and 69% lower risk of heart failure mortality (HR 0.31, 95% CI 0.11-0.87; p=0.03). Conclusions: Nearly 1/3 rd of patients with LVEF ≤35% who underwent CABG had a significant improvement in left ventricular systolic function, obviating the need for primary prevention ICD implantation. Post-operative LVEF improvement was associated with a lower risk of death. These results provide patients and clinicians data on the likelihood of ICD eligibility after CABG and support the practice of reassessment of LVEF after revascularization.
Abstract 10424: Spatial Ventricular Gradient Changes Predict Acute Pulmonary Embolism Severity
Authors: Mason Marcus, Hans Stabenau, Warren J Manning, Brett Carroll, Jonathan W Waks
Journal: Circulation (2021)

Introduction: The severity of an acute pulmonary embolism (PE) can be assessed using hemodynamics, right ventricular (RV) strain on imaging, and cardiac biomarkers. The spatial ventricular gradient (SVG) is a vectorcardiographic measurement acquired from a 12-lead ECG that reflects cardiac loading conditions via electromechanical coupling and could aid in risk stratification in acute PE. Hypothesis: SVG is correlated with RV strain, and predicts adverse events in patients with acute PE. Methods: Retrospective cohort study of patients with acute PE. ECG signs of RV strain (S1Q3T3, precordial T-wave inversions, RBBB); imaging (CT and TTE RV/LV ratios); and outcome data (30-day mortality, need for vasopressor or advanced therapy) were obtained. The SVG vector was regressed on degree of RV dysfunction. Odds of adverse outcome after PE were regressed on the SVG and covariates (imaging data, age, gender, ECG signs) using a logit model. Results: ECGs from 318 patients (48% male, age 62.2 ± 16.4 y) with acute PE were analyzed; 44 adverse events (13. 8%) were reported. Worse RV hypokinesis and decreasing tricuspid annular plane systolic excursion (TAPSE) were both associated with less positive X and Y, and a more positive SVG Z vector components (p&lt;0.001 for all). The Figure shows receiver operating characteristic (ROC) curves of models using conventional ECG, imaging, and SVG data. Compared to conventional ECG markers and imaging, the addition of SVG to imaging improved the area under the ROC curve from 0.62 vs 0.72 (p=0.013). Conclusion: The SVG vector is correlated with right heart dysfunction in acute PE. The SVG vector has a better prognostic value than traditional ECG markers, and may improve risk stratification in acute PE.
Abstract 11559: Acute and Chronic Effect of Heme on Vascular Function and Pulmonary Hypertension
Authors: Mathews Valuparampil Varghes, Joel James, Olga Rafikova, Ruslan Rafikov
Journal: Circulation (2021)

Introduction: Patients with hemolytic anemia are at high risk of developing lung disease. We recently reported that free heme in circulation causes acute lung endothelial barrier dysfunction via activation of MKK3/p38 signaling. However, we did not evaluate the effects of chronic heme infusion in the lungs. Hypothesis: Chronic free heme infusion will cause sustained activation of the MKK3/p38 pathway leading to inflammation and vascular remodeling in the lungs. Methods: Mitogen-activated protein kinase kinase-3 knockout (MKK3-KO) mice were used for this study. Acute group mice received heme 250μM for 24-hours by i.v injection as a single dose, and the chronic group mice received 2-weeks of continuous heme i.v injection using an osmotic minipump. Human pulmonary artery endothelial cells (HPAEC) were studied in endothelial cell dysfunction experiments. Results: Heme treatment (50μM) disrupts HPAEC endothelial barrier, tube formation and decreases HPAEC migration capacity suggesting direct heme involvement in the endothelial dysfunction. Chronic heme exposure of WT mice (250uM, 2wks) increased right ventricular (RV) systolic pressure (SP) (31.89±0.88mmHg), RV-hypertrophy (0.38±0.02), and pulmonary vascular remodeling (18.47±1.15 μm) compared to the MKK3-KO group (RVSP-29.33±0.69mmHg, Fulton index-0.33±0.01, and wall thickness-13.69±1.13μm, p&lt;0.05). Loss of tight junction proteins and activation of MKK3/p38/HSP27 axis was noticed in heme-treated WT. MKK3-KO significantly attenuated downstream targets of p38 such as Akt, STAT3, and ERK1/2. Furthermore, the MKK3-KO attenuated endothelial barrier dysfunction by maintaining the tight-junction protein, zona occludens-1 and reducing lung inflammatory cell infiltration. Cytokine multiplex analysis of plasma exhibited an inflammatory cytokine storm with a surge of 21-cytokines in WT mice, but the MKK3-KO mice were substantially protected. This includes IFN-g (1502 vs. 113 Fold Control (FC)), IL-1b (6.8 vs. 2.2 FC), IL-6 (221 vs. 6.9 FC), etc. Conclusion: Our findings suggest that free-heme triggers MKK3/p38 cascade activation resulting in the cytokines storm, endothelial barrier dysfunction, and proliferative signaling activation, all contributing to PH manifestation.
Abstract 11898: KLF10 Deficiency in CD4+ T Cells Exacerbates Angiotensin II-Induced Perivascular Fibrosis
Authors: Rulin Zhuang, Jingshu Chen, Henry Cheng, Carmel Assa, Anurag Jamaiyar, Arvind Pandey, Akm Wara, Mark W Feinberg
Journal: Circulation (2021)

Introduction: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Angiotensin II (Ang II) contributes to vascular disease via promoting T-cell activation and end-organ damage. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. Objective: Kruppel-like Factor 10 is a transcription factor expressed in T cell subsets. We sought to investigate the role of KLF10 in CD4+ T cells in regulating vascular damage in an AngII mouse model. Methods: CD4-targeted KLF10 deficient (TKO) and CD4-Cre (WT) mice were generated and subjected to 28 days of Ang II infusion. Endpoint characterization included fibrotic organ transcriptomic analysis, multi-organ histology, flow cytometry, cytokine analysis, myograph vasoreactivity, and cardiac echocardiography. Results: TKO mice showed enhanced perivascular fibrosis compared to WT mice by histological analysis in the aorta, heart, and kidney. TKO mice had vessels with enhanced vasoconstriction to phenylephrine, hearts with impaired global longitudinal strain by echo, and kidneys with elevated albumin/creatinine ratio. However, no change was found in blood pressure between TKO and WT. Plasma IL-9 and IL-15 were increased in TKO mice. IL-9 mRNA and secreted protein were also increased in activated TKO CD4+ T cells, as well as in Ang II treated WT-CD4+ T cells in vitro . Mechanistic studies revealed that KLF10 regulated Il9 transcription through interaction with promoter region of Il9 by ChIP assay. Notably, injection of anti-IL9 antibody reversed perivascular fibrosis in Ang II infused TKO mice. Conclusion: CD4+ T cell deficiency of Klf10 exacerbated perivascular fibrosis and multi-organ dysfunction in response to Ang II via upregulation of IL-9. Klf10 or IL-9 in T cells might represent novel therapeutic targets for the treatment of vascular or fibrotic diseases.
Reliability of Liquid Biopsy and Next Generation Sequencing in Monitoring Residual Disease Post-Hematopoietic Stem Cell Transplant
Authors: Maher Albitar, Hong Zhang, Andrew L. Pecora, Andrew Ip, Andre H. Goy, Jeffrey Justin Estella, Ivan De Dios, Wanlong Ma, Sukhdeep Kaur, Hyung C. Suh, Michele L. Donato, Scott D. Rowley
Journal: Blood (2021)
Abstract 9676: Inflammation Mediated Vitamin K Protective Effect Against Vascular Calcifications in Antiretroviral Treated People Living with HIV
Authors: Scott E Janus, Jared Durieux, Jamal Hajjari, Danielle Labbato, Grace McComsey
Journal: Circulation (2021)

Background: People living with HIV (PLWH) experience increased inflammation, risk of cardiovascular (CV) events, and coronary artery calcium scores (CACs). In cross-sectional analyses, vitamins D and K have been associated with CACs and may have an anti-inflammatory effect. The anti-inflammatory effects of Vitamins D and K in successfully treated PLWH is less understood. Methods: We prospectively recruited 237 PLWH on antiretroviral treatment and 67 HIV- healthy controls. CACs were derived from non-contrast CT and levels of 25-hydroxyvitamin D (vitamin D) and inactive vitamin K dependent dephosphorylated-uncarboxylated matrix G1a protein (MGP, marker of vitamin K deficiency) were measured in plasma. The relationship between inflammation markers, MGP, and vitamin D on CACs were estimated using zero-inflated negative binomial regression. Adjusted models included 25(OH)D, MGP, gender, race, age, and markers of inflammation. Results: Controls had lower median age (45.8 vs. 48.8; p=0.03) and a larger proportion of females (55.2% vs. 23.6%; p&lt;.0001). Among PLWH, &lt;1% had detectable viral load and the median CD4 was 682.0(IQR: 473.0, 899.0). 62.17% of the sample had zero CACs and 51.32% were vitamin D deficient (&lt;20 ng/mL). There was no difference in detectable CACs (p=0.19) or MGP (p=0.42) between PLWH and controls. In adjusted models, every one-unit increase in ( log2 )25(OH)D is associated with &gt;200% increase in the expected CACs among PLWH. Every one-unit increase in MGP (worse K status) decreases the probability of having CACs equal to zero 21.3% (p=0.01). Evidence suggests that the effects of 25(OH)D and MGP are inflammation mediated, specifically through VCAM and TNF-α pathways. Conclusion: Vitamins K deficiency is a modifiable preventive factor against coronary calcification in PLWH. Further research should determine whether vitamin K supplementation would reduce vascular calcification and risk of CV events in PLWH and increased inflammation