tbuckley/cabot-search huggingface dataset:
Abstract 13122: STK25 Regulates the Cardiac PKA Pathway in Human Cardiomyocytes
Authors: Xiaokan Zhang, Bryan Z Wang, Michael Kim, Manuel Tamargo, Trevor Nash, Rajesh Soni, Eric Li, Jenny Rao, Bohao Liu, Roberta I Lock, Gordana Vunjak-Novakovic, Barry Fine
Journal: Circulation (2021)

Hypothesis: STK25 regulates cell survival, metabolism and cardiac function through phosphorylating PKA R1α and modulating PKA signaling pathway in human cardiomyocytes. Background: Dysregulation of cardiac kinases are related with many cardiovascular diseases including hypertrophy, remodeling and ischemia injury. STK25 is a stress response kinase that regulates cell survival through modulating several signaling pathways and is involved in the metabolism regulation. However, the direct substrates and mechanism of STK25 remain undefined. Methods: CRISPR-Cas9 was used to generate a homozygous knockout (KO) of STK25 in induced pluripotent stem cell (iPSC) which were then differentiated into cardiomyocytes (iPSC-CMs) and used for engineered human cardiac tissue generation. Role of STK25 in gene expression, cell proliferation/apoptosis, metabolism and cardiac function were characterized. STK25 was quantified in human left ventricular tissue from heart failure (HF) patients. Results: In iPSC-CMs, phospho-proteomic analysis identified PKA signaling as the most significantly upregulated pathway by STK25 deletion. PKA regulatory subunit I α (R1α) was identified as a downstream substrate of STK25 and validated by IP. Loss of STK25 resulted in elevated PKA kinase activity and decreased phosphorylation of PKA targets implicated in cardiac contractility and Ca2+ handling, such as cardiac myosin-binding protein C (cMyBPC), cardiac troponin (cTnT), ryanodine receptor-2 (RyR2) and L-type calcium channel (CaV1.2). Further mechanistic studies revealed that STK25 mediates PKA activity through phosphorylation of the R1α regulatory subunit at S77/83 sites, leading to inhibition of PKA kinase activity. In functional assays, STK25 modulated cell cycle progression, proliferation, hypoxia induced apoptosis, beta adrenergic response, and mitochondrial respiration in iPSC-CMs. We also detected significant increase in STK25 expression and PKA R1α phosphorylation in HF patients versus normal control, demonstrating STK25 altered regulation in heart diseases. Conclusions: STK25 kinase is a critical regulator of the PKA pathway in human cardiomyocytes modulating cell growth, metabolism and cardiac function and is aberrantly expressed in heart failure.
Abstract 10736: Gut Dysbiosis and Altered Circulating Microbial Metabolites in Patients with Pulmonary Arterial Hypertension
Authors: Daphne Moutsoglou, Kenneth K Weir, Alexander Khoruts, Jasmine Tatah, Sasha Z Prisco, Kurt W Prins, Marc R Pritzker, Thenappan Thenappan
Journal: Circulation (2021)

Introduction: Inflammation plays a mechanistic role in pulmonary arterial hypertension (PAH); however, what triggers inflammation remains unclear. Hypothesis: PAH is characterized by gut dysbiosis and barrier dysfunction, leading to an altered burden of circulating microbial metabolic products, promoting disease. We aimed to characterize the gut microbiome and circulating microbial metabolic products in healthy controls and PAH patients. Methods: The V4 hypervariable region of the 16S rRNA gene was analyzed from fecal samples of 40 healthy controls and 57 PAH patients. Plasma was analyzed for interleukin (IL)-6, claudin-3, trimethylamine N-oxide (TMAO), short chain fatty acids, and secondary bile acids. Results: PAH patients had elevated plasma IL-6 (Fig 1A, P =.02), claudin-3, a measure of intestinal permeability (Fig 1B, P =.04), and TMAO (Fig 1C, P =.04), and reduced taurolithocholic acid (Fig 1D, P =.02). Short chain fatty acid levels were not significantly different (data not shown). Principal component analysis (PCOA) of pairwise Bray-Curtis dissimilarity showed distinct microbiome compositions (Fig 1E, P &lt;.001). The Shannon diversity index (Fig 1F, P &lt;.001) and species richness (Fig 1G, P =0.005) were lower in PAH patients. Linear discriminant analysis (LDA) of effect size revealed that PAH patients had increased relative abundances of Bacteroidetes and Proteobacteria and decreased relative abundances of Ruminococcaceae and Lachnospiraceae (Fig 1H). There was no difference in gut microbiome richness and Shannon diversity between patients with low, intermediate, and high-risk REVEAL scores (data not shown). Conclusions: PAH patients have distinct gut dysbiosis, increased intestinal permeability (claudin-3), and circulating microbial metabolic products. These findings support our hypothesis that microbiome-driven, pro-inflammatory signals may contribute to PAH pathogenesis.
NIMG-64. TYPE OF BONY INVOLVEMENT PREDICTS GENOMIC SUBGROUP IN SPHENOID WING MENINGIOMAS
Authors: Lan Jin, Mark Youngblood, Trisha Gupte, Shaurey Vetsa, Arushii Nadar, Tanyeri Barak, Kanat Yalcin, Stephanie Aguilera, Ketu Mishra-Gorur, Nicholas Blondin, S Bulent Omay, Renelle Pointdujour-Lim, Benjamin Judson, Michael Alperovich, Mariam Aboian, Declan McGuone, Murat Gunel, Zeynep Erson-Omay, Robert Fulbright, Jennifer Moliterno
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. METHODS Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as frank tumor invasion (TI), hyperostosis only (HOOs), or both (TI+HO). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Predictive logistic regression models were developed for genomic subgroups based on pre-operative clinical features. RESULTS Among 64 SWMs, 53% had HOO, 9% had TI, and 14% had TI+HO; nine SOMs were identified. Tumors with invasion (i.e., TI or TI+HO) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR: 27.6; p: 0.004), while hyperostosis only (without frank tumor invasion) were over 4 times more likely to have a TRAF7 mutation (OR: 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR: 10.21; p: 0.004). CONCLUSIONS SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers.
Tumour-infiltrating bystander CD8<sup>+</sup>T cells activated by IL-15 contribute to tumour control in non-small cell lung cancer
Authors: Galam Leem, Minwoo Jeon, Kun Woo Kim, Seongju Jeong, Seong Jin Choi, Yong Joon Lee, Eui-Soon Kim, Jae-Ik Lee, Seung Yeon Ha, Su-Hyung Park, Hyo Sup Shim, Jin Gu Lee, Shin Myung Kang, Eui-Cheol Shin
Journal: Thorax (2021)

Background Tumour-unrelated, virus-specific bystander CD8 + T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet. Methods We studied the characteristics of bystander CD8 + TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy. Results We show that bystander CD8 + TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8 + TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8 + TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8 + TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment. Conclusion Thus, the study demonstrates that bystander CD8 + TILs can be repurposed by IL-15 for tumour immunotherapy.
TMOD-26. MYC OVEREXPRESSION AND SMARCA4 LOSS IN GRANULE CELL PRECURSORS COOPERATE TO DRIVE MEDULLOBLASTOMA FORMATION IN MICE
Authors: Carolin Göbel, Dörthe Holdhof, Melanie Schoof, Catena Kresbach, Ulrich Schüller
Journal: Neuro-Oncology (2021)

Abstract Mutations in SMARCA4 are frequently identified in medulloblastoma, the most common pediatric malignant brain tumor. However, the functional significance of these mutations and their suitability as a therapeutic target remain largely unclear. Medulloblastomas are divided into 4 subgroups according to their localization, molecular biology, and clinical course: WNT, SHH, Group 3, and Group 4. Group 3 medulloblastomas are associated with the poorest outcome and frequently show amplifications of the oncogene MYC. Additionally, SMARCA4 is mutated in around 15 % of cases. The few mouse models developed for this entity so far all involve the overexpression of MYC, mostly in combination with other drivers. However, none of these models include alterations in Smarca4. In our approach, we combined an overexpression of MYC with a loss of SMARCA4 in granule cell precursors, which successfully induced tumor formation in mice. For this purpose, granule cell precursors were isolated from 7-day-old Math1-creER T2 ::Smarca4 fl/fl pups after tamoxifen induced loss of SMARCA4. MYC overexpression was achieved by lentiviral transduction and transduced cells were transplanted into immunodeficient CD1 nu/nu mice. Preliminary results within a small cohort showed tumor formation in 5/19 transplanted mice (26 %) after 6 months. Immunohistochemically, tumors all stained negative for SMARCA4. In a next step, additional cohorts will elucidate if tumor development is indeed accelerated by or even dependent on the loss of SMARCA4. Additionally, the neoplastic potential of tumor cells will be verified with the aid of secondary recipient mice. To evaluate to what extent the generated tumors are comparable to human Group 3 medulloblastomas, tumors will be extensively analyzed on a morphological, transcriptional, and epigenetic level. Altogether, we hope to establish a suitable mouse model for SMARCA4 mutated Group 3 medulloblastoma that will help to elucidate the role of SMARCA4 in tumor development and to identify new therapeutic targets.
Abstract 13531: Coronary-Cameral Fistulae Causing Coronary Steal Syndrome Inducing Polymorphic Ventricular Tachycardia
Authors: Thomas E Bigham, Ankit Bhargava, Akshay Chaku, Maan Jokhadar
Journal: Circulation (2021)

Background: Coronary-cameral fistulae are rare, and usually benign, anomalous connections between coronary artery and cardiac chambers. These fistulae are rarely large enough to cause ischemia, arrhythmia, and heart failure. Case: A 49 year-old female with a complicated medical history including numerous systemic arteriovenous malformations, high output heart failure, hypertrophic cardiomyopathy with MRI proven myocardial fibrosis, recurrent monomorphic ventricular tachycardia (VT), defibrillator placement, with recent VT ablation and sympathectomy presented to the coronary care unit for recurrent monomorphic VT. During her CCU course, this patient developed a distinctly different, incessant polymorphic VT with progression to ventricular fibrillation (VF). Decision-making: The patient was started on a procainamide infusion in addition to her amiodarone infusion. Her device pacing rate was increased to improve systemic perfusion. Unfortunately, this appeared to worsen the burden of polymorphic VT. She underwent emergent cardiac catheterization, which demonstrated multiple coronary cameral fistulae arising from all three major coronary vessels with brisk flow into the left ventricular cavity, concerning for coronary steal syndrome causing ischemia. To improve coronary diastolic filling time, the pacing rate was decreased. The largest fistula, the distal PDA to left ventricle, was embolized. She remained free of polymorphic VT for 13 days, but ultimately died due to complications of aspiration pneumonia with septic shock and multiorgan system failure. Conclusion: Acute myocardial ischemia is a common cause of polymorphic ventricular tachycardia. In this medically complicated patient with history of monomorphic VT suspected secondary to myocardial scar, her polymorphic VT was likely precipitated by the coronary-cameral fistulae causing coronary steal syndrome with improvement of her polymorphic VT after embolization and slowing heart rate with ischemia reduction.
Abstract MP211: NAD Redox Imbalance Exacerbates Diabetic Cardiomyopathy
Authors: Chi Fung Lee
Journal: Circulation Research (2021)

Diabetes and heart failure are linked to NAD redox imbalance, whose role in diabetic cardiomyopathy has not been directly tested. Streptozotocin-induced diabetes in WT mice for 16 weeks promoted declines in systolic and diastolic function, which associated with lowered cardiac NAD/NADH ratio (NAD redox imbalance). To test the hypothesis that , we employed mouse models with cardiac-specific manipulations of NAD redox states. Cardiac-specific Ndufs4-KO mice (cKO) exhibit lowered cardiac NAD/NADH ratio with normal baseline function, geometry and energetics. Control and cKO mice were challenged with 8-week diabetic stress. Metabolomic analyses of plasma collected after the diabetic stress showed similar hyperglycemia and dyslipidemia stresses in diabetic control and diabetic cKO mice. Chronic diabetic stress promoted systolic and diastolic dysfunctions in control mice, which were further exacerbated in diabetic cKO mice in both male and female cohorts. Collagen levels and transcript analyses of fibrosis and extracellular matrix-dependent pathways showed no change in diabetic cKO hearts, suggesting that cardiomyocyte dysfunction is a likely culprit for the exacerbated dysfunction. Increased protein acetylation, including SOD2-K68Ac, was observed in diabetic cKO hearts. Inhibited antioxidant function by SOD2-K68Ac promoted protein oxidation in diabetic cKO hearts, suggesting oxidative stress as a pathogenic mechanism. We next examined phosphorylation status of myofilament proteins in these diabetic hearts. MyBPC-S282Pi levels are suppressed in failing hearts and remained unchanged in diabetic cKO hearts. TnI-S150Pi increases myofilament calcium sensitivity and prolongs calcium dissociation, while TnI-S23/24Pi imposes the opposite effects. TnI-S150Pi levels were elevated in diabetic cKO hearts, while TnI-S23/24Pi levels unchanged. Therefore, exacerbated diastolic dysfunction in diabetic cKO hearts is due to the selective phosphorylation at TnI-S150. AMPK is activated by energetic stress and phosphorylates TnI-S150. ATP levels decreased, and AMP/ATP ratio increased in diabetic cKO hearts, implicating impaired energetics to promote TnI-S150Pi and dysfunction. Elevation of NAD levels normalized cardiac NAD redox balance in diabetic cKO hearts. Elevated levels of SOD2-K68Ac and TnI-S150Pi, exacerbated systolic and diastolic dysfunction in diabetic cKO hearts were all reversed by elevation of NAD levels. Dysfunction in diabetic control hearts was also ameliorated by elevation of NAD levels. These data collectively conclude that NAD redox imbalance is a positive mediator of the progression of diabetic cardiomyopathy.
Abstract 14165: Ultrasound-Accelerated Thrombolysis May Be the Preferred Catheter-Based Lytic Therapy for Pulmonary Embolism
Authors: Mary Potkonjak, Lolita Golemi, Nidhi Madan, Steve Attanasio
Journal: Circulation (2021)

Introduction: Pulmonary embolism (PE) is estimated to cause 100,000 deaths annually in the US. Systemic use of fibrinolytic drugs carries risks of significant bleeding. Catheter directed thrombolysis (CDT) delivers thrombolytic drugs directly to the site of the clot and in lower doses which may improve its safety profile. We aimed to investigate the safety and efficacy of CDT in intermediate risk PE and contemporary trends of follow-up cardiac testing in these patients. Methods: 75 patients who underwent CDT for intermediate risk PE at a single center from 2014-2021 were studied retrospectively. Outcomes included procedure related complications and mortality. Continuous variables are presented as mean±SD, categorical variables as percentages. Logistic regression and survival analysis was used. Data was analyzed in Stata/BE 17.0. Results: Demographics (Table 1), lab and imaging data (Table 2) were assessed for 75 patients. Troponin and BNP were elevated in 63.5% and 60% respectively. RV dilation was present in 86.7%. Ultrasound accelerated thrombolysis (EKOS) was performed in 80% and standard CDT in 20%. One procedural complication occurred, a patient undergoing standard CDT suffered a cardiac arrest and died. Major bleeding occurred in four patients but did not contribute to mortality. Mortality at 30 days and one year were 6.8% (5/73) and 13% (9/69) respectively. Only three deaths were attributed to cardiovascular causes. Those who underwent EKOS had 85.6% lower odds of death in 30 days (OR 0.14 (0.03-0.79), p=0.02) compared to CDT; however, our results are limited by a small sample size. Follow up imaging was assessed at 1 year (Table 3). Echo was most frequently performed in 45.3% of patients. Conclusions: EKOS for intermediate risk PE is a safe procedure with no procedural mortalities in our study. As follow up was poor, with less than 50% of the cohort receiving imaging, future directions should be aimed at ensuring these patients are monitored for long-term sequelae of PE.
Abstract 12650: Clinical Outcomes of Fractional Flow Reserve (FFR) versus Instantaneous Wave-Free Ratio (IFR) versus Coronary Angiography (CAG) Guided Cardiovascular Procedures, Including PCI (Percutaneous Coronary Intervention) and CABG (Coronary Artery Bypass Grafting): A Systematic Review and Meta-Analysis
Authors: Nso Nso, Khushal Choudhary, Sostanie Enoru, Jonathan D Marmur
Journal: Circulation (2021)

Background: Recent evidence from two systematic reviews and meta-analysis advocates the superiority of fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) guided PCI (percutaneous coronary intervention) and CABG (Coronary Artery Bypass Grafting) in improving the clinical outcomes of CAD (coronary artery disease) patients. We aimed to expand this evidence and comparatively analyze the efficacy/safety of FFR-guided, iFR-oriented, and CAG (coronary angiography)-guided PCI/CABG. Methods: We utilized PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework and extracted randomized controlled trials/ observational (retrospective/prospective studies) concerning FFR/iFR/CAG-guided PCI/CABG on 05/27/2021. We explored JSTOR, PubMed/Medline, Cochrane Library, EMBASE, Google Scholar, CINAHL, and Scopus to identify and track the articles of interest published from January 2005 until December 2020. We constructed forest plots and funnel plots to investigate several clinical endpoints related to FFR/iFR/CAG-oriented cardiovascular interventions. Results: The meta-analysis results indicated higher potential of FFR-guided PCI/CABG to minimize all-cause mortality (OR: 0.73, 95% CI 0.56, 0.94) (p=0.01), cardiovascular death (OR: 0.73, 95% CI 0.43, 1.24) (p=0.25), hospitalization (for heart failure, unstable angina, or chest pain) (OR: 0.73, 95% CI 0.42, 1.27), MACE (OR: 0.65, 95% CI 0.51, 0.82) (p=0.0005), bleeding (OR: 0.72, 95% CI 0.24, 2.09), MI (OR: 0.85, 95% CI 0.73, 0.99), and unplanned revascularization (OR: 0.61, 95% CI 0.40, 0.94) (p=0.03) compared to CAG-guided cardiovascular procedures. The results also proved non-inferiority of iFR-guided PCI/CABG to FFR-guided PCI/CABG (OR: 0.66, 95% CI 0.40, 1.11) (OR: 1.03, 95% CI 0.84, 1.27) (OR: 0.42, 95% CI 0.11, 1.62) (OR: 0.55, 95% CI 0.15, 2.05). Conclusion: The findings of this systematic review/meta-analysis increase the scope of replacing CAG-guided PCI/CABG with FFR/iFR-guided procedures to improve patient outcomes. Future studies should strengthen current evidence concerning FFR/iFR-guided cardiovascular interventions to enhance their utilization across wider subsets of patients with coronary artery disease.
IKZF1deletions Coupled with CD20 Expression Represents a Novel High-Risk Subtype in Adult B-Cell Progenitor Acute Lymphoblastic Leukemia
Authors: Bingqing Tang, Zhixiang Wang, Dainan Lin, Xianjun He, Zihong Cai, Kangyu Huang, Xuan Zhou, Ren Lin, Liu Xiaoli, Na Xu, Fen Huang, Jing Sun, Qifa Liu, Hongsheng Zhou
Journal: Blood (2021)
Abstract 13854: Association Between Pulmonary Function, Cardiac Structure and Function, and Cardiovascular Outcomes in the General Population
Authors: Ditte M Andersen, Niklas Johansen, Daniel Modin, Jacob Marott, Gorm B Jensen, Peter Schnohr, Pradeesh Sivapalan, Jens-Ulrik S Jensen, Rasmus Mogelvang, Tor Biering-Sørensen
Journal: Circulation (2021)

Introduction: We investigated the association between the lung function and cardiac structure and function, and how the lung function affects the prognostic value of cardiac structure and function in the general population. Methods: All participants from the 4 th Copenhagen City Heart Study examination round who had an echocardiography and spirometry performed were included in the present analysis. Participants were classified as having either normal lung function with a forced expiratory volume in one second (FEV1) &gt;=80% of expected or decreased lung function with FEV1&lt;80%.The endpoint consisted of cardiovascular death, acute myocardial infarction, or incident heart failure. Results: Participants (n=2,149) were followed for a median 14.4 years (IQR 10.8-14.9), and there was a total of 371 (17%) events. The mean age was 57 ± 16 years, 57% were women, 44% had hypertension, and 64% were current or previous smokers. Decreased lung function at baseline was associated with a lower left ventricular ejection fraction (LVEF), a higher left ventricular mass index (LVMI), and a higher E/e’. In univariable analysis, LVEF, LVMI, E/e’, and left atrial volume (LAV) were predictors of the composite outcome in both groups. After multivariable adjustment for clinical and echocardiographic parameters, only LVMI remained an independent predictor of the composite outcome in both groups (normal lung function: HR 1.04, 95% CI (1.01-1.07), p=0.010; decreased lung function: HR 1.06, 95% CI (1.01-1.10), p=0.009). LVEF and LAV remained predictors of the composite outcome only in participants with normal lung function. Conclusions: In participants from the general population, a FEV1 below 80% was associated with a lower LVEF, a higher LVMI and a higher E/e’. For participants with normal lung function, LVEF, LVMI, and LAV were independent predictors of adverse cardiovascular events. For participants with a FEV1 below 80%, only LVMI was an independent predictor of adverse cardiovascular events.
Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity
Authors: Lichao Wang, Binsheng Wang, Nathan S. Gasek, Yueying Zhou, Rachel L. Cohn, Dominique E. Martin, Wulin Zuo, William F. Flynn, Chun Guo, Evan R. Jellison, Taewan Kim, Larissa G.P. Langhi Prata, Allyson K. Palmer, Ming Li, Christina L. Inman, Lauren S. Barber, Iman M.A. Al-Naggar, Yanjiao Zhou, Wenqiang Du, None Kshitiz, George A. Kuchel, Alexander Meves, Tamar Tchkonia, James L. Kirkland, Paul Robson, Ming Xu
Journal: Cell Metabolism (2021)