tbuckley/cabot-search huggingface dataset:
TAMI-43. HYPOXIC REGULATION OF GLIOBLASTOMA TUMOR GROWTH THROUGH L(3)MBTL1
Authors: Ling-Kai Shih, Subhas Mukherjee, Daniel Brat
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the deadliest and most common of all primary brain tumors. Drosophila brain tumor models have uncovered signaling pathways regulating tumor growth that are highly conserved in GBM. Our search for a novel tumor suppressor using Drosophila led to Lethal (3) malignant brain tumor [l(3)mbt], temperature-sensitive mutants of which cause neuroepithelial tumor-like overproliferation in optic lobes. dL(3)MBT and its human orthologs L3MBTL1-L3MBTL4 all harbor Malignant Brain Tumor (MBT) domains that recognize methylated lysines on histone tails. Like dL(3)MBT, hL(3)MBTL1 acts as a chromatin compaction factor that represses transcription and inhibits cytokinesis in GBM cell lines. The highly hypoxic tumor microenvironment (TME) in GBM drives its progression, recurrence, and therapeutic resistance. However, it remains unclear if L(3)MBTL1 is regulated by TME cues to promote GBM growth. Based on this knowledge gap and our preliminary data, we hypothesize that hypoxia directly regulates L(3)MBTL1 in favor of GBM growth. Analysis of TCGA data for IDH-wildtype gliomas revealed that L3MBTL1 gene expression is downregulated in GBM, which are necrotic and severely hypoxic, compared to histologic grade 2/3 gliomas, which do not contain necrosis, indicating that hypoxia could potentially suppress L3MBTL1 to enhance glioma progression. TCGA data also revealed a number of HIF pathway and hypoxia-inducible genes strongly correlating with L3MBTL1 expression, including HIF1a and VHL. Using patient-derived GBM neurosphere cultures, we exposed glioma cells to hypoxia (1% O2 for 24hrs) and found that L3MBTL1 protein levels were suppressed compared to normoxia (21%). Under these same conditions, we found more rapid cell proliferation under hypoxia. Exploration of hypoxic TME regulation of the novel tumor suppressor L3MBTL1 in glioma progression has the potential to uncover novel mechanisms involving epigenetic modulation and potentially new therapeutic strategies.
Abstract P454: The Interaction Of P300 With Brg1 Acetylated The Histone H3 Globular Domain In Heart Failure
Authors: sho uehara, Tatsuya Morimoto
Journal: Circulation Research (2021)

Background: Epigenetic regulatory mechanisms such as histone post-translational modifications are involved in the development of heart failure. Although the acetylation of tail domains, such as H3K9, has been extensively studied, that of H3K122, the globular domain, has received much less attention. Acetylation of the globular domain directly activates transcription by destabilizing histone-DNA binding. However, the acetylation of these domains during the transition from left ventricular hypertrophy (LVH) to heart failure (HF) remains unknown. Methods and Results: Primary cultured cardiomyocytes prepared from neonatal rats were treated with phenylephrine (PE). PE increased the acetylation of H3K9 and H3K122. The acetylation of H3K9 and H3K122 on the promoters of ANF and BNP, which are hypertrophic reaction genes, was increased in cardiomyocyte hypertrophy. To investigate whether the transcriptional coactivator p300 is involved in the acetylation of H3K9 and H3K122, p300 knockdown was used. p300 knockdown suppressed PE-induced cardiomyocyte hypertrophy and the acetylation of H3K9 and H3K122. In Dahl-salt sensitive rats, in vivo chromatin-immunoprecipitation assays revealed that the acetylation of H3K9 on the promoter of the hypertrophic response genes was significantly increased in LVH, but the acetylation of H3K122 was not increased in LVH. However, H3K122 acetylation was significantly increased in HF. On the other hand, there was no difference in the amount of recruitment of p300 in LVH and HF. Interestingly, immunoprecipitation-WB showed that binding of p300 with BRG1, a key component of the SWI/SNF complex, was enhanced in HF. The recruitment of BRG1 increased significantly in HF compared to LVH. Moreover, PFI-3, a BRG1 inhibitor, significantly suppressed a PE-induced increase in cardiomyocyte surface area, the mRNA levels of ANF and BNP, and the acetylation of H3K9 and H3K122 in cultured cardiomyocytes. Conclusion: This study demonstrates that the acetylation of H3K122 is enhanced via the interaction of p300 and BRG1 in heart failure, providing novel insights into the epigenetic regulatory mechanism governing transcriptional activity in these processes.
Abstract 12677: Multidimensional Sleep Health is Associated With Cardiometabolic Health in a Nationally Representative Sample of US Adults
Authors: Nour Makarem, Carmela Alcantara, Sydney Musick, Odayme Quesada, Ziyu Chen, Parisa Tehranifar
Journal: Circulation (2021)

Introduction: Sleep characteristics have been independently linked to cardiometabolic health, but sleep dimensions do not occur in isolation. Multidimensional sleep health predicts CVD mortality; however, associations with cardiometabolic health have not been evaluated. Hypothesis: Favorable multidimensional sleep health would be related to lower odds for hypertension (HTN), type 2 diabetes (T2D), obesity, and central adiposity. Methods: Participants were 4,559 adults aged ≥20 y from the 2017-18 National Health and Nutrition Examination Survey. A multidimensional sleep health score was computed from self-reported sleep duration, timing/regularity, and latency, snoring habits, and daytime sleepiness (Table); scores of 0-1, 2-3, and 4-5 indicated poor, moderate, and ideal sleep health, respectively. Survey-weighted linear and logistic models examined associations of multidimensional sleep health with blood pressure (BP), fasting glucose, anthropometric measures, and odds of cardiometabolic disease. Results: Ideal vs. poor sleep health was related to 66%, 58%, 73%, and 69% lower odds of HTN, T2D, obesity, and central adiposity, respectively (Table), and a linear trend was detected across the gradients of sleep health. In linear models, those with ideal and moderate vs. poor sleep health had lower BP, fasting glucose, BMI, and waist size. When sleep dimensions were examined separately, never/rare snoring, not having difficulty falling asleep, and never/rare daytime sleepiness were related to up to 46%, 51%, 58%, and 54% lower odds of HTN, T2D, obesity, and central adiposity, respectively (p&lt;0.05). Sufficient sleep duration (7-9 h vs. &lt;7 h or ≥9 h) was related to 29% lower odds for HTN (OR (95%CI): 0.71 (0.56-0.92)). Conclusions: Poor sleep health was associated with prevalent HTN, T2D, obesity, and central adiposity in US adults. Prospective studies are needed to decipher the role of sleep health in lowering CVD risk and extending healthspan.
TMOD-03. A SWINE MODEL OF GLIOBLASTOMA INDUCED BY SOMATIC GENE MODIFICATION
Authors: Mandy Taisto, Barbara Tschida, Alexander Coutts, Jarryd Campbell, Stanislas Corbiere, Dylan Duerre, Adrienne Watson
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most common and malignant primary brain tumor. Novel therapeutic development for GBM is desperately needed, as the standard of care universally fails to cure patients and the 5-year survival rate remains extremely low. GBM therapeutic development is hampered by the lack of relevant preclinical models for preclinical studies. To mitigate this problem, we have developed a genetic model of GBM in outbred, immune-proficient swine which have comparable brain size and anatomy to humans. We developed methods for introducing genome engineering tools to minipig brain in vivo by direct injection of gene delivery reagents to the lateral ventricle, altering major signaling pathways frequently changed in human GBM. Using this technique, we have delivered a combination of expression vectors for oncogenes and targeted nucleases to disrupt tumor suppressor genes commonly altered in human GBM. We have altered six major human GBM-associated signaling pathways and modeled molecular GBM subclasses. We have also engineered a secreted tumor reporter that can be used to monitor tumor size through a simple blood test. This somatic cell gene-modification platform we have developed in the minipig allows us to reproduce the genetic heterogeneity seen in GBM and understand the impact of the tumor microenvironment, immune system, and response to therapy. This minipig model of GBM Is being used to test the standard of care against novel therapies in preclinical studies, and biopsy, surgical, imaging, and radiation therapy techniques are being optimized in this mode to improve clinical trial success rates and patient outcomes. Funding for this study is provided by the National Institutes of Health though SBIR grant # 1R43CA235837-01A1.
TAMI-39. INTEGRATION OF SPATIALLY RESOLVED TRANSCRIPTOMICS AND METABOLOMICS UNCOVERS HYPOXIA-DRIVEN ACCUMULATION OF GENOMIC INSTABILITIES IN HUMAN GLIOMA
Authors: Jan Kückelhaus, Paulina Will, Franz Ricklefs, Jasim Kada Benotmane, Kevin Joseph, Jürgen Beck, Oliver Schnell, Vidyha Ravi, Dieter Henrik Heiland
Journal: Neuro-Oncology (2021)

Abstract High-dimensional technologies have provided insights into transcriptional heterogeneity and dynamic plasticity which are hallmarks of brain tumors. Although scRNA-seq recovers the diversity of transcriptional states, their spatial context within the neuronal environment has remained unexplored. Here, we integrated spatially resolved transcriptomics and metabolomics to characterize the glioma landscape at multiple molecular levels. We integrated spatial transcriptomics (10X Visium, n= 28) and metabolomics (MALDI, n= 6) from primary and recurrent glioblastoma patients. Unsupervised cluster analysis and pattern recognition uncovered 5 spatially distinct transcriptional programs, shared across patients. These included three cell-specific developmental stages largely reflecting those that are part of recently suggested models. By integrating metabolome data, we identified an additional program encompassing reactive responses to hypoxia. Areas of hypoxic response were negatively correlated with proliferation (R2= -0.34, p&amp;lt; 0.001) and significantly enriched for gene expression signatures from the S-phase (p&amp;lt; 0.001). Modeling of transient spatial gradients using vector field predictions showed opposing vector directions of hypoxia response and migratory capacity, underpinning the “go-or-growth” theory, where cells either proliferate or migrate. Inferred copy-number alterations (CNA) revealed a significant increase in genomic instability, highly correlated to hypoxia response (R2= 0.78, p&amp;lt; 0.001). Near necrotic areas, we observed a significant accumulation of CNAs while proliferation was inhibited, and cells remained in the S-phase. We validated this hypothesis of hypoxia-driven accumulation of CNAs by chronic hypoxia cultures of primary patient-derived cell lines. A gain of chromosomal instability after long-term hypoxia was observed, suggesting that hypoxic areas in glioblastoma function as bioreactors for genomic instability. Our findings elucidate the evolution of resistant subclones in glioblastoma. They provide novel insights into the dynamic regulation and interaction between host and tumor and cast a new light on hypoxic and necrotic areas, which may represent the source of the heterogeneous and resistant nature of glioblastomas.
Abstract 9438: Unipolar Voltages Are Associated with Left Atrial Wall Thickness and Predict Atrial Fibrillation Recurrence After Pulmonary Vein Isolation
Authors: Masashi Kamioka, Takafumi Okuyama, Hiroaki Watanabe, Ayako Yokota, Tomonori Watanabe, Takahiro Komori, Tomoyuki Kabutoya, Yasushi Imai, Kazuomi Kario
Journal: Circulation (2021)

Introduction: This study was conducted to investigate the relationship between left atrial (LA) wall thickness and the corresponding local unipolar/bipolar voltages, and its impact on the atrial fibrillation (AF) recurrence. Methods: Two-hundred-forty-two AF patients (196 male; 62 ± 9 years) who underwent successful PVI were enrolled and classified into the 2 groups: AF-Free group (n = 172), AF did not recur during the mean follow-up periods of 18 ± 8 months; and AF-Rec group (n = 70), those who had AF recurrence. LA wall thickness along the pulmonary vein isolation (PVI) line was measured using computed tomography and the voltage heights were measured by 3D electroanatomical map. Results: Left-superior PV posterior, right-superior PV (RSPV) posterior and right-inferior PV posterior wall thickness in AF-Rec group was significantly thicker than that in AF-Fee group (P &lt; 0.001, respectively). RSPV posterior wall (RSPV-PW) thickness &gt; 1.5 mm was revealed as cut-off value for AF recurrence with the sensitivity (73%) and specificity (71%) (P &lt; 0.001), and was the independent predictor of AF recurrence (Hazard ratio (HR): 4.511, confidence interval: 2.637-7.717, P = 0.001). Although both of the bipolar and unipolar voltages were associated with RSPV-PW thickness, the latter had a stronger correlation (R 2 = 0.0519, P = 0.043 vs R 2 = 0.5099, P = 0.001, respectively). The unipolar voltages of 3.1 mV was defined as cut-off value for AF recurrence prediction (P = 0.001). Conclusions: The current study demonstrated that RSPV-PW hypertrophy had strong correlation with the local unipolar voltages, and that RSPV-PW thickness &gt; 1.5 mm and the unipolar voltage &gt; 3.1 mV can be predictor for AF recurrence, where we should intensively deliver radiofrequency energy for the durable PVI.
Abstract MP255: Intercellular Model Predicts Macrophage Signaling As A Driver Of Cardiac Fibroblast Response Post Myocardial Infarction
Authors: Mukti Chowkwale, Jeffrey J Saucerman
Journal: Circulation Research (2021)

Introduction: Post-myocardial infarction (MI), cardiac fibroblasts and macrophages work together to regulate tissue homeostasis and infarct repair. Macrophage-fibroblast interactions in healthy tissue are stable and resistant to perturbations. However, this robustness post-MI has not been assessed. This study designs and implements an intercellular communication model of macrophage-fibroblast crosstalk to determine drivers of infarct repair. Methods: An ordinary differential equation model of post-MI cellular dynamics was developed ( Figure 1A ). Model inputs are time courses of cardiomyocytes, neutrophils, and monocytes. These cells, along with simulated macrophages and fibroblasts, secrete chemokines and cytokines which directed cell proliferation, removal, and chemical secretion. The outputs are macrophage and fibroblast densities, secreted factor dynamics, and produced collagen. Model validation was done using published data in post-MI mice. A sensitivity analysis was conducted by knocking down individual parameters to identify key drivers of fibroblast collagen production. Results: The simulated trends matched the validation time courses. Of the 28 validation relationships, 12 were input-output, 7 were knockouts, and 9 were inhibitor relationships. The validation passed at 78.5%; the 6 failed validations were due to the independent nature of the input curves. Sensitivity analysis ( Figure 1B ) identified macrophage differentiation rate, removal rate, and transforming growth factor-beta (TGFB) secretion rate as pro-fibrotic. Prolonged exposure to TGFB and granulocyte-macrophage colony stimulating factor was anti-fibrotic. Several clustered parameters differentially regulated macrophages and collagen production. Conclusions: The multicellular model identified macrophage density as a pro-fibrotic driver in the healing infarct. Differential regulation of macrophages and collagen production was predicted by the model.
Abstract 10578: Outcomes of Tachy-Arrhythmias in Group 1 Pulmonary Arterial Hypertension versus Non-Group 1 Pulmonary Hypertension: A Comparison of Nationwide Analysis 10 Years Apart
Authors: Bisharah Rizvi, Rupak Desai
Journal: Circulation (2021)

Introduction: Cardiac arrhythmias are associated with increased morbidity and mortality in patients with pulmonary hypertension (PH). We study the prevalence and outcomes of tachyarrhythmia in group 1, pulmonary arterial Hypertension (PAH) compared to non-group 1 PH, a decade apart (2007 vs 2017). Methods: National inpatient Sample database was used to identify PAH and non-group 1 PH using the ICD9-CM and ICD-10 codes for 2007 and 2017 respectively. Total hospitalizations, prevalence and mortality of cardiac tachyarrhythmia were analyzed. Results: Hospitalizations for PAH decreased from 2007 (17,713) vs 2017 (9,330). Hospitalizations for non-group 1 PH increased from 2007 (476,357) vs. 2017 (1,084,395). The most common tachyarrhythmia in PAH group was Atrial fibrillation/flutter (35.4% vs. 35.1% (p=0.648)), followed by Ventricular tachycardia (VT) (3.1% vs. 3.5% (p=0.143)), Supraventricular tachycardia (SVT) (paroxysmal atrial tachycardia, atrio-ventricular reentrant tachycardia and atrio-ventricular nodal reentrant tachycardia) (0.9 vs. 3.2% (p=&lt;0.001)), then Ventricular fibrillation/flutter (0.3% vs. 0.3% (p=0.758)). Only SVT had significantly increased and none were associated with increased in-hospital mortality. Non-group 1 PH also had Atrial fibrillation/flutter (37.2% vs. 46.8% (p&lt;0.001)) as the most common arrhythmia, followed by VT (3.6% vs. 4.5% (p&lt;0.001)), then SVT 0.9% vs. 3.0% (p&lt;0.001) and Ventricular fibrillation/flutter (0.3% vs. 0.6%(p&lt;0.001)). There was significant increase in all tachyarrhythmia when comparing 2007 to 2017, and all arrhythmias were associated with increased in-hospital mortality. In-hospital cardiac arrest increased in both PAH group (1.0% vs. 1.6% (p&lt;0.001)) and non-group 1 PH (0.7% to 1.4% (p&lt;0.001)) and both were associated with increased in-hospital mortality (PAH group (OR 27.22, p&lt;0.001) vs. non-group 1 PH(OR 1.66, &lt;0.001)). Conclusions: This study shows that non-group 1 PH has higher prevalance of tachyarrhythmia, and is associated with higher mortality compared to Group 1 PAH. We need to come up with strategies for early prevention and treatment.
NIMG-44. PROGNOSTIC VALUE OF PH- AND OXYGEN-SENSITIVE MRI IN GLIOMA PATIENTS
Authors: Yao Jingwen, Akifumi Hagiwara, Talia Oughourlian, Chencai Wang, Catalina Raymond, Whitney Pope, Noriko Salamon, Albert Lai, Phioanh Nghiemphu, Richard Everson, Won Kim, Robert Prins, Linda Liau, Timothy Cloughesy, David Nathanson, Benjamin Ellingson
Journal: Neuro-Oncology (2021)

Abstract Hypoxia and tissue acidosis are two key features of the glioma microenvironment, both associated with a more aggressive phenotype through promotion of invasion, angiogenesis, and resistance to a vast number of therapies. In the current study, we demonstrate that higher levels of acidity and hypoxia in glioma are associated with worse prognosis by using simultaneous pH- and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). A total of 159 histologically confirmed adult glioma patients (WHO grade II: N = 42; grade III: N = 38; grade IV, N = 79) were retrospectively evaluated. All patients were scanned with a custom amine CEST-SAGE-EPI MRI pulse sequence at 3T. Magnetization transfer ratio asymmetry (MTRasym) at 3ppm was used as a measure of relative acidity, R2’ was used as a surrogate of hypoxia, and their product MTRasym×R2' was used to quantify the degree of both acidity and hypoxia. Cox regression was performed to evaluate prognostic factors for OS and PFS. Univariate results suggested higher hypoxia, R2' (HR = 1.44, p = 0.0002), and higher combined measure of acidity and hypoxia, MTRasym×R2' (HR = 1.14, p = 0.0008), were associated with a shorter OS. When considering age, treatment status, and IDH mutation status as covariates, R2' and MTRasym×R2' remained significantly associated with patient OS (R2': HR = 1.27, p = 0.045; MTRasym×R2': HR = 1.17, p = 0.002). Within the treatment naïve patients, tumor acidity MTRasym, was also associated with OS (HR = 3.72, p = 0.003). R2' and MTRasym×R2' were significantly associated with PFS, both using univariate (R2': p &amp;lt; 0.0001; MTRasym×R2': p &amp;lt; 0.0001) and multivariate analyses including clinical factors (R2': p = 0.010; MTRasym×R2': p &amp;lt; 0.0001). In summary, tumor acidity and hypoxia measured using pH- and oxygen-sensitive metabolic MRI are significant prognostic factors in glioma.
Differential Gene Expression in Circulating T-Cells in Long-Term Adolescent/Young Adult Hodgkin Lymphoma (AYAHL) Survivors and Their Unaffected Twins
Authors: Wendy Cozen, Marta Epeldegui, David V. Conti, Amie E. Hwang, Jun Wang, Larry Magpantay, Thomas M. Mack, Otoniel Martinez-Maza, Steve W Cole
Journal: Blood (2021)
Abstract 11853: Serum Matrix Metalloproteinase 2 is Associated With Lower Ventricular Stiffness and Suboptimal Outcomes in Children With Single Right Ventricle Physiology Who Are Under Consideration for Stage 3 Palliation
Authors: Shahryar M Chowdhury, Varsha Bandisode, John Rhodes, Eric M Graham, Andrew M Atz, Donald R Menick
Journal: Circulation (2021)

Background: Increased extracellular matrix (ECM) metabolism is associated with poor outcomes in numerous cardiovascular diseases. However, its relationship to outcomes in patients with single right ventricle physiology (SRV) is unknown. The objective of this study was to investigate the association of measures of ECM metabolism to outcomes in SRV patients under consideration for stage 3 palliation (S3P). Methods: SRV patients undergoing routine pre-S3P catheterization were prospectively enrolled. Serum matrix metalloproteinase 2 (MMP-2), cardiac magnetic resonance T1 mapping derived extracellular volume (ECV), and pressure-volume loop derived ventricular stiffness (β) by micro-conductance catheter were collected. Controls were age-matched children undergoing closure of clinically insignificant patent ductus arteriosus. SRV were divided into those who had an optimal outcome or suboptimal outcome (hemodynamic concern causing delay in S3P, length of stay ≥ 14 days, heart transplant or death in first year after S3P). Results: Of 30 patients, 15 had SRV and 15 were controls; 7 SRV patients had suboptimal outcome. Mean age was 4.2 ± 0.7 years. SRV patients with suboptimal outcome had lower β (p = 0.05) and ECV (p = 0.04) than patients with optimal outcome (Figure A and B, respectively). MMP-2 was lower in SRV patients with suboptimal outcome compared to SRV patients with optimal outcome and controls (Figure C) (p = 0.05). In SRV patients, MMP-2 correlated with β (r = 0.56, p = 0.03). Conclusion: In biventricular heart disease characterized by chronically increased afterload, MMP-2, ECV, and ventricular stiffness are elevated. In contrast, this study shows that SRV patients with lower MMP-2, ECV, and ventricular stiffness have worse outcomes at the time of S3P; this suggests immature ECM metabolism leads to poor outcomes in SRV patients. Future studies exploring the mechanism by which immature ECM and dysregulated ECM metabolism influence SRV outcomes are warranted.