tbuckley/cabot-search huggingface dataset:
Abstract 10279: Altered Myocardial Gene Expression in <i>H2-kbm1</i> Mice with Orexinergic Dysfunction and Heart Failure
Authors: Douglas Stoller, Kajari Dhar, Hesham Basma, Stephen J Bonasera, Brian D Lowes
Journal: Circulation (2021)

Introduction: Mice carrying a homozygous frameshift mutation of the class I major histocompatibility antigen H2-K1 (H2-Kbm1) exhibit impaired development of hypothalamic orexinergic neurons. Similar to mice lacking the hypocretin (orexin) 2 receptor, H2-Kbm1 mice develop dilated cardiomyopathy and systolic heart failure (HF) from an early age. Previous studies suggest response to orexinergic signaling is predictive of patient response to current HF pharmacotherapeutic regimes. Our goal was to characterize the myocardial gene expression profiles of H2-Kbm1 mice. Methods: RNA was isolated from mice hearts (wild type n=5, mutant n=7) via the Qiagen RNeasy Mini Kit. DNase treatment was done to limit contamination of genomic DNA. Gene expression was measured using Illumina nexteq500 and 550 sequencing systems from a DNA library generated via the NuGene library kit (10 ng RNA). RNA-seq data analyses including comparisons, volcano and heatmap plots were completed. Results: H2-Kbm1 mice differentially express 398 myocardial genes compared to control mice. Ingenuity pathway analysis indicates that these genes are involved in necrosis of cardiac muscle (z-score -1.8), cell death (z-score 1.6), and cardiac contractility (z-score -4). Upstream signaling analysis suggest regulation by Mir-122 (z-score 2.4), DNMT3 A and B (z-score 3.3 and 2.5), VEGF (z-score 4.6) and rosiglitazone (z-score -6.8). Canonical pathway analysis is shown in Figure 1. Conclusion: H2-Kbm1 mice develop heart failure with marked myocardial transcriptional abnormalities that lead to impaired cardiac contraction and cell death. Differentially expressed genes are predominantly involved in mitochondrial function, oxidative phosphorylation, sirtuin signaling and the TCA cycle. Regulation of these genes is associated with miR-122, DNA methylations by DNMT3 A &amp; B, VEGF and rosiglitazone signaling. The orexin pathway is a potential target for heart failure therapeutics.
DDRE-50. INVESTIGATING THE ROLE OF LonP1 IN GLIOBLASTOMA TUMOR PROGRESSION
Authors: Christopher Douglas, Daniela Bota, Kaijun Di, Bhaskar Das, Javier Lepe
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM), a WHO grade IV brain cancer, exhibits strong treatment resistance and a high rate of reoccurrence, which gives it a dismal prognosis, a 5% survival rate in the first 5 years. LonP1, a mitochondrial master regulator, can drive metabolic transformation, cytokine production, EMT, and treatment resistance in various cancer types, but its role in GBM remains unexplored. Our research group has previously shown that LonP1 is overexpressed in human malignant gliomas, particularly glioblastoma, and that this is associated with disease prognosis. Here, we present findings that demonstrate that LonP1 seems to drive enhanced tumor progression, invasiveness, angiogenesis in different high grade glioblastomas based on TCGA-subtype. Furthermore, in collaboration with Professor Bhaskar Das, we have validated a lead compound, BT317, with on-target inhibition of LonP1 protease activity. BT317 has enhanced activity against glioma stem cell lines (GSC) and has demonstrated low toxicity and efficacy in an intracranial xenograft model. This preliminary data highlights the potential of using combinatorial, pharmacological LonP1 and proteasome inhibition as a novel strategy for targeting specific subtypes of GBM.
China’s challenge in promoting older migrants’ health and wellbeing: a productive ageing perspective
Authors: Kuiyun Zhi, Yongjin Chen, Jin Huang
Journal: BMJ (2021)

Onarheim and colleagues discuss the health vulnerabilities and unmet health needs of migrant workers globally.1

Newly released census data and previous research show that China’s older migrant population has increased from 5 million to 18 million in the past two decades.234 These migrants have moved, without a local household registration, to urban areas to provide care for grandchildren (43%), retire closer to their adult children (25%), or pursue employment opportunities (23%); more than …
Abstract 14202: Perioperative Metabolites Are Associated With Neurodevelopmental Outcomes at One Year in Neonates Undergoing Cardiopulmonary Bypass
Authors: Jessica Heibel, Carolyn Reuland, Eric M Graham, Aurelie ROUX, David Graham, Cedric Manlhiot, Allen D Everett
Journal: Circulation (2021)

Introduction: Improving neurodevelopmental (ND) outcomes for children with congenital heart disease has become a priority. Known clinical and surgical risk factors do not fully capture differences in ND outcomes. The objective of this study was to determine if plasma metabolites at the time of neonatal cardiac surgery were association with ND outcomes at 1 year. Methods: A secondary analysis of a clinical trial in 110 neonates undergoing cardiac surgery was performed. Plasma samples obtained pre-op, immediately post-op and at 12 hours post op had LC/MS/MS metabolomic profiling with a 193-plex targeted metabolite assay covering &gt;366 metabolic pathways. Metabolite levels were compared to one-year neurodevelopmental outcomes measured by the Bayley Scales of Infant and Toddler Development III (BSID). Results: 40/193 metabolites were detected and quantified for analysis. Regression models utilizing metabolites and metabolite features identified associations with cognitive (n=5), language (n=4) and motor (n=10) BSID composite scores. Enrichment analysis disease pathways included seizures (tyrosine and isoleucine) and indoxyl sulfate, a known neurotoxic product from tryptophan synthesis. Conclusions: Perioperative metabolites may serve as biomarkers for prediction of 1-year ND outcomes and provide a scientific basis for targeted interventions to optimize perioperative care.
Abstract 12796: Fasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and Its Subtypes in Older Adults
Authors: Adam Oesterle, Petra Buzkova, Cara Pellegrini, Joachim H IX, Calvin Hirsch, Russell Tracy, David S Siscovick, Luc Djousse, Ken J Mukamal, Jorge R Kizer
Journal: Circulation (2021)

Introduction: Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and postprandial levels are under different homeostatic regulation. The relationships of fasting and postload glucose and NEFA with incident HF and its subtypes remain incompletely defined. Methods: We hypothesized that fasting and postload glucose and NEFA are positively associated with incident HF in older adults, with postload levels bearing stronger associations. Serum glucose and NEFA levels were measured during fasting and 2 hours post oral glucose tolerance test in the Cardiovascular Health Study. HF with preserved (HFpEF) and reduced ejection fraction (HFrEF) were examined secondarily. Results: Among 2238 people (age 78±4) with median follow-up of 9.9 years, there were 737 HF events (257 classifiable as HFpEF, 197 as HFrEF). After adjustment for demographic and lifestyle factors (main model), both fasting (HR per SD 1.11 [95% CI 1.01-1.23]) and postload (HR per SD 1.14 [1.05-1.24]) glucose was significantly associated with incident HF. No association was seen for fasting or postload NEFA. When adjusted for each other, only postload glucose (HR 1.11 [1.003-1.22]), but not fasting glucose (HR 1.06 [0.94-1.20]), remained associated with HF. Further adjustment for prevalent atherosclerotic cardiovascular disease, atrial fibrillation and other risk factors in the causal pathway did not affect the association for postload glucose, but eliminated that for fasting glucose. There was no interaction by sex, but associations for fasting and postload glucose appeared stronger with higher BMI (p&lt;0.025). Assessment of HF subtypes showed no associations for glucose or NEFA with HFpEF. Both fasting glucose (HR 1.23 [1.03-1.48]) and postload glucose (HR 1.24 [1.07-1.45]) were significantly associated with HFrEF, but relationships disappeared on mutual adjustment. Conclusions: Fasting and postload glucose, but not NEFA, were associated with incident HF, particularly HFrEF. The association proved especially robust for postload glucose, which reflects pancreatic β-cell insufficiency and skeletal muscle decline. Our findings suggest that targeting relevant pathways in these two organ-tissues could offer new approaches for HF prevention in elders.
STEM-25. ADENO-ASSOCIATED VIRUS INTRAVENTRICULAR INJECTION ALLOWS THE RESTRICTED TRANSDUCTION OF GLIOBLASTOMA CELLS NESTED IN THE PERI- AND SUB-VENTRICULAR ZONE IN A PATIENT-DERIVED ORTHOTOPIC XENOGRAFT MODEL
Authors: Arnaud Lombard, Emmanuel Di Valentin, Virginie Neirincx, Didier Martin, Bernard Rogister
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION: Glioblastoma (GBM) seems to arise from cells nested in the subventricular zone (SVZ), a neurogenic zone in the adult brain. After striatal engraftment of patient-derived GBM cells in mice, we showed that some tumor cells escape the tumor mass to colonize the SVZ. We aimed to determine if the SVZ-nested GBM cells could be highlighted by the intraventricular injection of a viral vector. MATERIALS AND METHODS: We determined the optimal Adeno-Associated Virus (AAV) serotype to transduce patient-derived GBM cells cultured in 3D (GB1). We studied the spreading of the virus 4 weeks after intraventricular injection in mice. We realized striatal engraftment with GB1 cells, previously transfected with a lentiviral construction in order to express the Red-Fluorescent-Protein (RFP) spontaneously, while they express Green-Fluorescent-Protein (eGFP) only in presence of Cre-recombinase. 10 weeks after engraftment, an AAV expressing Cre-Recombinase was injected in the lateral ventricle and mice were perfused at 14 weeks. RESULTS: AAV serotype DJ (AAVDJ) efficiently transduced GB1 cells. 4 weeks after intraventricular injection, the AAVDJ transduced cells in the SVZ and the medial part of the caudoputamen (mCP). The median of the longest distance between the right ventricle and the transduced cells in the mCP was 293.8µm [245 – 376.5]. In 5 mice, the median of the shortest distance between RFP-positive GBM cells and right ventricle was 580.1µm [535 – 785.1]. SVZ was not colonized and eGFP signal was not found. In the 4 other mice, SVZ was invaded and eGFP signal was detected. The median of the longest distance between the right ventricle and eGFP-positive tumor cells was 240.5µm [195.7 – 372.5]. The median of the eGFP volume was 9 499 404µm3. CONCLUSION: It is possible to transduce GBM cells nested in the peri- and sub-ventricular zone thanks to AAV intraventricular injection.
Abstract 12880: Neddylation Regulates Murine Cardiomyocyte Maturation
Authors: Jianqiu Zou, Juan Ayala, Wenjuan Wang, Rodney E Littlejohn, Jinxi Wang, Jiliang Zhou, Long-sheng Song, Jie Li, Huabo Su
Journal: Circulation (2021)

From birth to adulthood cardiomyocytes (CMs) undergo a complex maturation process characterized by drastic changes in cell size, ultrastructure, metabolism and gene expression. The molecular mechanisms regulating CM maturation remain poorly defined. Neddylation is a novel post-translational modification that covalently attaches a small ubiquitin-like protein, NEDD8, to target proteins. We found that deletion of NAE1, a critical NEDD8 E1 enzyme that triggers neddylation, in embryonic and perinatal mouse hearts via Nkx2.5 Cre and aMHC Cre , respectively, led to myocardial hypoplasia, heart failure and early lethality. The severe cardiac phenotypes are accompanied by disorganized sarcomere structure and defective fetal-to-adult gene transition, suggesting a possible role for neddylation in CM maturation. To rule out the confounding effect of secondary changes caused by perturbed CM differentiation and cardiac stress response in the mutant hearts, we used AAV9-cTnT-Cre to achieve mosaic knockout of NAE1 in postnatal hearts. High-dose AAV9 deleted NAE1 in 80% CMs and caused heart failure, whereas low-dose AVV9 deleted NAE1 in 30% CMs and preserved heart function. In the context of preserved cardiac function, CMs lacking NAE1 showed severe disrupted transverse tubules (T-tubules) network, which was further exacerbated in hearts with modest dysfunction. In contrast, T-tubule morphology was largely maintained in CMs with intact NAE1 expression from low-dose AAV9 infected hearts, as well as in CMs with deletion of one allele of NAE1, indicating a key, cell-autonomous role of neddylation in T-tubule maturation. Biochemical and histological analyses further revealed dysregulated metabolic and sarcomeric gene expression and disrupted sarcomere ultrastructure in high-dose AAV9 infected hearts, supporting defective CM maturation. In vitro, pharmacological inhibition of neddylation also impaired myofibril assembly in isolated neonatal and adult CMs. Together, our data reveal an important role of neddylation in CM maturation in the developing heart, warranting further investigations of detailed posttranslational mechanisms underlying CM maturation.
Abstract 10214: Stress Testing Prior to Abdominal Aortic Aneurysm Repair: What is Our Return on Investment?
Authors: Jesse Columbo, Aravind S Ponukumati, Stanislav Henkin, Salvatore T Scali, Mark A Creager, Richard J Powell, David Stone
Journal: Circulation (2021)

Introduction: The use of stress testing prior to abdominal aortic aneurysm (AAA) repair is highly variable. We examined the financial implications of this variation and its impact on postoperative cardiac events. Methods: We studied patients who underwent elective endovascular (EVAR) or open AAA repair at Vascular Quality Initiative participating centers from 2015–2019. We grouped centers into quintiles by their frequency of preoperative stress testing. We calculated rates of major adverse cardiovascular events (MACE), a composite of in-hospital myocardial infarction, stroke, heart failure, or death, for each quintile. We applied the charges for electrocardiographic, echocardiographic, and nuclear stress tests at our institution in 2019 to the study population to calculate expected charges per 1,000 patients. Results: We studied 27,978 patients who underwent EVAR (mean age: 73.5 ±8.5 years, 81.7% male) and 4,481 who underwent open AAA repair (mean age: 69.5 ±8.1 years, 75.1% male). Stratifying by quintile, stress test frequency ranged from 13.0% to 68.6% (mean: 37.9%) among EVAR patients and 15.9% to 85.0% (mean: 52.8%) among open AAA repair (Figure). The rate of MACE was 1.4% after EVAR and 10.2% after open AAA repair. MACE after EVAR increased with the frequency of stress testing and was 0.9% at 1 st quintile centers vs 1.7% at 5 th quintile centers (p-trend=0.033). There was no association between MACE and stress testing for open AAA repair (p-trend=0.192). The estimated charges for stress testing prior to EVAR was $125,806 per 1,000 patients at 1 st quintile centers, and $664,975 at 5 th quintile centers, while charges prior to open AAA repair were $153,861 per 1,000 patients at 1 st quintile centers, and $825,473 at 5 th quintile centers. Conclusions: More frequent stress testing is associated with high cost without a reduction in MACE. This lack of return on investment highlights the need for more judicious stress test use prior to AAA surgery.
Abstract 9759: Race Moderates the Relationship Between Anxiety and Quality of Life in Implantable Cardioverter Defibrillator Recipients
Authors: Jennifer L Miller, Misook L Chung, Muna H Hammash, Abigail Latimer, Melissa M Czarapata, Aaron Hesselson, Debra K Moser
Journal: Circulation (2021)

Introduction: The implantable cardioverter defibrillator (ICD) has significantly decreased mortality for populations at high risk for sudden cardiac arrest. Despite its effectiveness, this treatment modality comes with a high potential for psychological distress. The prevalence rate of anxiety in ICD recipients is 50%, with the highest levels reported in Black ICD recipients, yet little is known about the role of race in the relationship between anxiety and quality of life (QOL). Understanding racial disparities in the experience of ICD recipients has been limited due to low numbers of Black participants in research studies. This is reflective of the clinical reality that fewer Black patients for whom an ICD is appropriate are offered or accept the treatment. Methods: In this cross-sectional study we used the Hayes SPSS Process macro for moderation analysis (model 1) with 5000 bootstrap samples to determine whether race moderated the relationship between anxiety (Brief Symptom Inventory) and QOL (EURO-QOL-5D3L). Results: Using data from 136 participants (18% Black, 27% women with mean age 63 + 12 and education 14 + 3), we entered anxiety, race, and the interaction term into a simultaneous regression model while controlling for gender, age, education, depression, history of shock, and ICD knowledge. The interaction between anxiety and race was significant (B = -.1330, SE = .1339, p &lt; .015), suggesting that the effect of anxiety on QOL differed between Black and White ICD recipients. Together, the variables accounted for approximately 33% of the variance in QOL (R 2 = .33, F (1,126) = 6.08, p &lt; .001). Simple slope tests revealed a significant negative association between anxiety and QOL for Black ICD recipients (B = -.3712, SE = .05, p = .005) but not for White ICD recipients (B = -.0412, SE = .0478, p = .390). Conclusion: Assessment, recognition, and referral for treatment of anxiety in ICD recipients, particularly Black ICD recipients, may improve QOL for this population.
NIMG-43. ADVANCED MULTI-PARAMETRIC HYPERPOLARIZED 13C/1H IMAGING OF GBM
Authors: Adam Autry, Sana Vaziri, Marisa LaFontaine, Jeremy Gordon, Hsin-Yu Chen, Javier Villanueva-Meyer, Susan Chang, Jennifer Clarke, Duan Xu, Janine Lupo, Peder Larson, Daniel Vigneron, Yan Li
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The goal of this study was to characterize progressive and pseudoprogressive GBM using multi-parametric hyperpolarized (HP)-13C / 1H MRI. METHODS Dynamic HP-13C MRI was acquired from 13 patients with progressive GBM [patients (scans): 2(3) IDH-mutant; 11(13) IDH-wildtype] and 2 IDH-wildtype patients (3 scans) demonstrating pseudo-progression following intravenous injection of HP [1-13C]pyruvate. Frequency-selective echo-planar imaging (3s temporal resolution, 3.38 cm3 spatial resolution) captured [1-13C]pyruvate metabolism to [1-13C]lactate and 13C-bicarbonate in the brain. Dynamic 13C data were kinetically modeled to obtain the pyruvate-to-lactate conversion rate constant k PL and temporally summed to calculate 13C-metabolite percentiles and ratios (linearly interpolated 2x in-plane). 1H imaging included T2, post-Gd T1, perfusion (nCBV, %recovery), diffusion (ADC), and lactate-edited spectroscopy (CNI, choline-to-NAA index; 1H-lactate). The normal-appearing white matter (NAWM), non-enhancing lesion (NEL), and contrast-enhancing lesion (CEL) were segmented from 1H images. 13C-resolution masks were iteratively applied on a voxel-wise basis to evaluate 1H imaging parameters within each ROI and multi-parametric data were collectively evaluated using a mixed effects model in R. RESULTS Progressive IDH-mutant GBM compared to wildtype counterparts displayed increased perfusion %recovery (p &amp;lt; 0.001) and k PL (p &amp;lt; 0.01), together with reduced 1H-lactate (p &amp;lt; 0.001) and pyruvate percentile (p &amp;lt; 0.01), in the T2 lesion. Among IDH-wildtype progressive GBM, the CEL was distinguished from NEL/NAWM by increased nCBV (p &amp;lt; 0.05/0.001), 1H-lactate (p &amp;lt; 0.05/0.001); and decreased bicarbonate / lactate (p &amp;lt; 0.05/0.001). The CEL and NEL were collectively distinguished from NAWM by elevated CNI (p &amp;lt; 0.001/0.001), ADC (p &amp;lt; 0.05/0.001), pyruvate percentile (p &amp;lt; 0.001/0.001), lactate percentile (p &amp;lt; 0.001/0.001), and relative lactate / pyruvate (p &amp;lt; 0.001/0.05). Psuedo-progressive IDH-wildtype GBM displayed lower k PL (T2 Lesion; p &amp;lt; 0.01) and nCBV (CEL; p &amp;lt; 0.01) compared to progressive GBM. CONCLUSION HP-13C parameters can potentially augment proton imaging and demonstrated Warburg-associated metabolic alterations.
Abstract 13476: ROR2 Deficiency is Associated With Endothelial Dysfunction and Reduced Angiogenesis in Pulmonary Arterial Hypertension
Authors: Ananya Chakraborty, Abinaya Nathan, Stuti Agarwal, Mark Orcholski, Ke Yuan, Sandra Bonnet, Sebastien Bonnet, Vinicio A Dejesus Perez
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction and progressive loss of lung microvessels. Our group has shown that Wnt pathways are critical for pulmonary angiogenesis but the role of the Wnt/planar cell polarity specific receptor ROR2 in lung endothelial angiogenic responses is unknown. Hypothesis: We hypothesized that ROR2 is required for proper angiogenic responses in pulmonary microvascular endothelial cells (PMVECs) and its loss contributes to endothelial dysfunction in PAH. Methods and Results: Analysis of PAH lung tissues demonstrated reduced ROR2 expression within vascular lesions and in explanted PMVECs. ROR2 deficiency was associated with reduced proliferation and tube formation in response to VEGF-A, a major inducer of angiogenesis. We found that ROR2 promotes VEGF receptor 2 activation via direct phosphorylation of cytoplasmic residues (Y1175/Y951) and that restoring ROR2 expression in PAH PMVECs led to improved angiogenic responses. Besides angiogenic sprouting, we found that ROR2 is required for lung endothelial barrier formation by promoting the assembly of mature focal adhesions and adherens junctions through activation of Src and focal adhesion kinase (FAK). Compared to wild-type controls, endothelial-specific ROR2 knockout (ROR2 ECKO) mice demonstrated more severe hemodynamics, small vessel loss, and muscularization in chronic hypoxia. Moreover, ROR2 ECKO demonstrated severe RV dysfunction associated with reduced capillary density. We validated these findings in samples of decompensated RV tissue from PAH patients, monocrotaline, and Sugen-hypoxia rats which also demonstrated a significant reduction of ROR2 expression that correlated with RV capillary loss. Conclusion: ROR2 plays a protective role in the pulmonary and RV circulations and its loss prevents vessel repair in PAH. Targeting ROR2 could promote recovery of small vessel loss and RV adaptation in PAH.
JAK2 GGCC (46/1) Haplotype in Unprovoked Venous Thrombotic Events
Authors: Maged Al-Ammari, Abdul Ali Peer Zada, Ibraheem H. Motabi, Belal M. Albtoosh, Syed Y. Altaf, Imran K. Tailor, Mohammed S. Alnoamani, Syed Ziauddin A Zaidi, Mansour Alfayez, Nawal F Alshehry, Mohammed A. Marei
Journal: Blood (2021)