tbuckley/cabot-search huggingface dataset:
TMOD-16. HYPOXIA RESHAPES THE GLIOBLASTOMA MICROENVIRONMENT INVOKING NECROSIS AND TRIGGERING DISEASE PROGRESSION
Authors: Steven Markwell, Cheryl Olson, James Ross, Daniel Brat
Journal: Neuro-Oncology (2021)

Abstract Emerging necrosis within solid tumors corresponds with malignant progression. Current tumor model systems fail to adequately mimic the magnitude of post-necrotic restructuring within the microenvironment and remain overly reliant on post-mortem and descriptive analyses, obligating researchers to extrapolate causal relationships between necrosis and progression phenomena that emerge during tumor evolution. In glioblastoma (GBM; WHO grade 4), the most malignant primary brain tumor, vascular pathology and central necrosis precede rapid, radial expansion. Despite extensive genetic characterization in GBM, mechanisms enabling selective fitness within a hypoxic/anoxic setting remain poorly understood. Persistent nutrient deprivation culminates in necrosis, dramatically altering the tumor microenvironment (TME). We established mouse models that more aptly capture events found in human gliomas, exposing the dynamic temporal and spatial changes that facilitate expansive progression while including unique microenvironmental stressors typically absent from GBM animal models, specifically central necrosis. This model combines hypoxia-induced focal necrosis within GBM with real time intravital microscopy to capture TME restructuring and elucidate its impact on glioma progression. Our studies use genetically characterized patient-derived orthotopic GBM xenografts, alongside an immunocompetent RCAS/tv-a model, to determine how these processes impact disease progression and outcomes across multiple GBM molecular subtypes. Simultaneously, we employ in vitro models to scrutinize how hypoxia-related crosstalk between GBM, microglia and circulating monocytes alter tumor-associated macrophage (TAMs) recruitment and reprogramming. Our preliminary data suggests microenvironmental cues significantly alter microglia behavior and have demonstrated increased 3D invasion under hypoxic conditions as compared to normoxia. Monocyte invasion varies based on signals emanating from specific GBM subtypes, yet the signaling events that elicit differential responses remains unknown. However, exposure to any GBM conditioned media uniformly upregulates immunosuppressive TAM programming. Our ongoing investigations seek to uncover the mechanisms driving post-necrotic GBM evolution and reactive neuroinflammation
Abstract 105: Novel Functions For Synaptosomal-associated Protein 29 (snap29) In Cardiac Arrhythmias
Authors: Jie Wang, Jason Pellman, Robert Lyon, Yan Liang, Valeria Mezzano, Fabian Zanella, Jing Zhang, Vishal Nigam, Yusu Gu, Nancy Dalton, Kirk Peterson, Farah Sheikh
Journal: Circulation Research (2021)

Human genetic studies and mouse models have classically linked mutations/deficiencies in components of the desmosomal cell-cell junction to arrhythmogenic right ventricular cardiomyopathy (ARVC). However, growing evidence points to the importance of the desmosome in cardiac diseases beyond ARVC, which include electrical diseases that have no impact on cardiac structure/morphology. The mechanisms of how defects in cardiac desmosomal protein homeostasis drive these distinct forms of cardiac disease remain elusive to the field. To uncover mechanisms that underlie the distinct pathophysiology (structural versus non-structural) encompassed by desmosomal mutations/loss, we performed an unbiased yeast-two-hybrid screen using an adult human heart cDNA library and the desmosomal protein, desmoplakin (DSP) to uncover new regulators of cardiac desmosomal protein homeostasis. We identified synaptosomal-associated protein 29 (SNAP29), as a novel DSP-interacting protein in the adult human heart. Traditional functions of SNAP29 are to regulate membrane fusion and play a role in autophagy; however, its role at the desmosome and in the heart is undefined. We show that SNAP29 is a subcomponent of the cardiac desmosome, as it co-localizes with DSP in the adult heart and DSP-deficient hearts harbor loss of SNAP29. Cardiomyocyte-specific SNAP29 knockout (SNAP29-cKO) mice displayed baseline and pacing-induced ventricular arrhythmias in an age-dependent manner in the absence of cardiac structural and functional deficits. We show that a loss of a subset of desmosomal proteins and connexin43 as well as upregulation of selective autophagy-mediated degradation underlie SNAP29 deficient cardiomyocyte arrhythmias. In line with this, acute blockade of autophagy was sufficient to rescue desmosomal and connexin43 protein levels as well as arrhythmias in SNAP29 deficient cardiomyocytes. In conclusion, SNAP29 insulates a subset of desmosomal and gap junction proteins from selective autophagy-mediated degradation to restrict cardiac arrhythmias. Thus, loss of SNAP29-desmosome-gap junction interactome may predispose the heart to desmosomal based diseases of an electrical nature.
Abstract P451: Depletion Of Rbl2 Exacerbates Cardiomyocyte Apoptosis And Ischemia-reperfusion Injury By Augmenting E2f1-mediated Bnip3 Expression
Authors: Jingrui Chen, Yuening Liu, Peng Xia, Zhaokang Cheng
Journal: Circulation Research (2021)

Background: Reperfusion therapy, an effective treatment for myocardial infarction, triggers ischemia-reperfusion (I/R) injury and eventually may result in heart failure. Retinoblastoma-like 2 (Rbl2), a major retinoblastoma family member expressed in the heart, maintains the postmitotic state of adult cardiac myocytes. However, the role of Rbl2 in myocardial I/R injury remains unclear. We hypothesize that Rbl2 deficiency exacerbates myocardial injury following I/R. Methods and results: Wild type C57BL/6 (8–10-week, male) mice were subjected to 30 min of ischemia followed reperfusion. I/R induced phosphorylation of Rbl2 at Ser952, which has been associated with Rbl2 protein inactivation. To determine the role of Rbl2 in vivo, Rbl2-deficient mice and wild-type littermates were subjected to I/R and infarct size was evaluated by Evans blue/TTC staining. Rbl2 deficiency significantly increased infarct size at 24 h post I/R when compared with wild-type littermate controls. Echocardiography and Masson’s trichrome staining revealed that Rbl2 deficiency exacerbated I/R-induced cardiac dysfunction and fibrosis. Moreover, ablation of Rbl2 exacerbated I/R-induced cardiomyocyte apoptosis, as evidenced by the increased TUNEL positive signal. Consistently, knockdown of Rbl2 augmented H 2 O 2 -induced cleavage of PARP and caspase 3 in neonatal rat cardiomyocytes , suggesting that depletion of Rbl2 exacerbated oxidative stress-induced cardiomyocyte apoptosis. Mechanistically, both I/R and H 2 O 2 induced expression of the pro-apoptotic protein BNIP3, which was augmented by depletion of Rbl2. Since the BNIP3 promoter contains an E2F-binding site, we further examined the levels of the transcriptional activator E2F1 and the transcriptional repressor E2F4. Western blotting revealed that disruption of Rbl2 reduced E2F4 but increased E2F1 levels in mouse heart both at baseline and following I/R. Conclusion: Our findings suggest that Rbl2 deficiency exacerbates cardiomyocyte apoptosis and ischemia-reperfusion injury by augmenting E2F1-mediated BNIP3 expression.
Changes in ABC Transporter Expression during Hematopoiesis Cause Lineage-Biased Cytopenias in Patients Treated with Aurora Kinase Inhibitors
Authors: Brooke A. Furlong, Ryan R. Posey, David B. Chou, Christos Kyprianou, Lucy R. O'Sullivan, Rhiannon David, Suzanne Randle, Urszula Polanska, Jelena Urosevic, Jon Travers, John Hutchinson, Robert P. Hasserjian, Rachelle Prantil-Baun, Donald E. Ingber
Journal: Blood (2021)
Abstract 14007: Transcatheter Mitral Valve Replacement Among Patients With Chronic Kidney Disease: Insights From The National Readmissions Database
Authors: Ayman Elbadawi, MAHMOUD ABDELGHANY, Alexander Dang, Awad Javaid, Mennaallah Eid, DAVID PANIAGUA, Hani Jneid
Journal: Circulation (2021)

Introduction: There is a paucity of data regarding the outcomes of trans-septal transcatheter mitral valve replacement (TS-TMVR) among patients with chronic kidney disease (CKD). Methods: We queried the Nationwide Readmissions Database (2015-2018) for patients undergoing TS-TMVR. We identified patients with CKD (stages III or more). We conducted propensity score matching analysis to compare the outcomes of patients with versus without CKD. The main outcomes were in-hospital mortality and 30-day non-elective readmissions. Results: From 2015 to 2018, there were 2,017 discharge records for patients receiving TS-TMVR, of whom 733 (36.34%) had CKD. Among the CKD group, 76 (10.4%) required chronic dialysis. During the study time period, there was an increase in the uptake of TS-TMVR among patients with CKD (p&lt;0.001). Patients with CKD were older (73.311.1 vs. 71.213.2 years, p&lt;0.001), less likely to be women and more likely to have chronic heart failure, CAD and prior CABG. There was no difference in in-hospital mortality after TS-TMVR among those with versus without CKD in the matched cohorts (7.8% vs. 7.3%; OR 1.09; 95% CI: 0.64-1.80, p=0.78). Subgroup analysis showed no interaction between chronic dialysis status and in-hospital mortality after TS-TMVR. In the matched cohort, TS-TMVR among those with CKD was associated with higher rates of cardiogenic shock (12.3% vs. 7.6%, p=0.03), AKI (35.7% vs. 16.7%, p&lt;0.001), and new requirement for hemodialysis (5.4% vs. 1.5%, p=0.01) and longer median length of stay, (7[12] vs. 5 [8] days, p&lt;0.001). Patients with CKD were more likely to have 30-day non-elective readmissions (25.8% vs. 16.5%, p = 0.01), driven by more readmissions for bleeding/ anemia. Conclusions: TS-TMVR among patients with CKD is associated with increased risk for cardiogenic shock, worsening renal function requiring hemodialysis, but no increase in mortality when compared with non-CKD patients. A higher length of stay and 30-day readmission rate was observed in CKD patients versus non-CKD patients.
Abstract 10948: Post-Infarct Cardiac Remodeling Predictions with Machine Learning
Authors: Xavier Dieu, Floris Chabrun, FABRICE PRUNIER, Pascal Reynier, Alain p Furber, Gabriel Garcia, Loïc Bière, Delphine Mirebeau-Prunier
Journal: Circulation (2021)

Introduction: We sought to improve the risk prediction of 3-month left ventricular remodeling (LVR) occurrence after myocardial infarction (MI), using a state-of-the-art machine learning approach. Methods: We retrieved 135 variables, ranging from clinical, biological and cardiac magnetic resonance data, from 379 patients with ST-elevated myocardial infarction and processed them with a machine learning pipeline using advanced feature selection and modelling algorithms such as gradient boosting, neural networks or recurrent neural networks. Results: A baseline logistic regression model using known variables such as infarct size, creatine kinase peak, no reflow and cardiovascular risk factors, achieved an AUC of 0.71 on the test, with 67% sensitivity and 64 % specificity. In comparison, our best predictive model was a neural network using seven variables (in order of importance): creatine kinase, mean corpuscular volume, baseline left atrial surface, history of diabetes, history of hypertension, red blood cell distribution width, and creatinine. This model achieved an AUC of 0.78 on the test set, reaching a sensitivity of 92% and a specificity of 67%, outperforming the baseline model. Conclusions: We were able to achieve state-of-the-art performance with a high level of sensitivity for the prediction of a 3-month post-MI LVR. Our unbiased data-driven machine learning approach highlights the role of classical parameters alongside unexpected variables such as left atrial dilation at baseline, mean corpuscular volume and red blood cell distribution width whose role in the pathophysiology of post-MI cardiac remodeling remain to be clarified. The relative simplicity and the good availability of these parameters make our new approach suitable for clinical testing.
IMMU-13. COMBINED MODULATION OF THE TGF-Β PATHWAY AND GITR IMMUNE CHECKPOINT SIGNALING PROMOTES ANTI-TUMOR IMMUNITY IN SYNGENEIC GLIOMA MODELS
Authors: Daniela Lorizio, Michael Weller, Manuela Silginer, Alan Epstein, Patrick Roth
Journal: Neuro-Oncology (2021)

Abstract The profound local immunosuppressive microenvironment is one hallmark of glioblastoma, which results in resistance to most immunotherapeutic strategies that have been explored so far. Reverting this condition in order to reinvigorate anti-glioma immunity might be a promising therapeutic approach. Transforming growth factor (TGF)-β signaling is deregulated in different cancer types and contributes to the malignant phenotype of glioma cells. Glioma-derived TGF-β is also a major immunosuppressive factor in the tumor microenvironment. Furthermore, intratumoral regulatory T (Treg) cells and activated T effector cells express high levels of the co-stimulatory immune checkpoint glucocorticoid-induced tumor necrosis factor receptor (GITR). Agonistic anti-GITR antibodies have been explored in preclinical tumor models and are under investigation in clinical trials for the treatment of solid tumors. We evaluated the effect of TGF-β and GITR targeting on anti-tumor immune responses in syngeneic mouse glioma models. In co-culture settings, GITR modulation with a GITR ligand (GITRL)-Fc fusion protein, given alone or in combination with a pharmacological TGF-β receptor inhibitor, led to increased T cell activation. Furthermore, the combined targeting of the two pathways resulted in significantly higher immune cell-mediated tumor cell killing than either treatment alone. In vivo, TGF-β inhibition and GITR signaling modulation resulted in a higher fraction of long-term surviving glioma-bearing mice than single-agent treatment. Surviving mice were resistant to tumor re-challenge, suggesting adaptive immunity as an underlying mechanism. These data support the assumption that combined immunotherapeutic strategies may represent a promising approach for the treatment of glioma.
NCMP-17. BEWARE: ALL POSTERIOR FOSSA MASSES IN CHILDREN ARE NOT BRAIN TUMORS
Authors: Magimairajan Issai Vanan, Jie Li, Muhamad Almiski, Martin Bunge, Demitre Serletis, Sara Israels
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Isolated Myeloid sarcoma (MS) of the central nervous system (CNS-MS) is a very rare presentation of Acute Myeloid Leukemia (AML). A 10-year-old boy with a two-week history of intermittent headaches was referred to the emergency department (ED) by an optometrist for evaluation of bilateral papilledema. Physical examination in the ED confirmed the presence of papilledema with no other abnormal neurologic findings. Emergent MRI of the brain showed an avidly homogeneously enhancing extra-axial dural based mass in the right posterior fossa measuring 4.8 cm (AP) x 3.2 cm (CC) x 4.6cm (T), with significant mass effect and peri-tumoral vasogenic edema. Neuro-surgery consultation was obtained and complete blood count (CBC) was normal except for the presence of 13% blasts with occasional Auer rods seen on the peripheral blood smear. Bone marrow aspirate demonstrated 56% myeloblasts; A diagnosis of AML with CNS-MS (CNS-3c) was made and the initial lumbar puncture (LP) was deferred due to the risk of CNS herniation. Induction chemotherapy was initiated as per protocol. A CT scan done two weeks later showed complete resolution of the intracranial mass. DISCUSSION The incidental finding of papilledema, with imaging to investigate the intracranial pathology revealed a large posterior fossa mass in our patient. However, the atypical features of the mass (dural based extra-axial location; extensive infiltration into adjacent structures) and the finding of blasts with Auer rods in peripheral blood helped us to diagnose CNS-MS, and avoided an extensive neurosurgical procedure and a delay in definitive therapy. Our patient had a normal CBC and the review of the peripheral blood film by an experienced Hematologist was very crucial in making a clinical diagnosis of MS. CONCLUSION Myeloid sarcomas should be considered in the differential diagnosis of an intracranial mass, particularly when accompanied by abnormal findings in the CBC.
Abstract 10435: A Plea for Inclusion of Surface Echocardiography for Acute Coronary Syndrome in the Advanced Cardiac Life Support Algorithm
Authors: VIJU WILBEN, Muralidhar Kanchi, Vinil Kumar, Srinath Kumar
Journal: Circulation (2021)

Background: The AHA/ACC guidelines algorithm for Acute Coronary Syndrome (ACS) does not include echocardiographic evaluation in the assessment of chest pain. Such patients may be subjected to interventions based on ECG leading invasive procedures which may prove unnecessary. This study was performed to determine if a bedside echocardiography would help identify the conditions that do not need intervention and might possibly change the treatment pathway at the right time. Methods: In a prospective observational study design, adult patients presenting to acute emergency care with chest pain were included in the study. Patients exhibiting a significant ST change on a 12-lead ECG were subjected to bedside echocardiography, i.e. 2D transthoracic echocardiography (2D-TTE) The findings of echocardiography were correlated with ECG and coronary angiography for possible percutaneous coronary intervention. Results: Among the 385 patients in the study, 312 suffered acute coronary syndrome. In 18.7% patients presented to acute emergency care with chest pain, ST-T changes and were found to have causes other than ACS; and bedside echocardiography (2D-TTE) was able to identify 90.4% of those cases. From this study we conclude that bedside echocardiography had high specificity (90.4%) and sensitivity (97.43%) in identifying regional wall motion abnormality (RWMA) due to ACS and exclude non-ischemic causes of chest pain. Conclusion: Bedside echocardiography is recommended in patients with chest pain and ST-segment abnormality to avoid unnecessary delay in diagnosis and invasive interventions in non-acute coronary syndrome (ACS). Hence it is reasonable to include bedside echocardiography in either box 3 or 4 in the ACS algorithm.
DDRE-37. YB-1 AS A BIOMARKER FOR DRUG RESISTANCE AND TUMOUR PROGRESSION IN MEDULLOBLASTOMA
Authors: Louisa Taylor, Ian Kerr, Beth Coyle
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) relapse is the most significant unmet clinical challenge in childhood cancer. Recently it has become evident that MBs display altered biology at relapse, indicative of the emergence and expansion of a minor, therapy resistant cancer cell population. Thus, the examination of mechanisms underlying therapy resistance is of critical importance. Y-box binding protein 1 (YB-1) is a multi-functional oncoprotein whose elevated expression and nuclear accumulation correlate with drug resistance, metastasis and disease progression in numerous cancers, although little is known about the functional role of YB-1 in MB. Genomic analysis of large-scale publicly available patient datasets revealed YB-1 expression is significantly elevated across MB molecular subgroups and high expression correlates with poor overall survival. Immunohistochemical analysis of YB-1 localisation in patient TMAs revealed significant YB-1 nuclear accumulation, suggestive of elevated YB-1 nuclear activity in these patients. Treatment of Group 3 MB cell lines (D283MED and HDMB-03) with cisplatin and subsequent analysis by nuclear/cytoplasmic fractionation and confocal microscopy revealed significantly increased nuclear and overall YB-1 expression, indicating a role for YB-1 in cellular stress response. In support of this, ChIP analysis in D283MED and HDMB-03 cell lines confirmed YB-1 interaction with multi-drug transporter gene ABCB1, while stable YB-1 knockdown resulted in significantly reduced ABCB1 expression. Likewise, knockdown of YB-1 expression in D283MED cells results in increased susceptibility of cells to vincristine, supporting a role for YB-1 in the acquisition of drug resistance in MB cell lines. Finally, whole transcriptome sequencing of YB-1-knockdown HDMB-03 and D283MED cell lines indicated YB-1 regulation of a variety of cell death, survival and metabolic pathways. We are currently using ChIP-Seq analysis to identify targetable YB-1 downstream “hits” which drive these processes. Ultimately, we aim to identify druggable targets of YB-1 allowing us to establish more effective therapeutic options for the treatment of high-risk MB.
The Drive to Acquire Biallelic Hits Inversely Correlates with the Functional Impact of the Primary TP53 Lesion: The Complexity of TP53 Role Assessment
Authors: Waled Bahaj, Carmelo Gurnari, Tariq Kewan, Suresh Kumar Balasubramanian, Simona Pagliuca, Yogenthiran Saunthararajah, Laila Terkawi, Misam Zawit, Hassan Awada, Babal K. Jha, Valeria Visconte, Betty K. Hamilton, Hetty E. Carraway, Jaroslaw P. Maciejewski
Journal: Blood (2021)
Abstract 10345: Video-Based Deep Learning Model for Automated Assessment of Ejection Fraction in Pediatric Patients
Authors: Bryan He, David Ouyang, Leo Lopez, James Zou, Charitha D Reddy
Journal: Circulation (2021)

Introduction: Echocardiographic assessment of left ventricular (LV) systolic function by ejection fraction (EF) is crucial for diagnosis and monitoring in pediatric patients. EF requires manual tracing of the LV but measurement reproducibility is affected by diverse phenotypes, image quality, and operator skill. We sought to train a deep learning model (EchoNet-Peds) on a pediatric-specific video dataset to automatically segment the LV and estimate EF by 5/6 Area Length (AL) using two common views, the apical 4 chamber (A4C) and parasternal short axis (PSAX). Methods: EchoNet-Peds evaluated raw A4C and PSAX videos to segment the LV and predict the EF from the A4C and PSAX views. Eighty percent of the dataset was used for algorithm training, 10% for validation, and 10% for testing. We used the training set to predict the EF by AL, determined hyperparameters from the validation set, and reported results using 10-fold cross-validation on the test set. Results: The dataset included 1923 children (43% female) with 4400 echocardiogram studies. EFs ranged from 10% to 81% (61% ± 10.1) and ages from 0 to 18 years (10 ± 5.4 years). EchoNet-Peds achieved Dice Similarity Coefficients of 0.901 (0.895 - 0.907) and 0.887 (0.879 - 0.895) for segmenting the LV in A4C and PSAX views respectively. The A4C view predicts an EF by AL with an R2 of 0.73 (0.67 - 0.77) and the PSAX view predicts an R2 of 0.74 (0.70 - 0.77). Combining both predictions results in an overall R2 of 0.78 (0.74 - 0.81). The model performs well when stratified by sex, age, and body surface area (BSA), and improves in younger patients and lower BSA (Figure 1 b-d). Conclusions: EchoNet-Peds is the first demonstration that AI trained on a pediatric-specific dataset utilizing multiple views can accurately segment the LV and predict EF. The automated functionality of EchoNet-Peds can be used for real-time assessment of cardiac function despite pediatric heterogeneity.