tbuckley/cabot-search huggingface dataset:
EPCO-26. INTEGRATIVE MULTI-OMICS IDENTIFIES CONVERGING DEVELOPMENTAL ORIGINS OF DISTINCT MEDULLOBLASTOMA SUBGROUPS
Authors: Kyle Smith, Laure Bihannic, Brian Gudenas, Qingsong Gao, Parthiv Haldipur, Volker Hovestadt, Igor Iskusnykh, Viktor Chizhikov, Mei Deng, Ian Glass, Giles Robinson, Brent Orr, Zoltan Patay, Kimberly Aldinger, Kathleen Millen, Paul Northcott
Journal: Neuro-Oncology (2021)

Abstract Understanding the interplay between normal development and tumorigenesis, including the identification and characterization of lineage-specific origins of MB, is a fundamental challenge in the field. Recent studies have highlighted novel associations between biologically distinct MB subgroups and diverse murine cerebellar lineages via cross-species single-cell transcriptomics. Specifically, Group 4-MB correlated with the unipolar brush cell lineage and Group 3-MB resembled Nestin+ stem cells of the early cerebellum. However, these analyses were hampered by low resolution due to the sparsity of pertinent cerebellar cell types and the cross-species nature of the approach. Herein, we profoundly expand the depth of these rare developmental populations in the murine cerebellum using a combination of lineage tracing and integrative multi-omics. Isolation and enrichment of spatially and temporally unique developmental trajectories of key rhombic lip-derived glutamatergic lineages provided an enhanced reference for mapping MB subgroups based on molecular overlap, especially for poorly defined Group 3- and Group 4-MB. Further comparisons to a novel single-cell atlas of the human fetal cerebellum, companioned with laser-capture microdissected transcriptional and epigenetic datasets, reinforced developmental insights extracted from the mouse. Characterization of compartment-specific transcriptional programs and co-expression networks identified in the human upper rhombic lip implicated convergent cellular correlates of Group 3- and Group 4-MB, suggestive of a common developmental link. Together, our results strongly implicate developmental lineages of the upper rhombic lip as the probable origins of poorly defined Group 3- and Group 4-MB. These important findings will shape future efforts to accurately model the biological heterogeneity underlying these subgroups and provide unprecedented opportunities to explore their cellular and mechanistic basis.
TMOD-14. CONJOINED CLASS I AND II EPITOPES ENHANCE NEOANTIGEN-TARGETED ACTIVE IMMUNOTHERAPY
Authors: Adam Swartz, Kendra Congdon, Smita Nair, Qi-Jing Li, James Herndon, Carter Suryadevara, Katherine Riccione, Jessica Reedy, Sarah Cook, Gary Archer, Pam Norberg, Luis Sanchez-Perez, John Sampson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Cancer vaccines involve the administration of tumor-associated antigens into the host to generate anti-tumor T cell responses. Glioblastoma (GBM) is a disease with poor prognosis. GBM has a limited number of immunotherapeutic targets due to low mutational load, and is also highly heterogeneous; targeting a single antigen leads to antigen escape and tumor growth. METHODS VMDK mice were subcutaneously implanted with 750,000 SMA560 cells and on days 1 and 8 post implantation, mice were treated with 15 nmol of the universal helper epitope, P30, conjoined to the MHCI-restricted neoepitopes Odc1MHCI-P30 or Topbp1MHCI-P30. Human CD27 (hCD27) transgenic mice were intracranially implanted with CT2A-Odc1, followed by anti-CD27 and 15 nmol of Odc1MHCI-P30. B16.OVA or B16.F10 tumor cells were intracranially implanted in hCD27 mice and received SIINFEKL-P30 or Trp2-P30 conjoined peptides. Tumor growth, survival, or IFNγ secretion of splenic or tumor-infiltrating cells was assessed. RESULTS Unlike Odc1MHCI mixed with P30, conjoined Odc1MHCI-P30 had equivalent immunogenicity and anti-tumor efficacy to that observed with native long Odc1 peptide. Native long peptide of Topbp1 did not elicit an antitumor response, yet Topbp1MHCI-P30 caused an increase in numbers of IFNγ-secreting splenocytes and a decrease in tumor growth and similar to that seen with Odc1MHCI-P30 . Anti-CD27 treatment significantly increased numbers of IFNγ secreting splenocytes in Odc1MHCI-P30 vaccinated hCD27 mice, and the use of anti-CD27 with Odc1MHCI-P30 achieved long-term survival in 90% of tumor bearing hCD27 mice. Anti-CD27 synergized with SIINFEKL-P30 and Trp2-P30 to significantly improve survival after administration of these peptides. CONCLUSIONS Our work shows that poorly immunogenic neoantigens can be conjoined to P30 and used to generate an anti-tumor response in mouse models of GBM, and anti-tumor responses of conjoined peptides can be enhanced with anti-CD27 treatment. Together, these data demonstrate the efficacy of neoantigen vaccines for the treatment of heterogeneous GBM.
Abstract MP228: The Role Of Gut Microbiome Secreted Short Chain Fatty Acids In The Development Of Heart Failure With Preserved Ejection Fraction HFpEF
Authors: Jomana Hatahet, Raiza Bonomo, Tyler Cook, Chelsea R White, Chaitanya Gavini, Virginie Mansuy-Aubert, Gregory Aubert
Journal: Circulation Research (2021)

More than 50% of patients with heart failure are diagnosed with heart failure with preserved ejection fraction (HFpEF), and 80% of them are obese. It is a prominent disease with no available treatments. It is characterized by diastolic dysfunction that involves increase in left ventricle stiffness and decrease in its relaxation during diastole. To better understand the pathogenesis of obesity associated HFpEF, our studies focus on the early asymptomatic changes in cardiac mechanics that occurs before the increases in intracardiac pressure. Therefore, we have developed an obesity associated mouse model that we called pre-HFpEF where mice were fed either Normal Chow or Western Diet for 14 weeks. Our echocardiography measurements indicated the presence of early cardiac dysfunction consistent with obesity associated pre-HFpEF phenotype. Mice on WD had decrease in Global Longitudinal Strain (%GLS) and Longitudinal strain rate reverse (LSRr) indicating early signs of systolic and diastolic dysfunction, as well as increase in left ventricle anterior and posterior wall thickness during diastole (LVAWd, LVPWd). Obesity is also known to cause microbiome imbalance, which plays a significant role in the development of cardiovascular diseases through changes in short chains fatty acids, which are products of dietary fiber fermentation by the gut bacteria. In order to study the association between gut microbiome imbalance and HFpEF development, we treated our obese pre-HFpEF mice with fecal matter transplantation (FMT) from either lean or obese mice, and we found that FMT from lean mice led to significant improvements in systolic and diastolic dysfunction by increasing %GLS and LSRr and preventing hypertrophy by decreasing LVAWd and LVPWd. In addition, WD reduced butyrate producing bacteria, however circulating levels of butyrate were significantly increased with lean FMT treatment. Using an in-vitro approach to mimic WD we found butyrate treatment to inhibit the activation of NLRP3 inflammasome and NF-KB. Therefore, since FMT treatment improved cardiac dysfunction in obesity associated pre-HFpEF mice, and that butyrate is increased after FMT and can play a role in metabolic homeostasis, we predict that butyrate could be an important player in FMT improvements through cardiac metabolic regulation and cardiac inflammation suppression
Abstract 10502: Impact of Norwood Shunt Type on Cardiac Function and Clinical Outcomes in Survivors to Early Adolescence with Hypoplastic Left Heart Syndrome and Other Single Right Ventricular Anomalies: A Report from the Single Ventricle Reconstruction (SVR) III Study
Authors: Caren S Goldberg, Felicia Trachtenberg, J William Gaynor, William T Mahle, Chitra Ravishankar, Steven Schwartz, James F Cnota, Richard G Ohye, Russell Gongwer, Michael Taylor, Stephen Paridon, Peter C Frommelt, Katherine Afton, Andrew M Atz, Kristin Burns, Jon A Detterich, Kevin D Hill, Antonio G Cabrera, Alan B Lewis, Chritian Pizarro, Amee Shah, Jane W Newburger
Journal: Circulation (2021)

Introduction: The SVR Trial demonstrated that the right ventricle-to-pulmonary artery shunt (RVPAS) vs. modified Blalock-Taussig-Thomas shunt (MBTTS) at Norwood operation was associated with better early survival for children with hypoplastic left heart syndrome (HLHS). However, it remains unclear if shunt type is associated with cardiac function, morbidities or survival in older children. Methods: SVR Trial survivors were followed annually. Cardiac MRI and cycle ergometry were performed at 10-12 years (y) of age for SVR III participants. Outcomes were compared by shunt type received (presented) and intention to treat, using linear, Poisson and Cox proportional hazards regression. Results: Among 549 children in the SVR Trial, 237 of 313 eligible transplant-free survivors returned for follow-up at median (IQR) 10.9 (10.4-11.5) y. Transplant-free survival at 12 y was 59% for the RVPAS vs 54% for the MBTTS, with no difference in survival conditional on Stage II survival. Ejection fraction (EF) was measured by MRI in 168 participants, with no difference between groups (RVPAS median 53 [IQR 46-58] and MBTTS 52 [IQR 48-56], p=.38). In multivariable modeling, the percent variance in EF explained by pre-Norwood and Norwood variables including shunt type was low (R 2 &lt; .2). Cycle ergometry was performed in 181 participants with no difference by shunt type in peak VO 2 (ml/kg/minute) (RVPAS 30 [IQR 25-36] vs. MBTTS 29 [IQR 24-33], p=.26) or in peak work rate (RVPAS 67±24 watts vs MBTTS 66±20 watts, p=.61). By age 12 y, the RVPAS group had a higher rate of PLE (5% vs. 2%, p =.04) and catheter interventions (14 vs 10 per 100 pt-y; p=0.01). Otherwise the cumulative incidence of events and complications were similar for shunt groups with stroke in 7%, seizure 14%, plastic bronchitis 1%, atrial tachyarrhythmias 7% and ventricular tachyarrhythmias 3%. Conclusion: By 12 y after Norwood, shunt type has minimal effect on post-Stage II transplant-free survival, cardiac function or exercise performance. EF is preserved in most transplant-free survivors. However, low and declining transplant-free survival, poor exercise performance, and accruing morbidities highlight the critical need for innovative strategies to improve long-term outcomes in patients with HLHS.
CXCL10 chemokine regulates heterogeneity of the CD8+ T cell response and viral set point during chronic infection
Authors: Aleksandra J. Ozga, Melvyn T. Chow, Mateus E. Lopes, Rachel L. Servis, Mauro Di Pilato, Philippe Dehio, Jeffrey Lian, Thorsten R. Mempel, Andrew D. Luster
Journal: Immunity (2021)
Abstract 11949: Disease-Specific and Comorbidity-Related Polygenic Risk in Spontaneous Coronary Artery Dissection
Authors: Ingrid Tarr, Stephanie Hesselson, Siiri Iismaa, Michael Troup, Paul Young, Ketan Mishra, Claire Wong, Keerat Junday, David Humphreys, Sally Dunwoodie, Diane Fatkin, David Muller, Robert M Graham, Eleni Giannoulatou
Journal: Circulation (2021)

Introduction: Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute coronary syndrome that typically affects younger women (24-52 years). Several comorbidities have now been reported, including migraine, fibromuscular dysplasia (FMD), connective tissue disorders, anxiety, and depression. Associations between SCAD and other conditions, such as autoimmune disorders, have been reported but remain contentious. SCAD is known to have a genetic element: both common and rare variants have been associated with the disease and familial clustering has been identified. However, the genetic etiology is not well resolved although common variants have been identified between SCAD, FMD, and migraine. Aims: We sought to determine if there is a polygenic disease burden of common genetic variation in a cohort of sporadic SCAD cases, and shared genetics between SCAD and reported comorbidities via the application of polygenic risk scores (PRSs) for these comorbidities. Methods: A cohort of 173 sporadic European SCAD cases and 1314 European controls were genotyped (88 cases, 1127 healthy elderly controls and 76 non-SCAD cardiomyopathy-diseased patients by whole genome sequencing; 85 cases and 111 controls by Axiom UK Biobank and PMDA array, respectively). Differences in genetic risk was assessed for cases and controls using established PRS, specific to either SCAD or conditions reported to be comorbid. Results: SCAD cases showed significantly higher SCAD-PRS than did controls (WGS p = 1.372e-09; array p = 5.264e-05). In contrast, there were no differences in SCAD-PRS between non-SCAD patients and controls (WGS only: p-value = 0.291) and non-SCAD patients also had lower risk than SCAD cases (WGS only: p-value = 2.08e-07). Multiple PRS derived from comorbid disorders are currently being investigated in this cohort. Conclusions: We have shown that there is a common genetic risk element to SCAD, while genetic risk for, and, therefore, genetic overlap with, reported comorbidities in SCAD will be further discussed. These findings illustrate the role of common variants in SCAD etiology and may further contribute to our understanding of the mechanisms leading to SCAD formation.
EPCO-33. CELL-TYPE PROPORTION DECONVOLUTION OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS FROM SINGLE NUCLEI RNA-seq UNCOVERS UNDERLYING TRANSCRIPTOMIC CHANGES FROM BULK TUMOR RNA-seq COMPARED TO NORMAL BRAIN
Authors: Min Kyung Lee, Nasim Azizgolshani, Fred Kolling, Lananh Nguyen, George Zanazzi, Brock Christensen
Journal: Neuro-Oncology (2021)

Abstract Identifying transcriptomic alterations in pediatric central nervous system (pCNS) tumors often relies on transcriptomic profiles from bulk tissue RNA-sequencing that can be confounded by varying cell type proportions across tumor and normal brain tissues. We utilized single nuclei RNA-sequencing (snRNA-seq) and bulk RNA-seq in 33 pCNS tumors and 3 non-diseased pediatric brain tissue samples collected from the Norris Cotton Cancer Center to identify variation in gene expression in bulk tissue attributed to overrepresentation of specific cell-type populations when determining differentially expressed genes comparing pCNS tumors to normal pediatric brain tissues. snRNA-seq of 43,515 nuclei (mean = 1,209 nuclei/sample) revealed large proportions of astrocytes (median = 0.45, range = 0.24–0.93) and oligodendrocytes (median = 0.37, range = 0.00–0.66) in pCNS tumors. Compared to normal pediatric brain, proportions of astrocytes were significantly higher (P = 9.2E-03) and neurons were significantly lower (P = 9.4E-03) in pCNS tumors. Differential expression analyses comparing bulk RNA-sequencing data from pCNS tumors to normal pediatric brain identified 902 additional differentially expressed genes (# DE genes = 1,802) when adjusting for astrocyte and neuron proportions compared with unadjusted analysis (# DE genes = 900). In cell-type proportion unadjusted analysis, top DE genes included astrocyte-specific markers, GFAP and CIITA, both of which were found to be not significantly differentially expressed in cell-type proportion adjusted analysis. Indeed, pathways enrichment analysis revealed DE genes in unadjusted models were associated with processes of the neurons and astrocytes such as interferon signaling and postsynaptic signal transmission. After adjustment for astrocyte and neuron proportions, DE genes were associated with defensins and DNA replication-related processes. Our results highlight new potential biological pathways essential in pCNS tumors and indicate the significance of the distribution of varying cell types in tissue samples when conducting studies to investigate transcriptomic alterations in bulk tissue of pCNS tumors.
Abstract 14393: Deep Learning and Patient-Derived hiPSC Cardiomyocytes to Predict Drug Proarrhythmia
Authors: Ricardo Serrano, Dries A Feyen, Arne A Bruyneel, Anna P Hnatiuk Hnatiuk, Michelle M Vu, Prashila L Amatya, Isaac Perea-Gil, Maricela Prado, Timon Seeger, Joseph C Wu, Ioannis Karakikes, Mark Mercola
Journal: Circulation (2021)

Introduction: Drug safety initiatives globally have endorsed human iPSC-derived cardiomyocytes (hiPSC-CMs) as an in vitro model for predicting drug-induced cardiac arrhythmia. However, the extent to which human-defined features of in vitro arrhythmia, such as action potential prolongation and after depolarizations, predict actual clinical risk has been much debated. Hypothesis: Deep learning can be used to discriminate features of in vitro action potential features that associate with dangerous drugs and distinguish them from features evoked by safe drugs. Furthermore, the deep learning algorithm should be able to discern the influence of myopathic gene variants on drug-induced arrhythmia. Methods: We trained a deep neural network (DNN) to detect in vitro features of electrophysiological recordings induced by drugs with established clinical risk. The 40 drugs used in the study comprised high, intermediate, and low risk. Action potentials were optically recorded for each drug at 8 concentrations in iPSC-CMs from 3 healthy donors and in isogenic iPSC-CMs carrying 5 gene variants that cause dilated and hypertrophic cardiomyopathies. Multiple differentiation batches were evaluated for each. Results: The trained DNN accurately classified reference drugs according to high, intermediate, and low arrhythmic risk in people. The risk profile of the test drugs was similar across hiPSC-CMs from different healthy donors. The introduction of gene variants associated with arrhythmogenic cardiomyopathies increased the propensity of certain intermediate and high-risk drugs to induce arrhythmia. Conclusions: Deep learning can identify in vitro arrhythmic features that correlate with clinical arrhythmia and discern the influence of pathological gene variants on drug-induced arrhythmia.
The Significance of Chromosome 11 Abnormalities in Patients with AML
Authors: Anna Przybylowicz-Chalecka, Joanna Czerwinska-Rybak, Blazej Ratajczak, Zuzanna Kandula, Andrzej Szczepaniak, Malgorzata Jarmuz-Szymczak, Lidia Gil
Journal: Blood (2021)
Abstract 14392: Progression of Coronary Artery Calcium Score Predicts Higher Risk for Coronary Revascularization
Authors: Kevin Coy, Aditya singh, Mark Petrasko, Melissa Pham, Phillip Petrasko, Beatrice Rynders, Alexander Sjovold, Patryk Stys, Veronica Stys, Komaldeep Singh, Muhammad Hamza Saad Shaukat, Zoltan Varga, Catherine Hajek, Murat Sincan, Marian S Petrasko, Adam Stys, Tom Stys
Journal: Circulation (2021)

Introduction: The Coronary artery calcium (CAC) score is a powerful independent screening tool for coronary artery disease (CAD). Elevated CAC score has been significantly associated with increased rates of revascularization, however monitoring the progression of disease with a serial CAC score remains controversial. Hypothesis: The progression of the CAC score predicts the need for coronary revascularization. Methods: Data were analyzed retrospectively of patients who underwent two calcium scans between February 2008 and April 2021 as part of the Sanford Cardiovascular Prevention Program and were categorized into low (&lt;100), moderate (100-399), or high ≥400) CAC groups. Progression of the CAC score between two scans was analyzed and the need for clinically indicated revascularization (PCI vs CABG) was evaluated by the chi-square test. Results: A total of 5809 subjects were screened for CAC score. 54.3% were females and the mean age was 55.6 ±10.35 years. Progression of CAC score (Low to moderate/high, moderate to high) and need for revascularization was statistically significant (P&lt;0.001). In our study, patients who progressed from low to high and moderate to high CAC score category were found to have the highest rates of coronary revascularization, 11.92%, and 13.36 % respectively. Conclusions: In our study, patients who progressed to a high CAC score category were found to have a significantly increased need for revascularization. Repeating a CAC score in low to moderate risk patients may have clinical benefit and needs further investigation.
Enhancing the therapeutic efficacy of programmed death ligand 1 antibody for metastasized liver cancer by overcoming hepatic immunotolerance in mice
Authors: Bing Xin, Meixiang Yang, Panyisha Wu, Li Du, Xingyu Deng, Enfu Hui, Gen‐Sheng Feng
Journal: Hepatology (2021)

Abstract Background and Aims Immunotherapy with programmed cell death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) blockade has shown low response rates in liver cancer patients, with the underlying mechanisms unclear. To decipher a specific impact of the liver microenvironment, we compared the effects of anti‐PD‐L1 antibody (αPD‐L1) blockade on the same tumor grown s.c. or in the liver. Approach and Results We generated s.c. tumors in mice by inoculating MC38 colorectal cancer (CRC) cells under the skin and metastatic liver tumors by portal vein or splenic injection of CRC cells. Tumor‐bearing mice were treated by i.p. injection of αPD‐L1, polyinosinic:polycytidylic acid (poly[I:C]), or both. αPD‐L1 monotherapy significantly suppressed s.c. tumor growth, but showed no effect on metastatic liver tumors. However, the combination of αPD‐L1 with poly(I:C), an innate immunity‐stimulating reagent, robustly inhibited tumor progression in liver. The combination therapy effectively down‐regulated myeloid‐derived suppressor cells (MDSCs), but up‐regulated ratios of M1/M2 macrophages, CD8/CD4, and CD8/regulatory T (Treg) cells infiltrated into liver tumors and whole liver. A group of long‐lasting T‐bet + Eomes − PD‐1 − cytotoxic T cells was maintained in the combo‐treated liver, leading to resistance to tumor recurrence. Depleting macrophages or blocking type Ⅰ interferon signaling abrogated the synergistic antitumor effect of αPD‐L1 and poly(I:C), indicating a requirement of boosting innate immunity for optimized activation of cytotoxic T cells by PD‐1/PD‐L1 blockade. Conclusions The poor response of liver cancers to αPD‐L1 therapy is largely attributable to a unique hepatic immunotolerant microenvironment, independent of tumor origins or types. The success of a combinatorial immunotherapy relies on coordinated inhibition or activation of various innate and adaptive immune cell activities.
Abstract 13691: High Burden of Sensing Changes in Periprocedural TAVR Patients With Pre-Existing CIEDs Presents A Unique Challenge
Authors: Luai Madanat, Kuldeep Shah, David Haines, Nishaki Mehta
Journal: Circulation (2021)

Introduction: The data on the management of patients undergoing transcatheter aortic valve replacement (TAVR) with pre-existing cardiac implantable electronic devices (CIED) is scarce. Objective: We describe the R wave sensing changes following TAVR in a patient with CIED and describe CIED behavior peri procedurally in a high volume center over 8 years. Results: A 64 year old male patient with a history of non-ischemic cardiomyopathy and a secondary prevention dual-chamber ICD presented for generator change. Six months prior, he underwent TAVR (29mm ES S3). Post TAVR, he developed a new RBBB. Device interrogation revealed a significant drop in sensed R waves from 9mV to 1.5mV which temporally correlated with TAVR (Figure 1). Pacing thresholds and impedance were stable. Chest x-rays showed stable lead position. Given drop in R wave sensing, successful defibrillation threshold testing was performed with generator change. Of the 115 patients with pre-existing CIEDs undergoing TAVR between 2012-2020, 23.5% (27 patients) showed changes in sensing (mean 3.0±2.5mV) peri procedurally with minimal change in impedance or threshold with no correlation with QRS changes. Conclusions: To our knowledge, this is the 1st reported case of a change in sensed R waves due to conduction disturbance following TAVR. We hypothesize this occurred due to a change in the activation wavefront sensed by the right ventricular lead following the development of new RBBB. Up to a quarter of patients have sensing fluctuations in our experience. Consideration of pre and post device interrogation with TAVR could be of value.