tbuckley/cabot-search huggingface dataset:
Abstract MP227: Single Cell RNA Sequencing Analysis Reveals Insulin Signaling Defects In Cardiomyocytes Derived From A Novel Mouse Model Of Heart Failure With Preserved Ejection Fraction
Authors: Jijun Huang, Zhaojun Xiong, Shuxun Ren, Nancy Cao, Jianfang Liu, Yibin Wang, Chen Gao
Journal: Circulation Research (2021)

Heart failure with preserved ejection fraction (HFpEF) is an emerging form of heart failure worldwide with no effective therapies in contrast with heart failure with reserved ejection fraction (HFrEF). To simulate multiple risk-factors associated with HFpEF in clinic, we developed a HFpEF mouse model by introducing cardiac hypertrophy with transverse aortic constriction (TAC) in ObOb ( Lep ob/ob ) mice, which has intrinsic systemic metabolic dysfunctions including obesity and insulin resistance. We first validated pathological changes in diastolic but not systolic parameters in the Ob-TAC vs. Ob-sham mice up to 10 weeks post-TAC by echocardiography. To evaluate the global transcriptome change in difference cell types, we conducted single nuclei RNA sequencing (snRNA-seq) from whole hearts of lean mice (c57), ObOb, and Ob-TAC mice (male only). 10x genomic 3’ GEM kit was used to generate the cDNA library and sequencing was done by Novaseq SP platform. A total of 13k nuclei were recovered from QC, nFeature RNA (&amp;lt 2500) and mitochondrial gene (&amp;lt 5%) filtering. By UMAP dimension reduction analysis, we annotated major cardiac cell types in the integrated snRNA-seq dataset, including 3 clusters of Cardiomyocytes (CMs). By pathway analysis of the differentially expressed genes in each CM clusters, we found that insulin resistance and glucagon pathway were enriched among the up regulated genes in CMs in HFpEF vs. lean control, while cell migration, signal transduction including insulin substrates were down regulated. Thus, we hypothesized that the altered crosstalk between glucagon and insulin signaling might contribute to the development of HFpEF in this mouse modal. This hypothesis was validated in a proof-of-concept study showing significant improvement of HFpEF features by inhibiting the glucagon receptors post-TAC with injection of a glucagon receptor antagonist.
Abstract 14265: The Role Of Vesicle-incorporated Long Noncoding RNA H19 In Cardiovascular Disease
Authors: Katharina Maus, Rabiul Hosen, Feilx Jansen
Journal: Circulation (2021)

Background: Recent studies have demonstrated that pathogenesis of cardiovascular disease (CVD) includes higher levels of circulating extracellular vesicles (EVs). Those EVs can contain different types of cargoes including long noncoding RNAs (LncRNAs). Here we aim to elucidate the cellular function and mechanism of action of LncRNA H19 with particular interest in EV-mediated intercellular communication. Methods and Results: Loss of function of H19 was performed in vitro using RNA interference in vascular endothelial cells (ECs). After H19 loss of function, various assays were conducted to assess specific cellular properties and functions in both EV-donor and recipient cells. The cellular properties in terms of viability and apoptosis as well as the cellular functions regarding migration, proliferation, and angiogenesis were impaired in EV-donor cells. Intriguingly, both cellular properties and functions were improved in EV-recipient cells. Since our results indicated that the angiogenic sprouting was impaired in cells after knockdown of H19, we want to perform angiogenesis array to identify dysregulated genes that are involved in angiogenesis. To unravel the molecular mechanism of H19 further, we sought to identify binding partners of H19 to unveil how vesicle-incorporated H19 exerts it specific functions in CVDs and cardiovascular cells in vitro . Conclusion: Our data suggests that vesicular transport of H19 regulates the cellular properties and function of target ECs. Further investigation is required to identify specific H19 molecular mechanism of action that plays a crucial role in cardiovascular cells and disease. Figure 1: Schematic representation of EV-mediated intercellular transfer of lncRNA H19. LncRNA H19 can be transferred to the target cell via extracellular vesicles (EVs). Studies showed that H19 can exploit different regulatory functions endothelial cells.
Abstract 13457: Renin-Angiotensin System Inhibitor Exerts Prognostic Effect in HFpEF Patients With Low Chloride Level
Authors: Shota Shirotani, Kentaro Jujo, Makoto Kishihara, Shonosuke Watanabe, Nana Endo, Takuma Takada, Takuro Abe, Yuichiro Minami, Hagiwara Nobuhisa
Journal: Circulation (2021)

Background: Hypochloremia is associated with a poor prognosis of heart failure (HF) patients. Serum chloride level is known to be affected by serum renin secretion; however, this relationship is one of the least investigated field in HF patients. Renin-angiotensin system inhibitor (RASi) is recommended as a first-line medication for HF patients with reduced left ventricular ejection fraction (LVEF), but its prognostic effect is still controversial in HF patients with preserved EF (HFpEF). Hypothesis: The prognostic benefit of RASi depends on the baseline serum chloride level in HFpEF patients. Methods: This observational study included 1,913 consecutive patients who admitted to hospital due to worsening of HF and discharged alive. After excluding patients who received regular hemodialysis and those whose LVEF &lt;50%, 506 HFpEF patients were ultimately analyzed. They were divided into two groups by serum chloride levels at admission (Low-Chloride group: -101 mEq/L; High-Chloride group: 102- mEq/L), referred to prior reports. Death from any cause as the primary endpoint was compared between patients who received RASi at discharge and those who did not, in each chloride group. Results: During the observation period with 479 days of median follow-up, 77 (15%) died. Patients who received RASi had significantly lower mortality than those who did not, only in the Low-Chloride group (Log-rank: p=0.001, Figure ). In the multivariate Cox regression analysis with diverse covariates, the rate of risk reduction by RASi for the mortality was greater in patients in the Low-Chloride group than High-Chloride group (HR: 0.35 and 0.71, respectively). The prognostic advantages of RASi were evident in patients with low chloride level, but not in those with high chloride level at admission (P for interaction=0.027). Conclusion: In this observational study, the administration of RASi was associated with an improved prognosis of HFpEF patients only in low serum chloride level at admission.
TAMI-23. ANTIBODY COCKTAIL IMMUNOTHERAPY FOR GLIOBLASTOMA BY DUAL TARGETING OF IL-6 AND CD40
Authors: Fan Yang, Steven Brem, Yi Fan
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is refractory to current T cell-based immunotherapies such as checkpoint blockade. GBM is characterized by extensive infiltration of immunosuppressive macrophages that contribute to the treatment resistance. Here we develop a dual-targeting strategy to synergistically activate tumor-associated macrophages (Mφs), which efficiently overcomes GBM resistance to therapeutic blockade of the PD1 and CTLA4 checkpoints. Consistent with a pro-tumor role of IL-6 in alternative Mφ polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mφs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mφs. Combination of IL-6 inhibition with CD40 stimulation reverses Mφ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models. Notably, this antibody cocktail-based combination immunotherapy with checkpoint blockade almost doubles animal survival in the genetically engineered mouse GBM model and induces complete tumor regression in the GL261 model. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting therapeutic opportunities for GBM.
TAMI-05. FATTY ACID SYNTHESIS IS REQUIRED FOR HER2+ BREAST CANCER BRAIN METASTASIS
Authors: Gino Ferraro, Ahmed Ali, Alba Luengo, Amy Deik, Keene Abbott, Divya Bezwada, Landry Blanc, Brendan Prideaux, Xin Jin, Jessica Posada, Zohreh Amoozgar, Raphael Ferreira, Ivy Chen, Kamila Naxerova, Christopher Ng, Anna Westermark, Shawn Davidson, Dai Fukumura, Véronique Dartois, Clary Clish, Matthew Vander Heiden, Rakesh Jain
Journal: Neuro-Oncology (2021)

Abstract Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2-positive breast cancer and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in the brain. We determine that this phenotype is an adaptation to decreased lipid availability in the brain relative to other tissues, resulting in site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase reduces human epidermal growth factor receptor 2-positive breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.
Cytogenetically cryptic <i>TNIP1-PDGFRB</i> and <i>PCM1-FGFR1</i> fusion leading to myeloid/lymphoid neoplasms with eosinophilia (MLN-eo) in children
Authors: Ann-Cathrine Berking, Tim Flaadt, Yvonne Lisa Behrens, Andreas Reiter, Ayami Yoshimi, Alfred Leipold, Peter Lang, Ursula Holzer, Charlotte M. Niemeyer, Leticia Quintanilla-Martinez, Brigitte Schlegelberger, Brigitte Strahm, Gudrun Göhring
Journal: Blood (2021)
Abstract 13443: Multi-Center Independent Validation of an Automated Algorithm for Predicting Cardiorespiratory Deterioration Events in Single Ventricle Patients
Authors: Craig G Rusin, Sebastian Acosta, Eric Vu, Ken Brady, Carly Scahill, Brian Fonseca, Cindy Barrett, Janet Simsic, Andrew R Yates, Brenna Klepczynski, J W Gaynor, Dan J Penny
Journal: Circulation (2021)

Introduction: Sudden acute deterioration is common in patients with hypoplastic left heart syndrome and comparable lesions. Previous work by the investigators using a single-center cohort at Texas Children’s Hospital (TCH) resulted in a novel algorithm which can predict such events 1-2 hours in advance. Hypothesis: The TCH algorithm for predicting deterioration events in single ventricle patients 1-2 hours in advance can be translated to heart centers across the country without significant performance loss. Methods: A prospective study on infants undergoing cardiovascular surgical palliation at Children’s Colorado, Nationwide Children’s Hospital, and Children’s Hospital of Philadelphia between Oct 2018 to Apr 2020 was conducted. Subjects were admitted to the cardiovascular ICU (CVICU) immediately after stage-1 palliation and enrollment continued until stage-2 palliation was performed or the subject was discharged. All physiologic data from all subjects were recorded from bedside monitoring equipment using the Sickbay system (Medical Informatics Corp, Houston, TX) in both CVICU and step-down units. Instances of cardiorespiratory deterioration, defined as the need for CPR or endotracheal intubation, were identified. The existing predictive algorithm was applied without re-training to the data obtained from study sites. A 12-hour lead-in period was used to initialize the algorithm. The ROC area, true and false positive rates (TRP &amp; FPR) were used to quantify performance. Results: There were 58 subjects who met inclusion criteria across all sites. Median time between stage I &amp; II surgeries was 141 days (126-155 IQR). A total of 30 in-hospital deterioration events were observed. Twenty-one subjects experienced at least 1 event. Most (72%) events occurred 40 days after stage I surgery. Over 29K hours of data was collected from subjects. The ROC area was found to be 0.927 for predicting deterioration events 1-2 hours in advance of overt extremis. Conclusions: This study validated the performance of an existing predictive algorithm which provides a 1-2 hour early warning for cardiorespiratory deterioration events in children with single ventricle physiology during their interstage period using a large, independent, multi-center patient cohort.
The Prognostic Implication of Adult Comorbidity Evaluation 27 Score in CML Patients on Tyrosine-Kinase Inhibitors
Authors: Kunhwa Kim, Hagop Kantarjian, Elias J. Jabbour, Ghayas C. Issa, Farhad Ravandi, Courtney D. DiNardo, Marina Konopleva, Nitin Jain, Naveen Pemmaraju, Gautam Borthakur, Tapan M. Kadia, Guillermo Garcia-Manero, Kiyomi Morita, Sherry A. Pierce, Jorge E. Cortes, Koji Sasaki
Journal: Blood (2021)
Abstract 13419: Novel Methods to Quantify Limitation of Right Ventricular Exercise Reserve in Pulmonary Hypertension: Afterload vs Ventricular Interdependency
Authors: Farhan Raza, Callyn Kozitza, Christopher G Lechuga, Mohammed Merchant, Claudia E Korcarz, Corrado Philip, Daniel Seiter, Scott Reeder, Marlowe Eldridge, Oliver Wieben, Naomi Chesler
Journal: Circulation (2021)

Introduction: In this study, we report novel methods to investigate impact of pulmonary arterial (PA) afterload with impedance and ventricular interdependency with myocardial strain on right ventricular (RV) reserve with exercise and RV:PA coupling. Hypothesis: In pre-capillary pulmonary hypertension (PH), RV is conditioned to a higher contractility (end-systolic elastance: Ees) due to increased impedance and RV reserve is independent of left ventricle. However, in isolated post-capillary PH (Ipc-PH), RV is not conditioned due to lower impedance, yet contractility reserve is poor due to lower interventricular septal strain. Methods: In 4 subjects (Table 1), we performed invasive cardiopulmonary exercise tests with simultaneous echocardiogram for impedance quantification with spectral analysis, followed by real-time RV pressure volume loops (Figure 1A: data recorded at rest and every 25 watts till peak-exercise). Cardiac MRI was performed within 24-hours to assess myocardial function, strain, and 4D flow at rest and exercise in the bore. Results: The augmentation of RV contractility (Ees) with exercise is poor in Ipc-PH, despite an afterload (Ea) similar to the normal subject. The left ventricular septal strain is reduced in Ipc-PH which may indicate enhanced interventricular dependency. Due to increased afterload in pre-capillary PH, RV is conditioned to higher contractility (Ees), and RV reserve is possibly independent of the left ventricle. Conclusion: Our novel methods provide an opportunity to investigate mechanisms of poor RV reserve with exercise in different phenotypes of PH. We will further validate these preliminary findings in our ongoing studies.
STEM-01. PHAGE DISPLAY BIOPANNING IDENTIFIES AMOT REGULATING CELL MOTILITY OF BRAIN METASTATIC STEM-LIKE CELLS
Authors: Chunhua She, JongMyung Kim, Marine Potez, James Liu
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Metastatic brain tumors (MBTs) are the most common type of malignant brain tumors. Due to the deviation of MBTs from the parental tumors, the effective therapies for primary tumors often are not useful in brain metastases. Even more new intracranial lesions were developed though the primary lesion was under control. The model of brain metastatic stem-like cells (BMSCs) could partially explain the progression of intracranial lesions. Here we aimed to explore the biological behavior in cell motility of BMSCs and understand the potential mechanisms. METHODS In vitro and in vivo phage display biopanning strategies were used to isolate dodecapeptides that specifically target BMICs by selecting against primary lung cancer cells and normal brain cells. In silico analysis was used to derive specific protein targets in BMICs. Potential targets were narrowed down through analysis in patient databases and verified for their presence in BMIC through RT-PCR. Cell migration and adhesion in BMICs were analyzed using Transwell, scratch, and adhesion assays. Protein expression and cell morphology were detected by immunofluorescence. Immune blot was performed to detect the epithelial-mesenchymal related molecules and explore protein-protein interactions. RESULTS In silico analysis of BMSCs specific peptides revealed Angiomotin (Amot) as a potential target in BMSCs. Amot was found to be overexpressed in BMSCs compared to primary lung cancer cells. Kaplan-Meier analysis demonstrated Amot was negatively correlated with overall survival among lung adenocarcinoma patients. Functionally, knockdown of AMOT in BMSCs decreased the capability of cell migration and adhesion by reduced active Cdc42/Rac1 signals caused by downregulation of E-Cadherin. Amot was found to maintain the E-Cadherin in BMSCs through reducing ubiquitination of E-Cadherin. CONCLUSIONS Amot plays a role in promoting migration and adhesion in BMSCs through preservation of E-cadherin.
CTIM-14. RANDOMIZED PHASE II OPEN LABEL STUDY OF NIVOLUMAB PLUS STANDARD DOSE BEVACIZUMAB VS NIVOLUMAB PLUS LOW DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA (RGBM). NIVOLUMAB BENEFITS OLDER POPULATION
Authors: Manmeet Ahluwalia, David Peereboom, Yasmeen Rauf, Patrick Wen, David Reardon
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Approaches using anti-PD1 therapy alone in rGBM is of limited efficacy. VEGF is upregulated proangiogenic growth factor in GBM that contributes to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM. METHODS 90 patients with GBM at first recurrence were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) with bevacizumab at standard (10 mg/kg; Arm A) or at low dose (3 mg/kg; Arm B) IV Q2 weeks. Stratification included extent of resection, age, performance status and MGMT methylation status. Progression-free survival (PFS) and overall survival (OS) were compared between two arms. RESULTS 90 patients (Median age 60.6 years ranged 27.4-86.4, 67.8% male, median KPS 80) were enrolled between May 2018 and Jan 2020. Patients were followed in median 7.7 months (Range 0.7, 28.2). 35 patients were MGMT methylated and 53 patients were MGMT not hypermethylated and 2 were indeterminate. Overall Survival was not significantly different between arm A and arm B (1 year: 41.1 vs 37.7%, p=0.14), while OS was better for arm A in age &amp;gt; 60 (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P=0.046). OS was no different in the two arms for age ≤ 60 years (At 1-year: 35.6% vs 56.4; Median 8.0 vs 12.4 months; P=0.90). Most frequent toxicities ( &amp;gt;20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Toxicities in grade 3-4 were hypertension (7.8%), fatigue (5.6) and other non-neurological toxicities including DVT, PE, infection, and abnormal liver function. CONCLUSIONS Overall PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Nivolumab with standard bevacizumab seem to benefit patients older than 60 years old.
In Depth Analysis of Blastic Plasmacytoid Dendritic Cell Neoplasm Based on a Comprehensive Literature Database of Cases
Authors: Robert S. Ohgami, Phyu Aung, Alejandro Ariel Gru, Mohammad O Hussaini, Christiane Querfeld, Kelou Yao, Corinn Small, Sumanth Gollapudi, David L Jaye, Sa A Wang, Sheeja T Pullarkat, Tracy I. George
Journal: Blood (2021)
TMOD-15. CHARACTERIZATION OF THE MINIMAL RESIDUAL DISEASE STATE REVEALS DISTINCT EVOLUTIONARY TRAJECTORIES OF HUMAN GLIOBLASTOMA
Authors: Maleeha Qazi, Sabra Salim, Kevin R Brown, Neil Savage, Nicholas Mickolajewicz, Hong Han, Chirayu R Chokshi, Alireza Mansouri, Chitra Venugopal, Thomas Kislinger, Sidhartha Goyal, Jason Moffat, Sheila K Singh
Journal: Neuro-Oncology (2021)

Abstract Recurrence of solid tumors renders patients vulnerable to a distinctly advanced, highly treatment-refractory disease state that has an increased mutational burden and novel oncogenic drivers not detected at initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cancer cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profiled barcoded tumor cell populations through therapy at tumor initiation/engraftment, MRD and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors showed distinct patterns of recurrence in which clonal populations exhibited either a priori, pre-existing fitness, or equipotent fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing revealed a tumor-intrinsic immunomodulatory signature with strong prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from GBM patients at all stages of disease. Our results provide insight into the innate and therapy-driven dynamics of human glioblastoma, and the prognostic value of the interrogating of the MRD state in solid cancers.
NCMP-05. LEFT BASAL GANGLIA/INTERNAL CAPSULE GLIOBLASTOMA WITH MEMORY LOSS FROM CONTRALATERAL RADIATION INDUCED VASCULOPATHIES
Authors: Shannon Higgins, Andrew Lassman, Laura Lennihan, Joshua Willey, Tony Wang, Michael Sisti, Peter Shapiro, Esther Kim, Amily Koshy
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Radiation induced cerebral vasculopathy encompasses a complex and broad range of effects such as ischemia, hemorrhage, vascular malformation, capillary telangiectasias, and large vessel stenosis caused by pathological reorganization of tissue after radiation exposure. Necrosis and inflammation induce damage and demyelinating changes to other vessels over the corresponding areas that may occur months to years after brain irradiation. Here we report an unusual case of hemorrhagic basal ganglia/internal capsule glioblastoma followed by contralateral basal ganglia/internal capsule acute infarct with resulting acute transient global amnesia followed by chronic memory impairment. CASE REPORT A 58-year old man was diagnosed with a hemorrhagic left basal ganglia/internal capsule mass after presenting with severe headaches, agitation, and vomiting. Glioblastoma (IDH wild type by sequencing, MGMT unmethylated) was identified on resection. He underwent radiotherapy and concurrent and adjuvant (12 cycles) temozolomide. Serial surveillance brain MRI scans demonstrated multiple incidental vascular abnormalities including subacute right basal ganglia/internal capsule ischemic infarct, right temporal cavernoma, and right temporal intra-parenchymal hemorrhage approximately 1, 2, and 3 years after diagnosis, respectively. Approximately 4 years after diagnosis, he presented with transient global amnesia and imaging demonstrated right basal ganglia/internal capsule ischemic stroke. DISCUSSION Bilateral basal ganglia/internal capsule damage from stroke has been reported as causing memory impairment (Tatemichi TK et al, Neurology 1992;42:1966-79; PMID 1407580). Here we report memory impairment from unilateral basal ganglia/internal capsule tumor and contralateral infarct following brain radiotherapy as another mechanism of neurocognitive injury. Our case highlights the significance of continuing to surveil for these findings as new neurologic symptoms may mimic tumor progression.