tbuckley/cabot-search huggingface dataset:
TAMI-77. CHARACTERIZATION OF METABOLIC DIFFERENCES IN MENINGIOMAS USING TUMOR TISSUE AND PATIENT-DERIVED CELL LINES
Authors: Zach Rabow, Taryn Morningstar, Oliver Fiehn, Mirna Lechpammer
Journal: Neuro-Oncology (2021)

Abstract As more information emerges on metabolic changes in brain pathologies, mass spectrometry methodologies are needed to investigate cellular changes in primary brain tumors. Many approaches use technologies that lack sensitivity and selectivity, which hinders discovering potential novel diagnostic and prognostic features. Fresh frozen tissue from 26 patients (57% women, 43% men, age 21-67) underwent surgical resection for newly diagnosed meningiomas. We used patient-derived cell lines and arachnoid cells to validate and compare metabolic differences in patient tumor tissue. Primary metabolism (GC-TOF), lipidomics, and biogenic amines (RPLC and HILIC-HRMS) were analyzed using 10 mg of tissue and 1x106 cells. RESULTS: Primary metabolism and lipidomics showed significant differences between Grade I and Grade II tumors. We identified over one thousand total metabolites through authentic standards and MS2 fragmentation patterns. Ascorbic Acid was enriched in Grade I tumors compared to Grade II and enriched in tumors compared to non-neoplastic dura tissue from the same patient. Lysosomal activation in atypical meningiomas is indicated by a 2-fold increase (compared to Grade I tumors) of Bis(monoacylglycero)phosphate metabolites. We grouped metabolites into fifteen classes based on chemical ontology and function. Statistically significant differences were observed in total amino acids (AA), basic AA, cyclic AA, sulfur-containing AA, branched-chain AA, dipeptides, histidine-containing dipeptides, vitamins and cofactors, glutathione metabolites, acylcarnitine’s, sphingomyelins, phosphatidylethanolamines, phosphatidylinositol’s, cardiolipins, and nucleic acids. Thymine-containing nucleic acids and biogenic monoamines were 2-fold higher in Grade I compared to Grade II tumors. Using novel untargeted metabolomics, we found multiple classes of metabolites that were enriched in Grade II meningiomas compared to Grade I. This points towards possible pathways that drive malignancy and biomarkers that could be useful for diagnosis, grading, and treatment selection.
Abstract 13655: DUSP-1 May Be a Key Regulator of NK Cell Function in Obesity Potentially Accelerating Cardiovascular Disease in African American Women
Authors: Yvonne Baumer, Singh Komudi, Cristhian A Gutierrez Huerta, Veronica Gray, Turner S Briana, Valerie Mitchell, Billy Collins, Mehdi Pirooznia, Daniella M Schwartz, Tiffany Powell-wiley
Journal: Circulation (2021)

Background: Obesity disproportionately affects African American (AA) women and contributes to disparate cardiovascular disease (CVD) outcomes. Natural killer cells have been shown to be functionally impaired by obesity. However, underlying mechanisms regulating NK cell function in obesity are largely unknown. Therefore, we sought to elucidate potential signaling pathways involved in obesity-related NK cell function loss in AA women. Methods: All experiments were performed with freshly isolated naïve NK cells. NK cells were isolated from AA women (n=29; 15 BMI&lt;25, 14 BMI&gt;30). NK cell function was measured by flow cytometry by determining the ability of NK cells to degranulate towards K562 cells. NK cell gene expression profile was determined by RNA sequencing to identify important signaling pathways, which were verified using chemical pathway inhibitors. Publicly available datasets were analyzed to determine the importance of identified target genes. Results: NK cells isolated from AA women with obesity displayed diminished capacity to induce K562 cell death as determined by decreased degranulation (decreased surface CD107a expression and decreased intracellular IFNγ and TNFα expression). RNA sequencing analysis of NK cells isolated from lean vs AA women with obesity revealed 1645 significantly regulated genes with DUSP-1 being in the top 50 and displaying a 2.8-fold upregulation in AA women with obesity (p=0.0009). Furthermore, DUSP-1 gene expression was significantly correlated with BMI (R 2 =0.72, p=0.02). In vitro experiments revealed a DUSP-1 inhibitor to enhance NK cell function. Additionally, analysis of publicly available RNA sequencing dataset (GSE20129) in women revealed an increase of DUSP-1 mRNA expression in Black and Latinx women with CVD when compared to women without CVD group; this difference was not observed in White women. Conclusion: Our data demonstrate that NK cells are functionally impaired in NK cells isolated from AA women with obesity. We identified DUSP-1 as a crucial regulator of the observed NK cell dysfunction in obesity, which may be of particular importance in CVD development and progression in AA women, a population disproportionally affected by obesity and CVD.
Abstract 12547: The Association of Serum Cholesterol and Statin Use With All-Cause Mortality Across Estimated Glomerular Filtration Rate (eGFR) Levels in United States Veterans and NHANES Cohorts
Authors: Yousif Arif, Maria Marroquin, Yoko Narasaki, Jui-Ting Hsiung, Melissa Soohoo, Csaba Kovesdy, Kamyar Kalantar-Zadeh, Connie Rhee, Elani Streja
Journal: Circulation (2021)

Background: Chronic kidney disease (CKD) patients have displayed a paradoxical association between total cholesterol (TC) and mortality, where CKD patients with elevated TC did not display an increased mortality risk. However, this TC-mortality relationship amongst CKD patients requires further study using large databases to assess the impact CKD stage, pharmacologic therapy, and patient population has. Methods: Retrospectively, two cohorts were studied using LIPROVET and NHANES data. Among the cohorts, there were 2,131,536 LIPROVET US veterans examined from 2004-2006 and 39,899 NHANES patients from 1999-2014. We examined the association of TC and statin use with all-cause mortality in patients with eGFR &lt;60 and eGFR ≥60 mL/min/1.73m 2 using Cox Proportional Hazards model. Models were adjusted for demographics, comorbidities, smoking status, alcohol intake, income, education, laboratory measures, and medications. Those with TC≥200 mg/dL not on statin were used as reference. Results: The LIPROVET patients had a mean age of 63±14 and were 81% White and 5% female. LIPROVET patients with TC&lt;200 mg/dL not on statin had a higher mortality risk compared to reference across all levels of adjustment and eGFR. Whereas those on statin, regardless of TC levels, had a lower to null mortality risk in the fully adjusted model. NHANES patients had a mean age 48±19 and were 46% White and 50% male. NHANES patients with TC&lt;200 mg/dL not on statin had a trend of higher to null mortality risk compared to reference across eGFR groups after full adjustment. Those on statin, independent of TC levels, had a significantly lower mortality rate across all eGFR groups. Conclusion: Compared to patients with TC≥200mg/dL not on statin, patients with lower TC without statin had a higher mortality risk, while patients with statin had lower mortality risk regardless of TC level across all eGFR groups. Physicians may consider initiating or continuing statin therapy for CKD patients independent of TC level.
DDRE-13. PROSTAGLANDIN E RECEPTOR 3 (PTGER3) REGULATES RESISTANCE TO TUMOR TREATING FIELDS (TTFields) IN GLIOBLASTOMA CELLS
Authors: Dongjiang Chen, Son Le, Tarun Hutchinson, David Tran
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION TTFields, a novel approved therapy for GBM, employ alternating intermediate-frequency electric fields to disrupt mitotic macromolecules leading to chromosome mis-segregation and apoptosis. The addition of TTFields significantly improves survival. However, most patients eventually develop resistance to TTFields through an unknown mechanism. METHODS Multiple human GBM cell lines were treated with TTFields continuously using Inovitro, an in vitro TTFields system, until cells with relative resistance to killing by TTFields emerged. Temporal gene expression profiles were analyzed using NETZEN, an innovative deep-learning and gene network-based ranking computational algorithm, to identify resistance pathways, followed by experimental validation. RESULTS PTGER3, a Gαi-protein-coupled cell surface receptor, is the top ranked master regulator in the predicted resistance program, which is upregulated in GBM cells within 24 hrs of exposure to TTFields and further reinforced as resistance sets in. Forced expression of PTGER3 in sensitive GBM cells confers relative resistance to TTFields, while PTGER3 depletion in resistant cells re-sensitizes them to TTFields. Most importantly, pharmacological inhibition of PTGER3 using either aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors effectively prevent resistance from developing. Mechanistically, PTGER3 is rapidly translocated from the plasma membrane to the nucleus after TTFields exposure, where it interacts with ZNF488, a stemness transcription factor tightly linked to PTGER3 in our predicted network to initiate and maintain the resistance program. Indeed, TTFields resistance is associated with a transition to glioma stem cells (GSCs) as determined by increased neurosphere formation and orthotopic tumorigenesis in immunocompromised mice, and PTGER3 inhibition alone reverses the GSC transition leading to improved tumor control and survival. CONCLUSIONS PTGER3 is at the apex of a novel pathway that indispensably regulates TTFields resistance through a unique mechanism involving the physical nuclear translocation of this 7-transmembrane receptor. PTGER3 and its pathway are thus potential therapeutic targets to enhance therapeutic efficacy of TTFields.
DDRE-20. HIGH-THROUGHPUT SCREENING OF FDA-APPROVED COMPOUNDS IN GLIOMA AND GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTICS
Authors: Tadeusz Wroblewski, Philip Tatman, Anthony Fringuello, Sam Scherer, William Foreman, Denise Damek, Samy Youssef, Kevin Lillehei, David Ormond, Michael Graner
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioma and glioblastoma comprise 28% of all primary central nervous system tumors and cause the majority of primary brain tumor deaths. Despite substantial research into the molecular pathogenesis and genetic landscape of glioma, no currently approved therapies are curative for any glioma or glioblastoma. Patients with glioblastoma have an average survival time of 12-15 months, while patients with grade III gliomas have an average survival time of 3-5 years, and patients with grade II gliomas have an average survival time of 8-15 years. The lack of a curative treatment for these tumors necessitates additional research into novel therapies. METHODS In this study, we developed a high-throughput drug screen and culture system to identify existing FDA-approved therapies with the potential to inhibit glioma viability. RESULTS In total, we screened 39 tumors: 21 glioblastoma, 10 oligodendroglioma, and 8 astrocytoma. Carfilzomib was the most effective compound across the cohort, decreasing the average tumor viability to 39.0% +/- 16.5%SD. Regardless of tumor grade, MGMT methylation, EGFR amplification, tumor recurrence and etiology, tumor histology, prior treatment, and patient gender, carfilzomib significantly reduced cell viability in every tumor; though was not necessarily the most effective compound in each of these groups. We found HDAC inhibition to be the most effective treatment in grade 1 astrocytomas. However, HDAC inhibition was surpassed by carfilzomib and RNA transcription inhibitors in all higher grades. Interestingly, EGFR inhibition, while significantly effective in 36 tumors, was consistently less effective than carfilzomib across the cohort, though did surpass the effectiveness of HDAC inhibition in grade III gliomas. CONCLUSIONS FDA approved compounds can effectively inhibit glioma tumor viability. Specifically, carfilizomib holds great promise. Further in vivo studies are needed to confirm these findings.
Abstract 11718: Prevalence and Trends of Overweight and Obesity Among United States Veterans From 2002 to 2016
Authors: Tasnim F Imran, Yuk-lam Ho, Ahmed H Qavi, David Gagnon, Christopher J Odonnell, Kelly Cho, Peter Wilson, Michael Gaziano, Luc Djousse
Journal: Circulation (2021)

Objective: To present the age adjusted prevalence of obesity in men and women veterans by race and geographic region, and to examine the trends in body mass index over 14 years. Methods: We studied a random sample of one million adults from 2002 to 2016 who had height and weight measured at outpatient visits in the national Veterans Health Administration (VHA) electronic medical record system. We excluded those with prevalent cancer, gastric bypass procedures, and extremity amputations. We calculated the sex-specific and age adjusted prevalence of body mass index (obese &gt;30 kg/m 2 ) categories by self-reported race, and geographical region. Results: From a total of 791,392 men, and 50,928 women, average age was 68 years for men and 52 years for women in 2016. Mean BMI was 30 ± 6 kg/m 2 for men and 30 ± 7 kg/m 2 for women. In all, 13% (n=97,861) men and 25% (n=12,510) women were Black, 77% (n=573,232) men and 59% (n=29,538) women were White, 0.9% (n=6,479 ) men and 1.2% (n=613) women were Asian, 0.7% (n=5,202) men and 0.9% (n=473) women were Native Hawaiian/Pacific Islander, and 0.7% (n=4,490) men and 1% (n=510) women were American Indian. Over the 14-year period from 2002 to 2016, all racial groups were found to have a steady increase in prevalence of obesity except for Asians (Fig 1). Asian men and women had the lowest prevalence of obesity and morbid obesity (20% and 2% for men, 11% and 1% for women). Hawaiian or Pacific Islander and American Indian men and women had the highest increase in prevalence of morbid obesity comparing 2002 to 2016. Men and women in the Midwest had the highest prevalence of obesity and morbid obesity (32%, 6% for men and 31% and 8% for women). Women in the Northeast were found to have a decline in the prevalence of morbid obesity from 2002 to 2016. Conclusions: The prevalence of overweight and obesity has steadily increased in adult men and women veterans from 2002 to 2016 overall. However, there are differences across racial groups and geographic regions.
Abstract 13818: Polyoxazoline Modification of Bovine Pericardial Bioprosthetic Heart Valve Leaflets Mitigates Protein-Glycation Associated Structural Degeneration
Authors: Andrey Zakharchenko, Samuel Keeney, Ivan S Alferiev, Michael Chorny, Yingfei Xue, Hajime Takano, Stanley J Stachelek, Giovanni Ferrari, Robert LEVY
Journal: Circulation (2021)

Introduction: Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde treated bovine pericardium (BP) are widely used to treat heart valve disease. BHV dysfunction from structural valve degeneration (SVD) develops over time, often necessitating device replacement. SVD is associated with both calcification and the accumulation of advanced glycation end products (AGE) and serum proteins within BHV leaflets. Here, we introduce a new strategy for mitigating AGE-associated SVD by modifying BP with a poly(2-methyl-2-oxazoline) (POZ). Hypothesis: Attached POZ will prevent BP deterioration by mitigating serum protein and pro-inflammatory AGE uptake. Methods: Covalently modified BP-POZ was studied for its effects on serum albumin and AGE entry in vitro via a mass-uptake assay and immunostaining. Resistance of BP-POZ to oxidation was assessed in comparison to poly(ethylene glycol) (PEG). Macrophage studies assessed the inflammatory properties of BP-POZ. A juvenile rat subdermal model was used to study serum protein and AGE uptake and calcification within BP-POZ, with or without ethanol pretreatment. A heart valve pulse duplicator was used to assess the protective effects of BP-POZ on BHV hydrodynamics following accelerated glycation. Results: POZ mitigated the accumulation of serum albumin and AGE in vitro . After exposure to AGE and macrophages, POZ preserved BP collagen structure while TNFα levels remained at baseline. Under oxidation conditions, POZ retained its protective function, unlike PEG. In the rat model, POZ reduced BP AGE (p&lt;0.001) and albumin (p&lt;0.001) uptake. Ethanol pretreatment of BP-POZ was effective at reducing both AGE and calcification. POZ mitigated the hydrodynamic dysfunction of BHV exposed to accelerated glycation conditions (p&lt;0.001). Conclusions: SVD due to AGE and serum proteins can be effectively mitigated through POZ modification, that does not interfere with ethanol pretreatment mitigation of BP calcification.
Abstract 11291: Ectopic Olfactory Receptor Expression in Platelets as Novel Antithrombotic Targets
Authors: Anu Aggarwal, Matthew Godwin, Rohan Bhandari, Vara Prasad Josyula, Sharon Shim, Krystin Krauel, Matthew T Rondina, Larry Wagner, David Yule, Scott J CAMERON
Journal: Circulation (2021)

Introduction: Platelets are enriched in orphan G-protein-Coupled Receptors (GPCRs) that could potentially regulate platelet reactivity. A remote study in patients with hereditary anosmia reported dysfunctional platelet responses suggesting the presence of platelet olfactory receptor (ORs) that could regulate thrombosis. Hypothesis: Platelet ORs serve as an alternative pharmacological strategy to generate platelet cyclic adenosine monophosphate (cAMP) to prevent thrombosis. Methods: Ribonucleic Acid sequencing (mRNAseq) of human megakaryocytes (MKs) was conducted. Various ORs were validated in platelets by RT-qPCR and immunoblotting (IB). Reporter cell lines with stable integration of cloned ORs identified OR ligands and later validated in adult platelets. Fluorophores for OR second messengers (Fura2 for Ca 2+ and MQAE for Cl - ) and an ELISA for cAMP were used for adult platelets. Platelet reactivity in response to OR agonists was evaluated by FACS and aggregometry, and thrombosis by biomechanical platelet activation was evaluated using ex vivo microfluidics and flow cones to simulate disturbed flow (D-flow). OR agonist injection into mice and CRISPR-Cas9 OR knockdown was conducted, with platelet reactivity and thrombosis tested as proof-of-concept. Results: Only 15 of &gt;400 ORs in the genome were identified in MKs, and only 3 in all adult platelets (highest expression was OR2L13). A terpene family was identified as OR2L13 agonists, generating cAMP in the platelet, and structural modifications were made with IC 50 values in the low-high μM range for inhibiting agonist-induced platelet activation, ex vivo human blood thrombosis by microfluidics, and in vivo platelet activation in mice with prolonged tail bleeding. Deletion of OR2L13 (olfr168 -/- ) in mice augmented platelet reactivity with loss of OR agonist-mediated prolonged tail bleeding in olfr168 -/- . OR2L13 in human platelets is stored and trafficked by alpha granules following surface agonist stimulation and biomechanical activation. Conclusions: Like neurons, platelets have a fully functional OR signal transduction cascade which operates as a negative regulator of platelet reactivity and thrombosis in response to both chemical as well as biomechanical platelet activation.
Abstract 13665: Dapagliflozin Does Not Affect Left Ventricular Remodeling in Patients With Type 2 Diabetes. A Meta-Analysis of Phase IV Randomized Controlled Trials
Authors: Haris Bilal, Naira Saleem, arafat farooqui, Syed Mohammad Mazhar Uddin, Sanjay Maheshwari, Gerald Hollander, Jacob Shani
Journal: Circulation (2021)

Introduction: Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT-2) inhibitor approved for the treatment of Type-2 DM. Proposed mechanisms for its cardiovascular benefits include natriuresis, reduction in preload and afterload, and improved cardiac metabolism. Hypothesis: Dapagliflozin can reverse left ventricular remodeling in type-2 diabetics. Methods: Systematic review was performed to identify phase IV randomized controlled trials (RCTs) evaluating dapagliflozin vs placebo. Mean Difference (MD) of multiple parameters (along with 95% confidence intervals; CI) was extracted to compute pooled MD using RevMan v.5.3. Random effects model was employed when there was significant heterogeneity (&gt;40%, as assessed by I-squared). Results: Two RCTs were finalized (n=122; dapagliflozin 60, placebo 62). All patients (males 75, females 47) had type-2 DM and were more than 60 years old. Pooled analysis did not show significant difference in left ventricular remodeling with dapagliflozin as compared to placebo; (LV Mass Index reduction (g/m 2 ): MD -0.14, 95% CI -1.12 to 0.85; p=0.78, I 2 =0%). Dapagliflozin reduced systolic (MD -3.66; -7.29 to -0.02; p=0.05, I 2 =0%) and diastolic BP (MD -3.04; -5.75 to -0.32; p=0.03, I 2 =84%). Reduction in weight upto 3.4 kgs (MD -3.42; -4.48 to -2.36; p&lt;0.05, I 2 =59%) and HbA1c up to 3.7% (MD -3.76; -7.35 to -0.17; p=0.04, I 2 =14%) was observed with dapagliflozin. Dapagliflozin use improved hemoglobin (Hb) (MD 1.08; 0.50 to 1.66; p&lt;0.05, I 2 =95%) and hematocrit (Hct) (MD 2.90; 1.99 to 3.80; p&lt;0.05, I 2 =0%). No significant difference in ejection fraction (MD 0.77; -0.97 to 2.51; p=0.87, I 2 =0%), LV End-systolic volume (LV-ESV) (MD -1.02; -3.38 to 1.34; p=0.40, I 2 =0%), LV End-diastolic volume (LV-EDV) (MD -1.08; -6.40 to 4.24; p=0.69, I 2 =0%), stroke volume (SV) (MD 1.19; -1.66 to 4.04; p=0.41, I 2 =0%) and heart rate (MD -2.15; -5.14 to 0.85; p=0.16, I 2 =0%) was seen between two groups. Similarly, no change in creatinine (MD 2.14; -0.53 to 4.82; p=0.12, I 2 =0%) or eGFR (MD -1.34; -5.02 to 2.35; p=0.48, I 2 =24%) was observed. Conclusion: Dapagliflozin had no statistically significant effect on cardiac remodeling. However BP, weight, HbA1c, Hb and Hct improved significantly with dapagliflozin as compared to placebo over one year.
Abstract P470: Disrupted HRAS/GRB2 Signaling In Induced-cardiomyocytes Derived From Patients With Noonan Syndrome Carrying SOS1 Gene Mutation
Authors: VINOTH SIGAMANI, Narasimman Gurusamy, SHEEJA RAJASINGH, Rajasingh Johnson
Journal: Circulation Research (2021)

Background: Noonan syndrome (NS), a dominant autosomal genetic disorder that prevents normal development, and exhibits cardiac defects, which is estimated to appear in 50% to 90% of patients. Son of sevenless homolog 1 (SOS1) gene mutation has been identified as a major gene causing NS and attributes to the development of cardiomyopathy and congenital heart defects. SOS1 is a guanine nucleotide exchange factor for RAS and is known to interact with growth factor receptor-bound protein 2 (GRB2). Recently, we have generated induced pluripotent stem cells (iPSCs)-derived cardiomyocytes (iCMCs) from cardiac fibroblasts obtained from a NS patient carrying SOS1 gene variant 1654A&gt;G. Hypothesis: Since NS is known to have aberrant RAS-MAPK signaling, we hypothesize that iCMCs derived from NS patient (NS-iCMCs) may have atypical RAS signaling leading to the development of cardiomyopathy. Methods and Results: We have compared the normal skin fibroblast-derived iPSCs (N-iPSCs) and N-iCMCs with NS patient-derived induced NS-iPSCs and NS-iCMCs. Our qRT-PCR results showed that the mRNA expressions of signaling molecules HRAS, GRB2 and SOS1 were significantly decreased in NS-iCMCs compared with N-iCMCs (Figure A), and further confirmed through the protein expression by Western immunoblotting (Figure B). These results were in association with a significantly decreased mRNA and protein expressions of cardiac transcription factor GATA4, and structural proteins alpha sarcomeric actinin-2 (ACTN2), cardiac troponin T (TNNT2) and tropomyosin alpha-1 (TPM1) in NS-iCMCs compared with N-iCMCs. Further studies are underway to explore the difference in the guanine nucleotide exchange factor (GEF) activity and ERK activation between NS-iCMCs and N-iCMCs. Conclusion: Our current findings clearly indicate that the SOS1-associated signaling molecules HRAS and GRB2 were disrupted in NS-iCMCs, which may result in the development of cardiomyopathy in NS patients.