tbuckley/cabot-search huggingface dataset:
TMIC-31. GENETIC DRIVER-MUTATIONS DEFINE COMPOSITION AND PROPERTIES OF TUMOR-ASSOCIATED MYELOID CELLS IN GLIOBLASTOMA
Authors: Zhihong Chen, Jyothi Murukuti, Dolores Hambardzumyan
Journal: Neuro-Oncology (2018)

The GBM microenvironment is composed of numerous non-neoplastic cells, among which tumor-associated myeloid cells (TAMs) are the most abundant. TAMs are constituted of several different cell types, including brain microglia and bone-marrow-derived infiltrating cells, which can be further divided into inflammatory monocytes, monocyte-derived macrophages, and polymorphnuclear neutrophils. These myeloid cells are believed to promote tumor growth and immune evasion by expressing immune checkpoint proteins. Remarkable progress has been made in treating lung cancer and melanoma by using immune-checkpoint inhibitors; however, mixed results were obtained for its application in GBM. To examine how molecular-subtypes of GBM influence the composition and immunosuppression of tumor-associated myeloid cells, we used the RCAS/tv-a system, a somatic cell-specific gene transfer system, to generate de novo murine GBM (mGBM). By manipulating different known human oncogenic-driver mutations such as overexpressing PDGFB or EGFRVIII, or silencing NF1, we generated Proneural (PN), Classical (CL) and Mesenchymal (MES) GBMs respectively, which phenotypically resemble their human counterparts. We found that the majority (80%) of tumor-infiltrating myeloid cells in PN GBM are bone-marrow derived macrophages, whereas this number is significantly less in CL and MES mGBM. Interestingly, unique to MES, there is a significant presence (16%) of neutrophils in these tumors than in other subtypes (4%). Further characterization for subtype-specific expression of PD-L1, a druggable immune checkpoint molecule, by flow cytometry shows that MES has the highest expression of PD-L1 (Mean Fluorescent Intensity=13,000 ± 3,000), whereas the expression is lower (MFI=8,100 ± 2,000) in PN and lowest (MFI=5,900 ± 2,000) in CL. The current effort is devoted to examining how myeloid cells isolated from different subtypes can differentially suppress T cell functions; and how mice carry these subtypes respond to anti-PD-L1 therapy. Our findings illuminate the unique composition and functions of tumor-associated myeloid cells in different GBM subtypes, establishing a rationale to target these cells in this heterogeneous neoplasm.
Abstract 20030: Effect of Environmental Particulate Matter on Pulse Pressure in a Chinese Community-based Population
Authors: Long Zhang, Yi Zhang, Jia Jia, Dan D Xu, Fang F Fan, Xuan S Wang, Tian T Li, Yan Zhang
Journal: Circulation (2017)

Introduction: Pulse pressure(PP) is an indicator of atherosclerosis and associated with cardiovascular disease (CVD) risk. PM2.5 showed a close relationship with CVD in previous studies. However, t...
Abstract 17202: Comparative Performance of the R <sub>2</sub> Chads <sub>2</sub> , Chads <sub>2</sub> , and Cha <sub>2</sub> Ds <sub>2</sub> -vasc Scores in Atrial Fibrillation
Authors: Emily C O'Brien, DaJuanicia N Simon, Laine Thomas, Gregg C Fonarow, Peter R Kowey, Kenneth W Mahaffey, Jonathan P Piccini, Eric D Peterson
Journal: Circulation (2015)

Background . Existing scores to estimate stroke risk in atrial fibrillation (AF) have shown variable performance. We compared the predictive performance of the R 2 CHADS 2 score, which includes a term for renal dysfunction, to that of two existing stroke risk scores, CHADS 2 and CHA 2 DS 2 -VASc. Methods . We used data from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent AF in patients &gt;18 years. We examined the association between impaired renal function (CrCl&lt;60 mL/min) and 2-year risk of stroke/systemic embolism (SE) in separate Cox proportional hazards models with linear terms for CHADS 2 and CHA 2 DS 2 -VASc scores. We compared discrimination of the three scores using c-indices and evaluated calibration of R 2 CHADS 2 by comparing event rates in ORBIT to published rates from an external clinical trial population (ROCKET-AF) and an observational cohort (ATRIA). Results . We included N=9743 patients enrolled at 174 ORBIT-AF sites. The median age was 75 years (IQR 67-82), 89.5% were white, 42.5% were female, and 76.4% were taking oral anticoagulation (OAC). Over a median follow-up of 2 years, N=214 stroke/systemic embolism (SE) events occurred (1.00 per 100 pt.-years). Impaired renal function was present in 35.4% of patients and was associated (HR; 95% CI) with increased stroke/SE risk in unadjusted models (1.65; 1.27-2.14). This association was attenuated in models adjusting for CHADS 2 (1.21; 0.92, 1.60) or CHA 2 DS 2 -VASc (1.05; 0.79, 1.40). Discrimination (c-index; 95% CI) was similar for R 2 CHADS 2 , CHADS 2 and CHA 2 DS 2 -VASc; results were consistent by baseline OAC use (Table). Stroke/SE event rates in ORBIT were lower than those in two external populations for all levels of R 2 CHADS 2 . Conclusion: In a well-treated community patient population, renal dysfunction did not improve discrimination of traditional embolic risk models. Future studies examining the association between renal dysfunction and outcomes by type of OAC are needed.
IMMU-57. SEQUENTIAL TWO-RECEPTOR PRIMING CAR SYSTEM TO OVERCOME HETEROGENEOUS ANTIGEN EXPRESSION
Authors: Payal Watchmaker, Joseph Choe, Diego Carrera, Kira Downey, Maryam Shahin, Kole Roybal, Wendell Lim, Hideho Okada
Journal: Neuro-Oncology (2018)

Heterogeneous expression of target antigens can allow tumor escape from chimeric antigen receptor-transduced T-cell (CART) therapy targeting a single antigen. While epidermal growth factor receptor (EGFR)vIII represents a glioblastoma (GBM)-specific antigen, its expression is heterogeneous within the tumor. On the other hand, most other antigens expressed more uniformly in GBMs are non-mutated, glioma-associated antigens (GAAs), such as EphA2. Although these GAAs are not expressed in the normal brain, they are expressed at low levels in other normal organs. As a way to safely target GAAs in the tumor without attacking normal cells expressing the same GAAs outside of the brain, we adapted a novel synthetic Notch (synNotch) receptor system, and established a “prime and kill” sequential two-receptor CAR circuit: the first is a transcriptional CAR against EGFRvIII, and the second is a CAR against a GAA (e.g. EphA2). When the first CAR binds to EGFRvIII, it induces the expression of the second CAR. While the first CAR does not trigger the cytotoxic function itself, the second CAR mediates the cytotoxicity upon recognition of the target GAA. We have validated this system in vitro using the mixture of U87 GBM cells and those transduced with EGFRvIII. SynNotch CART effectively lysed both EGFRvIII+ and EGFRvIII-negative U87 cells when they are mixed, but never lysed EGFRvIII-negative cells in the absence of EGFRvIII+ cells. In immunocompromised mice bearing intracranial U87-EGFRvIII+/- tumors, intravenous infusion of synNotch CART resulted in long-term (over 60 days) survival and eradication of the heterogenous tumor in 5 of 8 mice. Furthermore, when mice also bear subcutaneous, EGFRvIII-negative U87 tumors along with the intracranial U87-EGFRvIII+/- tumors, synNotch CART did not affect the subcutaneous tumor, indicating the local but not systemic effects of synNotch CART. These data provide a strong basis for developing synNotch CART therapy for GBM.
TMOD-17. A NOVEL ADENOVIRAL-PERMISSIVE, IMMUNOCOMPETENT HAMSTER MODEL TO EVALUATE ONCOLYTIC ADENOVIRAL THERAPY FOR GLIOBLASTOMA
Authors: Lynette Phillips, Shoudong Li, Joy Gumin, Daniel Ledbetter, Anwar Hossain, Brittany Kerrigan, Candelaria Gomez-Manzano, Juan Fueyo, Frederick Lang
Journal: Neuro-Oncology (2018)

Treatment with the oncolytic adenovirus, Delta-24-RGD, resulted in dramatic tumor response in 20% of recurrent malignant glioma patients in a recent Phase I clinical trial. Studies in immunocompetent mice corroborate the patient data indicating that Delta-24-RGD effects are due to both direct tumor cell lysis and viral-mediated anti-tumor immune response. However, it is unclear why only a fraction of patients responds in this manner. Due to poor adenoviral replication in immunocompetent mouse models, the mechanisms by which Delta-24-RGD elicits an effective anti-tumor immune response remain poorly understood. Therefore, we sought to develop a syngeneic Syrian hamster glioma model that is both adenovirus replication-permissive and immunocompetent. We transformed hamster neural stem cells with hTERT, simian virus 40 large T antigen, and h-RasV12 and re-implanted the transformed cells into hamster brains where they developed into tumors. Hamster glioma stem cells (GSCs) were isolated from the resulting tumors and were re-implanted into naive hamster brains using a guide-screw system. In vitro, hamster GSCs supported viral replication and were susceptible to Delta-24-RGD mediated cell death. In vivo, hamster GSCs consistently developed into highly proliferative tumors resembling high-grade glioma. Following delivery of Delta-24-RGD by intratumoral injection, immunohistochemistry for viral proteins demonstrated viral infectivity and replication in hamster gliomas. Flow cytometric analysis of hamster gliomas revealed increased T-cell infiltration in Delta-24-RGD infected tumors. Delta-24-RGD treatment of tumor-bearing hamsters led to significantly increased survival compared to hamsters treated with PBS. In summary, we have developed an adenovirus-permissive, immunocompetent hamster glioma model that provides a novel platform in which to study the interactions between tumor cells, the host immune system, and oncolytic adenoviral therapy.
EXTH-27. INFLAMMATORY REPROGRAMMING OF GLIOMAS USING DELTA-24-RGDOX AND IMMUNOMETABOLIC ADJUVANTS
Authors: Teresa Nguyen, Yisel Rivera-Molina, Francisco Puerta Martinez, Xuejun Fan, Verlene Henry, Hong Jiang, Frederick Lang, Juan Fueyo, Candelaria Gomez-Manzano
Journal: Neuro-Oncology (2018)

The immunosupressive microenvironment of glioblastoma (GB) is responsible for the resistance to therapies and its dismal prognosis. Several lines of evidence have linked brain tumor metabolism and immunoresistance with the presence of active metabolic pathways. In this regard, activation of indolamine-2,3-dioxygenase (IDO) in regulatory T-cells favors tumor immunosuppression. We have observed that the implantation of tumors in mice generates an immunosuppressive environment characterized by overrepresentation of CD4+ regulatory T-cells and MDSCs. Treatment with the oncolytic adenovirus, Delta-24-RGD, has been shown to induce complete responses in a subset of GB patients by reprogramming the immune response. Moreover, the anti-tumor cytotoxic properties of T-cells can be enhanced by the addition of immune agonists, such as OX40L, a T-cell activator. We hypothesized that the combination of IDO inhibition (1MT or Indoximod) and Delta-24-RGD armed with the OX40 ligand (Delta-24-RGDOX) synergizes and have a therapeutic effect in GB. In this study, orthotopic GB were implanted in immunocompetent mouse and treated with the combination of D24-RGDOX and 1MT. Delta-24-RGDOX treatment resulted in a significant survival benefit compared to the control groups (mean survival, 46.5 vs. 38.5 days, P=0.02). Interestingly, the combination treatment of Delta-24-RGDOX and the IDO inhibitor induces complete tumor regression and the production of a higher percentage of long-term survivors compared to single therapy with Delta-24-RGDOX (mean survival, 46.5 vs. 108.5 days, P=0.03). Moreover, when the long-term glioma survivors were re-challenged with similar glioma cells, we observed 100% survival (P=0.002), indicating the establishment of immune memory by the combination therapy. Furthermore, functional studies showed a significant increase in anti-tumor activity of splenocytes from GB bearing treated mice that were treated with the combined therapy D24-RGDOX and Indoximod (P=0.009). These data support the use of immunometabolic adjuvants in combination with virotherapy as a potential treatment of patients with GB.
NIMG-15. DIFFERENTIATION OF IDH1 MUTANT AND WILD TYPE GLIOMAS USING pH- AND OXYGEN-SENSITIVE MOLECULAR MRI
Authors: Jingwen Yao, Ararat Chakhoyan, Benjamin Ellingson, Whitney Pope, Noriko Salamon, William Yong, Albert Lai, Linda Liau, Phioanh Nghiemphu, Timothy Cloughesy
Journal: Neuro-Oncology (2018)

The presence of isocitrate dehydrogenase 1 (IDH1) gene mutation (IDH1mut) in glioma patients is associated with longer survival compared to IDH1 wild-type (IDH1wt) patients. Non-invasive detection of IDH1 mutation could provide valuable diagnostic and prognostic information. Studies showed that IDH1mut correlated with decreased hypoxia-inducible-factor 1-alpha (HIF1α) expression and decreased level of glutamate. With a newly developed MRI technique using amine-CEST with spin-and-gradient echo EPI readout (CEST-SAGE-EPI), we simultaneously measure the pH-dependent chemical exchange effects and oxygen-sensitive reversible transverse relaxation rate (R2’). In the current study we propose a novel imaging biomarker, which is sensitive to hypoxia, amine proton concentration, and tissue acidity, providing a potential non-invasive approach to detect IDH1 mutation and monitor related metabolic changes. In this study, 25 patients with glioma (8 WHO grade II: 2 IDH1wt/6 IDH1mut, 11 WHO grade III: 4 IDH1wt/7 IDH1mut, 6 WHO grade IV: 5 IDH1wt/1 IDH1mut) underwent whole brain CEST-SAGE-EPI scanning (7:30 minutes) and anatomic imaging on 3T MRI scanners. Stereotactic MRI-guided biopsies/tissue resections were performed in 10 of the 25 patients (29 samples), and immunohistochemistry (IHC) staining for HIF1a expression was analyzed. The results showed a significantly higher product of magnetization transfer asymmetry (MTRasym) at 3.0ppm and R2’ in IDH1wt gliomas compared to IDH1mut gliomas (p=0.0033, Student’s t-test). The significantly higher MTRasymxR2’ persisted even when excluding grade IV gliomas (p=0.0063, Student’s t-test). The ROC of differentiating IDH1 mutation status with MTRasymxR2’ gave area under the curve (AUC) of 0.857 (sensitivity 85.71%, specificity 72.73%). The IHC staining of HIF1α showed a moderate positive correlation (Pearson’s correlation R=0.439, p=0.0360) with MTRasymxR2’. The results demonstrated the potential of using imaging biomarker, MTRasymxR2’, to detect IDH1 mutation status in gliomas, and to provide non-invasive information of tumor microenvironment.
COMP-21. WHY DETAILS MATTER – THE ROLE OF ALTERNATIVE SPLICING IN GLIOBLASTOMAS
Authors: Kristoffer Vitting-Seerup, Yi Chieh Lim, Petra Hamerlik
Journal: Neuro-Oncology (2018)

An often-overlooked aspect of cancer biology is the alternative usage of different isoforms, often called isoform switches. Isoform switches give rise to proteins with different functionalities due to differences in, amongst others, protein domains. These switches are both frequent and important in development, homeostasis, and many cancer types. It is however currently unknown whether isoform switches play a role in glioblastoma (GBM), which is among the deadliest of solid cancer types. To investigate the role of isoform switches in GBM, we integrated the RNA-Sequencing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) project creating the first large-scale isoform-resolution dataset containing normal brain tissue. Using this dataset, we identified hundreds of isoform switches with predicted functional consequences when comparing GBM and normal brain tissue. For a large fraction of GBM patients, isoform switches were more prevalent than deleterious mutations in cancer driver genes indicating their important role in gliomagenesis. This is further supported by the large number of isoform switches we find associated with poor survival outcomes of both GBM and other cancer types.
TMOD-07. LOCALIZATION OF ERLOTONIB RELATIVE TO MRI-BASED TUMOR EXTENT IN PDX GLIOBLASTOMA MODEL: TOWARDS A MATHEMATICAL MODEL FOR THE INTERFACE BETWEEN MRI AND DRUG DISTRIBUTION
Authors: Pamela Jackson, Sara Ranjbar, Elizabeth Randall, Michael Regan, Walid Abdelmoula, Begona Lopez, Susan Christine Massey, Leland Hu, Lihong He, Slobodan Macura, Jeffrey Agar, Jann Sarkaria, Nathalie Agar, Kristin Swanson
Journal: Neuro-Oncology (2018)

Clinical neuro-oncology relies on the hyperintensity of gadolinium (Gd) contrast agent on magnetic resonance imaging (MRI) in tumor regions to confirm that the blood-brain barrier (BBB) is locally compromised. While the extent of Gd hyperintensity may indicate that systemically administered drug is being distributed to the tumor regions, little is known about how a drug is distributed and how it may relate to the Gd hyperintensity. Additionally, glioblastomas (GBMs) are diffusely invading neoplasms with a significant fraction of the overall tumor cells spread peripheral to the Gd abnormality, which raises uncertainty as to how or if the rest of the diffuse tumor is affected by drug. Given the gap in understanding drug delivery to the brain, we propose a quantitative approach to model drug delivery in GBM based on MRI and matrix-assisted laser desorption/ionization mass spectroscopy imaging (MALDI). T2-weighted (T2) and T1-weighted with Gd contrast (T1Gd) MRI images were acquired for an animal with the GBM12 orthotopic GBM patient derived xenograft (PDX) line dosed with 100mg/kg erlotinib. A T1Gd region of interest (ROI) captured the Gd-associated hyperintensity. MALDI was performed and aligned with MRI images. A Drug ROI was created to represent the increased intensity of erlotinib on MALDI images. Since the Drug ROI encompassed the T1Gd ROI, we subtracted the two ROIs to create a ‘Drug No T1Gd’ ROI, which represented the drug region beyond the edge of the T1Gd ROI. A ‘Brain ROI’ was created to represent the region of the brain outside of the drug’s spread. The MALDI intensities for the three ROIs were all significantly different (p<0.05), with the T1Gd ROI having the highest mean, followed by the Drug No T1Gd and the Brain ROIs. By developing a quantitative understanding of drug distribution, we can make more robust predictions regarding treatment efficacy in the clinical setting.
Abstract 15556: PKG1α Oxidation is Required for Cardiac Anti-hypertrophic/Fibrotic Effects From PDE5 Inhibition but Not Soluble Guanylate Cyclase Activation
Authors: Taishi Nakamura, Guangshuo Zhu, Mark J Ranek, Kenichi Tsujita, David Kass
Journal: Circulation (2017)

Introduction: Clinical heart failure studies have explored the therapeutic potential of enhancing protein kinase G1α (PKG1α) activity by blocking cGMP-selective phosphodiesterase type 5 or by stimu...
TMIC-26. MiR-181a CONTROLS THE OSTEOPONTIN-MEDIATED IMMUNE CIRCUIT IN GLIOBLASTOMA
Authors: Anantha Marisetty, Jun Wei, Konrad Gabrusiewicz, Yuuri Hashimoto, Ling Kong, Martina Ott, Amy Heimberger
Journal: Neuro-Oncology (2018)

MiRNAs can silence a broad gene set, which may benefit heterogeneous tumors such as glioblastoma. Osteopontin has been shown to have an oncogenic role in a variety of cancers and may have immune modulatory effects on macrophages. The current study focuses on using miRNAs to target osteopontin in tumor cells and to modulate immune cells to elicit an antitumor effect. Genome-wide profiling followed by evaluation of expression levels of miRNAs and osteopontin were measured using quantitative real time PCR and ELISA in mouse and human glioblastoma and macrophages. Luciferase assays were used to determine the binding potential of miRNAs to osteopontin mRNA. miRNA mimics and forced overexpression using lentiviruses were used to target osteopontin in immune competent murine models of glioblastoma. Nano string profiling and Gene Set Enrichment Analysis (GSEA) were conducted to identify differences in biological states. Microarray analysis demonstrated that osteopontin was the most significantly upregulated gene in human glioblastoma-associated infiltrating macrophages that had originated from matched circulating monocytes, and this was validated using qPCR. Based on the 3`UTR sequence of osteopontin, bioinformatics tools identified 5 miRNAs that are conserved and would be able to modulate osteopontin expression. Luciferase assays confirmed that the miR-181 family regulates osteopontin expression. Overexpression of miR-181a in glioblastoma cells led to their decreased proliferation and increased apoptosis in vitro. miR-181a treatment of immune competent mice bearing intracranial glioblastoma demonstrated a 22% increase in median survival time relative to control mice (p=0.006). miR-181a controls osteopontin expression in both glioblastoma and macrophages by regulating their proliferation and apoptosis.
CBMT-04. INDUCING MITOCHONDRIAL OXIDATIVE STRESS AND TARGETING CELLULAR STRESS RESPONSE BY INHIBITION OF NAMPT, THE RATE LIMITING ENZYME IN THE NAD+ SALVAGE PATHWAY IN GLIOMA
Authors: Pratibha Sharma, William Senepides, Erkan Baloglu, Vinay Puduvalli
Journal: Neuro-Oncology (2018)

Pathways that regulate differential energy metabolism in gliomas have recently emerged as promising therapeutic targets. Nicotinamide Phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway regulates key metabolic processes preferentially used in glioma energy metabolism and essential for tumor cell biology and proliferation. This study examines the effects of NAMPT inhibition using KPT9274 and FK866 (NAMPTi) on cellular respiration, oxidative stress and cytotoxicity to better delineate the role and regulation of NAD salvage pathway in gliomas. Effects of NAMPTi on glycolysis and mitochondrial stress in gliomas and glioma stem cells (GSC) with varying IDH and MGMT status were measured including their oxidative state, basal cell respiration rate, maximum respiration capacity, spare respiratory capacity and proton leak using Agilent-Seahorse assay. Untargeted metabolomics was performed to analyze the effect of NAMPi on glioma cell metabolism. Effect of mitochondria dysfunction on cytotoxicity was measured by annexin-PI and CaspaseGlo assays. NAMPT inhibition caused NAD depletion, reduced ATP levels and PAK4 downregulation in gliomas. NAMPTi-treated cells showed reduction in basal cell respiration, spare and maximum respiration capacity indicating mitochondrial dysfunction and oxidative stress in glioma cells resulting in programed cell death. Untargeted metabolomics study indicated specific metabolic changes including accumulation of oxidized glutathione in NAMPTi-treated cells, indicating oxidative stress. Further, accumulation of metabolites indicative of a glycolytic pathway block and shunt towards the de novo purine synthesis pathway was seen. Further, glycolysis inhibition by NAMPTi was confirmed by glycolysis stress assays. Lastly, glycolysis inhibition and mitostress appeared to be related to a decrease in NAD+ dependent SIRT1 expression. NAMPTi cause profound disruption of mitochondrial function, induce oxidative stress and trigger cytotoxicity in GSC irrespective of MGMT promoter-methylation or IDH1 status. Targeting NAMPT is hence a novel therapeutic strategy that potentially circumvents tumor heterogeneity and can specifically disables tumor cell metabolism.