tbuckley/cabot-search huggingface dataset:
Abstract 18402: Human Atrial Fibrillation Drivers Seen Simultaneously by Focal Impulse and Rotor Mapping and High-resolution Optical Mapping
Authors: Brian J Hansen, Carey Briggs, Brandon T Moore, Thomas A Csepe, Ning Li, Jichao Zhao, Naga V Garikipati, Paul M Janssen, Peter J Mohler, John D Hummel, Vadim V Fedorov
Journal: Circulation (2015)

Background: A mechanism of AF maintenance has been suggested to be a limited number of patient-specific AF drivers seen by optical mapping in animals and now Focal Impulse and Rotor Mapping (FIRM) in patients. The higher resolution optical mapping can only be performed ex vivo and, thus, these two different mapping approaches have never been evaluated simultaneously in human hearts. Methods: Coronary-perfused explanted human atria (n=5, 19-57 y.o.) were optically mapped using voltage sensitive near-infrared di-4-ANBDQBS with 2-4 high resolution CMOS cameras (100x100 pixels with 330-1000μM resolution) simultaneously with a 64-electrode basket catheter or a 64-electrode custom flat catheter from either the endocardium or epicardium. AF (&gt;10 min, 6.8±2.1Hz) was induced by perfusion of adenosine (10-100μM) and/or isoproterenol (10-100nM). AF drivers were defined as localized stable reentrant activity in areas of highest dominant frequency for optical mapping, while unipolar signals from the catheters were analyzed using experienced FIRM user interpretation and RAP, a signal analysis tool that highlights driver regions on commercially available systems. Results: Optical mapping identified reentrant AF drivers in 7/8 episodes of AF in both the left and right atria. Interestingly, one episode of AF was driven by two competing reentrant drivers. Six AF drivers seen by optical mapping were also seen with the same location and rotation by FIRM, while FIRM identified an AF driver in an 8th episode from an endocardial basket that was unseen by optical mapping from the epicardium. In one episode, the intramural AF driver was only defined by dual sided optical mapping and unseen by endocardial FIRM. Conclusions: Our study demonstrates that most localized reentrant AF drivers in ex vivo human hearts have similar spatiotemporal characteristics whether identified by high resolution optical mapping or FIRM and may represent the clinical phenomena seen in AF patients.
ATIM-20. GAPVAC-101 TRIAL OF A HIGHLY PERSONALIZED PEPTIDE VACCINATION FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Wolfgang Wick, Pierre-Yves Dietrich, Norbert HIlf, Michael Platten, Katrin Frenzel, Arie Admon, Sjoerd van der Burg, Andreas von Deimling, Cecile Gouttefangeas, Judith Kroep, Francisco Martinez-Ricarte, Hideho Okada, Christian Ottensmeier, Berta Ponsati, Hans Poulsen, Stefan Stevanovic, Ghazaleh Tabatabai, Hans-Georg Rammensee, Ugur Sahin, Harpreet Singh-Jasuja
Journal: Neuro-Oncology (2018)

There is a need for treatment personalization as every cancer is molecularly unique. In addition glioblastoma (GB) are immunologically regarded as resistant, cold tumor with few targetable antigens available from mutations, thus demanding new personalized immunotherapies. So far outside Neuro-Oncology, T cells orchestrate impressive anti-tumor effects with checkpoint inhibitors, but also vaccines. The GAPVAC consortium established an immunotherapy, for which personalized selection of 2 peptide-based actively personalized vaccines (APVAC) per patient for treatment of newly diagnosed GB was based not only on whole-exome sequencing but also on human leukocyte antigen (HLA)-ligandome analyses providing insight into the actual presentation of relevant epitopes in the tumor. GAPVAC-101 (NCT02149225) enrolled 16 patients in a European phase I feasibility, safety and immunogenicity trial integrated into standard of care. For APVAC1, up to 7 peptides were selected from a trial specific warehouse based on individual biomarker data. Vaccination (i.d.) with GM-CSF and poly-ICLC in 15 patients started with the 1st adjuvant cycle of temozolomide (TMZ). For APVAC2, analyses revealed a median of 36 somatic, non-synonymous mutations in the patients tumors. From the 4th TMZ cycle, 11 patients received APVAC2 with usually 2 de novo antigens per patient selected according to mutation, actual or putative HLA presentation and immunogenicity. Overall 20 APVAC2 antigens incl. 14 mutated were vaccinated. Adverse events were largely reversible injection site reactions and two anaphylactic reactions and one increase in cerebral edema. Short, non-mutated APVAC1 antigens induced sustained CD8 responses with memory phenotype. Mutated APVAC2 antigens induced predominantly CD4 responses of favorable TH1 type. Median PFS and OS were 14.2 and 29 months from diagnosis, respectively, in patients that received 1 APVAC vaccination (N=15). CONCLUSION: Overall, GAPVAC displayed expected safety profiles and high biological activity indicating further development.
Is There a Role for Preoperative Platelet Function Testing in Patients Undergoing Cardiac Surgery During Antiplatelet Therapy?
Authors: Elisabeth Mahla, Udaya S. Tantry, Florian Prüller, Paul A. Gurbel
Journal: Circulation (2018)

Up to 11% of patients presenting with acute coronary syndromes undergo coronary artery bypass grafting. Guidelines largely recommend a one-size-fits-all preoperative discontinuation period for P2Y 12 receptor blockers to avoid bleeding. These recommendations do not account for highly variable pharmacodynamic responsiveness and for variable recovery of platelet reactivity following discontinuation of P2Y 12 receptor blockers. Several observational studies have demonstrated that an objective measurement of platelet function among these patients may reduce the waiting period while mitigating the risk of bleeding. Based on these findings, 2 recent guidelines included a Class IIa and IIb recommendation for platelet function testing in patients undergoing cardiac surgery. The following review article describes the rationale for discontinuation of dual antiplatelet therapy before cardiac surgery and the limitations with this approach, available platelet function assays to assess pharmacodynamic effects, and the association between platelet inhibition and other clinical factors with surgery-related bleeding. The information will assist the reader in determining which patients undergoing cardiac surgery might benefit from preoperative platelet function monitoring.
DEL-1 promotes macrophage efferocytosis and clearance of inflammation
Authors: Ioannis Kourtzelis, Xiaofei Li, Ioannis Mitroulis, Daniel Grosser, Tetsuhiro Kajikawa, Baomei Wang, Michal Grzybek, Janusz von Renesse, Aleksander Czogalla, Maria Troullinaki, Anaisa Ferreira, Christian Doreth, Klara Ruppova, Lan-Sun Chen, Kavita Hosur, Jong-Hyung Lim, Kyoung-Jin Chung, Sylvia Grossklaus, Anne Kathrin Tausche, Leo A. B. Joosten, Niki M. Moutsopoulos, Ben Wielockx, Antonio Castrillo, Jonathan M. Korostoff, Ünal Coskun, George Hajishengallis, Triantafyllos Chavakis
Journal: Nature Immunology (2018)
Abstract 18303: Lrp1 Regulates Metabolic Activity by Binding PPAR Gamma in Endothelium
Authors: Hua Mao, Xi Li, Pamela Lockyer, Liang Xie, Xinchun Pi
Journal: Circulation (2015)

Introduction: The endothelium is a biologically active barrier and the site of metabolic exchange between the circulation and underlying tissues. Endothelial dysfunction is a common feature for obesity, dyslipidemia and diabetes and other vascular related diseases. Our recent studies demonstrate that low density lipoprotein receptor-related protein 1 (LRP1) impacts a variety of biological processes such as lipid metabolism, endocytosis and signal transduction. However, the role of LRP1 in endothelial cells remains a mystery. Methods &amp; Results: The LRP1 flox/flox (LRP1 f/f ) mouse was bred to Tie2-Cre transgenic mouse to have LRP1 deleted in ECs and hematopoietic cells, resulting in inactivation of LRP1 gene function in these cells only. Both the LRP1 f/f ;Tie2Cre + mice and wild type mice were fed with high fat diet for 16 weeks. The LRP1 f/f ;Tie2Cre + mice displayed a smaller increase in adipose tissue weight, liver weight and body weight , compared to wild-type mice following high fat food feeding. In addition, we discovered that adipocyte size is significantly smaller in LRP1 f/f ;Tie2Cre + mice than wild type mice. In addition, LRP1 f/f ;Tie2Cre + mice are more sensitive to insulin following a bolus of glucose, demonstrated with the decreased glucose level in serum. The LRP1 f/f ;Tie2Cre + mice also had decreased levels of circulating resistin, adiponectin and leptin compared to wild type mice. In LRP1 f/f ;Tie2Cre + mouse liver, there are much less deposition of lipid droplets than the wild type liver. The study of lipid profiles shows a much smaller increase in cholesterol and HDL levels. In cultured mouse endothelial cells (MECs), we discovered that LRP1 binds PPARγ, an important protein that is known to regulate endothelium function and contribute to the regulation of systemic metabolic responses. LRP1 positively regulates PPARγ activity and affects lipid handling gene induction in MECs. Conclusions: Taken all together, our data suggest that endothelial LRP1 regulates systemic metabolic events possibly through binding PPARγ and thereby modulating endothelial activation. It provides novel mechanistic insights for the metabolic roles of endothelial LRP1 and expands the functional roles of endothelium.
IMMU-59. DETECTION OF HUMAN CYTOMEGALOVIRUS ANTIGENS IN MALIGNANT GLIOMAS AS AN IMMUNO-THERAPEUTIC TARGET
Authors: Stephen Ahn, Sin-Soo Jeun
Journal: Neuro-Oncology (2018)

Findings describing the existence of cytomegalovirus (CMV) antigens in glioblastoma have been controversial since first report in 2002 by Cobbs et al. Since this first publication, there were many studies to confirm the detection of CMV in malignant gliomas using a variety of methods such as immunohistochemistry, PCR, in situ hybridization, and immunofluorescence assay under confocal microscope. For confirming the presence of CMV proteins, we undertook immunofluorescence (IF) staining of CMV pp65 and IE-1 antigens in human primary malignant gliomas. Also, we investigated CMV specific CTL response on our primary cultured cells using pp65 or IE-1 specific CTLs obtained from healthy donors. First, we analyzed serum CMV immunoglobulin M and G index, and CMV DNA copy numbers using real-time(RT) PCR from 20 malignant glioma patients. All of patients showed positivity of IgG index and negativity of IgM and CMV DNA copy numbers. Second, we stained 15 primary malignant glioma cell lines using pp65 or IE-a specific antibody and the expression of CMV antigens were visualized by confocal fluorescence microscope. We found all positive results (15/15) in primary malignant gliomas, using fibroblast as a negative control and CMV-infected U87 as a positive control. Third, we generated pp65 or IE-1 specific CTLs using mRNA-pulsed dendritic cells from HLA partially matched heathy donors. Using theses CTLs, we revealed positive IFN-gamma ELISPOT assay results. We demonstrated not only the presence of CMV proteins (pp65, IE-1) in malignant gliomas but also elucidated that CMV could be an immuno-therapeutic target for adoptive cellular therapy.
A Trial of a Triple-Drug Treatment for Lymphatic Filariasis
Authors: Christopher L. King, James Suamani, Nelly Sanuku, Yao-Chieh Cheng, Samson Satofan, Brooke Mancuso, Charles W. Goss, Leanne J. Robinson, Peter M. Siba, Gary J. Weil, James W. Kazura
Journal: New England Journal of Medicine (2018)

The World Health Organization has targeted lymphatic filariasis for global elimination by 2020 with a strategy of mass drug administration. This trial tested whether a single dose of a three-drug regimen of ivermectin plus diethylcarbamazine plus albendazole results in a greater sustained clearance of microfilariae than a single dose of a two-drug regimen of diethylcarbamazine plus albendazole and is noninferior to the two-drug regimen administered once a year for 3 years.In a randomized, controlled trial involving adults from Papua New Guinea with Wuchereria bancrofti microfilaremia, we assigned 182 participants to receive a single dose of the three-drug regimen (60 participants), a single dose of the two-drug regimen (61 participants), or the two-drug regimen once a year for 3 years (61 participants). Clearance of microfilariae from the blood was measured at 12, 24, and 36 months after trial initiation.The three-drug regimen cleared microfilaremia in 55 of 57 participants (96%) at 12 months, in 52 of 54 participants (96%) at 24 months, and in 55 of 57 participants (96%) at 36 months. A single dose of the two-drug regimen cleared microfilaremia in 18 of 56 participants (32%) at 12 months, in 31 of 55 participants (56%) at 24 months, and in 43 of 52 participants (83%) at 36 months (P=0.02 for the three-drug regimen vs. a single dose of the two-drug regimen at 36 months). The two-drug regimen administered once a year for 3 years cleared microfilaremia in 20 of 59 participants (34%) at 12 months, in 42 of 56 participants (75%) at 24 months, and in 51 of 52 participants (98%) at 36 months (P=0.004 for noninferiority of the three-drug regimen vs. the two-drug regimen administered once a year for 3 years at 36 months). Moderate adverse events were more common in the group that received the three-drug regimen than in the combined two-drug-regimen groups (27% vs. 5%, P<0.001). There were no serious adverse events.The three-drug regimen induced clearance of microfilariae from the blood for 3 years in almost all participants who received the treatment and was superior to the two-drug regimen administered once and noninferior to the two-drug regimen administered once a year for 3 years. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01975441 .).
CBMT-44. METABOLIC PLASTICITY AND HETEROGENEITY IN IDH1MUT CELL LINES PRODUCES RESISTANCE TO GLUTAMINASE INHIBITION BY CB839
Authors: Victor Ruiz Rodado, Adrian Lita, Tyrone Dowdy, Alejandra Cavazos Saldana, Mark Gilbert, Mioara Larion
Journal: Neuro-Oncology (2018)

Mutant IDH1 (IDH1mut) gliomas have characteristic genetic and metabolic profiles and exhibit phenotype that is distinct from their wild-type counterparts. The glutamine/glutamate pathway has been hypothesized as a selective therapeutic target in IDH1mut gliomas. However, little information exists on the contribution of this pathway to the formation of D-2-hydroxyglutarate (D-2HG), a hallmark of IDHmut cells, and the metabolic consequences of inhibiting this pathway. We employed an untargeted metabolic profiling approach in order to detect metabolic changes arising from glutaminase (GLS) inhibition treatment. Subsequently, 13C metabolic tracing analysis through a combined Nuclear Magnetic Resonance and Liquid Chromatography-Mass Spectrometry approach, we explored the fate of glutamine and glucose under treatment with CB839 a glutaminase-GLS-inhibitor and their respective contributions to D-2HG formation. RESULTS AND The effects of CB839 on cellular proliferation differed among the cell lines tested, leading to designations of GLS-inhibition super-sensitive, -sensitive or -resistant. Our data indicates a decrease in the production of downstream metabolites of glutamate, including those involved in the TCA cycle, when treating the sensitive cells with CB839 (glutaminase -GLS- inhibitor). Notably, CB839-sensitive IDH1mut cells respond to GLS inhibition by upregulating glycolysis and lactate production. In contrast, CB839-resistant IDH1mut cell lines do not rely only on glutamine for the sustenance of TCA cycle. In these cells, glucose contribution to TCA is enough to compensate the downregulation of glutamine-derived TCA metabolites. This investigation reveals that the glutamine/glutamate pathway contributes differentially to D-2HG in a cell-line dependent fashion on a panel of IDHmut cell lines. Further, these results demonstrate that there is a heterogeneous landscape of IDH1mut metabolic phenotypes. This underscores the importance of detailed metabolic profiling of IDH1mut patients prior to the decision to target glutamine/glutamate pathway clinically.
EXTH-45. THE REPURPOSED CUSP9 REGIMEN EXERTS POTENT ANTI-NEOPLASTIC ACTIVITY AGAINST GLIOBLASTOMA CELLS IN VITRO
Authors: Marc-Eric Halatsch, Richard Eric Kast, Annika Dwucet, Markus Siegelin, Tim Heiland, Georg Karpel-Massler
Journal: Neuro-Oncology (2018)

Drug repurposing is a strategy to safely accelerate the clinical application of therapeutics that provide anti-cancer activity. CUSP9 represents such a therapeutic regime which includes nine repurposed drugs along with low-dose temozolomide. In this work, we examined the biological activity of the CUSP9 regimen in an in vitro setting of glioblastoma. MTT and soft-agar assays were used to examine cellular proliferation. Staining for Annexin V/PI and Western blotting were used to examine pro-apoptotic effects. A spheroid assay was performed to assess effects of the treatments on three-dimensional growth. Time-lapse microscopy, radius and transwell assays were performed to examine anti-migratory effects. Treatment with CUSP9 exerted profound anti-proliferative activity and inhibited anchorage-independent growth among a broad panel of established, primary cultured and glioma stem-like cells. These effects were accompanied by enhanced apoptosis as indicated by an increased fraction of Annexin V-positive cells and enhanced caspase-3 cleavage. Moreover, CUSP9 lead to significantly decreased 3-dimensional tumor formation. In addition, non-directed and directed movement of glioblastoma cells were significantly impaired following CUSP9 treatment. These data suggest that CUSP9 has potent anti-cancer activity in vitro which is currently further explored by a clinical trial being conducted at our institution (NCT02770378).
EPID-09. THE ROLE OF GENDER PHENOTYPE IN PAEDIATRIC CNS TUMOUR INCIDENCE AND SURVIVAL
Authors: Ryan Mathew, Sandeep Solanki, Wai Cheong Soon, Josie Hayes, Melpo Kapetanstrataki, Sarah Fleming, Roger Parslow, Sue Picton, Paul Chumas
Journal: Neuro-Oncology (2018)

The impact of patient gender in germinomas and medulloblastomas is a well-documented factor influencing incidence and outcome of these tumours, which may be due to differential susceptibility to tumourogenesis and treatment response between the genders. The role of gender phenotype in other paediatric CNS tumours is not as distinct. The Surveillance Epidemiology and End Result (SEER) registry (covering 28% of US patients) between 2000–11 was used to collect age-adjusted incidence and overall survival (OS) rates for common paediatric (<=19 years) CNS tumours - pilocytic astrocytoma (PA), anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), medulloblastoma (MB), sPNET, ependymoma (EP), germinoma (G) and pleomorphic xanthoastrocytoma (PXA). Patients with histologically confirmed, ICD-03 coded, first tumours, were included. Mortality was defined as any cause of death between 1–60 months of diagnosis. Results were statistically analysed by Incidence Rate Ratio (IRR), Kaplan-Meier and Log Rank (Cox Proportional Regression Hazard) Testing (p<0.05). A total of 5712 cases were registered (3169 male, 2543 female). Males exhibited the highest incidence of all tumours except PA. Comparing the opposite gender at the same ages, 1- and 5-year OS was better in males aged 3–4 years for MB, sPNETs, GBM and AA, females aged 0–19 years for MB, females aged 0–2 years and 15–19 years for AA; 5-year OS was better in females aged 0–2 years with EP; 1-year OS was better in males aged 3–4 year with AA. Population-based registries such as SEER can deliver credible data and minimise bias. Gender differences in both incidence and OS for different paediatric CNS tumours provide useful prognostic information for clinicians. Further research into possible hormonal and epigenetic differences may provide targets unique to males or females to tailor therapy.
DRES-14. PROTEIN AGGREGATE FORMATION PREDICTS CLINICAL RESPONSES TO EGFR TKIs
Authors: Pim French, Ya Gao, Maurice de Wit, Darlene Mercieca, Iris de Heer, Martin van Royen, Joachim Aerts, Peter Sillevis Smitt
Journal: Neuro-Oncology (2018)

EGFR tyrosine kinase inhibitors (TKIs) have thus-far not shown clinical benefit for glioma patients, which is in stark contrast to the benefit observed for patients with EGFR-mutated pulmonary adenocarcinomas (PA). We performed functional analysis on various EGFR-mutation constructs to better understand the differential sensitivity to EGFR TKIs. Response to EGFR TKIs was monitored using high-throughput automated imaging analysis, western blot, immunofluorescence, RT-QPCR, and immunoprecipitation-mass spectrometry (IP-MS). Addition of TKIs to cells ectopically expressing EGFR mutation constructs resulted in a rapid and strong formation of EGFR-protein aggregates. However, aggregates were found only cells expressing mutations common to PAs (n=3 mutations tested) but not in mutations common to gliomas (n=4) or those harboring secondary resistance mutations (n=1). Moreover, aggregates were only observed in TKIs with proven clinical benefit (erlotinib, gefitinib, dacomitinib or osimertinib) and not with a drug with no such benefit (lapatinib). We find a high concordance between the IC50 for viability of 13 cell lines harboring endogenous EGFR mutations (n=12 different mutations) and the IC50 of mutations to form protein aggregates. Patients harboring mutations that are sensitive to aggregate formation (IC50 < 500 nM) had significantly longer time to progression (median survival 7.5 vs 13 months, HR 0.25, P=0.012). These data demonstrate that formation of aggregates predicts response to EGFR TKIs in patients. The aggregates are formed, predominantly in the nucleus, first by a dephosphorylation of EGFR after which specific mutations and drugs both affect the (inactive) conformation state of EGFR. Such a state renders the protein more prone to aggregate formation and subsequent complete inactivation. Protein aggregation predicts response to EGFR TKIs. Since these aggregates inactivate all functions of the protein, the absence of aggregate formation with glioma specific mutations in EGFR explain why these tumors are insensitive to EGFR TKIs.
TMOD-30. ANTI-PD-L1 ANTIBODY ENHANCES RADIATION INDUCED ABSCOPAL RESPONSE IN MURINE BRAIN TUMORS
Authors: Chibawanye Ene, Shannon Kreuser, Courtney Crane, Eric Holland
Journal: Neuro-Oncology (2018)

Immunotherapy approaches for glioblastoma multiforme have been thus far largely unsuccessful, suggesting unappreciated complexity in glioma biology and immunology. The intra-tumoral heterogeneity of these intrinsic brain tumors results in therapies killing only a subset of the tumor cells; therefore, therapeutic success will require achieving and optimizing an “abscopal effect” where tumor cells not specifically targeted are recognized and attacked as bystanders by the immune system. We have modified an immune-competent, genetically-driven mouse glioma model where a portion of the tumor burden is treated and another untreated portion is used as a readout of therapeutic efficacy. We find that following radiation of one lesion, anti-PD-L1 therapy enhances the abscopal response (macrophages and T-cells) to the un-irradiated lesion. In gliomas with few baseline T-cells, the anti-PD-L1-enhanced abscopal response occurs as an anti-PD-L1-driven, macrophage-associated, and ERK-dependent increase in phagocytosis of tumor cells. Our results indicate that combined radiation and anti-PD-L1 therapy for gliomas results in peripherally-derived macrophages being responders in tumors with few baseline T-cells in the microenvironment.