tbuckley/cabot-search huggingface dataset:
PDTM-45. POSITIVE MODULATION OF NATIVE GABAA RECEPTORS IN MEDULLOBLASTOMA CANCER CELLS WITH BENZODIAZEPINES INDUCES RAPID MITOCHONDRIAL FRAGMENTATION AND TP53-DEPENDENT, CELL CYCLE-INDEPENDENT APOPTOSIS
Authors: Laura Kallay, Havva Keskin, Alexandra Ross, Olivia Moody, Kirsten Cottrill, Austin Nuckols, Guanguan Li, Taukir Ahmed, Farjana Rashid, Michael Stephen, Maxwell Xu, Deborah Martinson, Tobey Macdonald, Jeanne Kowalski, Xin Wang, Michael Taylor, James Cook, Andrew Jenkins, Daniel Pomeranz Krummel, Soma Sengupta
Journal: Neuro-Oncology (2018)

Medulloblastoma is the most common childhood malignant brain tumor. Children with highest morbidity have tumors that are TP53 wild-type and express high levels of MYC and GABRA5, which codes for the α-5 subunit of the ligand (chloride) gated GABAA receptor. Previously, we have established that the α-5 subunit of the GABAA receptor contributes to the assembly of a functional receptor in a subset of medulloblastoma cells and benzodiazepines, synthesized to function as α-5 selective ligands with psychotropic activity, impair viability1,2. Utilizing a TP53 wild-type medulloblastoma cell line with amplified MYC, high GABRA5 expression, and a functional α-5 GABAA receptor, we provide insight into how benzodiazepines impair cell viability by positively modulating the native GABAA receptors. We screened benzodiazepines to assess impact of varying chemical group identity on cell viability. The most potent benzodiazepine binds with specificity to ~1000 native receptors per cell with EC50 and IC50 values of ~0.8 micromolar. This binding evokes a 2 x 109 ions.sec-1 chloride flux, which morphologically elicits mitochondrial fragmentation, nuclei distention, and cellular blebbing. The cascade of events culminates in a caspase-mediated activation of apoptosis through the intrinsic pathway and a localization of pro-apoptotic Bcl-2-associated death promoter (BAD) protein. Benzodiazepines may be efficacious as anti-cancer therapeutics for medulloblastoma patients exhibiting a GABAA receptor expression signature by driving a chloride imbalance that leads to cell apoptosis. References: 1Sengupta, et al. α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. Acta Neuropathol. 2014; 127(4): 593–603. 2Jonas, et al. First in vivo testing of compounds targeting Group 3 medulloblastomas using an implantable microdevice as a new paradigm for drug development. J. Biomed. Nanotechnol. 2016; 12(6): 1297–1302.
High Prevalence of BTK Mutations on Ibrutinib Therapy after 3 Years of Treatment in a Real-Life Cohort of CLL Patients: A Study from the French Innovative Leukemia Organization (FILO) Group
Authors: Anne Quinquenel, Luc Matthieu Fornecker, Remi Letestu, Carole Fleury, Loic Ysebaert, Marie-Sarah Dilhuydy, Romain Guieze, Pierre Feugier, Damien Roos-Weil, Lise Willems, Anne-Sophie Michallet, Alain Jacques Delmer, Pietro Taverna, Judith A. Fox, Vincent Levy, Florence Cymbalista, Fanny Baran-Marszak
Journal: Blood (2018)
EXTH-69. MAGNETIC HYPERTHERMIA THERAPY OF EXPERIMENTAL GLIOBLASTOMA IN COMBINATION WITH CHEMORADIATION
Authors: Alexandros Bouras, Keon Mahmoudi, Dominique Bozec, Joe Gerald, Jesu Raj, Robert Ivkov, Constantinos Hadjipanayis
Journal: Neuro-Oncology (2018)

Fractionated radiation therapy (RT) combined with chemotherapy (temozolomide; TMZ), known as chemoradiation (CRT), has provided the greatest benefit to glioblastoma (GBM) patients. Magnetic hyperthermia therapy (MHT) consists of intratumoral heat generation after deposition of magnetic iron-oxide nanoparticles (MIONPs) that are subjected to an external alternating magnetic field (AMF). MHT may potentiate the cytotoxic effects of CRT on tumor cells. We have developed MIONPs that demonstrate heating efficacy for MHT. Intracranial heating efficacy and toxicity studies were performed in healthy mice using MIONPs solutions with a clinically relevant AMF treatment (450kHz, 200G) after convection-enhanced delivery (CED). Bioluminescence imaging (BLI) was used to assess the in vivo efficacy of intracranial MHT in combination with fractionated RT in a mouse syngeneic GBM model. A pilot survival study of athymic nude mice with invasive, therapy-resistant orthotopic human GBM intracranial xenografts was completed after combination treatment with MHT and CRT. Quantification of TMZ levels in intracranial xenografts and surrounding brain tissue after MHT was performed using liquid chromatography–mass spectrometry (LC-MS). A concentration-dependent temperature increase by the MIONPs after CED and an AMF was observed rapidly in the brain. No temperature elevation was observed in either the contralateral brain hemisphere or the rectum, supporting the localized intracranial heating effect. No severe acute and long-term side effects were observed after MIONP CED. A marked decrease in tumor size was found with MHT and RT by BLI. Significantly prolonged animal survival occurred with MHT and CRT in comparison to monotherapy. Increased TMZ levels were measured in xenografts and surrounding brain tissue after MHT and TMZ treatment. We have confirmed the safety and feasibility of intracranial MHT in a rodent glioma model. Furthermore, we have demonstrated the chemoradiosensitivity enhancement of therapy-resistant human GBM xenografts after MHT.
CBMT-46. MICROENVIRONMENT-DERIVED MITOCHONDRIA PRIME GLIOMA CHEMORESISTANCE BY AUGMENTING NAD+ METABOLISM AND PARP-DEPENDENT DNA REPAIR
Authors: Yang Liu, Yanxin Lu, Aiguo Li, Hua Song, Wei Zhang, Mark Gilbert, Chunzhang Yang
Journal: Neuro-Oncology (2018)

Mitochondria is the major organelle for cellular metabolism. Increasing evidence shows that mitochondria are released into the extracellular microenvironment and taken up by adjacent cells, reshaping the metabolism and other biological processes in the recipient cells. While knowledge of intercellular mitochondria transfer under normal physiology is expanding, the roles of mitochondria transfer in tumor microenvironment and disease outcome remains elusive. In this study, we established in vitro and in vivo models to aid in the understanding of mitochondrial transfer between astrocytes and glioma cells. We investigated the mitochondria population in extracellular vesicles (EV), and their influence on the recipient glioma cells, with focuses on NAD+ metabolism and PARP DNA repair pathway. The role of intercellular mitochondria was further validated in glioma xenograft model with chemotherapy. We demonstrated that mitochondria are released from normal astrocytes through EV and adopted by neighboring glioma cells. Moreover, mitochondrial transfer improved metabolism in recipient glioma cells, supporting the detoxification of chemotherapeutic agents and evoking treatment resistance. Mechanistically, mitochondria-derived NAD+ metabolic enzymes expanded the pool of NAD+ in recipient cancer cells, which fueled PARP DNA repair pathway with key cofactors. Targeting astrocyte mitochondria-releasing pathways not only increased the chemotherapy-derived cytotoxicity, reduced xenograft progression, but also improved disease outcome by prolonging overall survival. CONCLUSION: Our findings revealed that microenvironment-derived mitochondria transfer is a potential chemoresistance mechanism in cancer cells. Targeting intercellular mitochondria transfer may be important in reducing the capacity for cancer cells to recover from cancer treatment, thereby enhancing treatment efficacy.
Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy
Authors: Y.-P. Chen, Y.-Q. Wang, J.-W. Lv, Y.-Q. Li, M.L.K. Chua, Q.-T. Le, N. Lee, A. Dimitrios Colevas, T. Seiwert, D.N. Hayes, N. Riaz, J.B. Vermorken, B. O’Sullivan, Q.-M. He, X.-J. Yang, L.-L. Tang, Y.-P. Mao, Y. Sun, N. Liu, J. Ma
Journal: Annals of Oncology (2018)

Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups.A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation.Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-γ signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-β signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01).This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.
CSIG-07. COMPARATIVE RNA-SEQ ANALYSIS OF GLIOMAS OF DIFFERENT MALIGNANCY IDENTIFIES FYN AS A NOVEL REGULATOR OF GBM AGGRESSIVENESS
Authors: Andrea Comba, Padma Kadiyala, Patrick Dunn, Anna Argento, Priti Patel, Mahmoud Alghamri, Felipe Nunez, Maria G Castro, Pedro Lowenstein
Journal: Neuro-Oncology (2018)

Glioblastomas (GBM) are the most frequent and aggressive primary tumors of the brain. Fyn, a Src family kinase member, is overexpressed in human GBM. Its function, however, remains poorly understood. We analyzed the differential gene expression (DE) of highly malignant tumor (NPA: N-Ras/shp53/shATRx) compared to a less malignant one (NPAI: N-Ras/shp53/shATRx/IDH1R132H). Bioinformatics and network analysis identified Fyn as a highly connected node. This suggests that Fyn could be a regulator of GBM growth and progression. We therefore investigated the role of Fyn on glioma function in vitro and in vivo. Fyn expression levels in both human and mouse GBM cells correlated with tumor aggressiveness. Fyn knockdown in NP and NPA glioma cells decreased cell proliferation and migration. To test the activity of Fyn on tumor growth in vivo, we developed a Fyn-deficient glioma genetic model using the Sleeping Beauty transposase system. We induced Fyn knockdown in glioma tumors with different genetic drivers: NPF: N-Ras/shp53+shFyn, NPAF: N-Ras/shp53/shATRx+shFYN and NPDF: N-Ras/shp53/PDGFβ+shFYN. Fyn knockdown increased survival in all three genetically different tumors. The absence of Fyn reduced malignant neuropathological features such as pseudopalisades, ischemic necrosis, and microvascular proliferation. At the molecular level, RNA-Seq and DE analysis comparing NPF tumors with their controls, NP tumors (N-Ras/shp53) identified 573 differentially expressed genes. Bioinformatics analysis indicated altered activity in the following Gene Ontologies: “regulation of cell adhesion”, “inflammatory response”, and “positive regulation of cell motility”. In addition, signaling pathways significantly altered in their activity included “cell adhesion molecules (CAMs)”, “focal adhesion” and “ECM receptor interaction”. Our results indicate that Fyn would exert its effects by regulating cell motility and interactions with the ECM. We suggest that inhibiting Fyn activity, a novel regulator of glioma malignancy, could become a relevant treatment for GBM.
OP0283 Cross-disease meta-analysis in four systemic autoimmune diseases to identify shared genetic etiologies
Authors: M. Acosta-Herrera, M. Kerick, D. Gonzalez-Serna, C. Wijmenga, A. Franke, L. Padyukov, T. Vyse, M.E. Alarcon-Riquelme, M.D. Mayes, J. Martin, Scleroderma Genetics Consortium
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Cross-disease genome-wide association studies (GWAS) in autoimmune diseases (AIDs) has become a powerful tool to expose new genetic variants associated with disease susceptibility and to reveal shared biological mechanisms in the pathophysiology of these conditions. <h3>Objectives</h3> The goal of our study was to identify shared genetic etiologies by performing a large-scale meta-analysis of four systemic AIDs in individuals from European-descent populations, including rheumatoid arthritis [4595 cases and 3372 controls], systemic lupus erythematosus [3154 cases and 8775 controls], systemic sclerosis [2255 cases and 4407 controls] and myositis [1674 cases and 3150 controls] <h3>Methods</h3> PLINK and EIGENSTRAT were utilised for quality control and population stratification adjustments. Genotype imputation was performed using Minimac in the Michigan Imputation Server and the Haplotype Reference Consortium as reference panel. <h3>Results</h3> We meta-analysed ~6.5 million single nucleotide polymorphisms (SNPs) (MAF &gt;1%, Rsq &gt;0.3) across the four diseases and were able to identify 27 genome-wide significant independent loci with at least two diseases leading the association. Our new findings include five unreported shared risk loci: <i>NAB1</i>, <i>KPNA4-ARL14</i>, <i>DGQK</i>, <i>LIMK1</i>, and <i>PRR12</i>. The results from the meta-analysis were functionally enriched in transcription factor binding sites, promoter and enhancer histone marks and DNase cleavage hotspots in immune cell lines, as well as in epithelial and epidermal cell lines. This is consistent with the clinical manifestations across diseases related to the immune system and the connective tissue. Interestingly, several associated variants were able to modify the expression of the nearest genes and constitute shared expression quantitative trait loci across diseases. <h3>Conclusions</h3> These studies offer the opportunity to uncover new biological pathways, address patient classification based on their molecular taxonomy and provide an opportunity for drug repositioning by targeting shared mechanisms across diseases. <h3>Acknowledgements</h3> Partially funded by EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (115565), The Ministry of Economy and Competitiveness (SAF2015–66761 P), Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (P12-BIO-1395), and Juan de la Cierva fellowship (FJCI-2015–24028). <h3>Disclosure of Interest</h3> None declared
Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study
Authors: Martin H Voss, Albert Reising, Yuan Cheng, Parul Patel, Mahtab Marker, Fengshen Kuo, Timothy A Chan, Toni K Choueiri, James J Hsieh, A Ari Hakimi, Robert J Motzer
Journal: The Lancet Oncology (2018)
The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness
Authors: Daisy Melandri, Iva Zlatareva, Raphaël A. G. Chaleil, Robin J. Dart, Andrew Chancellor, Oliver Nussbaumer, Oxana Polyakova, Natalie A. Roberts, Daniela Wesch, Dieter Kabelitz, Peter M. Irving, Susan John, Salah Mansour, Paul A. Bates, Pierre Vantourout, Adrian C. Hayday
Journal: Nature Immunology (2018)
ACTR-36. A SINGLE ARM PHASE 2 STUDY OF THE DUAL mTORC1/mTORC2 INHIBITOR VISTUSERTIB PROVIDED ON AN INTERMITTENT SCHEDULE FOR NEUROFIBROMATOSIS 2 PATIENTS WITH PROGRESSIVE OR SYMPTOMATIC MENINGIOMAS
Authors: Scott Plotkin, Justin Jordan, Roberta Beauchamp, Alona Muzikansky, Anat Stemmer-Rachamimov, Vijaya Ramesh
Journal: Neuro-Oncology (2018)

Meningiomas are the second most common tumor in NF2 patients, with a cumulative prevalence of 80% by age 70 and a high prevalence of multiple meningiomas. Surgery remains standard of care for these tumors, yet outcomes remain suboptimal for many patients with multiple tumors. Loss of NF2 expression is associated with activation of the mTOR pathway, but treatment with the mTORC1 inhibitor everolimus is not associated with tumor shrinkage. We hypothesized that inhibition of both mTORC1 and mTORC2 pathways would result in increased activity against meningiomas. This single center, phase II, open label study evaluated adults (18 years) with NF2 and progressive meningiomas treated with vistusertib. Subjects received vistusertib 125 mg BID two consecutive days per week. Radiographic response was defined as 20% decrease in tumor volume from baseline. The primary endpoint was radiographic response rate in the target meningioma; secondary endpoints included radiographic response in non-target meningiomas and vestibular schwannomas. We enrolled 18 subjects (5M;13F) with a median age of 40 years (range 18–60 years). Baseline volume of target meningioma was 14.2 ml (range, 3.3–69.2 ml) and median pretreatment growth rate was 33%/year. A radiographic response was seen in 1/18 (6%) target meningiomas and in 2/20 (10%) of non-target meningiomas and in 2/21 (9.5%) of vestibular schwannomas. Three target meningiomas (17%) progressed during treatment. Seven subjects (39%) discontinued treatment by choice due to tolerability and 8 remain on study. Adverse events included fatigue, nausea, vomiting, anorexia, rash, mucositis, and hypophosphatemia. Vistusertib treatment is associated with radiographic response rates of 5–10% in meningiomas and schwannomas in NF2 patients, with only a minority of meningiomas progressing during treatment. Grade 2 toxicity led to treatment discontinuation in a significant minority of patients. Future analyses will address the relationship between tumor shrinkage and activation of TORC1/2 pathways in archival tumor specimens.
The Metabolic Functions of Vitamin B<sub>12</sub>
Authors: William S. Beck
Journal: New England Journal of Medicine (1962)

RAPID progress in any area of scientific inquiry does not ordinarily occur until the problems needing solution have been formulated in terms that elicit respect for their complexities. Usually, this is made possible by a small number of key contributions. The history of our understanding of vitamin B12 is a procession of such turning points. The most recent is undoubtedly the discovery of a coenzyme form of vitamin B12 by Barker and his associates1 in 1958. This brilliant contribution initiated a series of biochemical studies that have, at last, provided meaningful clues to the role of vitamin B . . .
Abstract 17730: The Appropriate Biomarker of a Cardiac Rehabilitation in the Patients With Post Abdominal Aortic Aneurysm Repair
Authors: Atsuko Nakayama, Masatoshi Nagayama, Hiroyuki Morita, Issei Komuro
Journal: Circulation (2015)

Introduction: The useful biomarkers of cardiac rehabilitation after post cardiovascular surgery are still unknown. This is the first report describing the markers of the effect of cardiac rehabilitation on prognosis after abdominal aortic aneurysm (AAA) surgery. Methods: We conducted an observed cohort study on 1330 patients receiving surgical repair of AAA in the multicenter in Tokyo from January 2003 to December 2014. The patients who had cardiac rehabilitation more than once a week for more than 3 months after surgery were classified into rehabilitation group. The patients in rehabilitation group underwent cardiopulmonary exercise testing (CPX) before and 3 months after surgery. Total 274 inspection items including blood culture, computerized tomography, carotid duplex, ankle-brachial index test, cardiac echography, respiratory function test and CPX were cyclopaedically analyzed. The results of blood culture in rehabilitation group were compared to those in non-rehabilitaion group before surgery, 14 days after and 30days after surgery. Results: The average age of patients was 73±8 years and the average follow-up period was 2.5±2.2 years. The 355 patients had cardiac rehabilitation after AAA repair, and the other 975 patients did not. Basal characteristics including age, gender, hypertension, dyslipidemia, diabetes, smoking and drugs were statistically similar in both groups. The predictors of the risk of major adverse cardiac events (MACE) after surgery were co-existence of coronary artery disease, non-intake of beta-blockers, non-intake of ARBs and nonparticipation in cardiac rehabilitation. The ROC curve analysis of the markers demonstrated no remarkable marker for the risk of MACE after surgery. But the level of CRP in rehabilitation group was lower 14 days and 30 days after surgery compared to which in non-rehabilitation group (4.5 ± 4.3 mg/dl vs. 5.9 ± 6.5 mg/dl, p&lt;0.001 and 4.2 ± 4.5 mg/dl vs. 6.5 ± 6.0 mg/dl, p&lt;0.001), although the level of CRP was similar in both groups before surgery. Conclusions: Cardiac rehabilitation in patients after AAA surgery improved the risk of MACE, and especially CRP may be useful as a convenient marker of effective rehabilitation for secondary prevention of arteriosclerosis.
IMMU-29. COMBINATION PD-1 BLOCKADE AND IRRADIATION OF BRAIN METASTASIS INDUCES AN EFFECTIVE ABSCOPAL EFFECT IN MELANOMA
Authors: Lukas Pfannenstiel, Corey McNeilly, Chaomei Xiang, Kai Kang, Claudia Marcela Diaz, Jennifer Yu, Brian Gastman
Journal: Neuro-Oncology (2018)

Nearly half of melanoma patients develop brain metastases during the course of their disease. Despite advances in both localized radiation and systemic immunotherapy, brain metastases remain difficult to treat, with most patients surviving less than 5 months from the time of diagnosis. While both treatment regimens have individually shown considerable promise in treating metastatic melanoma, there is interest in combining these strategies to take advantage of potential synergy. In order to study the ability of local radiation and anti-PD-1 immunotherapy to induce beneficial anti-tumor immune responses against distant, unirradiated tumors, we used two mouse models of metastatic melanoma in the brain, representing BRAF mutant and non-mutant tumors. Combination treatments produced a stronger systemic anti-tumor immune response than either treatment alone. This resulted in reduced tumor growth and larger numbers of activated, cytotoxic CD8+ T cells, even in the unirradiated tumor, indicative of an abscopal effect. The immune-mediated effects were present regardless of BRAF status. These data suggest that irradiation of brain metastases and anti-PD-1 immunotherapy together can induce abscopal anti-tumor responses that control both local and distant disease.
<i>Jak</i> -ing Up the Plaque’s Lipid Core…and Even More
Authors: Peter Libby, Roberto Molinaro, Rob S. Sellar, Benjamin L. Ebert
Journal: Circulation Research (2018)

U ntil recently, many viewed atherosclerosis as a lipid storage disease or a bland accumulation of proliferated smooth muscle cells.How the landscape has changed!Abundant evidence now implicates intertwining pathways of inflammation as crucial to atherogenesis and its clinical consequences. 1Inflammatory mediators modulate the functions of vascular wall cells that provoke the disease.Multiple cell types beckoned to enter the arterial intima during atherogenesis can produce these inflammatory mediators.Actions of monocyte/macrophages and T lymphocytes implicated both adaptive and innate immunity in atherosclerosis.Indeed, many leukocyte lineages participate in chronic inflammation in the plaque.Recent evidence points to the participation of the acute inflammatory cell, the polymorphonuclear leukocytes, in plaque complication.An ongoing struggle between proinflammatory and anti-inflammatory and proresolving stimuli determine the evolution of the plaque, from its initiation through its thrombotic complications.