tbuckley/cabot-search huggingface dataset:
IMMU-47. ANALYSIS OF IMMUNE RESPONSE AND STAT3 PATHWAY OF DE-NOVO AND RECURRENT GLIOBLASTOMA MULTIFORME
Authors: Dieter Henrik Heiland, Sabrina Heynckes, Irina Mader, Dietmar Pfeifer, Marco Prinz, Daniel Delev, Oliver Schnell
Journal: Neuro-Oncology (2017)

in different human DIPG cell lines; (2) generate and characterize siRNA oligonucleotides specifically targeting human IDO1 for an in vitro targeted approach to validate knockdown of IDO1 expression; and (3) generate and characterize gold nanoparticles for further targeted approach to inhibit IDO1.METHODS/STUDY: Unique patient-derived DIPG cell lines were grown in culture, stimulated with increasing concentrations of IFN-γ, and analyzed by levels of mRNA.IDO1 small inhibitory (si)RNA were created to target IDO1 specifically, and transfected into cells.Using the best siRNA for IDO1 inhibitions, SNAs were generated.RESULTS/ANTICIPATED RESULTS: IDO1 is expressed in different human pediatric DIPG cells at the mRNA level.We created siRNA that specifically targets IDO1 and preliminary results show overall decrease of IDO1 at the mRNA level.Generation of SNA is ongoing for targeted approach and improved blood brain barrier penetration & stability, with preliminary results showing siIDO1-SNAs inhibit IDO1 expression.Discussion/Significance of Impact: The overall poor prognosis of children with DIPG combined with the lack of effective therapies, emphasizes the importance of understanding the IDO1 pathway and the potential effects of IDO1 inhibition for therapeutically-modulating these devastating tumors.Our research confirms IDO1 presence in DIPG, and the use of nanotechnology and development of siRNA-SNAs for IDO1 inhibition has the capability of direct translatability of therapeutically-valuable data.
PDTM-02. NEXT-GENERATION SEQUENCING OF DIFFUSE INTRINSIC PONTINE GLIOMA CELLS REVEALS ALTERED EPIGENETIC REGULATION AND DISTINCT TUMOR SUBGROUPS
Authors: Amanda Saratsis, Tina Huang, Elizabeth Bartom, Stacy Marshall, Jin Qi, Rintaro Hashizume, C David James, Ali Shilatifard
Journal: Neuro-Oncology (2017)

Diffuse intrinsic pontine glioma (DIPG) is an infiltrative neoplasm with the highest mortality rate of all pediatric solid tumors. Recurrent somatic mutations of histone H3 isoforms result in methionine for lysine substitution (H3K27M) in 80% of DIPGs, thought to contribute to tumorigenesis via altered chromatin structure and function. To characterize the effects of the H3K27M mutation on gene expression, we analyzed the transcriptomes of rare DIPG primary cell lines with three distinct bioinformatics approaches. H3K27M DIPG (n=7), wild-type pediatric high-grade glioma (HGG, n=3), neural stem cells (n=1) and astrocytes (n=1) were analyzed (RNASeq, 50bp single end, Illumina NexSeq 500) in triplicate (36 runs). Reads were trimmed from 3’ to a final base quality score >30 (Trimmomatic), aligned to the human genome (UCSC hg19, Tophat), then normalized and quantified for 1) specific gene locus (GRanges), 2) exons of a specific gene locus (HTSeq), and 3) alternative splicing isoforms (Rsem). Differential expression was quantified (edgeR), with functional analyses for biological relevance of data sets (TopGO, Ingenuity Pathways Analysis). Epigenetic regulation of transcription, including increased EZH2 function (FC>5, p<0.05), SMARC4A inactivation (z-score >2), and Polymerase II activity at proximal promoter and enhancer regions (p>0.01), were identified in H3K27M mutant lines. Neurogenesis and neuronal differentiation were downregulated in H3K27M lines, consistent with morphologic changes observed in DIPG cell lines after EZH2 and BRD inhibition. Unsupervised clustering of GRanges and HTSeq demonstrated two DIPG subgroups, distinct from wild type and control lines. Rsem data demonstrates similar clustering of DIPGs, with less overlap of HGGs. We present novel transcriptome analysis of rare DIPG cell lines, indicating specific genes and signaling pathways that may promote tumor formation in the presence of H3K27M mutation. These data will be integrated with ChIP-Seq to correlate potential epigenetic mechanisms of aberrant transcriptional regulation secondary to H3K27M mutation.
Depletion of somatic mutations in splicing-associated sequences in cancer genomes
Authors: Laurence D. Hurst, Nizar N. Batada
Journal: Genome biology (2017)

An important goal of cancer genomics is to identify systematically cancer-causing mutations. A common approach is to identify sites with high ratios of non-synonymous to synonymous mutations; however, if synonymous mutations are under purifying selection, this methodology leads to identification of false-positive mutations. Here, using synonymous somatic mutations (SSMs) identified in over 4000 tumours across 15 different cancer types, we sought to test this assumption by focusing on coding regions required for splicing. Exon flanks, which are enriched for sequences required for splicing fidelity, have ~ 17% lower SSM density compared to exonic cores, even after excluding canonical splice sites. While it is impossible to eliminate a mutation bias of unknown cause, multiple lines of evidence support a purifying selection model above a mutational bias explanation. The flank/core difference is not explained by skewed nucleotide content, replication timing, nucleosome occupancy or deficiency in mismatch repair. The depletion is not seen in tumour suppressors, consistent with their role in positive tumour selection, but is otherwise observed in cancer-associated and non-cancer genes, both essential and non-essential. Consistent with a role in splicing modulation, exonic splice enhancers have a lower SSM density before and after controlling for nucleotide composition; moreover, flanks at the 5' end of the exons have significantly lower SSM density than at the 3' end. These results suggest that the observable mutational spectrum of cancer genomes is not simply a product of various mutational processes and positive selection, but might also be shaped by negative selection.
GENE-17. GENERATION OF A MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA HARBORING ACVR1 G328V AND H3.1 K27M MUTATIONS
Authors: Flor M Mendez, Felipe J Nunez, Carl Koschmann, Meghna Saxena, Neha Kamran, Marta Dzaman, Sheeba Pawar, Pedro R Lowenstein, Maria G Castro
Journal: Neuro-Oncology (2017)

Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brainstem tumor with no efficacious treatment. The most prevalent mutation occurs on the amino terminal tail at Lysine 27 (K27M) resulting in global hypomethylation of H3K27. The H3.1-K27M mutation is highly co-expressed with an activating mutation (G328V) in Activin-A receptor Type 1 (ACVR1), a bone morphogenetic protein (BMP) receptor. We used the Sleeping Beauty Transposase (SB) system to deliver plasmids encoding NRASV12 and a short hair pin for TP53 (shp53) in combination with ACVR1-G328V or H3.1-K27M, or both, into the lateral ventricle of neonatal mice, to generate endogenous tumors with DIPG mutations. Tumor development was monitored by measuring luciferase activity in vivo. Moribund stage animals were perfused and processed for histology. Additionally, tumor neurospheres (NS) were generated from moribund stage tumors. H3.1 K27M (MS=99 dpi) did not have a statistically significant effect on survival compared to the control group NRAS/shp53 (MS=80), however, tumors induced with NRAS/shp53/ACVR1 G328V (MS=119 dpi) had enhanced survival compared to control group NRAS/shp53 (p=0.0029). Tumors harboring NRAS/shp53/ACVR1 G328V/H3.1 K27M (MS=154) exhibit a synergistic increase in survival compared to the NRAS/shp53/H3.1 group (p<0.0001) and the NRAS/shp53/ACVR1G328V group (p=0.0137). In vitro and in vivo, tumors or tumor NS harboring ACVR1-G328V exhibit elevated phopho-Smad1/5, transducer of the BMP pathway, while those harboring H3.1-K27M exhibit decreased H3K27me3 and increased H3K27 acetylation levels compared to controls. In conclusion, the SB transposase system can be used to develop a mouse model that accurately represents the molecular biology of DIPGs with ACVR1-G328V and H3.1-K27M mutations. ACVR1-G328V and H3.1-K27M may induce a protective effect that prolongs survival through upregulation of the BMP-Smad1/5 pathway and epigenetic deregulation. In the future we aim to elucidate the mechanisms by which ACVR1 and H3.1-K27M mutations contribute to tumor initiation and progression to develop targeted therapies for DIPG.
Abstract P230: Markers of Hyperglycemia and Intracranial Atherosclerotic Stenosis by Magnetic Resonance Angiography
Authors: Akira Fujiyoshi, M.Fareed K Suri, Alvaro Alonso, Elizabeth Selvin, Haitao Chu, Eliseo Guallar, Ye Qiao, Yiyi Zhang, Bruce A Wasserman, Aaron R Folsom
Journal: Circulation (2016)

Introduction: Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke. Determinants of ICAS include conventional cardiovascular (CV) risk factors such as hypertension and dyslipidemia. The association of diabetes mellitus (DM) and/or hyperglycemia with ICAS, however, is less well documented. Hypothesis: In a community-based population, biomarkers of hyperglycemia will be cross-sectionally associated with prevalent ICAS independent of CV risk factors. Methods: Our analyses were conducted in a subsample of participants of the Atherosclerosis Risk in Communities (ARIC) Study who participated in the ARIC-Neurocognitive Study in 2011-13 with cerebrovascular magnetic resonance angiography and no history of stroke. For the present analyses, we grouped the participants into 3 categories based on the highest ICAS category among any of the intracranial arteries we assessed: “no stenosis”, “&lt;50%”, or “≥50% (including occlusion)”. Diagnosed diabetes was defined as self-reported physician diagnosis or use of antidiabetic medication. Ordinal logistic regression provided odds ratios of prevalent ICAS according to quintile of glucose or glycated hemoglobin (HbA1c) adjusted for CV risk factors. Results (Table): There were 1,658 individuals included in our study (age 67-90 years, women 58%, Black 29%), 31% (514/1658) had diagnosed diabetes, 10% (165/1658) had ≥50 % stenosis at any of the intracerebral arteries. In crude analyses, those with higher glucose and HbA1c were more likely to have ICAS among the non-diabetes and the diabetes. In logistic regression, highest quintile of glucose, relative to the lowest, had odds ratio of 2.26 (95% confidence interval 1.48, 3.45) for being in each successive ICAS category after adjustment for CV risk factors. Conclusion: Higher glucose and HbA1c were associated with higher odds of ICAS independent of CV risk factors. The finding suggests that hyperglycemia plays a role in pathogenesis of ICAS.
P3.02-049 The Evaluation of Circulating miRNA Expression in Plasma as the Epigenetic Marker of EGFR Mutation Status in NSCLC Patients
Authors: M. Florczuk, A. Szpechcinski, M. Komorowski, K. Duk, W. Kupis, P. Rudzinski, M. Bryl, T. Orlowski, J. Chorostowska-Wynimko
Journal: Journal of Thoracic Oncology (2017)
TMIC-11. TUMOR GENETICS AND MACROPHAGE ONTOGENY SHAPE THE INNATE IMMUNE RESPONSE TO GLIOMA
Authors: Soeren Mueller, Gary Kohanbash, Siyuan Liu, Diego Carrera, Payal Watchmaker, Naznin Jahan, Beatriz Alvarado, Dan Lim, Manish Aghi, Hideho Okada, Aaron Diaz
Journal: Neuro-Oncology (2017)

Responses to immunotherapies, such as immune-checkpoint blockade, can be dramatic. However, responses are highly variable across patients. Determining the influence of glioma genetics on leukocyte induction and education is critical to the application of emerging immunotherapies. To elucidate the contributions of tumor genetics and macrophage ontogeny in shaping the innate-immune response, we combined high-throughput single-cell RNA sequencing of 22 glioma patient biopsies and meta-analysis of over 1000 published transcriptomics and proteomics glioma datasets. We identified gene signatures specific to bone-marrow derived macrophages and central nervous system (CNS) resident microglia, respectively. We validated the utility of these signatures to separately purify microglia and bone-marrow macrophages prospectively from human gliomas. We compared the relative abundances of bone-marrow macrophages and CNS-resident microglia across glioma grades and subtypes. We find an increased infiltration of CNS-resident microglia in astrocytomas, compared to oligodendrogliomas or glioblastomas. By contrast, we find increased infiltration of bone-marrow derived macrophages in glioblastomas, particularly in the perivascular space and in necrotic regions. We compiled a comprehensive atlas of cell-surface receptors expressed by neoplastic cells and cognate ligands/agonists expressed by macrophages, based on our single-cell data. We found that glioma-infiltrating macrophages of bone-marrow origin more frequently expressed genes implicated in immunosuppression (e.g. IL10, DD1α) and tumor proliferation (e.g. OSM, WNT5A), when compared to CNS-resident microglia. We found that OSM and WNT5A enhance glioma proliferation in vitro.
A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia
Authors: Daniel J. DeAngelo, Andrew M. Brunner, Lillian Werner, David Avigan, Amir T. Fathi, Adam S. Sperling, Abigail Washington, Dina Stroopinsky, Jacalyn Rosenblatt, Malgorzata McMasters, Katarina Luptakova, Martha Wadleigh, David P. Steensma, Gabriela S. Hobbs, Eyal C. Attar, Philip C. Amrein, Benjamin L. Ebert, Richard M. Stone, Karen K. Ballen
Journal: American Journal of Hematology (2017)

Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose-escalation study. We enrolled 35 patients using a "3 + 3" design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD). Lenalidomide was initially given days 1-14 and MEC days 4-8; due to delayed count recovery, the protocol was amended to administer lenalidomide days 1-10. The dose of lenalidomide was then escalated starting at 5 mg/d (5-10-25-50). The primary objective was tolerability and MTD determination, with secondary outcomes including overall survival (OS). The MTD of lenalidomide combined with MEC was 50 mg/d days 1-10. Among the 35 enrolled patients, 12 achieved complete remission (CR) (34%, 90%CI 21-50%); 30-day mortality was 6% and 60-day mortality 13%. The median OS for all patients was 11.5 months. Among 17 patients treated at the MTD, 7 attained CR (41%); the median OS was not reached while 12-month OS was 61%. Following therapy with MEC and lenalidomide, patient CD4+ and CD8+ T-cells demonstrated increased inflammatory responses to autologous tumor lysate. The combination of MEC and lenalidomide is tolerable with an RP2D of lenalidomide 50 mg/d days 1-10, yielding encouraging response rates. Further studies are planned to explore the potential immunomodulatory effect of lenalidomide and MEC.
RARE-22. SINGLE-AGENT DABRAFENIB FOR INTRACRANIAL BRAFV600E-MUTATED HISTIOCYTOSIS
Authors: Ankush Bhatia, Gary Ulaner, Raajit Rampal, David Hyman, Omar Abdel-Wahab, Benjamin Durham, Julio Hajdenberg, Chezi Ganzel, Eli Diamond
Journal: Neuro-Oncology (2017)

Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and a mixed ECD/LCH phenotype are histiocytic neoplasms harboring BRAFV600E mutations in half or more cases. Intracranial manifestations of these diseases are refractory to conventional treatments and associated with morbidity and mortality. Studies have demonstrated that BRAFV600E-mutated ECD/LCH can be treated with vemurafenib with robust responses although treatment can be limited by toxicities or intolerance. The use of dabrafenib, an alternative BRAF inhibitor, has not been studied for the treatment of ECD and/or LCH. Also, there have been no attempts at treatment with dabrafenib in the setting of vemurafenib intolerance. We retrospectively analyzed 9 patients with BRAFV600E-mutated ECD or ECD/LCH, 7 with involvement of the cerebral hemispheres, posterior fossa, dura, or skullbase treated with dabrafenib. Patients were treated as (1) initial therapy, (2) following failure of chemotherapy or radiation, or (3) following discontinuation of vemurafenib because of toxicity or intolerance. Of the 9 patients, 6 had ECD and 3 had overlap ECD/LCH. 4 patients treated with dabrafenib as initial targeted therapy all had a clinical response, and 3 of 4 had a metabolic response by FDG-PET and/or resolution of cranial lesions by MRI. 5 patients initially treated with vemurafenib changed treatment to dabrafenib for toxicity or intolerance. 2 of these 5 patients with intracranial disease relapsed following cessation of vemurafenib and both recaptured a response with dabrafenib. The remaining 3 of 5 maintained their response to vemurafenib although 2 subsequently stopped treatment for intolerance. Here, we report outcomes of treatment with single-agent dabrafenib for ECD or ECD/LCH harboring the BRAFV600E mutation for which treatment induced or maintained a response in all intracranial lesions. Dabrafenib monotherapy can be considered as initial treatment for BRAFV600E-mutated intracranial histiocytosis or in the setting of vemurafenib intolerance.
P3.14-005 Treatment Response Measured on Cone Beam-CT During Concurrent Chemoradiation for NSCLC Patients
Authors: M. Kwint, B. Stam, M. Rossi, S. Burgers, E. Aalbersberg, J. Sonke, J. Belderbos, I. Walraven
Journal: Journal of Thoracic Oncology (2017)
PATH-31. ELEVATION OF YKL-40, NORMALIZED TO CERULOPLASMIN, IN CEREBROSPINAL FLUID IS ASSOCIATED WITH GLIOBLASTOMA RECURRENCE
Authors: Guangrong Lu, Ping Zhu, Rong Shao, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2017)

BACKGROUND: Depatuxizumab mafodotin (depatux-m, formerly , is an EGFR-targeted antibody conjugated to the antimicrotubule agent monomethylauristatin F (MMAF).In an ongoing Phase I study, response in recurrent glioblastoma (rGBM) correlated with EGFR amplification in pre-treatment, archival tumor tissue.However, the correlation with efficacy is imperfect, prompting a search for other biomarkers that predict benefit or resistance, including attention to mutations that could impact sensitivity to the microtubule inhibitor of the depatux-m molecule.METHODS: EGFR amplification was determined by fluorescence in situ hybridization (FISH) analysis; EGFR and EGFRvIII expression were determined by qRT-PCR.Complete transcriptome sequencing (RNAseq) and whole exome sequencing were performed on each tumor.CD3 protein expression was determined by immunohistochemistry.All testing was performed on archival tumor tissue.RESULTS: Mutations in several genes that could affect sensitivity to microtubule inhibitors were preferentially detected in the biopsies of responders to depatux-m.Knockdown of these genes by siRNA increased sensitivity of cell lines to depatux-m and a related microtubule inhibitor, monomethyl auristatin E (MMAE).RNAseq results demonstrated that genes associated with T cell immunity were more highly expressed in responders, and these tumors had increased T cell infiltrates as determined by CD3 immunohistochemistry. CONCLUSIONS: EGFR amplification is an important but imperfect predictor of response to depatux-m.Genomic profiling suggests mutations in certain genes, and T cell infiltrates, may associate with outcome but requires further study.Collectively, these data may be used to support rational drug combination therapy to increase efficacy of depatux-m.
P2.07-058 First-In-Human Study of JNJ-64041757, a Live Attenuated Listeria Monocytogenes Immunotherapy, for Non-Small Cell Lung Cancer
Authors: J. Brahmer, M. Johnson, M. Awad, A. Rajan, A. Allred, R. Knoblauch, E. Zudaire, M. Lorenzi, R. Hassan
Journal: Journal of Thoracic Oncology (2017)
PDTM-46. TARGETING METABOLIC ADAPTATION IN MYC DRIVEN PEDIATRIC NEURONAL TUMORS
Authors: Alberto Delaidelli, Gian Luca Negri, Asad Jan, Brandon Jansonius, Jonathan K M Lim, Gabriel Leprivier, Marcel Kool, Stefan M Pfister, Marc Remke, Michael Taylor, John M Maris, Poul H Sorensen
Journal: Neuro-Oncology (2017)

MYC family proteins are implicated in many human cancers, but their therapeutic targeting has proven challenging. MYCN and c-MYC amplification in childhood neuroblastoma (NB) and medulloblastoma (MB) are associated with aggressive disease and high mortality. Novel and effective therapeutic strategies are therefore urgently needed for these tumors. MYC-driven oncogenic transformation impairs cell survival under nutrient deprivation (ND), a characteristic stress condition within the tumor microenvironment. We recently identified eukaryotic Elongation Factor 2 Kinase (eEF2K) as a pivotal mediator of the adaptive response of tumor cells to ND. We therefore hypothesized that eEF2K facilitates the adaptation of MYCN/MYC amplified NB/MB to ND, and that inhibiting this pathway can impair tumor progression. To test our hypothesis, we first analyzed publicly available genomic databases and tissue microarrays for eEF2K expression in NB and MB, and for links between eEF2K, MYCN/MYC, and clinical outcome. Effects of eEF2K inhibition were evaluated on survival of MYCN/MYC amplified versus non-amplified NB/MB cell lines under ND. Finally, NB xenograft mouse models were used to confirm in vitro observations. Our results indicate that high eEF2K expression and activity are strongly predictive of poor outcome in NB and MB (p<0.001), and correlate significantly with MYCN/MYC amplification (p<0.001). Inhibition of eEF2K significantly decreases survival of MYCN/MYC amplified NB/MB cell lines in vitro under ND. Knockdown of eEF2K under caloric restriction determines a twofold growth decrease of MYCN amplified NB xenografts. eEF2K represents a critical mediator for the adaptive response of MYCN/MYC amplified NB and MB to acute metabolic stress, and is therefore a promising therapeutic target. Future therapeutic studies will aim to combine eEF2K pharmacological inhibition with caloric restriction mimetics such as metformin or glycolysis inhibitors, as eEF2K activity appears to be critical under metabolic stress conditions.
Arterially directed embolic therapy (ADET) with polyethylene glycol microspheres loaded with irinotecan for refractory liver metastases from colorectal cancer
Authors: G. Fiorentini, D. Sarti, R. Carandina, M. Nardella, L. Mulazzani, D. Barnes Navarro, F. Mugnos Gomez, O. Zoras, C. Aliberti
Journal: Annals of Oncology (2017)
Surveillance des salmonelles : les acquis et les nouveaux objectifs
Authors: W van Pelt
Journal: Eurosurveillance (1999)

Ce numero special d’Eurosurveillance traite des progres du reseau Enter-Net pour la surveillance et le controle des epidemies d’infections a salmonelles en Europe. Le reseau a etabli une base de donnees internationale, mise a jour regulierement, et une collaboration entre experts qui ont permis le succes de plusieurs actions de sante publique en Europe . L’article sur la multiresistance de Salmonella typhimurium en Republique Tcheque illustre l’interet de l’extension recente des activites du reseau a la surveillance de la resistance antimicrobienne des salmonelles et de son ouverture a d’autres pays europeens. L’article sur les bases pratiques des investigations d’intoxications alimentaires internationales, dont l’objectif est d’ameliorer l’efficacite des enquetes sur le vehicule et la source de la contamination, est le fruit de l’experience acquise par les participants d’Enter-net.