tbuckley/cabot-search huggingface dataset:
ACTR-79. ESTABLISHMENT OF CLINICAL PROTOCOL TARGETING CANCER STEM CELLS IN RECURRENT GLIOBLASTOMA USING HIGH-THROUGHPUT DRUG SCREENING
Authors: Erlend Skaga, Evgeny Kulesskiy, Marit Brynjulfsen, Cecilie Jonsgar Sandberg, Aija Kyttälä, Iver Arne Langmoen, Aki Laakso, Emília Gaál-Paavola, Markus Perola, Krister Wennerberg, Einar Osland Vik-Mo
Journal: Neuro-Oncology (2017)

Despite aggressive multimodal oncological treatment, glioblastoma (GBM) disease progresses within 10 months. Due to the lack of treatment options for the relapsed disease, enrollment in clinical trials may be the best option. However, the fundamental preclinical studies leading to clinical investigation are primarily conducted using biological material from primary GBM, thus inadequately reflecting the biology of the recurrent disease. As only a minority of relapsed patients undergoes secondary surgery, little data exists of cancer stem cell (CSC) biology in recurrent GBM (recGBM). The purpose of the study was to establish a clinical protocol targeting patient-specific CSCs in recGBM for individualized therapy. We aimed to establish patient-specific cell cultures yielding >107 cells within 6 weeks following surgery to enable high-throughput drug sensitivity and resistance testing (DSRT) to guide individualized therapy decisions before evidence of further progression. Tumor biopsy from ten patients operated for recGBM were cultured under serum-free, growth factor-enriched conditions. Cultures were evaluated by (i) cell yield and (ii) stem cell properties by assays of self-renewal capacity, expression of stem cell markers, lineage-specific differentiation and in vivo tumor formation. We found that 5/10 recGBM cultures reached the pre-determined cell yield counted in two independent laboratories. Additionally, 2/10 samples formed tumorspheres, but did not generate sufficient cell numbers. Stem cell properties were confirmed by functional assays. The five cultures yielding >107 cells were evaluated for DSRT measuring cell viability and cytotoxicity to >520 FDA-approved and investigational oncological drugs, representing multiple classes of targeted therapies and conventional chemotherapeutics. In the majority of samples from recGBM, patient-specific tumorsphere cultures enriched for CSCs can be established and propagated in serial passages. In the subset of patients to reach 107 cells we completed DSRT, allowing for an individualized evaluation of drug responses to be used in clinical decision-making and patient treatment.
IMMU-50. A NOVEL CHIMERIC MODEL TO ACCURATELY IDENTIFY TAMMs IN GLIOBLASTOMA
Authors: Amir Saam Youshani, Kenny Yu, Fiona Wilkinson, Claire O’Leary, Peter Cook, Aiyin Liao, Omar Pathmanaban, Christopher Waugh, Hannah Shorrock, Andrew MacDonald, Federico Roncaroli, Ian Kamaly-Asl, Brian Bigger
Journal: Neuro-Oncology (2017)

Glioblastoma is the most aggressive primary brain cancer with poor survival, but treatment strategies to improve prognosis have failed to materialise in over 30-years. Immune cells, in particular Tumour associated macrophages and microglia (TAMM) populate up to 40% of tumour bulk and are potential immunotherapy targets. However, functional roles of TAMM subpopulations still remain elusive and contradictory, due to limitations of existing mouse models and non-specific cell-surface markers used in human and rodent studies. To address these issues, we developed non-myeloablative chemotherapy conditioning regimen to transplant host mice expressing pan-leukocyte epitope CD45.1 with haematopoietic donor cells expressing congenic CD45.2, whilst retaining an intact recipient blood-brain barrier. Once 90% bone marrow chimerism was achieved at 12 weeks, we intracranially implanted GL261 murine glioblastoma cells into chimeric mice, recapitulating normal tumour development. Chimerism was used to overcome the bias of cell surface markers and reliably determine the origin of TAMM subpopulations. Immunofluorescence and multicolour hemisphere flow cytometry was used to accurately distinguish between peripheral macrophages and microglia. We show not only TAMMs, but multiple immune populations migrating to tumours and highlight marker sets such as CD11b/CD45 and Siglec-H/CX3CR1 ordinarily used to distinguish between microglia and macrophages to have significant co-staining from other leukocyte populations. Furthermore, TAMM microglia and macrophages are morphologically indistinguishable. To solve this problem, we identify a novel 4-marker set that separates TAMM into four subpopulations with ≥ 90% donor/recipient chimerism purity and succinctly illustrate the peripheral monocyte-macrophage differentiation axis. Overall, we have developed a novel chimeric model that preserves homeostatic brain microenvironment and achieves superior chimerism levels. Our results also emphasise a new 4-marker approach to subcategorising TAMM in glioblastoma. Applying this marker set for RNA sequencing of TAMM subpopulations and translating markers to human specimens will validate findings from an experimental glioblastoma model.
Mutational status and metastatic patteRn in a cohort Of ADvanced colorectal cancer patients: the ROAD study
Authors: E. Ongaro, G. De Maglio, L. Gerratana, M. Bonotto, S.K. Garattini, D. Basile, M. Cattaneo, V.J. Andreotti, F. Cortiula, A. Parnofiello, V. Fanotto, S. Pizzolitto, G.G. Cardellino, M. Casagrande, P. Ermacora, M. Giovannoni, D. Iacono, F. Puglisi, G. Aprile, N. Pella, G. Fasola
Journal: Annals of Oncology (2017)
P2.13-014 Computed Tomography-Based Radiomic Classifier Distinguishes Malignant from Benign Pulmonary Nodules in the National Lung Screening Trial
Authors: T. Peikert, F. Duan, S. Rajagopalan, R. Karwoski, Z. Qin, J. Sicks, R. Clay, R. Robb, B. Bartholmai, F. Maldonado
Journal: Journal of Thoracic Oncology (2017)
METB-03. AN INTEGRATED MULTI-OMICS APPROACH IDENTIFIES GENE-METABOLITE ASSOCIATIONS WITHIN THE INVASIVE REGION OF HIGH-GRADE GLIOMAS
Authors: James Wood, Dong-Hyun Kim, Stuart Smith, Anbarasu Lourdusamy, Marcos Castellanos-Uribe, Sean May, David Barrett, Richard Grundy, Ruman Rahman
Journal: Neuro-Oncology (2017)

High-grade glioma (HGG) cells invade brain parenchyma or migrate along existing brain structures including blood vessels and white matter tracts. Understanding the genetics and metabolism of HGG cells that have escaped maximal surgical resection remains a bottleneck to improved patient outcomes. Here, we report an integrated multi-omics approach to decipher a gene expression and metabolite profile associated with the invasive region of HGGs. Multi-region sampling was performed on five HGG patients during maximal surgical resection. The purported invasive region was identified based on adjacent white matter tract anatomy. Gene expression analysis and metabolite profiling was conducted using Affymetrix arrays and liquid chromatography-mass spectrometry, respectively. Linear modelling was applied to identify differentially expressed genes and metabolites between regions with gene-metabolite associations determined through canonical correlation analysis. Distinct gene expression profiles were observed for regions within individual tumours in line with intra-tumour heterogeneity of HGGs. The comparison of invasive region with other regions revealed 86 highly expressed genes (p-value FDR-corrected <0.05) with enrichment of biological processes such as myelination (KLK6 and MAL) and cell adhesion (CNTNAP4, CTNNA3, and HAPLN2). Metabolite profiling and class discrimination using OPLS-DA showed clear separation of invasive region that was significantly enriched for purine and pyrimidine metabolism. Correlation analysis of gene-metabolite associations with 88 differentially abundant metabolites identified creatinine with the strongest association with highly expressed genes. Knowledge of the genetic and metabolic drivers of HGG cells within the invasive region at the edge of surgical resection is therapeutically pertinent. We identify a distinct genetic and metabolic invasive region profile characterised by myelination and cell adhesion genes and purine and pyrimidine metabolism. Gene-metabolite correlation analysis highlights creatinine for further functional study. We provide proof-of-principle for integrated multi-omics approaches utilising invasive region tissue to identify biomarkers and targets for therapeutic evaluation.
MA 13.03 Quantitative Spatial Profiling of PD-1/PD-L1 Interaction Predicts Response to Adjuvant Chemotherapy Non–Small-Cell Lung Cancer
Authors: V. Velcheti, J. Bordeaux, N. Dakappagari, N. Pennell, J. Stevenson, M. Khunger, J. Kim, K. Schalper, D. Rimm
Journal: Journal of Thoracic Oncology (2017)
IMMU-26. TLR7 ACTIVATION IS ESSENTIAL FOR NK CELLS TO ELIMINATE GLIOMA TUMORS
Authors: Diana Shah, Padma Kadiyala, Neha Kamran, Gregory J Baker, Robert Doherty, Dan Zamler, Gabriel Nuñez, Maria G Castro, Pedro R Lowenstein
Journal: Neuro-Oncology (2017)

Our laboratory focuses on understanding anti-glioma immune responses and uses this information to develop new immunotherapies. Endogenous anti-glioma immune responses fail to control the disease due to the development of immune inhibitory mechanisms by glioma tumors. We developed an immune- and gene therapy for active immunization, based on Thymidine Kinase and Flt3L that stimulates a systemic adaptive immune response. This is now in a Phase I Clinical Trial (# NCT01811992). We have previously demonstrated that NK cells and myeloid cells mediate glioma rejection and identified galectin-1 expression as a mechanism of innate immune inhibition. To determine the underlying signaling pathways, we analyzed growth of intracranial NK-sensitive tumors in transgenic mice and in mice treated with blocking/depleting antibodies. We identified TLR7-MyD88 signaling as a key component for glioma rejection. Since IFN α/β is a major cytokine produced upon TLR7 activation, we blocked the IFN α/β receptor, which resulted in increased tumor growth. To determine the signaling pathway leading to TLR7-induced IFN α/β production, we analyzed tumor growth in mice lacking IFN α/β-regulating transcription factors IRF5 or IRF7. Our data indicate a major role for IRF5 and a minor role for IRF7. TLR7 expression and IFN α/β secretion are characteristic for pDCs. Depletion of pDCs suggested only a minor role for pDCs in the innate anti-glioma immune response. We propose a model of an innate anti-glioma immune circuit in which a tumor cell-derived TLR7 ligand activates myeloid cells, including pDCs. TLR7 activation results in IRF5/IRF7-mediated secretion of IFN α/β which in turn promotes glioma rejection by NK cells. Given the major role of TLR7 signaling in glioma rejection, therapeutic TLR7 stimulation could help eliminate GBM by bypassing the innate immune inhibition of glioma. Further characterization of this innate anti-glioma immune circuit will allow us to identify potential therapeutic targets.
P1.12-003 Photothermal Ablation of Lung Cancer by Low Power Near-Infrared Laser and Topical Injection of Indocyanine Green; A Preliminary Animal Study
Authors: K. Hirohashi, T. Anayama, H. Wada, T. Kato, K. Orihashi, K. Yasufuku
Journal: Journal of Thoracic Oncology (2017)
P3.02-055 Detecting ALK, ROS1 and RET Gene Translocations in Non-Small Cell Lung Cancer (NSCLC) with the NanoString Platform
Authors: H. Wang, A. Rijk, M. Aguirre, A. Wang, K. Wang, Z. Dastani, J. Agulnik, V. Cohen, D. Small, C. Pepe, L. Sakr, G. Kasymjanova, L. Van Kempen, A. Spatz
Journal: Journal of Thoracic Oncology (2017)
GENE-51. DNA DEMETHYLATION ARE LINKED WITH HIGH EXPRESSION OF STEM CELL-MARKERS IN DIFFUSE GLIOMAS
Authors: Yasuo Iwadate, Tomoo Matsutani
Journal: Neuro-Oncology (2017)

Demethylation of genomic DNA is a background of stem cell properties and contributes to the treatment resistance in diffuse gliomas. This study was designed to examine the correlation of the DNA methylation status and the expression of the stem cell genes with special reference to the isocitrate dehydrogenase-1 (IDH1) mutation and co-deletion of chromosome 1p/19q (1p/19q codel). Human diffuse glioma 148 cases were included in the study: oligodendroglioma WHO grade II 25 cases, anaplastic oligodendroglioma WHO grade III 35 cases, astrocytic tumors (DA/AA) 18 cases, and glioblastoma 70 cases. Immunohistochemical analyses of the stem cell markers including alkaline phosphatase (AP), CD133, and CD44 were performed. For representative cases, a comprehensive analysis of DNA methylation status using the HumanMethylation450 BeadChips was carried out to know its correlation with the expression of stem cell marker genes. Their correlation with the diagnostic hallmark such as IDH1 mutation, 1p/19q codel, and MGMT promoter methylation were also analyzed. Oligodendrogliomas had hypermethylated genomic DNA compared with DA/AA or GBM, and was accompanied by decreased expression of the stem cell marker genes irrespective of 1p/19q status or the histological grade. In contrast, DA/AA had hypomethylated DNA in the cases with wild–type IDH gene, and were accompanied with higher expression of stem cell genes and shorter survivals. The DNA methylation status of MGMT gene were well correlated with global genomic methylation status. These results show that oligodendroglioma without 1p/19q codeletion are actually exists which are definitely different from DA. Global DNA methylation status may contribute to a more accurate classification of diffuse gliomas.
Un Programa Nacional de formación en epidemiología de campo dio comienzo en Francia
Authors: B Helynck
Journal: Eurosurveillance (2002)

La formacion en epidemiologia de campo y la evaluacion de riesgos sanitarios es un elemento vital para la red de colaboradores del InVS (organismos, agencias e instituciones estatales). Las personas que trabajan en la vigilancia sanitaria necesitan de una cultura en comun y de unos patrones de intervencion coherentes que optimicen el rendimiento de los mecanismos de vigilancia y respuesta. Por este motivo, el InVS y la Escuela Nacional de Sanidad (Ecole Nationale de la Sante Publique; ENSP) trabajan desde hace varios anos en la elaboracion conjunta de un programa nacional de formacion.
P3.01-038 Impact on OS and PFS of 2nd and 3rd Generation TKI in EGFR Mt+ and ALK+ Patients: Results of the NOWEL Network
Authors: J. Roeper, M. Netchaeva, A. Lueers, C. Hallas, M. Falk, M. Tiemann, N. Neemann, L. Heukamp, C. Wesseler, G. Wiest, S. Sackmann, D. Ukena, F. Griesinger
Journal: Journal of Thoracic Oncology (2017)
JK226, a novel potential antitumor natural compound from the mushroom albatrellus confluens, inhibits tumor cells growth and induces apoptosis by targeting signal transduction pathways
Authors: Deven S. Dandekar, Bal L. Lokeshwar
Journal: Cancer Research (2005)

3076  Over the past several years, the concept of targeted biological therapy for the treatement of cancer had emerged. Numberous molecular targets of mechanism-based anticancer drugs have been identified. Altough some of them are etiologic to cancer, studies into the molecular mechanisms of cancer have revealed that, with a few exceptions, they are not cancer-specific. Besides, cancer cells usually acquire multiple genetic alterations. Parallel and redundant signaling pathways can support survival and growth of cancer cells. One promising therapeutic strategy for treating cancer is to specifically target signal transduction pathways that have a key role in oncogenic transformation and malignant progression. Therefore, an agent capable of affecting multiple targets in signal transduction pathways is considered to have great potential as antitumor agents. JK226 is a natural biologically active substance isolated from the fresh fruiting bodies of the mushroom Albarellus confluen, which has show various pharmacological and microbiological effects with limited or no toxicity. In previous experiments, we had found a novel activity of JK226, namely its ability to inhibit the growth of tumor cells by induction of apoptosis. To gain an insight into the moleular events of signal transducion pathways affected by JK226, cDNA expression microarray technology was employed. Twelve genes with a 2- to 5-fold relative expression difference were identified when nasopharyngeal carcinoma cell line CNE1 was treated with JK226 as compared with the non-treated group. Interestingly, a strong downregulation of mapkkk3, mapkk1 and mapkk5 were found. It shows the inhibition of members of MAPK signal transduction pathways as a key event mediating activity of JK226 in CNE1 cells. MAPKKK3, MAPKK1 and MAPKK5 are involved in ERK1/2 signal transduction pathway. Further, we found the phosphorylation of ERK1/2 was decreased in a dose-dependent manner after JK226 treatment by western blotting. Activated ERK is able to translocate to the nucleus where it phosphorylates a number of transcription factors regulating gene expression. We then examined the pathway downstream of ERK activation by employing the Mercury Pathway Profiling System (Clontech). The reults show that the transcriptional activation of CREB, NFκB, AP-1, SRF and c-Myc were markedly inhibited in a dose-dependent manner afte JK226 treatment. These findings suggest that JK226 inhibits growth and induce apoptosis in cancer cells by probably interfering with multiple targets in ERK1/2 signal transdcution pathway. Therefore, We believe JK226 may have the great poteintial to be developed into a novel anticancer agent with the further eluciation of molecular targets in signal transduction pathways affected by JK226. Key words: antitumor, signal transduction pathway, molecular targets
Obstructive Sleep Apnea during REM Sleep and Cardiovascular Disease
Authors: R. Nisha Aurora, Ciprian Crainiceanu, Daniel J. Gottlieb, Ji Soo Kim, Naresh M. Punjabi
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Obstructive sleep apnea (OSA) during REM sleep is a common disorder. Data on whether OSA that occurs predominantly during REM sleep is associated with health outcomes are limited.The present study examined the association between OSA during REM sleep and a composite cardiovascular endpoint in a community sample with and without prevalent cardiovascular disease.Full-montage home polysomnography was conducted as part of the Sleep Heart Health Study. The study cohort was followed for an average of 9.5 years, during which time cardiovascular events were assessed. Only participants with a non-REM apnea-hypopnea index (AHI) of less than 5 events/h were included. A composite cardiovascular endpoint was determined as the occurrence of nonfatal or fatal events, including myocardial infarction, coronary artery revascularization, congestive heart failure, and stroke. Proportional hazards regression was used to derive the adjusted hazards ratios for the composite cardiovascular endpoint.The sample consisted of 3,265 subjects with a non-REM AHI of less than 5.0 events/h. Using a REM AHI of less than 5.0 events/h as the reference group (n = 1,758), the adjusted hazards ratios for the composite cardiovascular endpoint in those with severe REM OSA (≥30 events/h; n = 180) was 1.35 (95% confidence interval, 0.98-1.85). Stratified analyses demonstrated that the association was most notable in those with prevalent cardiovascular disease and severe OSA during REM sleep with an adjusted hazards ratio of 2.56 (95% confidence interval, 1.46-4.47).Severe OSA that occurs primarily during REM sleep is associated with higher incidence of a composite cardiovascular endpoint, but in only those with prevalent cardiovascular disease.
Influenza burden, prevention, and treatment in asthma‐A scoping review by the <scp>EAACI</scp> Influenza in asthma task force
Authors: J. Schwarze, P. Openshaw, A. Jha, S. R. del Giacco, D. Firinu, O. Tsilochristou, G. Roberts, A. Selby, C. Akdis, I. Agache, A. Custovic, E. Heffler, G. Pinna, M. Khaitov, A. Nikonova, N. Papadopoulos, A. Akhlaq, U. Nurmatov, H. Renz, A. Sheikh, C. Skevaki
Journal: Allergy (2017)

Abstract To address uncertainties in the prevention and management of influenza in people with asthma, we performed a scoping review of the published literature on influenza burden; current vaccine recommendations; vaccination coverage; immunogenicity, efficacy, effectiveness, and safety of influenza vaccines; and the benefits of antiviral drugs in people with asthma. We found significant variation in the reported rates of influenza detection in individuals with acute asthma exacerbations making it unclear to what degree influenza causes exacerbations of underlying asthma. The strongest evidence of an association was seen in studies of children. Countries in the European Union currently recommend influenza vaccination of adults with asthma; however, coverage varied between regions. Coverage was lower among children with asthma. Limited data suggest that good seroprotection and seroconversion can be achieved in both children and adults with asthma and that vaccination confers a degree of protection against influenza illness and asthma‐related morbidity to children with asthma. There were insufficient data to determine efficacy in adults. Overall, influenza vaccines appeared to be safe for people with asthma. We identify knowledge gaps and make recommendations on future research needs in relation to influenza in patients with asthma.
Guidelines on the management of abnormal liver blood tests
Authors: Philip N Newsome, Rob Cramb, Suzanne M Davison, John F Dillon, Mark Foulerton, Edmund M Godfrey, Richard Hall, Ulrike Harrower, Mark Hudson, Andrew Langford, Anne Mackie, Robert Mitchell-Thain, Karen Sennett, Nicholas C Sheron, Julia Verne, Martine Walmsley, Andrew Yeoman
Journal: Gut (2017)

These updated guidelines on the management of abnormal liver blood tests have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines, which this document supersedes, were written in 2000 and have undergone extensive revision by members of the Guidelines Development Group (GDG). The GDG comprises representatives from patient/carer groups (British Liver Trust, Liver4life, PBC Foundation and PSC Support), elected members of the BSG liver section (including representatives from Scotland and Wales), British Association for the Study of the Liver (BASL), Specialist Advisory Committee in Clinical Biochemistry/Royal College of Pathology and Association for Clinical Biochemistry, British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), Public Health England (implementation and screening), Royal College of General Practice, British Society of Gastrointestinal and Abdominal Radiologists (BSGAR) and Society of Acute Medicine. The quality of evidence and grading of recommendations was appraised using the AGREE II tool. These guidelines deal specifically with the management of abnormal liver blood tests in children and adults in both primary and secondary care under the following subheadings: (1) What constitutes an abnormal liver blood test? (2) What constitutes a standard liver blood test panel? (3) When should liver blood tests be checked? (4) Does the extent and duration of abnormal liver blood tests determine subsequent investigation? (5) Response to abnormal liver blood tests. They are not designed to deal with the management of the underlying liver disease.
P2.03-036 Comparing the Efficacy/Toxicity of Osimertinib and First Line EGFR-TKI by Individual Patient Analysis
Authors: S. Narita, Y. Goto, J. Sato, R. Morita, S. Murakami, S. Kanda, H. Horinouchi, Y. Fujiwara, N. Yamamoto, Y. Ohe
Journal: Journal of Thoracic Oncology (2017)
P1.03-044 Exploratory Analysis of Lung Cancer Patients in a Phase Ib/II Trial of NC-6004 (Nanoparticle Cisplatin) plus Gemcitabine
Authors: L. Bazhenova, R. Tran, J. Grilley-Olson, N. Sharma, A. Combest, I. Bobe, A. Osada, K. Takahasi, J. Balkissoon, A. Camp, A. Masada, D. Reitsma, V. Subbiah
Journal: Journal of Thoracic Oncology (2017)