tbuckley/cabot-search huggingface dataset:
DRES-08. A NOVEL XENOGRAFT MODEL REVEALS A GENE CASCADE AND SERUM BIOMARKER DEFINING A MESENCHYMAL TRANSITION DURING THE EVOLUTION OF GLIOBLASTOMA RESISTANCE TO ANTI-ANGIOGENIC THERAPY
Authors: Arman Jahangiri, William Chen, Alan Nguyen, Jonathan Rick, Ruby Kuang, Maxim Sidorov, Patrick M Flanigan, Jeffrey R Wagner, W Shawn Carbonell, Garima Yagnik, Manish K Aghi
Journal: Neuro-Oncology (2017)

Bevacizumab treatment of glioblastoma is limited by transient response and acquired resistance. To study transcriptional changes underlying the evolution of bevacizumab resistance and identify resistance biomarkers, we created a novel multigenerational xenograft model of acquired bevacizumab resistance and performed microarray gene expression analysis on it. Subcutaneous glioblastoma xenografts were treated with bevacizumab, and the fastest growing tumor reimplanted into new mice, generating paired isogeneic responsive/resistant multigenerational xenografts. Human microarray analysis was performed on generation 1, 4 and 9 tumors. Utilizing a two-component normal mixture model, we identified genes exhibiting significant inter-generational variance between resistant versus responsive xenografts. Protein-protein interaction scores among these genes extracted from String 10 database were used as undirected edge weights in a network representation of significant genes. Gene set over-representation (GSO) analysis via ConsensusPathDB identified meaningful clusters and subnetworks mediating distinct pathways. Gene set enrichment analysis revealed overexpression across generations of mesenchymal subtype and metabolic gene signatures, peaking by generation four. Mesenchymal markers CD44, NT5E, SNAI2, and ZEB2 and pro-angiogenic genes FGF2, MMP1, HIF1A, UGCG, LPAR1, and ITGB3 were upregulated across generations. GSO identified angiogenesis as a significantly enriched ontology within the inflammatory response and ECM remodeling subnetworks identified by spectral clustering. Upregulated angiogenesis-related genes identified via GSO included inflammatory (COX2, IL6, IL1A) and angiogenic (TGFA, WNT5A, FGF2) factors. Array analysis revealed 3 secreted genes whose expression increased with each generation (FGF2, GREM1, CHI3L1), with CHI3L1 elevated in serum of patients with bevacizumab-resistant vs. bevacizumab-naïve glioblastomas (52.4 vs. 24.2 ng/mL). Bevacizumab resistance involves a mesenchymal and pro-angiogenic response supported by converging pathways involving inflammation, hypoxia, and ECM remodeling. Besides suggesting novel targets for preventing the evolution of resistance and offering a xenograft model for testing resistance inhibitors, our work reveals CHI3L1 as a blood biomarker of bevacizumab resistance worthy of further evaluation.
P1.04-011 Development of Novel Blood-Based Biomarker Assays in 1L Advanced/Metastatic NSCLC: Blood First Assay Screening Trial (BFAST)
Authors: T. Mok, R. Dziadziuszko, S. Peters, X. He, T. Riehl, E. Schleifman, S. Paul, S. Mocci, D. Shames, M. Mathisen, S. Gadgeel
Journal: Journal of Thoracic Oncology (2017)
P1.01-042 Dynamic ctDNA Assay by Next Generation Sequencing to Guide Targeted Therapy in Advanced Non-Small Cell Lung Cancer
Authors: D. Liu, H. Hou, N. Zhou, M. Jiang, J. Cong, C. Zhang, T. Li, H. Lv, J. Zhu, C. Hao, K. Liu, X. Zhang
Journal: Journal of Thoracic Oncology (2017)
Biomonitoring for traditional herbal medicinal products using DNA metabarcoding and single molecule, real-time sequencing
Authors: Tianyi Xin, Zhichao Xu, Jing Jia, Christine Leon, Songnian Hu, Yulin Lin, Subramanyam Ragupathy, Jingyuan Song, Steven G. Newmaster
Journal: Acta Pharmaceutica Sinica B (2017)

Global concerns have been paid to the potential hazard of traditional herbal medicinal products (THMPs). Substandard and counterfeit THMPs, including traditional Chinese patent medicine, health foods, dietary supplements, etc. are potential threats to public health. Recent marketplace studies using DNA barcoding have determined that the current quality control methods are not sufficient for ensuring the presence of authentic herbal ingredients and detection of contaminants/adulterants. An efficient biomonitoring method for THMPs is of great needed. Herein, metabarcoding and single-molecule, real-time (SMRT) sequencing were used to detect the multiple ingredients in Jiuwei Qianghuo Wan (JWQHW), a classical herbal prescription widely used in China for the last 800 years. Reference experimental mixtures and commercial JWQHW products from the marketplace were used to confirm the method. Successful SMRT sequencing results recovered 5416 and 4342 circular-consensus sequencing (CCS) reads belonging to the ITS2 and psbA-trnH regions. The results suggest that with the combination of metabarcoding and SMRT sequencing, it is repeatable, reliable, and sensitive enough to detect species in the THMPs, and the error in SMRT sequencing did not affect the ability to identify multiple prescribed species and several adulterants/contaminants. It has the potential for becoming a valuable tool for the biomonitoring of multi-ingredient THMPs. In this paper, metabarcoding and single-molecule, real-time (SMRT) sequencing were used to detect the multiple ingredients in Jiuwei Qianghuo Wan (JWQHW), a classical herbal prescription widely used in China for the last 800 years. Successful SMRT sequencing results recovered 5416 and 4342 circular-consensus sequencing (CCS) reads belonging to the ITS2 and psbA-trnH regions, suggesting the combination of metabarcoding and SMRT sequencing is a valuable tool for the biomonitoring of multi-ingredient THMPs.
Abstract MP60: Coronary Artery Calcium and Dementia Risk in the Multi-Ethnic Study of Atherosclerosis
Authors: Akira Fujiyoshi, David R Jacobs, Annette L Fitzpatrick, Alvaro Alonso, Daniel A Duprez, A. Richey Sharrett, Michael J Blaha, José A Luchsinger, Stephen R Rapp, Teresa Seeman
Journal: Circulation (2016)

Introduction: Vascular risk factors (VRFs) predict incident dementia. Coronary artery calcium (CAC), capturing cumulative VRFs exposure, may predict dementia beyond VRFs. Hypothesis: In a community-based sample, baseline CAC is associated with incident dementia independent of VRFs assessed at baseline and APOE -ε 4 genotype. Methods: Among 6,814 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), aged 45-84 years at baseline (2000-2002), we first identified candidate cases for incident all-cause dementia using hospital and death certificate ICD codes. For the analyses, we limited to cases whose diagnosis was validated using following criteria: 1) verifiable medical records available, 2) unlikely alternative diagnosis (e.g. delirium), and 3) written dementia diagnosis. Baseline CAC was categorized according to Agatston score (0, &gt; 0 to &lt;50, 50 to &lt;100, 100 to &lt;400, and ≥400). Cox models were used to obtain hazard ratios (HRs) adjusted for demographics, VRFs, APOE -ε 4, and incident stroke prior to dementia diagnosis. Results: We had complete data on 6,295 individuals for analysis with a mean follow-up of 11.1 years (208 validated cases). Crude rates of dementia were greater with higher baseline CAC categories. Adjusted HR of dementia per one higher CAC category was 1.14 (95%CI 1.03, 1.26) (see Table). The associations were similar when excluding interim incident coronary heart disease, or cardiovascular diseases, or using a model that accounted for competing risk of death with no dementia diagnosis. Conclusion: Higher CAC score measured at baseline was independently and significantly associated with increased risk of dementia. This finding is consistent with an important role for vascular injury in development of dementia.
SCDT-04. POLYION COMPLEX-MEDIATED INTRAVENOUS DELIVERY OF ANTISENSE OLIGONUCLEOTIDES AGAINST THE NOTCH-REGULATED NON-CODING RNA TUG1 IN GLIOMA
Authors: Atsushi Natsume, Keisuke Katsushima, Fumiharu Ohka, Keiko Shinjo, Kanjiro Miyata, Kazunori Kataoka, Yutaka Kondo
Journal: Neuro-Oncology (2017)

Long ncRNAs (lncRNAs) have been increasingly demonstrated to affect the tumor progression via altering chromatin structure and miRNA-mediated gene regulation. We found that Notch1 activation in glioma-stem cells (GSC) specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with polyion complex (PIC)-conjugated antisense oligonucleotides targeting TUG1 induced GSC differentiation and efficiently represses selective GSC growth in the mouse brain. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population. Further, PIC can be used intravenously to provide efficient and selective delivery to intracranial glioma at sufficient concentrations to acquire anti-tumor effects, and thus will become a potent drug delivery system.
Abstract P349: Kidney Function Modifies the Positive Association of Troponin With 30 Day Mortality After Myocardial Infarction
Authors: Jacqueline P Honerlaw, Yuk-Lam Ho, David R Gagnon, Xuan-Mai Nguyen, Rebecca J Song, Jason L Vassy, J M Gaziano, Kelly Cho, Luc Djousse, Peter W Wilson
Journal: Circulation (2017)

Introduction: Increased levels of cardiac troponin at the time of myocardial infarction (MI) have been shown to predict mortality. However, troponin is renally cleared and kidney function itself impacts mortality. We tested the hypothesis that baseline kidney function modifies the relationship between peak cardiac troponin I ratio (cTnI-R) and 30 day mortality after MI. Methods: Data from the Veterans Health Administration was used to create a national sample of hospitalized Veterans with a discharge diagnosis of MI between 2002 and 2015. The peak cTnI-R, calculated as the highest cTnI during the hospitalization compared to the upper limit of normal for each assay, was used as a proxy for the date of the MI event. Veterans with a history of cancer or blood vessel surgery 5 days before peak cTnI were excluded. The closest estimated glomerular filtration rate (eGFR) measured within 2 years prior to hospital admission was used as a marker of baseline kidney function. We created quartiles of peak cTnI-R and clinically relevant levels of eGFR (&lt;30, 30-44, 45-59, and 60+ ml/min/1.73 m 2 ) and fitted Cox regression adjusting for calendar year, age, length of hospital stay, region, diabetes, major mental health conditions and baseline use of diuretics, anti-hypertensives and anti-lipemics. We used subjects in the first quartile of troponin with eGFR of 60+ as common reference. Results: Among 56,073 Veterans hospitalized for MI, mean age was 67 and 98% were men. During 28 days mean follow up, 4,533 deaths occurred. 30 day mortality steadily increased across quartiles of peak cTnI-R; however, the increase in mortality was higher in eGFR below 30, suggesting effect modification of troponin-mortality relation by eGFR (p for interaction between eGFR and troponin 0.03) (Figure). Conclusions: Our data show that the positive relation of troponin with 30 day mortality post MI is modified by kidney function. Veterans with impaired kidney function carry a higher risk of 30 day mortality after MI compared to those with normal eGFR for a given troponin quartile.
OA 13.05 Immune, Molecular and T Cell Repertoire Landscape of 235 Resected Non-Small Cell Lung Cancers and Paired Normal Lung Tissues
Authors: A. Reuben, R. Gittelman, J. Zhang, R. Chen, K. Quek, L. Vence, I. Fernandez-Cubelo, C. Behrens, J. Gao, E. Yusko, R. Emerson, S. Benzeno, M. Vignali, C. Tipton, A. Jalali, W. Lee, C. Wu, J. Li, X. Wu, Y. Ye, A. Eterovic, L. Little, C. Gumbs, C. Bernatchez, C. Haymaker, M. Forget, L. Federico, T. Cascone, H. Robins, E. Roarty, J. Rodriguez, E. Parra, J. Wargo, J. Allison, P. Sharma, J. Zhang, J. Lee, B. Sepesi, S. Swisher, D. Gibbons, J. Heymach, A. Futreal, I. Wistuba, J. Zhang
Journal: Journal of Thoracic Oncology (2017)
P1.03-033 Long-Term Outcome of Histoculture Drug Response Assay Guided Adjuvant Chemotherapy in Patients with Non-Small Cell Lung Cancer
Authors: Y. Hirai, T. Yoshimasu, A. Fusamoto, Y. Aoishi, Y. Yata, H. Nishiguchi, T. Ohashi, M. Miyasaka, M. Kawago, S. Oura, Y. Nishimura
Journal: Journal of Thoracic Oncology (2017)
PUB047 Efficacy of EGFR-TKI for Lung Adenosquamous Cell Carcinoma Harboring EGFR Mutation
Authors: Y. Liu, X. Xia, W. Du, Y. Zhang, J. Xu, Y. Gong, J. Zhu, Z. Ding, F. Peng, M. Huang, Y. Xu, J. Wan, L. Ren, Y. Lu, B. Han, Y. Wang
Journal: Journal of Thoracic Oncology (2017)
IMMU-64. TRIPLE COMBINATION IMMUNOTHERAPY WITH VACCINATION, PD-1 BLOCKADE, AND OX40 LIGATION IS HIGHLY EFFECTIVE AGAINST MURINE INTRACRANIAL GLIOMA
Authors: Nusrat Jahan, Hammad Talat, Dipongkor Saha, William T Curry
Journal: Neuro-Oncology (2017)

The efficacy of single agent PD-1 blockade in glioma is uncertain. Effective immunotherapy will require combination approaches; we examined combination strategies based around PD-1 blockade, including use of irradiated GM-CSF expressing tumor cell vaccination (“GVAX”) and treatment with an agonizing anti-OX40 antibody. All studies were performed with GL261 or CT2A glioma cell lines injected into the right frontal lobes of C57/BL6 mice. Therapies were delivered either subcutaneously or intraperitoneally on days 3,6, and 9 after implantation of tumor. Spleens or brains were harvested on day 18 after tumor implantation for functional ELISPOT assays and flow cytometry analyses of brain inflammatory infiltrate. Combination GVAX and PD-1 blockade improves survival over either as monotherapy, as does combining PD-1 blockade with agonist anti-OX40 immunotherapy. PD-1/OX40 combination was more likely to be associated with long-term control, leading to cure in up to 30% of animals. Vaccination most consistently and significantly improved the CD8+/ FoxP3+ T lymphocyte ratio in the brains. Both anti-PD-1 and agonist anti-OX40 reduced the expression of phenotypic markers of T lymphocyte exhaustion in tumor-infiltrating cells. Triple combination immunotherapy (GVAX+anti PD-1+ agonist anti OX-40) yielded long-term tumor control in the majority of GL261 glioma-bearing mice, achieving 100% cure in most experiments. Triple immunotherapy drove the greatest increases in splenocyte expression of interferon-gamma and intereleukin-2. The intratumoral inflammatory infiltrate was characterized by a significantly higher CD4:CD8 lymphocyte ratio, while the percentage of CD4+FoxP3+ regulatory T lymphocytes declined to the greatest degree. Long-term survivors rejected rechallenge of tumor cells in the contralateral hemisphere; triple immunotherapy was associated with the strongest systemic CD4+CD44+CD62L- effector memory responses. Efficacy of PD-1 blockade against glioma can be improved by combination with either vaccination or OX40 ligation. Combining the three is highly effective against malignant glioma, likely through enhanced CD4+T lymphocyte activity in the tumor microenvironment.
Topical Timolol for Paronychia and Pseudopyogenic Granuloma in Patients Treated With Epidermal Growth Factor Receptor Inhibitors and Capecitabine
Authors: Xavier Cubiró, Sergi Planas-Ciudad, Mª Pilar Garcia-Muret, Lluís Puig
Journal: JAMA Dermatology (2017)

Topical Timolol for Paronychia and Pseudopyogenic Granuloma in Patients Treated With Epidermal Growth Factor Receptor Inhibitors and CapecitabineParonychia and pseudopyogenic granuloma (pseudo-PG) are relatively common and difficult-to-manage adverse effects in patients undergoing treatment with epidermal growth factor receptor inhibitors and capecitabine. 1ecently, Piraccini et al 2 reported the successful treatment of chemotherapy-induced
OA 05.05 Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial
Authors: M. Ahn, D.R. Camidge, M. Tiseo, K. Reckamp, K. Hansen, S. Kim, R. Huber, H. West, H. Groen, M. Hochmair, N. Leighl, S. Gettinger, C. Langer, L. Paz-Ares, E. Smit, E. Kim, W. Reichmann, D. Kerstein, D. Kim
Journal: Journal of Thoracic Oncology (2017)
P3.02-064 Epidermal Growth Factor Receptor Gene Mutation in Pleural Lavage Cytology Findings of Primary Lung Adenocarcinoma Cases
Authors: T. Inoue, M. Nishihira, O. Araki, Y. Karube, S. Maeda, S. Kobayashi, M. Chida
Journal: Journal of Thoracic Oncology (2017)
OA 18.03 Genomic Profiling Reveals Hedgehog Pathway Alterations in Vismodegib Sensitive Lung Squamous Cell Carcinoma
Authors: S. Ali, K. Fedorchak, P.J. Stephens, J. Ross, V. Miller, A. Schrock, A. Dowlati
Journal: Journal of Thoracic Oncology (2017)
TMOD-09. HUMAN PLURIPOTENT STEM CELL-BASED MODELS OF NEUROBLASTOMA
Authors: Miller Huang, Tina Zheng, Jeffrey Guo, Colin Sperring, Matthew Miller, Lauren McHenry, Qiqi Zhen, Branden Moriarity, Marianne Bronner, Bruce Conklin, David Largaespada, John Maris, Katherine Matthay, William Weiss
Journal: Neuro-Oncology (2017)

Neuroblastoma (NB) is a malignant tumor that accounts for ~15% of all pediatric cancer mortality. Nearly half of patients present with high-risk disease that has poor outcome, and the proto-oncogene MYCN is amplified in 45% of high-risk cases. Further, relapsed neuroblastoma demonstrates frequent activation of mitogen activated protein kinase (MAPK) signaling, including mutations in tumor suppressor NF1 and epigenetic silencing of the gene. Human induced pluripotent stem cells (iPSCs) represent a valuable tool by which to further dissect the genetic requirements of high-risk NB. Human iPSCs are superior to genetically engineered mouse models (GEMMs) at capturing the telomere biology and chromosomal landscape of primary human neuroblastoma. Further, they can be genetically manipulated to determine the genetic drivers of the disease. As proof of principle, we first differentiated normal human iPSCs toward trunk neural crest cells (NCC), the putative cells of origin for NB. We subsequently introduced established genetic drivers of NB (MYCN, ALK) and orthotopically implanted the resulting trunk NCCs into the renal capsules of immunocompromised mice. Three months post injection, tumors developed in 60% of MYCN/ALK mice, 10% in MYCN alone, and no tumors developed in ALK alone or empty vector. Tumors were transplantable and expressed markers typically found in NB, while lacking markers of other tumors such as rhabdomyosarcoma, Ewing sarcoma, and lymphoma. To show we can use our model to evaluate candidate drivers of NB, we knocked out NF1 in MYCN trunk NCCs using CRISPR/Cas9 and implanted these cells orthotopically in mice. 80% of mice with MYCN/NF1 modified cells developed tumors while NF1 knockout alone did not. Thus, we have generated the first human iPSC model of NB driven by MYCN and have shown the utility of our model in validating cooperating mutations. MH and TZ contributed equally to this work.
<scp>MP</scp>29‐02 reduces nasal hyperreactivity and nasal mediators in patients with house dust mite‐allergic rhinitis
Authors: I. Kortekaas Krohn, I. Callebaut, Y. A. Alpizar, B. Steelant, L. Van Gerven, P. S. Skov, A. Kasran, K. Talavera, M. M. Wouters, J. L. Ceuppens, S. F. Seys, P. W. Hellings
Journal: Allergy (2017)

Abstract Background Nasal hyperreactivity ( NHR ) is an important clinical feature of allergic rhinitis ( AR ). The efficacy of MP 29‐02 (azelastine hydrochloride ( AZE ) and fluticasone propionate [ FP ]) nasal spray on local inflammatory mediators and NHR in AR is unknown. We tested if MP 29‐02 decreases inflammatory mediators and NHR in AR and if this effect is due to restoration of nasal epithelial barrier function. Methods A 4‐week double‐blinded placebo‐controlled trial with MP 29‐02 treatment was conducted in 28 patients with house dust mite ( HDM ) AR . The presence of NHR was evaluated by measuring reduction in nasal flow upon cold dry air exposure. The effects of AZE ± FP on barrier integrity and airway inflammation were studied in a murine model of HDM ‐induced NHR and on reduced activation of murine sensory neurons and human mast cells. Results MP 29‐02 but not placebo reduced NHR ( P &lt; .0001 vs P = .21), levels of substance P ( P = .026 vs P = .941), and β‐hexosaminidase ( P = .036 vs P = .632) in human nasal secretions. In wild‐type C57 BL 6 mice, the reduction in β‐hexosaminidase levels ( P &lt; .0001) by AZE + FP treatment upon HDM challenge was found in parallel with a decreased transmucosal passage ( P = .0012) and completely reversed eosinophilic inflammation ( P = .0013). In vitro, repeated applications of AZE + FP desensitized sensory neurons expressing the transient receptor potential channels TRPA 1 and TRPV 1. AZE + FP reduced MC degranulation to the same extent as AZE alone. Conclusion MP 29‐02 treatment reduces inflammatory mediators and NHR in AR . The effects of AZE + FP on MC degranulation, nasal epithelial barrier integrity, and TRP channels provide novel insights into the pathophysiology of allergic rhinitis.
Cardiovascular Complications Over 5 Years and Their Association With Survival in the GERODIAB Cohort of Elderly French Patients With Type 2 Diabetes
Authors: Bernard Bauduceau, Jean-Pierre Le Floch, Serge Halimi, Christiane Verny, Jean Doucet
Journal: Diabetes Care (2017)

OBJECTIVE The GERODIAB study is a multicenter prospective observational study performed over 5 years in French patients aged 70 years or above with type 2 diabetes. This report deals with their cardiovascular complications and their relationship with survival. RESEARCH DESIGN AND METHODS Consecutive patients (n = 987, median age = 77 years) were included from 56 diabetes centers over 1 year. Individual characteristics, history and complications of diabetes, geriatric factors, and clinical and biological parameters were recorded. Survival was analyzed using the Kaplan-Meier method and proportional hazards regression models. RESULTS The frequency of cardiovascular complications increased from 47% at inclusion to 67% at 5 years. The most frequent complications were coronary heart disease (increasing from 30% to 41%) and vascular disease of the lower limbs (25% to 35%) and of the cerebral vessels (15% to 26%). Heart failure was less common, but its frequency doubled during the follow-up (9% to 20%). It was strongly associated with poor survival (P &amp;lt; 0.0001), as was vascular disease of the lower limbs (P = 0.0004), whereas coronary heart disease (P = 0.0056) and vascular disease of cerebral vessels (P = 0.026) had mild associations. Amputation (P &amp;lt; 0.0001) and foot wounds (P &amp;lt; 0.0001) were strongly associated with survival. In multivariate models, heart failure was the strongest predictor of poor survival (hazard ratio [HR] 1.96 [95% CI 1.45–2.64]; P &amp;lt; 0.0001). It remained significant when other factors were considered simultaneously (HR 1.92 [95% CI 1.43–2.58]; P &amp;lt; 0.0001). CONCLUSIONS Cardiovascular complications are associated with poor survival in elderly patients with type 2 diabetes, especially heart failure.
Vigilancia de las infecciones humanas por Campylobacter en Francia- Segunda parte -Implantación de la vigilancia nacional
Authors: A Gallay, F Simon, F. Mégraud
Journal: Eurosurveillance (2003)

En 2001, un ano despues del estudio de laboratorios microbiologicos que demostro la viabilidad de la vigilancia de infecciones por Campylobacter, se pregunto a 1.389 laboratorios privados si estarian dispuestos a participar. El elevado porcentaje de respuestas positivas (48%, 661) permitio implantar, el 1 de abril de 2002, la vigilancia de infecciones humanas por Campylobacter.