tbuckley/cabot-search huggingface dataset:
Abstract 949: Epigenetic silencing of microRNA-34a promotes cholangiocarcinoma growth by regulating Notch pathway
Authors: Hyunjoo Kwon, Kyoungsub Song, Chang Han, Jinqing Zhang, Nathan Ungerleider, Lu Yao, Tong Wu
Journal: Cancer Research (2016)

Abstract Aberrant expression and regulation of microRNAs (miRNAs) have been found in multiple cancers and their dysregulation importantly contribute to the tumorigenic processes. Among these miRNAs, miRNA-34a (miR-34a) functions as a tumor suppressor and its dysregulation has been reported in several cancers. In this study, we investigated epigenetic regulation and biological function of miR-34a in human cholangiocarcinoma cells. Our data indicate that miR-34a expression is epigenetically silenced in human cholangiocarcinoma cells (CCLP1, SG231, Hucct1 and TFK1) compared to the nonmalignant biliary epithelial cells (H69). Treatment of human cholangiocarcinoma cells with the DNA methylation inhibitor, 5’aza-2’deoxycytidine (5-Aza-CdR), or the EZH2 (enhancer of zeste 2 polycomb repressive complex 2) inhibitor, GSK126, enhanced the expression of miR-34a. In parallel, knockdown of EZH2 by shRNA also significantly decreased miR-34a expression in human cholangiocarcinoma cells. We further showed that DNA methylation and EZH2-mediated histone H3 lysine 27 trimethylation (H3K27Me3) repressed miR-34a gene expression, as determined by methylation-specific PCR and chromatin immunoprecipitation. The DNA methylation and EZH2-mediated H3K27Me3 independently repress miR-34a expression in cholangiocarcinoma cells since treatment of 5-Aza-CdR and GSK126 had no effect on H3K27me3 and DNMT1 levels, respectively. Functional analyses revealed that miR-34a mimic decreased cholangiocarcinoma cell proliferation, colony formation and migration, in vitro. Moreover, we identified Notch1, Notch2 and Jagged 1, which are the major receptors and ligands of the Notch pathway, as miR-34a target genes in cholangiocarcinoma cells. Accordingly, forced overexpression of miR-34a significantly decreased the expression of Notch1, Notch2 and Jagged1, as determined by Western blotting and qRT-PCR analyses. Our results provide novel evidence that miR-34a expression is epigenetically silenced by DNA methylation and EZH2 in human cholangiocarcinoma cells. Thus, epigenetic induction of miR-34a or miR-34a replacement therapy may represent a novel therapeutic approach for the treatment of cholangiocarcinoma. Citation Format: Hyunjoo Kwon, Kyoungsub Song, Chang Han, Jinqing Zhang, Nathan Ungerleider, Lu Yao, Tong Wu. Epigenetic silencing of microRNA-34a promotes cholangiocarcinoma growth by regulating Notch pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 949.
Resistance mechanisms to targeted therapies in <i>ROS1</i>+ and <i>ALK</i>+ non-small cell lung cancer.
Authors: Caroline Elizabeth McCoach, Anh T. Le, Dara Aisner, Katherine Gowan, Kenneth L Jones, Dan Merrick, Paul A. Bunn, William T. Purcell, Marileila Varella-Garcia, D. Ross Camidge, Robert Charles Doebele
Journal: Journal of Clinical Oncology (2016)

9065 Background: Non-small cell lung cancer (NSCLC) patients (pts) harboring ROS1 (ROS1+)and ALK gene fusions (ALK+) treated with oncogene-directed therapies experience significant improvements in response rates and progression free survival. Despite this initial benefit, tumors ultimately progress but may respond to next generation kinase inhibitors allowing for tailored therapy at the time of resistance. Here we report on the resistance mechanisms in the largest series of ROS1+ and an expanded cohort of ALK+ pts after progression on targeted therapy using next generation sequencing (NGS). Methods: Testing was performed on a total of 7 ROS1+ and 34 ALK+ pts, including 6 ALK+ pts with multiple biopsies. We analyzed tumor tissue from 3 pts with ROS1+ and 13ALK+ pts with a custom capture-based next NGS panel of 48 genes including ALK, ROS1, EGFR, and RAS using at least 50ng of DNA. The remainder of ALK and ROS1 tumor samples were subjected to a multiplex mutation assay and/or direct sequencing of DNA or RT-PCR products to evaluate for kinase domain mutations. ALK and ROS1 FISH were performed to evaluate for copy number alterations. Results: Of theROS1+ pts who demonstrated radiologic progression on crizotinib we found that 1/5 (20%)tumor samples harbored 2 different resistance mutations in the kinase domain of ROS1: the gatekeeper L2026M [19% variant allele frequency (VAF)] and also L1951R (9% VAF), neither of which have been reported in pts before. Of the ALK+ pts who progressed on crizotinib, ceritinib, alectinib, or brigatinib, 9/34 (26%) were found to have ALK kinase domain resistance mutations including a patient with a novel compound (in cis) mutation of S1206Y and E1210K and another patient with a G1202S, both following treatment with a next generation ALK inhibitor. One additional ALK+ patient was found to have an EGFR mutation, but no RAS mutations were identified in this updated series of resistance samples. Conclusions: Novel ROS1 and ALK resistance mutations were identified by a custom NGS panel, including 2 pts with coincident resistance mutations in a single tumor sample. Only 25% (10/39) of ALK+ and ROS1+ pts have kinase domain mutations suggesting other mechanisms of drug resistance in the majority of these pts.
Interference of New Drugs with Compatibility Testing for Blood Transfusion
Authors: Michael F Murphy, Larry J Dumont, Andreas Greinacher
Journal: New England Journal of Medicine (2016)

head circumference and a disproportionately high birth weight and length.Kass and Merlino note that our map indicates that A. aegypti may be present in New York City.Our map shows that this area is at the extreme northern potential range of A. aegypti.On the basis of their trapping of more than 1.2 million mosquitoes, Kass and Merlino question the presence of A. aegypti in New York City.Our map was based on modeling data by Monaghan et al. as well as on mosquito-collection data recorded in several databases and publications. [2]3][4] These sources indicate that A. aegypti may occasionally be identified as far north as coastal New Jersey, New York, Connecticut, and Rhode Island, probably as a result of warm-season introductions rather than permanent establishment.Given these considerations, and given that mosquito traps that are commonly used for West Nile virus surveillance rarely capture A. aegypti, it is not surprising that A.
Molecular Imaging of Gynecological Cancers: Ovarian Cancer as Role Model
Authors: E.G.E. De Vries, G.M. van Dam, A.W.J.M. Glaudemans, A.K.L. Reyners, A.G.J. van der Zee, G.A.P. Hospers, M.N. Lub-De Hooge
Journal: Annals of Oncology (2012)
A Novel PI3K Inhibitor Identified By a High Throughput Virtual Screen Displays Potent Activity Against Multiple Myeloma
Authors: Biyin Cao, Jingyu Zhu, Man Wang, Yang Yu, Huixin Qi, Kunkun Han, Zubin Zhang, Yuanying Zeng, Chunhua Qiao, Hongjian Zhang, Tingjun Hou, Xinliang Mao
Journal: Blood (2014)
Abstract 5056: RET-mediated invasion in three-dimensional microenvironment models
Authors: Sarah M. Maritan, Eric Y. Lian, Lois M. Mulligan
Journal: Cancer Research (2016)

Abstract RET is a receptor tyrosine kinase expressed in cells derived from the neural crest. RET activation and signalling is mediated by soluble ligands of the Glial Cell-Derived Neurotrophic Factor (GDNF) family. RET signalling plays critical roles during embryogenesis, mediating directional cell migration, proliferation, and survival. In addition to its normal developmental roles, oncogenic mutations or aberrant expression of RET are also linked to tumor spread and metastasis in multiple human tumor types. Specifically, activating mutations of RET have been identified in multiple-endocrine neoplasia type 2, while expression of wildtype RET is linked to increased local invasion in breast and pancreatic tumors. Previous studies of RET-mediated invasion and metastasis have used standard 2D culture methodologies, which may not be reflective of the in vivo microenvironment. Here, we have developed an in vitro 3D model of tumor growth, invasion, and metastasis to characterize the signals critical to these processes. Using SH-SY5Y cells, a neuroblastoma cell line that endogenously expresses RET, we assessed anchorage-independent growth and invasion into a surrounding collagen matrix in response to RET stimulation with GDNF. We have quantified the contributions of several RET downstream signalling pathways by individually blocking SRC, PI3K, FAK, STAT3, MEK, and integrin β-1 signals, for their effects on RET-mediated cell growth and invasion in 3D culture. Our data demonstrate that inhibiting either PI3K or MEK decreases the invasive potential of SH-SY5Y cells in response to RET activation, while inhibition of STAT3 had little effect. We have also shown that integrin β-1, FAK or SRC inhibition completely blocked invasion, consistent with an integrin dependent mode of invasion in SH-SY5Y cells. Additionally, we showed that FAK and SRC signalling were critical for SH-SY5Y survival in 3D microenvironments. While several RET-mediated signalling pathways have been implicated in cell motility and invasion in two-dimensional culture models, our findings suggest that specific signals may differ in their importance in a three-dimensional microenvironment. We are currently using our 3D models to further characterize the contributions of RET signalling to tumor cell invasiveness. These data may provide further insight into the role of RET expression in in vivo tumor spread. Citation Format: Sarah M. Maritan, Eric Y. Lian, Lois M. Mulligan. RET-mediated invasion in three-dimensional microenvironment models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5056.
Abstract 2514: Second generation HDAC inhibitor, Quisinostat reinstates RD3 in neuroblastoma CSCs and promotes stem cell differentiation
Authors: DINESH BABU SOMASUNDARAM, Natarajan Aravindan
Journal: Cancer Research (2016)

Abstract Recently, we characterized the adaptive stemness and extreme plasticity of neuroblastoma (NB) cancer stem cells (CSCs). Further, new to science, we defined the loss of retinal degeneration protein 3 (RD3) in high-risk NB and identified its novel tumor evolution stabilization function. Moreover our studies identified definitive contribution of HDACs in the evolution of progressive NB. Herein, we investigated the potential of pyrimidyl-hydroxamic acid HDAC inhibitor, Quisinostat in restoring RD3 and NB-CSCs differentiation. Well characterized CD133+-CD34+ human NB CSCs exposed to increasing concentrations (2.5, 5, 10, 100, 200nM, 1, 2, 4, 8μM) of quisinostat were examined for inhibition of HDACs (HDACs 1-11, QPCR analysis), transcriptional (QPCR) and translational (immunoblotting) restoration of RD3, CSCs cell viability (automated trypan exclusion assay) differentiation (real-time live cell imaging) and formation of organized tumorospheres (tumorosphere formation assay). Quisinostat inflicted complete inhibition of NB-CSCs cell viability at 100nM concentration and beyond. QPCR analysis revealed a dose-dependent inhibition of HDACs in NB CSCs with quisinostat. We observed a significant transcriptional/translational restoration of RD3 selectively at 100nM and above of quisinostat treatment. Live-cell imaging demonstrated a dose-dependent -loss of stemness behavior and -increased differentiation of NB CSCs with quisinostat treatment. Tumorosphere formation assay demonstrated complete inhibition of organized tumorospheres at/after 100nM treatment. These results imply that Quisinostat restores RD3 and promotes NB-CSCs differentiation. More importantly, selective dose-dependent specificity of HDAC inhibition by Quisinostatnt and, restoration of RD3 and regulation of stemness physiognomies at/above 100nM concentrations identifies that HDAC 7 could serve as a critical player in this setting. Taken together, these results for the first time identify the potential of quisinostat in the regulation of NB evolution and with further studies may serve as a potential drug deliverable in the treatment and cure of high-risk NB. Acknowledgements: Stephenson Cancer Center - Experimental Therapeutics Program, NIH COBRE 1P20GM103639-01. Citation Format: DINESH BABU SOMASUNDARAM, Natarajan Aravindan. Second generation HDAC inhibitor, Quisinostat reinstates RD3 in neuroblastoma CSCs and promotes stem cell differentiation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2514.
Application Of The Revised International Prognostic Scoring System In Korean Patients With MDS and Clinical Significance Of Clonal Evolution
Authors: Jae Hyeon Park, Si Nae Park, Jiseok Kwon, Kyongok Im, Jung Ah Kim, Qute Choi, Seon Young Kim, Sang Mee Hwang, Inho Kim, Sung-Soo Yoon, Seonyang Park, Dong Soon Lee
Journal: Blood (2013)
Preparation, optimization and in vitro–in vivo investigation for capsules of the choline salt of febuxostat
Authors: Xuemei Han, Wanpeng Qi, Wenxiang Dong, Mengran Guo, Panqin Ma, Jing Wang
Journal: Asian Journal of Pharmaceutical Sciences (2016)

The objective of the present study was to exhibit the enhanced water-solubility and in vivo oral absorption when febuxostat (FXT) became the salt formation of choline. The formation of the choline salt of febuxostat was confirmed by X-ray powder diffraction, infrared spectroscopy analysis and differential scanning calorimetry. The direct filling method was used to develop a capsule formulation. Cellactose 80 was used as the filler due to its good fluidity, while cross-linked polyvinylpyrrolidone (PVPP) and magnesium stearate (MS) were used as the disintegrant and lubricant, respectively. Then the in vitro release of the formulation was carried out in five different dissolution media including HCl solution (pH 1.2), acetate buffer (pH 4.5), phosphate buffer (pH 6.8 and pH 7.2) and water. Evident improvement of release for choline febuxostat (CXT) was presented in water while the dissolution degree was decreased for CXT in the medium of phosphate buffer (pH 6.8) in comparison with FXT. Furthermore, the pharmacokinetics of CXT was studied in rats using UPLC-MS/MS compared with FXT. The data acquired illustrated that AUC0-24h of CXT and FXT were 22,245.96 ± 7342.92 µg⋅h/l and 12,249.70 ± 2024.04 µg⋅h/l, respectively. The relative bioavailability of CXT to FXT was about 181.6% and the P value of AUC0-24h was less than 0.05. It showed significant difference between the two drugs after oral administration. In conclusion, the water-solubility and oral bioavailability were both improved remarkably for the choline salt of febuxostat and choline salinization was proved an effective way to increase the in vivo absorption for FXT.
Radiogenomics to characterize regional genetic heterogeneity in glioblastoma
Authors: Leland S. Hu, Shuluo Ning, Jennifer M. Eschbacher, Leslie C. Baxter, Nathan Gaw, Sara Ranjbar, Jonathan Plasencia, Amylou C. Dueck, Sen Peng, Kris A. Smith, Peter Nakaji, John P. Karis, C. Chad Quarles, Teresa Wu, Joseph C. Loftus, Robert B. Jenkins, Hugues Sicotte, Thomas M. Kollmeyer, Brian P. O'Neill, William Elmquist, Joseph M. Hoxworth, David Frakes, Jann Sarkaria, Kristin R. Swanson, Nhan L. Tran, Jing Li, J. Ross Mitchell
Journal: Neuro-Oncology (2016)

Abstract Background Glioblastoma (GBM) exhibits profound intratumoral genetic heterogeneity. Each tumor comprises multiple genetically distinct clonal populations with different therapeutic sensitivities. This has implications for targeted therapy and genetically informed paradigms. Contrast-enhanced (CE)-MRI and conventional sampling techniques have failed to resolve this heterogeneity, particularly for nonenhancing tumor populations. This study explores the feasibility of using multiparametric MRI and texture analysis to characterize regional genetic heterogeneity throughout MRI-enhancing and nonenhancing tumor segments. Methods We collected multiple image-guided biopsies from primary GBM patients throughout regions of enhancement (ENH) and nonenhancing parenchyma (so called brain-around-tumor, [BAT]). For each biopsy, we analyzed DNA copy number variants for core GBM driver genes reported by The Cancer Genome Atlas. We co-registered biopsy locations with MRI and texture maps to correlate regional genetic status with spatially matched imaging measurements. We also built multivariate predictive decision-tree models for each GBM driver gene and validated accuracies using leave-one-out-cross-validation (LOOCV). Results We collected 48 biopsies (13 tumors) and identified significant imaging correlations (univariate analysis) for 6 driver genes: EGFR, PDGFRA, PTEN, CDKN2A, RB1, and TP53. Predictive model accuracies (on LOOCV) varied by driver gene of interest. Highest accuracies were observed for PDGFRA (77.1%), EGFR (75%), CDKN2A (87.5%), and RB1 (87.5%), while lowest accuracy was observed in TP53 (37.5%). Models for 4 driver genes (EGFR, RB1, CDKN2A, and PTEN) showed higher accuracy in BAT samples (n = 16) compared with those from ENH segments (n = 32). Conclusion MRI and texture analysis can help characterize regional genetic heterogeneity, which offers potential diagnostic value under the paradigm of individualized oncology.
Abstract 2448: Suppression of MYCN-driven neuroblastoma malignant phenotype by telomerase-targeted tumor suppressor p53 transactivation
Authors: Terutaka Tanimoto, Hiroshi Tazawa, Hiroshi Noso, Takanori Oyama, Yasuo Urata, Shunsuke Kagawa, Takuo Noda, Toshiyoshi Fujiwara
Journal: Cancer Research (2016)

Abstract Background: Neuroblastoma (NB) is a primary malignant tumor in the peripheral sympathetic nervous system. High-risk group of NB has an unfavorable clinical course, even after treatment with current chemotherapy regimens and aggressive surgical resection. Therefore, a novel therapeutic strategy is needed for the treatment of high-risk group of NB. Recent accumulating evidences in whole-genome sequencing analysis have shown that human telomerase reverse transcriptase (hTERT) gene rearrangement and MYCN gene amplification are predictive biomarkers for the high-risk group of NB, in which massive transcriptional activation of hTERT mRNA was frequently observed. We recently developed two types of hTERT-driven oncolytic adenoviruses, OBP-301 and OBP-702, in which the hTERT promoter drives the expression of the viral E1A and E1B genes for tumor-specific virus replication, and OBP-702 further expresses tumor suppressor p53 protein. In this study, we investigated whether OBP-301 and OBP-702 inhibit cell viability and MYCN protein expression in human NB cells with different MYCN status. Methods: We used 3 human NB cell lines with or without MYCN amplification, including IMR-32 (MYCN-amplified), LA-N-5 (MYCN-amplified), SK-N-SH (MYCN-not amplified). The antitumor effects of OBP-301, OBP-702, and Ad-p53, a replication-defective adenovirus expressing p53 gene, were evaluated using XTT assay. Virus-induced apoptosis and MYCN suppression were analyzed by Western blot analysis. Results: OBP-301, OBP-702, and Ad-p53 suppressed the viability of all 3 NB cell lines, whereas OBP-702 showed the most profound anti-tumor effect especially in MYCN-amplified NB cells. OBP-702 induced higher p53 expression than Ad-p53, resulting in the p53-mediated apoptotic cell death. Although MYCN expression in NB cells with MYCN amplification was downregulated after infection with all types of adenoviruses, the inhibitory effect of OBP-702 was the strongest among these adenoviruses. Conclusions: These results suggest that a hTERT-driven oncolytic adenovirus OBP-702 is a promising antitumor agent to induce profound apoptotic cell death through p53 transactivation and MYCN suppression in human NB cells with or without MYCN amplification. In vivo experiments are under way to investigate the antitumor effect of OBP-702 against xenograft NB tumors. Citation Format: Terutaka Tanimoto, Hiroshi Tazawa, Hiroshi Noso, Takanori Oyama, Yasuo Urata, Shunsuke Kagawa, Takuo Noda, Toshiyoshi Fujiwara. Suppression of MYCN-driven neuroblastoma malignant phenotype by telomerase-targeted tumor suppressor p53 transactivation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2448.
Abstract 4289: C-reactive protein and risk of lung cancer: A pooled analysis of 20 prospective cohorts
Authors: David C. Muller, Allison M. Hodge, Gianluca Severi, Qiuyin Cai, Klaus Meyer, Kjell Grankvist, Arnulf Langhammer, Paul Brennan, Mattias Johansson
Journal: Cancer Research (2016)

Abstract Background: Inflammation may have an important role in the etiology of lung cancer, and several studies have reported that C-reactive protein (CRP) is associated with risk of lung cancer. To clarify this association, we conducted a pooled analysis of CRP and lung cancer risk using data from 20 prospective cohort studies. Methods: Within the NCI Cohort Consortium, we designed a prospective nested case-control study. Controls were selected from appropriate risk sets and were matched to cases on smoking status, sex, and age at blood draw. This analysis included 5,299 case-control pairs nested within 20 cohorts. Rate ratios (RR) and their 95% confidence intervals associated with a doubling in concentration of CRP were estimated using conditional logistic regression models. Results: Overall, higher circulating CRP was associated with an increased risk of lung cancer (RR 1.05, 95% CI [1.03, 1.08]). This association varied strongly by smoking status (p-heterogeneity &amp;lt; 0.01), being similar for current (1.09 [1.05, 1.13]) and former smokers (1.09 [1.04, 1.14]), but not for never smokers (0.95 [0.91, 1.00]). The association was strongest for cancers diagnosed less than 2 years after blood draw (1.21 [1.13, 1.29], p-heterogeneity &amp;lt; 0.01), and weakened as time between blood draw and diagnosis increased. The association was similar across all histological subtypes, with the exception of adenocarcinoma for which we observed no association. Conclusions: CRP is associated with risk of lung cancer. The fact that the association is restricted to ever-smokers, and is most prominent for cancers diagnosed in the first 2 years of follow-up, strongly suggests that CRP is not a causal risk factor, but rather a distal marker of disease. Citation Format: David C. Muller, Allison M. Hodge, Gianluca Severi, Qiuyin Cai, Klaus Meyer, Kjell Grankvist, Arnulf Langhammer, Paul Brennan, Mattias Johansson, Lung Cancer Cohort Consortium (LC3). C-reactive protein and risk of lung cancer: A pooled analysis of 20 prospective cohorts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4289.