bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4679: Novel pathway mutations in malignant mesothelioma revealed by high-throughput DNA and RNA sequencing
Authors: Miyanaga Akihiko , Masuda Mari , Tsuta Koji , Nakamura Yuka , Asamura Hisao , Gemma Akihiko , Yamada Tesshi 
Published: May 2015

Abstract
Background: Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. Because MM is usually diagnosed at an advanced stage and is largely unresponsive to conventional therapy, it is necessary to identify the signal pathways driving MM and to develop therapeutics specifically targeting these pathways.
Materials and Methods: We carried out RNA sequencing of 12 MM cell lines and 4 clinical samples and exome sequencing of 6 MM cells using a so-called next-generation sequencer. We further performed pathway-targeted genome sequencing of 23 paired samples of MM tumor and normal tissue.
Results: We identified 15 novel fusion genes by RNA sequencing and confirmed them by conventional Sanger sequencing and FISH analyses. We showed that the novel gene was included in both LOH and a fusion gene, and the gene which was critical tumor-suppressor roles caused two hit and was down-regulated. The gene has been identified as a central player of the emerging signaling pathway. We further identified the accumulation of mutations in 35% of the MMs by pathway-targeted genome sequencing.
Conclusions: We indicated the need for the discovering molecular targets in the novel pathway in MMs. Our findings provide novel insights into the pathogenesis of MM and unequivocally demonstrate the power of sequencing technologies in cancer research.
Citation Format: Akihiko Miyanaga, Mari Masuda, Koji Tsuta, Yuka Nakamura, Hisao Asamura, Akihiko Gemma, Tesshi Yamada. Novel pathway mutations in malignant mesothelioma revealed by high-throughput DNA and RNA sequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4679. doi:10.1158/1538-7445.AM2014-4679
Abstract 47: Y-box binding protein 1 is correlated with lymph node metastasis in intestinal type of gastric cancer
Authors: Guo TianTian , Yu Yingnan , Yip George Wai-Cheong , Baeg Gyeong Hun , Thike Aye Aye , Tan Puay-Hoon , Matsumoto Ken , Bay Boon Huat 
Published: May 2015

Abstract
Gastric cancer still ranks among the top ten most common cancer in the world, despite a declining trend in incidence. The multifunctional protein Y Box Binding Protein-1 (YB-1) is known to regulate transcription, translation, DNA repair and cellular response to drug treatment. This study evaluated the correlation between YB-1 protein expression levels with clinico-pathological characteristics in the intestinal type of gastric cancer, which was further validated with in vitro experimentation. Tissue microarrays (TMAs) were constructed from specimens obtained from 167 patients diagnosed with intestinal gastric cancer. Immunohistochemical analysis of the YB-1 protein was performed on the TMAs . The intensity of YB-1 staining in the intestinal type of gastric cancer was scored as absent to strong staining and the percentage of YB-1 immunostained cells was determined. YB-1 immunoreactivity was based on the weighted average intensity (WAI) for each specimen, which was calculated as the sum of percentages of stained cells for each intensity divided by the total percentage of stained cells. siRNA-mediated silencing of the YB-1 gene in MKN7 intestinal gastric cancer cells was verified by RT-PCR. Cell migration and invasion assays were carried out using commercially available kits. YB-1 immunostaining was present in all the cancer tissue samples examined. The YB-1 protein was observed to be predominantly expressed in the cytoplasm of the gastric cancer cells. Univariate analysis revealed that YB-1 immunohistochemical expression was significantly correlated with lymph node status and perforation. However, multivariate analysis showed that only YB-1 protein expression is an independent predictor of lymph node spread. Down-regulation of the YB-1 gene expression in MKN7 cells significantly inhibited cell migration and invasion, processes which are important in the metastatic cascade. The findings suggest that YB-1 expression is associated with metastasis in the intestinal type of gastric cancer and is a potential prognostic biomarker and therapeutic target in this subtype of gastric cancer.
Citation Format: TianTian Guo, Yingnan Yu, George Wai-Cheong Yip, Gyeong Hun Baeg, Aye Aye Thike, Puay-Hoon Tan, Ken Matsumoto, Boon Huat Bay. Y-box binding protein 1 is correlated with lymph node metastasis in intestinal type of gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 47. doi:10.1158/1538-7445.AM2014-47
Abstract 4717: Detection of the Cyclin J (CCNJ) as a new cancer-related gene in human hepatocellular carcinoma by using a method of triple combination array analysis
Authors: Takano Nao , Nomoto Shuji , Hishida Mitsuhiro , Inokawa Yoshikuni , Hayashi Masamichi , Kanda Mitsuro , Okamura Yukiyasu , Nishikawa Yoko , Tanaka Chie , Kobayashi Daisuke , Yamada Suguru , Nakayama Goro , Fujii Tsutomu , Sugimoto Hiroyuki , Koike Masahiko , Fujii Michitaka , Takeda Shin , Kodera Yasuhiro 
Published: May 2015

Abstract
Background: Hepatocellular carcinoma (HCC) has a high rate of recurrence and a poor prognosis. To detect genes correlated with HCC, we have developed a new technique, triple combination array analysis, consisting of methylation array, gene expression array and single nucleotide polymorphism (SNP) array analysis.
Methods: A surgical specimen obtained from a 68-year-old female HCC patient was analyzed using triple combination array analysis, which identified a candidate cancer-related gene of HCC. Subsequently, samples from nine cell lines and 48 HCC patients were evaluated for their methylation and expression status of the identified gene using methylation-specific polymerase chain reaction (MSP) and quantitative real-time reverse transcriptase PCR, respectively.
Results: Using the triple combination array analysis, cyclin J (CCNJ) was detected as a candidate cancer-related gene. CCNJ was located on chromosome 10q24.1 and the copy number, using SNP chip array, revealed no loss of heterozygosity. According to expression array results, The expression of CCNJ in tumor tissue decreased at two points of the expression array chip, and the decreased values of the chip were −1.3 and −2.3. CCNJ was found to be hypermethylated (methylation value 0.906, range 0-1.0) in cancer tissue compared with adjacent normal tissue (0.112) using the methylation array. Using MSP, hypermethylation of the promoter region of CCNJ was shown to occur in 37 (77.1%) tumor samples. CCNJ expression was significantly decreased in cases with methylation (p&lt;0.0001). Furthermore, HCC patients with methylated CCNJ had a significantly worse prognosis for recurrence-free survival (p=0.0353) and tended to have a worse prognosis for overall survival than those with unmethylated CCNJ (p=0.0838).
Conclusion: The present study indicates that triple combination array analysis is an effective method to detect novel genes related to HCC. We suggest that CCNJ acts as a cancer-related gene in HCC.
Citation Format: Nao Takano, Shuji Nomoto, Mitsuhiro Hishida, Yoshikuni Inokawa, Masamichi Hayashi, Mitsuro Kanda, Yukiyasu Okamura, Yoko Nishikawa, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Goro Nakayama, Tsutomu Fujii, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujii, Shin Takeda, Yasuhiro Kodera. Detection of the Cyclin J (CCNJ) as a new cancer-related gene in human hepatocellular carcinoma by using a method of triple combination array analysis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4717. doi:10.1158/1538-7445.AM2014-4717
Abstract 4729: Expression of lumican is negatively associated with the risk of biochemical recurrence in human prostate cancer
Authors: Velasco Marco A. De , Hatanaka Yuji , Oki Takashi , Kura Yurie , Yamamoto Yutaka , Yoshimura Kazuhiro , Shimizu Nobutaka , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: May 2015

Abstract
We used DNA chip technology in a genetically engineered mouse model of prostate cancer, and identified lumican as a candidate biomarker in prostate cancer progression. Lumican is a small leucine-rich extracellular matrix protein that has been shown to modulate cell migration and proliferation during embryonic development, and tissue repair. Expression and distinct glycosylation patterns of lumican in several tumor and stromal tissues has been shown to play important roles in vascular invasion, differentiation, proliferation, and invasion. Our goal was to determine the clinical value of lumican as a biomarker for human prostate cancer. In order to do so, we examined gene expression in publicly available databases and confirmed the protein expression in tissue microarrays constructed from prostatectomy cases. Protein expression was examined by immunohistochemistry and expression scores were compared with clinicopathological features and disease progression. Our analysis shows that in human prostate cancer, stromal expression of lumican correlated inversely with clinicopathological features associated with disease progression. In addition, biochemical recurrence was significantly longer for patients with high expression of stromal lumican. Our findings suggest that lumican may be a strong candidate prognostic biomarker and warrants prospective validation.
Citation Format: Marco A. De Velasco, Yuji Hatanaka, Takashi Oki, Yurie Kura, Yutaka Yamamoto, Kazuhiro Yoshimura, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Expression of lumican is negatively associated with the risk of biochemical recurrence in human prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4729. doi:10.1158/1538-7445.AM2014-4729
Abstract 473: TRIM59, a novel prognostic marker for gastric cancer, promotes tumorigenesis via ubiquitination and degradation of the p53 tumor suppressor
Authors: Zhou Zhicheng , Wang You , Li Jian , Cao Hui , Zhu Helen H. , Gao Wei-Qiang 
Published: May 2015

Abstract
As a key tumor suppressor, p53 plays crucial roles in gastric cancer initiation and progression. However, the underlying mechanisms for the down-regulation of p53 in gastric cancer patients are not fully understood. Several tripartite motif (TRIM) family proteins are identified to be involved in the tumorigenesis of multiple cancer types, but the significance and biological function of a new TRIM family protein, TRIM59, in terms of whether and how it affects p53 signaling in gastric cancer are largely unknown. We analyzed multiple microarray datasets from the Oncomine database and tested the expression level of TRIM59 in gastric tumors vs. their matched normal tissues and in gastric carcinoma cell lines using quantitative-polymerase chain reactions (Q-PCR) and immunohistochemical staining. We found Expression of TRIM59 was significantly up-regulated in gastric cancer and strongly associated with poor prognosis. TRIM59 knockdown led to significantly attenuated gastric cancer cell proliferation, clone formation, migration, and in vivo xenograft tumorigenicity, whereas over-expression of TRIM59 showed the opposite effects. Mechanistically, TRIM59 interacted with p53 and enhanced ubiquitination and degradation of the p53 protein. In addition, elevated expression of TRIM59 correlated with down-regulation of p53 target genes in human gastric tumors. In summary, TRIM59 is a novel prognostic marker for gastric cancer and promotes tumorigenesis through facilitating p53 ubiquitination and degradation.
Citation Format: Zhicheng Zhou, You Wang, Jian Li, Hui Cao, Helen He Zhu, Wei-Qiang Gao. TRIM59, a novel prognostic marker for gastric cancer, promotes tumorigenesis via ubiquitination and degradation of the p53 tumor suppressor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 473. doi:10.1158/1538-7445.AM2014-473
Abstract 4734: Activation of yap1 is significantly associated with poor prognosis and cetuximab resistance in colorectal cancer patients
Authors: Lee Keun-Wook , Lee Sung Sook , Kim Sang-Bae , Park Yun-Yong , Sohn Bo Hwa , Lee Hyun-Sung , Lee Ju-Seog 
Published: May 2015

Abstract
Purpose: To investigate the clinical significance of activation of YAP1, a newly identified oncogene in colorectal cancer (CRC).
Patients and Methods: A gene expression signature reflecting YAP1 activation was identified in CRC cells, and CRC patients were stratified into two groups according to this signature: activated YAP1 CRC (AYCC) or inactivated YAP1 CRC (IYCC). Stratified patients in six test cohorts were evaluated to determine the effect of the signature on CRC prognosis and response to treatment with cetuximab.
Results: The activated YAP1 signature was associated with poor prognosis for CRC in four independent patient cohorts with stage I-III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on the disease-free survival rate was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25-2.13; P &lt; .001]. In patients with stage IV CRC, AYCC patients had a poorer disease control rate and progression-free survival duration after cetuximab-based monotherapy than did IYCC patients (HR, 1.82; 95% CI, 1.05-3.16; P = .03). In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and cetuximab-based therapy was effective only in IYCC patients without KRAS mutations.
Conclusion: Activation of YAP1 is highly associated with poor prognosis for CRC and may be useful in identifying patients with CRC resistant to treatment with cetuximab.
Citation Format: Keun-Wook Lee, Sung Sook Lee, Sang-Bae Kim, Yun-Yong Park, Bo Hwa Sohn, Hyun-Sung Lee, Ju-Seog Lee. Activation of yap1 is significantly associated with poor prognosis and cetuximab resistance in colorectal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4734. doi:10.1158/1538-7445.AM2014-4734
Abstract 4746: Selective inhibition of mutant IDH1 via small molecule binding to the dimer interface
Authors: Deng Gejing , Licht Stuart , Shen Junqing , Yin Ming , McManus Jessica , Gee Patricia , He Tim , Gao Giang , Zhang Bailin , Mathieu Magali , Rak Alexey , Bedel Olivier , Shi Chaomei , Gross Stefan , Hoffmann Dietmar , Rooney Eamonn , Vassort Aurelie , Englaro Walter , Li Yi , Wiederschain Dmitri , Patel Vinod , Adrian Francisco , Cheng Hong 
Published: May 2015

Abstract
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitric acid to α-ketoglutaric acid (αKG). Point mutations in IDH1 and IDH2 confer a neomorphic enzymatic activity: the reduction of αKG to D-2-hydroxyglutaric acid (2HG), which acts as an oncometabolite by inducing hypermethylation of histones and DNA. IDH1 mutations (predominantly R132H) have been found in 50-80% of grade II gliomas. To find potential IDH1-targeted therapeutics, we conducted a full small-molecule HTS and hit validation campaign using recombinant R132H IDH1. This campaign identified Compound 1, which belongs to a phenol-azole series, as a potent and selective inhibitor of mutant IDH1. We investigated the mode of inhibition of Compound 1 and a published IDH1 mutant inhibitor with a different chemical scaffold (Compound 2). Steady-state kinetics and biophysical studies showed that both inhibitors reversibly interact with both free and substrate-bound enzyme at an allosteric site. A crystal structure of Compound 1 complexed with R132H demonstrates binding of the inhibitor at the dimer interface. A competitive binding study showed that Compound 2 competes with Compound 1, suggesting that Compound 2 also binds at the dimer interface. This is contrary to a previously published statement that Compound 2 is a competitive inhibitor with respect to αKG. In cancer cell lines engineered to produce high levels of 2HG, both inhibitors penetrate cells efficiently and inhibit 2HG production with minimal cell toxicity. This study indicates that the dimer interface pocket is a druggable binding site for IDH1 inhibitors, and suggests that Compound 1 is a promising new starting point for future structure-based drug discovery efforts.
Citation Format: Gejing Deng, Stuart Licht, Junqing Shen, Ming Yin, Jessica McManus, Patricia Gee, Tim He, Giang Gao, Bailin Zhang, Magali Mathieu, Alexey Rak, Olivier Bedel, Chaomei Shi, Stefan Gross, Dietmar Hoffmann, Eamonn Rooney, Aurelie Vassort, Walter Englaro, Yi Li, Dmitri Wiederschain, Vinod Patel, Francisco Adrian, Hong Cheng. Selective inhibition of mutant IDH1 via small molecule binding to the dimer interface. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4746. doi:10.1158/1538-7445.AM2014-4746
Abstract 4758: Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors
Authors: Lito Piro , Saborowski Anna , Yue Jingyin , Solomon Martha , Joseph Eric , Fellman Christof , Ohara Kazuhiro , Morikami Kenji , Miura Takaaki , Lucas Christine , Ishii Nobuya , Lowe Scott , Rosen Neal 
Published: May 2015

Abstract
MEK inhibitors are clinically active in BRAF V600E melanomas, but only marginally so in KRAS-mutant tumors. While MEK inhibitor treatment resulted in sustained inhibition of ERK phopshorylation in BRAF V600E tumors, it was associated with a rebound in ERK phosphorylation after prolonged exposure in KRAS mutant tumors. To understand this phenomenon, we performed an RNAi screen in a KRAS-mutant model and found that CRAF knockdown enhanced the antiproliferative effects of MEK inhibition both in vivo and in vitro. In agreement with previous findings, MEK inhibitor treatment in KRAS mutant cells resulted in CRAF reactivation and induction of MEK phosphorylation. However, MEK activated by CRAF was less susceptible to traditional MEK inhibitors, such as PD0325901, compared to when activated by BRAF V600E. Consistent with this observation, the rebound in ERK phosphorylation following MEK inhibitor treatment in KRAS mutant tumors was dependent on intact CRAF expression. Furthermore, traditional MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting these complexes enhanced the inhibition of CRAF-dependent ERK signaling. In an effort to identify more effective compounds we found that newer MEK inhibitors, such as trametinib and CH5126766, do not only target the catalytic activity of MEK, but in addition, they also impair its reactivation by CRAF. This occurs through two distinct mechanisms: trametinib disrupts RAF-MEK complex formation, as evidenced by co-immunoprecipitation of endogenous proteins and surface plasmon resonance assays with purified enzymes. Instead, CH512676 induces the interaction of MEK with RAF, yet it prevents the phosphorylation of MEK in this complex. To elucidate the mechanism responsible for the latter property, we determined the ternary structure of CH512676-bound MEK1. CH5126766 interacts with Asn 221 and Ser 222 residues in MEK1 to displace the activation segment and disrupt RAF-mediated phosphorylation. These data provide a blueprint for developing better MEK inhibitors that effectively inhibit ERK signaling in KRAS mutant tumors.
Citation Format: Piro Lito, Anna Saborowski, Jingyin Yue, Martha Solomon, Eric Joseph, Christof Fellman, Kazuhiro Ohara, Kenji Morikami, Takaaki Miura, Christine Lucas, Nobuya Ishii, Scott Lowe, Neal Rosen. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4758. doi:10.1158/1538-7445.AM2014-4758
Abstract 4765: Drug synergies observed for antibody and toxin components of SAR3419 ADC contribute to overall conjugate efficacy and can be combination drug or tumor cell line dependent
Authors: Rickles Richard J. , Giordano Thomas P. , Cotard Shakira F. , Grenier Jill M. , Romanelli Angela , Cai Ti 
Published: May 2015

Abstract
SAR3419, a novel antibody-drug conjugate (ADC), is composed of a humanized monoclonal IgG1 anti-CD19 antibody (huB4) attached by a cleavable linker to DM4, a derivative of cytotoxic agent maytansine (an inhibitor of microtubule polymerization). CD19 expression is restricted to B-cells and treatment of CD19-positive human lymphoma cells with SAR3419 can result in cell cycle arrest followed by apoptosis. As traditional monotherapies can rarely treat cancer effectively, particularly in non-solid tumours, a combination high throughput screen (cHTS) was performed where SAR3419 was combined with two hundred potential enhancer compounds across a panel of twenty cell lines using a 6x6 combination dose response matrix. The enhancer compounds compose a library of approved, emerging oncology drugs, and well-defined molecular probes. Robust synergies were observed between SAR3419 and PI3K inhibitors and examined further. Target/pathway inhibitor redundancy for the class of compounds served to validate PI3K inhibition as important for combination synergy. Surprisingly, for several of the cell lines, the molecular mechanism important for SAR3419-dependent combination activity is distinct. For example, for the Daudi and REC-1 tumor cell lines, PI3K inhibitor synergy can be attributed to the toxin DM4. In contrast for SU-DHL4 and SU-DHL6 cell lines, little combination activity is observed with toxin alone while the conjugate is strongly synergistic. By examining three-way combination activities (PI3K inhibitor x DM4 x huB4) using high resolution matrices, we show that the anti-CD19 antibody huB4 contributes to the synergy in the SU-DHL6 cell line and linkage of DM4 to huB4 (SAR3419) shifts both the potency and maximum activity for PI3K inhibitor combinations. The results demonstrate that the antibody component of an ADC can contribute to combination activity for specific drug pairings in a drug and cell-type specific manner and has wide ranging implications with respect to combination drug design.
Citation Format: Richard J. Rickles, Thomas P. Giordano, Shakira F. Cotard, Jill M. Grenier, Angela Romanelli, Ti Cai. Drug synergies observed for antibody and toxin components of SAR3419 ADC contribute to overall conjugate efficacy and can be combination drug or tumor cell line dependent. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4765. doi:10.1158/1538-7445.AM2014-4765