bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4726: Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells as a potential clinical biomarker
Authors: Watanabe Megumi , Kagawa Shunsuke , Ishida Michihiro , Hori Naoto , Kikuchi Satoru , Kuroda Shinji , Kishimoto Hiroyuki , Nishizaki Masahiko , Tazawa Hiroshi , Fujiwara Toshiyoshi 
Published: May 2015

Abstract
Peritoneal dissemination is a common pattern of metastasis in patients with gastric cancer, and associated with worse prognosis. Peritoneal lavage cytology during the operation is an important factor in predicting future development of peritoneal metastasis and determining the treatment strategy, but its sensitivity and specificity are unsatisfactory. TelomeScan is an adenovirus engineered to replicate and express GFP only in telomerase-activating tumor cells, so that we can easily detect viable cancer cells even among numerous normal cells. We hypothesized that TelomeScan might be applicable to detecting free cancer cells in peritoneal wash. Methods: Peritoneal washes were obtained from 42 gastric cancer patients during operation. The number of GFP-positive cells was determined for each sample and compared with cytology results and clinicopathological data Results: Clinical stage was ranged from IA to IV, and thirteen cases were diagnosed as class IV or class V by peritoneal lavage cytology. More than 10 GFP-positive cells were detected in 12 out of 42 cases, and these cases showed a worse prognosis when compared to the other 30 cases. Conclusion: We were able to detect gastric cancer cells as GFP-positive cells in peritoneal wash using TelomeScan. Furthermore, the presence of GFP-positive cells in peritoneal wash was associated with worse prognosis. These results suggest that number of cancer cells detected by TelomeScan in the peritoneal wash may have important clinical implication as prognostic and therapeutic biomarkers in gastric cancer.
Citation Format: Megumi Watanabe, Shunsuke Kagawa, Michihiro Ishida, Naoto Hori, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Hiroshi Tazawa, Toshiyoshi Fujiwara. Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells as a potential clinical biomarker. [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 4726. doi:10.1158/1538-7445.AM2014-4726
Abstract 4732: Vasohibine-1 negative and EZH2 positive may predict the prognosis of cholangiocarcinoma
Authors: Nakagawa Shigeki , Sakamoto Yasuo , Tokunaga Ryuma , Higashi Takaaki , Sakamoto Keita , Chikamoto Akira , Ishiko Takatoshi , Beppu Toru , Baba Hideo 
Published: May 2015

Abstract
Background: Vasohibin-1 (VASH1) is isolated as an endogenous angiogenesis inhibitor produced by the vascular endothelium, and the status of VASH1 expression has been documented in various cancer prognosis. Some reports shows that VASH1 was negatively regulated by enhancer of zeste homolog 2 (EZH2) epigenetically. The aim of this study was to assess the relationship between EZH2 and VASH1, and the prognostic value of this two molecules in intrahepatic cholangiocarcinoma (ICC) patients.
Method: We examine 47 cases of intrahepatic cholangiocarcinoma to which the R0 liver resection had been performed by our department between 1993 years and 2010. Immunohistochemical staining of VASH1 and EZH2 was performed using paraffin-embedded block, and we examined the relation among the expression of VASH1 and a clinicopathological factor (sex, age, tumor diameter, tumor number, differentiation level, microscopic vascular invasion, and metastasis in lymph node), EZH2 expression, recurrence-free survival (RFS) and overall survival (OS).
Result: VASH1 and EZH2 positivity was observed in 24 (51.1%) and 24 (51.1%) patients respectively, and VASH1 positivity was inversely correlated with EZH2 high expression (R=0.3870, p=0.0018). VASH1 positivity was not significantly correlate with RFS or OS. On the other hands, VASH1 negative and EZH2 positive was observed in 17 (36.2%) patients, and was a significant disadvantage to both RFS (relative risk (RR) 3.39, 95% confidence interval (CI) 1.28-8.67, p=0.0157) and OS (RR 3.69, 95% CI 1.20-11.2, 0.0237) in univariate Cox hazard analysis. In multivariate analysis, VASH1 negative and EZH2 positive group was an independent risk factor for both RFS (RR 4.19, 95% CI 1.33-13.13, p=0.0150), and OS (RR 8.11, 95% CI 2.01-42.1, p=0.0030).
Conclusion: The expression of VASH1 was inversely correlate with EZH2 expression. VASH1 negative and EZH2 positive was an independent risk factor for OS and DFS in ICC patients.
Citation Format: Shigeki Nakagawa, Yasuo Sakamoto, Ryuma Tokunaga, Takaaki Higashi, Keita Sakamoto, Akira Chikamoto, Takatoshi Ishiko, Toru Beppu, Hideo Baba. Vasohibine-1 negative and EZH2 positive may predict the prognosis of cholangiocarcinoma. [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 4732. doi:10.1158/1538-7445.AM2014-4732
Abstract 4733: p62/sequestosome 1, a potent prognostic factor, enhance cell proliferation in human colorectal carcinoma
Authors: Nakayama Shun , Suzuki Takashi , Yabuuchi Shinichi , Takagi Kiyoshi , Onodera Yoshiaki , Nakamura Yasuhiro , Watanabe Mika , Fujishima Fumiyoshi , Yoshida Hiroshi , Morikawa Takanori , Karasawa Hideaki , Sase Tomohiko , Naitoh Takeshi , Katayose Yu , Egawa Shinichi , Unno Michiaki , Sasano Hironobu 
Published: May 2015

Abstract
p62/sequestosome 1 (p62) is a multi-domain protein implicated in the selective degradation of ubiquitinated protein by autophagy, and it also functions as a scaffold protein in cell signaling pathways. p62 was recently reported to be accumulated in several types of human cancer cells, but the clinical significance and biological roles of p62 have remained largely unknown in colorectal carcinoma. p62 immunoreactivity was examined in 118 surgical specimens of human colorectal carcinomas using immunohistochemistry. p62 immunoreactivity was detected in about one third of the carcinoma cases, while it was negligible in the adjacent non-neoplastic epithelium. The immunohistochemical p62 status was significantly associated with synchronous liver metastasis in the carcinoma cases, and multivariate analysis further revealed the p62 status as an independent adverse prognostic factor for overall survival in the patients. We used 4 colon carcinoma cells in the in vitro studies to evaluate the functional roles of p62. The colon carcinoma cells transfected with p62-specific small interfering RNAs showed significantly decreased cell proliferation activities, and the colon carcinoma cells transfected with p62 expression plasmid showed significantly increased the cell proliferation activity. Results of in vitro studies indicated that p62 significantly promoted the cell proliferation of colorectal carcinoma cells, but the autophagic activity was not linked to the p62-mediated cell proliferation. These findings suggest that p62 promotes the proliferation of colon carcinoma cells mainly as a scaffold protein. The p62 status is a potent prognostic factor in human colorectal cancer patients, and could be an important specific therapeutic target of colorectal carcinoma that could improve the clinical outcome in the future.
Citation Format: Shun Nakayama, Takashi Suzuki, Shinichi Yabuuchi, Kiyoshi Takagi, Yoshiaki Onodera, Yasuhiro Nakamura, Mika Watanabe, Fumiyoshi Fujishima, Hiroshi Yoshida, Takanori Morikawa, Hideaki Karasawa, Tomohiko Sase, Takeshi Naitoh, Yu Katayose, Shinichi Egawa, Michiaki Unno, Hironobu Sasano. p62/sequestosome 1, a potent prognostic factor, enhance cell proliferation in human colorectal carcinoma. [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 4733. doi:10.1158/1538-7445.AM2014-4733
Abstract 4736: Inhibition of STAT3 sensitizes neuroblastoma xenografts cells to Etoposide
Authors: Yan Shuang , Thiele Carol 
Published: May 2015

Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for more than 7% of malignancies in patients younger than 15 years and causing 10% of all pediatric oncology deaths. Chemoresistance remains a major obstacle to the successful treatment of high-risk NB patients. Since STAT3 is a determinant of chemoresistance and associated with tumor recurrence in several adult tumor model systems, we investigated the biologic consequences of targeting STAT3 in neuroblastoma. Using a Tet-inducible STAT3 shRNA in 3 representative NB cell line models (AS, NGP and IMR32), inhibition of constitutively activated STAT3 (P-STAT3) in NB cells statistically decreased cell proliferation, colony formation and motility as defined by a wound healing assay. NB cell lines with decreased P-STAT3 exhibited increased sensitivity to cisplatin and etoposide-induced cell death (EC50 in each cell line decreased 52% to 80% compared with parental cell lines) which could be partially rescued by caspase inhibitor Z-VAD. In vivo, STAT3 inhibition by Tet-inducible STAT3 shRNA in AS had little effect on tumor growth and survival in tumor-bearing mice, however the combination of STAT3 inhibition with etoposide significantly decreased tumor growth and increased the survival of tumor-bearing mice (P=0.009). Our study supports the development of strategies targeting STAT3 inhibition in combination with conventional cytotoxic therapy for patients with high-risk NB.
Citation Format: Shuang Yan, Carol Thiele. Inhibition of STAT3 sensitizes neuroblastoma xenografts cells to Etoposide. [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 4736. doi:10.1158/1538-7445.AM2014-4736
Abstract 4741: SerpinA1 promotes gastric cancer progression through regulation of snail
Authors: Kwon Chae Hwa , Park Hye J. , Moon Hyun Jung , Lee Ja-Rang , Park Do Youn 
Published: May 2015

Abstract
In the previous study, we reported that serpin peptidase inhibitor clade A member 1 (serpinA1) were upregulated in snail overexpressing gastric cancer. Although the effect of serpinA1 has been studied in several cancers, there is no report that the expression of serpinA1 correlates with snail. In this study, we examined the relation between serpinA1 and snail, and the role of serpinA1 in gastric cancer. Overexpression of snail resulted in upregulation of serpinA1 in gastric cancer cells, AGS and MKN45 cells. Meanwhile, knockdown of snail inhibited serpinA1 expression. ChIP analysis showed that snail bind to serpinA1 promoter. Overexpression of snail increased snail recruitment to the serpinA1 promoter. Overexpression of serpinA1 increased the invasion and migration of gastric cancer cells, while knockdown of serpinA1 decreased invasion and migration. In addition, we validated the clinicopathological and prognostic significance of serpinA1 expression in 400 gastric cancer patients using immunohistochemistry analysis. SerpinA1 was observed in the cytoplasm of the tumor cells and stroma. Overexpression of serpinA1 was significantly associated with increased tumor size (P = 0.03), tumor progression (advanced T stage; P &lt; 0.0001), perineural invasion (P &lt; 0.0001), lymphovascular invasion (P &lt; 0.0001), lymph node metastases (P &lt; 0.0001) and shorter survival (P = 0.001). In conclusion, serpinA1 induce the invasion and migration of gastric cancer cells and the expression of serpinA1 is associated with the progression of gastric cancer. These results may provide a potential target to prevent gastric cancer invasion and metastasis.
Note: This abstract was not presented at the meeting.
Citation Format: Chae Hwa Kwon, Hye Ji Park, Hyun Jung Moon, Ja-Rang Lee, Do Youn Park. SerpinA1 promotes gastric cancer progression through regulation of snail. [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 4741. doi:10.1158/1538-7445.AM2014-4741
Abstract 4749: New benzazepine BET-inhibitors with improved oral bioavailability
Authors: Schmees Norbert , Haendler Bernard , Lejeune Pascale , Stresemann Antje , Neuhaus Roland , Siegel Stephan , Fernandez-Montalvan Amaury Ernesto , Weinmann Hilmar , Gekeler Volker 
Published: May 2015

Abstract
Bromodomain protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, binds to acetylated histone tails via its two bromodomains BD1 and BD2. It forms a complex with the positive transcription elongation factor b which controls phosphorylation of RNA polymerase II, ultimately leading to stimulation of transcription elongation. An essential role of BRD4 in cell proliferation and cancer growth has been reported in several recent studies.
The benzodiazepine JQ-1 is a strong antagonist of the binding of BRD4 to acetylated histone tails and has been used to elucidate the functions of the BET protein family members. JQ-1 is active in vivo in several therapeutic models but reveals a poor pharmacokinetic profile with high clearance and low oral bioavailability in animal studies. We investigated the benzodiazepine core of JQ-1 with the aim of optimization of oral bioavailability. Several possible core variations were identified that kept overall cellular activity but increased metabolic stability. The benzazepine BAY6356 was selected as a potent BET inhibitor with an improved overall pharmacokinetic profile and oral bioavailability between 60 and 100% in mouse, rat and dog. The strong antiproliferative activity observed in vitro in acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines was confirmed in vivo in the MOLM-13 (AML) and MOLP-8 (MM) tumor models implanted in SCID mice. Daily oral treatment at the Maximal Tolerated Dose of 30 mg/kg led to strong tumor reduction in MOLM-13 (17% T/C on day 13 post tumor implantation) and in MOLP-8 (4% T/C on day 19 post tumor implantation) xenografts (T/C≤ 40% = active, T/C≤10% = highly active, according to NCI criteria). In the MOLM-13 model, c-Myc down-regulation was shown in vivo. Furthermore, for a same total dose, intermittent dosing every other day or twice a week in the MOLP-8 model proved to be as active as daily dosing, demonstrating exposure-driven efficacy. These favorable preclinical data support the evaluation of BAY6356 for further development.
Citation Format: Norbert Schmees, Bernard Haendler, Pascale Lejeune, Antje Stresemann, Roland Neuhaus, Stephan Siegel, Amaury Ernesto Fernandez-Montalvan, Hilmar Weinmann, Volker Gekeler. New benzazepine BET-inhibitors with improved oral bioavailability. [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 4749. doi:10.1158/1538-7445.AM2014-4749
Abstract 4759: Integral role of the PI3K-AKT-mTOR pathway in DDR-mediated antitumor actions of PARP inhibitor in triple-negative breast carcinogenesis
Authors: Leyland-Jones Brian , Carlson Jennifer , Sun Yuliang , Friedman Lori , De Pradip , Dey Nandini 
Published: May 2015

Abstract
Background: The PI3K pathway, in addition to its pro-proliferative and anti-apoptotic effects on tumor cells, is known to contribute to DNA-damage repair (DDR). We hypothesized that GDC-0980, a dual PI3K-mTOR inhibitor, would potentiate an anti-tumor effect in BRCA-competent TNBC cells when combined with the PARP inhibitor, ABT888 and carboplatin. Methods: Athymic mice bearing BRCA-competent TNBC xenograft tumors were treated with GDC-0980 alone or in combination with ABT888 and carboplatin. Mechanism-based in vitro studies (MTT, CelltiterGLO, flow cytometry-based live/dead cell, cell cycle analyses, anchorage independent soft-agar, anchorage dependent 3D ON-TOP, apoptosis, cell signaling markers assays) using a panel of 5-7 BRCA-wt /mutant TNBC cell lines were performed. Results: GDC-0980 treatment led to DNA damage (increased pgH2AX; WB, IF), gain in PAR and a subsequent sensitization of BRCA-competent TNBC cells to ABT888 plus carboplatin in a time-dependent manner. The treatment (1) decreased proliferation signals (pAKT, pP70S6K, p4EBP1, pS6RP), PAR/PARP, PAR/pgH2AX, live/dead cell ratios, cell cycle progression and clonogenic 3D growth, and (2) increased apoptosis markers (cl-caspase3, 9, BIM, cl-PARP, and annexinV positivity). These effects were more pronounced in PTEN-null MDA-MB468 than in RAS/RAF mutated MDA-MB231 cells. Three-dimensional projection movie showed that (1) GDC-0980 alone attenuated nuclear pγH2AXS139 foci in MDA-MB468 cells at 24 hours and (2) cytoplasmic cl-caspase3 increased in GDC-0980+ABT888+carboplatin treated MDA-MB468 cells at 72 hours. Finally, GDC-0980 in combination with ABT888 plus carboplatin blocked the growth of established xenograft tumors by 80-90% with a concomitant decrease in tumor Ki67, cl-caspse3, pVEGFR, CD31, p4EBP1, and pS6RP IHC-levels. Conclusion: This is the first mechanism-based study to demonstrate the inhibition of DDR as another mode of action of GDC-0980. Our data revealed that in a BRCA-competent model, GDC-0980 enhanced the antitumor efficacy of ABT888 in the presence of carboplatin by inhibiting the DDR system in conjunction with inhibition of the PI3K-mTOR pathway mediated pro-proliferative and anti-apoptotic signals.
Citation Format: Brian Leyland-Jones, Jennifer Carlson, Yuliang Sun, Lori Friedman, Pradip De, Nandini Dey. Integral role of the PI3K-AKT-mTOR pathway in DDR-mediated antitumor actions of PARP inhibitor in triple-negative breast carcinogenesis. [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 4759. doi:10.1158/1538-7445.AM2014-4759
Abstract 4760: ER-β/Sp/NFκB/FLIP axis: Potential therapeutic target in prostate cancer
Authors: Yun Huiyoung , Xie Jianping , Batth Izhar Singh , Li Rong , Ghosh Rita , Kumar Addanki Pratap 
Published: May 2015

Abstract
Emergence of hormone-refractory prostate cancer is fatal for lack of effective, durable systemic therapeutic strategies. Therefore, discovery of novel approaches and agents that can prevent development of therapeutically resistant disease and its progression is critical for successful management of prostate cancer (PCA). One of the reasons for the inability to implement such strategies is an incomplete understanding of molecular events associated with the development of therapeutically resistant disease. Previously, we reported the anti-tumorigenic potential of 2-methoxyestradiol (2-ME2) both in vitro and in vivo. We showed that (i) transcription factor Sp1 activates while Sp3 inhibits Sp1-mediated transactivation of anti-apoptotic gene FLIP in androgen independent prostate cancer PC-3 cells, and that (ii) 2-ME2-mediated tumor growth inhibitory effects were accompanied by transcriptional down-regulation of FLIP through 745 bp (-503/+242) sequence elements. In order to fully understand the underlying molecular mechanism of 2-ME2 induced down-regulation of FLIP, we generated exonuclease deletion constructs and performed transient transfection assays. These studies led to identification of -121/+242 sequence containing putative bindings sites for NFκB, CREB and AR in addition to Sp1 with maximal promoter activity in androgen responsive (LNCaP) and androgen independent (PC-3 and DU145) cells. Using ChIP assays, we also observed the enrichment of these factors to the endogenous FLIP promoter. Furthermore, androgen stimulation enhanced promoter activity and recruitment of Sp1, NFκB to the FLIP promoter region in LNCaP cells. Surprisingly, we found DHT but not R1881 decreased FLIP promoter activity in DU145 cells. Further molecular investigations indicated enhanced expression of AKR1C3 (aldo-keto reductase) that catalyzes the conversion of DHT to 3β-Adiol (a potent ligand for ER-β) in response to 2-ME2 treatment in DU145 cells. In addition, not only 3β-Adiol treatment reduced proliferation of prostate cancer cell significantly but co-transfection with ER-β reduced FLIP promoter activity. Taken together, these results implicate an important role for ER-β/Sp/NFκB/FLIP in mediating 2-ME2 induced tumor growth inhibitory effects. Supported by VA-Merit Award and CA 135451 (APK).
Citation Format: Huiyoung Yun, Jianping Xie, Izhar Singh Batth, Rong Li, Rita Ghosh, Addanki Pratap Kumar. ER-β/Sp/NFκB/FLIP axis: Potential therapeutic target in 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 4760. doi:10.1158/1538-7445.AM2014-4760
Abstract 4779: DNMT3B (a de novo DNA methyltransferase) epigenetically regulates gene expression, independent of its DNA methyltransferase activity
Authors: Mitchell Khadijah A. , Easwaran Hariharan , Baylin Stephen B. 
Published: May 2015

Abstract
DNA methylation is one of several epigenetic mechanisms used by cells to control gene expression. The de novo methyltransferases, DNMT3a and DNMT3b, establish new methylation patterns during early development. DNMT1, the maintenance methyltransferase, ensures propagation of hemi-methylated DNA. Human cancers are characterized by aberrant DNA methylation patterns, including global hypomethylation and hypermethylation of promoters at tumor suppressor genes. This latter change leads to transcriptional silencing. Experimentally, DNMT1 is capable of transcriptional repression without its methyltransferase activity, partially through interactions with histone-modifying enzymes. We hypothesized DNMT3B may also be capable of modulating gene expression independently of its methyltransferase activity, by recruiting repressive epigenetic proteins to the promoters of endogenous DNMT3B targets.
Using an isogenic colorectal cancer cell culture model, we investigated the functional consequences of the removal and re-introduction of DNMT3B on target gene expression, methylation, and chromatin status. A stable genetic knock out cell line, transient shRNA knock down, and pharmacologic inhibition resulted in upregulation of a subset of candidate DNMT3B targets identified by gene expression arrays and validated by quantitative RT-PCR. Interestingly, reintroduction of both wild-type and catalytically dead mutant DNMT3B in the knockout cells transcriptionally repressed the same loci. Infinium 450K arrays were performed to assess DNA methylation status. As expected, the loss of DNMT3B did not result in significant changes in global methylation at TSS, CpG islands, shores, shelves, and UTRs. However, in selected of the above targets, locus-specific demethylation was identified. Overexpression of both wild-type and catalytically dead mutant DNMT3B failed to restore local methylation, in concert with transcriptional repression of these loci, further suggesting an alternative regulatory mechanism to explain transcriptional changes. Interactions of DNMT3B with other repressive proteins could account for the above transcriptional repression. ChIP studies revealed LSD1, a histone demethylase that represses transcription, is lost in the 3B knockout cells but is recruited back to the promoters of repressed DNMT3B target genes with DNMT3B insertion. These data strongly suggest DNMT3B possesses a non-canonical function as a scaffold protein for transcriptional repressors.
Citation Format: Khadijah A. Mitchell, Hariharan Easwaran, Stephen B. Baylin. DNMT3B (a de novo DNA methyltransferase) epigenetically regulates gene expression, independent of its DNA methyltransferase activity. [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 4779. doi:10.1158/1538-7445.AM2014-4779