bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5618: Polymorphisms in DNA repair genes are associated with endometrial cancer risk among Japanese women
Authors: Hosono Satoyo , Matsuo Keitaro , Ito Hidemi , Hirose Kaoru , Watanabe Miki , Nakanishi Toru , Tajima Kazuo , Tanaka Hideo 
Published: June 2012

Abstract
Common polymorphisms in DNA repair genes may affect an individual's capacity to repair damaged DNA. Although many former studies have reported an association between several types of cancers and DNA repair polymorphism, the association with endometrial cancer (EC) risk has not been investigated fully, especially in Asian population. To examine the association between DNA repair polymorphisms and postmenopausal EC risk, we conducted a case-control study with 91 EC cases (59 endometrioid adenocarcinoma and 32 other types of carcinoma) and 261 non-cancer female controls from database of Hospital based Epidemiologic Research Program at Aichi Cancer Center. We examined 16 coding SNPs (single nucleotide polymorphism) of 12 DNA repair genes (OGG1, MUTYH, XRCC1, APE1, ADPRT, XPA, XPC, XPD, ERCC1, RAD23B, XPG, ERCC6) by TaqMan Methods. We surveyed lifestyle/environmental information by self-administered questionnaire. Impact of each SNPs on EC risk was evaluated by multivariate unconditional logistic regression models. Further, we examined the gene-gene interaction.
We observed significant association between EC risk and rs1799782 (C&gt;T, Arg194Trp) of XRCC1 [CT: Odds ratio (OR) = 1.74, 95% confidence interval (95% CI) = 0.99-3.04, TT: OR = 2.76, 95% CI = 1.23-6.16; trend p = 0.007]; rs25487 (G&gt;A, Arg399Gln) of XRCC1 [GA: OR = 0.66, 95% CI = 0.39-1.12, AA: OR = 0.15, 95% CI = 0.02-1.16; trend p = 0.019]; rs1136410 (T&gt;C, Val762Ala) of ADPRT [TC: OR = 1.49, 95% CI = 0.84-2.64, CC: OR = 1.92, 95% CI = 0.88-4.18; trend p = 0.076]; and rs17655 (G&gt;C, Asp1104His) of XPG [GC: OR = 0.68, 95% CI = 0.39-1.21, CC: OR = 0.54, 95% CI = 0.26-1.12; trend p = 0.082]. Although both XRCC1 and ADPRT involve in base excision repair, gene-gene interaction of these polymorphisms were not significant; the interaction p between rs1799782 and rs25487 was 0.687; that between rs25487 and rs1136410 was 0.328.
In conclusion, we found significant association between EC risk among postmenopausal Japanese women and DNA repair polymorphisms. Gene-gene interactions between XRCC1 and ADPRT were not significant. These results suggests that DNA repair polymorphisms might be associated with etiology of EC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5618. doi:10.1158/1538-7445.AM2011-5618
Abstract 5619: Exploration of pleiotropic effects of cancer GWAS hits with risk of endometrial cancer in the PAGE study
Authors: Peters Ulrike , Fesinmeyer Megan , Carty Cara , Kocarnik Jonathan , Lin Yi , Haessler Jeffrey , Kooperberg Charles ,   PAGE Consortium
Published: June 2012

Abstract
Introduction: Endometrial cancer is the most common gynecological cancer in developed countries. While so far no genome-wide association study (GWAS) has been published for endometrial cancer this approach has been very successful in identifying susceptibility loci for various cancer sites. Interestingly, these GWAS have discovered susceptibility loci that are associated with multiple cancer sites, such as in the 8q24 or TERT-CLPTM1L locus. To comprehensively explore such pleiotropic effects for endometrial cancer we evaluated whether GWAS hits for different cancer sites are associated with risk of endometrial cancer.
Methods: We included 965 endometrial cancer cases and 5759 controls aged 50-79 years from the Women's Health Initiative, which were genotyped as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. We selected 175 single nucleotide polymorphisms (SNPs) previously shown to be associated with different cancer sites mostly in GWAS. We coded SNPs using additive genetic models and used logistic regression to estimate per allele odds ratios (OR) and 95% confidence intervals (CI). Race/ethnicity-specific models were adjusted for age and post-menopausal hormone use.
Results: Among whites the two most independent significant SNPs were rs7501939/17q12 [odds ratio (OR)=0.82; 95% confidential interval (CI)=0.74-0.92; p-value=3.4e-4], and rs4324715/5q31 (OR=0.85; 95%CI=0.76-0.94; p-value=1.5e-3). Interestingly, these two variants have been related to cancers of the male reproductive system (prostate and testicular cancer, respectively) in prior GWAS. When adjusting for multiple comparisons (p=2.86e-4) only one variant (rs7501939) remained marginally significant. The number of other ancestral groups, such as African American or Asian (n=72) was too small to allow separate analysis.
Conclusion: This first analysis suggests that susceptibility loci of the male reproductive system may be associated with endometrial cancer. The next step in this analysis will be to incorporate data from the other PAGE studies to improve the power, explore effects across different ethnicities and to expand our analysis to evaluate gene-environment interactions, particularly looking at hormone related factors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5619. doi:10.1158/1538-7445.AM2011-5619
Abstract 562: Multi-Kinase Inhibitor: AFPep inhibits the growth and invasion of U87 glioblastoma cells through inhibition of FAK, MAPK, and PKC
Authors: Mesfin Fassil B. , Riccio Alexander , Andersen Thomas T. , Bennett James 
Published: June 2012

Abstract
INTRODUCTION: Glioblastomas are the most frequent tumors of the central nervous system. Patients with a diagnosis of glioblastomas have poor prognosis, and new therapeutic agents are in demand for management of this disease. Here, we report on a novel multi-protein kinase inhibitor, AFPep, with regard to its effects on the growth, invasion, and localization in U87 cells.
METHODS: Proliferation/Invasion Assay: Cells were seeded into wells of plastic tissue culture plates and treated with various concentrations of AFPep. Crystal violet method was used to determine cell numbers. The Matrigel chemoinvasion assay was used to determine the effect of AFPep on U87 cell invasion. During Xenograft growth assay, U87 cells were solidified in fibrin clot and implanted under the kidney capsule of severe combined immunodeficient (SCID) mice. Various doses of AFPep were administrated i.p and tumor growth was monitored during survival laparotomy. Localization assay was performed by utilizing fluorescent-labeled AFPep. Multi-immunoblotting Assay was performed using Kinexus, the KinetworksTM methodology to screen for protein kinase expression profile in GBM before and after AFPep treatment.
RESULTS: AFPep inhibited the growth of U87 cells in culture with it is maximal effect at 10−7 M. Higher concentrations of AFPep (10−6M to 10−4M) inhibited the invasion of U87 cells in a dose dependent manner. Treatment of SCID mice bearing U87 xenografts with 4 mg/Kg/day AFPep resulted in a 50% inhibition of tumor growth. Further, AFPep-Bodipy appeared to be localized in mitochondria and interferes with phosphorylation of FAK, MAPK, and c-kit.
CONCLUSION: AFPep has an inhibitory effect on U87 cells. All studies to date have shown no toxicity. As such AFPep is expected to be tolerated and may be a new agent for the treatment of malignant glioblastomas
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 562. doi:10.1158/1538-7445.AM2011-562
Abstract 569: Shear stress radiatiosensitizes colon cancer cells by downregulating FAK via integrin β1
Authors: Luo Chi-Wen , Wu Chia-Ching , Ch'ang Hui-Ju Mandy 
Published: June 2012

Abstract
Introduction: Interstitial fluid flow plays important role in delivering anticancer agents to tumor tissue. Recent studies suggested that anti-angiogenic or vasculature disrupting agents may enhance the therapeutic effect of radiotherapy by regulating tumor blood flow and interstitial fluid pressure. Although the importance of interstitial fluid flow in modulating tumor microenvironment has been studied, the molecular mechanisms of shear flow on tumor cell survival and sensitivity to therapeutic agents have not been much explored. We would like to investigate the interaction of shear stress with irradiation on tumor cells.
Materials and methods: Human T84 and SW480 colon adenocarcinoma cells were used in this study. Cells were seeded onto glass slides pre-coated with fibronectin, and then subjected to 0-12 dyne/cm2 laminar shear stress in parallel plate flow chamber (PPFC) system for 0-24 hours. Cells were then exposed to 0-8Gy irradiation (IR) by a RS2000 X-ray irradiator. MTT and clonogenic assays were used to study cell survival. Tumor cell cycle and apoptosis were evaluated by flow cytometry and Western blot. Candidate signal molecules were measured by real time PCR and immunoblots with or without pretreatment with cyclohexamide or MG132.
Results: MTT and clonogenic assays revealed a synergistic effect of 24 hour- shear stress and IR on tumor cytotoxicity. Shear stress downregulates FAK, phosphor-FAK, AKT and phosphor-AKT expression but not ILK and GSK3B through integrin β1. Decreased protein expression was mainly through proteosomal degradation but not transcriptional suppression. By enhancing G2/M phase cell accumulation, shear stress increases tumor apoptosis after IR. The above phenomenon was not observed in IR pretreated with 3 hour-shear stress.
Conclusion: The above observation suggests that shear stress may enhance colon cancer cell radiation sensitivity by inducing G2/M arrest, and FAK protein degradation via integrin β1 signaling pathway
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 569. doi:10.1158/1538-7445.AM2011-569
Abstract 570: Radiation resistance of orthotopic glioblastoma xenografts is mediated by increasing CD133+ cell fraction, mobilizing G0 cells into G1 phase, and activating self-renewal and mesenchymal genes
Authors: Liu Zhi-gang , Zhao Xiu-mei , Baxter Patricia , Tao Ya-Lan , Su Jack , Adesina Adekunle , Chintagumpala Murali , Blaney Susan , Xia Yun-Fei , Li Xiao-Nan 
Published: June 2012

Abstract
Pediatric glioblastoma multiforme (pGBM) is a highly aggressive brain tumor with poor prognosis. Resistance to ionizing radiation, which is one of the major therapeutic regimes, is believed to play a critical role in tumor recurrence and ultimate treatment failure. However, little is known about the cellular and molecular mechanisms of radioresistance in pGBM, particularly the in vivo responses of tumor cells toward clinically relevant fractionated radiotherapy. To gain a better understanding of the radioresistance mechanisms, we administered fractionated radiation (2Gy per day × 5 times) to SCID mice bearing pre-established orthotopic xenograft tumors derived from two independent fresh patient tumors. Examination of the xenograft tumors immediately at the end of radiation treatment showed that the fractionated radiotherapy significantly increased the abundance of CD133+ tumor cells, and drove quiescent G0 phase cells (both CD133+ and CD133-) into G1 phase in both models. Immunohistochemical examination of key regulators of stem cell self-renewal revealed elevation of BMI-1 and SOX2 gene expression in vivo in the xenograft tumors. Additionally, we found that radiotherapy promoted mesenchymal transition, as the intensity and distribution of fibronectin, a mesenchymal marker, was remarkably enhanced. Further analysis of the recurrent xenograft tumors ∼ 5 weeks post-fractionated radiation showed that the increased CD133+ fraction, the elevated expressions of BMI-1 and SOX2 as well as fibronection were maintained. In conclusion, our data demonstrated, for the first time, that failure of radiotherapy is mediated by activated pathways related to self-renewal of cancer stem cells and mesenchymal transition. Since this study was conducted in vivo in clinically relevant animal models in a setting that is the closest to human brain tumors, our findings provided strong preclinical evidence to suggest that new stratigies are needed to inhibit these radiation triggered-pathways to improved therapeutic efficacy in pediatric GBM patient.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 570. doi:10.1158/1538-7445.AM2011-570
Abstract 576: Gadd45a sensitizes medulloblastoma cells to irradiation and modulates the cellular switch from migratory to stationary cell phase by downregulating MMP-9
Authors: Asuthkar Swapna , Nalla Arun Kumar , Dinh Dzung H. , Gujrati Meena , Mohanam Sanjeeva , Rao Jasti S. 
Published: June 2012

Abstract
Gadd45a protein is induced in medulloblastoma cell lines by treatment with ionizing radiation (IR), which requires p53 stabilization. The role of Gadd45a in IR-induced G2-M arrest of medulloblastoma cells is demonstrated by its increased binding to Cdc2, thereby inactivating Cdc2 kinase activity. Knockdown of Gadd45a alleviates G2-M blockage and results in decreased binding of Gadd45a to Cdc2. Further, the anti-tumorigenic role of Gadd45a is mediated by the negative regulation of β-catenin and its nuclear translocation, which might decrease the β-catenin/LEF-1-mediated transactivation of cell invasion proteins, such as MMP-9, examined in the present study. Overexpression of Gadd45a protein with IR treatment resulted in decreased nuclear levels of β-catenin, increased cytoplasmic levels of p-β-catenin, and increased distribution of β-catenin on membrane E and N-cadherins. The IR-treated control cells showed contrary results with demonstrated loss of E-cadherin, gain of N-cadherin, and inhibition of β-catenin binding to membrane cadherins as well as increased nuclear translocation of β-catenin. Zymography studies demonstrate the negative regulation of IR-induced MMP-9 activity by Gadd45a overexpression. Wound healing and Matrigel invasion assays confirmed the anti-tumorigenic and anti-metastatic role of Gadd45a in medulloblastoma cell lines. Furthermore, siRNA-mediated knockdown of MMP-9 results in prominent expression levels of Gadd45a protein in animal tumors. Thus, we confirm that overexpression of Gadd45a in combination with ionizing radiation has therapeutic implications by preventing recurrence of MMP-9-mediated cancer cell invasion and effectively containing cells in a static phase by maintaining CCA/CCI.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 576. doi:10.1158/1538-7445.AM2011-576
Abstract 578: Roles of mitochondrial protein kinases in targeted cancer therapy
Authors: Guo Tiannan , Kon Oi Lian , Sze Siu Kwan 
Published: June 2012

Abstract
Targeted cancer therapy is based on the curious dependence that some cancer cells have on a single oncogenic molecule, typically a protein kinase (the phenomenon of “oncogene addiction”). However, the molecular mechanisms of such dependence are incompletely understood. We have adopted a quantitative proteomic approach to investigate the phenomenon that MET-overexpressing cancer cells are paradoxically more sensitive to MET inhibition than cells with basal MET expression. Unexpectedly, we found that mitochondria are a direct target of MET kinase inhibition, in addition to inhibition of plasma membrane MET. Effects on activated MET in the mitochondria of cancer cells that are sensitive to MET inhibition could reflect a novel and critical non-canonical mechanism that contributes to the efficacy of MET-targeted therapeutics. We hypothesize that protein kinases which aberrantly translocate to mitochondria modulate mitochondrial proteins and functions. Here we have employed advanced LC-MS/MS-based stable isotope labeling with amino acids in cell culture (SILAC) quantitative phosphoproteomic approaches to identify, quantify and functionally annotate phosphorylated mitochondrial proteins of various cancer cell lines, including those that are sensitive or resistant to targeted agents. We identified several phosphorylated protein kinases e.g. MET, EGFR, HER2 and HER3, that were translocated to mitochondria of cancer cells. In addition to documenting the first kinome and phosphoproteome of mitochondria in cancer cells, we present evidence showing that the aberrant presence of protein kinases in mitochondria predicts sensitivity to specific kinase inhibitors. In conclusion, our data reveal a novel mitochondrial mechanism of oncogene addiction, and suggest that mitochondrial protein kinases might play decisive roles in molecularly-directed therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 578. doi:10.1158/1538-7445.AM2011-578
Abstract 58: Understanding target biology using protein interactomes
Authors: Mohan Amrita , Bhagwat Shripad V. , Epstein David M. , Miglarese Mark , Pachter Jonathan A. 
Published: June 2012

Abstract
The use of systematic genome-wide physical protein-protein interaction detection methods has led to the generation of large networks of putatively interconnected human proteins including a number of therapeutically relevant disease-associated proteins. These networks have intrinsic value for understanding the pathophysiology of proteins, identification of tractable drug targets within a network, and hypothesis generation with regard to potential pharmacodynamic and patient selection biomarkers for a drug target of interest.
Here, we present a novel approach to utilize a high-confidence human focal adhesion kinase (FAK) protein interaction network to better understand FAK target biology. FAK is a well-studied signaling protein known to directly control cellular motility via mechanosensing. As a large 125 kDa protein with both protein tyrosine kinase and scaffolding functions, FAK is particularly rich in its potential to interact with numerous proteins through SH2 and other interaction domains. By forming a diverse array of target interactions that regulate cytoskeletal structural changes, cellular adhesion, cell migration and cellular proliferation, FAK is believed to be a key regulator of several critical processes in tumorigenesis. It has also been established that human tumors often exhibit FAK gene amplification with resulting increased FAK expression which correlates with cancer progression and poor prognosis. Although the plausible roles of FAK have been well-elaborated, there are limited data available on the precise interplay of biological entities controlling the FAK signaling pathway. In this study, we built a prototypical model representing cross-talk between multiple proteins believed to be involved in the FAK signaling pathway. In doing so, we describe a step by step procedure to assemble a FAK interactome using integrative data mining procedures with publicly available interaction databases such as MINT, BioGRID, DIP and HPRD. Next, we filter this data set by incorporating confidence scores and lines of evidence available corresponding to each interaction to finally derive a high-confidence FAK interactome.
We propose that this approach to generate high-confidence protein interactomes could also be applied to other proteins of interest to facilitate a systems biology approach to elucidate additional biological pathways influencing tumorigenesis, metastasis and other disease states amenable to rational drug discovery.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 58. doi:10.1158/1538-7445.AM2011-58
Abstract 583: Inecalcitol, a 14-epi-analogue of 1,25D3, induces growth inhibition through apoptosis and cell cycle arrest in a squamous cell carcinoma model system
Authors: Ma Yingyu , Yu Wei-Dong , Kong Rui-Xian , Delansorne Remi , Trump Donald L. , Johnson Candace S. 
Published: June 2012

Abstract
Epidemiological and experimental studies have demonstrated that 1,25D3, the active vitamin D metabolite, has broad spectrum anti-tumor activity. However, hypercalcemia may limit its clinical application when administrated inappropriately. An orally available 14-epi-analogue of 1,25D3, inecalcitol (19-nor-14-epi-23-yne-1,25-(OH)2D3, TX522), has shown good clinical tolerance at high and frequent exposure without side effects and hypercalcemia. Therefore, we examined the antitumor activity of inecalcitol in a squamous cell carcinoma (SCC) model system. Inecalcitol at 10 or 100 nM readily induced vitamin D receptor expression in SCC cells. Inecalcitol suppressed SCC cell proliferation in a dose dependent manner as shown by MTT assays. SCC cells underwent G0/G1 cell cycle arrest following inecalcitol treatment, which was accompanied by the induction of p27 protein as shown by immunoblot analysis. Inecalcitol markedly induced apoptosis in SCC cells as examined by annexin V/7AAD staining and DNA fragmentation ELISA assays. The cleavages of caspases 8, 9, and 3 and PARP were observed following inecalcitol treatment in SCC cells. In addition, migration assay revealed that inecalcitol inhibited the motility of SCC cells. Inecalcitol also suppressed the invasion of SCC cells as assessed by Matrigel-based invasion assay. To have a better understanding of the effects of inecalcitol, 1,25D3-resistant variant of SCC (SCC-DR) were employed. The above findings were not observed in SCC-DR cells, indicating the critical role of inecalcitol. Our studies suggest that inecalcitol strongly suppress SCC growth through the promotion of apoptosis and cell cycle arrest. Inecalcitol also inhibits SCC migration and invasion. Thus, inecalcitol may be a promising 1,25D3 analogue for cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 583. doi:10.1158/1538-7445.AM2011-583