bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 895: Discriminant, identifiable plasma metabolites in pancreatic cancer-associated diabetes - candidate early-detection biomarkers
Authors: Urayama Shiro , Tolstikov Vladimir 
Published: May 2015

Abstract
Background: Pancreatic cancer (PDAC) has been associated with development of glucose intolerance and dysregulation. Based on our previous report of strong potential for existence of metabolite biomarkers for PDAC detection, in this study, we have pursued initial characterization of plasma metabolites for discriminating PDAC cases among diabetic patients as a means to delineate further subset of patients who may benefit from screening protocol.
Methods: IRB-approved prospectively collected database and corresponding plasma from UC Davis Pancreas Registry was searched for appropriate cases: PDAC patients with recent-onset diabetes (≤3yrs prior to the index PDAC diagnosis) (Grp 1) and non-PDAC patients with long history of diabetes mellitus (&gt;3 yrs) (Grp 2).
The plasma was processed and non-targeted GC/MS and targeted LC/MS were performed to assay for identifiable plasma metabolites. The data was processed and the peak intensity levels were normalized, scaled and identifiable metabolites were analyzed via metabolomics specific multivariate & bootstrap methods as well as ROC evaluation (Metaboanalyst & ROCCET) for visualization and biomarker development.
Results: We have identified 36 patients in Grp 1 and 22 patients for Grp 2. The metabolite specific multivariate and ROC analyses revealed specific features such as elaidic acid, uric acid, 2,3-propanediol, arachidonic acid, docosahexanoic acid, 5-oxo-EET, lysine, LysoPC(18:2), 9(10)-EpOME, LysoPC(16:0), sphingosine-1-phosphate and others as strong discriminators for recent-onset diabetic patients with pancreatic cancer. Such set yielded AUC of 0.964 with 15 features [CI=0.876-1].
Conclusion: We have demonstrated that an identifiable set of plasma metabolite biomarkers exists for discriminating diabetic patients with developing pancreatic cancer. These features could be utilized in a larger set of new-onset diabetic population for further validation in near-future study.
Citation Format: Shiro Urayama, Vladimir Tolstikov. Discriminant, identifiable plasma metabolites in pancreatic cancer-associated diabetes - candidate early-detection biomarkers. [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 895. doi:10.1158/1538-7445.AM2014-895
Abstract 900: Computing tumor growth rate across pre- and post-treatment periods uncovers anti-tumor activity in patients treated by a pan-CDK inhibitor (BAY1000394)
Authors: Hollebecque Antoine , Ferte Charles , Nitenberg Gerard , Felices Mathieu , Durand-Salmon Alexandre , Ocker Matthias , Soria Jean-Charles 
Published: May 2015

Abstract
Background: Recent studies suggest that tumor shrinkage as measured by RECIST 1.1 criteria may not be adequate to assess early signs of anti-tumor activity in phase I trials. The value of Tumor Growth Rate (TGR) evaluation in this context has been suggested. Methods: We analyzed the TGR of solid tumors from patients prospectively enrolled in a dose-escalation phase I trial investigating the pan-CDK inhibitor BAY1000394 on a 3 days on/4 days off 21 day treatment cycle. Only patients who had tumor imaging evaluation at least one month before the onset of the experimental treatment, a baseline tumor imaging, and at least one tumor evaluation after 2 cycles of treatment were eligible. Patient consent was obtained prior to analysis. We computed the TGR across the pre- (REFERENCE) and post-treatment (EXPERIMENTAL) evaluation, as described by Ferté et al (Clin Cancer Res, 2013) and compared these results to RECIST-based response evaluation. Each patient was used as his/her own control.Results: A total of twelve patients were eligible for both RECIST and TGR evaluation. At the time of first evaluation, 9 patients were classified as progressive disease (PD) and 3 as stable disease (SD) using RECIST. Conversely, TGR decreased in 6 out of 12 patients (median: - 9.8 %; CI 95% - 27.4 to 2.3), suggesting antitumor activity by the investigational drug. However, these 6 patients were classified as PD due to the occurrence of new lesions and then discontinued from the trial. They had small cell lung, colorectal, thymic, and bladder cancer. Interestingly, two patients suffering from ovary adenocarcinoma with durable SD (10 treatment cycles) had almost no tumor growth rate change between the REFERENCE and the EXPERIMENTAL period, suggesting no anti-tumor activity, and could potentially have been discontinued earlier from the trial. Conclusion: Computing the variation of TGR in the context of a phase 1 trial investigating a pan-CDK inhibitor reveals early signs of antitumor activity in specific patients, not previously identified by RECIST. Its use to guide the “go/no go” decision-making in the early drug development context is promising.
Citation Format: Antoine Hollebecque, Charles Ferte, Gerard Nitenberg, Mathieu Felices, Alexandre Durand-Salmon, Matthias Ocker, Jean-Charles Soria. Computing tumor growth rate across pre- and post-treatment periods uncovers anti-tumor activity in patients treated by a pan-CDK inhibitor (BAY1000394). [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 900. doi:10.1158/1538-7445.AM2014-900
Abstract 912: P21-activated kinase 4 (PAK4) as a predictive marker for gemcitabine in pancreatic cancer cell line
Authors: Moon Sung Ung , Kim Jin Won , Sung Ji Hea , Kang Mi Hyun , Chang Hyun , Lee Jeong Ok , Kim Yu Jung , Lee Keun Wook , Kim Jee Hyun , Bang Soo Mee , Lee Jong Seok 
Published: May 2015

Abstract
Pancreatic cancer is a highly lethal disease. Although gemcitabine is activelyused in pancreatic cancer, modest activity and relativeresistanceare revealed.P21-activated kinases(PAKs) are involved in cytoskeletal reorganization, gene transcription, cellproliferation and survival, and oncogenic transformation.The gene amplification and protein overexpression of PAK1 and PAK4were reported in pancreatic cancer, which were associated with K-ras mutation, MUC13 and Smad4. Therefore, we hypothesized that PAKs could predict the drug-sensitivity of gemcitabine in pancreatic cancer and could be a therapeutic target. Using cell viability assay of human pancreatic cancer cell lines (Capan1, Capan2, MIA-paca2, PANC1, Aspc1, SNU213, SNU410) for gemcitabine, Capan-2, PANC-1 and SNU-410 cell lines was identifiedas resistant cell lines for gemcitabine. Through western blots of molecules related with down-steam pathway and drug-sensitivity, higher expression of PAK4 and lower expression of human equilibrative nucleoside transporter 1 (hENT1) were associated with the resistance for gemcitabine. PAK4 down-regulation through siRNA induced the up-regulation of hENT1, which is well-known as predictive marker for gemcitabine activity. In resistance cell lines (Capan-2, PANC-1, SNU-410), down-regulation of PAK4 through siRNArestored the drug-sensitivity for gemcitabine. In conclusion, PAK4 can be a potential predictive marker and therapeutic target in gemcitabine chemotherapy for pancreatic cancer.
Citation Format: Sung Ung Moon, Jin Won Kim, Ji Hea Sung, Mi Hyun Kang, Hyun Chang, Jeong Ok Lee, Yu Jung Kim, Keun Wook Lee, Jee Hyun Kim, Soo Mee Bang, Jong Seok Lee. P21-activated kinase 4 (PAK4) as a predictive marker for gemcitabine in pancreatic cancer cell line. [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 912. doi:10.1158/1538-7445.AM2014-912
Abstract 917: Post-treatment changes in levels of TNF family ligands and XIAP may predict sensitivity to IAP antagonist CUDC-427
Authors: Atoyan Ruzanna , Samson Maria Elena S. , Hantzis Brianne , Ma Anna W. , Yin Ling , Borek Mylissa , Dellarocca Steven , Zifcak Brian , Xu Guangxin , Wang Jing 
Published: May 2015

Abstract
Inhibitors of apoptosis (IAP) proteins are a novel target for cancer therapy. Antagonists of IAP proteins have been shown to synergize with TNF receptor family signaling as well as with standard-of-care chemotherapeutics and targeted therapies. CUDC-427 is a potent, oral, monovalent IAP antagonist poised for more advanced clinical testing after completion of phase 1 trials using two different dosing schedules. Predictive biomarkers of response to CUDC-427 are expected to inform clinical development as monotherapy and in combination with other agents. In this study, we sought to identify potential markers of sensitivity to single-agent CUDC-427. Screening of more than 100 breast, ovarian and hematologic cancer cell lines using a viability assay identified several that are sensitive to CUDC-427 treatment. This sensitivity to CUDC-427 was associated with treatment-induced expression of TNFα or TRAIL in cell lines lacking basal levels of these TNF family ligands. In sensitive cell lines that express high basal levels of TNF family ligands prior to CUDC-427 treatment, induction of apoptosis was independent of NFκB signaling but dependent on caspase 8. Our results also confirmed that the addition of exogenous TNFα sensitized some but not all cell lines to CUDC-427 treatment, as previously reported by others. Interestingly, co-culture with stromal cells also sensitized certain hematologic cancer cell lines to CUDC-427 treatment. In addition, a decrease in XIAP levels was detected in cell lines that were highly sensitive to CUDC-427. These results suggest the potential for using TNF family ligand or XIAP levels pre- and post-treatment as predictive biomarkers of response to CUDC-427.
Citation Format: Ruzanna Atoyan, Maria Elena S. Samson, Brianne Hantzis, Anna W. Ma, Ling Yin, Mylissa Borek, Steven Dellarocca, Brian Zifcak, Guangxin Xu, Jing Wang. Post-treatment changes in levels of TNF family ligands and XIAP may predict sensitivity to IAP antagonist CUDC-427. [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 917. doi:10.1158/1538-7445.AM2014-917
Abstract 919: BIM as a predictive biomarker for VEGFR inhibitor in metastatic renal cell carcinoma
Authors: Kim Jee Hung , Lee Hoi Young , Kwon Woo Sun , Park Kyu Hyun , Lim Ho-yeong , Ahn Joong Bae , Chung Hyun Cheol , Rha Sun Young 
Published: May 2015

Abstract
Angiogenesis is an important target for metastatic renal cell carcinoma(mRCC), resulting in several VEGFR tyrosine-kinase inhibitors(TKIs)in clinical practice. Approximately 35% of mRCC patients do not get the benefit from TKIs treatment, including sunitinib, sorafenib or the other VEGF pathway blockers, due to resistance and/or drug induced toxicities. Despite these initial insights, no validated biomarkers that identify which mRCC patients benefit most from antiangiogenic therapy have been discovered. Pro-apoptotic Bcl-2 family member (BIM) is a particularly critical mediator of targeted therapy-induced apoptosis in solid tumors. BIM upregulation is required for TKI to induce apoptosis in tyrosine kinase driven cancer. According to recent several studies, BIM deletion polymorphism was identified as one of the primary resistant mechanisms of various TKIs in EGFR mutated NSCLC or CML. However, there has been no study that confirms germline BIM deletion could confer the resistance to several VEGFR TKIs in treatment with mRCC. Here, we evaluated the possibility of germline and tumor tissue BIM deletion as a potential biomarker for VEGFR TKI resistance in mRCC. BIM deletion polymorphism status of gDNA from 55 formalin fixed paraffin embedded(FFPE) tumor tissues and 98 peripheral blood mononucleated cells (PBMC) of mRCC patients was determined by separated PCR. BIM protein expression level was evaluated by immunohistochemistry. Among these samples, 19 samples overlapped FFPE and PBMC and these sample results were exactly the same comparing either wild type or deletion. BIM deletion(heterozygous) accounted for 18.2% of the 121 total mRCC patients.We observed these patients with BIM deletion showed poor prognosis with TKIs treatments (response rate of treatment with sunitinib in BIM wild group and BIM deletion group : 24.6% versus 16.7%). Our study identified BIM a possible genetic biomarker that can predict the efficacy to VEGFR TKIs treatment in mRCC patients. Especially, as germline BIM deletion in the PBMC showed the concurrdence with tissue polymorphysim, it might be feasible to predict the response to antiangiogenic agent therapy simply through simple blood sampling. In conclusion, BIM deletion polymorphism might be a useful candidate marker for selecting mRCC patients for TKIs treatment.
Citation Format: Jee Hung Kim, Hoi Young Lee, Woo Sun Kwon, Kyu Hyun Park, Ho-yeong Lim, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha. BIM as a predictive biomarker for VEGFR inhibitor in metastatic renal cell 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 919. doi:10.1158/1538-7445.AM2014-919
Abstract 925: Single nucleotide polypmorphisms in the estrogen receptor gene as a determining factor in Tamoxifen-treated ovarian cancer
Authors: Mojica Wilfrido , Mojica Paul , Sykes Don 
Published: May 2015

Abstract
Epithelial Ovarian Carcinomas (EOC) frequently present as late stage malignancies. Because of this lengthy, clinically silent period, a significant number of mutations may accumulate with each emerging clonal population. After surgical removal and chemotherapy, recurrent disease may still occur. Opting for hormonal therapy is a treatment consideration for those patients who have asymptomatic recurrence or, if they are not tolerating treatment well, may require a break from chemotherapy. However, because of the aggressive nature of EOC, hormonal treatment should be administered only if it will provide some efficacious benefit. The active metabolite of Tamoxifen (OH-tamoxifen) can function as a hormonal antagonistic agent to estrogen driven EOCs. However, single nucleotide variations and/or mutations in the ligand binding domain (LBD) of the estrogen receptor alpha (ESR1) gene may negatively affect the ability of OH-tamoxifen to bind and effect its desired action, resulting in wasted time and treatment. Identification of nucleotide variants/ mutations in the ESR1 LBD may be of clinical importance by identifying patients with EOC who may be better suited for treatment with other agents. In this study we identified twelve cases of ESR1(+) EOC in which the treating clinician had requested immunohistochemical confirmation of ESR1 expression. Four separate primer pairs were designed to encompass the amino acids responsible for OH-tamoxifen binding identified from a previous crystallography study. These same regions responsible for binding OH-tamoxifen were also queried in the dbSNP database for nucleotide variations. Representative tissue blocks with &gt;80% tumor content were selected from each case. DNA was extracted from formalin fixed, paraffin embedded tissue sections and subjected to the polymerase chain reaction creating 48 different samples. The resulting amplicons were purified and sequenced, followed by basic local alignment analysis to the most recent NCBI homo sapien gene annotation for the ESR1 gene. No variants were identified in the dbSNP database for the regions of interest. Our results found only one silent nucleotide variation which was located in exon 10. Prior to this study the justification for using tamoxifen in EOC was empiric. Our results indicate that the absence of nucleotide variations in the critical ESR1 LBD for OH-tamoxifen provide scientific evidence and support for its’ continued usage as an optional treatment modality in ESR1(+)EOC.
Citation Format: Wilfrido Mojica, Paul Mojica, Don Sykes. Single nucleotide polypmorphisms in the estrogen receptor gene as a determining factor in Tamoxifen-treated ovarian 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 925. doi:10.1158/1538-7445.AM2014-925
Abstract 929: Identification of ZBTB20 as a novel oncogene associated with the gender bias occurrence of hepatocellular carcinoma
Authors: Keng Vincent W. , Tschida Barbara R. , Kuka Timothy P. , Moriarity Branden S. , Bell Jason B. , Largaespada David A. 
Published: May 2015

Abstract
The role of zinc finger and BTB domain containing 20 (ZBTB20) in hepatocellular carcinoma (HCC) is not well defined, as there are many discrepancies in the literature regarding its role in liver tumorigenesis. ZBTB20 has been implicated to play a role in liver cancer as a potential oncogene where increased expression is associated with poor survival. Conversely, it has been shown to be a transcriptional repressor of the alpha-fetoprotein (Afp) gene in adult liver using knockout studies, and reduced levels of ZBTB20 allow for upregulation of AFP with increased tumor severity in certain cases of HCC. Zbtb20 was initially identified as a candidate liver cancer gene in a forward genetic screen using the Sleeping Beauty (SB) insertional mutagenesis system in mice. In order to determine the role of ZBTB20 in liver cancer, the SB transposon system was used as a genetic tool to randomly integrate ZBTB20-expression vectors into the genome of fumarylacetoacetate hydrolase (Fah)-deficient mouse hepatocytes by hydrodynamic injection. This method of reverse genetics is a powerful tool for in vivo validation of novel oncogenes and tumor suppressor genes. Hepatocytes transgenic for ZBTB20 and in the context of tumor protein p53 (TP53) inactivation developed liver tumors in a male gender bias manner. Although ZBTB20 induced hepatic hypertrophy in both genders, hepatomegaly was observed exclusively in male animals. Interestingly, activation of the ß-catenin (Ctnnb1) dependent Wnt signaling pathway was observed in all male experimental injected animals, indicating the role of Zbtb20 in this important pathway for liver tumorigenesis. Taken together, these results implicate the role of ZBTB20 as a novel oncogene involved in the gender bias occurrence of HCC.
Citation Format: Vincent W. Keng, Barbara R. Tschida, Timothy P. Kuka, Branden S. Moriarity, Jason B. Bell, David A. Largaespada. Identification of ZBTB20 as a novel oncogene associated with the gender bias occurrence of hepatocellular 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 929. doi:10.1158/1538-7445.AM2014-929
Abstract 94: The role of Pik3ca in uterine gland morphogenesis and fertility in mice
Authors: Shin Heesung , Kim Tae Hoon , Yoo Jung-Yoon , Zhao Jean J. , Lydon John P. , Ha Un-Hwan , Jeong Jae-Wook 
Published: May 2015

Abstract
Pik3ca mutations are frequently observed in endometrial carcinomas. Inappropriate activation of PI3Kα-mediated signaling results in increased AKT-dependent or AKT-independent signaling. The PI3K/AKT signaling pathway plays a critical role in the maintenance of equilibrium between cell survival and apoptosis. In order to investigate the role of Pik3ca in uterine function and tumorigenesis, we generated a mouse model in which Pik3ca gene expression is ablated specifically in the PR-expressing cells (PRcre/+ Pik3caf/f). Ablation of Pik3ca was confirmed by real time PCR, western blot, and immunohistochemical analysis of the uteri. PRcre/+ Pik3caf/f mice were subfertile due to defective uterine development. PRcre/+ Pik3caf/f mice showed significantly decreased uterine weight compared Pik3caf/f mice at 2 months of age. Interestingly, PRcre/+ Pik3caf/f mice exhibited a defect of endometrial gland development. Number of glandular epithelia were significantly decreased in PRcre/+ Pik3caf/f mice compared to control Pik3caf/f mice. The expression of Foxa2, a specific glandular epithelial marker, was significantly decreased in PRcre/+ Pik3caf/f mice and apoptosis was significantly increased in the luminal epithelium of PRcre/+ Pik3caf/f mice. These results indicate that Pik3ca plays a role in female fertility and uterine development.
(This work was supported by NIH U54 HD007495 to J.P.L, Basic Science Research Program (2010-0009047) funded by the MEST, Korea to U-H.H., and NIH R01 HD057873 and American Cancer Society Research Grant RSG-12-084-01-TBG to J.W.J.)
Citation Format: Heesung Shin, Tae Hoon Kim, Jung-Yoon Yoo, Jean J. Zhao, John P. Lydon, Un-Hwan Ha, Jae-Wook Jeong. The role of Pik3ca in uterine gland morphogenesis and fertility in mice. [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 94. doi:10.1158/1538-7445.AM2014-94
Abstract 958: Activation of COL11A1 by anticancer drugs through IGF-1R/PI3K pathway confers chemoresistance in ovarian cancer via activating NF-κB-mediated Twist1 expression
Authors: Wu Yi-Hui , Huang Yu-Fang , Chou Cheng-Yang 
Published: May 2015

Abstract
Epithelial ovarian carcinoma remains the most lethal gynecologic malignancy. While initial response to first-line therapy (consisting of surgical cytoreduction and combination platinum/taxane therapy) is usually effective, the majority of patients will ultimately recur with chemotherapy-resistant cancer and succumb to disease. Biomarkers that predict patient's responsiveness to chemotherapy might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the molecular mechanisms of collagen type XI alpha 1 (COL11A1) in chemo-resistance of ovarian cancer. We analyzed the expression profiles of 60 epithelial ovarian cancer tissue samples obtained at first cytoreductive surgery to identify genes linked with chemotherapy response. Among the 47 selected genes, collagen type XI alpha 1 (COL11A1) was the most highly elevated in chemo-resistance tumors. Small interference RNA-mediated specific reduction in COL11A1 protein levels increased the sensitivity to cisplatin and taxol in ovarian cancer cells. A combination of experimental approaches, including real-time RT-PCR, western blotting, luciferase assay and chromatin immunoprecipitation (ChIP) assays, showed that COL11A1 knockdown attenuated Twist1 expression and suppressed binding of NF-κB to its putative Twist1 promoter binding site, suggesting that the NF-κB/Twist1 axis is upregulated by COL11A1. Cisplatin and taxol treatment triggers the activation of IGF-1R/PI3K signaling cascades, leading to activation of COL11A1 and Twist1. Pharmacological inhibition of PI3K abrogated the cisplatin and taxol-triggered, COL11A1-dependent chemo-resistance. Furthermore, the c/EBPβ binding site on the COL11A1 promoter was identified as the major determinant of cisplatin and taxol-dependent COL11A1 activation. Analysis of 88 ovarian cancer patients indicated that high COL11A1 mRNA levels are significantly associated with high Twist1 mRNA levels and poor clinical outcome. We conclude that activation of COL11A1 by anti-cancer drugs through IGF-1R/PI3K pathway confers chemo-resistance in ovarian cancer cells via activating NF-κB-mediated Twist1 expression.
Citation Format: Yi-Hui Wu, Yu-Fang Huang, Cheng-Yang Chou. Activation of COL11A1 by anticancer drugs through IGF-1R/PI3K pathway confers chemoresistance in ovarian cancer via activating NF-κB-mediated Twist1 expression. [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 958. doi:10.1158/1538-7445.AM2014-958