bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1136: Synergistic inhibition of bioenergetic pathways in pancreatic cancer cells by mitochondria-targeted nitroxide and glycolytic inhibitors
Authors: Cheng Gang , Zielonka Jacek , Joseph Joy , Kalyanaraman Balaraman 
Published: August 2012

Abstract
Pancreatic adenocarcinoma is one of the most aggressive cancers with a high fatality rate. Currently available chemotherapy for treating pancreatic cancers is ineffective. Emerging research is focused on drugs targeting bioenergetic pathways in tumor cells. Despite decades of evidence that cancer cells have increased aerobic glycolysis, glycolytic inhibition has failed as a chemotherapeutic approach, due in part to enhanced systemic toxicity of antiglycolytic agents. We hypothesized that a combined inhibition of glycolysis and mitochondrial function may represent an alternate therapeutic approach that can potentially overcome the insufficiency of glycolytic inhibition alone. In this study we investigated the chemotherapeutic efficacy of combining mitochondria-targeted nitroxide, Mito-CP (a nitroxide, carboxy proxyl conjugated to a triphenylphosphonium (TPP+) moiety), and inhibitors of glycolysis, 2-deoxy-D-glucose (2-DG) or 3-bromopyruvate (3-BP) in pancreatic cancer cell lines, PANC-1 and MiaPaCa-2. The relative cytotoxicity and mitochondrial bioenergetic changes in pancreatic cancer cells were assessed. We observed that Mito-CP synergized with glycolytic inhibitors (2-DG or 3-BP) in inducing cell death. Using a Seahorse XF24 extracellular flux analyzer, we determined the combined effects of Mito-CP and 2-DG or 3-BP on cellular mitochondrial function and glycolytic function. The combined treatments induced fast and irreversible inhibition of mitochondrial functions and intracellular ATP depletion. Collectively, these results suggest that targeting mitochondrial bioenergetic metabolism with Mito-CP and glycolytic inhibitors such as 2-DG and 3-BP may be a promising chemotherapeutic strategy in pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1136. doi:1538-7445.AM2012-1136
Abstract 1139: Novel, cellular active inhibitors of G6PD, a key mediator of ROS-induced cellular stress
Authors: Jordan Allan M. , Hamilton Niall M. , Hamilton Nicola S. , Hitchin James R. , James Dominic I. , Jones Stuart D. , Lyons Amanda J. , March H. Nikki , Thomson Graeme J. , Waddell Ian D. , Ogilvie Donald J. 
Published: August 2012

Abstract
Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) and catalyses the oxidation of glucose-6-phosphate to glucono-δ-lactone-6-phosphate with the concomitant production of NADPH. Alongside an important role in the production of biosynthetic precursors such as ribonucleotides, this pathway is a major cellular source of NADPH. As such, the pathway plays a critical role in both the biosynthesis of fatty acids & cholesterol biosynthesis (thus supporting cell division) and maintaining glutathione in its reduced state (GSH), the latter ameliorating cellular stress arising from reactive oxygen species (ROS). Given these key roles, modulation of the pathway has potential therapeutic application, and inhibition of G6PD is an attractive target, particularly in combination with standard of care radiotherapy or cytotoxic drugs which can increase ROS. We have developed a series of novel steroid G6PD inhibitors which, in our hands, modulate flux through the PPP and increase ROS-induced stress in cells. This disclosure will describe some of our results in this area.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1139. doi:1538-7445.AM2012-1139
Abstract 114: Study of the high-grade ovarian cancer precursors in the oviduct
Authors: Hwang In Young , Yuan Ju , Ning Gang , Tay Seok Wei , Yamamoto Yusuke , Menghi Francesca , Liu Edison , Crum Christopher P. , McKeon Frank , Xian Wa 
Published: August 2012

Abstract
The discovery that many high-grade ovarian cancers originate in the oviduct has generated a paradigm shift in the field of ovarian cancer. The description of new entities in the oviduct that signify early phases of ovarian carcinogenesis, including both serous tubal intraepithelial carcinomas and their precursors the p53 signatures, has provided a tangible sequence of events leading to malignancy that can be linked to DNA damage and p53 mutations. However, it has become clear that other pathway disturbances also play a critical role in the early development of ovarian cancer. We hypothesize that molecular alterations present in morphologically normal oviductal epithelium from ovarian cancer patients reflect the earliest events in ovarian carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Whole-genome transcriptome analysis of laser microdissected oviductal epithelium from histologically normal ovarian cancer patients and controls was performed. We identified a set of aberrantly expressed genes in the oviductal epithelium from women who developed high-grade ovarian cancer and demonstrated some of these genes are also abnormally expressed in the ovarian cancers due to the genomic alterations. We further examined the function of these genes using three-dimensional cell culture system and mouse models. Our work demonstrates the synergistic effects of defective p53 pathway and other newly found pathways in driving early steps of ovarian cancer development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 114. doi:1538-7445.AM2012-114
Abstract 1141: Telomerase activity in relation to RET mutation status in medullary thyroid carcinoma
Authors: Wang Na , Zedenius Jan , Bäckdahl Martin , Larsson Catharina 
Published: August 2012

Abstract
Background: Medullary thyroid carcinoma (MTC) originates from parafollicular C cells of the thyroid gland, and are associated with activating constitutional or somatic mutations in the RET proto-oncogene. The common somatic mutation of codon 918 is associated with a less favorable clinical outcome. The catalytic component of telomerase, human telomerase reverse transcriptase (TERT) has been found to be reactivated in most human tumors. Objective: In this study, we aimed to investigate telomerase involvement in relation the RET mutational status in MTC. Design: Our study includes 43 cases of MTC from the Karolinska University Hospital. RET mutations were identified by sequencing of the hot spots in exons 10,_11-,_15-, and 16. Expression of the TERT gene, telomerase activity and telomere length were quantified. Result: Among the 43 cases, 18 carried a RET point mutation in exon15 or exon16 (Group I), 5/43 had a point mutation in exon 10 or 11 (Group II), and 20 were wild-type (Group III). Telomerase activity and TERT expression were closely associated. The TERT gene was expressed in 13/18 cases in Group I, in 0/5 in Group II and in 10/20 of Group III. The median telomerase activity was higher in Group I as compared to Groups II and III. Group I tumors showed the shortest relative telomere length. With regard to follow-up, cases with high telomerase activity and TERT gene expression in Group I had less favorable outcome. Conclusion: The findings suggest that TERT/telomerase activity may contribute to aggressive MTC in addition to, or as a consequence of, RET codon 918 mutations. The very low telomerase activity and TERT expression revealed in several of the MTC cases suggest the involvement of alternative mechanisms for telomere stabilization in the MTC entity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1141. doi:1538-7445.AM2012-1141
Abstract 1143: EZH2 promotes oral squamous cell carcinoma initiation and progression through epigenetic silencing of FHL1
Authors: Cao Wei , Chen Wantao 
Published: August 2012

Abstract
Oral squamous cell carcinoma (OSCC) is widely represented as a heterogeneous tumor with more aggressive phenotypes, but the basis for these characteristics remains unknown. In the current study, we show that up-regulation of the Polycomb complex histone methytransferase EZH2 is critical to maintain the malignant phenotypes in OSCC and associated significantly with oral squamous cell carcinoma development in patients with oral leukoplakia (OLP), which represents oral precancerous lesion as well as the worse prognosis of patients with locally advanced OSCC. Patients with OLP (n=76) and OSCC (n=124) from two independent cohort were included in this study. Immunohistochemical analyses on EZH2 in the two cohort revealed that the higher EZH2 levels were strongly associated with dysplasia (P &lt; 0.001) and OSCC development (P &lt; 0.0001) in patients with OLP, as well as worse overall survival (P = 0.001) and disease free survival (P = 0.002) in patients with locally advanced OSCC. Furthermore, upon EZH2 silencing by small interfering RNA (siRNA)-mediated knockdown, the proliferation, anchorage-independent growth and invasion potential of OLP cell line and OSCC cell lines were remarkably suppressed. Available publicly H3K27 modifications based on CpG array and three public microarray datasets (GEO) analyses identified human four-and-half LIM protein 1(FHL1) as a novel candidate target of EZH2 in OSCC. Further depletion of EZH2 by RNA interference (RNAi), the expression of FHL1 was notably restored in OLP and OSCC cell lines. In addition, ablation of FHL1 by RNA interference promoted significantly proliferation and invasion potential of OSCC cells. Together, our findings indicate that aberrantly elevated EZH2 promotes aggressive phenotypes of OLP and OSCC cells and plays a critical role in initiation and progression of OSCC. meanwhile, FHL1 may be a novel target of EZH2 for transcriptional repression in OSCC initiation and progression. ACKNOWLEDGMENTS: This study was supported by the National Natural Science Foundation of China (Grant No. 30973343), Projects of the Shanghai Science and Technology Committee (Grant No. 08JC1414400 and 10XD1402500) and the Shanghai Leading Academic Discipline Project (S30206).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1143. doi:1538-7445.AM2012-1143
Abstract 1145: Molecular markers of neoadjuvant chemotherapy and combined chemoradiotherapy response in patients with oropharynx squamous cell carcinoma
Authors: Hatakeyama Marcia , Reis-Rosa Luciana A. , Marchi Fábio A. , Spilborghs Graziela , Carvalho André L. , Nicolau Ulisses R. , Kowalski Luiz P. , Rogatto Silvia R. 
Published: August 2012

Abstract
The treatment currently considered standard for advanced oropharyngeal tumors involves concomitant chemo- and radiotherapy or surgery followed by adjuvant chemo- and radiotherapy. However, only 30 to 50% of patients with locally advanced disease survive more than three years, even with the advances in surgical techniques and the recognized benefits of therapy combined with radio- and chemotherapy. Treatment with induction TPF (docetaxel plus cisplatin and fluorouracil) chemotherapy followed by chemoradiotherapy was associated with a trend toward improved survival (Posner et al., 2007. N Engl J Med. 357:1705). The aim of this study was to investigate biological markers as potential predictors of response to chemotherapy and/or radiotherapy according to HPV infection in oropharyngeal carcinomas (OC). Thirty-two OC were evaluated by array CGH (4x180k, Agilent). A total of 35% of cases were HPV positives; HPV16 subtype was the most frequently detected (8/37), followed by subtype 18 (2/37). In general, HPV- cases showed a large number of copy number alterations (117 CNAs) in comparison with HPV+ samples. Losses on 7q22.1 and 14q12 were found exclusively in HPV+ tumors (p=0.044). Comparative analysis of genomic alterations among the patients which received combined chemoradiotherapy (22 cases) was done aiming to identify molecular markers that could predict the complete response (CR), partial response (PR) to treatment or progressive disease (PD). Tumors with CR showed a lower number of genomic alterations (90 CNAs versus 110 per cases in PR and PD). Losses at 1p21.3-p21.1 and gains on 10p13-p12.33 and 10p12.31-p12.1(p≤0.017) were exclusively found in patients with PD and PR. Overall survival (OS) analysis between HPV- and HPV+ cases demonstrated no significant differences (p&gt;0.05). HPV- tumors showed more complexity and genomic instability than HPV+ tumors. Genomic losses or gains at different loci have been reported in HPV- compared to few or no alterations in HPV+ cases. In this study, it was detected specific chromosomal imbalances associated with therapy response and consequently, putative candidates to be validated in a large series of cases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1145. doi:1538-7445.AM2012-1145
Abstract 1148: The relationship between the EMT status in primary lung adenocarcinomas and the DFS, and the results of the molecular analyses of lung adenocarcinoma with regard to the IGF1R and EMT status
Authors: Chikaishi Yasuhiro , Uramoto Hidetaka , Takenaka Masaru , Oka Soichi , Nakagawa Makoto , Shimokawa Hidehiko , So Tomoko , Hanagiri Takeshi , Tanaka Fumihiro 
Published: August 2012

Abstract
Background: Predicting the risk of distant micrometastasis of NSCLC after complete surgical resection is a significant problem to solve, and useful molecular markers that can predict recurrence have not yet been identified. The epithelial to mesenchymal transition (EMT) is an important contributor to the invasion and metastasis of epithelial-derived cancer. However, there is currently no data about the EMT status in primary NSCLC and its clinical usefulness to predict the recurrence and disease free survival (DFS). In addition, an association between insulin-like growth factor 1 (IGF1) and EMT-related molecules was reported, therefore, we also analyzed the association between the expression of IGF1R and EMT-related molecules. Methods: Tumor specimens were collected from 182 consecutive patients who underwent a complete resection for lung adenocarcinoma from 2003 to 2007 in our department. We analyzed the expression levels of EMT-related molecules (E-cadherin, gamma catenin and vimentin) in the primary lung adenocarcinoma by immunohistochemisty. We also analyzed the association between the expression of IGF1R and EMT-related molecules in the primary lung adenocarcinoma by immunohistochemisty. Results: The positive expression of E-cadherin, gamma catenin and vimentin was identified in 94 (51.4%), 82 (40.4%) and 32 (17.5%) patients, respectively. Their expression was not correlated with recurrence or disease-free survival (DFS) according to the survival analysis. Positive expression of IGF1R was detected in 43 (23.6%) patients, and its expression was significantly associated with the expression of E-cadherin and gamma-catenin, but not with vimentin.Conclusions: The EMT status in the primary tumor of NSCLC does not predict the recurrence and disease free survival. However, there was a significant association between the expression of IGF1R and several EMT-related proteins in patients with lung adenocarcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1148. doi:1538-7445.AM2012-1148
Abstract 1154: Genetic variation in NFκB signaling pathway genes in colorectal cancer susceptibility and survival
Authors: Ungerbäck Jonas , Belenki Dimitri , Fredrikson Mats , Elander Nils , Verma Deepti , Söderkvist Peter 
Published: August 2012

Abstract
PURPOSE: Genetic alterations in inflammatory genes are associated with chronic inflammatory bowel disease, a well-known risk factor for colorectal cancer (CRC). The purpose of this study was to investigate the association between alterations in inflammatory NFκB signaling pathway genes and CRC susceptibility and survival. EXPERIMENTAL DESIGN: Using 344 CRC cases and 793 randomly selected healthy individuals from southeastern Sweden, we examined seven polymorphisms in NFκB, TNFAIP3, NLRP3, CARD8 and TLR4 genes. Chi-square tests and multiple logistic regression analysis were used to test for associations between the SNPs and CRC susceptibility, while log-rank tests and Cox proportional hazard regression were used to examine the association between the SNPs and CRC-specific survival. Loss of heterozygosity and mutational analyses of TNFAIP3 were carried out in 137 and 79 tumors, respectively. RESULTS: Adjusted for age, gender and polypoid/ulcerative CRC phenotype, a panel of heterozygous and mutant TNFAIP3 (rs6920220), mutant NF B −94 ATTG ins/del and heterozygous NLRP3 (Q705K) was associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2 95% CI 2.5-10.9, P &lt; 0.001). Continuous or partial LOH of 6q23.3, the location of the TNFAIP3 gene was detected in 17% of the colorectal tumors while mutations in TNFAIP3 were detected in two out of 79 colorectal tumors (2.5%). CONCLUSIONS: We propose TNFAIP3 as a novel tumor suppressor in CRC and also present evidence that a panel of the TNFAIP3 (rs6920220), NF B −94 ATTG ins/del and NLRP3 (Q705K) polymorphisms could be used as a prognostic marker to identify patients at high risk for rapid CRC progression and poor survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1154. doi:1538-7445.AM2012-1154
Abstract 1159: Differential expression of BP1 and associated gene networks in breast cancer of African American women and Caucasian American women
Authors: Nguyen Thuan H. , Berg Patricia E. , Ghimbovschi Svetlana , Grizzle William E. 
Published: August 2012

Abstract
Introduction: BP1 is a transcription factor of the homeobox gene family activated in 89% of the tumors of African American women (AAW) compared with 57% of the tumors of Caucasian American women (CAW). AAW with breast cancer have larger tumors and an almost 50% higher mortality rate than CAW. BP1 expression is also associated with larger and more aggressive tumors, suggesting BP1 may contribute to the aggressiveness of tumors of AAW. Importantly, BP1 appears to be involved in the epithelial to mesenchymal transition (EMT), based on (i) activation of Twist, a trigger of EMT, (ii) decreased expression of epithelial markers, and (iii) increased expression of mesenchymal markers in cells engineered to overexpress BP1; EMT can lead to metastasis. Here we set out to identify molecular pathways underlying the discrepancy of breast cancer aggressiveness in AAW and CAW with particular attention to BP1 regulated pathways. Results: Cell line analysis. We analyzed five cell lines derived from tumors of AAW and five derived from CAW for EMT markers, including E-CADHERIN (epithelial) and VIMENTIN (mesenchymal). Interestingly, in both types of cell lines, two were epithelial, one was mesenchymal, and two were not classifiable. Two of the AAW derived cell lines and three of the CAW derived cell lines were further studied using microarrays. Preliminary analysis revealed that MYC, CASPASE3, and PPARG are overly represented in the cell lines derived from AAW compared to their CAW derived counterparts; these cell lines also overexpress BP1. Further studies will be performed to determine other pathways that may be differentially expressed in the cell lines from AAW and to determine whether BP1 regulates those pathways. Clinical studies. Tumor tissues from AAW and CAW, matched for age and stage of breast cancer, will be immunostained to determine differential expression of BP1 and EMT markers, and genes identified by microarray analysis as being regulated by BP1. Localization studies of BP1 protein revealed that the nuclear membrane stained most intensely for BP1, with nucleus &gt; cellular membrane &gt; cytoplasm staining. Nuclear and cytoplasmic staining for BP1 tended to be less for CAW than AAW. Conclusions: Our data identify several molecular pathways that may be preferentially activated in breast cancer of AAW. Genes that are overexpressed in tumors of AAW compared with tumors of CAW would make good targets for therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1159. doi:1538-7445.AM2012-1159