bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 314: Effect of dietary carbohydrates and exercise on prostate cancer progression in LNCaP xenograft model.
Authors: Ge Xiangfeng , Venier Natalie , Fleshner Neil , Klotz Laurence , Venkateswaran Vasundara 
Published: August 2014

Abstract
Introduction: Prostate cancer (PCa) is the second leading cause of death among North American men. There are many risk factors for PCa, dietary as well as physical activity play a role in the development and progression of the disease. Our lab has previously reported that increased intake of dietary carbohydrates was associated with increased tumor growth and activation of signaling pathways distal to the insulin receptor in a murine model of prostate cancer. In humans, one of the most potent stimulants for insulin production is glucose consumption and carbohydrate restriction reduces serum insulin and IGF-I levels to a greater extent than dietary fat restriction. Numerous studies have also found an inverse relationship between exercise and PCa progression. For example, a study by Barnard et al (2003) demonstrated that regular physical activity in PCa patients decreased serum insulin and IGF-I levels, and also elevated IGF binding protein I. However, the exact relationships between diet, exercise and PCa, as well as their underlying mechanisms, are unclear. Herein we aim to investigate the effect of sustained aerobic exercise on PCa tumour growth in animals placed on a high carbohydrate diet.
Methods: Athymic (6 -8 week old) nude mice (n=40) were inoculated subcutaneously with 1 million LNCaP cells. Mice were fed ad libitum with a high-carbohydrate (HC) diet or a low-carbohydrate (LC) diet. Animals were randomized into four groups: HC with and without exercise, LC with and without exercise. Exercise was implemented for 5 days/week (3 x 15 mins; 2-min breaks between cycles; 2.0-10.0 m/min) using a forced exercise wheel. Exercise was performed for a period of 10 weeks. Body weights, tumour volumes, and food consumption were recorded tri-weekly. Blood samples were obtained by sephenous vein bleeding at various times during the study period. Comparisons between groups over time were performed using RANOVA Type 3 Tests of Fixed Effects.
Results: There were no significant differences in animal weight and food consumption between groups. Tumour growth, wet tumour weights were not significantly different between groups. However it was very interesting to note that animals from the exercise group had a slower tumour growth rate compared to animals from the no exercise group.
Citation Format: Xiangfeng Ge, Natalie Venier, Neil Fleshner, Laurence Klotz, Vasundara Venkateswaran. Effect of dietary carbohydrates and exercise on prostate cancer progression in LNCaP xenograft model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 314. doi:10.1158/1538-7445.AM2013-314
Abstract 3142: Whole genome sequencing of oligodendrogliomas identifies genes mutated at a low frequency that contribute to tumor formation.
Authors: Erdem-Eraslan Lale , de Wit Maurice , Heijsman Daphne , Kremer Andreas , van der Spek Peter J. , Sillevis Smitt Peter A.E. , French Pim J. 
Published: August 2014

Abstract
Background: Causal genetic changes in oligodendrogliomas (OD) with 1p/19q codeletion include mutations in IDH1, IDH2, CIC and FUBP1. Here, we have performed whole genome sequencing on three ODs to determine whether additional genetic changes contribute to tumor formation.
Methods: We performed whole genome sequencing of DNA from 3 ODs grade III with 1p/19q codeletion and matched germline DNA. Targeted resequencing of identified genes was performed in an additional 32 ODs with 1p19q LOH (28/32) or partial loss of 1p (2/32), 19q (2/32). All mutations were validated by Sanger sequencing. Constructs of wildtype and mutated genes were subsequently generated (n=13), fused to GFP for visualization. Established cell lines were created to perform functional analysis.
Results: Whole genome sequencing identified a total of 55 mutations in coding exons (range 8-32 mutations per tumor), including the known molecular abnormalities in IDH1 (2/3), IDH2 (1/3), CIC (2/3) and FUBP1 (1/3). Mutations in the ATRX gene were not identified. In addition to these known genes, we identified mutations in additional genes, most of which were previously not implicated in ODs. We first examined the mutation frequency of these genes in an additional 32 tumors. No additional mutations were identified. We then performed functional analysis on a subset of these mutations. For ZNF238, we observed a difference in the sub cellular localization between wildtype and mutant contructs; the wildtype protein localized to the nucleus while the mutant protein is present in the cytoplasm. In addition, stably transfected ZNF238 mutant cell line shows increased proliferation compared to wildtype.
Conclusion: Our results confirm that mutations in IDH, CIC and FUBP1 are present at high frequency in oligodendrogliomas with 1p/19q loss. Functional analysis of infrequently mutated genes provide evidence that they contribute to oncogenesis.
Citation Format: Lale Erdem-Eraslan, Maurice de Wit, Daphne Heijsman, Andreas Kremer, Peter J. van der Spek, Peter A.E. Sillevis Smitt, Pim J. French. Whole genome sequencing of oligodendrogliomas identifies genes mutated at a low frequency that contribute to tumor formation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3142. doi:10.1158/1538-7445.AM2013-3142
Abstract 3154: Genomic landscape of metastatic colorectal cancer.
Authors: Krijgsman Oscar , Haan Josien , Carvalho Beatriz , Meijer Gerrit A. , Ylstra Bauke 
Published: August 2014

Abstract
Background: Colorectal cancer (CRC) results from the accumulation of multiple genetic and epigenetic alterations in the genome of colorectal epithelial cells. Next to large genomic DNA copy number changes, small focal alterations can be identified, often enriched for known cancer genes. However, not all tumors present the same pattern of alterations, as CRC is a heterogeneous disease. The varying underlying biology results in different clinical outcomes, such as response to treatment. The present study aimed to document the landscape of DNA copy number changes, with special focus on focal alterations, in primary tumors of a defined subset of colorectal cancer patients who develop metastatic disease and are eligible for systemic treatment. Material and methods: Tumors were selected from mCRC patients, who participated in two Dutch multicenter phase III clinical trials, i.e. CAIRO and CAIRO2 and were treated according to three different regimens . For all patients well-defined clinical data is available. Alterations were analyzed by high-resolution array comparative genomic hybridization (aCGH), with DNA isolated from formalin-fixed paraffin-embedded (FFPE) archival blocks of 349 patients. As a reference matched normal germ-line material was used. In this way only tumor specific alterations were identified. Also, frequent copy number variations present in the general population can be distinguished from actual somatic alterations. Results: Most frequently observed large chromosomal alterations were losses of chromosomes 8p and 18 and gains of chromosomes 7, 8q 13, and 20. Seven genomic regions were significantly associated with progression free survival (PFS). The focal alterations detected are significantly enriched for cancer genes and genes frequently mutated in colorectal cancer. The gene list includes PTEN, TP53, PARK2, A2BP2 and ATBP2 located in focal losses. On focal amplifications known drugtargets such as ERBB2, EGFR and VEGF were found. Conclusion: Based on initial results we hypothesize that DNA copy number profiling may be used for therapy selection and to guide individualized anticancer therapy. Chromosomal copy number alterations in CRC have been related to response to treatment. Moreover focal alterations were enriched for cancer genes. This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine
Citation Format: Oscar Krijgsman, Josien Haan, Beatriz Carvalho, Gerrit A. Meijer, Bauke Ylstra. Genomic landscape of metastatic colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3154. doi:10.1158/1538-7445.AM2013-3154
Abstract 3163: ZMAT3, a signature gene for sporadic osteosarcoma.
Authors: Baciu Cristina , Porat Rinnat , Pienkowska Margaret , Alon Noa , Wasserman Jonathan , Malkin David 
Published: August 2014

Abstract
Osteosarcoma (OS) is a primary bone malignancy with high incidence in children and young adults. It frequently occurs in patients with strong cancer history (Li-Fraumeni syndrome, retinoblastoma), but the etiology of sporadic OS is still uncertain. The present study is an intensive investigation on susceptibility to sporadic osteosarcoma by genome wide copy number analysis. We evaluated the hypothesis that germline copy number variants (CNVs) could act as a source of genetic susceptibility that may contribute to the development of sporadic osteosarcoma. We analyzed 78 sporadic pediatric OS cases and 2375 controls using Affymetrix SNP 6.0 Array.
Two independent methods, Genotyping Console™ (Affymetrix) and Birdsuite (Broad Institute) were employed to call for CNVs. Outliers with large genomic alterations and TP53 mutations were flagged and filtered out. Both bioinformatics methods show similar distribution of CNVs per chromosome, with slightly higher range depicted by Genotyping Console™, with an enriched set of CNVs in the diseased data. Bioinformatics analysis predicts overlap of copy number variable regions with several candidate genes (PIK3CA, STK11, AKT3, ZMAT3, BAI1), for selected samples. We validated these findings by performing real time quantitative PCR experiments that not only verified most of the computational results, but also identified more amplifications, in an extended selection of samples and regions. The most affected candidate gene, showing gain in 66% of osteosarcoma samples tested, is ZMAT3 (Chr. 3q26.32). A very recent method, digital droplet PCR (BioRAD), with very high sensitivity, also confirms qPCR results, although for a smaller number of samples.
In addition to calling for CNVs, pathways analyses have been also pursued, to address the hypothesis that disruption of multiple genes from the same pathway in the germline of a particular individual may cause susceptibility for developing osteosarcoma. DAVID software predicted several pathways that are enriched, p53 being one of them. Further investigations by KEGG suggest that several genes, including ZMAT3, are disrupted in the p53 signaling pathway. In order to validate these findings, functional assays on osteosarcoma derived lymphoblastoid cell lines are designed and currently in progress. In all, the current study suggests that ZMAT3 could represent a good candidate signature gene for susceptibility to sporadic osteosarcoma.
Citation Format: Cristina Baciu, Rinnat Porat, Margaret Pienkowska, Noa Alon, Jonathan Wasserman, David Malkin. ZMAT3, a signature gene for sporadic osteosarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3163. doi:10.1158/1538-7445.AM2013-3163
Abstract 3181: The genomic evolution of prostate cancer under the selective pressure of anti-androgen therapy.
Authors: Gsponer Joël R. , Dietsche Tanja , Rufle Alexander , Lenkiewicz Elisabeth , Zellweger Tobias , Bachmann Alexander , Von Hoff Daniel D. , Barrett M T. , Rentsch Cyrill , Ruiz Christian , Bubendorf Lukas 
Published: August 2014

Abstract
Background: The implementation of novel technologies such as array comparative genomic hybridization (aCGH) and next-generation sequencing has led to a deeper understanding of the genomic nature of cancer. However, these analyses have classically been done without respecting intra-tumor heterogeneity. Here, we applied a methodology that allows us analyzing the genomic profile of distinct tumor populations from individual tumors and their clonal evolution during the progression to castration-resistant disease. Methods: Matched pre- and post- hormone treated fresh frozen and/or formalin fixed prostate cancer samples were selected from our biobank. Clonal tumor populations were flow-sorted according to their nuclear DNA content. Sorted tumor populations were subjected to whole genome CGH and to full exome sequencing analyses by the use of Agilent SurePrint 2x400k microarrays and the SureSelect All Exon Kit, respectively. Results: The genomic analyses of the tumor samples underscore the presence of significant intra-tumoral heterogeneity. The analysis of matched tumor specimens allowed us to identify two particular patterns of tumor evolution during the progression after treatment: First, a more parallel pattern of tumor evolution, in which the ancestor population is breeding multiple aneuploid tumor clones. In this case, only the 2N ancestor population is able to withstand therapy by the acquisition of few specific genomic aberrations whereas the aneuploid populations are eradicated. Second, a more sequential pattern of tumor evolution with a tumor population that evolves out of a continuous line of clones. This population shows increasing signs of genomic instability over time, with a punctual event of chromothripsis (a massive destruction and rearrangement of chromosomal structures) resulting in castration-resistant clonal tumor populations. Conclusions: Genomic profiling of distinct clonal tumor populations during prostate cancer progression allows for analysis of intra-tumoral heterogeneity and the underlying clonal evolution. Importantly, this approach identifies genomic aberrations that were selected for under the pressure of hormone ablation therapy.
Citation Format: Joël R. Gsponer, Tanja Dietsche, Alexander Rufle, Elisabeth Lenkiewicz, Tobias Zellweger, Alexander Bachmann, Daniel D. Von Hoff, M T. Barrett, Cyrill Rentsch, Christian Ruiz, Lukas Bubendorf. The genomic evolution of prostate cancer under the selective pressure of anti-androgen therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3181. doi:10.1158/1538-7445.AM2013-3181
Abstract 3186: Characterizing the antitumor effects of inhibiting translation initiation in glioblastoma multiforme.
Authors: Rajakumar Arjuna K. , Nalbantoglu Josephine 
Published: August 2014

Abstract
Oncogene addiction is the process by which a tumor cell becomes increasingly dependent on the expression of a particular gene for the maintenance of its tumorigenicity. Alleviating this dependence via genetic or pharmacological means may profoundly inhibit tumor growth. However many cancers are not dependent on a single gene for survival. Glioblastoma Multiforme (GBM) presents itself with many genetic aberrations contributing to its aggressive phenotype. These include loss of PTEN, amplification of CDK4 and EGFR among others, making targeting a single genetic node ineffective where other oncogenic networks may buffer any therapeutic benefit. Over the last 10 years it has been shown that targeting protein translation initiation results in the simultaneous targeting of many oncogenic pathways. Translation initiation is highly implicated in tumorigenesis with over 10 initiation factors acting as either proto-oncogenes or tumor suppressors, the most well described being the eIF4E. The overexpression of eIF4E in many cancers results in messenger RNA discrimination giving rise to an increased translation of a subset of oncogenic mRNAs with highly structured 5’UTRs. However the precise role translation initiation plays in maintaining tumorigenicity in GBM and the subsequent anti-neoplastic properties of its inhibition are not known. Here, we characterize the anti-tumor effects of targeting protein translation in three glioblastoma cell lines U87MG, U251N and the highly aggressive U87ΔEGFR, using a small molecule inhibitor of eIF4E, 4EGI-1. We show that 4EGI-1 severely impairs cell survival over a 72 hour time interval, in a dose-dependent manner. This is marked by an arrest of cell proliferation starting at 24 hours, induction of apoptosis at 48 hours with increased annexin V staining and a decrease in cell motility. We found these effects coincide with a decrease in protein expression of several oncogenes with highly structured 5’UTRs after treatment with 4EGI-1 including cell proliferation proteins c-Myc and Cyclin D1 which are completely lost by 48 hours and regulators of apoptosis such as Bcl-xL, Mcl-1 and Survivin which decrease and are lost by 72 hours, while not affecting overall transcription of these genes. Our results demonstrate the sensitivity of gliomas towards inhibition of translation initiation. This further highlights translation regulation control as a strong force in cancer therapy, particularly in glioblastoma where options are limiting.
Citation Format: Arjuna K. Rajakumar, Josephine Nalbantoglu. Characterizing the antitumor effects of inhibiting translation initiation in glioblastoma multiforme. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3186. doi:10.1158/1538-7445.AM2013-3186
Abstract 3187: Nucleolin-induced cap-independent translational pathway involved in Sp1 accumulation in tumorigenesis.
Authors: Hsu Tsung-I , Hung Jan-Jong , Chang Wen-Chang 
Published: August 2014

Abstract
Sp1 is a transcriptional factor to regulate numbers genes related to cell proliferation, apoptosis and tumor progression. Previous studies indicate that Sp1 is induced significantly through modulating its transcriptional activity and protein stability. To detail study the level of Sp1 protein and mRNA in tumorigenesis found that Sp1 mRNA was just increased a little, but Sp1 protein was increased dramatically, implying that enhancement of translational activity by nucleion might be important in the Sp1 accumulation in tumor progression. Here we found a Y-shift motif within the 5’-UTR of the Sp1 mRNA, and to study the contribution in Sp1 level found that the 5’-URT could enhance the translational efficiency of Sp1. Using this Y-shift motif as a probe fished the interacted proteins. Several RNA binding proteins were identified by LC/MS/MS, and nucleolin is one of them. To further address the effect of nucleolin in Sp1 induction found that nucleolin overexpression did not alter the level of Sp1 mRNA, but increased the translational activity obviously. In addition, the signal transduction pathway was also studied, and found that EGFR and Kras pathways might be involved in the induction in the cap-independent pathway in Sp1 induction in tumorigenesis. Taken the previous studies and this study together, during tumor formation, several strategies including increasing the transcriptional activity, protein stability and translational efficiency were used to induce the Sp1 level to regulate many oncogenes to enhance the cancer progression.
Keywords: Nucleolin, Sp1, Cap-independent pathway,
Citation Format: Tsung-I Hsu, Jan-Jong Hung, Wen-Chang Chang. Nucleolin-induced cap-independent translational pathway involved in Sp1 accumulation in tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3187. doi:10.1158/1538-7445.AM2013-3187
Abstract 3190: Inhibition of the translation of A-myb mRNA by tumor suppressor protein Pdcd4.
Authors: Biyanee Abhiruchi , Klempnauer Karl-Heinz 
Published: August 2014

Abstract
Pdcd4 (Programmed cell death protein 4) was first identified as a protein to be expressed during apoptosis. Later it was shown that Pdcd4 acts as a tumor suppressor protein and regulates the cellular processes on various levels, encompassing transcription and translation. Pdcd4 interacts with the translation initiation factor eIF4A and inhibits its helicase activity which is required to unwind secondary structures in the 5’UTRs of mRNAs. Previous studies on artificial mRNAs have revealed that it inhibits the translation of mRNAs with secondary structures in their 5’ UTRs. Recently, c-myb mRNA was identified as a natural target RNA of Pdcd4. A-myb is a member of the myb family which is expressed in certain hematopoietic cells, such as B-cells, but also in certain non-hematopoietic cells. We have observed that Pdcd4 inhibits the translation of A-myb mRNA in co-transfection experiments using Pdcd4 expression vectors as well as on the endogenous level, as demonstrated by the analysis of a Pdcd4 knock-out model in the Chicken B-cell line DT40. We found that a mutant of Pdcd4 which no longer interacts with eIF4 is still able to inbihit the translation of A-myb RNA, suggesting that Pdcd4 acts in an eIF4A independent manner and contradicting the current view of how Pdcd4 suppresses translation. Similar to the situation in the case of c-myb RNA we have localized the Pdcd4 responsive region in the coding region of A-myb mRNA. We therefore conclude that Pdcd4 suppresses the translation of A-myb RNA by a novel mechanism. Ribosome density profiling technique is widely used nowadays to explore the topography of the various stages of translation. Currently we aim to exploit the technique of ribosome density profiling to further understand how Pdcd4 affects the translation of A-myb RNA.
Citation Format: Abhiruchi Biyanee, Karl-Heinz Klempnauer. Inhibition of the translation of A-myb mRNA by tumor suppressor protein Pdcd4. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3190. doi:10.1158/1538-7445.AM2013-3190