bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4924: Dysregulated transcriptional mechanisms that control crypt cell maturation: A mechanism that contributes to stem cell overpopulation during colon cancer development
Authors: Padmanabhan Jayasree , Gonye Greg , Zhang Tao , Boman Bruce M. 
Published: August 2012

Abstract
Our goal is to determine how transcriptional regulatory mechanisms that control crypt cell maturation in normal colonic epithelium, when dysregulated, lead to maturation arrest, tumor stem cell (SC) overpopulation and colorectal cancer (CRC) development. Accordingly, we studied changes in maturation during colon cancer development caused by APC mutations. Quantitative mapping of crypt cell subpopulations was done on colon tissues from FAP patients using markers for stem cells (SC), proliferating cells, cell-cycle arrest, and apoptosis. In normal human colon, mapping defined the sequential transitions in colonic crypts that enterocyte subpopulations undergo during their maturation from stem-to-proliferating-to-differentiated-to-apoptotic cells, illustrating the point that maturation is a process involving both proliferation and differentiation. In normal-appearing (heterozygous-mutant) and adenomatous (homozygous-mutant) FAP crypts, SC and proliferating cell subpopulations increasingly expanded towards the crypt top, while differentiated/apoptotic subpopulations in the upper crypt contracted, indicating that crypt cell maturation becomes progressively delayed. These data indicate that there are coordinated mechanisms that regulate maturation of crypt cells in normal crypts which become dysregulated in premalignant crypts. To investigate possible transcriptional regulation of a network of genes underlying maturation, we used bioinformatic tools to identify (i) genes that are co-expressed in the proliferating cell population and (ii) transcriptional regulatory elements (TREs) statistically enriched in the promoter regions among those genes. Computational analysis revealed (i) a specific cassette of sixty-six genes that are co-expressed with the markers used for mapping the proliferating cell population in the lower colonic crypt and (ii) eleven TREs that are significantly enriched in the promoter regions among genes in this gene set. Quantitative PCR and immunohistochemistry was then used to validate that the transcription factors (TFs), which correspond to the common TREs, are differentially expressed along the normal crypt axis and in normal colonic epithelium versus malignant colon tissues. Our results indicate that dysregulation of a transcriptional regulatory network contributes to delayed crypt cell maturation, SC overpopulation, and initiation and promotion of CRC. Accordingly, restoring maturation by targeting transcriptional pathways that control expression of multiple genes involved in crypt cell maturation may be a therapeutically effective approach to CRC treatment.
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 4924. doi:1538-7445.AM2012-4924
Abstract 4928: Deregulation of asymmetry genes in oligodendrogliomas and glioblastomas
Authors: Andor Noemi , Petritsch Claudia 
Published: August 2012

Abstract
BACKGROUND. Normal neural stem cells and NG2+ oligodendrocyte progenitors (OPC) undergo asymmetric cell division to generate a balanced number of self-renewing and differentiating progeny. Our recent studies showed that NG2+ OPC are the tumor-forming cells in oligodendrogliomas (ODG), a therapy-sensitive glioma. We provide cellular and molecular evidence that defects in asymmetric division of NG2+ OPC might contribute to tumor-initiation in oligodendrogliomas. In contrast, tumor-initiating cells in the highly resistant glioblastomas (GBM) express stem cell markers and show a high number of asymmetric divisions. We propose that distinct key asymmetry genes might be deregulated in the two types of tumor-initiating cells causing them to generate progeny with distinct therapy-sensitivity. Identifying these asymmetry key regulator networks will elucidate the mechanism by which tumor-initiating cells in gliomas maintain tumors and re-grow them after therapy. METHOD. A knowledge based network, consisting of asymmetry-genes and their transcriptional regulators, was constructed and refined by correlated gene expression. Subsequently, copy number and methylation were mapped onto the network and their impact on expression was assessed. In addition, the expression profiles of asymmetry genes within glioma samples were compared against their counterparts in normal brain samples and putative associations between expression and clinical outcome were tested. RESULTS. Our study has identified cancer- and differentiation associated transcription factors as putative regulators of asymmetry genes. In GBM tumors it was found that asymmetry genes are mostly affected by single copy gains and heterozygous deletions with an apparent influence on gene expression. When considered upon ODG tumors, the pattern of deregulation was distinct from that observed in GBM: for a subset of asymmetry genes a mutually exclusive deregulation was observable in either GBM or ODG, while another gene subset was progressively deregulated in ODG- and GBM. Taken together, our results indicate that asymmetry genes are distinctly regulated in ODG and GBM. We will discuss a model how this could contribute to distinct levels of therapy resistance.
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 4928. doi:1538-7445.AM2012-4928
Abstract 4934: Employing the Berg Interrogative Biology® systems platform to elucidate cellular signaling changes that contribute to the pathophysiology of hepatocellular carcinoma (HCC)
Authors: Du Min , Vishnudas Vivek , Lao Socheata C. , Luan Shen , Jimenez Joaquin J. , Li Jie , Sarangarajan Rangaprasad , Narain Niven R. 
Published: August 2012

Abstract
Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, ranked as the third most fatal cancer after lung and stomach carcinomas. The diverse etiology, high morbidity/mortality, lack of diagnostic markers for early diagnosis and the highly variable clinical course of HCC have hindered advances in diagnosis and treatment. After years of studying the HCC, the understanding of molecular mechanism operational in HCC remains incomplete. The genomic, transcriptomic and comparative proteomic profiles have yielded some important insights for HCC research. However, many studies focused on single aspect of the cellular changes associated with HCC, hindering the full understanding of biological systems in their true complexity and dynamics. We describe a novel approach combining the power of cell biology, integrated proteomics platforms and an informatics platform that generates causal protein networks. In order to delineate the role of post-translation modification and enzymes that partake in such mechanisms, we incorporated activity based proteomics employing kinase enrichment probes and phosphoproteome mapping of total proteins in HCC cellular models. Multikinase inhibitor Sorafenib, the first line chemotherapeuitc agent for the advanced HCC patients, was used to probe the global kinase activity and protein phosphorylation changes associated with this treatment. Comparative proteomics, phosphoproteome and kinase activity data was integrated into the AI based REFS™ informatics platform. Causal networks of protein interaction specifically from a functional stand point namely kinase activity and potential targets that kinases can phosphorylate were generated. In addition, using cellular functional read out, proteins/ kinases that modulate phosphorylation of targets and mechanistically drive pathophysiological cellular behavior were determined. The approach outlined here enables global characterization of cellular responses, insights into mechanisms of chemo sensitivity and potential targets/biomarkers for clinical management of HCC.
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 4934. doi:1538-7445.AM2012-4934
Abstract 4955: TIMP-1 inhibits apoptosis in lung adenocarcinoma cells via Bcl-2 interaction
Authors: Nalluri Srilatha , Gayatri Sitaram , Ohja Juhi , Rojiani Amyn M. , Rojiani Mumtaz V. 
Published: August 2012

Abstract
Tissue inhibitors of matrix metalloproteinases have multifunctional properties, orchestrating diverse biological activities. Previous studies revealed a novel function of TIMP-1 as an inhibitor of apoptosis in mammalian cells. However, the mechanisms by which TIMP-1 exerts its anti-apoptotic effect are not completely understood. The antiapoptotic effect has been correlated with higher levels of Bcl-Xl. Our earlier studies in a CNS model of metastasis, using HB-1, a TIMP-1 overexpressing lung adenocarcinoma cell line (H2009), resulted in more aggressive tumor kinetics and increased vasculature. The present study was undertaken to elucidate the role of TIMP-1 in apoptosis in our model. Utilizing an apoptosis -specific gene array, we found that TIMP-1 overexpression results in 3-fold increased expression of Bcl-2. H2009 and the TIMP1 over-expressing clone - HB1 were treated with staurosporine to induce apoptosis, followed by analysis for poly ADP-ribose polymerase (PARP) cleavage. HB1 showed marked reduction in PARP cleavage in comparison to the controls. Treatment of HB1 cells with ABT737, an inhibitor of Bcl-2, restored apoptosis resulting in PARP cleavage in this clone. To further confirm this mechanism, we induced transient inhibition of Bcl-2 with siRNA, which also restored PARP cleavage in the HB-1 clone. Thus both chemical and biological inhibition resulted in increased apoptosis. Additionally, immunoprecipitation of Bcl-2 from cell lysate co-immunoprecipitated TIMP-1 suggesting a direct interaction between TIMP-1 and Bcl-2. These investigations identify a relationship between TIMP-1 and Bcl-2 in apoptosis inhibition, contributing to aggressive tumor kinetics, utilizing non-MMP dependent mechanisms.
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 4955. doi:1538-7445.AM2012-4955
Abstract 496: Isolation and characterization of a highly invasive subpopulation from MDA-MB-231 breast cancer cells
Authors: Pfeffer Ulrich , Amaro Adriana , Maffei Massimiliano , Mirisola Valentina , Esposito Alessia I. , Astigiano Simonetta , Viale Maurizio , Zunino Annalisa , Giaretti Walter , Angelini Giovanna 
Published: August 2012

Abstract
The acquisition of an invasive phenotype is a pre-requisite for metastasis. We set out to develop cellular systems that can mirror transient and stbale molecular alterations that confer an invasive phenotype to breast cancer cells. We observed that it is possible to isolate invasive subpopulations from moderately invasive cancer cell lines. Enrichment of invasive sub-populations of MDA-MB-231 breast cancer cells in three successive preparative invasion assays in Matrigel covered Boyden chambers yielded a highly invasive cell line. Prolonged cultivation of these cells did not abolish the invasive phenotype although not all phenotypic changes acquired during selection are maintained by long term cultures. Genetic analyses of these cells by cytogenetics and array based comparative genome hybridization revealed many genetic alterations including increased ploidy. The flow cytometric DNA Index (DI) changes from 1.28 to 2.28. Cells with DI 2.28 constitute 1.4% of the parental cell line. Whole genome SNP analysis shows that the two populations are genetically related excluding any cell contamination. The invasive cells proliferate and undergo apoptosis similar to the parental cells. Commitment to apoptosis is increased since invasive cells respond more strongly to curcumin or peroxide induced apoptosis. Invasive cells show relative resistance to the cytotoxic, alkylating agent Doxorubicin and increased sensitivity to the anti-mitotic drugs Vincristine and Taxol. Increased resistance to the topoisomerase II inhibitor Mitoxantrone is observed only transiently in invasive cells and lost in long term cultures. Similarly, the chemokines CXCL1 and -2 are transiently upregulated. Response to the anti-diabetic drug Metformin showed a reduced sensibility for invasive cells in terms of growth inhibition (IC50). Gene expression profiling shows complex alterations in gene expression. Many of the genes that are differentially expressed in highly versus moderately invasive cells are differentially expressed in human breast cancer cases with and without distant metastasis and correlate with disease free survival. The invasive phenotype is not related to stem cell features nor to epithelial mesenchymal transition. These cells constitute a novel model for tumor progression. Tumorigenicity and metastatic potential in vivo are currently being tested.
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 496. doi:1538-7445.AM2012-496
Abstract 4960: The role of YY1 in paclitaxel-induced cytotoxicity in epithelial ovarian cancer
Authors: Ota Tsuyoshi , Ota Takayo , Chien Jeremy , Shridhar Viji , Kurachi Hirohisa 
Published: August 2012

Abstract
The Yin Yang 1 (YY1) transcription factor is a member of Polycomb protein family, with important roles in development, differentiation, replication and cell proliferation. While YY1 expression is correlated with survival in serous ovarian cancer, its role in chemotherapeutic agent-mediated cytotoxicity is not known. Immunoblot analysis revealed that YY1 is highly expressed in ovarian cancer cell lines, but not in immortalized ovarian surface epithelial (OSE) cell lines, suggesting a possible role of YY1 in ovarian carcinogenesis. shRNA mediated stable downregulation of YY1 resulted in inhibition of proliferation by CyQuant assay in SKOV3 and SKOV3ip cells. While YY1 downregulation increased the sensitivity against paclitaxel in both cell lines compared to nontargeted cells (NTC) as determined by MTT and clonogenic assays, it had no effect on sensitivity to cisplatin-mediated cytotoxicity. YY1 downregulated clones treated with paclitaxel resulted in an increase in cleavage of poly (ADP-ribose) polymerase and caspase-3/7 activity compared to NTC clones treated with it in SKOV3 and SKOV3ip1 cells. To determine the mechanism of paclitaxel sensitivity modulated by YY1, we performed cell cycle analysis and determined the expression of microtubules at protein level. Cell cycle analysis showed that downregulation of YY1 decreased the proportion of G0/G1 phase with corresponding increase in cells accumulating both S and G2/M phases in SKOV3 and SKOV3ip1 cells. Using nocodazole which synchronizes cells into mitotic phase, we found that blocking mitotic exit by YY1 knockdown slowed the cyclin B1 proteolysis, thus allowing more time for death initiation by paclitaxel. Immunoblot analysis showed that downregulation of YY1 increased the acetylation of alpha-tubulin and attenuated betaIII-tubulin expression compared to NTC cells. Immunoprecipitation and immunofluorescence assays revealed that YY1 interacts with HDAC6 which deacetylates alpha-tubulin and these proteins co-localized in mitotic phase, suggesting that dysfunction of HDAC6 by downregulation of YY1 could lead to microtubules stabilization, resulting in the paclitaxel-induced apoptosis by blocking mitotic exit. Moreover, nude mice bearing xenografts with stable downregulation of YY1 in SKOV3ip1 were more sensitive to paclitaxel-induced cytotoxicity compared to xenografts of NTC cells. Additionally immunohistchemical staining showed a decrease in betaIII-tubulin expression in tumor of YY1 downregulated clones compared to that of NTC clones. Collectively, these results indicate that YY1 acts as a modulator of microtubules expression and might be therapeutically targeted against epithelial ovarian 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 4960. doi:1538-7445.AM2012-4960
Abstract 4970: Convergence of protein kinase and caspase signaling: A mechanism for pathological rewiring of survival pathways by protein kinase CK2
Authors: Turowec Jacob P. , Duncan James S. , Li Shawn , Gloor Greg , Litchfield David W. 
Published: August 2012

Abstract
Crosstalk between protein kinases and caspases has become evident in light of the observation that phosphorylation within the caspase cleavage motif impairs proteolysis. Given that phosphorylation networks and sensitivity to apoptotic cues are altered in cancer signaling, we sought to investigate if the negative regulation of caspase-mediated degradation by protein phosphorylation is a global mechanism that manifests in changes to cancer cell survival. To systematically investigate the extent to which phosphorylation regulates the caspase degradome, we employed a combination of peptide cleavage assays, database mining, and N-terminomics. These studies revealed that phosphorylation could potentially regulate the cleavage of a significant proportion of caspase substrates. One notable example of phosphorylation-regulated caspase cleavage was the observation that pro-caspase-3 itself is phosphorylated in a manner that prevents subsequent cleavage and activation by upstream initiator caspases. To further examine the role of phosphorylation in regulating the activation of caspase-3, we investigated the phosphorylation of pro-caspase-3-FLAG in HeLa cells transfected with each of the catalytic isoforms of protein kinase CK2 in the presence or absence of the regulatory CK2β subunit. These studies suggest that the activation of caspase-3 could be regulated by CK2 in cells. Coupled with the observations that CK2 is constitutively activity and expressed at elevated levels in a number of different cancers, our observations suggest that increased levels of CK2 could lead to a pathological phosphorylation of pro-caspase-3 to prevent its activation and promote cancer cell 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 4970. doi:1538-7445.AM2012-4970
Abstract 5047: Dysregulated microRNAs in cervical neoplasm
Authors: Wong Yick Fu , Cheung Tak Hong , Man Mimi Kwun Nok , Yu Mei Yun , Yim So Fan , Siu Nelson S.S. , Lo Keith W.K. , Doran Graeme , Wong Raymond R.Y. , Wang Vivian W. , Smith David I. , Worley Michael J. , Chung Tony K.H. 
Published: August 2012

Abstract
MicroRNAs (miRNAs) play an important role in a variety of physiological processes as well as pathophysiological processes, including cancinogenesis. This study was to identify a distinct miRNA expression signature for cervical intraepithelial neoplasia (CIN) and to reveal individual miRNAs that may be involved in the development of cervical carcinoma. Expression profiling using quantitative real-time RT-PCR of 202 miRNAs was performed on micro-dissected high-grade CIN (CIN 2/3) tissues as compared to normal cervical epithelium. The expression of 12 miRNAs including miR-518a, miR-34b, miR-34c, miR-20b, miR-338, miR-9, miR-512-5p, miR-424, miR-345, miR-10a, miR-193b and miR-203 were significantly different between high-grade CIN and normal epithelium. This miRNA signature was further validated by an independent set of high-grade CIN tissue. The same characteristic signature can also be used to distinguish cervical squamous cell carcinoma (SCC) from normal controls. Target prediction analysis revealed that these dysregulated miRNAs control the apoptosis signaling pathway and cell cycle regulation. These findings contribute to understanding of the pathogenesis of cervical carcinoma at the molecular level.
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 5047. doi:1538-7445.AM2012-5047
Abstract 5053: MicroRNA expression profile of astrocytoma according to its malignant potential in Puerto Rican brain tumor samples
Authors: Rivera-Díaz Mónica , Quintero Mario , Billoch Jorge , Marcos Maria , Echevarría Ileabett , Vivas-Meji Pablo E. 
Published: August 2012

Abstract
Astrocytoma, the tumor of astrocytic glial cells, is the most common type of central nervous system (CNS) neoplasms, accounting for more than 60% of all primary brain tumors. As histology-based classification is highly subjective, there is a need for more robust histology-independent molecular classifiers. Although different gene expression and genome-wide array-CGH expression profiles have been use for classification, these expression signatures are yet to be translated to utility in clinical settings suggesting that these studies require further characterization and validation. Micro RNAs (miRNAs) are endogenous, short (19-24 nucleotides) non-protein-coding RNAs that regulate gene expression at the post-transcriptional level. Alterations in the expression profiles of many miRNAs have been described in numerous human tumors. Recent evident indicate that the grade types of astrocytoma could be better classified by using a micro miRNA expression profiles compared with histological or gene expression analysis. Thus, the aim of this project was to construct a miRNA expression profile of astrocytoma according to its malignant potential in Puerto Rican brain tumor samples. Archived formalin-fixed paraffin-embedded (FFPE) samples were used in this study. Not shown in previous literature, our preliminary results showed that miR-27b was more abundant in high grade vs. low grade astrocytoma. Although, miRNA profiling appears to be a very promising tool, nonetheless, further validation of these discriminatory miRNAs in a large number of patients and in independent studies is necessary before clinical application becomes realistic.
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 5053. doi:1538-7445.AM2012-5053