bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2968: TH17 cells in early pancreatic tumorigenesis
Authors: McAllister Florencia , Bailey Jennifer M. , Roeser Jeffrey , Blake Danielle T. , Wick Elizabeth C. , Sears Cynthia L. , Jaffee Elizabeth M. , Kolls Jay K. , Drake Charles G. , Pardoll Drew M. , Leach Steven D. 
Published: August 2012

Abstract
Activating Kras mutations have been detected in 30% of pancreatic intraepithelial neoplasias (PanIN), increasing to 100% in advanced pancreatic ductal adenocarcinoma (PDAC). Chronic pancreatitis is a risk factor for PDAC and cigarette smoking, the most important single risk factor for PDAC, has been recently associated with chronic pancreatic inflammation. The central hypothesis guiding our work is that inflammatory cells recruited to the pancreas in response to chronic injury can interact with epithelial cells harboring activated KrasG12D, affecting the progression of PanIN lesions. Further understanding of this interaction would be fundamental to generate effective chemopreventive strategies in high risk populations. To test this hypothesis, we have used the Mist1:CreERT2; LSL-KrasG12D mice in which the LSL KrasG12D allele is activated specifically in the acinar compartment of adult mice, leading to the rapid formation of PanIN with a classic “ductal” phenotype. We have established a model of chronic inflammation- induced pancreatic tumorigenesis that results in significant acceleration in the initiation and progression of PanIN lesions at 4 weeks after the activation of Kras. We have found that TH17 cells, a subtype of CD4+ T-helper cells known to play an active role in other models of inflammation- induced tumorigenesis, are rapidly recruited to the pancreas after Kras activation and are further increased in the presence of concomitant chronic pancreatic inflammation induced by cerulein injections. The differentiation of CD4+T cells into TH17 requires IL-6 and TGF-B, and both factors are increased in the pancreatic tumor microenvironment. Finally, Stat3, a key transcription factor that determines the differentiation of Th17 lineage, is activated in cells infiltrating early PanIN lesions. We are currently evaluating both genetic ablation of TH17 cells and neutralizing antibodies against IL-17 as novel therapeutics strategies in murine PanIN.
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 2968. doi:1538-7445.AM2012-2968
Abstract 2976: KSHV-initiated Notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesenchymal transition
Authors: Pekkonen Pirita , Cheng Fang , Sugiyama Nami , Henderson Stephen , Rantanen Ville , Aavikko Mervi , Hautaniemi Sampsa , Aaltonen Lauri , Boshoff Chris , Alitalo Kari , Lehti Kaisa , Ojala Päivi M. 
Published: August 2012

Abstract
Kaposi sarcoma (KS), an angioproliferative disease associated with Kaposi sarcoma herpesvirus (KSHV) infection, harbors a diversity of cell types ranging from endothelial to mesenchymal cells of unclear origin. Using a novel three-dimensional (3D) cell model, we have demonstrated that KSHV induces transcriptional reprogramming of primary lymphatic endothelial cells (LEC) to mesenchymal cells via endothelial-to-mesenchymal transition (EndMT). As EndMT induction has been described in response to activation of the TGF-beta or Notch pathways, inhibitor studies were used to decipher their roles in our 3D system. Inhibition of the Notch pathway dramatically attenuated the EndMT in KSHV infected LECs (K-LECs) in 3D whereas inhibition or activation of the TGF-β pathway did not have any effect. Two viral gene products, vFLIP and vGPCR, were found to trigger Notch signaling and lead to the KSHV-induced EndMT. As Notch activation has been shown to inhibit angiogenic and lymphangiogenic sprouting, we assessed the effect of VEGFA or -C stimulation on the 3D K-LECs. Interestingly, VEGFA/C stimulation induced a dramatic outgrowth of (lymph)angiogenic sprouts and inhibited the KSHV-induced EndMT in the 3D K-LECs. This suggests that the KSHV-induced Notch signaling and mesenchymal reprogramming can override the lymphangiogenic properties of LECs in the absence of VEGF-A/C stimulation. These results further corroborate the central role of Notch signaling as a critical determinant for the lymphangiogenic vs. mesenchymal fate of LECs. The 3D K-LEC transcriptome showed significant up-regulation of invasion related genes over the uninfected control. Intriguingly, comparison of the GEM profiles of the 3D K-LECs and KS biopsies, genes with similar co-regulation were found and included those involved both in EMT/EndMT and invasive processes. Using a panel of specific inhibitors we found a membrane associated matrix metalloproteinase MT1-MMP to be the major MMP involved in this process. Our data further identifies Notch as a previously unrecognized upstream regulator of MT1-MMP, and demonstrates that MT1-MMP as such is sufficient to induce EndMT in 3D cultured LECs. Mesenchymal markers and MT1-MMP were found co-distributed in the same cells with LANA in primary KS tumors suggesting that virus-induced EndMT may contribute to development of KS by giving rise to invasive cells, and providing the virus a permissive microenvironment for efficient spread of the viral genomes.
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 2976. doi:1538-7445.AM2012-2976
Abstract 2983: Nkx3.1 and c-Myc co-regulate shared target genes involved in prostate cancer
Authors: Anderson Philip D. , McKissic Sydika A. , Logan Monica , Roh Meejeon , Franco Omar , Wang Jie , Doubinskaia Irina , van der Meer Riet , Hayward Simon , Eischen Christine , Eltoum Isam-Eldin A. , Abdulkadir Sarki A. 
Published: August 2012

Abstract
Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and may be mediated by synergistic regulation of the expression of pro- and anti-tumorigenic target genes. However, the mechanisms by which oncogenic mutations cooperatively regulate downstream target gene expression remain largely unknown. Here we used chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) and gene expression analyses to identify direct targets of the prostate tumor suppressor Nkx3.1 in the mouse prostate. Our analysis showed that a significant fraction of Nkx3.1 targets are also targets of the oncoprotein c-Myc, suggesting that these two proteins may cooperate in prostate tumorigenesis by directly co-regulating a common set of target genes. Using ChIP, we confirmed binding of Nkx3.1 and c-Myc to the regulatory regions of shared target genes in mouse and human prostate epithelial cells. In conditional mutant mice, loss of Nkx3.1 cooperates with concurrent overexpression of c-MYC to promote prostate tumorigenesis. Furthermore, dysregulation of the shared NKX3.1/c-MYC target gene set was associated with relapse in human prostate tumors. We propose that co-regulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism for the cooperativity of oncogenic mutations during tumorigenesis.
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 2983. doi:1538-7445.AM2012-2983
Abstract 2991: Web-based access for whole genome analyses of gene expression, DNA copy number, microRNA transcript levels, drug activity, and their pattern comparisons for the NCI-60
Authors: Reinhold William C. , Sunshine Margot , Varma Sudir , Liu Hongfang , Weinstein John N. , Morris Joel , Doroshow James , Pommier Yves 
Published: August 2012

Abstract
High-throughput data is increasingly being integrated into the fields of biology, molecular biology, and pharmacology. However, a difficult problem has been the rapid and fluid access to and integration of this data, which tends to reside in huge unwieldy databases. One set of cell lines with substantial potential for benefit from this type of access and integration is the NCI-60 cancerous cell lines. We present here a set of tools within our CellMiner web-application designed to address this need for the areas of transcript expression, microRNA expression, gene DNA copy number, and drug activity. CellMiner allows the user to rapidly access data for relative levels of transcript expression for 18,532 genes, 360 microRNAs, and 16,861 compounds including 91 Food and Drug Administration (FDA)-approved drugs. These levels in turn create patterns across the NCI-60 that can be compared to one another using our “pattern match” tool. Together, these tools allow one to query the data for potential relationships between these parameters, in a manner specific to a users area of expertise and interest, in a rapid and flexible manner without the need for expertise in computer science or bioinformatics. The output will be demonstrated with cancer interesting microRNAs 18a, 21, 29a, 30c-2, 30d, and 31, cancer interesting genes ABCB1, ATM, ATR, BRCA2, and TP53, and the clinically relevant drugs belinostat, crizotinib, pazopanib, selumetinib and tanespimycin.
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 2991. doi:1538-7445.AM2012-2991
Abstract 2992: Analysis of divergent hypoxic gene expression data in prostate cancer cell lines suggests novel tumor progression biomarkers
Authors: Kimbro Kevin Sean , Rudd James , Tesfay Assefa , Zheng Gaolin , Williams-Devane Clarlynda 
Published: August 2012

Abstract
Decreased oxygen tension which can be caused by isolation of solid tumor cells from vascularization is hypothesized to lead cause migration, adaptation, or death. These cellular endpoints require transcriptional regulation of genes that are involved in numerous metabolic and physiological processes. We hypothesize those differences in transcriptional regulation account for variation of cellular response to a hypoxic environment (i.e. metastasis). To test this hypothesis, we characterized the difference in hypoxic gene expression of two isogenic cell lines (LnCap and C4-2) which differ in metastatic potential. In three independent experiments, cell lines (LnCAP and C-42) were incubated in a hypoxic or normoxic environment and pathway analysis was performed on the list of genes whose expression was significantly different. Analysis of the divergent hypoxic gene expression data (i.e. 641 genes) supported significant changes in starch and sucrose pathways (i.e. UDP glucoronosyltransferases), and cardiac arteriolopathy (i.e. DPP4). Differences in gene expression (i.e. 300 genes) between LNCaP and C4-2 were noted under normoxic conditions and included genes related to cell cycle (i.e. CDKN1B, JUNB, and CYR61) and cell differentiation (i.e. ID2, ID3, and HBP1). C4-2 cells are much more metastatic than LNCaP cells from which they were derived. Differences in response to hypoxia may reflect a strategy used by the C4-2 cell line to escape or survive in a hypoxic environment. Transcript profiles may have prognostic or diagnostic value for distinguishing the propensity for prostate cells to metastasize, and those genes that assist in hypoxic survival of C4-2 may be therapeutic targets for PCa. Continued investigation will identify the contributions of these genes to the metastatic process and clarify the downstream transcriptional networks involved in this facet of tumor progression.
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 2992. doi:1538-7445.AM2012-2992
Abstract 2995: Identifying subtypes of colorectal cancer tumors and cell lines with treatment relevance using iterative clustering (iNMF)
Authors: Beran Garry , Schlicker Andreas , Chresta Christine M. , McWalter Gael , Pritchard Alison , Weston Susie , Runswick Sarah , Davenport Sara , Heathcote Kerry , Alferez Denis , Orphanides George , French Tim , Wessels Lodewyk FA 
Published: August 2012

Abstract
Genetic and epigenetic features such as KRAS mutation status have been used to define colorectal cancer (CRC) subtypes and to take treatment decisions. In order to develop new targeted drugs, however, it is necessary to gain a better understanding of the molecular differences of CRC subtypes. We developed a new unsupervised approach for stratifying tumor samples using genome-wide mRNA expression data. Our method is based on the iterative application of non-negative matrix factorization (iNMF) on randomly selected sets of genes. In a sample set consisting of 63 CRC tumors, we identified two dominant subtypes. These subtypes were highly concordant with the epithelial-mesenchymal-transition (EMT) gene expression signatures consistent with recent publications. However further stratification of the tumor samples revealed five subtypes. These subtypes exhibit distinct differences, most notably differential activation of specific signaling pathways. Importantly, assessment of this method and derived subtype gene signatures stratified several independent, published datasets, suggesting that the signatures capture disease-relevant intrinsic features of CRC. Furthermore, application of the gene signatures to expression data obtained from three independent colon cell line panels revealed that the tumor subtypes were represented in all these different panels. Additional integration of pharmacological response data allowed us to identify several targeted compounds showing differential response across the subtypes. The CRC stratification obtained with our new method, iNMF, offers valuable insight into the differences between CRC subtypes at a functional level. Most importantly, it captures features of the disease that are highly relevant for the development of new targeted drugs in defined CRC patient sub-populations.
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 2995. doi:1538-7445.AM2012-2995
Abstract 3008: Shared gene expression alterations in prostate cancer and histologically benign prostate from patients with prostate cancer
Authors: Kosari Farhad , Cheville John C. , Ida Cristiane M. , Karnes R Jeffrey , Leontovich Alexey A. , Sebo Thomas J. , Erdogan Sibel , Murphy Stephen J. , Vasmatzis George 
Published: August 2012

Abstract
The frequent observations of heterogeneous tumor foci in prostate cancers indicate that the molecular changes induced by carcinogenic insult take place over wide areas within the diseased prostate. These ‘field effect’ alterations provide important clues regarding the initiation of prostate cancer (PCa) and suggest targets for cancer prevention or biomarkers for early detection. However, PCa field effect biomarkers that have passed independent validation are lacking largely because these alterations are subtle and difficult to distinguish from unrelated small changes in gene expression in the benign prostate. We postulated that shared expression alterations in PCa and in benign prostate tissue in prostate glands that contain prostate cancer (BPC) would have a higher potential for independent validation than alterations identified in BPC alone. Expression analyses was performed on PCa (n = 37) and unmatched BPC (n = 36) and contrasted with benign prostate glands (BP) from patients free of prostate cancer (n =28). These analyses identified gene alterations that were concomitantly present in both PCa and BPC. The majority of the selected markers were validated by quantitative RT-PCR in an independent set of BPC (n = 33) and BP (n =18). Validated markers included genes and non-exonic sequences not previously associated with PCa field effect. A statistical model based on CCNB1 and non-exonic NACA locus discriminated between BPC and BP in the RT-PCR set and in an external microarray dataset with accuracies of 0.84 and 0.90, respectively. Genes with predominant expression in prostate stroma were identified by expression profiling of stroma and epithelial cells collected by laser captured microdissection. Pathway analysis identified enriched GO categories in BPC stroma including PDGFR signaling. These results validate our approach for finding PCa field effect alterations and demonstrate a prostate cancer transcriptome fingerprint in the adjacent non-neoplastic cells.
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 3008. doi:1538-7445.AM2012-3008
Abstract 3074: NAD(P)H:quinone oxidoreductase 1 stabilizes C/EBPα from 20S proteasomal degradation leading to protection against myeloproliferative disease
Authors: Xu Junkang , Jaiswal Anil 
Published: August 2012

Abstract
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoprotein that protects cells against radiation and chemical induced oxidative stress. Disruption of NQO1 gene in mice leads to α-radiation-induced myeloproliferative disease. In the present study, we demonstrate that myeloid differentiation factor C/EBPα is degraded by 20S proteasome, and that NQO1 could salvage C/EBPα from 20S proteasomal degradation. Coimmunoprecipitation studies showed that NQO1, C/EBPα and 20S all interacted with each other. Deletion and site-directed mutagenesis studies demonstrated that NQO1 and 20S competed for the same binding region in C/EBPβ. Mutagenesis study also revealed that NQO1Y127/Y129 required for NADH binding is essential for NQO1 stabilization of C/EBPβ. Exposure of mice and HL-60 cells to α-radiation led to increased NQO1 and decreased 20S interaction with C/EBPβ, which resulted in stabilization of C/EBPα and protection against α-radiation-induced myeloproliferative diseases. This mechanism might provide day-to-day protection to bone marrow against adverse effects of radiation and chemical exposure, which has significant effect on individuals carrying hetero- or homozygous NQO1P187S mutation.
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 3074. doi:1538-7445.AM2012-3074
Abstract 3079: Akt interacts and phosphorylates PHF20, a transcription factor binding to and inducing p53
Authors: Kim Donghwa , Park Sungman , Yan Fei , He Lili , Cheng Jin Q. 
Published: August 2012

Abstract
Akt regulates a diverse arrays of cellular function, including apoptosis, cellular proliferation, differentiation, and metabolism. While a number of molecules have been identified as upstream regulators or downstream targets, the mechanism by which Akt regulates these cellular processes remains elusive. Here, we identified a novel transcription factor, PHF20, which binds to Akt and p53. PHF20 is an evolutionarily conserved protein. We showed that PHF20 is a transcriptional factor and transactivates p53. Furthermore, the interaction of PHF20 and p53 led to stabilize p53. Akt phosphorylates PHF20 in vitro and in vivo, which resulted in change of PHF20 nuclear localization and disassociation of p53 from PHF20 as well as decrease of p53 expression at mRNA and protein levels. In addition, knockdown of PHF20 reduces whereas ectopic expression of PHF20 increases p53 expression. These data suggest that PHF20 is a novel substrate of Akt and plays an important role in maintaining normal p53 function.
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 3079. doi:1538-7445.AM2012-3079
Abstract 3083: Dual-specificity phosphatase-2 (DUSP2) negatively control cyclooxygenase-2 (COX-2) expression in cancer cells
Authors: Lin Shih-Chieh , Tsai Shaw-Jenq 
Published: August 2012

Abstract
Cyclooxygenase-2 (COX-2), an inducible form of cyclooxygenase, plays a crucial role in the development of cancer via its enzymatic product, prostaglandin E2 (PGE2). Clinical studies reveal that COX-2 is overexpressed in numerous types of cancers, and is associated with increase of angiogenesis, metastasis, and drug resistance. Although nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, have been used for cancer therapy; they have serious side effects in many aspects. Therefore, to explore the underlying mechanism of COX-2 overexpression during cancer progression is critical for developing more efficient and safer way to block COX-2 function. Previously, we have found that the expression of dual-specificity phosphatase-2 (DUSP2), a MAPK-specific phosphatase, is markedly reduced in many kinds of cancers. Here, we identified that COX-2 was a potential downstream target gene of DUSP2. In vitro studies demonstrate that knockdown of DUSP2 significantly increases COX-2 expression and PGE2 production while overexpression of DUSP2 reduces those in cancer cells. Xenografted mouse study further reveals that levels of DUSP2 are reduced during cancer development, which is inversely correlated with COX-2 expression. Re-expression of DUSP2 during tumor progression inhibits COX-2 expression and suppresses tumor growth while knockdown of DUSP2 increases COX-2 expression and enhances tumor growth. These results implied that COX-2 overexpression was due to loss of DUSP2 expression in cancer. Furthermore, we found that hypoxia represses DUSP2 expression resulting in COX-2 overexpression. Taken together, we have demonstrated for the first time that aberrant expression of COX-2 during tumor development is regulated by hypoxia-mediated DUSP2 downregulation. Our data also suggest that DUSP2 is a good molecular target for cancer 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 3083. doi:1538-7445.AM2012-3083