bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-459: An essay concerning the molecular prediction of disease outcome in melanoma patients
Authors: Gschaider Melanie , Neumann Friederike , Peters Bettina , Lenz Florian , Cibena Micheal , Goiser Malgorzata , Wolf Ingrid , Wenzel Jörg , Mauch Cornelia , Schreiner Wolfgang , Wagner Stephan N. 
Published: August 2012

Abstract
Melanoma is the most lethal form of skin cancer. Current prognostic clinical and histopathological parameters are insufficient to accurately predict the outcome of individual patients. Several studies have claimed gene expression signatures to predict survival or metastasis of primary melanoma patients. However, the reproducibility among these studies is disappointingly low and led to the development of guidelines on statistical analysis and reporting of gene expression data for cancer outcome. We carefully followed these guidelines when we used gene expression data from primary human melanoma samples to identify gene signatures predictive for disease outcome. The class comparison dataset was established using microarray data from non-metastatic and metastatic primary melanoma samples. The top 50 differentially expressed genes were identified by Significance Analysis of Microarrays and used in an independent gene expression data set of primary melanomas for prediction. Multivariate Cox regression analysis determined the classifier revealing the best predictive value. This classifier comprised the Duffy blood group chemokine receptor and the ribosomal protein S27-like and defined the cutoff positions for favorable and detrimental disease outcome, respectively. We report this classifier as an essay to provide molecular information supplementary to standard morphological prognostic factors.
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 LB-459. doi:1538-7445.AM2012-LB-459
Abstract LB-468: miR-345 downregulation is associated with apoptosis resistance in pancreatic cancer: therapeutic implications
Authors: Srivastava Sanjeev K. , Bhardwaj Arun , Arora Sumit , Singh Seema , McClellan Steven , Wang Bin , Grizzle William E. , Singh Ajay P. 
Published: August 2012

Abstract
Resistance to apoptosis is one of the mechanisms underlying the highly metastatic and drug-resistant nature of pancreatic malignancy, which currently stands as the fourth leading cause of cancer-related death. Recent studies have identified several differentially-expressed microRNAs in pancreatic cancer, including miR-345, which is among the top aberrantly-expressed genes exhibiting significant downregulation. In this study, we have investigated the functional consequences of miR-345 downregulation in pancreatic cancer. We observed that miR-345 was significantly downregulated in our set of pancreatic cancer tissues as compared to the normal pancreas. Furthermore, a relative decrease in miR-345 levels was observed in poorly-differentiated pancreatic cancer cell lines as compared to the well-differentiated cell lines. Ectopic expression of miR-345 in two pancreatic cancer cell lines, MiaPaCa and Panc1, led to reduced cell viability and induction of apoptosis. miR-345 overexpressing pancreatic cancer cells exhibited loss of mitochondrial membrane potential, release of cytochrome c, activation of caspases 3/7 and PARP1 cleavage. In addition, we also observed translocation of apoptosis inducing factor (AIF) from mitochondria to nucleus and increased DNA fragmentation in miR-345 overexpressing pancreatic cancer cells. All these effects were reversed upon treatment of miR-345 overexpressing pancreatic cancer cells with anti-miR-345 oligonucleotides, thus confirming the role of miR-345 in apoptosis induction. Based on in silico analysis, we identified BCL2 as a candidate miR-345 target gene and experimentally validated the direct targeting of the 3′ UTR of BCL2 using a luciferase reporter assay. Consistent with this, miR-345 overexpressing pancreatic cancer cells exhibited a downregulated expression of BCL2 at the protein level. When we allowed unopposed exogenous expression of BCL2, it rescued pancreatic cancer cells from miR-345-induced apoptosis. Altogether, our data suggest that miR-345 downregulation is associated with gain of apoptosis resistance, and restoring its expression may have therapeutic effects 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 LB-468. doi:1538-7445.AM2012-LB-468
Abstract LB-471: Upregulation of miR-196a and HOTAIR is associated with the malignancy of gastrointestinal stromal tumors
Authors: Suzuki Hiromu , Nojima Masanori , Maruyama Reo , Yamamoto Eiichiro , Imai Kohzoh , Shinomura Yasuhisa 
Published: August 2012

Abstract
Although dysregulation of microRNA (miRNA) expression is a common feature of human malignancies, its involvement in gastrointestinal stromal tumors (GISTs) is not fully understood. In the present study, we aimed to identify miRNAs associated with the malignant potential of GISTs. miRNA microarray analysis enabled us to detect the frequent upregulation of miR-196a in high-risk GISTs. Quantitative RT-PCR analysis of 56 fresh frozen and 100 formalin-fixed paraffin-embedded (FFPE) specimens confirmed that overexpression of miR-196a is associated with a high-risk grade, metastasis and poor survival among GIST patients (hazard ratio, 9.1; P &lt; 0.001). The miR-196a genes are located within the HOX gene clusters, and gene expression microarray analysis revealed that HOXC genes and a large intergenic non-coding RNA (lincRNA), HOTAIR, were concurrently upregulated in GISTs overexpressing miR-196a. Elevated HOTAIR expression was also strongly associated with the high-risk category, metastasis and poor clinical outcome of GISTs (hazard ratio, 9.0; P = 0.034). RNAi-mediated knockdown of HOTAIR suppressed the invasiveness of GIST cells, and induced a significant change in the expression profile of genes that included previously reported HOTAIR target genes. This is the first report of concurrent overexpression of HOX genes and collinear non-coding RNAs in human malignancy, and our data suggest that miR-196a and HOTAIR could be useful biomarkers and novel therapeutic targets in malignant GISTs.
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 LB-471. doi:1538-7445.AM2012-LB-471
Abstract LB-472: p63 inhibits epithelial - mesenchymal transition by promoting the expression of miR205 in human bladder cancer cells
Authors: Tran Mai N. , Choi Woonyoung , Navai Neema , Wszolek Matthew F. , Lee I-ling C. , Siefker-Radtke Arlene O. , McConkey David J. 
Published: August 2012

Abstract
Epithelial - mesenchymal transition (EMT) is a physiological process in normal tissue development and wound healing that has been shown to play important roles in tumor metastasis, “stemness,” and drug resistance. Therefore, it is critical to understand the molecular mechanisms that control EMT. EMT is typically characterized by the loss of the epithelial marker E-cadherin and gain of the transcriptional repressors of E-cadherin (Zeb1, Zeb2, Twist, SnaiI, and Slug). MicroRNAs belonging to the mir200 family and miR205 are involved in EMT through suppression of Zeb1 and Zeb2. Recently, p53 has been demonstrated to regulate EMT by transcriptionally activating the microRNA mir-200c, which in turn suppresses Zeb1; however, the mechanisms controlling miR205 remain elusive. We noticed that expression of the p53 homologue p63 correlates with the expression of E-cadherin in bladder cancer cell lines, suggesting that p63 might participate in regulating EMT. Consistent with this idea, expression of p63 and miR205 are strongly correlated with each other in a large panel of bladder cancer cell lines. Interestingly, stably knocking down (KD) p63 in two epithelial cell lines (UM-UC6 and UM-UC14) repressed the expression of miR205. Consistent with the role of miR205 in suppressing Zeb1, p63 knockdown resulted in increased expression of Zeb1 in the UM-UC6 cells, and this effect was reversed by expression of exogenous miR205. p63 knockdown reduced both the primary and mature forms of miR205, suggesting that p63 might transcriptionally activate miR205 gene expression. Intriguingly, chromatin immunoprecipitation (ChIP) revealed that p63 binds to a putative regulatory region of miR205 in UM-UC6 and UM-UC14. Furthermore, the acetylated histone H3 mark (indicative of active/open chromatin) was enriched in the region encompassing the p63 binding site. Together, our data identifies p63 as an important repressor of EMT via its ability to promote expression of miR205, which represses Zeb1 expression.
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 LB-472. doi:1538-7445.AM2012-LB-472
Abstract LB-474: Estrogen receptor regulated long non coding RNA: An evolving paradigm in prostate cancer progression
Authors: Chakravarty Dimple , Sboner Andrea , Giannopoulou Eugenia , Elemento Olivier , Fox Archa , Rubin Mark 
Published: August 2012

Abstract
Prostate cancer is the second leading cause of cancer death in men. Anti-androgen therapy has been the preferred modality of treatment for several years, however prostate tumor co-opts alternate molecular mechanisms to overcome need for androgen and thereby become “castrate resistant”. Several prognostic markers have received functional evaluation in clinical setting; unfortunately current biomarkers are not accurate enough to predict disease progression and/or response to anti-androgen therapy. Thus there is an unmet need for novel biomarkers. Several studies have indicated that Estrogen receptor (ER) plays an important role in different types of tumors and while the importance of ER/E2 signaling pathway has been extensively investigated in breast cancer and other gynecological malignancies, the impact of this pathway on malignancies associated with other tissues like prostate warrants further investigation. Here we report a novel ERα- lncRNA signaling axis in prostate cancer progression. Our data provides compelling evidence to demonstrate that expression of ERα can “over-ride” requirement of androgens or androgen receptor during prostate cancer progression. Using a combination of ChIP-seq and RNA-seq approach we successfully identified a compendium of ER regulated lncRNA. We have utilized several biochemical assays and invivo xenograft studies to demonstrate the oncogenic relevance of ERα regulated lncRNA. Expression of lncRNA correlated well with clinicopathological variables in several patient cohorts. Finally we have tested therapeutic efficacy of targeting these oncogenic lncRNA using siRNA encapsulated chitosan based nanoparticles either single or in combination with current treatment modalities. In conclusion we have identified ER-regulated lncRNA as novel biomarkers for prostate cancer progression and therapy resistance in patients with advanced PCa.
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 LB-474. doi:1538-7445.AM2012-LB-474
Abstract LB-480: MicroRNA in situ hybridization techniques: Co-detection of target protein and image analysis-based quantitation
Authors: Nielsen Boye S. , Moller Trine , Holmstrom Kim 
Published: August 2012

Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that constitute a novel group of biomarkers with exciting functions in cell differentiation, proliferation and apoptosis by mediating degradation or destabilization of target mRNAs. Expression profiling provides identification of disease-related miRNAs; however, questions towards molecular interactions in vivo remain un-answered. In situ hybridization (ISH) allows visualization the miRNAs in histological sections and thereby allows determination of specific cellular origin, which is an essential step for understanding the miRNAs role in any biological setting. We have developed fast double fluorescence and quantitative ISH technologies that facilitates interpretation of roles for miRNA in cancer progression. On a semi-automated platform, HistoFlex, the double fluorescence assay can be completed within 2 hours without loss of sensitivity and specificity. In order to characterize the miR-21 positive cells in the breast cancer stroma, we combined miR-21 ISH with smooth muscle α-actin in a double fluorescence assay, and found that most, but not all miR-21 positive cells, are smooth muscle α-actin positive and include both myofibroblasts and myoepithelial cells in the neoplastic tissue. Subsequent combination of miR-21 ISH and programmed cell death-4 (PDCD4) immunofluorescence showed differential expression in many but not all miR-21 positive cells. The findings suggest that PDCD4 (mRNA), as a predicted miR-21 target according to sequence alignment, may also take place in vivo. Thus, a role of miR-21 in cell survival and apoptosis is likely. miRNA ISH also allows quantitative estimation of miRNA expression levels in archived formalin-fixed and paraffin embedded tissue samples. Using chromogenic detection of miRNA and subsequent image analysis, semi-quantitative expression estimates can be obtained, which can be used for correlation with clinical parameters, such as drug response, diagnosis, prognosis and other molecular profiles. We have established an automated 1-day assay that provides quantitative estimates with a precision of app. 15%. We also show that a quantitative estimate obtained in one paraffin section with tumor tissue is representative for the whole tumor. For clinical applications, we present data showing that the miRNA ISH signal can be quantified in routinely processed paraffin samples from colon and breast cancer, and that this approach can provide novel diagnostic possibilities.
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 LB-480. doi:1538-7445.AM2012-LB-480
Abstract LB-483: p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
Authors: Davalos Albert R. , Kawahara Misako , Malhotra Gautam , Beausejour Christian , Rodier Francis , Campisi Judith 
Published: August 2012

Abstract
Cellular senescence irreversibly arrests the proliferation of cells at risk for malignant transformation in part through activities of the transcriptional regulator and tumor suppressor p53. Cells that senesce owing to DNA damage also secrete many biologically active factors, including inflammatory cytokines such as IL-6. The High Mobility Group Box 1 (HMGB1) protein is unusual in having two distinct functions. Intracellularly, it binds chromatin and modulates transcription, including stimulating p53 activity. In addition, necrosis or microbial infection causes HMGB1 leakage or active secretion, respectively, whereupon it functions as an extracellular Alarmin to signal tissue damage and promote tissue regeneration, stem cell recruitment and immune activation. We show that HMGB1 is largely nuclear in non-senescent human and mouse fibroblasts and epithelial cells, but is actively exported from the nucleus and secreted by senescent cells. In culture and in vivo, HMGB1 re-localization occurred prior to the appearance of other hallmarks of senescence, and depended on the function of p53, but not the upstream p53 activator ATM. Old mice contained significantly higher levels of HMGB1 in serum compared to young animals. Disruption of HMGB1 stoichiometry, either by overexpression or depletion, induced a p53-dependent senescence growth arrest, but only HMGB1 overexpression, not HMGB1 depletion, promoted IL-6 secretion. Senescence-associated secretion required endogenous and secreted HMGB1 because deletion of endogenous HMGB1 – or addition of an HMGB1 blocking antibody - attenuated IL-6 secretion. Recombinant HMGB1 protein induced IL-6 secretion in cells depleted, but not harboring, endogenous HMGB1. Depletion of endogenous HMGB1 promoted NF-κ B transcriptional activity in cells cultured with recombinant HMGB1. Our findings identify a novel biological setting (senescence), independent of necrosis or microbial infection, in which HMGB1 secretion occurs, and link senescence-dependent HMGB1 redistribution to p53 activity and inflammatory cytokine secretion.
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 LB-483. doi:1538-7445.AM2012-LB-483
Abstract LB-486: Overexpression of a mutated, constitutively active HIF2α promotes the carcinogenesis of TRACK mouse
Authors: Fu Leiping , Wang Gang , Shevchuk Maria M. , Nanus David M. , Gudas Lorraine J. 
Published: August 2012

Abstract
Background: VHL disease patients have an increased risk of developing clear cell renal cell carcinomas (ccRCC). Increased expression of HIF1α and/or HIF2α has been proposed as a key step in ccRCC carcinogenesis. We recently reported a mouse model of VHL renal cancer, the TRACK model (Fu et al, Cancer research. 2011;71(21):6848-56.). In the TRACK model, proximal tubule (PT) cell overexpression of a triple mutant (P402A, P564A and N803A) HIF1α in the mouse mimics human VHL kidney disease. Methods: Here we report a mouse model expressing a triple mutant (P405A, P531A and N847A) HIF2α in PT cells. Mutant HIF2α was expressed in both WT and HIF1α-expressing C57BL/6 mice. Results: Transgenic (TG) mice expressing this HIF2α construct specifically in PT cells exhibit vacuolization consistent with glycogen accumulation and hydropic degeneration. The activation of HIF2α was confirmed by increased expression of HIF2α target genes, e.g. CA9. Neoplastic transformation was not observed in the kidneys of HIF2α TG+ mice. In HIF1α/HIF2α-expressing mice, disorganized PT cells mimicking in situ carcinoma was observed in 5 mo old mouse kidneys, which was seen only at 14 mo in mice expressing only mutant HIF1α. Conclusions: These data suggest HIF2α accelerates carcinogenesis in the mutant HIF1α TRACK model. These mouse models provide excellent models to study VHL renal disease and carcinogenesis, and provide an opportunity for chemoprevention studies.
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 LB-486. doi:1538-7445.AM2012-LB-486
Abstract LB-495: Myeloid-derived suppressor cells promote cancer-associated fibroblast migration and carcinoma cell invasion
Authors: Shaw Aubie K. , Novitskiy Sergey , Moses Harold L. 
Published: August 2012

Abstract
Metastasis the most devastating part of cancer, yet we know very little about the earliest steps of metastasis. Myeloid-Derived Suppressor Cells (MDSC) are CD11b+, Gr-1+ bone marrow-derived cells that have been shown to promote tumor development by suppressing T cells. In addition to immune suppression, MDSC can promote metastasis. MDSC localize to the invasive edges of primary tumors and promote breast cancer lung metastasis. Localized invasion of cancer cells is the earliest step of metastasis and fibroblasts are required for breast cancer cell invasion. Fibroblasts remodel the ECM and leave tracks for collective migration of carcinoma cells. These studies seek to identify the mechanism of MDSC promotion of metastasis by determining if MDSC can stimulate fibroblast migration and lead localized carcinoma invasion. Freshly isolated MDSC from a mammary tumor-bearing mouse increase fibroblast migration. TGFβRII-/- fibroblasts demonstrate a further increase in migration in response to MDSC, suggesting that TGFβ signaling is not required for MDSC promotion of fibroblast migration. MDSC secretions act directly on fibroblasts since conditioned medium from MDSC increases fibroblast migration to the same extent as live MDSC. Antibody array analysis identified several MDSC secreted proteins, including CXCL11, CXCL15, FGF2, IGF-I, IL-4 and Shh. MDSC increase carcinoma cell invasion through Matrigel, but only when fibroblasts are present. MDSC treatment of fibroblasts stimulates Akt and ERK1/2 phosphorylation and loss of secreted proteins, including SDF-1, TIMP-1, TNFα and VEGF. Analysis of subsets of MDSC identified that monocytic MDSC (CD11b+, Ly6Chi, Ly6G-) increase fibroblast migration more than other myeloid cell populations. Tumor-derived MDSC promote fibroblast migration more that splenic MDSC. These studies show that MDSC can lead fibroblasts to stimulate carcinoma invasion and suggest that perivascular MDSC may be the earliest stimulus for localized invasion during metastasis.
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 LB-495. doi:1538-7445.AM2012-LB-495