bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1999: Aberrant expression of HOX transcript in ovarian carcinoma
Authors: Thompson Kevin J. , Southern G. Kirk , Bahrani-Mostafavi Zahra , Mostafavi M. Taghi , Tait David L. 
Published: February 2011

Abstract
Ovarian cancer is a complex disease phenotype that is challenging to diagnose, primarily because patients tend to remain non-symptomatic until after metastasis has initiated. For those individuals identified early in the disease progression the survival rate is promising, but for the majority, diagnosed late, the 5-year survival rate is dismal. Our eventual goal is to identify a panel of circulating markers that distinguish early onset of the disease. In particular, we have examined the homeobox (HOX) transcript family of genes, known to be involved in cancer progression. These genes are intrinsic cellular factors regulating positional development during embryogenesis and bone formation, and are documented upstream regulators of 16 signaling pathways.
Methods: The tissue-specific gene expression from 35 human ovarian tissue samples, using Affymetrix GeneFocusTM microarrays was examined. The microarray analysis was performed on tissues from 8 normal ovaries, 12 benign and 15 malignant epithelial tumors. Microarray output was processed with a stringent data cleansing pipeline to ensure the investigated genes can be unambiguously interpreted.
Results: ANOVA analysis reveals a significant alteration in the HOX expression profiles between ovarian tumorous and non-tumorous tissues. While several members of the homeobox gene family are reported to be differentially expressed, we observed a significant shift from healthy HOXC6 expression to an aberrant HOXB2 expression. Whereas non-tumorous tissue demonstrated elevated levels of HOXC6 mRNA transcript, the malignant tissues demonstrated elevated levels of HOXB2 transcript. A possible consequence of the aberrant HOX expression levels is to increase the production and hence the paracrine signaling of osteopontin (SPP1), which is reported to be negatively regulated by a SMAD-HOX interaction. Osteopontin has been correlated to cancer progression, metastasis, and patient survival. We observed a significant correlation between elevated SPP1 expression and the observed HOX disregulation.
Conclusion: We demonstrated a correlation between malignant associated SPP1 upregulation and aberrant HOX transcript regulation. These alterations in transcript and protein levels are significant to the epithelial microenvironment. These results have been validated by qRT-PCR and IHC and confirmed with additional patient specimens. The correlation between these two events needs to be further investigated as to their significance in the progression of the disease and as potential candidate biomarkers for ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1999.
Abstract 2: Naked CanScript, an 18-base pair sequence, has tumor cell-specific promoter activity in vivo: Implications for targeted gene therapy
Authors: Sawicki Janet A. , Huang Yu-Hung , Cozzitorto Joseph , Langer Robert , Anderson Daniel G. , Brody Jonathan R. 
Published: February 2011

Abstract
The MSLN gene encodes mesothelin and is highly active in several human malignancies including ovarian, pancreatic, bronchial, gastroesophageal, cervical, endometrial, and biliary carcinomas. The high cancer cell-specific activity of MSLN is attributable to an 18-bp upstream enhancer, CanScript, which selectively elevates transcription upon binding of TEF-1, a transcription enhancer factor, to a MCAT motif. It has previously been shown that three concatemerized copies of CanScript produce a 30-fold enhancement over a SV40 minimal promoter in MSLN-expressing cancer cells (Cancer Res. 2007 Oct 1;67(19):9055-65). To determine whether incorporation of CanScript into gene constructs may have application in enhancing activity of promoters used in cancer-targeting gene therapy strategies, we generated several luciferase reporter gene constructs having different cell type-specific promoters (MSLN, HE-4, PSA) and different copy numbers of CanScript (1X, 2X, 3X, 6X). We transfected multiple cell lines, including MSLN+ (ovarian and pancreatic) and MSLN− (liver, lung, and prostate) tumor cells, with these DNA constructs, and measured luciferase activity 48 hrs later. To replicate an in vivo therapeutic setting, we used nanoparticles to deliver the constructs to the peritoneal space of healthy and ovarian-tumor bearing mice, and measured gene expression in tumors and multiple organs by optical imaging. Surprisingly, we determined that an 18-bp CanScript sequence activates gene expression in a cell-specific manner in the absence of any other promoter sequence, and that amplification of CanScript in combination with either the MSLN or HE4 promoter sequences, i.e., two gene promoters that are highly active in ovarian cancer cells, significantly enhances their activity proportional to the number of copies of CanScript, in MSLN+ cells, including MSLN+ HE4− pancreatic cells, but has little effect in MSLN− cells. These results support the use of CanScript when increased, specific gene expression is desired to improve therapeutic efficacy in tumor cells in which MSLN is highly active.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2.
Abstract 2002: Cell reprogramming by hypoxia
Authors: Luigi Varesio , Fardin Paolo , Versteeg Rogier , Blengio Fabiola , Barla Annalisa , Bosco Maria Carla 
Published: February 2011

Abstract
Background
Low oxygen tension (hypoxia) is an important determinant in tumor progression. In this study we assess the prognostic value of an in vitro derived hypoxia gene signature in neuroblastoma patients.
Material and Methods l1-l2 regularization framework has been applied on gene expression profiles of 11 neuroblastoma cell lines to define the neuroblastoma hypoxia signature. We applied k-means clustering on the expression level of the signature 62 probesets to segregate 88 neuroblastoma patients and subgroups obtained by common risk factors stratification. We analyzed the classes by Kaplan-Meier curves and log-rank test for overall survival (OS) and event-free survival (EFS). Multivariate Cox analysis was performed to define the predictive power of the signature.
Results
The neuroblastoma hypoxia signature distinguished two groups of neuroblastoma patients classifying them as poor prognosis (21 patients), those having OS rate of 25.5% and EFS rate of 27.7%, and as good prognosis (67 patients), those having OS rate of 73.2% and EFS rate of 67.7%. The poor prognosis patients show an over-expression of the hypoxia probesets. Multivariate Cox analysis revealed that the neuroblastoma hypoxia signature is a significant independent predictor after controlling for commonly used risk factors. When applied to MYCN not amplified patients, the hypoxia signature was capable to stratify patients with OS rate of 24.2% and EFS rate of 27.3% for the patients with poor prognosis, compared with OS rate of 81.4% and EFS rate of 74.8% for the patients with good prognosis.
Conclusions
We demonstrate that the NB-hypo signature is a significant prognostic factor capable of stratify neuroblastoma patients. Furthermore, we obtained the proof of principle that the approach of hypoxia genes selection from in vitro controlled tumor cell lines, is a feasible method to identify specific contribution of the microenvironment to the tumors’ biology.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2002.
Abstract 2006: Mathematical and computational models for cellular space in cancer growth
Authors: Olsen Megan , Sitaraman Ramesh , Siegelmann-Danieli Nava , Siegelmann Hava 
Published: February 2011

Abstract
This study investigates the dependency of tumor cell growth on specific spatial regulations for both normal and tumor cells. In general it is known that cellular growth is affected by contact inhibition, but many models fail to include this aspect explicitly. Our work studies the extent to which spatial constraints and interactions between normal and tumor cells affect tumor growth.
We model spatial constraints via a set of differential equations, modified from the classic logistic equation. These equations represent the hallmarks of cancer, with the addition of spatial rules based on the ratio of living tumor to normal cells in the tissue. Four different sets of equations are analyzed and compared, each representing a different potential scenario of how tumor and normal cells differ in their views of space. Most computational models of cancer do not investigate the interactions between normal cells and tumor cells, and our approach demonstrates that these interactions are crucial for modeling and understanding cancer growth.
Our results provide a delineation of when tumor growth will take over an area versus when it will be slowed or stopped for each type of spatial constraint. Our results indicate that different combinations of spatial regulations cause different outcomes in tumor growth. They also demonstrate that cells following the same set of rules for proliferation, death, and mutation meet different outcomes given a change in spatial constraints. Thus, an accurate modeling of spatial interactions between two cellular populations is crucial to adequately examine tumor cells. Our results suggest that a treatment assuming one set of rules will fail if another set of rules is in place. Further, if we learn to modify these spatial rules in a tissue then tumor growth could be decreased. Our work also implies that to be able to use computational models for evaluating options for treatment proper spatial rules must be taken into account in the model.
In conclusion, we recognize that the influence of contact inhibition on different populations of cells can drive one cancer to take over the system, while it can significantly slow the growth of another. Such spatial constraints are extremely crucial to modeling and understanding cancer growth and in evaluating options for treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2006.
Abstract 2009: A new repressive network module in Ewing's Sarcoma
Authors: Kauer Maximilian O. , Jug Gunhild , Niedan Stephan , Walker Robert L. , Meltzer Paul S. , Kovar Heinrich 
Published: February 2011

Abstract
The EWS-FLI1 chimeric transcription factor characteristic of Ewing's sarcoma family tumors (ESFT) constitutes the prototype of an aberrant ETS transcription factor causally involved in oncogenesis. However, the mechanisms of transcriptional regulation leading to ETS driven tumorigensis are poorly understood. Previously, we have successfully established and tested a research plan that proceeds from genomics data production, via bioinformatic generation of specific hypotheses to functional elucidation of EWS-FLI1 associated transcription network modules. In-silico analysis of time-resolved expression data revealed enrichment of ETS binding motifs in early EWS-FLI1 activated target genes, while EWS-FLI1 repressed genes showed most prominently enrichment of recognition motifs for forkhead box (FOX) proteins. Other motifs significantly co-occurring in the same promoter with FOX motifs were mainly containing homeobox domains (POU, SOX, NKX, CDP, TGIF). Concentrating on the EWS-FLI1 repressed transcriptional network most FOX proteins (FOXO1, FOXO3, FOXD1 and FOXN3) in the data set were found to be EWS-FLI1 repressed. Promoters of two of these genes, FOXO1 and FOXO3, were directly bound by EWS-FLI1 in a ChIP-seq experiment, and were also expressed at lower levels in ESFT than in mesenchymal progenitor cells which constitute a likely cell of origin for ESFT. Furthermore, bioinformatic analysis showed that FOX motifs were significantly co-enriched with ETS motifs in promoters of the same gene for ∼4% of all genes. Thus, we hypothesize that EWS-FLI1 exerts a major part of its repressive effect via inhibition of FOX proteins and may also directly (co-)repress a subset of these genes. In depth dissection of this newly identified repressive module of the EWS-FLI1 transcription network is performed by ectopic expression, RNA interference (RNAi) and reporter gene technologies combined with mutation analysis, and chromatin immunoprecipitation and protein co-immunoprecipitation.
This study was funded by: “European Embryonal Tumor Pipeline” 6th framework program of the European Commission, (STREP “E.E.T. Pipeline” contract LSHC-CT-2006-037260), and by funds from the Austrian Research Fund FWF.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2009.
Abstract 2014: An estrogen receptor - centered network for probing anti-estrogen drug resistance with siRNA screening technology
Authors: Nasto Rochelle E. , Serebriiskii Ilya , Jablonski Sandra A. , Johnson Michael D. , Clarke Robert , Weiner Louis M. , Golemis Erica A. 
Published: February 2011

Abstract
De novo and acquired drug resistance pose significant problems for the effective treatment of estrogen-receptor (ER) positive breast cancers. We hypothesized that changes in the action of proteins interacting with core components of the estrogen response machinery may be responsible for such resistance, and that inhibition of these proteins may modulate response to hormonal therapies. To test this idea, we created a 631 gene network using ERα (ESR1), ERβ (ESR2), estrogen related receptors α (ESRRA) and γ (ESRRG), and aromatase as seed genes. The addition of genes to the network was selectively based on connectedness to the 5 seed genes. We used a set of bioinformatic resources including protein-protein interactions (PPIs), protein complexes, canonical pathways and estrogen responsive genes, to generate candidates for insertion into this network.
An siRNA library has been developed from these 631 genes, for use in screening of breast cancer cell lines. Our primary goal is to identify networks of candidate genes involved in resistance to estrogen pathway-targeted drugs, corresponding to genes that reduce cell viability specifically in the presence of the hormonal therapies fulvestrant and tamoxifen. We have used MCF7/LCC1 cells (tamoxifen sensitive/fulvestrant sensitive), MCF7/LCC2 (tamoxifen resistant/fulvestrant sensitive) and MCF7/LCC9 (tamoxifen resistant/ fulvestrant resistant) cell lines as syngeneic models with varying drug resistance profiles for these experiments. In addition, we are identifying genes that differentially affect the intrinsic viability of these cell lines, and thus should illuminate the mechanism of their resistance to hormonal therapies. Our goal is to elucidate a network of regulators of anti-estrogen resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2014.
Abstract 2020: MiR-210 modulates the hypoxic response in endothelial and ovarian cancer cells
Authors: Subramanian Indira V. , Ghosh Goutam , Joshi Hemant , Zheng Yan , Benyumov Alexey , Ramakrishnan Sundaram 
Published: February 2011

Abstract
Tumor growth and progression is intricately linked to hypoxia induced adaptive changes. Hypoxia is known to alter chemosensitivity, upregulation of putative cancer initiating stem cells and the microenvironment. The multitude of these changes is brought about by differential gene expression. Hypoxia inducible transcription factor-1 alpha (HIF-α) is a key transducer of altered gene expression under low oxygen or ischemia. In addition to the transcriptional activation of multiple genes, hypoxia also alters miRNA levels in tumor and vascular endothelial cells. miRNAs are small noncoding RNAs ∼22 nucleotides in length representing 1%-2% of the eukaryotic transcriptome. We used microarrays to determine relative changes in 467 miRNAs in endothelial and MA148 ovarian cancer cells exposed to hypoxia. One of the miRNAs, miR-210 was significantly up-regulated under hypoxia by microarray analysis (2-fold, P &lt;0.01). miR-210 expression changes were validated by RT-qPCR. Exogenous over expression of miR-210 in endothelial cells increased their proliferative capacity and induced angiogenesis. These effects were reversed by morpholino antagomiR specific for miR-210. In-vivo studies using transgenic zebrafish showed that miR-210 can increase angiogenesis which could be readily reversed by morpholino antagomiR. These studied together showed that miR-210 plays an important role in angiognenesis. We then over-expressed miR-210 in ovarian cancer cells. While in vitro growth rate was not altered, over expression of miR-210 changed the kinetics of tumor growth. Taken together, these data implicate an important role for mir-210 in hypoxia induced adaptive changes in tumor microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2020.
Abstract 2027: Proteomic analysis identifies pathways regulated by miR-34a
Authors: Chen Qing-Rong , Yu Li-Rong , Cheuk Adam , Song Young , Wei Jun , Chung Joon-Yong , Hewitt Stephen , Veenstra Timothy D. , Khan Javed 
Published: February 2011

Abstract
MicroRNA 34a (miR-34a) is an important tumor suppressor gene and has been identified as a miRNA component of the p53 network. To better understand the biological pathways involved in miR-34a action, we performed parallel global protein and mRNA expression profiling on miR-34a treated neuroblastoma cells (IMR32 cells) using isotope-coded affinity tags (ICAT) and Affymetrix U133plus2 microarray respectively. Global profile suggests a mild overall mRNA expression changes in miR-34a treated cells, but systematic protein level changes have been detected. A total of 1495 proteins represented by 2 or more peptides were identified from the quantitative ICAT analysis, of which 143 and 192 proteins are significantly up- or down-regulated in miR-34a treated cells. Several of these down-regulated proteins contain seed sequences for miR-34a. Pathway analysis of the differentially expressed proteins shows the enrichment of apoptosis and cell death in up-regulated proteins, and DNA replication and cell cycle processes in the down-regulated proteins in miR-34a treated cells. Biological network analysis of direct interaction between differentially expressed proteins suggests that YY1 as well as its downstream proteins are significantly inhibited by miR-34a. Western blotting confirmed the suppression of YY1 protein expression by miR-34a. MiR-34a might target YY1 through miR-34a-binding site in the 3’ UTR of YY1. YY1 is a ubiquitous transcription factor and it is a negative regulator of p53. YY1 has been associated with cell proliferation, anti-apoptosis, tumorigenesis and metastatic potential. Therefore the elucidation of the role of YY1 may shed important light on tumor suppressive function of miRNA-34a.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2027.
Abstract 2030: Wnt/beta-catenin signaling acts as a master regulator of microRNA-181 expression in hepatocellular carcinoma
Authors: Ji Junfang , Yamashita Taro , Liu Hongjun , Finkel Toren , Wang Xin Wei 
Published: February 2011

Abstract
Hepatocellular carcinoma (HCC) is a malignant cancer with the observable heterogeneity and microRNAs (miRNAs) are functional associated with the tumorignesis of HCC. We recently identified that a group of HCC cells isolated with epithelial cell adhesion molecular (EpCAM) antibody are hepatic cancer stem cells (CSCs). In EpCAM+ hepatic CSCs, all miR-181 family members are highly expressed and Wnt/beta-catenin signaling is activated. Here, we investigated whether Wnt/beta-catenin signaling could regulate miR-181s expression in HCC. We first detected the association of beta-catenin and miR-181s expression in vitro and in vivo, and found that they were positively correlated. Further, the expression of miR-181s was induced following the activation of Wnt/beta-catenin signaling by the employment of Wnt10B conditioned media, LiCl, and transfection of beta-catenin and Tcf4. Meanwhile, the level of miR-181s was decreased after the inactivation of Wnt/beta-catenin signaling with induction of adenomatosis polyposis coli and transfection of beta-catenin siRNA. Moreover, we found Tcf4 associated with the promoter region of miR-181a-2 and miR-181b-2, in which there existed 7 classic Tcf4 binding elements. Taken together, our data indicate that miR-181s could be activated by Wnt/beta-catenin signaling and the transcript of miR-181a-2 and miR-181b-2 is a novel target of Tcf4/beta-catenin complex in HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2030.