bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2007: Concurrent gene promoter hypermethylation and allele loss occurs infrequently in head and neck squamous cell carcinomas
Authors: Poage Graham M. , Christensen Brock C. , Houseman E. Andres , McClean Michael D. , Wiencke John K. , Posner Marshall R. , Clark John R. , Nelson Heather H. , Marsit Carmen J. , Kelsey Karl T. 
Published: February 2011

Abstract
Malignancies arise as a result of environmental insults that cause an accumulation of molecular changes in the genomes and epigenomes of the affected somatic cells. Numerous models have been described that outline the set of consequential alterations for different tumor types throughout carcinogenesis. The implication of Knudson's two-hit hypothesis for inactivation of tumor suppressor genes, with regards to the emerging field of integrative genomics, is that this gene silencing can be achieved through deletion of one allele and hypermethylation of the other. We aimed to characterize this process in the upper airway epithelium through an array-based molecular investigation of 19 head and neck squamous cell carcinomas (HNSCCs). We utilized a genome-wide integrated approach, combining data from DNA methylation arrays (&gt;1400 loci) with SNP-based resequencing (&gt;500K loci) copy number data, and a novel analytical approach involving model-based clustering methods. We found that while methylation and gene copy number were well-correlated for a number of loci, few tumor suppressors exhibited concomitant silencing alterations. In fact, of the commonly altered genes in this disease only CDKN2A possessed both hypermethylation and allele loss, and only at one locus for a minority of tumors (3/18). Three tumors also lacked one copy of the maintenance methyltransferase gene, DNMT1, and these samples had a lower average methylation across all loci measured than those with a normal copy number (P&lt;0.0001) at this site. Our results suggest that coordination of molecular mechanisms rarely occurs at single genes; however they may be linked through global regulatory processes affecting the patterns of coordinated alterations in order to control carcinogenic gene pathways. A thorough understanding of these alteration patterns and integration of such molecular processes are critical for the identification of cellular targets/biomarkers in HNSCC and for rational therapeutic administration.
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 2007.
Abstract 2010: A Network Phenotyping Strategy (NPS) for HCC identifies distinct coherent survival groupings from observed clinical traits
Authors: Pancoska Petr , Carr Brian I. , Branch Robert A. 
Published: February 2011

Abstract
Background: HCC is a complex disease with tumor growth replacing adjacent liver. Our initial hypothesis was that tumor traits and loss of liver function are independent processes. We examined this, seeking evidence of coherent discrete structure with respect to survival. Methods: NPS was used to analyze 970 patients with biopsy-proven, non-surgical HCC, all followed prospectively until death. We assumed stochasticity with respect to timing of diagnosis and ambiguity of each variable with respect to survival and used a combination of k-partite graph-based analysis with statistical processing of pairwise dependencies of clinical data ordered by survival, each characterized by the mean of clinical parameters of the 100 patients with the closest survival, for 678 survivals. Results: NPS clearly identified heterogeneity, with 3 distinctive phenotypes based on coherence of multiple variables. Each had different survival ranges with trends of collinear relationships between bilirubin, AFP, alkaline phosphatase, SGOT and GGTP. In patients &gt;70 years, the larger the tumor the higher the biochemical values, with the trends decreasing with longer survival. Above 80 years, bilirubin and AFP were normal, with long survival, 330-1250 days. There were 2 groups of younger patients (&lt;55 years). One, with 30-45 days survival, had a similar profile to the older group. In the other, with 90-330 days survival, the profile was for multiple small tumors to trend with biochemical values. A striking finding was the close correlation in trends for AFP against bilirubin, alkaline phosphatase, GGTP or SGOT values, suggesting that liver damage parameters and tumor parameters were not independent factors, but might be inter-twined, especially in older patients. Conclusions: This NPS analysis does not support the hypothesis that tumor growth and cirrhotic damage are independent, but are intertwined processes. Furthermore, we have evidence based on coherence between variables that the growth rates for unifocal tumors of equivalent size are faster in the young than in the elderly. NPS provides useful insights to design future genomic studies to compare different phenotypes and understand the different pathophysiological processes involved.
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 2010.
Abstract 2012: Off-target drug effects due to retroactivity in signaling pathways
Authors: Wynn Michelle , Ventura Alejandra , Garcia Hector , Merajver Sofia 
Published: February 2011

Abstract
A majority of targeted cancer therapeutics involve the specific inhibition of a molecular target in a signal transduction pathway. It is well known that targeted therapies, such as kinase inhibitors, may have effects on pathways other than those specifically targeted, whether by non-specific interactions or by indirect pathway cross-talk effects. The simplest view of signal transduction entails a cascade of molecular events initiated by the recognition of a stimulus and culminating in the chemical alteration of an effector molecule. We have recently shown that cascades can exhibit bidirectional signal propagation without the addition of regulatory feedback connections via a phenomenon termed retroactivity. Thus, retroactivity represents another potential source of off-target effects in signaling cascades.
We have extended our previous work to a computational model which allows us to characterize the significance of the upstream off-target effect via retroactivity with a series of simple signaling networks using physiologically relevant parameters values. We aim to understand the dynamics of cancer signaling by integrating systems biology based models of signaling dynamics into our experimental investigations of breast cancer with the intent of both directing experiments and making predictions. One of the signaling networks we studied takes the form of two independent signaling cascades which have no regulatory feedback connections but are activated by the same upstream kinase. Our results suggest that under physiologically relevant conditions the application of an inhibitor near the bottom of one cascade can produce a significant change in concentration of a protein in the other cascade, even without a regulatory feedback connection between the two cascades. Developing a deeper understanding of bidirectional signal propagation in signal transduction pathways will be vitally important in the effort to develop safer and more effective targeted cancer therapies. Our modeling results challenge the notion that information in cascades only flows in the cell surface-to-nucleus direction and suggests that a perturbation applied within a cascade can produce both an upstream and a downstream effect. The notion of an upstream off-target effect is completely novel and may have significant implications if the perturbation takes the form of an inhibitory therapeutic drug.
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 2012.
Abstract 2013: Integrative genomic studies pertaining to cigarette smoke and human lung carcinogenesis
Authors: Yang Maocheng , Xi Sichuan , Liu Fang , Rao Mahadev , Schrump David S. 
Published: February 2011

Abstract
Lung cancer is a major cause of cancer deaths worldwide. Whereas the vast majority of these neoplasms are directly attributable to cigarette abuse, the molecular mechanisms contributing to tobacco- associated pulmonary carcinogenesis are not well understood. In the present study, we utilized microarray techniques and systems biology analysis to investigate global mRNA and microRNA (miRNA) expression profiles during lung cancer progression using an in-vitro model. Four sets of cell lines were chosen to examine miRNA/mRNA signatures during lung cancer progression, including primary normal human bronchial epithelia (NHBE) as well as small airway epithelial cells (SAEC), immortalized human bronchial epithelial cells (HBEC), a lung cancer line (H1975) derived from a non-smoker, and three lung cancer lines (H1299, Calu-6 and A549) derived from smokers. Cells were cultured in normal media (NM) with or without cigarette smoke condensate (CSC), the DNA demethylating agent, 5 aza-2’ deoxycytidine (DAC), and the histone deacetylase inhibitor Depsipeptide (DP) to examine how cigarette smoke and epigenetic events may affect global mRNA and miRNA expression during pulmonary carcinogenesis. Based on global mRNA/miRNA expression clustering, primary respiratory epithelial cells, immortalized HBEC, and smoker as well as non-smoker derived lung cancer lines were readily distinguished from one another. Each cell group exhibited its own special set of miRNAs /mRNAs, which were over or under-expressed relative to primary cells. Comparison of miRNA profiles in CSC-treated vs untreated NHBE, SAEC, HBEC, A549 and Calu-6 cells revealed that cigarette smoke induces over-expression of miR-21 and miR-31. MiR-21 and miR-31 were also significantly over-expressed in smoker-derived A549 and Calu-6 lung cancer cells relative to non-smoker-derived H1975. In addition, differential gene expression profiles were observed in smoker-derived vs non-smoker derived lung cancer cells. A group of miRNAs/ mRNA were preferentially modulated by sequential DAC/DP treatment in these cultured cells. Further analysis of differentially expressed miRNAs/mRNAs observed in this model system may provide new insight regarding molecular mechanisms associated with pulmonary carcinogenesis, and reveal novel biomarkers for lung cancer diagnosis and prognosis.
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 2013.
Abstract 2015: Patient-specific pathway analysis using DIGMA identifies key activities in multiple cancers
Authors: Benz Stephen , Vaske Charles , Sanborn J. Zachary , Stuart Joshua , Haussler David 
Published: February 2011

Abstract
Cancer is a disease of genomic perturbations that lead to dysregulation of multiple pathways within the cellular system. While common pathways are believed to be shared within specific cancer types, the mechanisms of why particular patients respond differently to treatment is not fully understood. Current -omics studies such as The Cancer Genome Atlas (TCGA) and Stand Up To Cancer (SU2C) have attempted to address this issue by using large-scale whole-genome measurements of mRNA expression, DNA copy number, and epigenetic features. Typical analysis of these measurements relies on integrating data from multiple samples to distinguish signal from noise. However, few analytical methods allow for sample-specific differences to identify features and pathways that are significant for prognosis and clinical treatment classifications.
We developed a pathway inference method called DIGMA (Directed and Integrated Graphical Modeling of Activities) to identify patient- and sample-specific pathway activities. DIGMA is capable of inferring individual gene and protein level measurements within pathways as well as overall pathway alterations specific to an individual tumor. DIGMA models each gene's “Central Dogma” within an overall pathway structure using probabilistic graphical models (PGMs). Individual -omic measurements are attached to their represented protein within the network and proteins are connected using interactions defined in curated pathway models. This representation is flexible enough to support any number of -omics measurements, which can be connected to the protein and pathway in biologically meaningful ways.
Applying our method to TCGA ovarian serous carcinoma and glioblastoma multiforme samples identified pathways both significantly activated across a large majority of the cohort as well as pathways useful for classification of samples that responded well to treatment. We used random simulations to measure the significance of the pathway activities and establish a false discovery rate. These results suggest the ability to identify critical intervention points for therapeutics at a sample-specific level.
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 2015.
Abstract 2019: Molecular pathways involved in docetaxel (D)-resistance hormone-independent prostate cancer (HIPC) cells
Authors: Marín-Aguilera Mercedes , Codony-Servat Jordi , Kalko Susana G. , Gascón Pere , Mellado Begoña 
Published: February 2011

Abstract
Background: D-based chemotherapy is the standard therapy of metastatic HIPC. However, only approximately 50% of patients respond to this treatment and most of them eventually develop resistance to the therapy. The molecular events that lead to D-resistance in HIPC are not well established.
Objectives: To determine the main molecular pathways responsible for D-resistance in two different HIPC cells lines.
Methodology: DU-145 and PC3 cell lines were converted to D-resistant cells (DU-145R and PC3R, respectively) by means of exposing parental cells to increasing doses of D. Affymetrix U133 Plus 2.0 whole genome arrays were used to compare global gene expression between these four cell lines. Genes, pathways and networks, commonly deregulated in both DU-145R and PC3R cells respect their parental cell lines, were analyzed in detail. Changes in expression of a subset of genes were confirmed by real-time RT-PCR.
Results: Differential expression of 321 genes (P&lt;0.05 Bonferroni corrected and logFC&gt;1.2) was found to be common in DU-145R and PC3R cells. Pathway and network analysis showed that these genes were particularly involved in cellular growth and proliferation, gene expression, cellular movement, cellular development, cell death and cell cycle. Other related functions are infection mechanism, cellular assembly and organization, tissue morphology, antigen presentation and cell-mediated immune response. RT-PCR confirmed differential expression in genes related with epithelial-mesenquimal transition (e-CADHERIN, α-CATENIN, VIMENTIN, SNAIL and TWIST), NFkB related genes (IL-6, IL-8, c-REL, P50 and P65) and ErbB signalling pathway family genes (EGFR and HER3).
Conclusions: These data reveals a set of gene networks involved in HIPC D-resistance. Key genes from these networks should be investigated further as new targets for potential therapeutic development.
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 2019.
Abstract 2022: The WAVE3-dependent cancer cell invasion is regulated by miR-31 during cancer progression and metastasis
Authors: Sossey-Alaoui Khalid 
Published: February 2011

Abstract
MicroRNAs are small non-coding RNAs that are directly involved in the regulation of gene expression by either translational repression or degradation of target mRNAs. Because of the high level of conservation of the target motifs, known as seed sequences, within the 3′-untranslated regions (UTR), a single microRNA can regulate numerous target genes simultaneously, providing a mechanism for this class of RNAs to serve as master regulators of gene expression. Loss of expression of miR-31 has recently been suggested to be associated with cancer progression and metastasis (1). Our previous studies reported a very significant correlation between the expression levels of WAVE3, an actin cytoskeleton remodeling protein, and advanced stages of breast cancer, clearly supporting the function of WAVE3 as a metastasis promoter protein (2). Here we show that the activity of WAVE3 to promote cancer cell invasion is regulated by miR-31 microRNA. We also show a clear inverse correlation between expression levels of WAVE3 and miR-31in invasive versus non-invasive cancer cells. miR-31 directly targets the 3’-UTR of the WAVE3 mRNA and inhibits its expression in the invasive cancer cells. The miR-31-mediated down-regulation of WAVE3 results in a significant reduction in the invasive phenotype of cancer cells, which is specific to the loss of WAVE3 expression since re-expression of a miR-31-resistant form of WAVE3 reverses miR-31-mediated inhibition of cancer cell invasion. We finally report a correlation between the expression levels of WAVE3 and miR-31 in non-invasive vs highly invasive primary human breast cancer tumors. In conclusion, a novel mechanism for the regulation of WAVE3 expression in cancer cells has been identified, which controls the invasive properties of cancer cells. The present study also identifies a critical role for WAVE3, downstream of miR-31, in at least one of the multiple steps that govern the invasion-metastasis cascade.
References:
1-Valastyan et al., A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 137:1032-1046. 2009.
2-Sossey-Alaoui et al., Down-regulation of WAVE3, a metastasis promoter gene, inhibits invasion and metastasis of breast cancer cells. Am J Pathol. 170:2112-2121. 2007.
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 2022.
Abstract 2024: Over-expression of miR-106b in metastatic hepatocellular carcinoma using an orthotopic metastasis animal model
Authors: Yau Wing Lung , Pang Roberta Wen Chi , Lee Terence Kin Wah , Wo Jana Yim Hung , Poon Ronnie Tung Ping 
Published: February 2011

Abstract
Hepatocellular carcinoma (HCC) is one the most fatal cancers worldwide. Early diagnosis is crucial for curing the disease. However, patients are often diagnosis at late-stage with distant metastasis, and the prognosis of metastatic HCC is poor. Molecular pathological studies confirm that gene expression alteration plays a critical role in disease progression. Recently it has been discovered that microRNA (miRNA) can alter the gene expression at post-transcription level. This study aimed to elucidate the role of miRNA in development of metastatic HCC using an orthotopic animal model and the molecular pathway involved.
Orthotopic metastasis animal model was established by implanting HCC cell lines onto the liver of the SCID mice. Tumor growth was monitored by in vivo imaging system. Primary tumor and lung metastasis were observed after 12 weeks of inoculation. Tumor were then excised and established into primary tumor cell lines (PT) and lung metastatic cell lines (LM). Functional studies comparing the PT and LM cell lines derived from HCC cell line PLC demonstrated higher cell invasion and migration ability in the metastatic cell line compared with the primary tumor cell line. In addition, the LM cell line possessed more stress fiber than the PT cell line. The PLC-derived cell lines and another metastatic HCC cell line, MHCC97H-derived cell lines were subjected to the miRNA microarray analysis. Fifteen human miRNAs were found to be differentially expressed in the LM cell lines when compared to the PT cell lines. miR-106b was one of the miRNAs which was over-expressed in LM cell lines. We further confirmed our findings in HCC clinical sample and found that miR-106b was over-expressed in HCC tumor compared with the adjacent non-tumor tissue, and its expression was significantly associated with the tumor grade (p=0.018). MicroRNA knock-down study was performed by using the miR-106b LNA knock-down probe. The miR-106b knock-down reverted the cell migration phenotype, and fluorescent staining of stress fiber formation showed that the miR-106b knock-down cells have less stress fiber formation than the parental cell lines and the scramble control. We further studied the expression of E-cadherin in PLC-PT, PLC-LM, the scramble control and the miR-106b knock-down cell lines. Our result demonstrated that miR-106b expression inversely correlated with E-cadherin level. Since decrease of E-cadherin expression is the hallmark for epithelia-mesenchymal transition (EMT), further studies will focus on the role of miR-106b in EMT of HCC cells.
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 2024.
Abstract 2028: miR-433 attenuates the spindle assembly checkpoint (SAC) response to paclitaxel
Authors: Furlong Fiona M. , Prencipe Maria , McGoldrick Alo , McGettigan Paul , Carney Desmond , Doyle Emma , Kay Elaine , McCann Amanda 
Published: February 2011

Abstract
Paclitaxel is a microtubule inhibitory chemotherapeutic drug which is increasingly used for the treatment of solid tumours. In vitro studies have demonstrated that attenuating the spindle assemble checkpoint (SAC) alters the post-mitotic responses to paclitaxel. Furthermore, the aberrant expression of a number of the SAC proteins, MAD2, BUBR1, and Aurora A kinase, are associated with poor patient prognosis. We have identified a microRNA, miR-433, that regulates the expression of MAD2. Over-expression of miR-433 in HeLa cells induced downregulation of MAD2 mRNA and protein expression. We have also shown that HeLa cells over-expressing miR-433 and treated with paclitaxel are no longer capable of cyclin B stabilisation and thus have lost the ability to activate the SAC in response to paclitaxel. In addition, cell viability assays showed that HeLa cells over-expressing miR-433 and treated with paclitaxel have an attenuated response to pacilitaxel compared to microRNA scrambled controls. We have characterised the levels of miR-433, MAD2 gene expression and MAD2 protein levels in a cohort of ovarian cancer cell lines. Cell viability assays on this cohort revealed that responsiveness to paclitaxel is associated with high MAD2 protein expression and low miR-433 expression. We hypothesise that the expression of miR-433 when deregulated in cancer leads to altered MAD2 expression and a compromised SAC, a key feature underlying drug resistance to paclitaxel.
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 2028.