bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4972: High-throughput functional profiling of dedifferentiated liposarcoma cell lines
Authors: Banerji Shantanu , Barretina Jordi , Crago Aimee , Frederick Abbie , Okamoto Michael , Weir Barbara , Cowley Glenn , Root David , Ladanyi Marc , Singer Sam , Meyerson Matthew L. 
Published: June 2012

Abstract
We previously profiled several adult soft-tissue sarcoma subtypes using sequencing, copy number analysis, and gene expression arrays. This high-throughput genetic profiling revealed dozens of candidate genes deserving of further functional validation.
To prioritize genes, we performed a pooled shRNA screen to identify essential genes in liposarcoma. Dedifferentiated liposarcoma (DDLS) served as a model for this approach as multiple robust cell lines are available. Five DDLS cell lines (DDLS8817, LPS141, FU-DDLS-1, RDD8107, and LP6) were infected with a pool of 54,020 lentiviral shRNAs targeting ∼11,000 genes (median 5 shRNAs per gene) and passaged for 16 doublings. DNA was extracted and hairpin sequences were PCR amplified and hybridized to a custom microarray that interrogates all shRNAs in the pool. shRNAs were ranked according to their differential abundance between early and late passages. Genes corresponding to the most significantly depleted shRNAs are presumed to affect cell proliferation and are candidate oncogenes.
We compared the pattern of hairpin depletion in the DDLS cell lines to a panel of over 60 cell lines representing other common cancers screened with the same pooled shRNA library. The 5 DDLS cell lines clustered into 3 distinct groups. Only one gene appeared to be essential in all 3 groups: WWTR1 (TAZ1), a master-regulator of adipocyte differentiation. Twenty-eight genes appeared essential in at least two DDLS groups including MDM2 and ZBTB2, both reported to negatively regulate the tumor suppressor gene TP53. Low-throughput in vitro experiments have confirmed that WWTR1 knockdown using two shRNA clones inhibits LPS141 proliferation by 78 and 75% after 4 days as compared to scramble (p=0.004 and 0.06 respectively).
Our complementary genome-scaled functional screen has confirmed a known oncogene in DDLS and revealed additional candidate genes that appear to have a role in proliferation. Further integration of existing datasets may nominate additional genes essential for liposarcoma pathogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4972. doi:10.1158/1538-7445.AM2011-4972
Abstract 4974: Allele-specific mRNA and protein expression on genetic variants of CCNE1 associated with risk of bladder cancer
Authors: Kohaar Indu , Fu Yi-Ping , Tang Wei , Tarway McAnthony , Muchmore Brian , Porter-Gill Patricia , Prokunina-Olsson Ludmila 
Published: June 2012

Abstract
A single nucleotide polymorphism (SNP), rs8102137, located 6 Kb upstream from the cyclin E1 gene (CCNE1) on chromosome 19q12, has recently been identified as a risk factor for bladder cancer (OR, p=1.7×10-11, Rothman et al, Nat Gen, 2010). We found a higher expression of CCNE1 mRNA in cDNA samples from bladder tumors (n=42) compared to adjacent normal bladder tissue (n=41, 3.7 fold, p=2.7×10-12). However, the expression did not correlate with genotypes of rs8102137. We also performed allelic expression imbalance (AEI) using a coding synonymous variation in the last exon (rs7257694, Ser390Ser) that is in high LD with the GWAS rs8102137 (normal bladder tissue samples, n = 41, D’=1.0, r2=0.815 and in HapMap CEU samples, n=60, D’=0.95, r2=0.68). In normal and tumor tissue samples heterozygous for both SNPs, the risk variant of rs8102137 was associated with lower expression of allele T of rs7257694 (p=2.2×10-4 in normal samples and 1.11×10-10 in tumor samples).
Western blot protein analysis with bladder tissue and prostate cell lines lysates showed that this allele-specific difference in mRNA expression is likely to be related to two protein isoforms that showed a differential pattern of expression dependent on rs8102137 and rs7257694 genotypes. CCNE1 regulates cell cycle G1/S transition, and alternative protein forms may have differential functions in cell cycle regulation, thereby affecting the risk of cancer. Alternative splicing forms of CCNE1 have been cloned and their functional analysis is ongoing.
In conclusion, our results suggest that bladder cancer associated genetic variants within the CCNE1 gene may affect mRNA splicing and protein structure of the gene, contributing to altered regulation of cell cycle and risk of bladder and other cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4974. doi:10.1158/1538-7445.AM2011-4974
Abstract 4984: Association of PTEN and p16 mutational status with MITF expression may provide a novel context for a phenotype switch in melanoma
Authors: Brooks Bradford R. , Yin Holly , Chow Donald , Sereduk Chris , Koeman Julie , Qian Chaonan , MacKeigan Jeffrey P. , Jung Sungwon , Kim Seungchan , Xu Mai , Weeraratna Ashani , Brown Kevin M. , Trent Jeffrey 
Published: June 2012

Abstract
For the last decade, array-based genomic screening has significantly advanced our understanding of genes involved in cancer development and progression. Moreover, genes identified in those screenings have subsequently been the focus of drug development efforts, ultimately leading to clinical trials. However, the efficient translation of cancer genomics results into the development of more effective therapeutics has been limited in part by the need for robust, high-throughput, functional validation of genes and pathways of interest in well-defined model systems. In order to identify new therapeutic targets in melanoma genomes, we have applied high-throughput RNA interference (RNAi) screening to well-characterized melanoma cell lines. We characterized a panel of 65 melanoma cell lines for genome-wide copy number changes and gene expression, as well as the mutation status of known melanoma genes (BRAF, HRAS, NRAS, KRAS, PTEN, CDKN2A, and TP53). From this panel, 18 cell lines were screened against some 1,250 genes (696 kinases, 550 supplemental; 4 siRNAs per gene) to identify modifiers of melanoma cell survival. A striking finding from our data is that MITF expression appears to be a determinant of invasive context and, furthermore, is associated with changes in both p16 and PTEN status. In the cell lines we examined, high MITF expression correlated with wild-type PTEN status, whereas PTEN was deleted or mutated in 30-35% of cell lines having low MITF expression. Similarly, p16 was unaltered in 40-45% of the cell lines that had high MITF expression but remained unaltered in only 20-25% of low MITF-expressing cell lines. The loss of p16 and PTEN are correlated with an aggressive phenotype in melanoma, and we confirmed by Western analysis that in cell lines with high MITF, p16 is present, but in cell lines with low MITF, p16 expression is absent. In agreement with the current literature, no association could be found with BRAF mutational status. Moreover, these data confirm that MITF is associated with the switch in phenotype from a proliferative to an invasive state in melanoma in a BRAF-independent manner, which in turn is associated with an increase in WNT5A expression, a change we previously have suggested is a critical determinant of melanoma metastasis. Results to be presented, aligned with new studies of sequence variants of MITF (Brown et al., unpublished), may help define a novel context for invasive potential of the important disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4984. doi:10.1158/1538-7445.AM2011-4984
Abstract 4985: The UCSC Cancer Genomics Browser
Authors: Zhu Jingchun , Sanborn J. Zachary , Benz Stephen C. , Craft Brian , Szeto Christopher , Kober Kord M. , Goldman Mary , Meyer Laurence , Vaske Charles , Collisson Eric , Stuart Joshua , Haussler David 
Published: June 2012

Abstract
The UCSC Cancer Genomics Browser (https://genome-cancer.ucsc.edu) comprises a suite of web-based tools to integrate, visualize and analyze cancer genomics and clinical data. The browser displays whole-genome views of genome-wide experimental measurements for multiple samples alongside their associated clinical information. Multiple datasets can be viewed simultaneously as coordinated “heatmap tracks” to compare across studies or different data modalities. Users can order, filter, aggregate, classify, and display data interactively based on any given feature set including clinical features, annotated biological pathways, and user-contributed collections of genes. Integrated standard statistical tools provide dynamic quantitative analysis within all available datasets. The browser hosts a growing body of publicly available cancer genomics data from a variety of cancer types, including data generated from the Cancer Genome Atlas project. Multiple consortiums use the browser on confidential prepublication data enabled by private installations. Many new features have been added, including the hgMicroscope tumor image viewer, hgSignature for real-time genomic signature evaluation on any browser track, and PARADIGM pathway tracks to display integrative pathway activities. The browser is integrated with the UCSC Genome Browser; thus inheriting and integrating the Genome Browser's rich set of human biology and genetics data that enhances the interpretability of the cancer genomics data.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4985. doi:10.1158/1538-7445.AM2011-4985
Abstract 4992: A Sox2-EGFR positive feedback loop contributes to oncogenesis of lung cancer
Authors: Chou Yu-Ting , Lee Chih-Chan , Lin Sheng-Chieh , Wu Cheng-Wen 
Published: June 2012

Abstract
Sox2, a core transcription factor regulating self-renewal of stem cells, is highly expressed in a subset of lung cancer. Nonetheless, how Sox2 contributes to lung tumorigenesis is still elusive. In this study, we report the discovery and mechanistic characterization of the Sox2 as an oncogene in lung cancer cells and its role as a key mediator of EGFR expression. Ectopic expression of Sox2 promoted cell proliferation and anchorage-independent cell growth. Knockdown of Sox2 induced autophagic death and attenuated oncogenic properties of lung cancer. A cDNA microarray analysis and immunoblotting revealed that Sox2 induced expression of EGFR, which contributed to tumorigenesis of lung cancer. In support of this notion, Sox2 bound to the EGFR promoter and enhanced its activity. In addition, EGFR activation or ectopic expression of c-Myc induced Sox2 expression in lung cancer, suggesting that Sox2-EGFR positive feedback loop promotes oncogenesis of lung cancer via a c-Myc dependent pathway. Indeed, c-Myc bond to Sox2 promoter and enhanced its expression under EGFR stimulation. Overexpression of Sox2 promoted tumor growth with increased EGFR expression in xenograft mouse model, and knockdown of Sox2 inhibited tumor growth with attenuated EGFR expression. Our findings suggest that Sox2 could induce EGFR mediated oncogene addiction in lung cancer, with potential applications as a novel therapeutic target for lung cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4992. doi:10.1158/1538-7445.AM2011-4992
Abstract 4993: Nicotine induced EMT and metastasis of human NSCLC : Role of beta-arrestin-1
Authors: Pillai Smitha , Trevino Jose , Rawal Bhupendra , Singh Sandeep , Li Xueli , Schell Michael , Haura Eric , Bepler Gerold , Chellappan Srikumar 
Published: June 2012

Abstract
Cigarette smoking is a major risk factor in the development of non-small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, an active component of tobacco smoke has been found to induce proliferation, invasion and epithelial-mesenchymal transition in NSCLC cell lines and promote the metastasis of NSCLC in mice. Nicotine induces cell proliferation utilizing a scaffolding protein, β-arrestin-1, which translocates to nucleus and associates with E2F1 transcription factor in response to nicotine stimulation. Here we demonstrate that mesenchymal markers such as vimentin and fibronectin are E2F1 regulated and β-arrestin-1 is involved in regulating nicotine induced expression of these genes. Vimentin and fibronectin promoters were E2F responsive and E2F1 could be detected on these promoters by chromatin immunoprecipitation (ChIP) assays. Depletion of β-arrestin-1 resulted in down-regulation of vimentin and fibronectin expression as well as inhibition of nicotine induced invasion of cells. Quantitative RT-PCR conducted on patient samples revealed a significant correlation between the levels of β-arrestin-1 and the expression of these genes. A microarray analysis conducted on nicotine stimulated parental A549 cells and those lacking β-arrestin-1 showed that about 290 genes were upregulated in the absence of β-arrestin-1, while 787 genes were downregulated. These included genes for transcription factors, growth factor receptors and signaling molecules. We further analyzed the global association of β-arrestin-1 in the genomic region upon nicotine stimulation by ChIP-sequencing and found that β-arrestin-1 is recruited on the promoters of many genes that regulate EMT such as ZEB2 (Zinc Finger E-box Binding Homeobox-2) as well as other regulatory pathways. ChIP assays conducted on NSCLC cell lines revealed the association of β-arrestin-1 on ZEB1 (Zinc Finger E-box Binding Homeobox-1) and ZEB2 promoters. Depletion of β-arrestin-1 in A549 cells resulted in the downregulation of ZEB1 and ZEB2. Additionally, in an orthotopic lung cancer model in SCID-beige mice, implantation of A549-luciferase stable cells lacking β-arrestin-1 showed a decrease in primary tumor growth and also resulted in significantly lower levels of nicotine-induced metastasis when compared to controls. Taken together, these data suggest that β-arrestin-1 contributes to nicotine induced progression and metastasis of NSCLC, especially in patients exposed to tobacco smoke. Further, β-arrestin-1 and its associated molecules might be targeted for the development of novel agents to combat NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4993. doi:10.1158/1538-7445.AM2011-4993
Abstract 50: An informatic approach to rational selection of cell lines modeling complex clinicopathologic phenotypes based on gene expression: The COXEN algorithm
Authors: Smith Steven C. , Theodorescu Dan 
Published: June 2012

Abstract
A perennial issue in biomedical research regards validation of the relevance of experimentally tractable model systems to disease characteristics of interest. In the study of many types of cancer, this often operationally means selection of a cell line or a number of cell line models for perturbation within in vitro or in vivo models of disease progression or treatment. However, many classic cell lines are of uncertain provenance, may have been isolated from tumors staged and graded decades ago in a fashion of limited interpretability with regards to current care, or have exhibited drifting phenotypes in intervening years. One example is that of the classic bladder cancer cell line, T24, isolated from a sample of “verified grade III papillomatosis of the bladder” in 1973, which has given rise to isogenically verified metastatic variants like T24T (1). We recently have reported an algorithm, called COXEN (COeXpression ExtrapolatioN), which uses concordant gene expression signatures of complex clinicopathologic phenotypes to infer interpretable and predictable relationships between disparate cell line and tumor populations, despite significantly different global transcriptional differences. While prior reports have used COXEN to predict chemotherapeutic response in clinical trials a priori based on signatures from cell lines (2,3), herein we report an application of the reverse analysis, using signatures of clinicopathologic characteristics in tumors including invasion, nodal metastasis, and poor survival to select from a panel of forty bladder cancer cell lines models reflecting with highest fidelity the transcriptional patterns underlying the parameter of interest. We find that this approach validates some cell line model systems of bladder cancer and proposes new uses for others. This approach, widely adaptable to other tumor histologies, may provide important guidance for selection of appropriate models to test therapies targeted at clinically important phenotypes.
(1) Harding MA et al. Cancer Res 2002.
(2) Lee JK et al. PNAS 2007.
(3) Williams et al. Cancer Res 2009.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 50. doi:10.1158/1538-7445.AM2011-50
Abstract 5007: WT1 promotes tumor growth and vascularization by regulating matrix metalloproteinase 9 in Ewing's sarcoma xenografts
Authors: Katuri Varalakshmi , Hammers Hans- Joerg , Gerber Stephanie , Qiu Xiaofei , Montgomery Elizabeth , Loeb David M. 
Published: June 2012

Abstract
WT1, a zinc-finger transcription factor, is expressed in tumors of varied origins including sarcomas. High level WT1 expression often correlates with poor patient survival. The role of WT1 in sarcoma biology and the mechanism by which high WT1 expression confers a poor prognosis are both unclear. The aim of this study is to investigate the effect of WT1 expression on sarcoma growth and angiogenesis. We transfected the WT1-null Ewing's sarcoma cell line SK-ES-1 with one of two major WT1 isoforms, and used shRNA to silence WT1 expression in the WT1-positive Ewing's sarcoma cell line MHH-ES. Cells were injected into the flanks of immune deficient mice and tumor growth was monitored. Tumors arising fromWT1-expressing SK-ES-1 cells grew faster than control, while tumors arising from WT1-silenced MHH-ES cells grew more slowly than control. Because our laboratory and others have shown that WT1 regulates VEGF expression, we evaluated tumor vascularity using the endothelial cell marker CD31 and the pericyte marker αSMA. In xenografted SK-ES-1 cells, quantification of CD31 positive area in WT1 expressing tumors showed 60 -70 % more compared to the controls. In contrast, CD31 expression is abolished in tumors arising from WT1-silenced MHH-ES cells. To investigate the mechanism by which WT1 affects tumor growth and vascularity, we performed a gene expression profiling in SK-ES-1 cells expressing different isoforms of WT1. We identified a number of genes up- or downregulated by WT1, including matrix metalloproteinase-9 (MMP9). Luciferase reporter assays showed that WT1 can upregulate MMP9 promoter activity in transiently transfected NIH3T3 cells. Also, immunohistochemical analysis showed increased MMP9 expression in WT1-expressing tumors. Finally, imunohistochemical analysis of primary Ewing's sarcoma samples showed correlated expression of WT1, VEGF, and MMP9. Taken together, our data suggest that WT1 promotes tumor growth and angiogenesis, perhaps via upregulation of MMP9. Increased tumor angiogenesis may lead to more aggressive tumors and a worse outcome for patients, explaining the effect of WT1 on prognosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5007. doi:10.1158/1538-7445.AM2011-5007
Abstract 5024: Effects of aerobic training to improve cardiovascular function and prevent cardiac remodeling after cytotoxic therapy in early breast cancer
Authors: Jones Lee , Dolinsky Vernon , Haykowsky Mark , Patterson Ian , Jones Lee , Allen Jason , Scott Jessica , Rogan Kyle , Khouri Michael , Hornsby Whitney , Young Martin , Peppercorn Jeffrey , Kimmick Gretchen , Dyck Jason 
Published: June 2012

Abstract
Background: It is well-established that doxorubicin (DOX)-containing chemotherapy causes progressive cardiomyopathy clinically manifest as decreased left ventricular ejection fraction (LVEF). The effects of DOX on the other organ components of oxygen (O2) transport and utilization that govern global aerobic reserve capacity are poorly characterized.
Methods and Results: To test our research questions, we established a mouse model of DOX in which female mice were subjected to DOX (8mg.kg.wk-1) or placebo (CON) (0.9% saline) for 4 weeks. Transthoracic echocardiography was performed to assess left ventricular wall thickness, volumes and LVEF, determined from M-mode tracings at baseline and 8 weeks. As expected, LV systolic volumes were higher and fractional shortening and LVEF were lower in the DOX group compared to CON after 8 weeks (p's &lt;0.05). There was no change in effective arterial elastance (i.e. peripheral resistance, total lumped vascular compliance and characteristic impedance) following DOX however these mice had significantly decreased expression of proteins responsible for oxidative phosphorylation / mitochondrial biogenesis in the solelus muscle relative to CON mice (p&lt;0.05). Injury to O2 transport organs led to significant reductions in global aerobic capacity (as measured by time to exhaustion on a motorized treadmill) in DOX compared with CON animals (p&lt;0.05). Next, we tested whether aerobic training could prevent DOX-induced injury. Mice were subjected treadmill running, 5 d.wk-1, 18m.min-1, 45 mins/session for 8 wks during concurrent DOX (8mg.kg.wk-1) therapy (DOX+AT), DOX (8mg.kg.wk-1) only, or CON (0.9% saline). DOX-induced injury was completely abrogated by chronic aerobic training, which prevented injury in all organ components of O2 transport / utilization cumulating in preserved aerobic capacity. In patients with newly diagnosed operable breast cancer (n=20), DOX-containing chemotherapy caused a significant decline in aerobic capacity (p&lt;0.05) despite normal LVEF and endothelial function. Supervised aerobic training completely averted this effect.
Conclusions: Our findings have important implications for the identification and protection against DOX-induced acute and late-occurring injury as well as optimizing therapeutic dosing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5024. doi:10.1158/1538-7445.AM2011-5024