bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-319: Microarray CGH profiling predicts survival after a diagnosis of epithelial ovarian cancer and identifies novel candidate therapeutic targets
Authors: Jones Christopher , Morris James , Sher Tanya , Ghani Sumera , Jacobs Ian J. , Hogdall Estrid , Blaakær Jan , Kruger-Kjaer Susanne , Christensen Lise , Hogdall Claus , Ramus Susan , Gayther Simon , MacKay Alan 
Published: July 2012

Abstract
There is a need to identify novel therapeutic targets and better prognostic markers for ovarian cancer. Previous studies have shown that somatic genetic alterations are associated with clinicopathological features of cancers, and array comparative genomic hybridisation (aCGH) analysis is an excellent tool for providing detailed genetic profiles of a tumour from archival material. In this study we performed aCGH analysis on 116 primary stage III/IV serous ovarian adenocarcinomas and used a combined univariate and iterative SVM-based approach to identify regions of chromosomal alteration whose copy number status is associated with survival. Cases were stratified according to survival probability (Pr), identifying 39 good survivors (Pr&lt;0.33) and 39 poor survivors (Pr&gt;0.67). We then identified genomic regions of either common gain/loss in all 116 cases, or in which copy number status differed between the extremes of survival. A sub-set of data from these regions in the 78 cases at the extreme ends of survival was supplied to an iterative Support Vector Machine (SVM) routine, which ranked regions by their contribution to accurate survival classification and refined their boundaries. Hierarchical cluster analysis confirmed the potential of the minimal intervals of these regions to predict survival. A SVM was then validated with independent data and shown to be able to accurately classify survival. The highest-ranked chromosome regions contain candidate genes that may represent prognostic markers and/or therapeutic targets for ovarian cancer. One region, containing the CCNE1 gene, is frequently amplified in tumours and has recently been shown to be a prognostic marker for ovarian cancer in other studies. Other regions contain genes involved in pathways that stimulate ovarian cancer cell growth, motility and drug resistance. This study demonstrates the power of tumour profiling in cancer samples to identify prognostic signatures and clues to the underlying biology of tumour development, if the study design is rigorous in the selection of tightly stratified patient subgroups and in the application of the correct computational methodologies. These results require validation in larger sample sizes; but the ability to perform whole genomic profiling in formalin fixed tissues and the establishment of consortia to bring together multiple studies (e.g. the international ovarian cancer association consortium) makes this possible.
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 LB-319. doi:10.1158/1538-7445.AM2011-LB-319
Abstract LB-331: Protein expression signatures of epidermal growth factor receptor inhibition
Authors: Myers Matt , Liebler Daniel C. 
Published: July 2012

Abstract
We have applied standardized shotgun and multiple reaction monitoring (MRM) proteomic platforms to detect protein expression changes associated with epidermal growth factor receptor (EGFR) stimulation and inhibition in A431 carcinoma cells. These experiments compared proliferating, stimulated (30 nmol EGF, 4h) with cells co-treated with EGF and either cetuximab (10 μg/ml) or gefitinib (500 nmol). The analyses are done by shotgun proteomics with liquid chromatography-tandem mass spectrometry (LC-MS/MS), using isoelectric focusing of peptide mixtures, followed by reverse phase LC-MS/MS on a Thermo LTQ instrument. Protein inventories (≥2 peptides per protein at 5% peptide FDR) for each set were approximately 3800 proteins at &lt; 3% protein FDR. Differential protein expression was estimated by comparison of spectral count data with a generalized linear modeling (GLM) approach. EGF stimulation induced expression changes in 148 proteins. Effects of the inhibitors on this “stimulation signature” were then determined by GLM comparisons of spectral count data for cetuximab- and gefitinib-treated cell proteomes. These analyses identified 13 proteins whose EGF-induced expression was reversed by both drugs, 15 proteins reversed by cetuximab and 57 proteins reversed by gefitinib. Targeted MRM analysis verified differential expression of the 13 proteins reversed by both drugs, which comprise an “EGF inhibition signature”. These include the transcription factors c-Jun and JunD and the cell cycle inhibitor Cip1, which were upregulated by EGF and the protein CCDC50, which was decreased by EGF. MRM analyses also identified EGF-induced protein expression changes that were selectively reversed by either cetuximab or gefitinib. Serum deprivation, rather than EGF stimulation may account for a subset of the 106 protein changes that were not reversed by inhibitors in EGF treated cells. Our analyses also identified 87 and 149 proteins that were not affected by EGF, yet were significantly altered by cetuximab and gefitinib, respectively. Activation of the EGFR axis is typically measured via the phosphorylation status of EGFR tyrosine kinase substrates and downstream targets, but these measurements are difficult to achieve in tissues due to the low abundance of phosphorylated protein forms and the challenge of preserving phosphorylation status during sample preparation. Protein expression changes directed by EGFR activation may provide more robust measures of EGFR activation and inhibition. Ongoing studies will test the hypothesis that an EGF inhibition signature provides an early index of therapeutic responses to EGFR-targeted cancer therapies. (Supported by NIH Grant U54CA126479)
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 LB-331. doi:10.1158/1538-7445.AM2011-LB-331
Abstract LB-334: Imaging caspase dependent cell death as a surrogate for efficacy of cancer therapeutics
Authors: Galbán Stefanie , Lafferty Michael , Sharkey Lisa M. , Schinske Katrina A. , Merchant Rahim F. , Ross Brian D. , Rehemtulla A 
Published: July 2012

Abstract
Induction of cell death in malignant lesions still represents the major goal in the treatment of cancer patients. Imaging of apoptosis would enhance the development of optimal dosing, schedule and combination therapies. Here we used a luciferase biosensor (Promega) and developed a bioluminescent assay system with optimized signal to noise for the detection of cell death in vitro and in living animals. Using D54-MG cells stably expressing the reporter, we demonstrate that TRAIL treatment resulted in a 100–200 fold induction of bioluminescence activity which correlated with cell death as demonstrated by increased cleavage of Caspase-3. Furthermore inhibition of apoptosis using the pan caspase inhibitor Z-VAD-FMK resulted in inhibition of reporter activity. The utility of this cell death reporter was further demonstrated in human glioma xenografted tumors wherein induction of apoptosis was correlated with reporter activation. The high signal to noise and dynamic range of reporter activity provides for a sensitive and quantitative surrogate for evaluation of experimental therapeutics. In addition, the ability to image repeatedly provides a unique opportunity to understand the dynamics of cell death in response to specific drugs or combination therapies. We are also investigating the application of this technology in a high throughput screening of compound and targeted siRNA libraries in diverse cells and in pre-clinical cancer mouse models.
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 LB-334. doi:10.1158/1538-7445.AM2011-LB-334
Abstract LB-335: DHODH regulates transcriptional elongation during melanoma evolution: insights from zebrafish screening
Authors: White Richard M. , Zon Leonard I. 
Published: July 2012

Abstract
Melanoma cells are derived from the neural crest, a transient, multipotent tissue present only during embryogenesis. Using zebrafish models, we aimed to determine whether these embryonic neural crest gene programs would make therapeutic targets in melanoma. Transgenic zebrafish expressing BRAFV600E under the mitf promoter develop melanoma when crossed with p53 mutants. From the earliest stages of transformation, and throughout overt tumorigenesis, these tumors express multiple embryonic neural crest progenitor markers such as SOX10, EDNRB and MITF. Human melanomas were similar: 50–75% expressed progenitor markers, but only 15% expressed the differentiation marker DCT. We performed a chemical genetic screen in zebrafish embryos to identify suppressors of the neural crest gene program to determine their therapeutic utility. Of 2000 small molecules, we found one class, inhibitors of the enzyme DHODH, that led to a complete abrogation of neural crest development during embryogenesis. Treated animals were essentially albino, devoid of all derivative melanocytes that eventually give rise to melanoma. Developmentally, DHODH suppression exerts this effect by blocking transcriptional elongation of genes such as MITF, in a manner dependent upon the elongation factor SUPT5H. In melanoma cells, we measured transcriptional elongation after DHODH inhibition via RNA pol II chromatin immunprecipitation coupled with massively parallel sequencing (ChIP-Seq). Similar to embryonic development, inhibiting DHODH leads to a defect in transcriptional elongation at select loci. We then tested whether leflunomide, a DHODH inhibitor approved for rheumatoid arthritis, could block melanoma growth. Either alone, or in combination with the BRAFV600E inhibitor PLX4032, leflunomide led to a dramatic decrease in melanoma growth in vitro and in vivo. These studies suggest that modulating the neural crest identity of melanoma cells is a distinct therapeutic avenue that is likely to cooperate with inhibiting oncogenic mutations such as BRAFV600E. We plan to extend this work into the clinical trial setting, highlighting the rapidity with which discoveries in zebrafish can be translated into the clinic.
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 LB-335. doi:10.1158/1538-7445.AM2011-LB-335
Abstract LB-338: Stabilisation of MAD2 expression through inhibition of miR-433; A novel mechanism for restoring chemo-responsiveness in ovarian tumours
Authors: Furlong Fiona M. , Phelan Sine , McGoldrick Alo , Maguire Aoife , Fitzpatrick Patricia , O'Toole Sharon , Shiels Orla , O'Leary John J. , McCann Amanda 
Published: July 2012

Abstract
Epithelial ovarian carcinoma (EOC) is characterised by late diagnosis and recurrences, both of which contribute to the high morbidity and mortality of this cancer. Unfortunately, EOC has an innate susceptibility to become chemo-resistant. Specifically, up to 30% of patients may not respond to current standard chemotherapy (paclitaxel and platinum in combination) and of those who have an initial response, some patients relapse within a few months. Therefore, in order to improve patient outcome it is crucial to establish what factors influence a patients' individualised response to chemotherapy. We analysed MAD2 protein expression in a patient cohort of 35 ovarian tumours and a panel of 5 ovarian cancer cell lines. We have demonstrated that low nuclear MAD2 expression intensity was significantly associated with chemo-resistant ovarian tumours (p=0.0136). Moreover, in vitro studies of the 5 ovarian cancer cell lines revealed that reduced MAD2 expression was associated with paclitaxel resistance. In silico analysis identified a putative miR-433 binding domain in the MAD2 3′UTR and expression profiling of miR-433 in the ovarian cancer cell lines showed that low MAD2 protein expression was associated with high miR-433 levels. In vitro over-expression of miR-433 attenuated MAD2 protein expression with a concomitant increase in cellular resistance to paclitaxel. Over-expression of a morpholino oligonucleotide that blocks miR-433 binding to MAD2 3′UTR stabilised MAD2 protein expression and protects from miR-433 induced degradation. Furthermore, miR-433 expression analysis in 35 ovarian tumour samples revealed that high miR-433 expression was associated with advanced stage presentations (p=0.0236). In conclusion, ovarian tumours that display low nuclear MAD2 intensity are chemo-resistant and stabilising MAD2 expression by antagonising miR-433 activity is a potential mechanism for restoring chemo-responsiveness in these tumours.
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 LB-338. doi:10.1158/1538-7445.AM2011-LB-338
Abstract LB-349: Differential expression of microRNAs in oligodendrogliomas of different grades of malignancy
Authors: Serafini Luciano Neder , Panepucci Rodrigo A. , Tirapelli Daniela P. C. , Oliveira Viviane C. , Monteiro Patricia , Simoes Deise L. , Silva Wilson A. , Carlotti Carlos G. 
Published: July 2012

Abstract
MicroRNAs (miRNAs) are large tiny regulatory RNAs found ubiquitously in plants, insects and mammals. More recently, miRNAs have also been implicated in oncogenesis, acting as tumor suppressors or oncogenes. The role of miRNAs in glioma progression has been intensively investigated chiefly in glioblastomas, the most prevalent malignant glioma. However, there are few data regarding to miRNA expression in oligodendrogliomas. The main goal of this study was to evaluate miRNAs and mRNAs that are differentially expressed in a series of grade II and III oligodendrogliomas (7 per group, with duplicates) in order to obtain miRNAs that correlate with their putative target-mRNAs. After microdissection and diagnosis confirmation, miRNAs and mRNAs expression were evaluate using microarray-based expression profiling platforms (723 transcripts and 41,000 genes, respectively) at same tumor specimens. As controls, samples of temporal lobe white matter from patients operated for clinical intractable complex partial seizures were used (n = 16). Fifteen and 29 miRNAs transcripts were relatively hyper- and hypoexpressed in anaplastic oligodendrogliomas; however, after matching of miRNAs and putative target-mRNAs expressions, only 4 miRNAs transcripts remained overexpressed in which target genes have pivotal role in key cell signaling pathways. Similarly, 20 of 29 miRNAs transcripts remained down regulated. Of these, 4 miRNAs that were previously described as to be involved in cell differentiation in embryonic stem cells (ESC) are being validated through their target genes by real time PCR. Herein, we were able to identify putative oncogenic miRNAs that can be operating in oligodendrogliomas progression, expanding our knowledge about tumor biology and disclosing possible molecular targets for treatment proposals.
Support: FAPESP (Grant Proc. No. 05972–2)
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 LB-349. doi:10.1158/1538-7445.AM2011-LB-349
Abstract LB-422: Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis
Authors: Tammela Tuomas , Saaristo Anne , Holopainen Tanja , Ylä-Herttuala Seppo , Andersson Leif C. , Virolainen Susanna , Immonen Ilkka , Alitalo Kari 
Published: July 2012

Abstract
The dissemination of tumor cells (metastasis) from the primary tumor is the principal cause of death in cancer patients. The lymphatic vessels serve as a key conduit for metastasizing tumor cells, which often colonize the lymph nodes first. Although the primary tumor and lymph nodes invaded by tumor cells are removed during surgery, tumor cells inside lymphatic vessels are not removed. Here, we demonstrate tumor cell growth inside lymphatic vessels in mice bearing mouse melanoma tumors or human lung tumors and in a human melanoma patient, suggesting that these in-transit tumor cells give rise to metastases. We selectively destroyed lymphatic vessels using photodynamic therapy with the benzoporphyrin derivative verteporfin in mice and pigs. Destruction of tumor-draining lymphatic vessels also eradicated intralymphatic tumor cells, and prevented in-transit metastasis of mouse melanoma cells and subsequent relapse. Photodynamic therapy, when combined with anti-lymphangiogenic therapy, prevented further tumor invasion of lymphatic vessels and may provide a way to eradicate in-transit tumor cells in patients.
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 LB-422. doi:10.1158/1538-7445.AM2011-LB-422
Abstract LB-427: Unique properties of hepatocarcinogenesis-resistant DRH rat hepatocytes linked or not linked to the Drh1 locus on rat chromosome 1
Authors: Hashimoto Norikazu , Yamamoto Masahiro , Miyakoshi Masaaki , Tanaka Hiroki , Ogawa Katsuhiro 
Published: July 2012

Abstract
DRH rats were established by the selective mating of Donryu rat progeny that exhibited resistance to hepatocarcinogenesis. DRH rats show smaller and fewer preneoplastic hepatocytic lesions than ordinary rats after treatment with hepatocarcinogenic regimens, and these traits have been assigned to two major genetic loci, Drh1 on chromosome 1 and Drh2 on chromosome 4. The DRH hepatocytes have the unique properties such as low proliferation after lead nitrate (LN) treatment, resistance to hepatotoxic chemicals and small cell size. If some of these properties are linked to the Drh1 or Drh2 loci, the properties may be related to the mechanism(s) of the hepatocarcinogenesis-resistance in DRH rats. In this study, to explore what properties are linked to the Drh1 locus, we compared hepatocytes of DRH.F344-Drh1 rats, a congenic DRH strain in which the DRH chromosomal region including the Drh1 locus was substituted by that of F344 rats, were compared with hepatocytes of Donryu, DRH and F344 rats. After LN treatment, although DRH hepatocytes proliferated at low rate, DRH.F344-Drh1 hepatocytes proliferated at high rate comparable to Donryu and F344 hepatocytes. In addition, the DRH.F344-Drh1 livers showed high p38 MAPK dephosphorylation after LN treatment like Donryu and F344 livers, while such p38 MAPK dephosphrylation was not seen in the DRH liver. However, increase of TNF-α, IL-6 and Cox2 mRNA and NFκB/Stat3 activation in the liver was almost at the same degree in Donryu, DRH and DRH.F344-Drh1 rats, suggesting that the low responses to LN in the DRH hepatocytes were not dependent on low cytokine/Cox2 activation but rather due to the inherent properties of DRH hepatocytes. After 200 mg/Kg diethylnitrosamine (DEN) or 5 ml/Kg CCl4 treatment, severe hepatic injury occurred in DRH.F344-Drh-1 rats like Donryu and F344 rats, while its degree was much less in DRH. On the other hand, the DRH.F344-Drh1 as well as DRH hepatocytes exhibited lower proliferation after the EGF or HGF treatment in vitro than Donryu and F344 hepatocytes. Furthermore, the nuclear size of DRH.F344-Drh1 hepatocytes was comparable to that of DRH hepatocytes, which was smaller than those of Donryu and F344 hepatocytes. These findings indicate that the Drh1 locus is linked to the low responses to LN and hepatotoxin resistance in DRH hepatocytes, but not to low proliferation in vitro and small nuclear size. (Supported by the grants from the Japanese Ministry of Education, Science, Culture and Sports.)
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 LB-427. doi:10.1158/1538-7445.AM2011-LB-427
Abstract LB-433: Examination of the oncogenic potential of XMRV in prostate epithelial cells
Authors: Comeaux Brennen , Zolochevska Olga , Figueiredo Marxa L. 
Published: July 2012

Abstract
Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirus closely related to murine leukemia viruses, which cause a variety of cancers and immunological and neurological diseases in mice. Whether XMRV plays a role in cancer and other diseases remains controversial; some studies show a possible association, but there is currently no evidence that the virus is a causal agent for disease. Our hypothesis was that the 3′ long terminal repeat (LTR) from the XMRV genome is responsible for its oncogenic activity in prostate cells. We chose three regions from the XMRV 3′ LTR and tested the potential of these regions in transactivating a cellular gene promoter whose homolog is transactivated by MMLV in mouse cells. We examined the transactivation potential in pre-cancerous and a panel of cancerous prostate epithelial cells. Our results showed that for certain 3′LTR regions induce nearly full transactivating activity, while others might comprise inhibitory regions. Therefore, to better understand the mechanism by which the XMRV 3′ LTR regions might be inducing or inhibiting transactivation, we tested their ability to transactivate cellular genes related to transformation. We used as reporters plasmids containing binding sites for cellular transcription factors. The results showed several similarities in transactivation, suggesting common activation pathways for 3′LTR transactivating activity. Finally, we tested if XMRV infection could enhance oncogenicity potential of prostate precancerous and cancerous cell lines. We examined this in vitro by assessing the rate of colony formation in soft agar, and in vivo, using xenograft assays. The results suggested that cell lines infected with XMRV had enhanced in vitro colony formation, as well as enhanced in vivo growth, however, addition of another tumorigenic genetic alteration was required in conjunction with XMRV-infection to induce enhanced tumor growth. Our data suggests that the XMRV 3′LTR may have a transactivating activity on cellular genes, and that XMRV might have a transforming activity in prostate cancer cells, most likely stimulating promotion/progression of tumorigenesis, and not ‘initiation’ of tumorigenesis. These results are highly novel since they represent for the first examinations of the role of XMRV in tumorigenesis of prostate epithelial cell lines in vitro and in vivo and examinations of the 3′LTR context of the virus upon transactivation of cellular genes as a potential mechanism of cellular transformation.
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 LB-433. doi:10.1158/1538-7445.AM2011-LB-433