bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2962: Histone H3.3 mutations drive paediatric glioblastoma through upregulation of MYCN.
Authors: Bjerke Lynn , Mackay Alan , Nandhabalan Meera , Burford Anna , Jury Alexa , Popov Sergey , Bax Dorine , Carvalho Diana , Taylor Katy , Vinci Mara , Bajrami Illirjana , McGonnell Imelda , Lord Chris , Reis Rui , Hargrave Darren , Ashworth Alan , Workman Paul , Jones Chris 
Published: August 2014

Abstract
Glioblastomas of children and young adults (pGBM) have a median survival of only 12-15 months and are clinically and biologically distinct from histologically similar cancers in older adults. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A, occurring either at or close to key residues marked by methylation for regulation of transcription - K27 and G34. The G34 mutation is specific to tumours of the cerebral hemispheres and is associated with a distinct age of incidence (16 yrs) and gene expression signature compared to K27 and wild-type tumours. ChIP-Seq for the activating K36 trimethylation mark (H3K36me3) mark of G34V mutant KNS42 pGBM cells identified 156 genes differentially bound and expressed compared to wild-type pGBM control. The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem cell maintenance, cell fate decisions and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene which is causative of glioblastomas when expressed in the correct developmental context. A synthetic lethality siRNA screen revealed this driving aberration to be selectively targetable in this patient population by inhibiting kinases responsible for stabilisation of the protein such as AURKA and CHK1. We thus provide the mechanistic explanation for how the first histone gene mutation in human disease biology acts to deliver MYCN, a potent tumorigenic initiator, into a stem cell compartment of the developing forebrain, selectively giving rise to incurable cerebral hemispheric glioblastoma. Employing synthetic lethal approaches to these mutant tumour cells provides a rational way to develop novel and highly selective treatment strategies.
Citation Format: Lynn Bjerke, Alan Mackay, Meera Nandhabalan, Anna Burford, Alexa Jury, Sergey Popov, Dorine Bax, Diana Carvalho, Katy Taylor, Mara Vinci, Illirjana Bajrami, Imelda McGonnell, Chris Lord, Rui Reis, Darren Hargrave, Alan Ashworth, Paul Workman, Chris Jones. Histone H3.3 mutations drive paediatric glioblastoma through upregulation of MYCN. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2962. doi:10.1158/1538-7445.AM2013-2962
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2971: Methylation-mediated silencing of microRNAs during cervical carcinogenesis.
Authors: Wilting Saskia Marije , Verlaat Wina , Jaspers Annelieke , Makazaji Nour A. , Agami Reuven , Meijer Chris JLM , Snijders Peter JF , Steenbergen Renske DM 
Published: August 2014

Abstract
Deregulated expression of microRNAs (miRNAs) is common and biologically relevant in cervical carcinogenesis and appears only partly related to chromosomal changes. We recently identified 34 miRNAs showing decreased expression in cervical high-grade precursor lesions and carcinomas not associated with a chromosomal loss, 6 of which were located within a CpG island. This study aimed to investigate to what extent these miRNAs are subject to DNA methylation-mediated silencing in cervical carcinogenesis.
Methylation-specific PCR (MSP) analysis on a cell line panel representing different stages of human papillomavirus (HPV) induced transformation revealed an increase in methylation of hsa-miR-149, -203, and -375 with progression to malignancy, whereas expression of these miRNAs was restored upon treatment with a demethylating agent. All three miRNAs showed significantly increased levels of methylation in cervical carcinomas, whereas methylation levels of hsa-miR-203 and -375 were also significantly increased in high-grade cervical intraepithelial neoplasia (CIN). A pilot analysis showed that increased hsa-miR-203 methylation was also detectable in HPV-positive cervical scrapes of women with high-grade CIN compared to controls. Similar to recent findings on hsa-miR-375, ectopic expression of hsa-miR-203 in cervical cancer cells decreased both the proliferation rate and anchorage independent growth.
We found evidence for methylation-mediated silencing of hsa-miR-149, -203 and -375 in cervical cancer. Methylation of the latter two was already apparent in precancerous lesions and represent functionally relevant events in HPV-mediated transformation. In addition, as demonstrated for hsa-miR-203, these methylated miRNAs may provide valuable markers for assessment of the presence of (pre)cancerous cervical lesions in HPV-positive women.
Citation Format: Saskia Marije Wilting, Wina Verlaat, Annelieke Jaspers, Nour A. Makazaji, Reuven Agami, Chris JLM Meijer, Peter JF Snijders, Renske DM Steenbergen. Methylation-mediated silencing of microRNAs during cervical carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2971. doi:10.1158/1538-7445.AM2013-2971
Abstract 2975: Rad21, as a high order chromatin architecture molecule, regulates global gene transcription.
Authors: Yun Jiyeon , Song Sang-Hyun , Kang Jee-Youn , Kim Hwang-Phill , Han Sae-Won , Oh Do-Youn , Im Seock-Ah , Bang Yung-Jue , Kim Tae-You 
Published: August 2014

Abstract
Rad21 is a subunit of cohesin complex, which is well known to be involved in sister chromatid cohesion at mitotic phase. In recent studies, Rad21 has been also known to be associated with long-range chromosome interaction to dynamically regulate gene transcription. However, Very little is known about Rad21-mediated high order chromatin structure and global changes in gene transcription in human cancer.
In this study, we silenced Rad21 gene using Lenti-virus knockdown system and performed transcriptome analysis to verify the changes in gene transcription by knockdown of Rad21. Among genes showing significant transcription changes by the reduction of Rad21, we chose several target genes decreasing its transcription and checked the transcriptional change with passaging over a 60 day period. Interestingly, the change in transcription level of some genes appeared by the earliest passage time point, whereas those of other genes arose during the course of long-term passage. Consistent with gene transcription changes, results from a ChIP assay demonstrated that Rad21-knockdown cells showed low level of Rad21 occupancy and active histone marks (H3K4me3 and Pol2) on the target genes, indicating that dynamic histone modifications also contribute to regulation of the target genes.
To figure out whether the reduction of Rad21 binding directly affects the chromatin loops, we applied Chromosome Conformation Capture (3C) -qPCR in Rad21-knockdown cells. The results demonstrated that the decreased Rad21 expression cause overal reduction of locus interaction on the target genes, indicating that Rad21 binding was directly required for long-range interactions at the target gene regions and gene transcription regulation.
Taken together, the results of our study demonstrated that long-range chromosome interaction mediated by Rad21 can dynamically regulate global gene transcription in human cancer cells, indicating that it may be important for cancer development.
Citation Format: Jiyeon Yun, Sang-Hyun Song, Jee-Youn Kang, Hwang-Phill Kim, Sae-Won Han, Do-Youn Oh, Seock-Ah Im, Yung-Jue Bang, Tae-You Kim. Rad21, as a high order chromatin architecture molecule, regulates global gene transcription. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2975. doi:10.1158/1538-7445.AM2013-2975
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 298: Breast cancer malignancy and drug sensitivity are regulated by mammaglobin 1.
Authors: Picot Nadia , Beauregard Annie-Pier , Guerette Roxann , Jean Stéphanie , Robichaud Gilles A. 
Published: August 2014

Abstract
Breast cancer metastasis, a complex process enabling tumour cells dissemination, accounts for more than 90% of breast cancer mortality. The identification of genes involved in breast cancer metastasis is thus essential mitigate disease progression
One of these factors, mammaglobin 1 (MGB1), is specifically expressed in mammary epithelial tissues and overexpressed in mammary cancers. Normally, MGB1 plays an essential role in cellular homeostasis. More recently, studies show that MGB1 is a useful biomarker for prognostic application and the detection of metastastatic breast cancer. However, no studies reveal the cellular and molecular function of MGB1 in this disease. We therefore set out to elucidate the role of MGB1 in breast cancer processes.
We developed a breast cancer model with conditioned MGB1 expression to assess the molecular and cellular processes regulated by that protein which lead to breast cancer cell malignancy. After investigation, we observed that loss of MGB1 expression led to the reduction of cancer cell growth which was supported by the suppression of p38, JNK, ERK and NFκB activities. We also found that MGB1 promotes cell migration which is supported through increased activities of FAK and matrix metalloproteinases. MGB1 also seems to foster epithelial to mesenchymal transitioning of cancer cells via the activation of Snail, Twist and Zeb1 pathways. Interestingly, we also found that MGB1 confers breast cancer cell sensitivity to apoptosis and to various anti-cancer drug treatments.
Our study provides the first in dept molecular elucidation of MGB1 function in breast cancer processes. In summary, it extends our knowledge on the biology of breast cancer malignancy and gives us new tools to achieve new therapeutic and diagnostic strategies against this disease.
Citation Format: Nadia Picot, Annie-Pier Beauregard, Roxann Guerette, Stéphanie Jean, Gilles A. Robichaud. Breast cancer malignancy and drug sensitivity are regulated by mammaglobin 1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 298. doi:10.1158/1538-7445.AM2013-298
Abstract 2988: DOK2 suppression by methylation induces platinum resistance via suppression of apoptosis in ovarian cancer cells.
Authors: Lum Elena , Vigliotti Michele , Banerjee Nilanjana , Cutter Noelle , Kamalakaran Sitharthan , Wrzeszczynski Kazimierz , Khan Sohail , Dimitrova Nevenka , Levine Douglas , Lucito Robert 
Published: August 2014

Abstract
Ovarian cancers are highly heterogeneous and while chemotherapy is the preferred treatment, many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur will become resistant. Recent evidence suggests that epigenetic deregulation may be a key factor in the onset and maintenance of chemoresistance. To examine the ovarian epigenome, we first analyzed a set of 43 primary ovarian tumors and 9 normal ovarian samples. Since therapy response is a significant issue for ovarian cancer patients we analyzed the epigenetic differences that segregate with platinum response. We then associated expression data to identify genes with expression changes potentially altered by promoter methylation to generate a list of candidate platinum resistance genes. Next, we developed a tissue culture carboplatin resistance screen to determine which candidates functionally affect resistance. The screen utilized pools of shRNAs of the candidate genes to identify genes that when repressed allowed survival from carboplatin treatment, in order to validate that our epigenetics screen identified genes involved in resistance. Of the genes identified in the screen we further characterized one gene, docking protein 2 (DOK2), an adapter protein downstream of tyrosine kinase, to determine if we could elucidate what mechanism was used to increase resistance. Our analysis determined that loss of DOK2 decreased the level of apoptosis in response to carboplatin. In addition, we determined that in cells with reduced DOK2, the level of anoikis was decreased, a mechanism of possible importance in ovarian cancer where there is a large number of cells floating in ascites. Functional analysis of the DOK2 genes ability to affect resistance validates this approach to finding genes involved in carboplatin resistance.
Citation Format: Elena Lum, Michele Vigliotti, Nilanjana Banerjee, Noelle Cutter, Sitharthan Kamalakaran, Kazimierz Wrzeszczynski, Sohail Khan, Nevenka Dimitrova, Douglas Levine, Robert Lucito. DOK2 suppression by methylation induces platinum resistance via suppression of apoptosis in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2988. doi:10.1158/1538-7445.AM2013-2988
Abstract 2992: Stringent analysis of large-scale siRNA screens identifies a kinase fusion oncogene.
Authors: Ruefli-Brasse Astrid A. , Hart Cynthia , Fajardo Liza , Swearingen Elissa , Wong Linda , Sakamoto Doreen , Hale Kari , Ge Huanying , McDowell Jeffery , Ramachandran Bharath , Cosgrove Elissa , Watson J.E.Vivienne , Ragan Seamus , Ragan Seamus , Kassner Paul , Kassner Paul , Quon Kim 
Published: August 2014

Abstract
The interpretation of RNAi knockdown experiments can be challenging due to the extensive off-target effects exhibited by siRNAs and shRNAs. This has led to the reporting of results that cannot be independently verified, or to the identification of putative cancer targets that are insufficiently robust to support industrial drug discovery efforts. The problems associated with off target effects are particularly acute in high throughput RNAi screens, whose results often differ wildly between laboratories using different experimental platforms. As a result, the validity of published large-scale RNAi screens has recently been called into question.
Here we report results from large scale RNAi screens to identify genes essential for the proliferation or survival of cancer cells. To overcome the inherent liabilities of RNAi screens, we have increased the experimental power by using typically 8, and up to 20 RNAi triggers per gene, and have developed novel statistical algorithms that exploit this increased power. Importantly, this approach allows the calculation of a false discovery rate (FDR) that accurately predicts the ability of results to be confirmed by independent labs using independent reagents, solving a key issue of such screens. Using a stringent FDR cutoff of 5%, known essential genes and driver oncogenes such as KRAS, ERBB2 and BRAF are readily identified, demonstrating the robustness and power of the method. We have also identified a number of novel cancer targets. We present the identification and genetic and pharmacological validation of one of these targets, a kinase present as a fusion partner in multiple fusion oncogenes in primary tumors. Our data demonstrate that large-scale RNAi screens can be a robust and independently verifiable tool to uncover previously unknown cancer vulnerabilities which have yet to be characterized despite extensive genomic sequencing efforts.
Citation Format: Astrid A. Ruefli-Brasse, Cynthia Hart, Liza Fajardo, Elissa Swearingen, Linda Wong, Doreen Sakamoto, Kari Hale, Huanying Ge, Jeffery McDowell, Bharath Ramachandran, Elissa Cosgrove, J.E.Vivienne Watson, Seamus Ragan, Seamus Ragan, Paul Kassner, Paul Kassner, Kim Quon. Stringent analysis of large-scale siRNA screens identifies a kinase fusion oncogene. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2992. doi:10.1158/1538-7445.AM2013-2992
Abstract 2996: Systematic functional identification of driver mutations for individual ovarian cancers.
Authors: Mori Seiichi , Fujiwara Takeshi , Yokomizo Takako , Iwase Haruko , Kato Kazuyoshi , Nakashima Yukie , Kawaguchi Tokuichi , Noda Tetsuo 
Published: August 2014

Abstract
Although epithelial ovarian cancer is an intractable cancer and the overall five-year survival rate is approximately 40 to 50%, clinically effective molecular-targeted therapeutics to treat ovarian cancer has not been available thus far. Recent progress of massively parallel sequencing technologies has been enabling us to identify substantial number of genomic aberrations including somatic mutations, indels and translocations in variable cancer types exemplified by epithelial ovarian cancer and non-small cell lung cancer. However, it is still very difficult to identify a ‘driver’ gene, which is functionally relevant for cancer growth, from hundreds of mutations that are usually found from a single cancer sample of an individual patient. An in vitro cultured cell line, which is originated from a clinical sample, can be utilized to assess functions of the genes that are identified to have somatic aberrations in the paired clinical tumor. We have been establishing multiple ovarian cancer cell lines derived from clinical samples and analyzing pairs of the cell lines and clinical samples with exon-capture sequencing. The genes, which are somatically mutated and shared in a pair of cell line and clinical sample, are targeted with RNA interference in the cell line, and subsequently the effect on cell proliferation and survival is examined. As such, a driver mutation for an individual cancer can be identified by a set of experimental perturbations. Identified driver mutations would be then validated with publicly available databases and with clinical archive samples. We believe this approach can increase an opportunity to identify molecular targets in ovarian cancer therapeutics.
Citation Format: Seiichi Mori, Takeshi Fujiwara, Takako Yokomizo, Haruko Iwase, Kazuyoshi Kato, Yukie Nakashima, Tokuichi Kawaguchi, Tetsuo Noda. Systematic functional identification of driver mutations for individual ovarian cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2996. doi:10.1158/1538-7445.AM2013-2996
Abstract 300: CTGF is overexpression in asbestos-induced malignant mesothelioma and promotes beta-catenin-T-cell factor/Lef signaling.
Authors: Jiang Li 
Published: August 2014

Abstract
It is a well-known fact that malignant mesothelioma is primarily caused by the exposure to asbestos. Due to the widespread use of asbestos, cases of malignant mesothelioma are increasing at a dramatic rate. Histopathological examinations have revealed different subtypes of malignant mesothelioma. Based on cellular morphology, it is classified into epithelial (EM), sarcomatous (SM) and biphasic (BM) (containing a mixture of epithelial and sarcomatous cells) subtypes. Although sarcomatous mesothelioma is not as common as epithelial mesothelioma, it is recognized as the most aggressive type of malignant mesothelioma and patients diagnosed with this type of mesothelioma usually have a remarkably short survival period. Driven by the interest to know what are the molecular mechanisms underlying the relatively more aggressive phenotype of sarcomatous mesothelioma, we have initiated our study.
From the microarray results, we have singled out a candidate gene (connective tissue growth factor, CTGF) whose expression is significantly increased in SM samples compared to the EM and normal control. We found CTGF regulated mesothelioma cells, especial SM cells proliferation, migration, invasion via activating β-catenin-T-cell factor/Lef signaling pathway. Mesothelioma cells decreased proliferation, migration, invasion after knockdown CTGF. We injected mesothelioma cells or CTGF-knockdown mesothelioma cells into nude mice. The tumor size of CTGF-knockdown mesothelioma injection is significant smaller than non-treated mesothelioma, especially in SM. We also found a causal association between high CTGF expression and the poor prognosis of sarcomatous mesothelioma and that the underlying molecular mechanism is related to the promotion of EMT (epithelial-mesenchymal transition) by CTGF. Many EMT regulators including Slug, Snail and Twist have been activated when over-expressed CTGF in EM. Conversely, the MET also is found when knockdown CTGF in SM.
Our study is expected to have a great impact by offering novel therapeutic targets which are urgently needed at present. Our preliminary data appears to be very promising and we are highly confident that through the manipulation of our candidate gene, we will be able to at least greatly reduce the malignancy of sarcomatous subtype of mesothelioma and extend patient's lifespan, if not fully cure it.
Citation Format: Li Jiang. CTGF is overexpression in asbestos-induced malignant mesothelioma and promotes beta-catenin-T-cell factor/Lef signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 300. doi:10.1158/1538-7445.AM2013-300
Abstract 3001: Aberrantly up-regulated synaptotagmin-like 2 (SYTL2) promotes tumorigenesis of ovarian cancer cells .
Authors: Kim Sung-hoon , Mok Samuel C. , Wei Wei , Vinod Vathipadiekal , Mohapatra Gayatry , Birrer Michael 
Published: August 2014

Abstract
Epithelial ovarian cancer is the fifth leading cause of cancer-related death among woman and has the highest case-fatality rate among gynecologic cancers. Recently, microarray based high-throughput studies have characterized the genomics of epithelial ovarian cancer. These studies have revealed extensive DNA copy number alterations with large areas of gene amplification. There are however little data identifying the genes critical for the clinicopathologic characteristics of this tumor. Here, we describe an analysis of 11q14 amplicon which has been found in 25% of serous ovarian cancers. Among the genes in the 11q14 amplicon we validate an increased DNA copy number of SYTL2 in patient samples and show that this gene has the strongest negative prognostic power. Ectopic overexpression of SYTL2 in ovarian cancer cell lines A2780 and A224 showed increases in cell proliferation, colony formation, migration and invasion in vitro. In nude mice xenograft models, SYTL2 expression in A2780 cells resulted in increased tumor formation. SYTL2 may act through a novel mechanism by enhancing the secretion of Wnt-3a while having minimal effects on its expression. In summary, our data suggest SYTL2 has oncogenic effcst in ovarian cancer and may contribute to the progression of the disease.
Citation Format: Sung-hoon Kim, Samuel C. Mok, Wei Wei, Vathipadiekal Vinod, Gayatry Mohapatra, Michael Birrer. Aberrantly up-regulated synaptotagmin-like 2 (SYTL2) promotes tumorigenesis of ovarian cancer cells . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3001. doi:10.1158/1538-7445.AM2013-3001