bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1430: Characterization of the medulloblastoma splice-ome reveals subgroup-specific changes in alternative splicing and isoform expression patterns
Authors: Dubuc Adrian M. , Morrissy Sorana , Kloosterhof Nanne , Northcott Paul , Yu Emily , Peacock John , French Pim , Taylor Michael 
Published: August 2012

Abstract
Medulloblastoma candidate gene approaches have previously identified alternative splicing and isoform expression changes affecting genes critical for cerebellar development and medulloblastoma pathogenesis. Here we present a bioinformatic characterization of the medulloblastoma splice-ome in 103 primary tumors and 14 normal cerebella samples. Medulloblastomas display a statistically significant increase in alternative splicing relative to normal fetal cerebella (2.3-times; P&lt;6.47E-8), with splicing patterns that are specific to each molecular subgroup. Unsupervised hierarchical clustering of alternatively spliced genes accurately assigns medulloblastomas to their correct subgroup. One-third of all medulloblastomas (n=26) display a ‘hyper-spliced’ phenotype, with median splicing levels four-times greater than non-hyperspliced tumors. Hyperspliced medulloblastomas show a relatively worse overall survival (P&lt;3.08E-2), and are seen across all molecular subgroups. Our analysis identifies previously reported splicing events targeting ERBB4 (mixed MB), GLI1 (SHH) and PTCH1 (SHH), supporting our approach. Subgroup-specific pathway analysis of alternatively spliced genes reveals extensive deregulation of neuronal pathways in non-WNT medulloblastomas, with the specific targeting of genes important for axonal guidance, synaptic transmission and neuronal differentiation. Finally, we present evidence for putative regulation of alternative splicing by antisense transcription. These data further demonstrate the differences between medulloblastoma subgroups, and highlight alternative splicing and isoform expression as a mechanism contributing to the transcriptional heterogeneity between subgroups, and perhaps to subgroup specific pathogenic mechanisms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1430. doi:1538-7445.AM2012-1430
Abstract 1432: The heterogeneous genomic landscape of posterior fossa ependymoma
Authors: Witt Hendrik , Mack Stephen C. , Bender Sebastian , Ryzhova Marina , Martin Sill , Isserlin Ruth , Jones David T. W. , Northcott Paul A. , Till Milde , Remke Marc , Benner Axel , Hielscher Thomas , Gupta Nalin , Garcia Livia , Weiss William A. , Betrand Kelsey , van Meter Timothy , von Deimling Andreas , Rutkowski Stefan , Pietsch Torsten , Kulozik Andreas E. , Cho Yoon-Jae , Tabori Uri , Hawkins Cynthia E. , Witt Olaf , Bader Gary D. , Rutka James T. , Lichter Peter , Korshunov Andrey , Taylor Michael D. , Pfister Stefan M. 
Published: August 2012

Abstract
Brain tumors are the most common cause of cancer-related death in childhood. Ependymomas, are the third most common pediatric brain tumor. The disease remains incurable for about 45% of patients even after gross total resection and radiotherapy. Despite showing a very homogeneous histological picture, ependymomas display distinct molecular behavior, which supports the existence of several independent entities of the disease. We examined two non-overlapping cohorts of 102 and 75 ependymomas by mRNA expression profiling, on two different array platforms (Affymetrix, Agilent). When performing multiple statistical clustering methods (unsupervised consensus NMF and consensus HCL), we could consistently identify three major clusters, including two subgroups of posterior fossa (PF) ependymoma, a variant common in children and associated with heterogeneous clinical outcome. Subgroup-specific chromosome aberrations of PF tumors were detected by aCGH, and biological signaling pathways distinguishing PF subgroups were identified by gene set enrichment analysis and visualized in Cytoscape. We validated the most significantly classifying markers of each subgroup by immunohistochemistry on a tissue microarray containing an independent set of 265 PF ependymomas. Our findings delineate two subgroups of PF ependymoma (groups A and B) which are demographically, transcriptionally, genetically, and clinically distinct. Group A patients are younger, have laterally located tumors with a balanced genome, more frequently develop secondary metastases and are much more likely to have an extremely poor outcome as compared with group B patients. Based on a multi-variate Cox proportional-hazards model, our identified markers have the strongest independent prognostic value among demographic and molecular variables with Hazard ratios of 8.45 (PFS) and 10.55 (OS). Prognostic significance and predictive impact is being validated in the GPOH HIT2000 Ependymoma study. The identification of two distinct subgroups of PF ependymoma, and markers applicable for their clinical distinction, will allow for better prognostication of individual cases, independent of age, level of resection and WHO grade, and also for stratification in future ependymoma clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1432. doi:1538-7445.AM2012-1432
Abstract 145: MicroRNA-23b Expression is Regulated by VHL and effects on Glioma Cell survival and invasion
Authors: Han Lei , Chen Lingchao , Zhang Kailiang , Shi Zhendong , Zhang Junxia , Zhang Anling , Wang Yongzhi , Song Yijun , Zheng Yongri , Jiang Tao , Pu Peiyu , Jiang Chuanlu , Kang Chunsheng 
Published: August 2012

Abstract
Background Glioblastoma is the most common malignant primary brain tumor in adults. While increasing evidence indicates that the deregulation of miRNAs is involved in a wide range of human cancers, the roles and potential mechanisms of miRNA in glioma development and progression are still largely unknown. Methods The expression of miR-23b in 48 clinical samples and five glioma cell lines with different grades was examined by FISH and qRT-PCR. Flow cytometry, Annexin V method, Colony formation assay, and Transwell cell invasion test were used to detect the proliferation and invasive activity of the tumor cells before and after transfection with AS-miR-23b of glioma cells. Luciferase assay and western blot analysis were used to examine that VHL is a direct target of miR-23b. In vivo anti-glioma effect of AS-miR-23b was investigated using subcutaneous xenograft models. Results We identified that expression of miR-23b is elevated in both glioma tissue samples and glioma cells by real-time PCR and FISH analyses. Knock-down of miR-23b expression triggered growth inhibition, induced apoptosis and suppressed invasion of glioma cells in vitro. Luciferase assay and western blot analysis revealed that VHL is a direct target of miR-23b. As such, restored expression of VHL inhibited glioma cell survival and induced apoptosis. Mechanistic investigation revealed that miR-23b deletion decreased HIF-1α/VEGF expression and suppressed β-catenin/Tcf-4 transcription activity in a VHL-dependent manner. Furthermore, expression of VHL was inversely correlated with miR-23b in glioblastoma samples and was predictive of patient survival in a retrospective analysis. Conclusion In summary, we demonstrate that down-regulation of miR-23b inhibits survival and invasion of glioma by repressing expression of VHL. Genetic restoration of VHL bypassed the effects of miR-23b overexpression, suppressing the ranscriptional activities of both the HIF/VEGF and β-catenin/Tcf-4 pathways. Based upon these observations, we propose that anti-angiogenic therapy for glioma could benefit from adjuvent miRNA therapy targeting the HIF1α and β-catenin/Tcf-4 pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 145. doi:1538-7445.AM2012-145
Abstract 1451: DAB2IP, a novel tumor suppressor protein modulates prostate cancer cell death in response to the combined treatment of ionizing radiation and a DNA-PKcs inhibitor NU7441
Authors: Yu Lan , Hsu Feng-Ming , Hsieh Jer-Tsong , Saha Debabrata 
Published: August 2012

Abstract
Introduction: Prostate cancer (PCa) is the most common malignancy (25%) and the second leading cause of cancer-related death (10%) in U.S. men. Radiation treatment, which is noninvasive and well tolerated, is one of the front line therapeutic interventions in the management of localized PCa. However, significant proportions of high-risk patients fail therapy and develop metastatic disease. DAB2IP, which is a novel member of the Ras GTPase-activating protein family and a regulator of PI3K/Akt activity, is often downregulated and associated with aggressive prostate cancer (PCa). The purpose of this study is to investigate the radio-sensitizing property of a novel DNA-PKcs inhibitor, NU7441, in DAB2IP- deficient human PCa cells. Methods: We have developed DAB2IP deficient and proficient PCa cell lines (C4-2, PC3) for this study. We performed clonogenic surviving fraction analysis, DNA double strand break repair kinetics, cell cycle analysis, TUNEL assays, immunofluorescence, immunoblot, apoptosis and autophagy assays to investigate the mechanism of radiosensitization of NU7441 in these PCa cells. Results: Clonogenic surviving fraction analysis indicates a strong radiosensitizing ability of NU7441 in PCa cells deficient in DAB2IP. This is primarily due to robust G2-M block and persistent DNA double strand break in response to the combined treatment of radiation and NU7441. We clearly demonstrate that the presence of DAB2IP modulates prostate cancer cell death when treated with radiation and NU7441. Apoptotic cell death was prominent in PCa cells proficient in DAB2IP whereas, robust autophagic cell death was noticed in DAB2IP deficient PCa cells. Conclusion: Our study clearly shows that NU7441, a novel DNA-PKcs inhibitor, is a potent radiosensitizer in aggressive PCa cells. Furthermore, our study indicates that DAB2IP may act as an important factor in PCa cell death after combined treatment Nu7441 and radiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1451. doi:1538-7445.AM2012-1451
Abstract 1456: Sulfasalazine sensitizes glioblastoma cells to radiation treatment
Authors: Sleire Linda , Wang Jian , Heggdal Jan , Pedersen Paal-Henning , Enger Per Øyvind 
Published: August 2012

Abstract
Glioblastoma (GBM) is a lethal cancer with a limited response to ionizing radiation. Recent studies suggest that Sulfasalazine (SAS), a drug used to treat inflammatory bowel disease, inhibits the Xc- antiporter system in glioma cells, thereby blocking their uptake of cystein. Since the availability of cystein is a rate limiting step in intracellular antioxidant production, we wanted to investigate whether sulfasalazine sensitizes glioma cells to radiation. Expression of xCT, the catalytic subunit of system Xc-, was found in 30 patient GBM biopsies. SAS effect on glioma cell growth was investigated using an electric cell substrate impedance sensing (ECIS) instrument. All glioma cell lines showed altered growth curves in response to SAS treatment. To assess the effect of blocking the antiporter, intracellular levels of the antioxidant glutathione were measured. With increasing doses of SAS, glutathione levels decreased in a dose response manner. In addition, cysteine was added to the medium to see if the cells could survive high doses of SAS. U251 glioma cells were treated with escalating doses of SAS, alone or in combination with radiation (8 Gy). Nuclear integrity was evaluated to estimate cell death following treatment, as well as the presence of double stranded breaks. In addition, cell death and viability were investigated using live/dead staining and the MTS assay. All treatment groups exhibited increased rates of cell death compared to untreated controls. A combination of SAS and radiation resulted in higher levels of cell death, than radiation or SAS administered alone. In order to assess whether this can be exploited therapeutically, we are preparing to treat nude rats harbouring glioblastoma biopsy xenografts with SAS, alone or in combination with gamma knife radiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1456. doi:1538-7445.AM2012-1456
Abstract 146: MicroRNA-150 expression induces differentiation of myeloid leukemias
Authors: Morris Valerie A. , Zhang Ailin , Oehler Vivian G. 
Published: August 2012

Abstract
Blocked myeloid differentiation is a major feature of chronic myeloid leukemia (CML) disease progression and acute myeloid leukemia (AML). Normal myeloid differentiation is a tightly controlled process involving the coordinated action of specific transcription factors, which are dysregulated by chromosomal translocations, DNA mutations, epigenetic changes, and aberrant gene and microRNA (miRNA) expression in leukemias. Previously, we identified decreased miR-150 expression in CML and AML cell lines and primary cells when compared to normal bone marrow, and determined miR-150 expression is decreased in CML by the Bcr-Abl fusion protein. Furthermore, lentiviral expression of miR-150 in AML cell lines and primary CML patient samples induced myeloid differentiation as detected by CD11b expression, morphologic differentiation, and colony forming ability in methylcellulose, both in the absence and presence of the differentiating agents. In this study, we elucidated the targets responsible for miR-150 induced differentiation. Expression of the validated miR-150 target MYB, a transcription factor involved in blocking differentiation in progenitor cells, was only decreased in miR-150 expressing cells in the presence of differentiating agent all-trans retinoic acid (ATRA). Furthermore, lentiviral overexpression of MYB lacking miR-150 binding sites in the 3′-UTR partially decreased the CD11b expression in the presence and absence of ATRA in both control and miR-150 expressing HL60 cells. These results suggest additional miR-150 targets are involved in differentiation besides MYB. To identify additional miRNA-150 targets, we profiled changes in mRNAs associated with the RNA-induced silencing complex (RISC) using RNA-immunoprecipitation of Ago2 followed by microarray gene expression profiling in miR-150 versus control HL60 cells. Furthermore, although almost all functional investigations have focused on the mature strand, we have found that miR-150 and its partner star strand miR-150* are expressed at almost equal levels in normal myeloid hematopoietic cells, and are investigating the individual contributions of their separate targets in induction of differentiation. In conclusion, miR-150 expression promotes myeloid differentiation through targeting transcription factor MYB and additional targets, while downregulation of miR-150 in myeloid leukemias contributes to the block in differentiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 146. doi:1538-7445.AM2012-146
Abstract 147: ER-α36 plays an important role in estrogen-dependent growth of gastric cancer cell line BGC823
Authors: Zou Feng , Deng Hao , Zhen Hongyan , Wang Xuming , Liu Lijiang 
Published: August 2012

Abstract
Aims: We aimed to investigate the role of estrogen-development signal in growth of gastric cancer cell, and the expression and location change of new estrogen receptor ER-α36 in gastric cancer cell when dealt with estrogen. Methods: Gastric cancer BGC823 was chosen as research model and 17β- estradiol (E2) was used to deal with cell. Cell growth was examined by WST-1 method and assayed by microplate reader. ER-α36 expression in mRNA and protein level was assayed by RT-PCR and Western-blot methods and was quantitated. The location of ER-α36 in cell was examined by immunofluorenscence methods. Result: The cell numbers significantly increased in all E2 treatment groups compared with control group and the number of the cell was more at 48h than 24h in E2 treatment groups (p&lt;0.05), but with E2 concentration increased, cell growth rate slowed down. ER-α36 mRNA expressions of all E2 treatment groups were more than that of control group at 24h and 48h, and had a concentration-dependent of E2 (p&lt;0.05). ER-α36 protein expression had a concentration-dependent of E2 and was less at 48h than 24h in E2 treatment groups (p&lt;0.05). E2 treatment groups’ protein expression were more than control group's at 24h (p&lt;0.05), and were less than control group's at 48h (p&lt;0.05). ER-α36 is localized on the membrane and cytoplasm of BGC823 cell, and its location did not change dealt with E2. Conclusion: E2 could promote the growth of BGC823 cell, and estrogen in different concentration may play different role in the growth regulation of gastric cancer. ER-α36 could response to estrogen-dependent signaling of growth and may transmit it through a membrane-based pathway in gastric cancer. There were regulations in transcription and translation of ER-α36 in gastric cancer. ER-α36 was an important estrogen receptor in gastric cancer and may be a potential predicted marker of gastric cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 147. doi:1538-7445.AM2012-147
Abstract 1485: The role of angiopoietin family members in the progression of ovarian cancer
Authors: Brunckhorst Melissa K. , Yu Qin 
Published: August 2012

Abstract
Despite advances in surgical debulking, radiation, and chemotherapy over the past few decades, ovarian carcinoma remains the most deadly gynecological malignancy. This is largely due to the lack of early stage detection manifesting in approximately 80% of patients presenting with metastatic disease at the time of diagnosis. Current chemotherapeutic drugs are effective only for a short period as patients with advance disease eventually develop resistance despite significant initial responses. Thus, there is a pressing need for the identification of novel therapeutic targets in ovarian cancer. Mounting evidence suggests that the Angiopoietin/Tie-2 functional axis has wide-ranging effects on tumor angiogenesis and progression of a variety of cancer types, however, the expression profiles and biological effects of the Angiopoietin family members on ovarian cancer remain largely unknown. Our data show for the first time that Ang-1, Ang-2 and Ang-4 are expressed in ovarian cancer cell lines and patient samples from both primary and secondary tumor lesions. More specifically, patient tumors revealed a unique localization pattern of Angiopoietin family members whereby Ang-1 and Ang-2 are robustly expressed in tumor cells and stroma, whereas Ang-4 expression is predominately in the tumor stroma. In addition, we show that overexpression of Ang-4 and Ang-2 and, to a lesser extent, Ang-1, promotes subcutaneous growth of ovarian cancer cells and results in accelerated ascites formation and poor survival in an orthotopic ovarian cancer mouse model. Immunohistochemical analysis of orthotopic tumors suggests the pro-growth effects of Ang-1 and Ang-4 are mediated through increased tumor cell proliferation as determined by positive Ki67 staining. Our results also demonstrated that ovarian cancer cells express Tie-2 receptor tyrosine kinase (RTK), the angiopoietin receptor. The expression of Tie-2, as well as angiopoietin family members, by ovarian cancer cells suggests the potential of an Angiopoietin/Tie-2 autocrine loop. Lastly, further analysis suggests the potential role of angiopoietins in increasing the amount of cancer associated fibroblasts (CAFs) in the tumor microenvironment. Taken together, our data suggest that the Angiopoietin/Tie-2 functional axis is a significant player in ovarian cancer progression and is a potential target for ovarian cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1485. doi:1538-7445.AM2012-1485
Abstract 1498: Breast adipose mesenchymal stem cells and mammary fibrosis
Authors: Bristol Molly L. , Sachs Patrick , Wang Xu , Zhao Min , Elmore Lynn 
Published: August 2012

Abstract
Introduction: At a biochemical level, the most common symptom of aging and its related pathologies (i.e. cancer) is the accumulation of altered or abnormal proteins. Aberrant proteins can induce oxygen free radical generation and inflammation; additionally an abnormal inflammatory response can lead to over-production and deposition of extracellular matrix (ECM) components, leading to fibrosis. The linkage between fibrosis and cancer is well established in the lung; alternatively breast fibrosis is a less understood phenomenon. Fibrosis is characterized by the excess production and altered composition and crosslinking of the ECM. Myofibroblasts are the principal mediators of fibrosis, producing abundant ECM as well as inflammatory and angiogenic factors; chronic tissue fibrosis is associated with tumor development. Likewise, stromal cells within the breast tumor microenvironment can provide tumor-promoting effects. Yet, very little is known regarding the role of local-adipose mesenchymal stem cells (MSCs) in the development of cancer. Objectives: If breast density and fibrosis are both associated with less fat and more connective tissue, we reason that resident breast MSCs (b-MSCs) are chemoattracted toward mammary glandular elements where they trigger a desmoplastic response characterized by their transdifferentiation into myofibroblasts, rather than differentiating along an adipocytic lineage; thus proposing that b-MSCs, an understudied yet abundant stromal constituent, contribute early in the development of breast cancer. Moreover, if b-MSCs contribute to fibrosis, it is critical to understand and deter this early fibrotic initiation factor. Preliminary Data, Methodology, and Future Directions: Affymetrix data, qRT-PCR, and western blotting results reveal that undifferentiated b-MSCs constitutively express multiple matrix metalloproteinases and chemokine receptors, which could guide these stromal cells from local fat stores into the parenchyma, activating a cascade of events leading to fibrosis. qRT-PCR reveals b-MSCs express multiple members of the epidermal growth factor (EGF) receptor family, most notably HER1. Soluble heparin binding epidermal growth factor (HB-EGF) and EGF modestly effects b-MSC growth, but markedly enhances migration. Moreover, HB-EGF and EGF interfere with adipogenic differentiation. Future studies will analyze the fibrogenic response initiated by b-MSCs in co-culture with normal, pre-malignant and malignant breast epithelial cells and evaluate the effectiveness of the dipeptide, carnosine, on reducing fibrogenesis. Support: This work was supported by a DOD Breast Cancer Research Program Idea Award (BC094734) to L.E.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1498. doi:1538-7445.AM2012-1498