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Author Emery, I.F.; Gopalan, A.; Wood, S.; Chow, K.-H.; Battelli, C.; George, J.; Blaszyk, H.; Florman, J.; Yun, K. url  doi
openurl 
  Title Expression and function of ABCG2 and XIAP in glioblastomas Type Journal Article
  Year 2017 Publication Journal of Neuro-Oncology Abbreviated Journal J Neurooncol  
  Volume 133 Issue (up) 1 Pages 47-57  
  Keywords Abcg2; Glioblastoma; Glioma stem cells; Ko143; Xiap  
  Abstract Despite multimodal treatment that includes surgery, radiation and chemotherapy, virtually all glioblastomas (GBM) recur, indicating that these interventions are insufficient to eradicate all malignant cells. To identify potential new therapeutic targets in GBMs, we examined the expression and function of proteins that are associated with therapy resistance and cancer cell survival. We measured the expression of eight such proteins in 50 GBM samples by immunohistochemistry and analyzed patient survival. We report that GBM patients with high expression of ABCG2 (also called BCRP) or XIAP at the protein level had worse survival than those with low expression. The adjusted hazard ratio for ABCG2 was 2.35 and for XIAP was 2.65. Since glioma stem cells (GSCs) have been shown to be more resistant than bulk tumor cells to anti-cancer therapies and to express high levels of these proteins, we also sought to determine if ABCG2 and XIAP have functional roles in GSCs. We used small molecule inhibitors to treat patient-derived GBM tumorspheres in vitro and observed that inhibitors of ABCG2, Ko143 and fumitremorgin, significantly reduced self-renewal. These results suggest that ABCG2 and XIAP proteins may be useful indicators of patient survival and that inhibition of ABCG2 may be a promising therapeutic strategy in GBMs.  
  Address Peak Center for Brain and Pituitary Tumors, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX, 77030, USA. kyun@houstonmethodist.org  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0167-594X ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28432589 Approved no  
  Call Number ref @ user @ Serial 96591  
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Author Batista, K.M.P.; Eulate-Beramendi, S.A. de; Pina, K.Y.A.R. de; Figueira, P.R.; Canal, A.F.; Chasin, J.M.A.; Meilan, A.; Ugalde, R.; Vega, I.F. url  doi
openurl 
  Title Mesenchymal/proangiogenic factor YKL-40 related to glioblastomas and its relationship with the subventricular zone Type Journal Article
  Year 2017 Publication Folia Neuropathologica Abbreviated Journal Folia Neuropathol  
  Volume 55 Issue (up) 1 Pages 14-22  
  Keywords Ykl-40; glioblastoma; glioblastoma stem cells; subventricular zone  
  Abstract <i>Glioblastoma is the most common primary brain tumor. Despite multimodality therapy with aggressive microsurgical resection and adjuvant chemotherapy and radiotherapy, the median survival is below 15 months. Glioblastomas are heterogeneous tumors with high resistance to most chemotherapeutic drugs. According to reliable evidence, YKL-40, one of the best investigated chitinase-like protein, may facilitate invasion, migration and angiogenesis, and could be also responsible for temozolomide resistance in glioblastoma, thus conferring a dismal prognosis. Previous studies have demonstrated that glioblastoma stem cells give rise to endothelial cells through an YKL-40 influence. Such factor is closely related to the subventricular zone. This review focuses on the most recent theories involving the possible relationship between topographic gliomagenesis related to the subventricular zone and YKL-40.</i>.  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1509-572X ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28430288 Approved no  
  Call Number ref @ user @ Serial 96592  
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Author Khalifa, J.; Tensaouti, F.; Lusque, A.; Plas, B.; Lotterie, J.-A.; Benouaich-Amiel, A.; Uro-Coste, E.; Lubrano, V.; Cohen-Jonathan Moyal, E. url  doi
openurl 
  Title Subventricular zones: new key targets for glioblastoma treatment Type Journal Article
  Year 2017 Publication Radiation Oncology (London, England) Abbreviated Journal Radiat Oncol  
  Volume 12 Issue (up) 1 Pages 67  
  Keywords Glioblastoma; Prognostic factors; Radiotherapy; Stem-cell niche; Subventricular Zone  
  Abstract BACKGROUND: We aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma. METHODS: Forty-three patients with primary diagnosed glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS). RESULTS: Median age was 59 years (range: 25-85). Median follow-up, OS and TTP were 22.7 months (range 7.5-69.7 months), 22.7 months (95% CI 14.5-26.2 months) and 6.4 months (95% CI 4.4-9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p = 0.014) and TTP (4.6 vs 12.9 months, p = 0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p = 0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR = 3.07, p = 0.012 and HR = 2.67, p = 0.047, respectively). CONCLUSION: Our results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.  
  Address INSERM U1037, Centre de Recherche contre le Cancer de Toulouse, 1 avenue Irene Joliot-Curie, Toulouse Cedex, 31059, France  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1748-717X ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28424082 Approved no  
  Call Number ref @ user @ Serial 96593  
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Author Celiku, O.; Tandle, A.; Chung, J.-Y.; Hewitt, S.M.; Camphausen, K.; Shankavaram, U. url  doi
openurl 
  Title Computational analysis of the mesenchymal signature landscape in gliomas Type Journal Article
  Year 2017 Publication BMC Medical Genomics Abbreviated Journal BMC Med Genomics  
  Volume 10 Issue (up) 1 Pages 13  
  Keywords Cd44; Computational modeling; Epithelial to mesenchymal transition; Glioma  
  Abstract BACKGROUND: Epithelial to mesenchymal transition, and mimicking processes, contribute to cancer invasion and metastasis, and are known to be responsible for resistance to various therapeutic agents in many cancers. While a number of studies have proposed molecular signatures that characterize the spectrum of such transition, more work is needed to understand how the mesenchymal signature (MS) is regulated in non-epithelial cancers like gliomas, to identify markers with the most prognostic significance, and potential for therapeutic targeting. RESULTS: Computational analysis of 275 glioma samples from “The Cancer Genome Atlas” was used to identify the regulatory changes between low grade gliomas with little expression of MS, and high grade glioblastomas with high expression of MS. TF (transcription factor)-gene regulatory networks were constructed for each of the cohorts, and 5 major pathways and 118 transcription factors were identified as involved in the differential regulation of the networks. The most significant pathway – Extracellular matrix organization – was further analyzed for prognostic relevance. A 20-gene signature was identified as having prognostic significance (HR (hazard ratio) 3.2, 95% CI (confidence interval) = 1.53-8.33), after controlling for known prognostic factors (age, and glioma grade). The signature's significance was validated in an independent data set. The putative stem cell marker CD44 was biologically validated in glioma cell lines and brain tissue samples. CONCLUSIONS: Our results suggest that the differences between low grade gliomas and high grade glioblastoma are associated with differential expression of the signature genes, raising the possibility that targeting these genes might prolong survival in glioma patients.  
  Address Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 10 Center Drive, Bldg. 10, Rm. B3B70, Bethesda, MD, 20892, USA. uma@mail.nih.gov  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1755-8794 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28279210 Approved no  
  Call Number ref @ user @ Serial 96602  
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Author Jensen, S.S.; Petterson, S.A.; Halle, B.; Aaberg-Jessen, C.; Kristensen, B.W. url  doi
openurl 
  Title Effects of the lysosomal destabilizing drug siramesine on glioblastoma in vitro and in vivo Type Journal Article
  Year 2017 Publication BMC Cancer Abbreviated Journal BMC Cancer  
  Volume 17 Issue (up) 1 Pages 178  
  Keywords Brain slice cultures; Cancer stem cell; Glioblastoma; Lysosomes; Siramesine; Spheroids  
  Abstract BACKGROUND: Glioblastoma is the most frequent and most malignant brain tumor with the patients having a median survival of only 14.6 months. Although glioblastoma patients are treated with surgery, radiation and chemotherapy recurrence is inevitable. A stem-like population of radio- and chemoresistant brain tumor-initiating cells combined with the invasive properties of the tumors is believed to be critical for treatment resistance. In the present study, the aim was to investigate the effect of a novel therapeutic strategy using the lysosomotropic detergent siramesine on glioblastomas. METHODS: Standard glioma cell lines and patient-derived spheroids cultures with tumor-initiating stem-like cells were used to investigate effects of siramesine on proliferation and cell death. Responsible mechanisms were investigated by inhibitors of caspases and cathepsins. Effects of siramesine on migrating tumor cells were investigated by a flat surface migration assay and by implanting spheroids into organotypic rat brain slice cultures followed by confocal time-lapse imaging. Finally the effect of siramesine was investigated in an orthotopic mouse glioblastoma model. Results obtained in vitro and in vivo were confirmed by immunohistochemical staining of histological sections of spheroids, spheroids in brain slice cultures and tumors in mice brains. RESULTS: The results showed that siramesine killed standard glioma cell lines in vitro, and loss of acridine orange staining suggested a compromised lysosomal membrane. Co-treatment of the cell lines with inhibitors of caspases and cathepsins suggested differential involvement in cell death. Siramesine caused tumor cell death and reduced secondary spheroid formation of patient-derived spheroid cultures. In the flat surface migration model siramesine caused tumor cell death and inhibited tumor cell migration. This could not be reproduced in the organotypic three dimensional spheroid-brain slice culture model or in the mice xenograft model. CONCLUSIONS: In conclusion the in vitro results obtained with tumor cells and spheroids suggest a potential of lysosomal destabilizing drugs in killing glioblastoma cells, but siramesine was without effect in the organotypic spheroid-brain slice culture model and the in vivo xenograft model.  
  Address Institute of Clinical Research, University of Southern Denmark, Winslowparken 19.3, 5000, Odense C, Denmark. bjarne.winther.kristensen@rsyd.dk  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1471-2407 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28270132 Approved no  
  Call Number ref @ user @ Serial 96603  
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