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Author Luedi, M.M.; Singh, S.K.; Mosley, J.C.; Hatami, M.; Gumin, J.; Sulman, E.P.; Lang, F.F.; Stueber, F.; Zinn, P.O.; Colen, R.R. url  doi
openurl 
  Title A Dexamethasone-regulated Gene Signature Is Prognostic for Poor Survival in Glioblastoma Patients Type Journal Article
  Year 2017 Publication (down) Journal of Neurosurgical Anesthesiology Abbreviated Journal J Neurosurg Anesthesiol  
  Volume 29 Issue 1 Pages 46-58  
  Keywords Animals; Antineoplastic Agents, Hormonal/*pharmacology; Apoptosis; Blotting, Western; Brain Neoplasms/*mortality; Cell Line, Tumor; Cell Survival; Dexamethasone/*pharmacology; Flow Cytometry; Gene Expression Regulation, Neoplastic/*drug effects; Glioblastoma/*mortality; Humans; Mice; Prognosis; Stem Cells/drug effects; Survival Analysis  
  Abstract BACKGROUND: Dexamethasone is reported to induce both tumor-suppressive and tumor-promoting effects. The purpose of this study was to identify the genomic impact of dexamethasone in glioblastoma stem cell (GSC) lines and its prognostic value; furthermore, to identify drugs that can counter these side effects of dexamethasone exposure. METHODS: We utilized 3 independent GSC lines with tumorigenic potential for this study. Whole-genome expression profiling and pathway analyses were done with dexamethasone-exposed and control cells. GSCs were also co-exposed to dexamethasone and temozolomide. Risk scores were calculated for most affected genes, and their associations with survival in The Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data databases. In silico Connectivity Map analysis identified camptothecin as antagonist to dexamethasone-induced negative effects. RESULTS: Pathway analyses predicted an activation of dexamethasone network (z-score: 2.908). Top activated canonical pathways included “role of breast cancer 1 in DNA damage response” (P=1.07E-04). GSCs were protected against temozolomide-induced apoptosis when coincubated with dexamethasone. Altered cellular functions included cell movement, cell survival, and apoptosis with z-scores of 2.815, 5.137, and -3.122, respectively. CCAAT/enhancer binding protein beta (CEBPB) was activated in a dose dependent manner specifically in slow-dividing “stem-like” cells. CEBPB was activated in dexamethasone-treated orthotopic tumors. Patients with high risk scores had significantly shorter survival. Camptothecin was validated as potential partial neutralizer of dexamethasone-induced oncogenic effects. CONCLUSIONS: Dexamethasone exposure induces a genetic program and CEBPB expression in GSCs that adversely affects key cellular functions and response to therapeutics. High risk scores associated with these genes have negative prognostic value in patients. Our findings further suggest camptothecin as a potential neutralizer of adverse dexamethasone-mediated effects.  
  Address *Department of Anesthesiology, Bern University Hospital Inselspital, Bern, Switzerland Departments of daggerCancer Systems Imaging double daggerDiagnostic Imaging section signNeurosurgery and Brain Tumor Center parallelRadiation Oncology, Division of Radiation Oncology #Neurosurgery, Cancer Systems Imaging, and Cancer Biology **Cancer Systems Imaging, and Diagnostic Imaging, The University of Texas MD Anderson Cancer Center paragraph signDepartment of Neurosurgery, Baylor College of Medicine, Houston, TX  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0898-4921 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27653222 Approved no  
  Call Number ref @ user @ Serial 96635  
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Author Bijangi-Vishehsaraei, K.; Reza Saadatzadeh, M.; Wang, H.; Nguyen, A.; Kamocka, M.M.; Cai, W.; Cohen-Gadol, A.A.; Halum, S.L.; Sarkaria, J.N.; Pollok, K.E.; Safa, A.R. url  doi
openurl 
  Title Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways Type Journal Article
  Year 2017 Publication (down) Journal of Neurosurgery Abbreviated Journal J Neurosurg  
  Volume Issue Pages 1-12  
  Keywords CCCP = carbonyl cyanide m-chlorophenylhydrazone; DMSO = dimethyl sulfoxide; DSB = double-strand break; EGF = epidermal growth factor; FACS = fluorescence-activated cell sorting; FGF = fibroblast growth factor; GBM = glioblastoma; GSC = glioblastoma stem cell; IC50 = 50% inhibition of cell survival; MRC = mitochondrial respiratory chain; MSC = mesenchymal stromal cell; NAC = N-acetylcysteine; NSG = nonobese diabetic scid gamma; PE = phycoerythrin; ROS = reactive oxygen species; SFN = sulforaphane; SSB = single-strand break; apoptosis; cancer stem cells; glioblastoma; oncology; sulforaphane  
  Abstract OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of gamma-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.  
  Address Departments of 2 Pharmacology and Toxicology and  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0022-3085 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28059653 Approved no  
  Call Number ref @ user @ Serial 96613  
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Author Rosager, A.M.; Sorensen, M.D.; Dahlrot, R.H.; Boldt, H.B.; Hansen, S.; Lathia, J.D.; Kristensen, B.W. url  doi
openurl 
  Title Expression and prognostic value of JAM-A in gliomas Type Journal Article
  Year 2017 Publication (down) Journal of Neuro-Oncology Abbreviated Journal J Neurooncol  
  Volume Issue Pages  
  Keywords Astrocytic brain tumors; Glioma; Junctional adhesion molecule-A; Prognosis; Tumor stem cell  
  Abstract Gliomas are among the most lethal cancers, being highly resistant to both chemo- and radiotherapy. The expression of junctional adhesion molecule-A (JAM-A) was recently identified on the surface of stem cell-like brain tumor-initiating cells and suggested to function as a unique glioblastoma niche adhesion factor influencing the tumorigenic potential of brain tumor-initiating cells. We have recently identified high JAM-A expression to be associated with poor outcome in glioblastomas, and our aim was to further investigate the expression of JAM-A in gliomas focusing especially on the prognostic value in WHO grade II and III gliomas. JAM-A protein expression was evaluated by immunohistochemistry and advanced quantitative image analysis with continuous estimates of staining intensity. The JAM-A antibody stained tumor cell membranes and cytoplasm to various extent in different glioma subtypes, and the intensity was higher in glioblastomas than low-grade gliomas. We could not detect an association with overall survival in patients with grade II and III tumors. Double-immunofluorescence stainings in glioblastomas revealed co-expression of JAM-A with CD133, SOX2, nestin, and GFAP in tumor cells as well as some co-expression with the microglial/macrophage marker IBA-1. In conclusion, JAM-A expression was higher in glioblastomas compared to low-grade gliomas and co-localized with recognized stem cell markers suggesting an association of JAM-A with glioma aggressiveness. No significant association between JAM-A expression and overall survival was found in grade II and III gliomas. Further research is needed to determine the function and clinical impact of JAM-A in gliomas.  
  Address Department of Clinical Research, University of Southern Denmark, Winslowparken 19, 3rd floor, 5000, Odense, Denmark  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  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:28677106 Approved no  
  Call Number ref @ user @ Serial 96579  
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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 (down) Journal of Neuro-Oncology Abbreviated Journal J Neurooncol  
  Volume 133 Issue 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  
  Publisher Place of Publication Editor  
  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 Azoulay, M.; Santos, F.; Shenouda, G.; Petrecca, K.; Oweida, A.; Guiot, M.C.; Owen, S.; Panet-Raymond, V.; Souhami, L.; Abdulkarim, B.S. url  doi
openurl 
  Title Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution Type Journal Article
  Year 2017 Publication (down) Journal of Neuro-Oncology Abbreviated Journal J Neurooncol  
  Volume 132 Issue 3 Pages 419-426  
  Keywords Bevacizumab; Glioblastoma; Radiation; Recurrence; Surgery; Temozolomide  
  Abstract The optimal management of recurrent glioblastoma (GBM) has yet to be determined. We aim to assess the benefits of re-operation and salvage therapies (chemotherapy and/or re-irradiation) for recurrent GBM and to identify prognostic factors associated with better survival. All patients who underwent surgery for GBM between January 2005 and December 2012 followed by adjuvant radiotherapy, and who developed GBM recurrence on imaging were included in this retrospective study. Univariate and multivariate analysis was performed using Cox models in order to identify factors associated with overall survival (OS). One hundred and eighty patients treated to a dose of 60 Gy were diagnosed with recurrent GBM. At a median follow-up time of 6.2 months, the median survival (MS) from time of recurrence was 6.6 months. Sixty-nine patients underwent repeat surgery for recurrence based on imaging. To establish the benefits of repeat surgery and salvage therapies, 68 patients who underwent repeat surgery were matched to patients who did not based on extent of initial resection and presence of subventricular zone involvement at recurrence. MS for patients who underwent re-operation was 9.6 months, compared to 5.3 months for patients who did not have repeat surgery (p < 0.0001). Multivariate analysis in the matched pairs confirmed that repeat surgery with the addition of other salvage treatment can significantly affect patient outcome (HR 0.53). Re-operation with additional salvage therapies for recurrent GBM provides survival prolongation at the time of progression.  
  Address Department of Oncology, Division of Radiation Oncology, Cedars Cancer Centre, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada. bassam.abdulkarim@mcgill.ca  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  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:28374095 Approved no  
  Call Number ref @ user @ Serial 96599  
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