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Author Chen, C.; Kim, W.-Y.; Jiang, P. url  doi
openurl 
  Title Humanized neuronal chimeric mouse brain generated by neonatally engrafted human iPSC-derived primitive neural progenitor cells Type Journal Article
  Year 2016 Publication JCI Insight Abbreviated Journal JCI Insight  
  Volume 1 Issue 19 Pages (down) e88632  
  Keywords  
  Abstract The creation of a humanized chimeric mouse nervous system permits the study of human neural development and disease pathogenesis using human cells in vivo. Humanized glial chimeric mice with the brain and spinal cord being colonized by human glial cells have been successfully generated. However, generation of humanized chimeric mouse brains repopulated by human neurons to possess a high degree of chimerism have not been well studied. Here we created humanized neuronal chimeric mouse brains by neonatally engrafting the distinct and highly neurogenic human induced pluripotent stem cell (hiPSC)-derived rosette-type primitive neural progenitors. These neural progenitors predominantly differentiate to neurons, which disperse widely throughout the mouse brain with infiltration of the cerebral cortex and hippocampus at 6 and 13 months after transplantation. Building upon the hiPSC technology, we propose that this potentially unique humanized neuronal chimeric mouse model will provide profound opportunities to define the structure, function, and plasticity of neural networks containing human neurons derived from a broad variety of neurological disorders.  
  Address Department of Developmental Neuroscience, Munroe-Meyer Institute,; Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, Nebraska, USA  
  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 2379-3708 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27882348 Approved no  
  Call Number ref @ user @ Serial 95912  
Permanent link to this record
 

 
Author Stankovic, N.D.; Hoppmann, N.; Teodorczyk, M.; Kim, E.L.; Bros, M.; Giese, A.; Zipp, F.; Schmidt, M.H.H. url  doi
openurl 
  Title No role of IFITM3 in brain tumor formation in vivo Type Journal Article
  Year 2016 Publication Oncotarget Abbreviated Journal Oncotarget  
  Volume 7 Issue 52 Pages (down) 86388-86405  
  Keywords Ifitm3; brain tumors; cancer stem cells; glioma; irradiation  
  Abstract Glioblastoma multiforme (GBM) is one of the most lethal solid tumors in adults. Despite aggressive treatment approaches for patients, GBM recurrence is inevitable, in part due to the existence of stem-like brain tumor-propagating cells (BTPCs), which produce factors rendering them resistant to radio- and chemotherapy. Comparative transcriptome analysis of irradiated, patient-derived BTPCs revealed a significant upregulation of the interferon-inducible transmembrane protein 3 (IFITM3), suggesting the protein as a factor mediating radio resistance. Previously, IFITM3 has been described to affect glioma cells; therefore, the role of IFITM3 in the formation and progression of brain tumors has been investigated in vivo. Intracranial implantation studies using radio-selected BTPCs alongside non-irradiated parental BTPCs in immunodeficient mice displayed no influence of irradiation on animal survival. Furthermore, gain and loss of function studies using BTPCs ectopically expressing IFITM3 or having IFITM3 down-modulated by a shRNA approach, did affect neither tumor growth nor animal survival. Additionally, a syngeneic model based on the mouse glioma cell line GL261 was applied in order to consider the possibility that IFITM3 relies on an intact immune system to unfold its tumorigenic potential. GL261 cells ectopically expressing IFITM3 were implanted into the striatum of immunocompetent mice without influencing the survival of glioma-bearing animals. Lastly, the vasculature and the extent of microglia/macrophage invasion into the tumor were studied in BTPC and GL261 tumors but neither parameter was altered by IFITM3. This report presents for the first time that IFITM3 is upregulated in patient-derived BTPCs upon irradiation but does not affect brain tumor formation or progression in vivo.  
  Address German Cancer Research Center (DKFZ), Heidelberg, Germany  
  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 1949-2553 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27835870 Approved no  
  Call Number ref @ user @ Serial 96625  
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Author Yadav, V.N.; Zamler, D.; Baker, G.J.; Kadiyala, P.; Erdreich-Epstein, A.; DeCarvalho, A.C.; Mikkelsen, T.; Castro, M.G.; Lowenstein, P.R. url  doi
openurl 
  Title CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis: A genetic knockdown study Type Journal Article
  Year 2016 Publication Oncotarget Abbreviated Journal Oncotarget  
  Volume 7 Issue 50 Pages (down) 83701-83719  
  Keywords CXCR4 knockdown; autovascularization; combination therapies; glioma radiotherapy resistance; perivascular invasion  
  Abstract Glioblastoma (GBM) is a highly invasive brain tumor. Perivascular invasion, autovascularization and vascular co-option occur throughout the disease and lead to tumor invasion and progression. The molecular basis for perivascular invasion, i.e., the interaction of glioma tumor cells with endothelial cells is not well characterized. Recent studies indicate that glioma cells have increased expression of CXCR4. We investigated the in-vivo role of CXCR4 in perivascular invasion of glioma cells using shRNA-mediated knock down of CXCR4. We show that primary cultures of human glioma stem cells HF2303 and mouse glioma GL26-Cit cells exhibit significant migration towards human (HBMVE) and mouse (MBVE) brain microvascular endothelial cells. Blocking CXCR4 on tumor cells with AMD3100 in-vitro, inhibits migration of GL26-Cit and HF2303 toward MBVE and HBMVE cells. Additionally, genetic down regulation of CXCR4 in mouse glioma GL26-Cit cells inhibits their in-vitro migration towards MBVE cells; in an in-vivo intracranial mouse model, these cells display reduced tumor growth and perivascular invasion, leading to increased survival. Quantitative analysis of brain sections showed that CXCR4 knockdown tumors are less invasive. Lastly, we tested the effects of radiation on CXCR4 knock down GL26-Cit cells in an orthotopic brain tumor model. Radiation treatment increased apoptosis of CXCR4 downregulated tumor cells and prolonged median survival. In summary, our data suggest that CXCR4 signaling is critical for perivascular invasion of GBM cells and targeting this receptor makes tumors less invasive and more sensitive to radiation therapy. Combination of CXCR4 knock down and radiation treatment might improve the efficacy of GBM therapy.  
  Address Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA  
  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 1949-2553 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27863376 Approved no  
  Call Number ref @ user @ Serial 96623  
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Author Maachani, U.B.; Shankavaram, U.; Kramp, T.; Tofilon, P.J.; Camphausen, K.; Tandle, A.T. url  doi
openurl 
  Title FOXM1 and STAT3 interaction confers radioresistance in glioblastoma cells Type Journal Article
  Year 2016 Publication Oncotarget Abbreviated Journal Oncotarget  
  Volume 7 Issue 47 Pages (down) 77365-77377  
  Keywords Foxm1; Stat3; glioblastoma multiforme; glioma stem cells; radio resistance  
  Abstract Glioblastoma multiforme (GBM) continues to be the most frequently diagnosed and lethal primary brain tumor. Adjuvant chemo-radiotherapy remains the standard of care following surgical resection. In this study, using reverse phase protein arrays (RPPAs), we assessed the biological effects of radiation on signaling pathways to identify potential radiosensitizing molecular targets. We identified subsets of proteins with clearly concordant/discordant behavior between irradiated and non-irradiated GBM cells in vitro and in vivo. Moreover, we observed high expression of Forkhead box protein M1 (FOXM1) in irradiated GBM cells both in vitro and in vivo. Recent evidence of FOXM1 as a master regulator of metastasis and its important role in maintaining neural, progenitor, and GBM stem cells, intrigued us to validate it as a radiosensitizing target. Here we show that FOXM1 inhibition radiosensitizes GBM cells by abrogating genes associated with cell cycle progression and DNA repair, suggesting its role in cellular response to radiation. Further, we demonstrate that radiation induced stimulation of FOXM1 expression is dependent on STAT3 activation. Co-immunoprecipitation and co-localization assays revealed physical interaction of FOXM1 with phosphorylated STAT3 under radiation treatment. In conclusion, we hypothesize that FOXM1 regulates radioresistance via STAT3 in GBM cells. We also, show GBM patients with high FOXM1 expression have poor prognosis. Collectively our observations might open novel opportunities for targeting FOXM1 for effective GBM therapy.  
  Address Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA  
  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 1949-2553 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27764801 Approved no  
  Call Number ref @ user @ Serial 96631  
Permanent link to this record
 

 
Author Wei, L.; Su, Y.-K.; Lin, C.-M.; Chao, T.-Y.; Huang, S.-P.; Huynh, T.-T.; Jan, H.-J.; Whang-Peng, J.; Chiou, J.-F.; Wu, A.T.H.; Hsiao, M. url  doi
openurl 
  Title Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes Type Journal Article
  Year 2016 Publication Oncotarget Abbreviated Journal Oncotarget  
  Volume 7 Issue 43 Pages (down) 69961-69975  
  Keywords Bruton's tyrosine kinase; cancer stem cells; glioma; ibrutinib  
  Abstract Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM.  
  Address Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan  
  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 1949-2553 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27564106 Approved no  
  Call Number ref @ user @ Serial 96637  
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