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  1. Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma

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    Friesen, Claudia; Hormann, Inis; Roscher, Mareike; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf; Debatin, Klaus-Michael; Miltner, Erich

    2014-01-01

    Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis. Downregulation of cAMP sensitizes tumor cells for anti-cancer treatment. Opioid receptor agonists triggering opioid receptors can activate inhibitory Gi proteins, which, in turn, block adenylyl cyclase activity reducing cAMP. In this study, we show that downregulation of cAMP by opioid receptor activation improves the effectiveness of anti-cancer drugs in treatment of glioblastoma. The µ-opioid receptor agonist D,L-methadone sensitizes glioblastoma as well as the untreatable glioblastoma stem cells for doxorubicin-induced apoptosis and activation of apoptosis pathways by reversing deficient caspase activation and deficient downregulation of XIAP and Bcl-xL, playing critical roles in glioblastomas’ resistance. Blocking opioid receptors using the opioid receptor antagonist naloxone or increasing intracellular cAMP by 3-isobutyl-1-methylxanthine (IBMX) strongly reduced opioid receptor agonist-induced sensitization for doxorubicin. In addition, the opioid receptor agonist D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux, whereas doxorubicin increased opioid receptor expression in glioblastomas. Furthermore, opioid receptor activation using D,L-methadone inhibited tumor growth significantly in vivo. Our findings suggest that opioid receptor activation triggering downregulation of cAMP is a promising strategy to inhibit tumor growth and to improve the effectiveness of anti-cancer drugs in treatment of glioblastoma and in killing glioblastoma stem cells. PMID:24626197

  2. Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma

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    Dinesh K. Singh

    2017-01-01

    Full Text Available Efforts to identify and target glioblastoma (GBM drivers have primarily focused on receptor tyrosine kinases (RTKs. Clinical benefits, however, have been elusive. Here, we identify an SRY-related box 2 (SOX2 transcriptional regulatory network that is independent of upstream RTKs and capable of driving glioma-initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2 and zinc-finger E-box binding homeobox 1 (ZEB1, which are frequently co-expressed irrespective of driver mutations, as potential SOX2 targets. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor-suppressor-deficient astrocytes into glioma-initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.

  3. Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma.

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    Singh, Dinesh K; Kollipara, Rahul K; Vemireddy, Vamsidara; Yang, Xiao-Li; Sun, Yuxiao; Regmi, Nanda; Klingler, Stefan; Hatanpaa, Kimmo J; Raisanen, Jack; Cho, Steve K; Sirasanagandla, Shyam; Nannepaga, Suraj; Piccirillo, Sara; Mashimo, Tomoyuki; Wang, Shan; Humphries, Caroline G; Mickey, Bruce; Maher, Elizabeth A; Zheng, Hongwu; Kim, Ryung S; Kittler, Ralf; Bachoo, Robert M

    2017-01-24

    Efforts to identify and target glioblastoma (GBM) drivers have primarily focused on receptor tyrosine kinases (RTKs). Clinical benefits, however, have been elusive. Here, we identify an SRY-related box 2 (SOX2) transcriptional regulatory network that is independent of upstream RTKs and capable of driving glioma-initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2) and zinc-finger E-box binding homeobox 1 (ZEB1), which are frequently co-expressed irrespective of driver mutations, as potential SOX2 targets. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor-suppressor-deficient astrocytes into glioma-initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.

  4. KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway.

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    Li, H; Jiang, X; Yu, Y; Huang, W; Xing, H; Agar, N Y; Yang, H W; Yang, B; Carroll, R S; Johnson, M D

    2015-03-12

    Aberrant splicing of the cyclin-dependent kinase-associated phosphatase, KAP, promotes glioblastoma invasion in a Cdc2-dependent manner. However, the mechanism by which this occurs is unknown. Here we show that miR-26a, which is often amplified in glioblastoma, promotes invasion in phosphatase and tensin homolog (PTEN)-competent and PTEN-deficient glioblastoma cells by directly downregulating KAP expression. Mechanistically, we find that KAP binds and activates ROCK2. Thus, RNA-mediated downregulation of KAP leads to decreased ROCK2 activity and this, in turn, increases Rac1-mediated invasion. In addition, the decrease in KAP expression activates the cyclin-dependent kinase, Cdk2, and this directly promotes invasion by increasing retinoblastoma phosphorylation, E2F-dependent Cdc2 expression and Cdc2-mediated inactivation of the actomyosin inhibitor, caldesmon. Importantly, glioblastoma cell invasion mediated by this pathway can be antagonized by Cdk2/Cdc2 inhibitors in vitro and in vivo. Thus, two distinct RNA-based mechanisms activate this novel KAP/ROCK2/Cdk2-dependent invasion pathway in glioblastoma.

  5. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

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    Mitchell, Duane A; Batich, Kristen A; Gunn, Michael D; Huang, Min-Nung; Sanchez-Perez, Luis; Nair, Smita K; Congdon, Kendra L; Reap, Elizabeth A; Archer, Gary E; Desjardins, Annick; Friedman, Allan H; Friedman, Henry S; Herndon, James E; Coan, April; McLendon, Roger E; Reardon, David A; Vredenburgh, James J; Bigner, Darell D; Sampson, John H

    2015-03-19

    After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

  6. The prognostic IDH1( R132 ) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma

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    Bleeker, F.E.; Atai, N.A.; Lamba, S.; Jonker, A.; Rijkeboer, D.; Bosch, K.S.; Tigchelaar, W.; Troost, D.; Vandertop, W.P.; Bardelli, A.; van Noorden, C.J.F.

    2010-01-01

    Somatic mutations in the isocitrate dehydrogenase 1 gene (IDH1) occur at high frequency in gliomas and seem to be a prognostic factor for survival in glioblastoma patients. In our set of 98 glioblastoma patients, IDH1 ( R132 ) mutations were associated with improved survival of 1 year on average, af

  7. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities.

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    Filbin, Mariella Gruber; Dabral, Sukriti K; Pazyra-Murphy, Maria F; Ramkissoon, Shakti; Kung, Andrew L; Pak, Ekaterina; Chung, Jarom; Theisen, Matthew A; Sun, Yanping; Franchetti, Yoko; Sun, Yu; Shulman, David S; Redjal, Navid; Tabak, Barbara; Beroukhim, Rameen; Wang, Qi; Zhao, Jean; Dorsch, Marion; Buonamici, Silvia; Ligon, Keith L; Kelleher, Joseph F; Segal, Rosalind A

    2013-11-01

    In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.

  8. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.

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    Jeffrey C Lee

    2006-12-01

    Full Text Available BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132 of glioblastomas and 12.5% (1/8 of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

  9. Cytotoxic activity of interferon alpha induced dendritic cells as a biomarker of glioblastoma

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    Mishinov, S. V.; Stupak, V. V.; Tyrinova, T. V.; Leplina, O. Yu.; Ostanin, A. A.; Chernykh, E. R.

    2016-08-01

    Dendritic cells (DCs) are the most potent antigen presenting cells that can play direct role in anti-tumor immune response as killer cells. DC tumoricidal activity can be stimulated greatly by type I IFN (IFNα and IFNβ). In the present study, we examined cytostatic and cytotoxic activity of monocyte-derived IFNα-induced DCs generated from patients with brain glioma and evaluated the potential use of these parameters in diagnostics of high-grade gliomas. Herein, we demonstrated that patient DCs do not possess the ability to inhibit the growth of tumor HEp-2 cell line but low-grade and high-grade glioma patients do not differ significantly in DC cytostatic activity. However, glioma patient DCs are characterized by reduced cytotoxic activity against HEp-2 cells. The impairment of DC cytotoxic function is observed mainly in glioblastoma patients. The cytotoxic activity of DCs against HEp-2 cells below 9% is an informative marker for glioblastomas.

  10. Radiotherapy planning for glioblastoma based on a tumor growth model: Improving target volume delineation

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    Unkelbach, Jan; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A

    2013-01-01

    Glioblastoma are known to infiltrate the brain parenchyma instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In clinical practice, a uniform margin is applied to account for microscopic spread of disease. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth: Anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain...

  11. Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation

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    Unkelbach, Jan; Menze, Bjoern H.; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A.

    2014-02-01

    Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

  12. Metabolic patterns and biotransformation activities of resveratrol in human glioblastoma cells: relevance with therapeutic efficacies.

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    Xiao-Hong Shu

    Full Text Available BACKGROUND: Trans-resveratrol rather than its biotransformed monosulfate metabolite exerts anti-medulloblastoma effects by suppressing STAT3 activation. Nevertheless, its effects on human glioblastoma cells are variable due to certain unknown reason(s. METHODOLOGY/PRINCIPAL FINDINGS: Citing resveratrol-sensitive UW228-3 medulloblastoma cell line and primarily cultured rat brain cells/PBCs as controls, the effect of resveratrol on LN-18 human glioblastoma cells and its relevance with metabolic pattern(s, brain-associated sulfotransferase/SULT expression and the statuses of STAT3 signaling and protein inhibitor of activated STAT3 (PIAS3 were elucidated by multiple experimental approaches. Meanwhile, the expression patterns of three SULTs (SULT1A1, 1C2 and 4A1 in human glioblastoma tumors were profiled immunohistochemically. The results revealed that 100 µM resveratrol-treated LN-18 generated the same metabolites as UW228-3 cells, while additional metabolite in molecular weight of 403.0992 in negative ion mode was found in PBCs. Neither growth arrest nor apoptosis was found in resveratrol-treated LN-18 and PBC cells. Upon resveratrol treatment, the levels of SULT1A1, 1C2 and 4A1 expression in LN-18 cells were more up-regulated than that expressed in UW228-3 cells and close to the levels in PBCs. Immunohistochemical staining showed that 42.0%, 27.1% and 19.6% of 149 glioblastoma cases produced similar SULT1A1, 1C2 and 4A1 levels as that of tumor-surrounding tissues. Unlike the situation in UW228-3 cells, STAT3 signaling remained activated and its protein inhibitor PIAS3 was restricted in the cytosol of resveratrol-treated LN-18 cells. No nuclear translocation of STAT3 and PIAS3 was observed in resveratrol-treated PBCs. Treatment with STAT3 chemical inhibitor, AG490, committed majority of LN-18 and UW228-3 cells but not PBCs to apoptosis within 48 hours. CONCLUSIONS/SIGNIFICANCE: LN-18 glioblastoma cells are insensitive to resveratrol due to the

  13. STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications

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    Kim, Jennifer E.; Patel, Mira; Ruzevick, Jacob; Jackson, Christopher M.; Lim, Michael, E-mail: mlim3@jhmi.edu [Department of Neurosurgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Phipps Building Rm 123, Baltimore, MD 21287 (United States)

    2014-02-10

    Signal transducer and activator of transcription 3 (STAT3) is a potent regulator of gliomagenesis through its induction of angiogenesis, host immunosuppression, and tumor invasion. Gain of function mutations result in constitutive activation of STAT3 in glioma cells, making STAT3 an attractive target for inhibition in cancer therapy. Nevertheless, some studies show that STAT3 also participates in terminal differentiation and apoptosis of various cell lines and in glioma with phosphatase and tensin homolog (PTEN)-deficient genetic backgrounds. In light of these findings, the utility of STAT3 as a prognostic indicator and as a target of drug therapies will be contingent on a more nuanced understanding of its pro- and anti-tumorigenic effects.

  14. Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

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    Chakrabarti, Mrinmay; Ray, Swapan K

    2016-03-01

    Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo.

  15. EGFR as a therapeutic target in glioblastoma

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    David M Siebert

    2012-01-01

    Full Text Available The tyrosine kinase receptor epidermal growth factor receptor (EGFR can be activated by several ligands, thus triggering downstream pathways regulating cell growth and survival. Its dysregula­tion is particularly important for the development and progression of astrocytomas. After the description of its role in glioblastomas (WHO grade IV astrocytomas, an overview on the therapeutic strategies target­ing EGFR is provided. It analyzes the past and ongoing trials concerning the small molecule tyro­sine kinase inhibitors, i.e. gefitinib, erlotinib and the combination therapies, the EGFR vaccina­tion strategies, the antibodies directed against EGFR and finally the intracranially administered EGFR-targeted therapies. As our understanding of the underlying molecular aberrancies in glioblastoma grows, our ability to better target specific subtypes of glioblastoma should improve. Molecular biomarker enriched clinical trials may lead to improved patient outcomes.

  16. Valproic Acid Use During Radiation Therapy for Glioblastoma Associated With Improved Survival

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    Barker, Christopher A., E-mail: barkerc@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Bishop, Andrew J.; Chang, Maria; Beal, Kathryn; Chan, Timothy A. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2013-07-01

    Purpose: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS). Methods and Materials: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS. Results: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, −0.09 to 1.17), independently of RTOG RPA class and seizure history. Conclusions: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted.

  17. [Biology molecular of glioblastomas].

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    Franco-Hernández, C; Martínez-Glez, V; Rey, J A

    2007-10-01

    Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anapalsic astrocytoma (secondary glioblastoma). The molecular alteration most frequent in these tumor-like types is the loss of heterozygosity on chromosome 10, in which several genes have been identified as tumors suppressor. The TP53/MDM2/P14arf and CDK4/RB1/ P16ink4 genetic pathways involved in cycle control are deregulated in the majority of gliomas as well as genes that promote the cellular division, EGFR. Finally the increase of growth and angiogenics factors is also involved in the development of glioblastomas. One of the objectives of molecular biology in tumors of glial ancestry is to try to find the genetic alterations that allow to approach better the classification of glioblastomas, its evolution prediction and treatment. The new pathmolecular classification of gliomas should improve the old one, especially being concerned about the oncogenesis and heterogeneity of these tumors. It is desirable that this classification had clinical applicability and integrates new molecular findings with some known histological features with pronostic value. In this paper we review the most frequent molecular mechanisms involved in the patogenesis of glioblastomas.

  18. Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3.

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    Guryanova, Olga A; Wu, Qiulian; Cheng, Lin; Lathia, Justin D; Huang, Zhi; Yang, Jinbo; MacSwords, Jennifer; Eyler, Christine E; McLendon, Roger E; Heddleston, John M; Shou, Weinian; Hambardzumyan, Dolores; Lee, Jeongwu; Hjelmeland, Anita B; Sloan, Andrew E; Bredel, Markus; Stark, George R; Rich, Jeremy N; Bao, Shideng

    2011-04-12

    Glioblastomas display cellular hierarchies containing tumor-propagating glioblastoma stem cells (GSCs). STAT3 is a critical signaling node in GSC maintenance but molecular mechanisms underlying STAT3 activation in GSCs are poorly defined. Here we demonstrate that the bone marrow X-linked (BMX) nonreceptor tyrosine kinase activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. BMX is differentially expressed in GSCs relative to nonstem cancer cells and neural progenitors. BMX knockdown potently inhibited STAT3 activation, expression of GSC transcription factors, and growth of GSC-derived intracranial tumors. Constitutively active STAT3 rescued the effects of BMX downregulation, supporting that BMX signals through STAT3 in GSCs. These data demonstrate that BMX represents a GSC therapeutic target and reinforces the importance of STAT3 signaling in stem-like cancer phenotypes.

  19. Tectal glioblastoma Glioblastoma tetal

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    Feres Chaddad Neto

    2007-12-01

    Full Text Available Brain stem gliomas are a heterogeneous group of neoplasms arising mostly in paediatric patients. Tectal plate gliomas represent a particular type of brain stem tumours usually with a benign, indolent clinical course, presenting with signs of raised intracranial hipertension due to supra-tentorialhydrocephalous caused by aqueductal stenosis. Seldom high-grade lesions arise in this location with tremendous therapeutic implications. When a malignant tumour is clinically and radiographically suspected a biopsy should be performed to obtain histhological confirmation. Treatment is then planned in a case-by-case basis. We present the case of a glioblastoma of the tectal plate in a 22 years-old woman operated upon by a supracerebellar-infratentorial approach.Os gliomas do tronco cerebral são um grupo heterogêneo de neoplasias que acometem habitualmente crianças. Os gliomas da placa quadrigeminal representam um tipo particular de tumores do tronco cerebral, habitualmente com um curso benigno e indolente, surgindo com sinais de hipertensão intracraniana devido a hidrocefalia supra-tentorial provocada por compressão do aqueduto cerebral. Raramente surgem lesões de alto grau nesta região, mas as implicações terapêuticas são tremendas. Quando existe suspeita clínica e imagiológica de que se trata de lesão maligna, esta deve ser biopsada para se obter confirmação histológica. O tratamento deve então ser planejado caso a caso. Apresentamos o caso de glioblastoma da placa quadrigeminal em uma paciente de 22 anos intervencionado por via supracerebelar-infratentorial.

  20. p53 Small Molecule Inhibitor Enhances Temozolomide Cytotoxic Activity against Intracranial Glioblastoma Xenografts

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    Dinca, Eduard B.; Lu, Kan V.; Sarkaria, Jann N.; Pieper, Russell O.; Prados, Michael D.; Haas-Kogan, Daphne A.; VandenBerg, Scott R.; Berger, Mitchel S.; James, C. David

    2010-01-01

    In this study we investigated corresponding precursor and active forms of a p53 small molecule inhibitor for effect on temozolomide (TMZ) anti-tumor activity against glioblastoma (GBM), using both in vitro and in vivo experimental approaches. Results from in vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased when GBMs with wild-type p53 were co-treated with the active form of p53 inhibitor, and this heightened cytotoxic response was accompanied by increased PARP cleavage as well as elevated cellular phospho-H2AX. Analysis of the same series of GBMs, as intracranial xenografts in athymic mice, and administering corresponding p53 inhibitor precursor, that is converted to the active compound in vivo, yielded results consistent with the in vitro analyses: i.e., TMZ + p53 inhibitor precursor co-treatment, of three distinct wild-type p53 GBM xenografts, resulted in significant enhancement of TMZ anti-tumor effect relative to treatment with TMZ alone, as indicated by serial bioluminescence monitoring as well as survival analysis (p < 0.001 for co-treatment survival benefit in each case). Mice receiving intracranial injection with p53 null GBM showed similar survival benefit from TMZ treatment regardless of the presence or absence of p53 inhibitor precursor. In total, our results indicate that the p53 active and precursor inhibitor pair enhance TMZ cytotoxicity in vitro and in vivo, respectively, and do so in a p53-dependent manner. PMID:19074867

  1. Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

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    Brown, Kristine E; Chagoya, Gustavo; Kwatra, Shawn G; Yen, Timothy; Keir, Stephen T; Cooter, Mary; Hoadley, Katherine A; Rasheed, Ahmed; Lipp, Eric S; Mclendon, Roger; Ali-Osman, Francis; Bigner, Darell D; Sampson, John H; Kwatra, Madan M

    2015-06-01

    The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential

  2. A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation.

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    Chen, Xishan; Tai, Lingyu; Gao, Jie; Qian, Jianchang; Zhang, Mingfei; Li, Beibei; Xie, Cao; Lu, Linwei; Lu, Wuyuan; Lu, Weiyue

    2015-11-28

    Antagonizing MDM2 and MDMX to activate the tumor suppressor protein p53 is an attractive therapeutic paradigm for the treatment of glioblastoma multiforme (GBM). However, challenges remain with respect to the poor ability of p53 activators to efficiently cross the blood-brain barrier and/or blood-brain tumor barrier and to specifically target tumor cells. To circumvent these problems, we developed a cyclic RGD peptide-conjugated poly(ethylene glycol)-co-poly(lactic acid) polymeric micelle (RGD-M) that carried a stapled peptide antagonist of both MDM2 and MDMX (sPMI). The peptide-carrying micelle RGD-M/sPMI was prepared via film-hydration method with high encapsulation efficiency and loading capacity as well as ideal size distribution. Micelle encapsulation dramatically increased the solubility of sPMI, thus alleviating its serum sequestration. In vitro studies showed that RGD-M/sPMI efficiently inhibited the proliferation of glioma cells in the presence of serum by activating the p53 signaling pathway. Further, RGD-M/sPMI exerted potent tumor growth inhibitory activity against human glioblastoma in nude mouse xenograft models. Importantly, the combination of RGD-M/sPMI and temozolomide--a standard chemotherapy drug for GBM increased antitumor efficacy against glioblastoma in experimental animals. Our results validate a combination therapy using p53 activators with temozolomide as a more effective treatment for GBM.

  3. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB signaling in glioblastoma cancer stem cells regulates the Notch pathway.

    Science.gov (United States)

    Garner, Jo Meagan; Fan, Meiyun; Yang, Chuan He; Du, Ziyun; Sims, Michelle; Davidoff, Andrew M; Pfeffer, Lawrence M

    2013-09-06

    Malignant gliomas are locally aggressive, highly vascular tumors that have a dismal prognosis, and present therapies provide little improvement in the disease course and outcome. Many types of malignancies, including glioblastoma, originate from a population of cancer stem cells (CSCs) that are able to initiate and maintain tumors. Although CSCs only represent a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance drives tumorigenesis. Therefore, it is imperative to identify pathways associated with CSCs to devise strategies to selectively target them. In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. Glioma CSCs were isolated and maintained in vitro using an adherent culture system, and the biological properties were compared with the traditional cultures of CSCs grown as multicellular spheres under nonadherent culture conditions. Interestingly, both adherent and spheroid glioma CSCs show constitutive activation of the STAT3/NF-κB signaling pathway and up-regulation of STAT3- and NF-κB-dependent genes. Gene expression profiling also identified components of the Notch pathway as being deregulated in glioma CSCs, and the deregulated expression of these genes was sensitive to treatment with STAT3 and NF-κB inhibitors. This finding is particularly important because Notch signaling appears to play a key role in CSCs in a variety of cancers and controls cell fate determination, survival, proliferation, and the maintenance of stem cells. The constitutive activation of STAT3 and NF-κB signaling pathways that leads to the regulation of Notch pathway genes in glioma CSCs identifies novel therapeutic targets for the treatment of glioma.

  4. Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Jun Feng

    2016-01-01

    Full Text Available Overcoming temozolomide (TMZ resistance is a great challenge in glioblastoma (GBM treatment. Nicotinamide phosphoribosyltransferase (NAMPT is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp. alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100 μM-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment.

  5. Analysis of the c-src gene product structure, abundance, and protein kinase activity in human neuroblastoma and glioblastoma cells.

    Science.gov (United States)

    O'Shaughnessy, J; Deseau, V; Amini, S; Rosen, N; Bolen, J B

    1987-01-01

    We have compared in different human neuroblastoma cell lines and human glioblastoma cells the expression level, structure, and tyrosine-specific protein kinase activity of pp60c-src. Our results show that not all human neuroblastoma cell lines express pp60c-src molecules with amino-terminal structural alterations. In neuroblastoma cells which possess pp60c-src with altered gel migration, the diminished polyacrylamide gel mobility of pp60c-src was found not to be dependent upon amino-terminal phosphorylations since extensive treatment of these molecules with phosphatase did not significantly change their gel migration properties. Similar differences in gel migration were observed when RNA from the various neuroblastoma and glioblastoma cells was translated in vitro using either rabbit reticulocyte or wheat germ lysates. White the level of c-src mRNA in the different cells analyzed was found to be similar, the abundance of pp60c-src in these same cells was found to vary by as much as 12-fold. This suggests that the abundance of pp60c-src in human neuroendocrine tumors is regulated through post-transcriptional and/or post-translational events which may be related to the stage of neuronal differentiation of the cells. Based upon determination of pp60c-src abundance by immunoblot analysis, we demonstrate that pp60c-src molecules derived from human neuroblastoma and glioblastoma cells have very similar in vitro protein kinase activities.

  6. NFKBIA Deletion in Glioblastomas

    Science.gov (United States)

    Bredel, Markus; Scholtens, Denise M.; Yadav, Ajay K.; Alvarez, Angel A.; Renfrow, Jaclyn J.; Chandler, James P.; Yu, Irene L.Y.; Carro, Maria S.; Dai, Fangping; Tagge, Michael J.; Ferrarese, Roberto; Bredel, Claudia; Phillips, Heidi S.; Lukac, Paul J.; Robe, Pierre A.; Weyerbrock, Astrid; Vogel, Hannes; Dubner, Steven; Mobley, Bret; He, Xiaolin; Scheck, Adrienne C.; Sikic, Branimir I.; Aldape, Kenneth D.; Chakravarti, Arnab; Harsh, Griffith R.

    2013-01-01

    BACKGROUND Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor-α), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR. METHODS We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons. RESULTS NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O6-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease. CONCLUSIONS Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival. PMID:21175304

  7. High IFIT1 expression predicts improved clinical outcome, and IFIT1 along with MGMT more accurately predicts prognosis in newly diagnosed glioblastoma.

    Science.gov (United States)

    Zhang, Jin-Feng; Chen, Yao; Lin, Guo-Shi; Zhang, Jian-Dong; Tang, Wen-Long; Huang, Jian-Huang; Chen, Jin-Shou; Wang, Xing-Fu; Lin, Zhi-Xiong

    2016-06-01

    Interferon-induced protein with tetratricopeptide repeat 1 (IFIT1) plays a key role in growth suppression and apoptosis promotion in cancer cells. Interferon was reported to induce the expression of IFIT1 and inhibit the expression of O-6-methylguanine-DNA methyltransferase (MGMT).This study aimed to investigate the expression of IFIT1, the correlation between IFIT1 and MGMT, and their impact on the clinical outcome in newly diagnosed glioblastoma. The expression of IFIT1 and MGMT and their correlation were investigated in the tumor tissues from 70 patients with newly diagnosed glioblastoma. The effects on progression-free survival and overall survival were evaluated. Of 70 cases, 57 (81.4%) tissue samples showed high expression of IFIT1 by immunostaining. The χ(2) test indicated that the expression of IFIT1 and MGMT was negatively correlated (r = -0.288, P = .016). Univariate and multivariate analyses confirmed high IFIT1 expression as a favorable prognostic indicator for progression-free survival (P = .005 and .017) and overall survival (P = .001 and .001), respectively. Patients with 2 favorable factors (high IFIT1 and low MGMT) had an improved prognosis as compared with others. The results demonstrated significantly increased expression of IFIT1 in newly diagnosed glioblastoma tissue. The negative correlation between IFIT1 and MGMT expression may be triggered by interferon. High IFIT1 can be a predictive biomarker of favorable clinical outcome, and IFIT1 along with MGMT more accurately predicts prognosis in newly diagnosed glioblastoma.

  8. Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma

    DEFF Research Database (Denmark)

    Persson, Morten; Nedergaard, Mette K; Brandt-Larsen, Malene

    2016-01-01

    an orthotopic xenograft model of glioblastoma. Tumor growth was monitored using bioluminescence imaging. Five to six weeks after inoculation, all mice were scanned with small-animal PET/CT using two new uPAR PET ligands ((64)Cu-NOTA-AE105 and (68)Ga-NOTA-AE105) and, for comparison, O-(2-(18)F...

  9. NETRIN-4 protects glioblastoma cells FROM temozolomide induced senescence.

    Directory of Open Access Journals (Sweden)

    Li Li

    Full Text Available Glioblastoma multiforme is the most common primary tumor of the central nervous system. The drug temozolomide (TMZ prolongs lifespan in many glioblastoma patients. The sensitivity of glioblastoma cells to TMZ is interfered by many factors, such as the expression of O-6-methylguanine-DNA methyltransferase (MGMT and activation of AKT signaling. We have recently identified the interaction between netrin-4 (NTN4 and integrin beta-4 (ITGB4, which promotes glioblastoma cell proliferation via activating AKT-mTOR signaling pathway. In the current work we have explored the effect of NTN4/ITGB4 interaction on TMZ induced glioblastoma cell senescence. We report here that the suppression of either ITGB4 or NTN4 in glioblastoma cell lines significantly enhances cellular senescence. The sensitivity of GBM cells to TMZ was primarily determined by the expression of MGMT. To omit the effect of MGMT, we concentrated on the cell lines devoid of expression of MGMT. NTN4 partially inhibited TMZ induced cell senescence and rescued AKT from dephosphorylation in U251MG cells, a cell line bearing decent levels of ITGB4. However, addition of exogenous NTN4 displayed no significant effect on TMZ induced senescence rescue or AKT activation in U87MG cells, which expressed ITGB4 at low levels. Furthermore, overexpression of ITGB4 combined with exogenous NTN4 significantly attenuated U87MG cell senescence induced by TMZ. These data suggest that NTN4 protects glioblastoma cells from TMZ induced senescence, probably via rescuing TMZ triggered ITGB4 dependent AKT dephosphorylation. This suggests that interfering the interaction between NTN4 and ITGB4 or concomitant use of the inhibitors of the AKT pathway may improve the therapeutic efficiency of TMZ.

  10. NETRIN-4 protects glioblastoma cells FROM temozolomide induced senescence.

    Science.gov (United States)

    Li, Li; Hu, Yizhou; Ylivinkka, Irene; Li, Huini; Chen, Ping; Keski-Oja, Jorma; Hyytiäinen, Marko

    2013-01-01

    Glioblastoma multiforme is the most common primary tumor of the central nervous system. The drug temozolomide (TMZ) prolongs lifespan in many glioblastoma patients. The sensitivity of glioblastoma cells to TMZ is interfered by many factors, such as the expression of O-6-methylguanine-DNA methyltransferase (MGMT) and activation of AKT signaling. We have recently identified the interaction between netrin-4 (NTN4) and integrin beta-4 (ITGB4), which promotes glioblastoma cell proliferation via activating AKT-mTOR signaling pathway. In the current work we have explored the effect of NTN4/ITGB4 interaction on TMZ induced glioblastoma cell senescence. We report here that the suppression of either ITGB4 or NTN4 in glioblastoma cell lines significantly enhances cellular senescence. The sensitivity of GBM cells to TMZ was primarily determined by the expression of MGMT. To omit the effect of MGMT, we concentrated on the cell lines devoid of expression of MGMT. NTN4 partially inhibited TMZ induced cell senescence and rescued AKT from dephosphorylation in U251MG cells, a cell line bearing decent levels of ITGB4. However, addition of exogenous NTN4 displayed no significant effect on TMZ induced senescence rescue or AKT activation in U87MG cells, which expressed ITGB4 at low levels. Furthermore, overexpression of ITGB4 combined with exogenous NTN4 significantly attenuated U87MG cell senescence induced by TMZ. These data suggest that NTN4 protects glioblastoma cells from TMZ induced senescence, probably via rescuing TMZ triggered ITGB4 dependent AKT dephosphorylation. This suggests that interfering the interaction between NTN4 and ITGB4 or concomitant use of the inhibitors of the AKT pathway may improve the therapeutic efficiency of TMZ.

  11. Improved Outcomes with Intensity Modulated Radiation Therapy Combined with Temozolomide for Newly Diagnosed Glioblastoma Multiforme

    Directory of Open Access Journals (Sweden)

    Noel J. Aherne

    2014-01-01

    Full Text Available Purpose. Glioblastoma multiforme (GBM is optimally treated by maximal debulking followed by combined chemoradiation. Intensity modulated radiation therapy (IMRT is gaining widespread acceptance in other tumour sites, although evidence to support its use over three-dimensional conformal radiation therapy (3DCRT in the treatment of gliomas is currently lacking. We examined the survival outcomes for patients with GBM treated with IMRT and Temozolomide. Methods and Materials. In all, 31 patients with GBM were treated with IMRT and 23 of these received chemoradiation with Temozolomide. We correlated survival outcomes with patient functional status, extent of surgery, radiation dose, and use of chemotherapy. Results. Median survival for all patients was 11.3 months, with a median survival of 7.2 months for patients receiving 40.05 Gray (Gy and a median survival of 17.4 months for patients receiving 60 Gy. Conclusions. We report one of the few series of IMRT in patients with GBM. In our group, median survival for those receiving 60 Gy with Temozolomide compared favourably to the combined therapy arm of the largest randomised trial of chemoradiation versus radiation to date (17.4 months versus 14.6 months. We propose that IMRT should be considered as an alternative to 3DCRT for patients with GBM.

  12. CDBG Public Improvements Activity

    Data.gov (United States)

    Department of Housing and Urban Development — CDBG activity related to public improvements, including senior centers, youth centers, parks, street improvements, water/sewer improvements, child care centers, fire...

  13. Level of Notch activation determines the effect on growth and stem cell-like features in glioblastoma multiforme neurosphere cultures

    DEFF Research Database (Denmark)

    Kristoffersen, Karina; Villingshøj, Mette; Poulsen, Hans Skovgaard;

    2013-01-01

    Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in glioblastoma multiforme (GBM) and they are assigned a central role in tumor initiation, progression and relapse. The Notch pathway is important for maintenance and cell fate decisions...... in the normal NSC population. Notch signaling is often deregulated in GBM and recent results suggest that this pathway plays a significant role in bCSC as well. We therefore wished to further elucidate the role of Notch activation in GBM-derived bCSC....

  14. Xanthohumol induces apoptosis in human malignant glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways.

    Science.gov (United States)

    Festa, Michela; Capasso, Anna; D'Acunto, Cosimo W; Masullo, Milena; Rossi, Adriano G; Pizza, Cosimo; Piacente, Sonia

    2011-12-27

    The effect of the biologically active prenylated chalcone and potential anticancer agent xanthohumol (1) has been investigated on apoptosis of the T98G human malignant glioblastoma cell line. Compound 1 decreased the viability of T98G cells by induction of apoptosis in a time- and concentration-dependent manner. Apoptosis induced by 1 was associated with activation of caspase-3, caspase-9, and PARP cleavage and was mediated by the mitochondrial pathway, as exemplified by mitochondrial depolarization, cytochrome c release, and downregulation of the antiapoptotic Bcl-2 protein. Xanthohumol induced intracellular reactive oxygen species (ROS), an effect that was reduced by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC). Intracellular ROS production appeared essential for the activation of the mitochondrial pathway and induction of apoptosis after exposure to 1. Oxidative stress due to treatment with 1 was associated with MAPK activation, as determined by ERK1/2 and p38 phosphorylation. Phosphorylation of ERK1/2 and p38 was attenuated using NAC to inhibit ROS production. After treatment with 1, ROS provided a specific environment that resulted in MAPK-induced cell death, with this effect reduced by the ERK1/2 specific inhibitor PD98059 and partially inhibited by the p38 inhibitor SB203580. These findings suggest that xanthohumol (1) is a potential chemotherapeutic agent for the treatment of glioblastoma multiforme.

  15. Improved survival for elderly married glioblastoma patients. Better treatment delivery, less toxicity, and fewer disease complications

    Energy Technology Data Exchange (ETDEWEB)

    Putz, Florian; Goerig, Nicole; Knippen, Stefan; Gryc, Thomas; Semrau, Sabine; Lettmaier, Sebastian; Fietkau, Rainer [Friedrich-Alexander-University Erlangen-Nuremberg, Department of Radiation Oncology, Erlangen (Germany); Putz, Tobias [University of Bamberg, Professorship of Demography, Bamberg (Germany); Eyuepoglu, Ilker; Roessler, Karl [Friedrich-Alexander-University Erlangen-Nuremberg, Department of Neurosurgery, Erlangen (Germany)

    2016-11-15

    Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies. A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail. Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m{sup 2} vs. 33.1 mg/m{sup 2}; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004). We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies. (orig.) [German] Fuer verheiratete Patienten mit malignen Gliomen ist ein verbessertes Gesamtueberleben gut beschrieben. Die zugrunde liegenden Mechanismen konnten bislang jedoch in den verfuegbaren bevoelkerungsbezogenen Arbeiten nicht erklaert werden. Eine Serie von 57 aelteren Patienten mit

  16. Potential applications of image-guided radiotherapy for brain metastases and glioblastoma to improve patient quality of life

    Directory of Open Access Journals (Sweden)

    Nam Phong Nguyen

    2013-11-01

    Full Text Available Treatment of glioblastoma multiforme (GBM and brain metastasis remains a challenge because of the poor survival and the potential for brain damage following radiation. Despite concurrent chemotherapy and radiation dose escalation, local recurrence remains the predominant pattern of failure in GBM most likely secondary to repopulation of cancer stem cells. Even though radiotherapy is highly effective for local control of radio-resistant tumors such as melanoma and renal cell cancer, systemic disease progression is the cause of death in most patients with brain metastasis. Preservation of quality of life of cancer survivors is the main issue for patients with brain metastasis. Image-guided radiotherapy (IGRT by virtue of precise radiation dose delivery may reduce treatment time of patients with GBM without excessive toxicity and potentially improve neurocognitive function with preservation of local control in patients with brain metastasis. Future prospective trials for primary brain tumors or brain metastasis should include IGRT to assess its efficacy to improve patient quality of life.

  17. Ionizing Radiation in Glioblastoma Initiating Cells

    Directory of Open Access Journals (Sweden)

    Maricruz eRivera

    2013-04-01

    Full Text Available Glioblastoma is the most common primary malignant brain tumor in adults with a median survival of 12-15 months with treatment consisting of surgical resection followed by ionizing radiation (IR and chemotherapy. Even aggressive treatment is often palliative due to near universal recurrence. Therapeutic resistance has been linked to a subpopulation of GBM cells with stem-cell like properties termed glioblastoma initiating cells (GICs. Recent efforts have focused on elucidating resistance mechanisms activated in GICs in response to IR. Among these, GICs preferentially activate the DNA damage response (DDR to result in a faster rate of double-strand break (DSB repair induced by IR as compared to the bulk tumor cells. IR also activates NOTCH and the hepatic growth factor (HGF receptor, c-MET, signaling cascades that play critical roles in promoting proliferation, invasion, and resistance to apoptosis. These pathways are preferentially activated in GICs and represent targets for pharmacologic intervention. While IR provides the benefit of improved survival, it paradoxically promotes selection of more malignant cellular phenotypes of glioblastoma. As reviewed here, finding effective combinations of radiation and molecular inhibitors to target GICs and non-GICs is essential for the development of more effective therapies.

  18. Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition.

    Science.gov (United States)

    Kahlert, Ulf D; Maciaczyk, Donata; Doostkam, Soroush; Orr, Brent A; Simons, Brian; Bogiel, Tomasz; Reithmeier, Thomas; Prinz, Marco; Schubert, Jörg; Niedermann, Gabriele; Brabletz, Thomas; Eberhart, Charles G; Nikkhah, Guido; Maciaczyk, Jaroslaw

    2012-12-01

    Here we show that activation of the canonical WNT/β-catenin pathway increases the expression of stem cell genes and promotes the migratory and invasive capacity of glioblastoma. Modulation of WNT signaling alters the expression of epithelial-to-mesenchymal transition activators, suggesting a role of this process in the regulation of glioma motility. Using immunohistochemistry in patient-derived glioblastoma samples we showed higher numbers of cells with intranuclear signal for β-catenin in the infiltrating edge of tumor compared to central tumor parenchyma. These findings suggest that canonical WNT/β-catenin pathway is a critical regulator of GBM invasion and may represent a potential therapeutic target.

  19. NETRIN-4 Protects Glioblastoma Cells FROM Temozolomide Induced Senescence

    OpenAIRE

    Li Li; Yizhou Hu; Irene Ylivinkka; Huini Li; Ping Chen; Jorma Keski-Oja; Marko Hyytiäinen

    2013-01-01

    Glioblastoma multiforme is the most common primary tumor of the central nervous system. The drug temozolomide (TMZ) prolongs lifespan in many glioblastoma patients. The sensitivity of glioblastoma cells to TMZ is interfered by many factors, such as the expression of O-6-methylguanine-DNA methyltransferase (MGMT) and activation of AKT signaling. We have recently identified the interaction between netrin-4 (NTN4) and integrin beta-4 (ITGB4), which promotes glioblastoma cell proliferation via ac...

  20. Glioblastoma stem cells resistant to temozolomide-induced autophagy

    Institute of Scientific and Technical Information of China (English)

    FU Jun; LIU Zhi-gang; LIU Xiao-mei; CHEN Fu-rong; SHI Hong-liu; PANG Jesse Chung-sean; NG Ho-keung; CHEN Zhong-ping

    2009-01-01

    Background Recent studies have demonstrated the existence of a small fraction of cells with features of primitive neural progenitor cells and tumor-initiating function in brain tumors. These cells might represent primary therapeutic target for complete eradication of the tumors. This study aimed to determine the resistant phenotype of glioblastoma stem cells (GSCs) to temozolomide (TMZ) and to explore the possible molecular mechanisms underlying TMZ resistance.Methods Freshly resected glioblastoma specimen was collected and magnetic isolation of GSCs was carded out using the Miltenyi Biotec CD133 Celt isolation kit. The cytotoxic effect of TMZ on CD133+ and CD133- glioblastoma cells was determined by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Autophagy-related proteins (Beclin-1, LC3 and Atg5) and cleaved caspase-3 (p17) were analyzed by Westem blotting. Immunofluorescent staining was used to detect Atg5, glial fibrillary acidic protein (GFAP) and CD133 expression in glioblastoma cells. Statistical analysis was carried out using SPSS 10.0 software. For all tests, the level of statistical significance was set at P <0.05.Results CD133+ glioblastoma cells exhibited neurosphere-like growth in vitro and high expression of CD133 stem cell marker. The growth-inhibiting rate in CD133- glioblastoma cells treated with 5 or 50 pmol/L TMZ was significantly higher than that in CD133+ glioblastoma cells ((14.36±3.75)% vs (2.54±1.36)% or (25.95±5.25)% vs (2.72±1.84)%, respectively, P <0.05). Atg5, LC3-ll and Beclin-1 levels were significantly lower in CD133+ glioblastoma cells than those in autologous CD133- cells after TMZ treatment (P <0.05). Caspase-3 was mildly activated only in CD133- glioblastoma cells after exposure to TMZ (P <0.05). Immunofluorescent staining revealed elevated expression of Atg5 in GFAP* cells following TMZ treatment.Conclusions The GSCs display strong capability of tumor's resistance to TMZ. This resistance is

  1. The role of factor inhibiting HIF (FIH-1 in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Enfeng Wang

    Full Text Available Glioblastoma multiforme (GBM accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1, which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis.

  2. Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells.

    Science.gov (United States)

    Hira, Vashendriya V V; Verbovšek, Urška; Breznik, Barbara; Srdič, Matic; Novinec, Marko; Kakar, Hala; Wormer, Jill; der Swaan, Britt Van; Lenarčič, Brigita; Juliano, Luiz; Mehta, Shwetal; Van Noorden, Cornelis J F; Lah, Tamara T

    2017-03-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor with poor patient survival that is at least partly caused by malignant and therapy-resistant glioma stem-like cells (GSLCs) that are protected in GSLC niches. Previously, we have shown that the chemo-attractant stromal-derived factor-1α (SDF-1α), its C-X-C receptor type 4 (CXCR4) and the cysteine protease cathepsin K (CatK) are localized in GSLC niches in glioblastoma. Here, we investigated whether SDF-1α is a niche factor that through its interactions with CXCR4 and/or its second receptor CXCR7 on GSLCs facilitates their homing to niches. Furthermore, we aimed to prove that SDF-1α cleavage by CatK inactivates SDF-1α and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1α after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1α at 3 sites in the N-terminus, which is the region of SDF-1α that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1α and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1α had chemotactic activity whereas CatK cleavage products of SDF-1α did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1α. This implies that CatK activity facilitates migration of GSLCs out of niches. We propose that activation of CatK may be a promising strategy to prevent homing of GSLCs in niches and thus render these cells sensitive to chemotherapy and radiation.

  3. Degradable Organically-Derivatized Polyoxometalate with Enhanced Activity against Glioblastoma Cell Line

    Science.gov (United States)

    She, Shan; Bian, Shengtai; Huo, Ruichao; Chen, Kun; Huang, Zehuan; Zhang, Jiangwei; Hao, Jian; Wei, Yongge

    2016-09-01

    High efficacy and low toxicity are critical for cancer treatment. Polyoxometalates (POMs) have been reported as potential candidates for cancer therapy. On accounts of the slow clearance of POMs, leading to long-term toxicity, the clinical application of POMs in cancer treatment is restricted. To address this problem, a degradable organoimido derivative of hexamolybdate is developed by modifying it with a cleavable organic group, leading to its degradation. Of note, this derivative exhibits favourable pharmacodynamics towards human malignant glioma cell (U251), the ability to penetrate across blood brain barrier and low toxicity towards rat pheochromocytoma cell (PC12). This line of research develops an effective POM-based agent for glioblastoma inhibition and will pave a new way to construct degradable anticancer agents for clinical cancer therapy.

  4. In vivo glioblastoma growth is reduced by apyrase activity in a rat glioma model

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    Meurer Luise

    2006-09-01

    Full Text Available Abstract Background ATP is an important signalling molecule in the peripheral and central nervous system. Both glioma growth and tumor resection induces cell death, thus liberating nucleotides to the extracellular medium. Nucleotides are hydrolyzed very slowly by gliomas when compared with astrocytes and induce neuronal cell death and glioma proliferation. The objective of the present study was to test the involvement of extracellular ATP in glioblastoma growth in a rat glioma model. Methods To deplete the extracellular ATP, the enzyme apyrase was tested on the treatment of gliomas implanted in the rats CNS. One million glioma C6 cells in 3 microliters of DMEM/FCS were injected in the right striata of male Wistar rats, 250–270 g. After 20 days, the rats were decapitated and the brain sectioning and stained with hematoxylin and eosine. We performed immunohistochemical experiments with Ki67, CD31 and VEGF. Total RNA was isolated from cultured glioma C6 cells and the cDNA was analyzed by Real Time-PCR with primers for the NTPDase family. Results C6 glioma cells effectively have a low expression of all NTPDases investigated, in comparison with normal astrocytes. The implanted glioma co-injected with apyrase had a significant reduction in the tumor size (p Conclusion These results indicate that the participation of extracellular ATP and the ecto-nucleotidases may be associated with the development of this type of brain tumor in an in vivo glioma model.

  5. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma.

    Science.gov (United States)

    Tardito, Saverio; Oudin, Anaïs; Ahmed, Shafiq U; Fack, Fred; Keunen, Olivier; Zheng, Liang; Miletic, Hrvoje; Sakariassen, Per Øystein; Weinstock, Adam; Wagner, Allon; Lindsay, Susan L; Hock, Andreas K; Barnett, Susan C; Ruppin, Eytan; Mørkve, Svein Harald; Lund-Johansen, Morten; Chalmers, Anthony J; Bjerkvig, Rolf; Niclou, Simone P; Gottlieb, Eyal

    2015-12-01

    L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, (13)C-glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes.

  6. Next-generation repeat-free FISH probes for DNA amplification in glioblastoma in vivo: Improving patient selection to MDM2-targeted inhibitors.

    Science.gov (United States)

    Brunelli, Matteo; Eccher, Albino; Cima, Luca; Trippini, Tobia; Pedron, Serena; Chilosi, Marco; Barbareschi, Mattia; Scarpa, Aldo; Pinna, Giampietro; Cabrini, Giulio; Pilotto, Sara; Carbognin, Luisa; Bria, Emilio; Tortora, Giampaolo; Fioravanzo, Adele; Schiavo, Nicola; Meglio, Mario; Sava, Teodoro; Belli, Laura; Martignoni, Guido; Ghimenton, Claudio

    2017-01-01

    A next-generation FISH probe mapping to the MDM2 locus-specific region has recently been designed. The level of MDM2 gene amplification (high versus low) may allow selection of patients for cancer treatment with MDM2 inhibitors and may predict their responsiveness. We investigated the spectrum of MDM2 gene alterations using the new probes in vivo after visualizing single neoplastic cells in situ from a series of glioblastomas. Signals from next-generation repeat-free FISH interphase probes were identified in tissue microarrays that included 3 spots for each of the 48 cases. The murine double minutes (MDM2)-specific DNA probe and the satellite enumeration probe for chromosome 12 were used. Three cases (6%) showed more than 25 signals (high gene amplification), and 7 (15%) showed 3-10 signals (gains); among these, 4 cases (8%) had an equal number of MDM2 and centromeric signals on chromosome 12 (polyploidy). Genomic heterogeneity was observed only in 3 cases with low gene amplification. In our series, 6% of glioblastomas exhibited high MDM2 amplification (in vivo) with a pattern related to the known double minutes/chromothripsis phenomenon (in situ), and only cases with low amplification showed genomic heterogeneity. We concluded that the rate of MDM2 gene amplification can be a useful predictive biomarker to improve patient selection.

  7. Piperlongumine Inhibits Migration of Glioblastoma Cells via Activation of ROS-Dependent p38 and JNK Signaling Pathways

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    Qian Rong Liu

    2014-01-01

    Full Text Available Piperlongumine (PL is recently found to kill cancer cells selectively and effectively via targeting reactive oxygen species (ROS responses. To further explore the therapeutic effects of PL in cancers, we investigated the role and mechanisms of PL in cancer cell migration. PL effectively inhibited the migration of human glioma (LN229 or U87 MG cells but not normal astrocytes in the scratch-wound culture model. PL did not alter EdU+-cells and cdc2, cdc25c, or cyclin D1 expression in our model. PL increased ROS (measured by DCFH-DA, reduced glutathione, activated p38 and JNK, increased IκBα, and suppressed NFκB in LN229 cells after scratching. All the biological effects of PL in scratched LN229 cells were completely abolished by the antioxidant N-acetyl-L-cysteine (NAC. Pharmacological administration of specific p38 (SB203580 or JNK (SP600125 inhibitors significantly reduced the inhibitory effects of PL on LN229 cell migration and NFκB activity in scratch-wound and/or transwell models. PL prevented the deformation of migrated LN229 cells while NAC, SB203580, or SP600125 reversed PL-induced morphological changes of migrated cells. These results suggest potential therapeutic effects of PL in the treatment and prevention of highly malignant tumors such as glioblastoma multiforme (GBM in the brain by suppressing tumor invasion and metastasis.

  8. Evaluation of the cytotoxic activity of Hypericum spp. on human glioblastoma A1235 and breast cancer MDA MB-231 cells.

    Science.gov (United States)

    Madunić, Josip; Matulić, Maja; Friščić, Maja; Pilepić, Kroata Hazler

    2016-11-01

    Cytotoxic activity of 16 Hypericum ethanolic extracts was evaluated by MTT assay on two human cancer cell lines: glioblastoma A1235 and breast cancer MDA MB-231. Morphology and the type of induced cell death were determined using light and fluorescence microscopy. The majority of Hypericum extracts had no significant cytotoxic effect on MDA MB-231 cells. Eight extracts exhibited mild cytotoxic effect on A1235 cells after 24 h incubation, ranging from 8.0% (H. patulum) to 21.7% (H. oblongifolium). After 72 h of treatment, the strongest inhibition of A1235 viability was observed for extracts of H. androsaemum (26.4-43.9%), H. balearicum (25.8-36.3%), H. delphicum (14.8-27.4%) and H. densiflorum (11.2-24.1%). Micro-scopic examination of cells showed apoptosis as the dominant type of cell death. Due to observed high viability of treated cells, we propose that cytotoxic effects of Hypericum extracts could be related to alternations/interruptions in the cell cycle.

  9. ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis.

    Science.gov (United States)

    Galeano, F; Rossetti, C; Tomaselli, S; Cifaldi, L; Lezzerini, M; Pezzullo, M; Boldrini, R; Massimi, L; Di Rocco, C M; Locatelli, F; Gallo, A

    2013-02-21

    Grade IV astrocytoma or glioblastoma multiforme (GBM) is one of the most aggressive and lethal tumors affecting humans. ADAR2-mediated A-to-I RNA editing, an essential post-transcriptional modification event in brain, is impaired in GBMs and astrocytoma cell lines. However, the role of ADAR2 editing in astrocytomas remains to be defined. Here, we show that ADAR2 editing rescue in astrocytomas prevents tumor growth in vivo and modulates an important cell cycle pathway involving the Skp2/p21/p27 proteins, often altered in glioblastoma. We demonstrate that ADAR2 deaminase activity is essential to inhibit tumor growth. Indeed, we identify the phosphatase CDC14B, which acts upstream of the Skp2/p21/p27 pathway, as a novel and critical ADAR2 target gene involved in glioblastoma growth. Specifically, ADAR2-mediated editing on CDC14B pre-mRNA increases its expression with a consequent reduction of the Skp2 target protein, as shown both in vitro and in vivo. We found that, compared to normal brain, both CDC14B editing and expression are progressively impaired in astrocytomas from grade I to IV, being very low in GBMs. These findings (1) demonstrate that post-transcriptional A-to-I RNA editing might be crucial for glioblastoma pathogenesis, (2) identify ADAR2-editing enzyme as a novel candidate tumor suppressor gene and (3) provide proof of principle that ADAR2 or its substrates may represent a suitable target(s) for possible novel, more effective and less toxic approaches to the treatment of GBMs.

  10. Radiomic Profiling of Glioblastoma: Identifying an Imaging Predictor of Patient Survival with Improved Performance over Established Clinical and Radiologic Risk Models.

    Science.gov (United States)

    Kickingereder, Philipp; Burth, Sina; Wick, Antje; Götz, Michael; Eidel, Oliver; Schlemmer, Heinz-Peter; Maier-Hein, Klaus H; Wick, Wolfgang; Bendszus, Martin; Radbruch, Alexander; Bonekamp, David

    2016-09-01

    Purpose To evaluate whether radiomic feature-based magnetic resonance (MR) imaging signatures allow prediction of survival and stratification of patients with newly diagnosed glioblastoma with improved accuracy compared with that of established clinical and radiologic risk models. Materials and Methods Retrospective evaluation of data was approved by the local ethics committee and informed consent was waived. A total of 119 patients (allocated in a 2:1 ratio to a discovery [n = 79] or validation [n = 40] set) with newly diagnosed glioblastoma were subjected to radiomic feature extraction (12 190 features extracted, including first-order, volume, shape, and texture features) from the multiparametric (contrast material-enhanced T1-weighted and fluid-attenuated inversion-recovery imaging sequences) and multiregional (contrast-enhanced and unenhanced) tumor volumes. Radiomic features of patients in the discovery set were subjected to a supervised principal component (SPC) analysis to predict progression-free survival (PFS) and overall survival (OS) and were validated in the validation set. The performance of a Cox proportional hazards model with the SPC analysis predictor was assessed with C index and integrated Brier scores (IBS, lower scores indicating higher accuracy) and compared with Cox models based on clinical (age and Karnofsky performance score) and radiologic (Gaussian normalized relative cerebral blood volume and apparent diffusion coefficient) parameters. Results SPC analysis allowed stratification based on 11 features of patients in the discovery set into a low- or high-risk group for PFS (hazard ratio [HR], 2.43; P = .002) and OS (HR, 4.33; P radiologic (OS: IBS, 0.175; C index, 0.603; PFS: IBS, 0.149; C index, 0.554) and clinical risk models (OS: IBS, 0.161, C index, 0.640; PFS: IBS, 0.139; C index, 0.599). The performance of the SPC analysis model was further improved when combined with clinical data (OS: IBS, 0.142; C index, 0.696; PFS: IBS, 0.132; C

  11. Immunosuppressive mechanisms in glioblastoma.

    Science.gov (United States)

    Nduom, Edjah K; Weller, Michael; Heimberger, Amy B

    2015-11-01

    Despite maximal surgical and medical therapy, the treatment of glioblastoma remains a seriously vexing problem, with median survival well under 2 years and few long-term survivors. Targeted therapy has yet to produce significant advances in treatment of these lesions in spite of advanced molecular characterization of glioblastoma and glioblastoma cancer stem cells. Recently, immunotherapy has emerged as a promising mode for some of the hardest to treat tumors, including metastatic melanoma. Although immunotherapy has been evaluated in glioblastoma in the past with limited success, better understanding of the failures of these therapies could lead to more successful treatments in the future. Furthermore, there is a persistent challenge for the use of immune therapy to treat glioblastoma secondary to the existence of redundant mechanisms of tumor-mediated immune suppression. Here we will address these mechanisms of immunosuppression in glioblastoma and therapeutic approaches.

  12. Antitumor activity of F90,an epidermal growth factor receptor tyrosine kinase inhibitor,on glioblastoma cell line SHG-44

    Institute of Scientific and Technical Information of China (English)

    LIU Fang-jun; GUI Song-bai; LI Chu-zhong; SUN Ze-lin; ZHANG Ya-zhuo

    2008-01-01

    Background Over-expression of epidermal growth factor receptor (EGFR) is thought to be related to cell proliferation,invasion,metastasis,resistance to chemoradiotherapy and poor prognosis of various human cancers.Forty percent to fifty percent of glioblastoma multiforme (GBM) possess deregulated EGFR,which may contribute to the aggressive and refractory course of GBM.Therefore,blockade of EGFR signal transduction may be a promising treatment strategy for GBM.Methods MIT assay,cell growth curve assay and tumor xenograft model were used to evaluate the antitumor activity of F90 against SHG-44 in vitro and in vivo.Western blot assay was applied to evaluate the expression of p-EGFR,p-ERK1,p-JNK,p-P38,Bcl2 and P53 proteins.Results F90 inhibited the cell proliferation in a dose-dependent manner in vitro.The growth of SHG-44 tumor xenografts was suppressed by F90 at a high dose level (100 mg.kg-1.d-1).Phosphorylation of EGFR and activated downstream signaling proteins,such as ERK1,JNK and P38,were found to be depressed after incubation with F90 for 48 hours in vitro.Down-regulated Bcl2 protein and up-regulated P53 protein were also observed.Conclueions The results demonstrate that F90 is effective in inhibiting the proliferation of SHG-44 cells in vitro and tumor growth in vivo,suggesting that F90 may be a new therapeutic option for treatment of GBM.

  13. Porfimer-sodium (Photofrin-II) in combination with ionizing radiation inhibits tumor-initiating cell proliferation and improves glioblastoma treatment efficacy.

    Science.gov (United States)

    Benayoun, Liat; Schaffer, Moshe; Bril, Rotem; Gingis-Velitski, Svetlana; Segal, Ehud; Nevelsky, Alexsander; Satchi-Fainaro, Ronit; Shaked, Yuval

    2013-01-01

    Tumor relapse and tumor cell repopulation has been explained partially by the drug-free break period between successive conventional treatments. Strategies to overcome tumor relapse have been proposed, such as the use of chemotherapeutic drugs or radiation in small, frequent fractionated doses without an extended break period between treatment intervals. Yet, tumors usually acquire resistance and eventually escape the therapy. Several mechanisms have been proposed to explain the resistance of tumors to therapy, one of which involves the cancer stem cell or tumor-initiating cell (TIC) concept. TICs are believed to resist many conventional therapies, in part due to their slow proliferation and self-renewal capacities. Therefore, emerging efforts to eradicate TICs are being undertaken. Here we show that treatment with Photofrin II, among the most frequently used photosensitizers, sensitized a TIC-enriched U-87MG human glioblastoma cell to radiation, and improve treatment outcome when used in combination with radiotherapy. A U-87MG tumor cell population enriched with radiation-resistant TICs becomes radio-sensitive, and an inhibition of cell proliferation and an increase in apoptosis are found in the presence of Photofrin II. Furthermore, U-87MG tumors implanted in mice treated with Photofrin II and radiation exhibit a significant reduction in angiogenesis and vasculogenesis, and an increased percentage of apoptotic TICs when compared with tumors grown in mice treated with radiation alone. Collectively, our results offer a new possible explanation for the therapeutic effects of radiosensitizing agents, and suggest that combinatorial treatment modalities can effectively prolong treatment outcome of glioblastoma tumors by inhibiting tumor growth mediated by TICs.

  14. Lentivirus-Mediated Nox4 shRNA Invasion and Angiogenesis and Enhances Radiosensitivity in Human Glioblastoma

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    Yongsheng Li

    2014-01-01

    Full Text Available Radioresistance remains a significant therapeutic obstacle in glioblastoma. Reactive oxygen species (ROS are associated with multiple cellular functions such as cell proliferation and apoptosis. Nox4 NADPH oxidase is abundantly expressed and has proven to be a major source of ROS production in glioblastoma. Here we investigated the effects of Nox4 on GBM tumor cell invasion, angiogenesis, and radiosensitivity. A lentiviral shRNA vector was utilized to stably knockdown Nox4 in U87MG and U251 glioblastoma cells. ROS production was measured by flow cytometry using the fluorescent probe DCFH-DA. Radiosensitivity was evaluated by clonogenic assay and survival curve was generated. Cell proliferation activity was assessed by a cell counting proliferation assay and invasion/migration potential by Matrigel invasion assay. Tube-like structure formation assay was used to evaluate angiogenesis ability in vitro and VEGF expression was assessed by MTT assay. Nox4 knockdown reduced ROS production significantly and suppressed glioblastoma cells proliferation and invasion and tumor associated angiogenesis and increased their radiosensitivity in vitro. Our results indicate that Nox4 may play a crucial role in tumor invasion, angiogenesis, and radioresistance in glioblastoma. Inhibition of Nox4 by lentivirus-mediated shRNA could be a strategy to overcome radioresistance and then improve its therapeutic efficacy for glioblastoma.

  15. Unique anti-glioblastoma activities of hypericin are at the crossroad of biochemical and epigenetic events and culminate in tumor cell differentiation.

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    Naama Dror

    Full Text Available Failure of conventional therapies to alleviate glioblastoma (GBM fosters search for novel therapeutic strategies. These include epigenetic modulators as histone deacetylase inhibitors (HDACi, which relax abnormally compact tumor cell chromatin organization, enabling cells to overcome blockage in differentiation. However, in clinical settings, HDACi efficacy is confined to subsets of hematologic malignancies. We reasoned that molecules targeting multiple epigenetic mechanisms may exhibit superior anti-cancer activities. We focused on the redox perylene-quinone Hypericin (HYP and showed that HYP targets Hsp90 for polyubiquitination, degradation and inactivation. Hsp90 is implicated in mediating inheritable epigenetic modifications transferable to progeny. We therefore examined if HYP can induce epigenetic alterations in GBM cells and show here that HYP indeed, targets multiple mechanisms in human glioblastoma tumor cell lines via unique manners. These elicit major epigenetic signature changes in key developmentally regulated genes. HYP induces neuroglial tumor cell differentiation modulating the cytoarchitecture, neuroglial differentiation antigen expression and causes exit from cell proliferation cycles. Such activities characterize HDACi however HYP is not an HDAC inhibitor. Instead, HYP effectively down-regulates expression of Class-I HDACs, creating marked deficiencies in HDACs cellular contents, leading to histones H3 and H4 hyperacetylation. Expression of EZH2, the Polycomb repressor complex-2 catalytic subunit, which trimethylates histone H3K27 is also suppressed. The resulting histone hyperacetylation and diminished H3K27-trimethylation relax chromatin structure, activating gene transcription including differentiation-promoting genes. DNMT profiles are also modulated increasing global DNA methylation. HYP induces unique epigenetic down-regulations of HDACs, EZH2 and DNMTs, remodeling chromatin structure and culminating in tumor cell

  16. Ruta graveolens L. induces death of glioblastoma cells and neural progenitors, but not of neurons, via ERK 1/2 and AKT activation.

    Science.gov (United States)

    Gentile, Maria Teresa; Ciniglia, Claudia; Reccia, Mafalda G; Volpicelli, Floriana; Gatti, Monica; Thellung, Stefano; Florio, Tullio; Melone, Mariarosa A B; Colucci-D'Amato, Luca

    2015-01-01

    Glioblastoma multiforme is a highly aggressive brain tumor whose prognosis is very poor. Due to early invasion of brain parenchyma, its complete surgical removal is nearly impossible, and even after aggressive combined treatment (association of surgery and chemo- and radio-therapy) five-year survival is only about 10%. Natural products are sources of novel compounds endowed with therapeutic properties in many human diseases, including cancer. Here, we report that the water extract of Ruta graveolens L., commonly known as rue, induces death in different glioblastoma cell lines (U87MG, C6 and U138) widely used to test novel drugs in preclinical studies. Ruta graveolens' effect was mediated by ERK1/2 and AKT activation, and the inhibition of these pathways, via PD98058 and wortmannin, reverted its antiproliferative activity. Rue extract also affects survival of neural precursor cells (A1) obtained from embryonic mouse CNS. As in the case of glioma cells, rue stimulates the activation of ERK1/2 and AKT in A1 cells, whereas their blockade by pharmacological inhibitors prevents cell death. Interestingly, upon induction of differentiation and cell cycle exit, A1 cells become resistant to rue's noxious effects but not to those of temozolomide and cisplatin, two alkylating agents widely used in glioblastoma therapy. Finally, rutin, a major component of the Ruta graveolens water extract, failed to cause cell death, suggesting that rutin by itself is not responsible for the observed effects. In conclusion, we report that rue extracts induce glioma cell death, discriminating between proliferating/undifferentiated and non-proliferating/differentiated neurons. Thus, it can be a promising tool to isolate novel drugs and also to discover targets for therapeutic intervention.

  17. A radioisotope-nondependent high-sensitivity method for measuring the activity of glioblastoma-related O(6)-methylguanine DNA methyltransferase.

    Science.gov (United States)

    Hongo, Aya; Gu, Ran; Suzuki, Miho; Nemoto, Naoto; Nishigaki, Koichi

    2015-07-01

    O(6)-Methylguanine DNA methyltransferase (MGMT) cancels the anticancer effect of temozolomide (drug for glioblastoma), which introduces methylation to DNA. Therefore, developing an MGMT inhibitor is a promising strategy for the treatment of this cancer. For this purpose, a sensitive detection method that does not depend on the conventional radioisotope (RI) method was developed. This was realized by a fluorescence-based method that measured the amount of cleavable restriction sites demethylated by the action of MGMT; this method was enhanced by introducing a polymerase chain reaction (PCR) amplification step. As an assay of enzyme activity, 20-fold higher sensitivity (subnanomolar) was attained compared with our and others' fluorescence-based approaches.

  18. Mechanism of Anti-glioblastoma Effect of Temzolomide Involved in ROS-Mediated SIRT 1 Pathway

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    Yuan Jiang

    2014-03-01

    Full Text Available Objective: To explore the new molecular mechanism of anti-tumor effect of temzolomide (TMZon glioblastoma cell strain. Methods: MTT methods and Hoechst 33342 staining method were applied to determine the effect of TMZ on the proliferation and apoptosis of glioblastoma cell strains U251 and SHG44, while flow cytometry was used to detect the impact of TMZ on cellular cycles. Additionally, DCFH-DA probe was adopted to test intracellular reactive oxygen species (ROS level while Real-time PCR and Western blot tests were applied to determine the influence of TMZ on SIRT1 expression. Results: TMZ in different concentrations added into glioblastoma cell strain for 72 h could concentration-dependently inhibit the proliferation of glioblastoma cells, 100 μmol/L of which could also block cells in phase G2/M and improve cellular apoptosis. In addition, TMZ could evidently increase intracellular ROS level so as to activate SIRT1. Conclusion: The mechanism of anti-tumor effect of TMZ on glioblastoma may be associated with ROS-induced SIRT1 pathway, providing theoretical basis for the clinical efficacy of TMZ.

  19. Mechanism of Anti-glioblastoma Effect of Temzolomide Involved in ROS-Mediated SIRT 1 Pathway

    Institute of Scientific and Technical Information of China (English)

    Jiang Yuan; Sun Yan; Yuan Yuan

    2014-01-01

    Objective:To explore the new molecular mechanism of anti-tumor effect of temzolomide (TMZ) on glioblastoma cell strain. Methods:MTT methods and Hoechst 33342 staining method were applied to determine the effect of TMZ on the proliferation and apoptosis of glioblastoma cell strains U251 and SHG44, while lfow cytometry was used to detect the impact of TMZ on cellular cycles. Additionally, DCFH-DA probe was adopted to test intracellular reactive oxygen species (ROS) level while Real-time PCR and Western blot tests were applied to determine the inlfuence of TMZ on SIRT1 expression. Results: TMZ in different concentrations added into glioblastoma cell strain for 72 h could concentration-dependently inhibit the proliferation of glioblastoma cells, 100 μmol/L of which could also block cells in phase G2/M and improve cellular apoptosis. In addition, TMZ could evidently increase intracellular ROS level so as to activate SIRT1. Conclusion: The mechanism of anti-tumor effect of TMZ on glioblastoma may be associated with ROS-induced SIRT1 pathway, providing theoretical basis for the clinical efifcacy of TMZ.

  20. Small ubiquitin-like modifier 1-3 conjugation [corrected] is activated in human astrocytic brain tumors and is required for glioblastoma cell survival.

    Science.gov (United States)

    Yang, Wei; Wang, Liangli; Roehn, Gabriele; Pearlstein, Robert D; Ali-Osman, Francis; Pan, Hongjie; Goldbrunner, Roland; Krantz, Matthew; Harms, Christoph; Paschen, Wulf

    2013-01-01

    Small ubiquitin-like modifier (SUMO1-3) constitutes a group of proteins that conjugate to lysine residues of target proteins thereby modifying their activity, stability, and subcellular localization. A large number of SUMO target proteins are transcription factors and other nuclear proteins involved in gene expression. Furthermore, SUMO conjugation plays key roles in genome stability, quality control of newly synthesized proteins, proteasomal degradation of proteins, and DNA damage repair. Any marked increase in levels of SUMO-conjugated proteins is therefore expected to have a major impact on the fate of cells. We show here that SUMO conjugation is activated in human astrocytic brain tumors. Levels of both SUMO1- and SUMO2/3-conjugated proteins were markedly increased in tumor samples. The effect was least pronounced in low-grade astrocytoma (WHO Grade II) and most pronounced in glioblastoma multiforme (WHO Grade IV). We also found a marked rise in levels of Ubc9, the only SUMO conjugation enzyme identified so far. Blocking SUMO1-3 conjugation in glioblastoma cells by silencing their expression blocked DNA synthesis, cell growth, and clonogenic survival of cells. It also resulted in DNA-dependent protein kinase-induced phosphorylation of H2AX, indicative of DNA double-strand damage, and G(2) /M cell cycle arrest. Collectively, these findings highlight the pivotal role of SUMO conjugation in DNA damage repair processes and imply that the SUMO conjugation pathway could be a new target of therapeutic intervention aimed at increasing the sensitivity of glioblastomas to radiotherapy and chemotherapy.

  1. Long-Term Survival and Improved Quality of Life following Multiple Repeat Gamma Knife Radiosurgeries for Recurrent Glioblastoma Multiforme: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Erik W. Larson

    2013-01-01

    Full Text Available The management of glioblastoma multiforme (GBM is in most cases complex and must be specifically tailored to the needs of the patient with the goals of extended survival and improved quality of life. Despite advancements in therapy, treatment outcomes remain almost universally poor. Salvage treatment options for the recurrence of the disease is an area of intense study. The following case highlights the utility of Gamma Knife Radiosurgery (GKRS as a salvage treatment. In this clinical situation, three sequential GKRS treatments led to prolonged survival (beyond four years after diagnosis and improved quality of life in a patient who was unable to receive further chemotherapy regimens and was unwilling to undergo further aggressive resection. To date, there have been few reports of three or more sequential GKRS treatment sessions utilized as salvage therapy for recurrent GBM in patients who can no longer tolerate chemotherapy. This report provides evidence that aggressive local treatment with GKRS at the time of recurrence may be appropriate, depending on a patient’s individual clinical situation, and can lead to prolonged survival and improved quality of life.

  2. Antineoplastic activity of taurolidine and its derivatives on human ex vivo glioblastoma bulk cells and cancer stem cells

    OpenAIRE

    Kälin, M B

    2010-01-01

    Despite multimodal therapy, patients suffering from glioblastoma (GBM) still have a dismal prognosis. The identification of cancer stem cells (CSC) in brain tumour tissue, yielded hope that the vulnerable target to combat GBM has been found. Several study groups worldwide concentrate nowadays on therapeutic strategies that effectively target CSC. Since in our laboratory has been revealed that taurolidine, a derivate of the amino acid taurin, displays a potent antineoplastic effect in human gl...

  3. PM-07LOSS OF ATRX DECREASES SURVIVAL AND IMPROVES RESPONSE TO DNA DAMAGING AGENTS IN A NOVEL MOUSE MODEL OF GLIOBLASTOMA

    OpenAIRE

    Koschmann, Carl; Calinescu, Alexandra; Thomas, Daniel; Kamran, Neha; Nunez-Aguilera, Felipe; Dzaman, Marta; Lemons, Rosie; Li, Youping; Roh, Haeji; Lowenstein, Pedro; Castro, Maria

    2014-01-01

    Pediatric glioblastoma (GBM) remains one of the most difficult childhood tumors to treat. ATRX is a histone chaperone protein that is mutated primarily in younger patients with GBM. No previous animal model has demonstrated the effect of ATRX loss on GBM formation. We cloned an ATRX knockdown sequence into a Sleeping Beauty (SB) transposase-responsive plasmid (shATRX) for insertion into host genomic DNA. Glioblastomas were induced in mice by injecting plasmids encoding SB transposase/ lucifer...

  4. Multiple extraneural metastasis of glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    J. Undabeitia

    2015-04-01

    Full Text Available Introduction. Glioblastoma multiforme is the most frequent primary tumor in the brain. Despite improvements in its surgical, chemotherapy and radiotherapy treatment, prognosis remains poor. Extracranial metastases of glioblastoma are a rare complication in this disease. Its appearance has been described in lung, liver, bone or lymph nodes. Case report. We describe the case of a 20 year-old patient who complained of a subacute-onset headache. In the MRI an enhancing right temporal lesion was detected suggesting a high grade glioma as first diagnosis. Surgery was performed, obtaining a gross total resection of the lesion. Our patient underwent adjuvant radiotherapy and chemotherapy treatment, according to our hospital´s protocol. Five months after initial surgery our patient complained of chest pain and a hacking cough. A thoracic-abdominal-pelvic CT scan was obtained, which showed bilateral lung infiltrates with pleural effusion, a pancreatic nodule and several vertebral lytic lesions. The lung lesions were biopsied. The pathologic diagnosis was metastatic glioblastoma multiforme. The patient died eight months after initial diagnosis. Conclusion. Extracranial metastases of glioblastoma remain a rare event although its incidence is increasing, probably due to the improvement in survival among these patients and better imaging techniques. The mechanisms for extracranial dissemination of glioblastoma are not entirely known, as several theories exist in this regard. Physicians must be aware of this complication and keep it in mind as a differential diagnosis to improve the quality of life of our patients.

  5. Synthesis of tetrahydrohonokiol derivates and their evaluation for cytotoxic activity against CCRF-CEM leukemia, U251 glioblastoma and HCT-116 colon cancer cells.

    Science.gov (United States)

    Bernaskova, Marketa; Kretschmer, Nadine; Schuehly, Wolfgang; Huefner, Antje; Weis, Robert; Bauer, Rudolf

    2014-01-20

    Biphenyl neolignans such as honokiol and magnolol, which are the major active constituents of the Asian medicinal plant Magnolia officinalis, are known to exert a multitude of pharmacological and biological activities. Among these, cytotoxic and tumor growth inhibitory activity against various tumour cell lines are well-documented. To further elucidate the cytotoxic effects of honokiol derivatives, derivatizations were performed using tetrahydrohonokiol as a scaffold. The derivatizations comprised the introduction of functional groups, e.g., nitro and amino groups, as well as alkylation. This way, 18 derivatives, of which 13 were previously undescribed compounds, were evaluated against CCRF-CEM leukemia cells, U251 glioblastoma and HCT-116 colon cancer cells. The results revealed no significant cytotoxic effects in any of the three tested cell lines at a test concentration of 10 µM.

  6. Synthesis of Tetrahydrohonokiol Derivates and Their Evaluation for Cytotoxic Activity against CCRF-CEM Leukemia, U251 Glioblastoma and HCT-116 Colon Cancer Cells

    Directory of Open Access Journals (Sweden)

    Marketa Bernaskova

    2014-01-01

    Full Text Available Biphenyl neolignans such as honokiol and magnolol, which are the major active constituents of the Asian medicinal plant Magnolia officinalis, are known to exert a multitude of pharmacological and biological activities. Among these, cytotoxic and tumor growth inhibitory activity against various tumour cell lines are well-documented. To further elucidate the cytotoxic effects of honokiol derivatives, derivatizations were performed using tetrahydrohonokiol as a scaffold. The derivatizations comprised the introduction of functional groups, e.g., nitro and amino groups, as well as alkylation. This way, 18 derivatives, of which 13 were previously undescribed compounds, were evaluated against CCRF-CEM leukemia cells, U251 glioblastoma and HCT-116 colon cancer cells. The results revealed no significant cytotoxic effects in any of the three tested cell lines at a test concentration of 10 µM.

  7. Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma?

    Science.gov (United States)

    Clarke, Jennifer L; Ennis, Michele M; Yung, W K Alfred; Chang, Susan M; Wen, Patrick Y; Cloughesy, Timothy F; Deangelis, Lisa M; Robins, H Ian; Lieberman, Frank S; Fine, Howard A; Abrey, Lauren; Gilbert, Mark R; Mehta, Minesh; Kuhn, John G; Aldape, Kenneth D; Lamborn, Kathleen R; Prados, Michael D

    2011-10-01

    Historically, the North American Brain Tumor Consortium used 6-month progression-free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes. Two data sets were analyzed. The first included 511 patients enrolled during the period 1998-2005, 105 of whom had surgery (excluding biopsies) during the study or ≤ 30 days prior to registration. Analysis was stratified on the basis of whether temozolomide was part of the protocol treatment regimen. The second data set included 247 patients enrolled during 2005-2008, 103 of whom underwent surgery during the clinical trial or immediately prior to study registration. A combined data set consisting of all patients who did not receive temozolomide was also compiled. No statistically significant difference in PFS6 or OS was found between the surgery and nonsurgery groups in either data set alone or in the combined data set (P > .45). We conclude that PFS6 and OS results for patients with and without surgical intervention at the time of progression are similar, allowing data from these patients to be combined in assessing the benefit of new treatments without the need for stratification or other statistical adjustment.

  8. Emerging Biomarkers in Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    McNamara, Mairéad G.; Sahebjam, Solmaz; Mason, Warren P., E-mail: warren.mason@uhn.ca [Pencer Brain Tumor Centre, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9 (Canada)

    2013-08-22

    Glioblastoma, the most common primary brain tumor, has few available therapies providing significant improvement in survival. Molecular signatures associated with tumor aggressiveness as well as with disease progression and their relation to differences in signaling pathways implicated in gliomagenesis have recently been described. A number of biomarkers which have potential in diagnosis, prognosis and prediction of response to therapy have been identified and along with imaging modalities could contribute to the clinical management of GBM. Molecular biomarkers including O(6)-methlyguanine-DNA-methyltransferase (MGMT) promoter and deoxyribonucleic acid (DNA) methylation, loss of heterozygosity (LOH) of chromosomes 1p and 19q, loss of heterozygosity 10q, isocitrate dehydrogenase (IDH) mutations, epidermal growth factor receptor (EGFR), epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, phosphatase and tensin homolog (PTEN), p16INK4a gene, cytochrome c oxidase (CcO), phospholipid metabolites, telomerase messenger expression (hTERT messenger ribonucleic acid [mRNA]), microRNAs (miRNAs), cancer stem cell markers and imaging modalities as potential biomarkers are discussed. Inclusion of emerging biomarkers in prospective clinical trials is warranted in an effort for more effective personalized therapy in the future.

  9. Both mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 and phosphatidylinositide-3-OH kinase (PI3K)/Akt pathways regulate activation of E-twenty-six (ETS)-like transcription factor 1 (Elk-1) in U138 glioblastoma cells.

    Science.gov (United States)

    Mut, Melike; Lule, Sevda; Demir, Ozlem; Kurnaz, Isil Aksan; Vural, Imran

    2012-02-01

    Epidermal growth factor (EGF) and its receptor (EGFR) have been shown to play a significant role in the pathogenesis of glioblastoma. In our study, the EGFR was stimulated with EGF in human U138 glioblastoma cells. We show that the activated mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 pathway phosphorylated the E twenty-six (ETS)-like transcription factor 1 (Elk-1) mainly at serine 383 residue. Mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, UO126 and ERK inhibitor II, FR180204 blocked the Elk-1 phosphorylation and activation. The phosphatidylinositide-3-OH kinase (PI3K)/Akt pathway was also involved in the Elk-1 activation. Activation of the Elk-1 led to an increased survival and a proliferative response with the EGF stimulation in the U138 glioblastoma cells. Knocking-down the Elk-1 using an RNA interference technique caused a decrease in survival of the unstimulated U138 glioblastoma cells and also decreased the proliferative response to the EGF stimulation. The Elk-1 transcription factor was important for the survival and proliferation of U138 glioblastoma cells upon the stimulation of EGFR with EGF. The MAPK/ERK1/2 and PI3K/Akt pathways regulated this response via activation of the Elk-1 transcription factor. The Elk-1 may be one of the convergence points for pathways located downstream of EGFR in glioblastoma cells. Utilization of the Elk-1 as a therapeutic target may lead to a novel strategy in treatment of glioblastoma.

  10. Coordination of glioblastoma cell motility by PKCι

    Directory of Open Access Journals (Sweden)

    Baldwin R Mitchell

    2010-09-01

    Full Text Available Abstract Background Glioblastoma is one of the deadliest forms of cancer, in part because of its highly invasive nature. The tumor suppressor PTEN is frequently mutated in glioblastoma and is known to contribute to the invasive phenotype. However the downstream events that promote invasion are not fully understood. PTEN loss leads to activation of the atypical protein kinase C, PKCι. We have previously shown that PKCι is required for glioblastoma cell invasion, primarily by enhancing cell motility. Here we have used time-lapse videomicroscopy to more precisely define the role of PKCι in glioblastoma. Results Glioblastoma cells in which PKCι was either depleted by shRNA or inhibited pharmacologically were unable to coordinate the formation of a single leading edge lamellipod. Instead, some cells generated multiple small, short-lived protrusions while others generated a diffuse leading edge that formed around the entire circumference of the cell. Confocal microscopy showed that this behavior was associated with altered behavior of the cytoskeletal protein Lgl, which is known to be inactivated by PKCι phosphorylation. Lgl in control cells localized to the lamellipod leading edge and did not associate with its binding partner non-muscle myosin II, consistent with it being in an inactive state. In PKCι-depleted cells, Lgl was concentrated at multiple sites at the periphery of the cell and remained in association with non-muscle myosin II. Videomicroscopy also identified a novel role for PKCι in the cell cycle. Cells in which PKCι was either depleted by shRNA or inhibited pharmacologically entered mitosis normally, but showed marked delays in completing mitosis. Conclusions PKCι promotes glioblastoma motility by coordinating the formation of a single leading edge lamellipod and has a role in remodeling the cytoskeleton at the lamellipod leading edge, promoting the dissociation of Lgl from non-muscle myosin II. In addition PKCι is required

  11. DNA Damage-Induced NF-κB Activation in Human Glioblastoma Cells Promotes miR-181b Expression and Cell Proliferation

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    Rui-Xue Xu

    2015-01-01

    Full Text Available Background: Glioblastoma (GBM is the most common and most aggressive form of brain cancer. After surgery, radiotherapy is the mainstay of treatment for GBM patients. Unfortunately, the vast majority of GBM patients fail responding to radiotherapy because GBM cells remain highly resistant to radiation. Radiotherapy-induced DNA damage response may correlate with therapeutic resistance. Methods: Ionizing radiation (IR was used to induce DNA damage. Cell proliferation and migration were detected by wound-healing, MTT and apoptosis assays. Dual-luciferase assays and Western blot analysis were performed to evaluate NF-κB activation and validate microRNA targets. Real-time PCR was used to study mRNA and microRNA levels. Results: IR-induced DNA damage activated NF-κB in GBM cells which promoted expression of IL-6, IL-8 and Bcl-xL, thereby contributing to cell survival and invasion. Knockdown SENP2 expression enhanced NF-κB essential modulator (NEMO SUMOylation and NF-κB activity following IR exposure. miR-181b targets SENP2 and positively regulated NF-κB activity. Conclusion: NF-κB activation by DNA damage in GBM cells confers resistance to radiation-induced death.

  12. Irinotecan and Bevacizumab in Glioblastoma-A Review

    Directory of Open Access Journals (Sweden)

    1M. T. Shahid

    2014-03-01

    Full Text Available Glioblastoma is a common brain tumor having comparatively poor prognosis. Bevacizumab and irinotecan are found to be effective in the treatment of recurrent glioblastoma. The present review covers investigations made on the mentioned drugs in the past decade. As compared to other chemotherapeutic agents, the drugs have shown greater activity and overall survival when used as monotherapeutic agents or in combination with other drugs. Still some work needs to be done in establishing clear role of both the drugs in newly diagnosed glioblastoma, especially, role of irinotecan needs clarity.

  13. Improved Active Vibration Isolation Systems

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The control force, feedback gain, and actuator stroke of several active vibration isolation systems were analyzed based on a single-layer active vibration isolation system. The analysis shows that the feedback gain and actuator stroke cannot be selected independently and the active isolation system design must make a compromise between the feedback gain and actuator stroke. The performance of active isolation systems can be improved by the joint vibration reduction using an active vibration isolation system with an adaptive dynamic vibration absorber. The results show that the joint vibration reduction method can successfully avoid the compromise between the feedback gain and actuator stroke. The control force and the object vibration amplitude are also greatly reduced.

  14. Transcriptional Regulatory Networks Activated by PI3K and ERK Transduced Growth Signals in Human Glioblastoma Cells

    Institute of Scientific and Technical Information of China (English)

    Peter M. Haverty; Zhi-Ping Weng; Ulla Hansen

    2005-01-01

    Determining how cells regulate their transcriptional response to extracellular signals is key to the understanding of complex eukaryotic systems. This study was initiated with the goals of furthering the study of mammalian transcriptional regulation and analyzing the relative benefits of related computational methodologies. One dataset available for such an analysis involved gene expression profiling of the early growth factor response to platelet derived growth factor (PDGF)in a human glioblastoma cell line; this study differentiated genes whose expression was regulated by signaling through the phosphoinositide-3-kinase (PI3K) versus the extracellular-signal regulated kinase (ERK) pathways. We have compared the inferred transcription factors from this previous study with additional predictions of regulatory transcription factors using two alternative promoter sequence analysis techniques. This comparative analysis, in which the algorithms predict overlapping,although not identical, sets of factors, argues for meticulous benchmarking of promoter sequence analysis methods to determine the positive and negative attributes that contribute to their varying results. Finally, we inferred transcriptional regulatory networks deriving from various signaling pathways using the CARRIE program suite. These networks not only included previously described transcriptional features of the response to growth signals, but also predicted new regulatory features for the propagation and modulation of the growth signal.

  15. Radiation induced glioblastoma. A case report

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Naoki; Kayama, Takamasa; Sakurada, Kaori; Saino, Makoto; Kuroki, Akira [Yamagata Univ. (Japan). School of Medicine

    2000-05-01

    We report a surgical case of a 54-year-old woman with a radiation induced glioblastoma. At the age of 34, the patient was diagnosed to have a non-functioning pituitary adenoma. It was partially removed followed by 50 Gy focal irradiation with a 5 x 5 cm lateral opposed field. Twenty years later, she suffered from rapidly increasing symptoms such as aphasia and right hemiparesis. MRI showed a large mass lesion in the left temporal lobe as well as small mass lesions in the brain stem and the right medial temporal lobe. These lesions situated within the irradiated field. Magnetic resonance spectroscopy revealed relatively high lactate signal and decreased N-acetyl aspartate, choline, creatine and phosphocreatine signals. Increased lactate signal meant anaerobic metabolism that suggested the existence of a rapidly growing malignant tumor. Thus, we planned surgical removal of the left temporal lesion with the diagnosis of a radiation induced malignant glioma. The histological examination revealed a glioblastoma with radiation necrosis. MIB-1 staining index was 65%. Postoperatively, her symptoms improved, but she died from pneumonia 1 month after the surgery. A autopsy was obtained. The lesion of the left temporal lobe was found to have continuity to the lesion in the midbrain, the pons and the right temporal lobe as well. High MIB-1 staining index suggested that a radiation induced glioblastoma had high proliferative potential comparing with a de novo and secondary glioblastoma. (author)

  16. Impact of Human Immunodeficiency Virus in the Pathogenesis and Outcome of Patients with Glioblastoma Multiforme

    OpenAIRE

    Choy, Winward; Lagman, Carlito; Lee, Seung J.; Bui, Timothy T; Safaee, Michael; Yang, Isaac

    2016-01-01

    Background Improvement in antiviral therapies have been accompanied by an increased frequency of non-Acquired Immune Deficiency Syndrome (AIDS) defining malignancies, such as glioblastoma multiforme. Here, we investigated all reported cases of human immunodeficiency virus (HIV)-positive patients with glioblastoma and evaluated their clinical outcomes. A comprehensive review of the molecular pathogenetic mechanisms underlying glioblastoma development in the setting of HIV/AIDS is provided. Met...

  17. MicroRNA as potential biomarkers in Glioblastoma.

    Science.gov (United States)

    Areeb, Zammam; Stylli, Stanley S; Koldej, Rachel; Ritchie, David S; Siegal, Tali; Morokoff, Andrew P; Kaye, Andrew H; Luwor, Rodney B

    2015-11-01

    Glioblastoma is the most aggressive and lethal tumour of the central nervous system and as such the identification of reliable prognostic and predictive biomarkers for patient survival and tumour recurrence is paramount. MicroRNA detection has rapidly emerged as potential biomarkers, in patients with glioblastoma. Over the last decade, analysis of miRNA in laboratory based studies have yielded several candidates as potential biomarkers however, the accepted use of these candidates in the clinic is yet to be validated. Here we will examine the use of miRNA signatures to improve glioblastoma stratification into subgroups and summarise recent advances made in miRNA examination as potential biomarkers for glioblastoma progression and recurrence.

  18. BC3EE2,9B, a synthetic carbazole derivative, upregulates autophagy and synergistically sensitizes human GBM8901 glioblastoma cells to temozolomide.

    Science.gov (United States)

    Chen, Chien-Min; Syu, Jhih-Pu; Way, Tzong-Der; Huang, Li-Jiau; Kuo, Sheng-Chu; Lin, Chung-Tien; Lin, Chih-Li

    2015-11-01

    Glioblastoma multiforme (GBM) is the most fatal form of human brain cancer. Although temozolomide (TMZ), an oral alkylating chemotherapeutic agent, improves the survival rate, the prognosis of patients with GBM remains poor. Naturally occurring carbazole alkaloids isolated from curry leaves (Murraya koenigii Spreng.) have been shown to possess a wide range of anticancer properties. However, the effects of carbazole derivatives on glioblastoma cells remain poorly understood. In the present study, anti‑glioblastoma profiles of a series of synthetic carbazole derivatives were evaluated in vitro. The most promising derivative in this series was BC3EE2,9B, which showed significant anti‑proliferative effects in GBM8401 and GBM8901 cells. BC3EE2,9B also triggered cell‑cycle arrest, most prominently at the G1 stage, and suppressed glioblastoma cell invasion and migration. Furthermore, BC3EE2,9B induced autophagy‑mediated cell death and synergistically sensitized GBM cells to TMZ cytotoxicity. The possible mechanism underlying BC3EE2,9B‑induced autophagy may involve activation of adenosine monophosphate-activated protein kinase and the attenuation of the Akt and mammalian target of the rapamycin downstream signaling pathway. Taken together, the present results provide molecular evidence for the mode of action governing the ability of BC3EE2,9B to sensitize drug‑resistant glioblastoma cells to the chemotherapeutic agent TMZ.

  19. AXL as a modulator of sunitinib response in glioblastoma cell lines

    OpenAIRE

    Martinho, Olga Catarina Lopes; Zucca, Luís Eduardo; Reis,R.M.

    2015-01-01

    Receptor tyrosine kinase (RTK) targeted therapy has been explored for glioblastoma treatment. However, it is unclear which RTK inhibitors are the most effective and there are no predictive biomarkers available. We recently identified the RTK AXL as a putative target for the pan-RTK inhibitors cediranib and sunitinib, which are under clinical trials for glioblastoma patients. Here, we provide evidence that AXL activity can modulate sunitinib response in glioblastoma cell lines. We found that A...

  20. Salinomycin encapsulated nanoparticles as a targeting vehicle for glioblastoma cells.

    Science.gov (United States)

    Tığlı Aydın, R Seda; Kaynak, Gökçe; Gümüşderelioğlu, Menemşe

    2016-02-01

    Salinomycin has been introduced as a novel alternative to traditional anti-cancer drugs. The aim of this study was to test a strategy designed to deliver salinomycin to glioblastoma cells in vitro. Salinomycin-encapsulated polysorbate 80-coated poly(lactic-co-glycolic acid) nanoparticles (P80-SAL-PLGA) were prepared and characterized with respect to particle size, morphology, thermal properties, drug encapsulation efficiency and controlled salinomycin-release behaviour. The in vitro cellular uptake of P80-SAL-PLGA (5 and 10 µM) or uncoated nanoparticles was assessed in T98G human glioblastoma cells, and the cell viability was investigated with respect to anti-growth activities. SAL, which was successfully transported to T98G glioblastoma cells via P80 coated nanoparticles (∼14% within 60 min), greatly decreased (p salinomycin delivery system in the treatment of human glioblastoma.

  1. Immunological Evasion in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Roxana Magaña-Maldonado

    2016-01-01

    Full Text Available Glioblastoma is the most aggressive tumor in Central Nervous System in adults. Among its features, modulation of immune system stands out. Although immune system is capable of detecting and eliminating tumor cells mainly by cytotoxic T and NK cells, tumor microenvironment suppresses an effective response through recruitment of modulator cells such as regulatory T cells, monocyte-derived suppressor cells, M2 macrophages, and microglia as well as secretion of immunomodulators including IL-6, IL-10, CSF-1, TGF-β, and CCL2. Other mechanisms that induce immunosuppression include enzymes as indolamine 2,3-dioxygenase. For this reason it is important to develop new therapies that avoid this immune evasion to promote an effective response against glioblastoma.

  2. FoxM1 Drives a Feed-forward STAT3-activation Signaling Loop that Promotes the Self-renewal and Tumorigenicity of Glioblastoma Stem-like Cells

    Science.gov (United States)

    Gong, Ai-hua; Wei, Ping; Zhang, Sicong; Yao, Jun; Yuan, Ying; Zhou, Ai-dong; Lang, Frederick F.; Heimberger, Amy B.; Rao, Ganesh; Huang, Suyun

    2015-01-01

    The growth factor PDGF controls the development of glioblastoma (GBM) but its contribution to the function of GBM stem-like cells (GSC) has been little studied. Here we report that the transcription factor FoxM1 promotes PDGFA-STAT3 signaling to drive GSC self-renewal and tumorigenicity. In GBM we found a positive correlation between expression of FoxM1 and PDGF-A. In GSC and mouse neural stem cells, FoxM1 bound to the PDGF-A promoter to upregulate PDGF-A expression, acting to maintain the stem-like qualities of GSC in part through this mechanism. Analysis of the human cancer genomic database TCGA revealed that GBM express higher levels of STAT3, a PDGF-A effector signaling molecule, as compared with normal brain. FoxM1 regulated STAT3 transcription through interactions with the β-catenin/TCF4 complex. FoxM1 deficiency inhibited PDGF-A and STAT3 expression in neural stem cells and GSC, abolishing their stem-like and tumorigenic properties. Further mechanistic investigations defined a FoxM1-PDGFA-STAT3 feed-forward pathway that was sufficient to confer stem-like properties to glioma cells. Collectively, our findings showed how FoxM1 activates expression of PDGF-A and STAT3 in a pathway required to maintain the self-renewal and tumorigenicity of glioma stem-like cells. PMID:25832656

  3. Microarray Analysis in Glioblastomas

    Science.gov (United States)

    Bhawe, Kaumudi M.; Aghi, Manish K.

    2016-01-01

    Microarray analysis in glioblastomas is done using either cell lines or patient samples as starting material. A survey of the current literature points to transcript-based microarrays and immunohistochemistry (IHC)-based tissue microarrays as being the preferred methods of choice in cancers of neurological origin. Microarray analysis may be carried out for various purposes including the following: To correlate gene expression signatures of glioblastoma cell lines or tumors with response to chemotherapy (DeLay et al., Clin Cancer Res 18(10):2930–2942, 2012)To correlate gene expression patterns with biological features like proliferation or invasiveness of the glioblastoma cells (Jiang et al., PLoS One 8(6):e66008, 2013)To discover new tumor classificatory systems based on gene expression signature, and to correlate therapeutic response and prognosis with these signatures (Huse et al., Annu Rev Med 64(1):59–70, 2013; Verhaak et al., Cancer Cell 17(1):98–110, 2010) While investigators can sometimes use archived tumor gene expression data available from repositories such as the NCBI Gene Expression Omnibus to answer their questions, new arrays must often be run to adequately answer specific questions. Here, we provide a detailed description of microarray methodologies, how to select the appropriate methodology for a given question, and analytical strategies that can be used. Experimental methodology for protein microarrays is outside the scope of this chapter, but basic sample preparation techniques for transcript-based microarrays are included here. PMID:26113463

  4. Strategies in Gene Therapy for Glioblastoma

    OpenAIRE

    2013-01-01

    Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strate...

  5. Dexamethasone protected human glioblastoma U87MG cells from temozolomide induced apoptosis by maintaining Bax:Bcl-2 ratio and preventing proteolytic activities

    Directory of Open Access Journals (Sweden)

    Patel Sunil J

    2004-12-01

    Full Text Available Abstract Background Glioblastoma is the deadliest and most prevalent brain tumor. Dexamethasone (DXM is a commonly used steroid for treating glioblastoma patients for alleviation of vasogenic edema and pain prior to treatment with chemotherapeutic drugs. Temozolomide (TMZ, an alkylating agent, has recently been introduced in clinical trials for treating glioblastoma. Here, we evaluated the modulatory effect of DXM on TMZ induced apoptosis in human glioblastoma U87MG cells. Results Freshly grown cells were treated with different doses of DXM or TMZ for 6 h followed by incubation in a drug-free medium for 48 h. Wright staining and ApopTag assay showed no apoptosis in cells treated with 40 μM DXM but considerable amounts of apoptosis in cells treated with 100 μM TMZ. Apoptosis in TMZ treated cells was associated with an increase in intracellular free [Ca2+], as determined by fura-2 assay. Western blot analyses showed alternations in the levels of Bax (pro-apoptotic and Bcl-2 (anti-apoptotic proteins resulting in increased Bax:Bcl-2 ratio in TMZ treated cells. Western blot analyses also detected overexpression of calpain and caspase-3, which cleaved 270 kD α-spectrin at specific sites for generation of 145 and 120 kD spectrin break down products (SBDPs, respectively. However, 1-h pretreatment of cells with 40 μM DXM dramatically decreased TMZ induced apoptosis, decreasing Bax:Bcl-2 ratio and SBDPs. Conclusion Our results revealed an antagonistic effect of DXM on TMZ induced apoptosis in human glioblastoma U87MG cells, implying that treatment of glioblastoma patients with DXM prior to chemotherapy with TMZ might result in an undesirable clinical outcome.

  6. Cytomegalovirus pp71 protein is expressed in human glioblastoma and promotes pro-angiogenic signaling by activation of stem cell factor.

    Directory of Open Access Journals (Sweden)

    Lisa A Matlaf

    Full Text Available Glioblastoma multiforme (GBM is a highly malignant primary central nervous system neoplasm characterized by tumor cell invasion, robust angiogenesis, and a mean survival of 15 months. Human cytomegalovirus (HCMV infection is present in >90% of GBMs, although the role the virus plays in GBM pathogenesis is unclear. We report here that HCMV pp71, a viral protein previously shown to promote cell cycle progression, is present in a majority of human GBMs and is preferentially expressed in the CD133+, cancer stem-like cell population. Overexpression of pp71 in adult neural precursor cells resulted in potent induction of stem cell factor (SCF, an important pro-angiogenic factor in GBM. Using double immunofluorescence, we demonstrate in situ co-localization of pp71 and SCF in clinical GBM specimens. pp71 overexpression in both normal and transformed glial cells increased SCF secretion and this effect was specific, since siRNA mediated knockdown of pp71 or treatment with the antiviral drug cidofovir resulted in decreased expression and secretion of SCF by HCMV-infected cells. pp71- induced upregulation of SCF resulted in downstream activation of its putative endothelial cell receptor, c-kit, and angiogenesis as measured by increased capillary tube formation in vitro. We demonstrate that pp71 induces a pro-inflammatory response via activation of NFΚB signaling which drives SCF expression. Furthermore, we show that pp71 levels and NFKB activation are selectively augmented in the mesenchymal subtype of human GBMs, characterized by worst patient outcome, suggesting that HCMV pp71-induced paracrine signaling may contribute to the aggressive phenotype of this human malignancy.

  7. Genetics and epigenetics of glioblastoma: applications and overall incidence of IDH1 mutation

    Directory of Open Access Journals (Sweden)

    Xuan eZong

    2016-01-01

    Full Text Available Glioblastoma is the most fatal brain cancer found in humans. Patients suffering from glioblastoma have a dismal prognosis, with a median survival of 15 months. The tumor may develop rapidly de novo in older patients or through progression from anaplastic astrocytomas in younger patients if glioblastoma is primary or secondary, respectively. During the past decade, significant advances have been made in the understanding of processes leading to glioblastoma, and several important genetic defects that appear to be important for the development and progression of this tumor have been identified. Particularly, the discovery of recurrent mutations in the isocitrate dehydrogenase 1 (IDH1 gene has shed new light on the molecular landscape in glioblastoma. Indeed, emerging research on the consequences of mutant IDH1 protein expression suggests that its neomorphic enzymatic activity catalyzing the production of the oncometabolite 2-hydroxyglutarate influences a range of cellular programs that affect the epigenome and contribute to glioblastoma development. One of the exciting observations is the presence of IDH1 mutation in the vast majority of secondary glioblastoma, while it is almost absent in primary glioblastoma. Growing data indicate that this particular mutation has clinical and prognostic importance and will become a critical early distinction in diagnosis of glioblastoma.

  8. Radiation Therapy for the Treatment of Recurrent Glioblastoma: An Overview

    Energy Technology Data Exchange (ETDEWEB)

    Amelio, Dante; Amichetti, Maurizio, E-mail: amelio@atrep.it [ATreP-Agenzia Provinciale per la Protonterapia, Via F.lli Perini 181, Trento 38122 (Italy)

    2012-03-07

    Despite the therapeutic advances in neuro-oncology, most patients with glioblastoma ultimately experience local progression/relapse. Re-irradiation has been poorly viewed in the past, mainly due to the overestimated risk of side effects using conventional radiotherapy. To date, thanks to the improvement of several delivery techniques, together with improved imaging capabilities, re-irradiation is a viable salvage treatment option to manage such clinical scenario. A literature overview on the feasibility and efficacy of the different irradiation modalities for recurrent glioblastoma along with considerations on areas of improvement are provided.

  9. CXCL12 MODULATION OF CXCR4 AND CXCR7 ACTIVITY IN HUMAN GLIOBLASTOMA STEM-LIKE CELLS AND REGULATION OF THE TUMOR MICROENVIRONMENT

    Directory of Open Access Journals (Sweden)

    Roberto eWurth

    2014-05-01

    Full Text Available Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells.Glioblastoma (GBM is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem–like cells (CSCs is believed to be the main responsible for tumor cell dissemination to the brain.GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g. CXCL12 causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4.This review covers recent developments on the role of CXCL12/CXCR4-CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include

  10. HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma.

    Science.gov (United States)

    Wang, Zhihao; Hu, Pengchao; Tang, Fang; Lian, Haiwei; Chen, Xiong; Zhang, Yingying; He, Xiaohua; Liu, Wanhong; Xie, Conghua

    2016-08-28

    Histone deacetylases are considered to be among the most promising targets in drug development for cancer therapy. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme that regulates many biological processes involved in tumorigenesis through its deacetylase and ubiquitin-binding activities. Here, we report that HDAC6 is overexpressed in glioblastoma tissues and cell lines. Overexpression of HDAC6 promotes the proliferation and spheroid formation of glioblastoma cells. HDAC6 overexpression confers resistance to temozolomide (TMZ) mediated cell proliferation inhibition and apoptosis induction. Conversely, knockdown of HDAC6 inhibits cell proliferation, impairs spheroid formation and sensitizes glioblastoma cells to TMZ. The inhibition of HDAC6 deacetylase activity by selective inhibitors inhibits the proliferation of glioblastoma cells and induces apoptosis. HDAC6 selective inhibitors can sensitize glioblastoma cells to TMZ. Moreover, we showed that HDAC6 mediated EGFR stabilization might partly account for its oncogenic role in glioblastoma. TMZ resistant glioblastoma cells showed higher expression of HDAC6 and more activation of EGFR. HDAC6 inhibitors decrease EGFR protein levels and impair the activation of the EGFR pathway. Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of glioblastoma.

  11. Kaurene diterpene induces apoptosis in U87 human malignant glioblastoma cells by suppression of anti-apoptotic signals and activation of cysteine proteases

    Directory of Open Access Journals (Sweden)

    F.S. Lizarte Neto

    2013-01-01

    Full Text Available Gliomas are the most common and malignant primary brain tumors in humans. Studies have shown that classes of kaurene diterpene have anti-tumor activity related to their ability to induce apoptosis. We investigated the response of the human glioblastoma cell line U87 to treatment with ent-kaur-16-en-19-oic acid (kaurenoic acid, KA. We analyzed cell survival and the induction of apoptosis using flow cytometry and annexin V staining. Additionally, the expression of anti-apoptotic (c-FLIP and miR-21 and apoptotic (Fas, caspase-3 and caspase-8 genes was analyzed by relative quantification (real-time PCR of mRNA levels in U87 cells that were either untreated or treated with KA (30, 50, or 70 µM for 24, 48, and 72 h. U87 cells treated with KA demonstrated reduced viability, and an increase in annexin V- and annexin V/PI-positive cells was observed. The percentage of apoptotic cells was 9% for control cells, 26% for cells submitted to 48 h of treatment with 50 µM KA, and 31% for cells submitted to 48 h of treatment with 70 µM KA. Similarly, in U87 cells treated with KA for 48 h, we observed an increase in the expression of apoptotic genes (caspase-8, -3 and a decrease in the expression of anti-apoptotic genes (miR-21 and c-FLIP. KA possesses several interesting properties and induces apoptosis through a unique mechanism. Further experiments will be necessary to determine if KA may be used as a lead compound for the development of new chemotherapeutic drugs for the treatment of primary brain tumors.

  12. The Error-Prone DNA Polymerase κ Promotes Temozolomide Resistance in Glioblastoma through Rad17-Dependent Activation of ATR-Chk1 Signaling.

    Science.gov (United States)

    Peng, Chenghao; Chen, Zhengxin; Wang, Shuai; Wang, Hong-Wei; Qiu, Wenjin; Zhao, Lin; Xu, Ran; Luo, Hui; Chen, Yuanyuan; Chen, Dan; You, Yongping; Liu, Ning; Wang, Huibo

    2016-04-15

    The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of human cancers, including glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that Pol κ, an error-prone polymerase that participates in translesion DNA synthesis, was significantly upregulated in GBM cell lines and tumor tissues following temozolomide treatment. Overexpression of Pol κ in temozolomide-sensitive GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in orthotopic xenograft mouse models. Mechanistically, depletion of Pol κ disrupted homologous recombination (HR)-mediated repair and restart of stalled replication forks, impaired the activation of ATR-Chk1 signaling, and delayed cell-cycle re-entry and progression. Further investigation of the relationship between Pol κ and temozolomide revealed that Pol κ inactivation facilitated temozolomide-induced Rad17 ubiquitination and proteasomal degradation, subsequently silencing ATR-Chk1 signaling and leading to defective HR repair and the reversal of temozolomide resistance. Moreover, overexpression of Rad17 in Pol κ-depleted GBM cells restored HR efficiency, promoted the clearance of temozolomide-induced DNA breaks, and desensitized cells to the cytotoxic effects of temozolomide observed in the absence of Pol κ. Finally, we found that Pol κ overexpression correlated with poor prognosis in GBM patients undergoing temozolomide therapy. Collectively, our findings identify a potential mechanism by which GBM cells develop resistance to temozolomide and suggest that targeting the DNA damage tolerance pathway may be beneficial for overcoming resistance. Cancer Res; 76(8); 2340-53. ©2016 AACR.

  13. Kaurene diterpene induces apoptosis in U87 human malignant glioblastoma cells by suppression of anti-apoptotic signals and activation of cysteine proteases

    Energy Technology Data Exchange (ETDEWEB)

    Lizarte, F.S. Neto; Tirapelli, D.P.C. [Universidade de São Paulo, Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP (Brazil); Ambrosio, S.R. [Universidade de Franca, Núcleo de Pesquisa em Ciências e Tecnologia, Franca, SP (Brazil); Tirapelli, C.R. [Universidade de São Paulo, Laboratório de Farmacologia, Departamento de Enfermagem Psiquiátrica e Ciências Humanas, Escola de Enfermagem de Ribeirão Preto, Ribeirão Preto, SP (Brazil); Oliveira, F.M. [Universidade de São Paulo, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP (Brazil); Novais, P.C. [Universidade de São Paulo, Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP (Brazil); Peria, F.M.; Oliveira, H.F. [Universidade de São Paulo, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP (Brazil); Carlotti, C.G. Junior; Tirapelli, L.F. [Universidade de São Paulo, Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP (Brazil)

    2013-01-11

    Gliomas are the most common and malignant primary brain tumors in humans. Studies have shown that classes of kaurene diterpene have anti-tumor activity related to their ability to induce apoptosis. We investigated the response of the human glioblastoma cell line U87 to treatment with ent-kaur-16-en-19-oic acid (kaurenoic acid, KA). We analyzed cell survival and the induction of apoptosis using flow cytometry and annexin V staining. Additionally, the expression of anti-apoptotic (c-FLIP and miR-21) and apoptotic (Fas, caspase-3 and caspase-8) genes was analyzed by relative quantification (real-time PCR) of mRNA levels in U87 cells that were either untreated or treated with KA (30, 50, or 70 µM) for 24, 48, and 72 h. U87 cells treated with KA demonstrated reduced viability, and an increase in annexin V- and annexin V/PI-positive cells was observed. The percentage of apoptotic cells was 9% for control cells, 26% for cells submitted to 48 h of treatment with 50 µM KA, and 31% for cells submitted to 48 h of treatment with 70 µM KA. Similarly, in U87 cells treated with KA for 48 h, we observed an increase in the expression of apoptotic genes (caspase-8, -3) and a decrease in the expression of anti-apoptotic genes (miR-21 and c-FLIP). KA possesses several interesting properties and induces apoptosis through a unique mechanism. Further experiments will be necessary to determine if KA may be used as a lead compound for the development of new chemotherapeutic drugs for the treatment of primary brain tumors.

  14. Kaurene diterpene induces apoptosis in U87 human malignant glioblastoma cells by suppression of anti-apoptotic signals and activation of cysteine proteases.

    Science.gov (United States)

    Lizarte Neto, F S; Tirapelli, D P C; Ambrosio, S R; Tirapelli, C R; Oliveira, F M; Novais, P C; Peria, F M; Oliveira, H F; Carlotti Junior, C G; Tirapelli, L F

    2013-01-01

    Gliomas are the most common and malignant primary brain tumors in humans. Studies have shown that classes of kaurene diterpene have anti-tumor activity related to their ability to induce apoptosis. We investigated the response of the human glioblastoma cell line U87 to treatment with ent-kaur-16-en-19-oic acid (kaurenoic acid, KA). We analyzed cell survival and the induction of apoptosis using flow cytometry and annexin V staining. Additionally, the expression of anti-apoptotic (c-FLIP and miR-21) and apoptotic (Fas, caspase-3 and caspase-8) genes was analyzed by relative quantification (real-time PCR) of mRNA levels in U87 cells that were either untreated or treated with KA (30, 50, or 70 µM) for 24, 48, and 72 h. U87 cells treated with KA demonstrated reduced viability, and an increase in annexin V- and annexin V/PI-positive cells was observed. The percentage of apoptotic cells was 9% for control cells, 26% for cells submitted to 48 h of treatment with 50 µM KA, and 31% for cells submitted to 48 h of treatment with 70 µM KA. Similarly, in U87 cells treated with KA for 48 h, we observed an increase in the expression of apoptotic genes (caspase-8, -3) and a decrease in the expression of anti-apoptotic genes (miR-21 and c-FLIP). KA possesses several interesting properties and induces apoptosis through a unique mechanism. Further experiments will be necessary to determine if KA may be used as a lead compound for the development of new chemotherapeutic drugs for the treatment of primary brain tumors.

  15. Genomic understanding of glioblastoma expanded

    Science.gov (United States)

    Glioblastoma multiforme (GBM) was the first cancer type to be systematically studied by TCGA in 2008. In a new, complementary report, TCGA experts examined more than 590 GBM samples--the largest to date utilizing genomic characterization techniques and ne

  16. Current management of glioblastoma multiforme

    OpenAIRE

    Moscote-Salazar Luís Rafael; Meneses-García Carlos; Sáenz-Amuruz Miguel; Penagos Pedro; Zubieta Camilo; Romero Alfredo

    2010-01-01

    The glioblastoma multiforme is a agressive tumor in the brain. Despite aggressive multimodal treatment including surgical excision, local and systemic chemotherapy, median survival is in the range of 12 months. Patients with glioblastoma multiforme are considered to receive only palliative treatment with no hope of cure. Surgical resection is based on the premise that provides themaximum possible lengthen survival but with lower neurological deficit. Radiation therapy increases the duration o...

  17. Role of Receptor Tyrosine Kinases and Their Ligands in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Estefanía Carrasco-García

    2014-04-01

    Full Text Available Glioblastoma multiforme is the most frequent, aggressive and fatal type of brain tumor. Glioblastomas are characterized by their infiltrating nature, high proliferation rate and resistance to chemotherapy and radiation. Recently, oncologic therapy experienced a rapid evolution towards “targeted therapy,” which is the employment of drugs directed against particular targets that play essential roles in proliferation, survival and invasiveness of cancer cells. A number of molecules involved in signal transduction pathways are used as molecular targets for the treatment of various tumors. In fact, inhibitors of these molecules have already entered the clinic or are undergoing clinical trials. Cellular receptors are clear examples of such targets and in the case of glioblastoma multiforme, some of these receptors and their ligands have become relevant. In this review, the importance of glioblastoma multiforme in signaling pathways initiated by extracellular tyrosine kinase receptors such as EGFR, PDGFR and IGF-1R will be discussed. We will describe their ligands, family members, structure, activation mechanism, downstream molecules, as well as the interaction among these pathways. Lastly, we will provide an up-to-date review of the current targeted therapies in cancer, in particular glioblastoma that employ inhibitors of these pathways and their benefits.

  18. Opposing signaling of ROCK1 and ROCK2 determines the switching of substrate specificity and the mode of migration of glioblastoma cells.

    Science.gov (United States)

    Mertsch, Sonja; Thanos, Solon

    2014-04-01

    Despite current advances in therapy, the prognosis of patients with glioblastoma has not improved sufficiently in recent decades. This is due mainly to the highly invasive capacity of glioma cells. Little is known about the mechanisms underlying this particular characteristic. While the Rho-kinase (ROCK)-dependent signaling pathways involved in glioma migration have yet to be determined, they show promise as one of the candidates in targeted glioblastoma therapy. There are two ROCK isoforms: ROCK1, which is upregulated in glioblastoma tissue compared to normal brain tissue, and ROCK2, which is also expressed in normal brain tissue. Blockage of both of these ROCK isoforms with pharmacologic inhibitors regulates the migration process. We examined the activities of ROCK1 and ROCK2 using knockdown cell lines and the newly developed stripe assay. Selective knockdown of either ROCK1 or ROCK2 exerted antidromic effects on glioma migration: while ROCK1 deletion altered the substrate-dependent migration, deletion of ROCK2 did not. Furthermore, ROCK1 knockdown reduced cell proliferation, whereas ROCK2 knockdown enhanced it. Along the signaling pathways, key regulators of the ROCK pathway are differentially affected by ROCK1 and ROCK2. These data suggest that the balanced activation of ROCKs is responsible for the substrate-specific migration and the proliferation of glioblastoma cells.

  19. A clinical review of treatment outcomes in glioblastoma multiforme - the validation in a non-trial population of the results of a randomised Phase III clinical trial: has a more radical approach improved survival?

    LENUS (Irish Health Repository)

    Rock, K

    2012-01-03

    Objective: Glioblastoma multiforme (GBM) accounts for up to 60% of all malignant primary brain tumours in adults, occurring in 2-3 cases per 100 000 in Europe and North America. In 2005, a Phase III clinical trial demonstrated a significant improvement in survival over 2, and subsequently, 5 years with the addition of concurrent and adjuvant temozolomide (TMZ) to radical radiotherapy (RT) (Stupp R, Hegi M, van den Bent M, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009:10:459-66). The aim of this study was to investigate if the demonstrated improved survival in the literature translated to clinical practice.Methods: This was a retrospective study including all patients with histologically proven GBM diagnosed from 1999 to 2008 and treated with adjuvant RT at our institution. A total of 273 patients were identified. Statistical analysis was carried out using SPSS v18.Results: The median survival for the whole group (n = 273) over the 10-year period was 7.6 months (95% confidence interval 6.7-8.4 months). Overall, the cumulative probability of survival at 1 and 2 years was 31.5 and 9.4%, respectively. In total, 146 patients received radical RT. 103 patients were treated with radical RT and TMZ and 43 patients received radical RT alone. The median survival for patients receiving radical RT with TMZ was 13.4 months (95% CI 10.9-15.8 months) vs 8.8 months for radical RT alone (95% CI 6.9 - 10.7 months, p = 0.006). 2-year survival figures were 21.2 vs 4.7%, respectively. On multivariate analysis, independent predictors of survival included KPS, RT dose, TMZ and extent of surgery. The strongest predictors of poorer outcome based on the hazard ratio were palliative RT, followed by not receiving TMZ chemotherapy, then KPS <90 and a biopsy only surgical approach.Conclusion: This paper demonstrates

  20. A clinical review of treatment outcomes in glioblastoma multiforme - the validation in a non-trial population of the results of a randomised Phase III clinical trial: has a more radical approach improved survival?

    LENUS (Irish Health Repository)

    2012-02-01

    Objective: Glioblastoma multiforme (GBM) accounts for up to 60% of all malignant primary brain tumours in adults, occurring in 2-3 cases per 100 000 in Europe and North America. In 2005, a Phase III clinical trial demonstrated a significant improvement in survival over 2, and subsequently, 5 years with the addition of concurrent and adjuvant temozolomide (TMZ) to radical radiotherapy (RT) (Stupp R, Hegi M, van den Bent M, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009:10:459-66). The aim of this study was to investigate if the demonstrated improved survival in the literature translated to clinical practice.Methods: This was a retrospective study including all patients with histologically proven GBM diagnosed from 1999 to 2008 and treated with adjuvant RT at our institution. A total of 273 patients were identified. Statistical analysis was carried out using SPSS v18.Results: The median survival for the whole group (n = 273) over the 10-year period was 7.6 months (95% confidence interval 6.7-8.4 months). Overall, the cumulative probability of survival at 1 and 2 years was 31.5 and 9.4%, respectively. In total, 146 patients received radical RT. 103 patients were treated with radical RT and TMZ and 43 patients received radical RT alone. The median survival for patients receiving radical RT with TMZ was 13.4 months (95% CI 10.9-15.8 months) vs 8.8 months for radical RT alone (95% CI 6.9 - 10.7 months, p = 0.006). 2-year survival figures were 21.2 vs 4.7%, respectively. On multivariate analysis, independent predictors of survival included KPS, RT dose, TMZ and extent of surgery. The strongest predictors of poorer outcome based on the hazard ratio were palliative RT, followed by not receiving TMZ chemotherapy, then KPS <90 and a biopsy only surgical approach.Conclusion: This paper demonstrates improved

  1. IMPROVING CAUSE DETECTION SYSTEMS WITH ACTIVE LEARNING

    Data.gov (United States)

    National Aeronautics and Space Administration — IMPROVING CAUSE DETECTION SYSTEMS WITH ACTIVE LEARNING ISAAC PERSING AND VINCENT NG Abstract. Active learning has been successfully applied to many natural language...

  2. Rac1+ cells distributed in accordance with CD 133+ cells in glioblastomas and the elevated invasiveness of CD 133+ glioma cells with higher Rac1 activity

    Institute of Scientific and Technical Information of China (English)

    ZHANG Bin; SUN Jian; YU Sheng-ping; CHEN Cong; LIU Bin; LIU Zhi-feng; REN Bing-cheng; MING Hao-lang; YANG Xue-jun

    2012-01-01

    Background Recent studies have suggested that cancer stem cells are one of the major causes for tumor recurrence due to their resistance to radiotherapy and chemotherapy.Although the highly invasive nature of glioblastoma (GBM)cells is also implicated in the failure of current therapies,it is not clear how glioma stem cells (GSCs) are involved in invasiveness.Rac1 activity is necessary for inducing reorganization of actin cytoskeleton and cell movement.In this study,we aimed to investigate the distribution characteristics of CD133+ cells and Rac1+ cells in GBM as well as Rac1 activity in CD133+ GBM cells,and analyze the migration and invasion potential of these cells.Methods A series of 21 patients with GBM were admitted consecutively and received tumor resection in Tianjin Medical University General Hospital during the first half of the year 2011.Tissue specimens were collected both from the peripheral and the central parts for each tumor under magnetic resonance imaging (MRI) navigation guidance.Immunohistochemical staining was used to detect the CD133+ cells and Rac1+ cells distribution in GBM specimens.Double-labeling immunofluorescence was further used to analyze CD133 and Rac1 co-expression and the relationship between CD133+ cells distribution and Rac1 expression.Serum-free medium culture and magnetic sorting were used to isolate CD133+ cells from U87 cell line.Rac1 activation assay was conducted to assess the activation of Rac1 in CD133+ and CD133-U87 cells.The migration and invasive ability of CD133+ and CD133-U87 cells were determined by cell migration and invasion assays in vitro.Student's t-test and one-way analysis of variance (ANOVA) test were used to determine statistical significance in this study.Results In the central parts of GBMs,CD133+ cells were found to cluster around necrosis and occasionally cluster around the vessels under the microscope by immunohistological staining.In the peripheral parts of the tumors,CD133+ cells were lined up along

  3. CD133/CD15 defines distinct cell subpopulations with differential in vitro clonogenic activity and stem cell-related gene expression profile in in vitro propagated glioblastoma multiforme-derived cell line with a PNET-like component.

    Science.gov (United States)

    Kahlert, Ulf D; Bender, Noemi O; Maciaczyk, Donata; Bogiel, Tomasz; Bar, Eli E; Eberhart, Charles G; Nikkhah, Guido; Maciaczyk, Jarosław

    2012-01-01

    Glioblastoma multiforme (GBM), as many other solid tumours, contains a subpopulation of cells termed cancer stem-like cells responsible for the initiation and propagation of tumour growth. However, a unique immunophenotype/surface antigen composition for the clear identification of brain tumour stem cells (BTSC) has not yet been found. Here we report a novel code of cell surface markers for the identification of different cell subpopulations in neurospheres derived from a GBM with a primitive neuroectodermal tumour (PNET)-like component (GBM-PNET). These subgroups differ in their CD133/CD15 expression pattern and resemble cells with different stem-like genotype and developmental pathway activation levels. Strikingly, clonogenic analysis of cultures differentially expressing the investigated markers enabled the identification of distinct subpopulations of cells endowed with stem cell characteristics. High clonogenicity could be found in CD133(-)/CD15(-) and CD133(+)/CD15(+) but not in CD133(-)/CD15(+) cells. Moreover, cell subpopulations with pronounced clonogenic growth were characterized by high expression of stem cell-related genes. Interestingly, these observations were unique for GBM-PNET and differed from ordinary GBM cultures derived from tumours lacking a PNET component. This work elucidates the complex molecular heterogeneity of in vitro propagated glioblastoma-derived cells and potentially contributes to the development of novel diagnostic modalities aiming at the identification of the brain tumour stem-like cell population in a subgroup of GBMs.

  4. Algorithmic three-dimensional analysis of tumor shape in MRI improves prognosis of survival in glioblastoma: a multi-institutional study.

    Science.gov (United States)

    Czarnek, Nicholas; Clark, Kal; Peters, Katherine B; Mazurowski, Maciej A

    2017-03-01

    In this retrospective, IRB-exempt study, we analyzed data from 68 patients diagnosed with glioblastoma (GBM) in two institutions and investigated the relationship between tumor shape, quantified using algorithmic analysis of magnetic resonance images, and survival. Each patient's Fluid Attenuated Inversion Recovery (FLAIR) abnormality and enhancing tumor were manually delineated, and tumor shape was analyzed by automatic computer algorithms. Five features were automatically extracted from the images to quantify the extent of irregularity in tumor shape in two and three dimensions. Univariate Cox proportional hazard regression analysis was performed to determine how prognostic each feature was of survival. Kaplan Meier analysis was performed to illustrate the prognostic value of each feature. To determine whether the proposed quantitative shape features have additional prognostic value compared with standard clinical features, we controlled for tumor volume, patient age, and Karnofsky Performance Score (KPS). The FLAIR-based bounding ellipsoid volume ratio (BEVR), a 3D complexity measure, was strongly prognostic of survival, with a hazard ratio of 0.36 (95% CI 0.20-0.65), and remained significant in regression analysis after controlling for other clinical factors (P = 0.0061). Three enhancing-tumor based shape features were prognostic of survival independently of clinical factors: BEVR (P = 0.0008), margin fluctuation (P = 0.0013), and angular standard deviation (P = 0.0078). Algorithmically assessed tumor shape is statistically significantly prognostic of survival for patients with GBM independently of patient age, KPS, and tumor volume. This shows promise for extending the utility of MR imaging in treatment of GBM patients.

  5. Remodelling the vascular microenvironment of glioblastoma with alpha-particles

    Science.gov (United States)

    Behling, Katja; Maguire, William F.; Di Gialleonardo, Valentina; Heeb, Lukas E.M.; Hassan, Iman F.; Veach, Darren R.; Keshari, Kayvan R.; Gutin, Philip H.; Scheinberg, David A.; McDevitt, Michael R.

    2016-01-01

    Rationale Tumors escape anti-angiogenic therapy by activation of pro-angiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We investigated targeted α-particle therapy with 225Ac-E4G10 as an anti-vascular approach and previously showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here we investigate changes in tumor-vascular morphology and functionality caused by 225Ac-E4G10. Methods We investigated remodeling of tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4 kBq dose of 225Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphological changes in the tumor blood brain barrier microenvironment. Multi-color flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted magnetic resonance imaged functional changes of the tumor vascular network. Results The mechanism of drug action is a combination of glioblastoma vascular microenvironment remodeling, edema relief, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis was lessened and resulted in increased perfusion and reduced diffusion. Pharmacological uptake of dasatinib into tumor was enhanced following α-particle therapy. Conclusion Targeted anti-vascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of Platelet-derived growth factor driven glioblastoma. PMID:27261519

  6. Glioblastoma with spinal seeding

    Energy Technology Data Exchange (ETDEWEB)

    Fakhrai, N.; Fazeny-Doerner, B.; Marosi, C. [Clinical Div. of Oncology, Dept. of Medicine I, Univ. of Vienna (Austria); Czech, T. [Dept. of Neurosurgery, Univ. of Vienna (Austria); Diekmann, K. [Dept. of Radiooncology, Univ. of Vienna (Austria); Birner, P.; Hainfellner, J.A. [Clinical Inst. for Neurology, Univ. of Vienna (Austria); Prayer, D. [Dept. of Neuroradiology, Univ. of Vienna (Austria)

    2004-07-01

    Background: extracranial seeding of glioblastoma multiforme (GBM) is very rare and its development depends on several factors. This case report describes two patients suffering from GBM with spinal seeding. In both cases, the anatomic localization of the primary tumor close to the cerebrospinal fluid (CSF) was the main factor for spinal seeding. Case reports: two patients with GBM and spinal seeding are presented. After diagnosis of spinal seeding, both patients were highly symptomatic from their spinal lesions. Case 1 experienced severe pain requiring opiates, and case 2 had paresis of lower limbs as well as urinary retention/incontinence. Both patients were treated with spinal radiation therapy. Nevertheless, they died 3 months after diagnosis of spinal seeding. Results: in both patients the diagnosis of spinal seeding was made at the time of cranial recurrence. Both tumors showed close contact to the CSF initially. Even though the patients underwent intensive treatment, it was not possible to keep them in a symptom-free state. Conclusion: because of short survival periods, patients deserve optimal pain management and dedicated palliative care. (orig.)

  7. A comprehensive profile of recurrent glioblastoma

    DEFF Research Database (Denmark)

    Campos, B.; Olsen, Lars Rønn; Urup, T.;

    2016-01-01

    In spite of relentless efforts to devise new treatment strategies, primary glioblastomas invariably recur as aggressive, therapy-resistant relapses and patients rapidly succumb to these tumors. Many therapeutic agents are first tested in clinical trials involving recurrent glioblastomas. Remarkably......, however, fundamental knowledge on the biology of recurrent glioblastoma is just slowly emerging. Here, we review current knowledge on recurrent glioblastoma and ask whether and how therapies change intra-tumor heterogeneity, molecular traits and growth pattern of glioblastoma, and to which extent...... this information can be exploited for therapeutic decision-making. We conclude that the ability to characterize and predict therapy-induced changes in recurrent glioblastoma will determine, whether, one day, glioblastoma can be contained in a state of chronic disease.Oncogene advance online publication, 4 April...

  8. 5-ALA based photodynamic management of glioblastoma

    Science.gov (United States)

    Rühm, Adrian; Stepp, Herbert; Beyer, Wolfgang; Hennig, Georg; Pongratz, Thomas; Sroka, Ronald; Schnell, Oliver; Tonn, Jörg-Christian; Kreth, Friedrich-Wilhelm

    2014-03-01

    Objective: Improvement of the clinical outcome of glioblastoma (GBM) patients by employment of fluorescence and photosensitization on the basis of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX). Methods: In this report the focus is laid on the use of tumor selective PpIX fluorescence for stereotactic biopsy sampling and intra-operative treatment monitoring. In addition, our current concept for treatment planning is presented. For stereotactic interstitial photodynamic therapy (iPDT), radial diffusers were implanted into the contrast enhancing tumor volume. Spectroscopic measurements of laser light transmission and fluorescence between adjacent fibers were performed prior, during and post PDT. Results: PpIX concentrations in primary glioblastoma tissue show high intra- and inter-patient variability, but are usually sufficient for an effective PDT. During individual treatment attempts with 5-ALA based GBM-iPDT, transmission and fluorescence measurements between radial diffusers gave the following results: 1. In some cases, transmission after PDT is considerably reduced compared to the value before PDT, which may be attributable to a depletion of oxygenated hemoglobin and/or diffuse bleeding. 2. PpIX fluorescence is efficiently photobleached during PDT in all cases. Conclusion: iPDT with assessment of PpIX fluorescence and photobleaching is a promising treatment option. Individualization of treatment parameters appears to bear a potential to further improve clinical outcomes.

  9. Aberrant expression of Notch1, HES1, and DTX1 genes in glioblastoma formalin-fixed paraffin-embedded tissues.

    Science.gov (United States)

    Narayanappa, Rajeswari; Rout, Pritilata; Aithal, Madhuri G S; Chand, Ashis Kumar

    2016-05-01

    Glioblastoma is the most common malignant brain tumor accounting for more than 54 % of all gliomas. Despite aggressive treatments, median survival remains less than 1 year. This might be due to the unavailability of effective molecular diagnostic markers and targeted therapy. Thus, it is essential to discover molecular mechanisms underlying disease by identifying dysregulated pathways involved in tumorigenesis. Notch signaling is one such pathway which plays an important role in determining cell fates. Since it is found to play a critical role in many cancers, we investigated the role of Notch genes in glioblastoma with an aim to identify biomarkers that can improve diagnosis. Using real-time PCR, we assessed the expression of Notch genes including receptors (Notch1, Notch2, Notch3, and Notch4), ligands (JAG1, JAG2, and DLL3), downstream targets (HES1 and HEY2), regulator Deltex1 (DTX1), inhibitor NUMB along with transcriptional co-activator MAML1, and a component of gamma-secretase complex APH1A in 15 formalin-fixed paraffin-embedded (FFPE) patient samples. Relative quantification was done by the 2(-ΔΔCt) method; the data are presented as fold change in gene expression normalized to an internal control gene and relative to the calibrator. The data revealed aberrant expression of Notch genes in glioblastoma compared to normal brain. More than 85 % of samples showed high Notch1 (P = 0.0397) gene expression and low HES1 (P = 0.011) and DTX1 (P = 0.0001) gene expression. Our results clearly show aberrant expression of Notch genes in glioblastoma which can be used as putative biomarkers together with histopathological observation to improve diagnosis, therapeutic strategies, and patient prognosis.

  10. Kynurenine signaling increases DNA polymerase kappa expression and promotes genomic instability in glioblastoma cells

    Science.gov (United States)

    Bostian, April C.L.; Maddukuri, Leena; Reed, Megan R.; Savenka, Tatsiana; Hartman, Jessica H.; Davis, Lauren; Pouncey, Dakota L.; Miller, Grover P.; Eoff, Robert L.

    2015-01-01

    Over-expression of the translesion synthesis polymerase (TLS pol) hpol κ in glioblastomas has been linked to a poor patient prognosis; however, the mechanism promoting higher expression in these tumors remains unknown. We determined that activation of the aryl hydrocarbon receptor (AhR) pathway in glioblastoma cells leads to increased hpol κ mRNA and protein levels. We blocked nuclear translocation and DNA binding by the AhR in glioblastoma cells using a small-molecule and observed decreased hpol κ expression. Pharmacological inhibition of tryptophan-2,3-dioxygenase (TDO), the enzyme largely responsible for activating the AhR in glioblastomas, led to a decrease in the endogenous AhR agonist kynurenine (Kyn) and a corresponding decrease in hpol κ protein levels. Importantly, we discovered that inhibiting TDO activity, AhR signaling, or suppressing hpol κ expression with RNA interference led to decreased chromosomal damage in glioblastoma cells. Epistasis assays further supported the idea that TDO activity, activation of AhR signaling and the resulting over-expression of hpol κ function primarily in the same pathway to increase endogenous DNA damage. These findings indicate that up-regulation of hpol κ through glioblastoma-specific TDO activity and activation of AhR signaling likely contributes to the high levels of replication stress and genomic instability observed in these tumors. PMID:26651356

  11. Angiotensinogen and HLA class II predict bevacizumab response in recurrent glioblastoma patients

    DEFF Research Database (Denmark)

    Urup, Thomas; Michaelsen, Signe Regner; Olsen, Lars Rønn;

    2016-01-01

    Background: Bevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers for bevac......Background: Bevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers...... for bevacizumab response in recurrent glioblastoma patients. Methods: The study included a total of 82 recurrent glioblastoma patients treated with bevacizumab combination therapy whom were both response and biomarker evaluable. Gene expression of tumor tissue was analyzed by using a customized Nano...

  12. Small-Molecule XIAP Inhibitors Enhance γ-Irradiation-Induced Apoptosis in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Sri Hari Krishna Vellanki

    2009-08-01

    Full Text Available Because evasion of apoptosis can cause radioresistance of glioblastoma, there is a need to design rational strategies that counter apoptosis resistance. In the present study, we investigated the potential of targeting the antiapoptotic protein XIAP for the radiosensitization of glioblastoma. Here, we report that small-molecule XIAP inhibitors significantly enhance γ-irradiation-induced loss of viability and apoptosis and cooperate with γ-irradiation to suppress clonogenic survival of glioblastoma cells. Analysis of molecular mechanisms reveals that XIAP inhibitors act in concert with γ-irradiation to cause mitochondrial outer membrane permeabilization, caspase activation, and caspasedependent apoptosis. Importantly, XIAP inhibitors also sensitize primary cultured glioblastoma cells derived from surgical specimens as well as glioblastoma-initiating stemlike cancer stem cells for γ-irradiation. In contrast, they do not increase the toxicity of γ-irradiation on some nonmalignant cells of the central nervous system, including rat neurons or glial cells, pointing to some tumor selectivity. In conclusion, by demonstrating for the first time that smallmolecule XIAP inhibitors increase the radiosensitivity of glioblastoma cells while sparing normal cells of the central nervous system, our findings build the rationale for further (preclinical development of XIAP inhibitors in combination with γ-irradiation in glioblastoma.

  13. Key concepts in glioblastoma therapy

    DEFF Research Database (Denmark)

    Bartek, Jiri; Ng, Kimberly; Bartek, Jiri;

    2012-01-01

    Glioblastoma is the most common form of primary brain cancer and remains one of the most aggressive forms of human cancer. Current standard of care involves maximal surgical resection followed by concurrent therapy with radiation and the DNA alkylating agent temozolomide. Despite this aggressive...

  14. Corticosteroids compromise survival in glioblastoma.

    Science.gov (United States)

    Pitter, Kenneth L; Tamagno, Ilaria; Alikhanyan, Kristina; Hosni-Ahmed, Amira; Pattwell, Siobhan S; Donnola, Shannon; Dai, Charles; Ozawa, Tatsuya; Chang, Maria; Chan, Timothy A; Beal, Kathryn; Bishop, Andrew J; Barker, Christopher A; Jones, Terreia S; Hentschel, Bettina; Gorlia, Thierry; Schlegel, Uwe; Stupp, Roger; Weller, Michael; Holland, Eric C; Hambardzumyan, Dolores

    2016-05-01

    Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten

  15. Glioblastoma care in the elderly.

    Science.gov (United States)

    Jordan, Justin T; Gerstner, Elizabeth R; Batchelor, Tracy T; Cahill, Daniel P; Plotkin, Scott R

    2016-01-15

    Glioblastoma is common among elderly patients, a group in which comorbidities and a poor prognosis raise important considerations when designing neuro-oncologic care. Although the standard of care for nonelderly patients with glioblastoma includes maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide, the safety and efficacy of these modalities in elderly patients are less certain given the population's underrepresentation in many clinical trials. The authors reviewed the clinical trial literature for reports on the treatment of elderly patients with glioblastoma to provide evidence-based guidance for practitioners. In elderly patients with glioblastoma, there is a survival advantage for those who undergo maximal safe resection, which likely includes an incremental benefit with increasing completeness of resection. Radiotherapy extends survival in selected patients, and hypofractionation appears to be more tolerable than standard fractionation. In addition, temozolomide chemotherapy is safe and extends the survival of patients with tumors that harbor O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The combination of standard radiation with concurrent and adjuvant temozolomide has not been studied in this population. Although many questions remain unanswered regarding the treatment of glioblastoma in elderly patients, the available evidence provides a framework on which providers may base individual treatment decisions. The importance of tumor biomarkers is increasingly apparent in elderly patients, for whom the therapeutic efficacy of any treatment must be weighed against its potential toxicity. MGMT promoter methylation status has specifically demonstrated utility in predicting the efficacy of temozolomide and should be considered in treatment decisions when possible. Cancer 2016;122:189-197. © 2015 American Cancer Society.

  16. Restricted calorie ketogenic diet for the treatment of glioblastoma multiforme.

    Science.gov (United States)

    Maroon, Joseph; Bost, Jeffrey; Amos, Austin; Zuccoli, Giulio

    2013-08-01

    Glioblastoma multiforme is the most common malignant primary brain tumor in adults and generally considered to be universally fatal. Glioblastoma multiforme accounts for 12% to 15% of all intracranial neoplasms and affects 2 to 3 adults per every 100,000 in the United States annually. In children glioblastoma multiforme accounts for only approximately 7% to 9% of central nervous system tumors. The mean survival rate in adults after diagnosis ranges from 12 to 18 months with standard therapy and 3 to 6 months without therapy. The prognosis in children is better compared to adult tumor onset with a mean survival of approximately 4 years following gross total surgical resection and chemotherapy. There have been few advances in the treatment of glioblastoma multiforme in the past 40 years beyond surgery, radiotherapy, chemotherapy, and corticosteroids. For this reason a restrictive calorie ketogenic diet, similar to that used in children to control drug resistant seizure activity, has been advanced as an alternative adjunctive treatment to help prolonged survival. This article reviews the science of tumor metabolism and discusses the mechanism of calorie restriction, cellular energy metabolism, and how dietary induced ketosis can inhibit cancer cell's energy supply to slow tumor growth.

  17. Strategies of temozolomide in future glioblastoma treatment

    Directory of Open Access Journals (Sweden)

    Lee CY

    2017-01-01

    Full Text Available Chooi Yeng Lee School of Pharmacy, Monash University Malaysia, Selangor, Malaysia Abstract: Glioblastoma multiforme (GBM may be one of the most challenging brain tumors to treat, as patients generally do not live more than 2 years. This review aimed to give a timely review of potential future treatments for GBM by looking at the latest strategies, involving mainly the use of temozolomide (TMZ. Although these studies were carried out either in vitro or in rodents, the findings collectively suggested that we are moving toward developing a more efficacious therapy for GBM patients. Nanoparticles preparation was, by far, the most extensively studied strategy for targeted brain delivery. Therefore, the first section of this review presents a treatment strategy using TMZ-loaded nanocarriers, which encompassed nanoparticles, nanoliposomes, and nanosponges. Besides nanocarriers, new complexes that were formed between TMZ and another chemical agent or molecule have shown increased cytotoxicity and antitumor activity. Another approach was by reducing GBM cell resistance to TMZ, and this was achieved either through the suppression of metabolic change occurring in the cells, inhibition of the DNA repair protein, or up-regulation of the protein that mediates autophagy. Finally, the review collates a list of substances that have demonstrated the ability to suppress tumor cell growth. Keywords: cellular resistance, glioblastoma multiforme, nanoparticles, targeted delivery, temozolomide

  18. NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma

    OpenAIRE

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenogr...

  19. Genetics of glioblastoma: a window into its imaging and histopathologic variability.

    Science.gov (United States)

    Belden, Clifford J; Valdes, Pablo A; Ran, Cong; Pastel, David A; Harris, Brent T; Fadul, Camilo E; Israel, Mark A; Paulsen, Keith; Roberts, David W

    2011-10-01

    Glioblastoma is a highly malignant brain tumor that relentlessly defies therapy. Efforts over the past decade have begun to tease out the biochemical details that lead to its aggressive behavior and poor prognosis. There is hope that this new understanding will lead to improved treatment strategies for patients with glioblastoma, in the form of targeted, molecularly based therapies that are individualized to specific changes in individual tumors. However, these new therapies have the potential to fundamentally alter the biologic behavior of glioblastoma and, as a result, its imaging appearance. Knowledge about common genetic alterations and the resultant cellular and tissue changes (ie, induced angiogenesis and abnormal cell survival, proliferation, and invasion) in glioblastomas is important as a basis for understanding imaging findings before treatment. It is equally critical that radiologists understand which genetic pathway is targeted by each specific therapeutic agent or class of agents in order to accurately interpret changes in the imaging appearances of treated tumors.

  20. miR-340 inhibits glioblastoma cell proliferation by suppressing CDK6, cyclin-D1 and cyclin-D2

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xuesong; Gong, Xuhai [Department of Neurology, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163001 (China); Chen, Jing [Department of Neurology, Daqing Longnan Hospital, Daqing, Heilongjiang, 163001 China (China); Zhang, Jinghui [Department of Cardiology, The Fourth Hospital of Harbin City, Harbin, Heilongjiang 150026 (China); Sun, Jiahang [Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086 (China); Guo, Mian, E-mail: guomian_hyd@163.com [Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086 (China)

    2015-05-08

    Glioblastoma development is often associated with alteration in the activity and expression of cell cycle regulators, such as cyclin-dependent kinases (CKDs) and cyclins, resulting in aberrant cell proliferation. Recent studies have highlighted the pivotal roles of miRNAs in controlling the development and growth of glioblastoma. Here, we provide evidence for a function of miR-340 in the inhibition of glioblastoma cell proliferation. We found that miR-340 is downregulated in human glioblastoma tissue samples and several established glioblastoma cell lines. Proliferation and neurosphere formation assays revealed that miR-340 plays an oncosuppressive role in glioblastoma, and that its ectopic expression causes significant defect in glioblastoma cell growth. Further, using bioinformatics, luciferase assay and western blot, we found that miR-340 specifically targets the 3′UTRs of CDK6, cyclin-D1 and cyclin-D2, leading to the arrest of glioblastoma cells in the G0/G1 cell cycle phase. Confirming these results, we found that re-introducing CDK6, cyclin-D1 or cyclin-D2 expression partially, but significantly, rescues cells from the suppression of cell proliferation and cell cycle arrest mediated by miR-340. Collectively, our results demonstrate that miR-340 plays a tumor-suppressive role in glioblastoma and may be useful as a diagnostic biomarker and/or a therapeutic avenue for glioblastoma. - Highlights: • miR-340 is downregulated in glioblastoma samples and cell lines. • miR-340 inhibits glioblastoma cell proliferation. • miR-340 directly targets CDK6, cyclin-D1, and cyclin-D2. • miR-340 regulates glioblastoma cell proliferation via CDK6, cyclin-D1 and cyclin-D2.

  1. Software Engineering Improvement Activities/Plan

    Science.gov (United States)

    2003-01-01

    bd Systems personnel accomplished the technical responsibilities for this reporting period, as planned. A close working relationship was maintained with personnel of the MSFC Avionics Department Software Group (ED14). Work accomplishments included development, evaluation, and enhancement of a software cost model, performing literature search and evaluation of software tools available for code analysis and requirements analysis, and participating in other relevant software engineering activities. Monthly reports were submitted. This support was provided to the Flight Software Group/ED 1 4 in accomplishing the software engineering improvement engineering activities of the Marshall Space Flight Center (MSFC) Software Engineering Improvement Plan.

  2. Inhibition of glioblastoma cell proliferation, migration and invasion by the proteasome antagonist carfilzomib.

    Science.gov (United States)

    Areeb, Zammam; Stylli, Stanley S; Ware, Thomas M B; Harris, Nicole C; Shukla, Lipi; Shayan, Ramin; Paradiso, Lucia; Li, Bo; Morokoff, Andrew P; Kaye, Andrew H; Luwor, Rodney B

    2016-05-01

    Glioblastoma multiforme is the most aggressive and lethal tumor of the central nervous system with limited treatment strategies on offer, and as such the identification of effective novel therapeutic agents is paramount. To examine the efficacy of proteasome inhibitors, we tested bortezomib, carfilzomib, nafamostat mesylate, gabexate mesylate and acetylsalicylic acid on glioblastoma cell viability, migration and invasion. Both bortezomib and carfilzomib produced significant reduction of cell viability, while nafamostat mesylate, gabexate mesylate and acetylsalicylic acid did not. Subsequent testing showed that carfilzomib significantly reduced cell viability at nM concentrations. Carfilzomib also reduced cell migration, secretion and activation of MMP2 and also cell invasion of all four glioblastoma cells tested. In summary, carfilzomib represents a novel, yet FDA-approved agent for the treatment of glioblastoma multiforme.

  3. Expression of tumor necrosis factor related apoptosis inducing ligand receptor in glioblastoma

    Institute of Scientific and Technical Information of China (English)

    Dongling Gao; Zhongwei Zhao; Hongxin Zhang; Lan Zhang; Kuisheng Chen; Yunhan Zhang

    2008-01-01

    BACKGROUND: Receptors for tumor necrosis factor related apoptosis inducing ligand (TRAIL) include death receptor 4, death receptor 5, decoy receptor 1, and decoy receptor 2. Activation of death receptor 4 and 5 selectively kills tumor cells.OBJECTIVE: To detect TRAIL receptor expression in glioblastoma by immunohistochemistry and RT-PCR and to compare this expression to that in normal brain tissue.DESIGN: Observational analysis.SETTING: Department of Pathology, the First Affiliated Hospital of Zhengzhou University; Henan Tumor Pathology Key Laboratory.PARTICIPANTS: Twenty-five patients (17 males and 8 females) who received glioblastoma resection were selected from the Fifth Affiliated Hospital of Zhengzhou University, between September 2003 to June 2004. All glioblastoma samples were diagnosed pathologically. Twenty patients (12 males and 8 females) with craniocerebral injury who received normal brain tissue resection were selected in the same time period. There were no significant differences in sex and age between glioblastoma patients or between craniocerebral injury patients (P>0.05). All patients and appropriate relatives provided informed consent, and this study was approved by the local research ethics committee.METHODS: Polyclonal antibody against TRAIL receptors and an immunohistochemical kit (batch number: 200502) were purchased from Boster Company, Wuhan. Immunohistochemistry: Expression of death receptor 4, death receptor 5, decoy receptor 1, and decoy receptor 2 were observed in both glioblastoma and normal brain tissue. The experiment was performed according to the kit instructions, and positive staining was brown-yellow. Assessment: There were no positive signals (-); weakly positive signals, positive cells75% (++++). Evaluation: Expression levels of TRAIL receptors were estimated in both normal brain tissue and glioblastoma. Expression of decoy receptor 1 and decoy receptor 2 mRNA in glioblastoma were detected by reverse transcription polymerase

  4. Identification of Hedgehog pathway responsive glioblastomas by isocitrate dehydrogenase mutation.

    Science.gov (United States)

    Gerardo Valadez, J; Grover, Vandana K; Carter, Melissa D; Calcutt, M Wade; Abiria, Sunday A; Lundberg, Christopher J; Williams, Thomas V; Cooper, Michael K

    2013-01-28

    The Hedgehog (Hh) pathway regulates the growth of a subset of adult gliomas and better definition of Hh-responsive subtypes could enhance the clinical utility of monitoring and targeting this pathway in patients. Somatic mutations of the isocitrate dehydrogenase (IDH) genes occur frequently in WHO grades II and III gliomas and WHO grade IV secondary glioblastomas. Hh pathway activation in WHO grades II and III gliomas suggests that it might also be operational in glioblastomas that developed from lower-grade lesions. To evaluate this possibility and to better define the molecular and histopathological glioma subtypes that are Hh-responsive, IDH genes were sequenced in adult glioma specimens assayed for an operant Hh pathway. The proportions of grades II-IV specimens with IDH mutations correlated with the proportions that expressed elevated levels of the Hh gene target PTCH1. Indices of an operational Hh pathway were measured in all primary cultures and xenografts derived from IDH-mutant glioma specimens, including IDH-mutant glioblastomas. In contrast, the Hh pathway was not operational in glioblastomas that lacked IDH mutation or history of antecedent lower-grade disease. IDH mutation is not required for an operant pathway however, as significant Hh pathway modulation was also measured in grade III gliomas with wild-type IDH sequences. These results indicate that the Hh pathway is operational in grades II and III gliomas and glioblastomas with molecular or histopathological evidence for evolvement from lower-grade gliomas. Lastly, these findings suggest that gliomas sharing this molecularly defined route of progression arise in Hh-responsive cell types.

  5. Recurrent Glioblastoma: Where we stand

    Directory of Open Access Journals (Sweden)

    Sanjoy Roy

    2015-01-01

    Full Text Available Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment with targeted agents or cytotoxic chemotherapy, reirradiation, or radiosurgery. Research into novel therapies is investigating alternative temozolomide regimens, convection-enhanced delivery, immunotherapy, gene therapy, antiangiogenic agents, poly ADP ribose polymerase inhibitors, or cancer stem cell signaling pathways. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy.

  6. Chimeric enzymes with improved cellulase activities

    Science.gov (United States)

    Xu, Qi; Baker, John O; Himmel, Michael E

    2015-03-31

    Nucleic acid molecules encoding chimeric cellulase polypeptides that exhibit improved cellulase activities are disclosed herein. The chimeric cellulase polypeptides encoded by these nucleic acids and methods to produce the cellulases are also described, along with methods of using chimeric cellulases for the conversion of cellulose to sugars such as glucose.

  7. Targeting glioblastoma via intranasal administration of Ff bacteriophages

    Science.gov (United States)

    Dor-On, Eyal; Solomon, Beka

    2015-01-01

    Bacteriophages (phages) are ubiquitous viruses that control the growth and diversity of bacteria. Although they have no tropism to mammalian cells, accumulated evidence suggests that phages are not neutral to the mammalian macro-host and can promote immunomodulatory and anti-tumorigenic activities. Here we demonstrate that Ff phages that do not display any proteins or peptides could inhibit the growth of subcutaneous glioblastoma tumors in mice and that this activity is mediated in part by lipopolysaccharide molecules attached to their virion. Using the intranasal route, a non-invasive approach to deliver therapeutics directly to the CNS, we further show that phages rapidly accumulate in the brains of mice and could attenuate progression of orthotopic glioblastoma. Taken together, this study provides new insight into phages non-bacterial activities and demonstrates the feasibility of delivering Ff phages intranasally to treat brain malignancies. PMID:26074908

  8. Targeting glioblastoma via intranasal administration of Ff bacteriophages

    Directory of Open Access Journals (Sweden)

    Eyal eDor-On

    2015-05-01

    Full Text Available Bacteriophages (phages are ubiquitous viruses that control the growth and diversity of bacteria. Although they have no tropism to mammalian cells, accumulated evidence suggests that phages are not neutral to the mammalian macro-host and can promote immunomodulatory and anti-tumorigenic activities. Here we demonstrate that Ff phages that do not display any proteins or peptides could inhibit the growth of subcutaneous glioblastoma tumors in mice and that this activity is mediated in part by lipopolysaccharide molecules attached to their virion. Using the intranasal route, a non-invasive approach to deliver therapeutics directly to the CNS, we further show that phages rapidly accumulate in the brains of mice and could attenuate progression of orthotopic glioblastoma. Taken together, this study provides new insight into phages non-bacterial activities and demonstrates the feasibility of delivering Ff phages intranasally to treat brain malignancies.

  9. Targeting glioblastoma via intranasal administration of Ff bacteriophages.

    Science.gov (United States)

    Dor-On, Eyal; Solomon, Beka

    2015-01-01

    Bacteriophages (phages) are ubiquitous viruses that control the growth and diversity of bacteria. Although they have no tropism to mammalian cells, accumulated evidence suggests that phages are not neutral to the mammalian macro-host and can promote immunomodulatory and anti-tumorigenic activities. Here we demonstrate that Ff phages that do not display any proteins or peptides could inhibit the growth of subcutaneous glioblastoma tumors in mice and that this activity is mediated in part by lipopolysaccharide molecules attached to their virion. Using the intranasal route, a non-invasive approach to deliver therapeutics directly to the CNS, we further show that phages rapidly accumulate in the brains of mice and could attenuate progression of orthotopic glioblastoma. Taken together, this study provides new insight into phages non-bacterial activities and demonstrates the feasibility of delivering Ff phages intranasally to treat brain malignancies.

  10. Glioblastoma Multiforme Therapy and Mechanisms of Resistance

    Directory of Open Access Journals (Sweden)

    Yulian P. Ramirez

    2013-11-01

    Full Text Available Glioblastoma multiforme (GBM is a grade IV brain tumor characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy. The current standard of care, comprised of surgical resection followed by radiation and the chemotherapeutic agent temozolomide, only provides patients with a 12–14 month survival period post-diagnosis. Long-term survival for GBM patients remains uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. In this review we will describe the mechanisms of resistance, and how they may be overcome to improve the survival of GBM patients by implementing novel chemotherapy drugs, new drug combinations and new approaches relating to DNA damage, angiogenesis and autophagy.

  11. Radiotherapy in Glioblastoma: the Past, the Present and the Future.

    Science.gov (United States)

    Gzell, C; Back, M; Wheeler, H; Bailey, D; Foote, M

    2017-01-01

    The aim of this review is to explore the changing utility of radiotherapy in the treatment of patients with glioblastoma over the past 60 years. Together with surgery, radiotherapy has always been the cornerstone of treatment of glioblastoma, but techniques have significantly advanced over this time. The exploration of early two-dimensional techniques, investigation of dose escalation, concomitant chemotherapy and modern techniques, including intensity-modulated radiotherapy, image-guided radiotherapy, and volumetric-modulated arc therapy will be covered. In addition, current controversies including decreasing margin size, re-irradiation, treatment of elderly patients, and novel imaging tracers will be discussed. Future directions including immunotherapy and tumour treating fields are examined. Radiotherapy-based treatments cannot rely solely on advances in chemotherapy or immunotherapy to improve the overall survival of patients with glioblastoma. Radiation oncology needs to continue to develop and improve the delivery, target definition, and dose of radiotherapy to these patients to improve their survival and the toxicity associated with treatment.

  12. 组织因子/因子Ⅶ激活PI3K/Akt信号途径调控阿霉素诱导人胶质母细胞瘤细胞凋亡的研究%Tissue factor/FⅦ regulates doxorubicin-induced apoptosis in glioblastoma via activating PI3K/Akt signaling

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: To investigate the role of tissue factor (TF) in chemotherapeutic reagent - induced apoptosis on human glioblastoma and explore its mechanism. Methods: The expression of TF was examined by Western blotting. The cytotoxicity of doxorubicin was determined by WST assay. The activation of Caspase-3 and PARP induced by adoxorubicin were tested by Western blotting. Results: Human glioblastoma ceil line U373MG expressed high level of TF while LN-229was with low-TF level. The chemotherapeutic reagent doxorubicin revealed stronger cytotoxic effect on high-TF U373MGcells than low-TF LN-229 cells. Enforced strong expression of TF was achieved by transfection of TF-pcDNA3 combinant on LN-229 cells in a dose-dependent manner. Enforced TF expression in transfected LN-229 cells not only impaired the doxorubicin-induced cleavage of Caspase-3 and PARP, but also inhibited the cytotoxic effect of doxorubicin. Furthermore,activation of Akt was strong in high-TF U373MG cells but weak in low-TF LN-229 cells. Incubation of factor Ⅶ (FⅦ) with enforced TF-expressing LN-229 cells increased the phosphorylation of Akt in a time-dependent manner. Conclusion: These results suggest that over-expression of TF on glioblastoma could inhibit doxorubicin-induced apoptosis. Interaction of FⅦand TF activates the downstream PI3K/Akt pathway. Tumor-derived over-expression of TF might play a role in chemotherapy resistance in glioblastoma, at lest in part, by activating PI3K/Akt-mediated survival and anti-apoptotic mechanism through theinteraction of TF/FⅦ signaling.

  13. In vitro analysis of neurospheres derived from glioblastoma primary culture: a novel methodology paradigm.

    Directory of Open Access Journals (Sweden)

    Lorena Favaro Pavon

    2014-01-01

    Full Text Available Glioblastomas are the most lethal primary brain tumour frequently relapse or progress as focal masses after radiation, suggesting that only a fraction of tumour cells are responsible for the tumor regrowth. The identification of a brain tumour cell subpopulation with potent tumorigenic activity supports the cancer stem cell hypothesis in solid tumours. The goal of this study was to determine a methodology for the establishment of primary human glioblastoma stem cell lines. Our aim was achieved by taking the following approaches: i the establishment of primary glioblastoma cell culture; ii isolation of neurospheres derived from glioblastoma primary culture and derived straight from the tumor; iii CD133 microbeads purified neurospheres by MACS, iv Formation of subspheres in the CD133+ population, v Study of the expression level of GFAP, CD133, Nestin, Nanog, CD34 and Sox2 markers on tumor subspheres. Here, we describe a successful method for isolation of CD133+ cell population and establishment of glioblastoma neurospheres from this primary culture, which are more robust than the ones derived straight from the tumor. Highlight that the neurospheres derived from glioblatoma primary culture showed 89% expression of CD133+ cells, whereas tumor-derived neurospheres showed a 60% expression of CD133+ cells. These results show a higher concentration of CD133+ cells in neurospheres derived from glioblastoma primary culture. These CD133+ fractions were able to further generate subspheres. The subspheres derived from glioblastoma primary culture presented a well defined morphology while the ones derived form the fresh tumor were sparce and less robust. The negative fraction of CD133 cells was unable to generate subspheres. The tumor subspheres expressed GFAP, CD133, Nestin and Nanog. The present study describes an optimization of isolation of neurospheres/subspheres derived from glioblastoma primary culture by process of selection of CD133+ adherent stem

  14. Mutational profiling of kinases in glioblastoma

    NARCIS (Netherlands)

    F.E. Bleeker (Fonnet); S. Lamba (Simona); C. Zanon (Carlo); R.J. Molenaar (Remco J.); T. Hulsebos (Theo); D. Troost (Dirk); A.A.G. van Tilborg (Angela); W.P. Vandertop (Peter); S. Leenstra (Sieger); C.J.F. van Noorden (Cornelis); A. Bardelli (Alberto)

    2014-01-01

    textabstractBackground: Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma.Methods: Database mining and a literature search identified 76 kinases that have been found to

  15. Extracellular sphingosine-1-phosphate: a novel actor in human glioblastoma stem cell survival.

    Directory of Open Access Journals (Sweden)

    Elena Riccitelli

    Full Text Available Glioblastomas are the most frequent and aggressive intracranial neoplasms in humans, and despite advances and the introduction of the alkylating agent temozolomide in therapy have improved patient survival, resistance mechanisms limit benefits. Recent studies support that glioblastoma stem-like cells (GSCs, a cell subpopulation within the tumour, are involved in the aberrant expansion and therapy resistance properties of glioblastomas, through still unclear mechanisms. Emerging evidence suggests that sphingosine-1-phosphate (S1P a potent onco-promoter able to act as extracellular signal, favours malignant and chemoresistance properties in GSCs. Notwithstanding, the origin of S1P in the GSC environment remains unknown. We investigated S1P metabolism, release, and role in cell survival properties of GSCs isolated from either U87-MG cell line or a primary culture of human glioblastoma. We show that both GSC models, grown as neurospheres and expressing GSC markers, are resistant to temozolomide, despite not expressing the DNA repair protein MGMT, a major contributor to temozolomide-resistance. Pulse experiments with labelled sphingosine revealed that both GSC types are able to rapidly phosphorylate the long-chain base, and that the newly produced S1P is efficiently degraded. Of relevance, we found that S1P was present in GSC extracellular medium, its level being significantly higher than in U87-MG cells, and that the extracellular/intracellular ratio of S1P was about ten-fold higher in GSCs. The activity of sphingosine kinases was undetectable in GSC media, suggesting that mechanisms of S1P transport to the extracellular environment are constitutive in GSCs. In addition we found that an inhibitor of S1P biosynthesis made GSCs sensitive to temozolomide (TMZ, and that exogenous S1P reverted this effect, thus involving extracellular S1P as a GSC survival signal in TMZ resistance. Altogether our data implicate for the first time GSCs as a pivotal source

  16. Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8.

    Directory of Open Access Journals (Sweden)

    Diana Aguilar-Morante

    Full Text Available BACKGROUND: Thiadiazolidinones (TDZD are small heterocyclic compounds first described as non-ATP competitive inhibitors of glycogen synthase kinase 3β (GSK-3β. In this study, we analyzed the effects of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8, on murine GL261 cells growth in vitro and on the growth of established intracerebral murine gliomas in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Our data show that TDZD-8 decreased proliferation and induced apoptosis of GL261 glioblastoma cells in vitro, delayed tumor growth in vivo, and augmented animal survival. These effects were associated with an early activation of extracellular signal-regulated kinase (ERK pathway and increased expression of EGR-1 and p21 genes. Also, we observed a sustained activation of the ERK pathway, a concomitant phosphorylation and activation of ribosomal S6 kinase (p90RSK and an inactivation of GSK-3β by phosphorylation at Ser 9. Finally, treatment of glioblastoma stem cells with TDZD-8 resulted in an inhibition of proliferation and self-renewal of these cells. CONCLUSIONS/SIGNIFICANCE: Our results suggest that TDZD-8 uses a novel mechanism to target glioblastoma cells, and that malignant progenitor population could be a target of this compound.

  17. Genetic alterations in primary glioblastomas in Japan.

    Science.gov (United States)

    Fukushima, Takao; Favereaux, Alexandre; Huang, Hervé; Shimizu, Tsuneo; Yonekawa, Yasuhiro; Nakazato, Yoichi; Ohagki, Hiroko

    2006-01-01

    Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a

  18. Immune phenotypes predict survival in patients with glioblastoma multiforme

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    Haouraa Mostafa

    2016-09-01

    Full Text Available Abstract Background Glioblastoma multiforme (GBM, a common primary malignant brain tumor, rarely disseminates beyond the central nervous system and has a very bad prognosis. The current study aimed at the analysis of immunological control in individual patients with GBM. Methods Immune phenotypes and plasma biomarkers of GBM patients were determined at the time of diagnosis using flow cytometry and ELISA, respectively. Results Using descriptive statistics, we found that immune anomalies were distinct in individual patients. Defined marker profiles proved highly relevant for survival. A remarkable relation between activated NK cells and improved survival in GBM patients was in contrast to increased CD39 and IL-10 in patients with a detrimental course and very short survival. Recursive partitioning analysis (RPA and Cox proportional hazards models substantiated the relevance of absolute numbers of CD8 cells and low numbers of CD39 cells for better survival. Conclusions Defined alterations of the immune system may guide the course of disease in patients with GBM and may be prognostically valuable for longitudinal studies or can be applied for immune intervention.

  19. Ecological Factors Improving Efficiency of Business Activities

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    Kononova G. A.

    2015-01-01

    Full Text Available The economic importance of optimizing the environmental situation from the perspective of an entrepreneur are assessed in the article. The classification of administrative decisions taken in the course of the business activities is proposed. The authors identified a group of solutions directly providing optimization of environment external to the enterprise, solutions that have an indirect positive impact on the environment and solutions that improve ecology of industrial premises. The nature of economic effect of resulting solutions of various types is taken into account. Vectors of influence of working conditions on the economic results of business activities are described. The nature and strength of the impact of model management decisions results of business activities are defined. Key performance indicators of entrepreneurial activity are identified: employee productivity, the amount of revenue and profitability, solvency, staff stability, the competitiveness of enterprises. Grouping the costs of ecological parameters optimization of the production environment is proposed. Relationship between level of working conditions and socio-psychological climate in the collective enterprise is disclosed. The methods of motivation of entrepreneurs in solving of environmental, production problems are considered. The role of training entrepreneurs engaged of medium and small businesses are underlined especially. Thus, in the article the relationship between environmental and economic problems of entrepreneurial activity is investigated. Role and opportunities of entrepreneurs in solving these problems are defined and structured.

  20. Current concepts in glioblastoma imaging

    Institute of Scientific and Technical Information of China (English)

    George Alexiou; Spyridon Tsiouris; Haralabos Bougias; Spyridon Voulgaris; Andreas Fotopoulos

    2012-01-01

    Glioblastoma (GBM, WHO grade Ⅳ) is the most common and the most malignant primary brain tumor occurring during adulthood, with an annual incidence of 5 cases per 100 000. Treatment involves surgical resection, followed by radiotherapy and concomitant and adjuvant temozolomide. Despite multimodality treatment, the median survival time is 15 months. Herewith we discuss the value of neuroimaging in differentiating GBM from other types of brain tumors, in guiding tumor biopsy, in making non-invasive assessment of tumor's aggressiveness, in estimating overall prognosis, in differentiating treatment -induced brain necrosis from tumor recurrence and in assessing response to treatment.

  1. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial) : a randomised controlled phase 2 trial

    NARCIS (Netherlands)

    Taal, Walter; Oosterkamp, Hendrika M.; Walenkamp, Annemiek M. E.; Dubbink, Hendrikus J.; Beerepoot, Laurens V.; Hanse, Monique C. J.; Buter, Jan; Honkoop, Aafke H.; Boerman, Dolf; de Vos, Filip Y. F.; Dinjens, Winand N. M.; Enting, Roeline; Taphoorn, Martin J. B.; van den Berkmortel, Franchette W. P. J.; Jansen, Rob L. H.; Brandsma, Dieta; Bromberg, Jacoline E. C.; van Heuvel, Irene; Vernhout, Rene M.; van der Holt, Bronno; van den Bent, Martin J.

    2014-01-01

    BACKGROUND: Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high resp

  2. Targeting SOX2 as a therapeutic strategy in glioblastoma

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    Ander Matheu

    2016-10-01

    Full Text Available Glioblastoma is the most common and malignant brain cancer in adults. Current therapy consisting of surgery followed by radiation and temozolomide therapy has moderate success rate and the tumor reappears. Among the features that a cancer cell must have to survive the therapeutic treatment and reconstitute the tumor is the ability to self-renewal. Therefore, it is vital to identify the molecular mechanisms that regulate this activity.SOX2 is a transcription factor whose activity has been associated with the maintenance of the undifferentiated state of cancer stem cells in several tissues including the brain. Several groups have detected SOX2 levels increased in biopsies of glioblastoma patients, with highest levels associated to poor outcome. Therefore, SOX2 silencing might be a novel therapeutic approach to combat cancer and particularly brain tumors.In this review, we will summarize the current knowledge about SOX2 in glioblastoma and recapitulate several strategies, which have been recently described targeting SOX2 in this malignancy.

  3. Fenofibrate induces ketone body production in melanoma and glioblastoma cells

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    Maja M Grabacka

    2016-02-01

    Full Text Available Ketone bodies (beta-hydroxybutyrate, bHB, acetoacetate are mainly produced in the liver during prolonged fasting or starvation. bHB is a very efficient energy substrate for sustaining ATP production in peripheral tissues; importantly its consumption is preferred over glucose. However, the majority of malignant cells, particularly cancer cells of neuroectodermal origin such as glioblastoma, are not able to use ketone bodies as a source of energy. Here, we report a novel observation that fenofibrate, a synthetic peroxisome proliferator-activated receptor alpha (PPARa agonist, induces bHB production in melanoma and glioblastoma cells, as well as in neurospheres composed of nontransformed cells. Unexpectedly, this effect is not dependent on PPARa activity or its expression level. The fenofibrate-induced ketogenesis is accompanied by growth arrest and down-regulation of transketolase, but the NADP/NADPH and GSH/GSSG ratios remain unaffected. Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic therapeutic approaches against glioblastoma.

  4. Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

    Science.gov (United States)

    Wilk, Anna; Wyczechowska, Dorota; Zapata, Adriana; Dean, Matthew; Mullinax, Jennifer; Marrero, Luis; Parsons, Christopher; Peruzzi, Francesca; Culicchia, Frank; Ochoa, Augusto; Grabacka, Maja

    2014-01-01

    Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPARα). FF and several other agonists of PPARα have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPARα-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARα-dependent metabolic switch from glycolysis to fatty acid β-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase–mammalian target of rapamycin–autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells. PMID:25332241

  5. Diminished monocytic HLA-DR expression and ex vivo cytokine secretion capacity in patients with glioblastoma: effect of tumor extirpation.

    Science.gov (United States)

    Woiciechowsky, C; Asadullah, K; Nestler, D; Schöning, B; Glöckner, F; Döcke, W D; Volk, H D

    1998-04-15

    Severe immunodysregulation on lymphocyte level has been described in patients with glioblastoma and is likely involved into its unfavorable prognosis. Although the major importance of monocytic cells for immunoregulation is well established, only very limited data exist regarding the monocyte status in glioblastoma patients. Here we demonstrate a markedly diminished monocytic HLA-DR expression and ex vivo cytokine secretion capacity (TNF-alpha, IL-1beta, IL-10) as signs for monocyte deactivation in glioblastoma patients but not in patients with astrocytoma. As known in immunocompromised patients from other reasons, monocyte deactivation indicate global immunodepression associated with an enhanced risk of infectious complications. Interestingly, tumor resection resulted in partial recovery from the monocytic deactivation. This suggests that the glioblastoma itself contributed to this phenomenon. However, IL-10 and the active forms of transforming growth factor-beta2 and -beta1, which are produced by glioblastoma cells and known to inhibit monocyte function, were not detectable in plasma in our patients. Moreover, low levels of the adrenocorticotropic hormone and cortisol excluded hypothalamo-pituitary-adrenal axis involvement. So, further investigations are necessary to clarify the mechanism. The demonstrated severe glioblastoma-associated monocytic deactivation may contribute to its unfavorable prognosis. Therefore, monocytes may represent target cells for new adjuvant immunotherapies in glioblastoma.

  6. Clinical Neuropathology mini-review 6-2015: PD-L1: emerging biomarker in glioblastoma?

    Science.gov (United States)

    Preusser, Matthias; Berghoff, Anna S; Wick, Wolfgang; Weller, Michael

    2015-01-01

    Programmed death 1 (PD-1, CD279) and programmed death ligand 1 (PD-L1, CD274) are involved in generating tumor-associated immunosuppression by suppression of T-cell proliferation and interleukin 2 (IL-2) production and immune checkpoint inhibitors targeting these molecules are showing compelling activity against a variety of human cancers. PD-L1 expression has shown a positive association with response to PD-1 inhibition in noncentral nervous system (CNS) tumors, e.g., melanoma or non-small cell lung cancer, and is discussed as a potential predictive biomarker for patient selection in these tumor types. This review summarizes current knowledge and potential clinical implications of PD-L1 expression in glioblastoma. At present, the following conclusions are drawn: (a) functional data support a role for PD-1/PD-L1 in tumor-associated immunosuppression in glioblastoma; (b) the incidence of PD-L1-expressing glioblastomas seems to be relatively high in comparison to other tumor types, however, the reported rates of glioblastomas with PD-L1 protein expression vary and range from 61 to 88%; (c) there is considerable variability in the methodology of PD-L1 assessment in glioblastoma across studies with heterogeneity in utilized antibodies, tissue sampling strategies, immunohistochemical staining protocols, cut-off definitions, and evaluated staining patterns; (d) there are conflicting data on the prognostic role and so far no data on the predictive role of PD-L1 gene and protein expression in glioblastoma. In summary, the ongoing clinical studies evaluating the activity of PD-1/PD-L1 inhibitors in glioblastoma need to be complemented with well designed and stringently executed studies to understand the influence of PD-1/PD-L1 expression on therapy response or failure and to develop robust means of PD-L1 assessment for meaningful biomarker development.

  7. Rare clinical form of glioblastoma multiforme

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    Maria Ejma

    2014-03-01

    Full Text Available Glioblastoma multiforme (glioblastoma multiforme - GBM is the most malignant tumor classified by WHO. It is also the most common primary CNS tumor with a very aggressive course and unfavourable prognosis, usually develops in adults, and is typically located supratentorially in the fronto-temporal region. However, the literature describes an unusual position of GBM (e.g. spinal cord, pons, pineal region, familial gliomas unconnected with the family of gliomas predisposed to the occurrence of syndromes, unusual glioma and metastatic sites, gliomas transplanted with organs. In this paper, based on the available literature, the authors discuss an unusual and rare form of glioblastoma multiforme.

  8. A Combination of Radiosurgery and Soluble Tissue Factor Enhances Vascular Targeting for Experimental Glioblastoma

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    Jian Tu

    2013-01-01

    Full Text Available Radiosurgery for glioblastoma is limited to the development of resistance, allowing tumor cells to survive and initiate tumor recurrence. Based on our previous work that coadministration of tissue factor and lipopolysaccharide following radiosurgery selectively induced thrombosis in cerebral arteriovenous malformations, achieving thrombosis of 69% of the capillaries and 39% of medium sized vessels, we hypothesized that a rapid and selective shutdown of the capillaries in glioblastoma vasculature would decrease the delivery of oxygen and nutrients, reducing tumor growth, preventing intracranial hypertension, and improving life expectancy. Glioblastoma was formed by implantation of GL261 cells into C57Bl/6 mouse brain. Mice were intravenously injected tissue factor, lipopolysaccharide, a combination of both, or placebo 24 hours after radiosurgery. Control mice received both agents after sham irradiation. Coadministration of tissue factor and lipopolysaccharide led to the formation of thrombi in up to 87 ± 8% of the capillaries and 46 ± 4% of medium sized vessels within glioblastoma. The survival rate of mice in this group was 80% versus no survivor in placebo controls 30 days after irradiation. Animal body weight increased with time in this group (r=0.88, P=0.0001. Thus, radiosurgery enhanced treatment with tissue factor, and lipopolysaccharide selectively induces thrombosis in glioblastoma vasculature, improving life expectancy.

  9. Long-term survival in glioblastoma: methyl guanine methyl transferase (MGMT promoter methylation as independent favourable prognostic factor

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    Smrdel Uros

    2016-12-01

    Full Text Available In spite of significant improvement after multi-modality treatment, prognosis of most patients with glioblastoma remains poor. Standard clinical prognostic factors (age, gender, extent of surgery and performance status do not clearly predict long-term survival. The aim of this case-control study was to evaluate immuno-histochemical and genetic characteristics of the tumour as additional prognostic factors in glioblastoma.

  10. Leptomeningeal dissemination in glioblastoma; an inspection of risk factors, treatment, and outcomes at a single institution.

    Science.gov (United States)

    Mandel, Jacob J; Yust-Katz, Shlomit; Cachia, David; Wu, Jimin; Liu, Diane; de Groot, John F; Yung, Alfred W K; Gilbert, Mark R

    2014-12-01

    There are few studies reporting the incidence of leptomeningeal dissemination (LMD) in patients with glioblastoma; only small case series have been published. Consequently, there are no established standards of care for these patients. Therefore, we undertook this retrospective review to evaluate a large series of patients with glioblastoma treated at MD Anderson Cancer Center to estimate the incidence of LMD and assess the impact of a variety of treatment modalities. Analysis was performed on 595 patients with glioblastoma treated on clinical trials from 2006 to 2012. The diagnosis of LMD was made by imaging or positive cerebrospinal fluid cytology in 24 patients. An additional 12 patients with known LMD diagnosed during this same period were included to evaluate the impact of treatment on outcome for a total of 36 patients. LMD developed in 4.0 % (24/595 patients) of the clinical trial cohort. Median survival from glioblastoma diagnosis was 16.0 months. Estimated median time of glioblastoma diagnosis to LMD was 11.9 months. Median overall survival from the time of LMD diagnosis was 3.5 months. Patients treated for LMD with chemotherapy/targeted therapy and radiation had a significantly prolonged survival (7.7 months) compared to chemotherapy/targeted therapy alone, radiation alone or palliative care. LMD remains an uncommon event in patients with glioblastoma. Patients treated aggressively with chemotherapy/targeted therapy and radiation had the longest median survival following diagnosis of LMD. However, patients receiving chemotherapy/targeted therapy and radiation were younger and this may have influenced survival. Given the overall poor outcomes, improved therapeutic approaches are needed for glioblastoma patients with LMD.

  11. Cysteine catabolism: a novel metabolic pathway contributing to glioblastoma growth.

    Science.gov (United States)

    Prabhu, Antony; Sarcar, Bhaswati; Kahali, Soumen; Yuan, Zhigang; Johnson, Joseph J; Adam, Klaus-Peter; Kensicki, Elizabeth; Chinnaiyan, Prakash

    2014-02-01

    The relevance of cysteine metabolism in cancer has gained considerable interest in recent years, largely focusing on its role in generating the antioxidant glutathione. Through metabolomic profiling using a combination of high-throughput liquid and gas chromatography-based mass spectrometry on a total of 69 patient-derived glioma specimens, this report documents the discovery of a parallel pathway involving cysteine catabolism that results in the accumulation of cysteine sulfinic acid (CSA) in glioblastoma. These studies identified CSA to rank as one of the top metabolites differentiating glioblastoma from low-grade glioma. There was strong intratumoral concordance of CSA levels with expression of its biosynthetic enzyme cysteine dioxygenase 1 (CDO1). Studies designed to determine the biologic consequence of this metabolic pathway identified its capacity to inhibit oxidative phosphorylation in glioblastoma cells, which was determined by decreased cellular respiration, decreased ATP production, and increased mitochondrial membrane potential following pathway activation. CSA-induced attenuation of oxidative phosphorylation was attributed to inhibition of the regulatory enzyme pyruvate dehydrogenase. Studies performed in vivo abrogating the CDO1/CSA axis using a lentiviral-mediated short hairpin RNA approach resulted in significant tumor growth inhibition in a glioblastoma mouse model, supporting the potential for this metabolic pathway to serve as a therapeutic target. Collectively, we identified a novel, targetable metabolic pathway involving cysteine catabolism contributing to the growth of aggressive high-grade gliomas. These findings serve as a framework for future investigations designed to more comprehensively determine the clinical application of this metabolic pathway and its contributory role in tumorigenesis.

  12. p53 isoform profiling in glioblastoma and injured brain.

    Science.gov (United States)

    Takahashi, R; Giannini, C; Sarkaria, J N; Schroeder, M; Rogers, J; Mastroeni, D; Scrable, H

    2013-06-27

    The tumor suppressor p53 has been found to be the most commonly mutated gene in human cancers; however, the frequency of p53 mutations varies from 10 to 70% across different cancer types. This variability can partly be explained by inactivating mechanisms aside from direct genomic polymorphisms. The p53 gene encodes 12 isoforms, some of which can modulate full-length p53 activity in cancer. In this study, we characterized p53 isoform expression patterns in glioblastoma, gliosis, non-tumor brain and neural progenitor cells by SDS-PAGE, immunoblot, mass spectrometry and reverse transcription-PCR. We found that the most consistently expressed isoform in glioblastoma, Δ40p53, was uniquely expressed in regenerative processes, such as those involving neural progenitor cells and gliosis compared with tumor samples. Isoform profiling of glioblastoma tissues revealed the presence of both Δ40p53 and full-length p53, neither of which were detected in non-tumor cerebral cortex. Upon xenograft propagation of tumors, p53 levels increased. The variability of overall p53 expression and relative levels of isoforms suggest fluctuations in subpopulations of cells with greater or lesser capacity for proliferation, which can change as the tumor evolves under different growth conditions.

  13. Why is there a lack of consensus on molecular subgroups of glioblastoma? Understanding the nature of biological and statistical variability in glioblastoma expression data.

    Directory of Open Access Journals (Sweden)

    Nicholas F Marko

    Full Text Available INTRODUCTION: Gene expression patterns characterizing clinically-relevant molecular subgroups of glioblastoma are difficult to reproduce. We suspect a combination of biological and analytic factors confounds interpretation of glioblastoma expression data. We seek to clarify the nature and relative contributions of these factors, to focus additional investigations, and to improve the accuracy and consistency of translational glioblastoma analyses. METHODS: We analyzed gene expression and clinical data for 340 glioblastomas in The Cancer Genome Atlas (TCGA. We developed a logic model to analyze potential sources of biological, technical, and analytic variability and used standard linear classifiers and linear dimensional reduction algorithms to investigate the nature and relative contributions of each factor. RESULTS: Commonly-described sources of classification error, including individual sample characteristics, batch effects, and analytic and technical noise make measurable but proportionally minor contributions to inconsistent molecular classification. Our analysis suggests that three, previously underappreciated factors may account for a larger fraction of classification errors: inherent non-linear/non-orthogonal relationships among the genes used in conjunction with classification algorithms that assume linearity; skewed data distributions assumed to be Gaussian; and biologic variability (noise among tumors, of which we propose three types. CONCLUSIONS: Our analysis of the TCGA data demonstrates a contributory role for technical factors in molecular classification inconsistencies in glioblastoma but also suggests that biological variability, abnormal data distribution, and non-linear relationships among genes may be responsible for a proportionally larger component of classification error. These findings may have important implications for both glioblastoma research and for translational application of other large-volume biological databases.

  14. Molecular heterogeneity in glioblastoma: potential clinical implications

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    Nicole Renee Parker

    2015-03-01

    Full Text Available Glioblastomas, (grade 4 astrocytomas, are aggressive primary brain tumors characterized by histopathological heterogeneity. High resolution sequencing technologies have shown that these tumors also feature significant inter-tumoral molecular heterogeneity. Molecular subtyping of these tumors has revealed several predictive and prognostic biomarkers. However, intra-tumoral heterogeneity may undermine the use of single biopsy analysis for determining tumor genotype and has implications for potential targeted therapies. The clinical relevance and theories of tumoral molecular heterogeneity in glioblastoma are discussed.

  15. Efficacy of temozolomide and bevacizumab for the treatment of leptomeningeal dissemination of recurrent glioblastoma: A case report.

    Science.gov (United States)

    Okita, Yoshiko; Nonaka, Masahiro; Umehara, Toru; Kanemura, Yonehiro; Kodama, Yoshinori; Mano, Masayuki; Nakajima, Shin

    2015-04-01

    The prognosis of leptomeningeal dissemination of recurrent glioblastoma is poor, and chemotherapy results in minimal palliative efficacy. Temozolomide (TMZ) is an established therapy for patients with malignant glioma and the standard of care in parenchymal gliomas; however, few reports have been published with regard to its use for the treatment of leptomeningeal dissemination. Only one report has indicated the radiographic response of leptomeningeal dissemination to a TMZ rechallenge, suggesting a potential causative effect. While bevacizumab is an effective therapy for recurrent glioblastoma, its effect on leptomeningeal dissemination of recurrent glioblastoma remains unclear. The present study reports a case of leptomeningeal dissemination of recurrent glioblastoma in which transient neurological and radiological improvement was observed following chemotherapy with TMZ and bevacizumab. However, five months after the diagnosis of leptomeningeal dissemination the patient succumbed to the disease.

  16. USING FUN ACTIVITIES TO IMPROVE LISTENING SKILL

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    Hanna Andyani

    2015-12-01

    Full Text Available Based on the researcher’s experience in teaching English at MTsN Mojokerto, there are three problems dealing with the teaching of listening especially for the third year students: 1 most of the students’ scores on listening test are still under the minimum passing criterion (KKM, which is 60; 2 most students are not very enthusiastic in listening activities; 3 it is difficult for students to understand native speech in a tape recorder. Based on the problems, the main purpose of the study is to improve the ninth grade students’ listening skill using Fun Activity in the form of Games at MTsN Mojokerto. The design of this study was Classroom Action Research. The instruments were the listening tests, observation checklist and questionnaires. With the implementation of the games, the criteria of success were successfully achieved in Cycle 2. 74% of the total number of the students could get the scores more than 60 and 90% have positive responses on the implementation of games. Keywords: tic tac toe game, running dictation game, whispering game, listening skill

  17. Strategies in Gene Therapy for Glioblastoma

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    Mariano S. Viapiano

    2013-10-01

    Full Text Available Glioblastoma (GBM is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy.

  18. Strategies in Gene Therapy for Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S., E-mail: mviapiano@partners.org [Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 (United States)

    2013-10-22

    Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy.

  19. Pro-inflammatory gene expression in solid glioblastoma microenvironment and in hypoxic stem cells from human glioblastoma

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    Santoro Antonio

    2011-04-01

    Full Text Available Abstract Background Adaptation to hypoxia and consequent pro-inflammatory gene expression of prostate and breast carcinomas have been implicated in the progression toward cancer malignant phenotype. Only partial data are available for the human tumor glioblastoma multiforme (GBM. The aim of our study was to analyze the hypoxic and pro-inflammatory microenvironment in GBMs and to demonstrate that in a stem/progenitor cell line derived from human glioblastoma (GBM-SCs, hypoxia activates a coordinated inflammatory response, evidencing an invasive and migratory phenotype. Methods From each of 10 human solid glioblastomas, clinically and histopathologically characterized, we obtained three surgical samples taken from the center and the periphery of the tumor, and from adjacent host normal tissue. Molecular and morphological analyses were carried out using quantitative real-time PCR and western blot (WB. GBM stem and differentiated cells were incubated under hypoxic conditions and analyzed for pro-inflammatory gene expression and for invasive/migratory behavior. Results A panel of selected representative pro-inflammatory genes (RAGE and P2X7R, COX2, NOS2 and, PTX3 were analyzed, comparing tumor, peritumor and host normal tissues. Tumors containing leukocyte infiltrates (as assessed using CD45 immunohistochemistry were excluded. Selected genes were overexpressed in the central regions of the tumors (i.e. in the more hypoxic areas, less expressed in peripheral regions, and poorly expressed or absent in adjacent normal host tissues. Western blot analysis confirmed that the corresponding pro-inflammatory proteins were also differently expressed. Hypoxic stem cell lines showed a clear time-dependent activation of the entire panel of pro-inflammatory genes as compared to differentiated tumor cells. Biological assays showed that invasive and migratory behavior was strengthened by hypoxia only in GBM stem cells. Conclusions In human solid glioblastoma we have

  20. Precise glioblastoma targeting by AS1411 aptamer-functionalized poly (l-γ-glutamylglutamine)-paclitaxel nanoconjugates.

    Science.gov (United States)

    Luo, Zimiao; Yan, Zhiqiang; Jin, Kai; Pang, Qiang; Jiang, Ting; Lu, Heng; Liu, Xianping; Pang, Zhiqing; Yu, Lei; Jiang, Xinguo

    2017-03-15

    Chemotherapy is still the main adjuvant strategy after surgery in glioblastoma therapy. As the main obstacles of chemotherapeutic drugs for glioblastoma treatment, the blood brain barrier (BBB) and non-specific delivery to non-tumor tissues greatly limit the accumulation of drugs into tumor tissues and simultaneously cause serious toxicity to nearby normal tissues which altogether compromised the chemotherapeutic effect. In the present study, we established an aptamer AS1411-functionalized poly (l-γ-glutamyl-glutamine)-paclitaxel (PGG-PTX) nanoconjugates drug delivery system (AS1411-PGG-PTX), providing an advantageous solution of combining the precisely active targeting and the optimized solubilization of paclitaxel. The receptor nucleolin, highly expressed in glioblastoma U87 MG cells as well as neo-vascular endothelial cells, mediated the binding and endocytosis of AS1411-PGG-PTX nanoconjugates, leading to significantly enhanced uptake of AS1411-PGG-PTX nanoconjugates by tumor cells and three-dimension tumor spheroids, and intensive pro-apoptosis effect of AS1411-PGG-PTX nanoconjugates. In vivo fluorescence imaging and tissue distribution further demonstrated the higher tumor distribution of AS1411-PGG-PTX as compared with PGG-PTX. As a result, the AS1411-PGG-PTX nanoconjugates presented the best anti-glioblastoma effect with prolonged median survival time and most tumor cell apoptosis in vivo as compared with other groups. In conclusion, the AS1411-PGG-PTX nanoconjugates exhibited a promising targeting delivery strategy for glioblastoma therapy.

  1. Upfront Bevacizumab and Temozolomide or Fotemustine before Radiotherapy for Patients with Glioblastoma and Severe Neurological Impairment at Diagnosis

    Directory of Open Access Journals (Sweden)

    Celina Bihan

    2012-09-01

    Full Text Available Unresectable glioblastomas with severe neurological impairment at diagnosis have a poor prognosis. The conventional approach using a temozolomide-based chemoradiotherapy has limited efficiency on patients in the RTOG RPA V–VI classes. The activity of the antiangiogenic monoclonal antibody bevacizumab is well defined in recurrent glioblastoma, despite the fact that its impact on survival is not yet established. We wondered if neoadjuvant bevacizumab, used as upfront treatment in combination with a cytotoxic agent, was tolerable and active on neurological signs in patients with severe alteration of the neurological status due to the tumor being located in functional areas. Eight patients received intravenous bevacizumab, 10 mg/kg every 2 weeks, and either oral temozolomide (150–200 mg/m2/day for 5 days every 4 weeks or intravenous fotemustine (80 mg/m2 every 2 weeks. After an average of 5 cycles of bevacizumab, a clinical improvement of neurological functions was recorded in 8/8 patients who could then receive radiotherapy at a conventional dose (60 Gy in 30 fractions with continuation of bevacizumab and the cytotoxic agent. Four out of the 8 patients benefited from a durable stabilization and experienced an unusually long survival in such a bad situation at diagnosis. In conclusion, neoadjuvant bevacizumab with chemotherapy appears to be feasible and efficient in a category of patients from the RTOG RPA V–VI classes, by allowing the completion of full-dose radiotherapy. A clinical trial is planned to confirm these retrospective observations.

  2. Targeting Netrin-1 in glioblastoma stem-like cells inhibits growth, invasion, and angiogenesis.

    Science.gov (United States)

    Sanvoranart, Tanwarat; Supokawej, Aungkura; Kheolamai, Pakpoom; U-Pratya, Yaowalak; Poungvarin, Niphon; Sathornsumetee, Sith; Issaragrisil, Surapol

    2016-11-01

    Glioblastoma (GBM) is an aggressive malignant brain tumor that still lacks effective therapy. Glioblastoma stem cells (GBM-SCs) were identified to contribute to aggressive phenotypes and poor clinical outcomes for GBM. Netrin-1, an axon guidance molecule, has been found in several tumors in adults. However, the role of Netrin-1 in GBM-SCs remains largely unknown. In this study, CD133-positive U251 GBM cells were used as a putative GBM-SC population to identify the functions of Netrin-1. Using lentiviral transduction, Netrin-1 miR RNAi vectors were transduced into CD133-positive U251 cells. We demonstrated that cell proliferation and survival were decreased following targeted deletion of Netrin-1. Cell invasion was dramatically diminished in Netrin-1 knockdown GBM-SCs. Moreover, Netrin-1 knockdown GBM-SCs exhibited less proangiogenic activity. In conclusion, Netrin-1 may represent a therapeutic target in glioblastoma.

  3. Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme

    DEFF Research Database (Denmark)

    Michaelsen, Signe Regner; Christensen, Ib Jarle; Grunnet, Kirsten

    2013-01-01

    Although implementation of temozolomide (TMZ) as a part of primary therapy for glioblastoma multiforme (GBM) has resulted in improved patient survival, the disease is still incurable. Previous studies have correlated various parameters to survival, although no single parameter has yet been identi...

  4. Strategies of temozolomide in future glioblastoma treatment

    Science.gov (United States)

    Lee, Chooi Yeng

    2017-01-01

    Glioblastoma multiforme (GBM) may be one of the most challenging brain tumors to treat, as patients generally do not live more than 2 years. This review aimed to give a timely review of potential future treatments for GBM by looking at the latest strategies, involving mainly the use of temozolomide (TMZ). Although these studies were carried out either in vitro or in rodents, the findings collectively suggested that we are moving toward developing a more efficacious therapy for GBM patients. Nanoparticles preparation was, by far, the most extensively studied strategy for targeted brain delivery. Therefore, the first section of this review presents a treatment strategy using TMZ-loaded nanocarriers, which encompassed nanoparticles, nanoliposomes, and nanosponges. Besides nanocarriers, new complexes that were formed between TMZ and another chemical agent or molecule have shown increased cytotoxicity and antitumor activity. Another approach was by reducing GBM cell resistance to TMZ, and this was achieved either through the suppression of metabolic change occurring in the cells, inhibition of the DNA repair protein, or up-regulation of the protein that mediates autophagy. Finally, the review collates a list of substances that have demonstrated the ability to suppress tumor cell growth. PMID:28123308

  5. Epithelioid/rhabdoid glioblastoma: a highly aggressive subtype of glioblastoma.

    Science.gov (United States)

    Sugimoto, Kazutaka; Ideguchi, Makoto; Kimura, Tokuhiro; Kajiwara, Koji; Imoto, Hirochika; Sadahiro, Hirokazu; Ishii, Aya; Kawano, Hiroo; Ikeda, Eiji; Suzuki, Michiyasu

    2016-04-01

    Epithelioid glioblastoma (GBM) and rhabdoid GBM are rare variants that are morphologically similar, but there is no consensus on the characteristics of each disease. These tumors have aggressive features of early recurrence and leptomeningeal dissemination and tend to develop in younger patients compared to typical GBM. The prognosis is normally worse than typical GBM, even with intensive chemoradiotherapy after surgical resection. Thus, accurate diagnosis and effective therapy for epithelioid/rhabdoid GBM are required. Four consecutive patients aged 16-48 years were diagnosed with epithelioid/rhabdoid GBM by pathological and immunohistochemical analysis at Yamaguchi University Hospital from 2006 to 2012. Two of these patients had relatively long-term survival (19 and 23 months after diagnosis). Two cases had a BRAF V600E mutation, whereas no ATRX mutation was present in any cases. All patients suffered leptomeningeal and/or spinal dissemination that worsened their prognosis. These results illustrate the need for a new therapeutic approach, such as molecular targeted drug therapy like BRAF inhibition, in addition to standard chemoradiotherapy for typical GBM.

  6. A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma.

    Directory of Open Access Journals (Sweden)

    Renee D Read

    Full Text Available Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations that activate receptor tyrosine kinase (RTK and Pi-3 kinase (PI3K signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic glial tumors that display many features of human glioblastoma. In both human and Drosophila, activation of the RTK and PI3K pathways stimulates Akt signaling along with other as-yet-unknown changes that drive oncogenesis. We used this Drosophila glioblastoma model to perform a kinome-wide genetic screen for new genes required for RTK- and PI3K-dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian glioblastoma models and human tumors. Our results revealed that the atypical kinases RIOK1 and RIOK2 are overexpressed in glioblastoma cells in an Akt-dependent manner. Moreover, we found that overexpressed RIOK2 formed a complex with RIOK1, mTor, and mTor-complex-2 components, and that overexpressed RIOK2 upregulated Akt signaling and promoted tumorigenesis in murine astrocytes. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity in glioblastoma cells by inducing p53 activity through the RpL11-dependent ribosomal stress checkpoint. These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into defects underlying glioblastoma and related cancers and may reveal new therapeutic opportunities for these cancers.

  7. Advance Care Planning in Glioblastoma Patients

    Directory of Open Access Journals (Sweden)

    Lara Fritz

    2016-11-01

    Full Text Available Despite multimodal treatment with surgery, radiotherapy and chemotherapy, glioblastoma is an incurable disease with a poor prognosis. During the disease course, glioblastoma patients may experience progressive neurological deficits, symptoms of increased intracranial pressure such as drowsiness and headache, incontinence, seizures and progressive cognitive dysfunction. These patients not only have cancer, but also a progressive brain disease. This may seriously interfere with their ability to make their own decisions regarding treatment. It is therefore warranted to involve glioblastoma patients early in the disease trajectory in treatment decision-making on their future care, including the end of life (EOL care, which can be achieved with Advance Care Planning (ACP. Although ACP, by definition, aims at timely involvement of patients and proxies in decision-making on future care, the optimal moment to initiate ACP discussions in the disease trajectory of glioblastoma patients remains controversial. Moreover, the disease-specific content of these ACP discussions needs to be established. In this article, we will first describe the history of patient participation in treatment decision-making, including the shift towards ACP. Secondly, we will describe the possible role of ACP for glioblastoma patients, with the specific aim of treatment of disease-specific symptoms such as somnolence and dysphagia, epileptic seizures, headache, and personality changes, agitation and delirium in the EOL phase, and the importance of timing of ACP discussions in this patient population.

  8. Physical Activity Improves Quality of Life

    Science.gov (United States)

    ... and an 80% increased risk of death from cardiovascular disease. Becoming more active can help lower your blood pressure and also boost your levels of good cholesterol. Physical activity prolongs your optimal health. Without regular physical activity, the body slowly loses ...

  9. Successfully improving physical activity behavior after rehabilitation

    NARCIS (Netherlands)

    van der Ploeg, Hidde P; Streppel, Kitty R M; van der Beek, Allard J; van der Woude, Luc H V; Vollenbroek-Hutten, Miriam M R; van Harten, Wim H; van Mechelen, Willem; van der Woude, Lucas

    2007-01-01

    PURPOSE: To determine the effects of the physical activity promotion programs Rehabilitation & Sports (R&S) and Active after Rehabilitation (AaR) on sport and daily physical activity 1 year after in- or outpatient rehabilitation. DESIGN: Subjects in intervention rehabilitation centers were randomize

  10. Galectin-1, a gene preferentially expressed at the tumor margin, promotes glioblastoma cell invasion

    Directory of Open Access Journals (Sweden)

    Toussaint L

    2012-05-01

    Full Text Available Abstract Background High-grade gliomas, including glioblastomas (GBMs, are recalcitrant to local therapy in part because of their ability to invade the normal brain parenchyma surrounding these tumors. Animal models capable of recapitulating glioblastoma invasion may help identify mediators of this aggressive phenotype. Methods Patient-derived glioblastoma lines have been propagated in our laboratories and orthotopically xenografted into the brains of immunocompromized mice. Invasive cells at the tumor periphery were isolated using laser capture microdissection. The mRNA expression profile of these cells was compared to expression at the tumor core, using normal mouse brain to control for host contamination. Galectin-1, a target identified by screening the resulting data, was stably over-expressed in the U87MG cell line. Sub-clones were assayed for attachment, proliferation, migration, invasion, and in vivo tumor phenotype. Results Expression microarray data identified galectin-1 as the most potent marker (p-value 4.0 x 10-8 to identify GBM cells between tumor-brain interface as compared to the tumor core. Over-expression of galectin-1 enhanced migration and invasion in vitro. In vivo, tumors expressing high galectin-1 levels showed enhanced invasion and decreased host survival. Conclusions In conclusion, cells at the margin of glioblastoma, in comparison to tumor core cells, have enhanced expression of mediators of invasion. Galectin-1 is likely one such mediator. Previous studies, along with the current one, have proven galectin-1 to be important in the migration and invasion of glioblastoma cells, in GBM neoangiogenesis, and also, potentially, in GBM immune privilege. Targeting this molecule may offer clinical improvement to the current standard of glioblastoma therapy, i.e. radiation, temozolomide, anti-angiogenic therapy, and vaccinotherapy.

  11. Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma

    Directory of Open Access Journals (Sweden)

    Miyuki Uno

    2011-01-01

    Full Text Available OBJECTIVES: 1 To correlate the methylation status of the O6-methylguanine-DNA-methyltransferase (MGMT promoter to its gene and protein expression levels in glioblastoma and 2 to determine the most reliable method for using MGMT to predict the response to adjuvant therapy in patients with glioblastoma. BACKGROUND: The MGMT gene is epigenetically silenced by promoter hypermethylation in gliomas, and this modification has emerged as a relevant predictor of therapeutic response. METHODS: Fifty-one cases of glioblastoma were analyzed for MGMT promoter methylation by methylation-specific PCR and pyrosequencing, gene expression by real time polymerase chain reaction, and protein expression by immunohistochemistry. RESULTS: MGMT promoter methylation was found in 43.1% of glioblastoma by methylation-specific PCR and 38.8% by pyrosequencing. A low level of MGMT gene expression was correlated with positive MGMT promoter methylation (p = 0.001. However, no correlation was found between promoter methylation and MGMT protein expression (p = 0.297. The mean survival time of glioblastoma patients submitted to adjuvant therapy was significantly higher among patients with MGMT promoter methylation (log rank = 0.025 by methylation-specific PCR and 0.004 by pyrosequencing, and methylation was an independent predictive factor that was associated with improved prognosis by multivariate analysis. DISCUSSION AND CONCLUSION: MGMT promoter methylation status was a more reliable predictor of susceptibility to adjuvant therapy and prognosis of glioblastoma than were MGMT protein or gene expression levels. Methylation-specific polymerase chain reaction and pyrosequencing methods were both sensitive methods for determining MGMT promoter methylation status using DNA extracted from frozen tissue.

  12. Effects of stratospheric radiations on human glioblastoma cells.

    Science.gov (United States)

    Cerù, Maria Paola; Amicarelli, Fernanda; Cristiano, Loredana; Colafarina, Sabrina; Aimola, Pierpaolo; Falone, Stefano; Cinque, Benedetta; Ursini, Ornella; Moscardelli, Roberto; Ragni, Pietro

    2005-01-01

    The aim of this work was to evaluate the effect of stratospheric radiations on neural tumour cells. ADF human glioblastoma cells were hosted on a stratospheric balloon within the 2002 biological experiment campaign of the Italian Space Agency. The flight at an average height of 37 km lasted about 24 hrs. Cell morphology, number and viability, cell cycle and apoptosis, some antioxidant enzymes and proteins involved in cell cycle regulation, DNA repair and gene expression were studied. Stratospheric radiations caused a significant decrease in cell number, as well as a block of proliferation, but not apoptosis or necrosis. Radiations also induced activation and induction of some antioxidant enzymes, increase in DNA repair-related proteins (p53 and Proliferating Cell Nuclear Antigen) and variations of the transcription factors Peroxisome Proliferator-Activated Receptors. Morphologically, test cells exhibited more electron dense cytoplasm and less condensed chromatin than controls and modification of their surfaces. Our results indicate that glioblastoma cells, exposed to continuous stratospheric radiations for 24 hrs, show activation of cell cycle check point, decrease of cell number, variations of Peroxisome Proliferator-Activated Receptors and increase of Reactive Oxygen Species-scavenging enzymes.

  13. Autophagy enhancement contributes to the synergistic effect of vitamin D in temozolomide-based glioblastoma chemotherapy

    Science.gov (United States)

    BAK, DONG-HO; KANG, SEONG HEE; CHOI, DU RI; GIL, MI NA; YU, KWANG SIK; JEONG, JI HEUN; LEE, NAM-SEOB; LEE, JE-HUN; JEONG, YOUNG-GIL; KIM, DONG KWAN; KIM, DO-KYUNG; KIM, JWA-JIN; HAN, SEUNG-YUN

    2016-01-01

    Temozolomide (TMZ), an alkylating agent, is recommended as the initial treatment for high-grade glioblastoma. TMZ is widely used, but its short half-life and the frequency of tumor resistance limit its therapeutic efficacy. In the present study, the anticancer effect of vitamin D (VD) combined with TMZ upon glioblastoma was determined, and the underlying mechanism of this effect was identified. Through cell viability, clonogenic and wound healing assays, the current study demonstrated that treatment of a C6 glioblastoma cell line with TMZ and VD resulted in significantly increased in vitro antitumor effects compared with either VD or TMZ alone. Autophagy, hypothesized to be the dominant mechanism underlying TMZ-based tumor cell death, was maximally activated in TMZ and VD co-treated C6 cells. This was demonstrated by ultrastructural observations of autophagosomes, increased size and number of microtubule-associated protein 1 light chain 3 (LC3) puncta and increased conversion of LC3-I to LC3-II. However, the extent of apoptosis was not significantly different between cells treated with TMZ and VD and those treated with TMZ alone. Addition of the autophagy inhibitor 3-methyladenine markedly inhibited the anticancer effect of TMZ and VD treatment, indicating that the chemosensitizing effect of VD in TMZ-based glioblastoma therapy is generated through enhancement of cytotoxic autophagy. TMZ and VD co-treatment also significantly inhibited tumor progression and prolonged survival duration in rat glioblastoma orthotopic xenograft models when compared with TMZ treatment alone. These in vivo results are concordant with the aforementioned in vitro results, together revealing that the combined use of TMZ and VD exerts synergistic antitumor effects on rat models of glioblastoma and may represent an effective therapeutic strategy. PMID:27313664

  14. TSPO Imaging in Glioblastoma Multiforme

    DEFF Research Database (Denmark)

    Jensen, Per; Feng, Ling; Law, Ian

    2015-01-01

    -CLINDE is superior to (18)F-FET in predicting progression of glioblastoma multiforme (GBM) at follow-up. METHODS: Three patients with World Health Organization grade IV GBM were scanned with (123)I-CLINDE SPECT, (18)F-FET PET, and gadolinium-enhanced MR imaging. Molecular imaging data were compared with follow......UNLABELLED: Here we compare translocator protein (TSPO) imaging using 6-chloro-2-(4'-(123)I-iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide SPECT ((123)I-CLINDE) and amino acid transport imaging using O-(2-(18)F-fluoroethyl)-l-tyrosine PET ((18)F-FET) and investigate whether (123)I......-up gadolinium-enhanced MR images or contrast-enhanced CT scans. RESULTS: The percentage overlap between volumes of interest (VOIs) of increased (18)F-FET uptake and (123)I-CLINDE binding was variable (12%-42%). The percentage overlap of MR imaging baseline VOIs was greater for (18)F-FET (79%-93%) than (123)I...

  15. Evolving Molecular Genetics of Glioblastoma

    Institute of Scientific and Technical Information of China (English)

    Qiu-Ju Li; Jin-Quan Cai; Cheng-Yin Liu

    2016-01-01

    Objective: To summary the recent advances in molecular research of glioblastoma (GBM) and current trends in personalized therapy of this disease.Data Sources: Data cited in this review were obtained mainly from PubMed in English up to 2015, with keywords "molecular", "genetics", "GBM", "isocitrate dehydrogenase", "telomerase reverse transcriptase", "epidermal growth factor receptor", "PTPRZ1-MET", and "clinical treatment".Study Selection: Articles regarding the morphological pathology of GBM, the epidemiology of GBM, genetic alteration of GBM, and the development of treatment for GBM patients were identified, retrieved, and reviewed.Results: There is a large amount of data supporting the view that these recurrent genetic aberrations occur in a specific context of cellular origin, co-oncogenic hits and are present in distinct patient populations.Primary and secondary GBMs are distinct disease entities that affect different age groups of patients and develop through distinct genetic aberrations.These differences are important, especially because they may affect sensitivity to radio-and chemo-therapy and should thus be considered in the identification of targets for novel therapeutic approaches.Conclusion: This review highlights the molecular and genetic alterations of GBM, indicating that they are of potential value in the diagnosis and treatment for patients with GBM.

  16. Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells.

    Science.gov (United States)

    Ignarro, Raffaela Silvestre; Facchini, Gustavo; Vieira, André Schwambach; De Melo, Daniela Rodrigues; Lopes-Cendes, Iscia; Castilho, Roger Frigério; Rogerio, Fabio

    2016-07-01

    Temozolomide (TMZ) is an alkylating agent used to treat glioblastoma. This tumor type synthesizes the antioxidant glutathione through system X c (-) , which is inhibited by sulfasalazine (SAS). We exposed A172 and T98G human glioblastoma cells to a presumably clinically relevant concentration of TMZ (25 µM) and/or 0.5 mM SAS for 1, 3, or 5 days and assessed cell viability. For both cell lines, TMZ alone did not alter viability at any time point, while the coadministration of TMZ and SAS significantly reduced cell viability after 5 days. The drug combination exerted a synergistic effect on A172 cells after 3 and 5 days. Therefore, this particular lineage was subjected to complementary analyses on the genetic (transcriptome) and functional (glutathione and proliferating cell nuclear antigen (PCNA) protein) levels. Cellular pathways containing differentially expressed genes related to the cell cycle were modified by TMZ alone. On the other hand, SAS regulated pathways associated with glutathione metabolism and synthesis, irrespective of TMZ. Moreover, SAS, but not TMZ, depleted the total glutathione level. Compared with the vehicle-treated cells, the level of PCNA protein was lower in cells treated with TMZ alone or in combination with SAS. In conclusion, our data showed that the association of TMZ and SAS is cytotoxic to T98G and A172 cells, thus providing useful insights for improving TMZ clinical efficacy through testing this novel drug combination. Moreover, the present study not only reports original information on differential gene expression in glioblastoma cells exposed to TMZ and/or SAS but also describes an antiproliferative effect of TMZ, which has not yet been observed in A172 cells.

  17. Current data and strategy in glioblastoma multiforme

    Science.gov (United States)

    Dinca, EB

    2009-01-01

    Glioblastoma multiforme (GBM) or astrocytoma grade Ⅳ on WHO classification is the most aggressive and the most frequent of all primary brain tumors. Glioblastoma is multiforme , resistant to therapeutic interventions illustrating the heterogeneity exhibited by this tumor in its every aspect, including clinical presentation, pathology, genetic signature. Current data and treatment strategy in GBM are presented focusing on basic science data and key clinical aspects like surgery, including personal experience; adjuvant modalities: radiotherapy, chemotherapy, but also for experimental approaches. Therapeutic attitude in recurrent GBM is also widely discussed. PMID:20108752

  18. Radiation and concomitant chemotherapy for patients with glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    Salvador Vill; Carme Bala; Slvia Comas

    2014-01-01

    Postoperative external beam radiotherapy was considered the standard adjuvant treatment for patients with glioblastoma multiforme until the advent of using the drug temozolomide (TMZ) in addition to radiotherapy. High-dose volume should be focal, minimizing whole brain irradiation. Modern imaging, using several magnetic resonance sequences, has improved the planning target volume definition. The total dose delivered should be in the range of 60 Gy in fraction sizes of 1.8-2.0 Gy. Currently, TMZ concomitant and adjuvant to radiotherapy has become the standard of care for glioblastoma multiforme patients. Radiotherapy dose-intensification and radiosensitizer approaches have not improved the outcome. In spite of the lack of high quality evidence, stereotactic radiotherapy can be considered for a selected group of patients. For elderly patients, data suggest that the same survival benefit can be achieved with similar morbidity using a shorter course of radiotherapy (hypofractionation). Elderly patients with tumors that exhibit methylation of the O-6-methylguanine-DNA methyltransferase promoter can benefit from TMZ alone.

  19. Glioblastoma cancer stem cells: Biomarker and therapeutic advances.

    Science.gov (United States)

    Pointer, Kelli B; Clark, Paul A; Zorniak, Michael; Alrfaei, Bahauddeen M; Kuo, John S

    2014-05-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans. It accounts for fifty-two percent of primary brain malignancies in the United States and twenty percent of all primary intracranial tumors. Despite the current standard therapies of maximal safe surgical resection followed by temozolomide and radiotherapy, the median patient survival is still less than 2 years due to inevitable tumor recurrence. Glioblastoma cancer stem cells (GSCs) are a subgroup of tumor cells that are radiation and chemotherapy resistant and likely contribute to rapid tumor recurrence. In order to gain a better understanding of the many GBM-associated mutations, analysis of the GBM cancer genome is on-going; however, innovative strategies to target GSCs and overcome tumor resistance are needed to improve patient survival. Cancer stem cell biology studies reveal basic understandings of GSC resistance patterns and therapeutic responses. Membrane proteomics using phage and yeast display libraries provides a method to identify novel antibodies and surface antigens to better recognize, isolate, and target GSCs. Altogether, basic GBM and GSC genetics and proteomics studies combined with strategies to discover GSC-targeting agents could lead to novel treatments that significantly improve patient survival and quality of life.

  20. Signal transduction molecule patterns indicating potential glioblastoma therapy approaches

    Directory of Open Access Journals (Sweden)

    Cruceru ML

    2013-11-01

    Full Text Available Maria Linda Cruceru,1 Ana-Maria Enciu,1,2,7 Adrian Claudiu Popa,1,3 Radu Albulescu,2,4,7 Monica Neagu,2,7 Cristiana Pistol Tanase,2,7 Stefan N Constantinescu5–7 1Carol Davila University of Medicine and Pharmacy, Department of Cellular and Molecular Medicine, Bucharest, Romania; 2Victor Babes National Institute of Pathology, Bucharest, Romania; 3Army Centre for Medical Research, Bucharest, Romania; 4National Institute for Chemical Pharmaceutical R&D, Bucharest, Romania; 5de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; 6Ludwig Institute for Cancer Research, Brussels, Belgium; 7Operational Sectorial Programme for Competitive Economic Growth Canbioprot at Victor Babes National Institute of Pathology, Bucharest, Romania Purpose: The expression of an array of signaling molecules, along with the assessment of real-time cell proliferation, has been performed in U87 glioma cell line and in patients’ glioblastoma established cell cultures in order to provide a better understanding of cellular and molecular events involved in glioblastoma pathogenesis. Experimental therapy was performed using a phosphatydylinositol-3´-kinase (PI3K inhibitor. Patients and methods: xMAP technology was employed to assess expression levels of several signal transduction molecules and real-time xCELLigence platform for cell behavior. Results: PI3K inhibition induced the most significant effects on global signaling pathways in patient-derived cell cultures, especially on members of the mitogen-activated protein-kinase family, P70S6 serine-threonine kinase, and cAMP response element-binding protein expression and further prevented tumor cell proliferation. Conclusion: The PI3K pathway might be a prime target for glioblastoma treatment. Keywords: personalized medicine, PI3K inhibitor, targeted therapy, xCELLigence, xMAP analysis

  1. PTEN loss represses glioblastoma tumor initiating cell differentiation via inactivation of Lgl1.

    Science.gov (United States)

    Gont, Alexander; Hanson, Jennifer E L; Lavictoire, Sylvie J; Parolin, Doris A; Daneshmand, Manijeh; Restall, Ian J; Soucie, Mathieu; Nicholas, Garth; Woulfe, John; Kassam, Amin; Da Silva, Vasco F; Lorimer, Ian A J

    2013-08-01

    Glioblastoma multiforme is an aggressive and incurable type of brain tumor. A subset of undifferentiated glioblastoma cells, known as glioblastoma tumor initiating cells (GTICs), has an essential role in the malignancy of this disease and also appears to mediate resistance to radiation therapy and chemotherapy. GTICs retain the ability to differentiate into cells with reduced malignant potential, but the signaling pathways controlling differentiation are not fully understood at this time. PTEN loss is a very common in glioblastoma multiforme and leads to aberrant activation of the phosphoinositide 3-kinase pathway. Increased signalling through this pathway leads to activation of multiple protein kinases, including atypical protein kinase C. In Drosophila, active atypical protein kinase C has been shown to promote the self-renewal of neuroblasts, inhibiting their differentiation along a neuronal lineage. This effect is mediated by atypical protein kinase c-mediated phosphorylation and inactivation of Lgl, a protein that was first characterized as a tumour suppressor in Drosophila. The effects of the atypical protein kinase C/Lgl pathway on the differentiation status of GTICs, and its potential link to PTEN loss, have not been assessed previously. Here we show that PTEN loss leads to the phosphorylation and inactivation of Lgl by atypical protein kinase C in glioblastoma cells. Re-expression of PTEN in GTICs promoted their differentiation along a neuronal lineage. This effect was also seen when atypical protein kinase C was knocked down using RNA interference, and when a non-phosphorylatable, constitutively active form of Lgl was expressed in GTICs. Thus PTEN loss, acting via atypical protein kinase C activation and Lgl inactivation, helps to maintain GTICs in an undifferentiated state.

  2. mTORC2 modulates feedback regulation of p38 MAPK activity via DUSP10/MKP5 to confer differential responses to PP242 in glioblastoma

    Science.gov (United States)

    Benavides-Serrato, Angelica; Anderson, Lauren; Holmes, Brent; Cloninger, Cheri; Artinian, Nicholas; Bashir, Tariq; Gera, Joseph

    2014-01-01

    Dual-specificity phosphatases (DUSPs) dephosphorylate MAP kinases (MAPKs) resulting in their inactivation. Activation of MAPK signaling leads to enhanced DUSP expression, thus establishing feedback regulation of the MAPK pathway. The DUSPs are subject to regulation at the post-translational level via phosphorylation resulting in alterations of protein stability. Here we report that mTORC2 function leads to stabilization of the p38 MAPK phosphatase, DUSP10, thereby inhibiting p38 activity. We demonstrate that mTORC2 binds DUSP10 and phosphorylates DUSP10 on serine residues 224 and 230. These phosphorylation events block DUSP10 turnover resulting in inactivation of p38 signaling. We further show that insulin-stimulated PI3K/mTORC2 signaling regulates DUSP10 stability and p38 activity. Importantly, knockdown of DUSP10 or ectopic overexpression of nonphosphorylatable or phosphomimetic DUSP10 mutants was sufficient to confer differential mTOR kinase inhibitor responses to GBM cells in vitro and in murine xenografts. Finally, DUSP10 was shown to be overexpressed in a significant number of GBM patients. These data demonstrate the ability of the mTORC2 pathway to exert regulatory effects on the DUSP10/p38 feedback loop to control the cellular effects of mTOR kinase inhibitors in GBM and support the use of DUSP10 expression as a surrogate biomarker to predict responsiveness. PMID:25568665

  3. Identification of RIP1 as a critical mediator of Smac mimetic-mediated sensitization of glioblastoma cells for Drozitumab-induced apoptosis

    Science.gov (United States)

    Cristofanon, S; Abhari, B A; Krueger, M; Tchoghandjian, A; Momma, S; Calaminus, C; Vucic, D; Pichler, B J; Fulda, S

    2015-01-01

    This study aims at evaluating the combination of the tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL)-receptor 2 (TRAIL-R2)-specific antibody Drozitumab and the Smac mimetic BV6 in preclinical glioblastoma models. To this end, the effect of BV6 and/or Drozitumab on apoptosis induction and signaling pathways was analyzed in glioblastoma cell lines, primary glioblastoma cultures and glioblastoma stem-like cells. Here, we report that BV6 and Drozitumab synergistically induce apoptosis and reduce colony formation in several glioblastoma cell lines (combination index<0.1). Also, BV6 profoundly enhances Drozitumab-induced apoptosis in primary glioblastoma cultures and glioblastoma stem-like cells. Importantly, BV6 cooperates with Drozitumab to suppress tumor growth in two glioblastoma in vivo models including an orthotopic, intracranial mouse model, underlining the clinical relevance of these findings. Mechanistic studies reveal that BV6 and Drozitumab act in concert to trigger the formation of a cytosolic receptor-interacting protein (RIP) 1/Fas-associated via death domain (FADD)/caspase-8-containing complex and subsequent activation of caspase-8 and -3. BV6- and Drozitumab-induced apoptosis is blocked by the caspase inhibitor zVAD.fmk, pointing to caspase-dependent apoptosis. RNA interference-mediated silencing of RIP1 almost completely abolishes the BV6-conferred sensitization to Drozitumab-induced apoptosis, indicating that the synergism critically depends on RIP1 expression. In contrast, both necrostatin-1, a RIP1 kinase inhibitor, and Enbrel, a TNFα-blocking antibody, do not interfere with BV6/Drozitumab-induced apoptosis, demonstrating that apoptosis occurs independently of RIP1 kinase activity or an autocrine TNFα loop. In conclusion, the rational combination of BV6 and Drozitumab presents a promising approach to trigger apoptosis in glioblastoma, which warrants further investigation. PMID:25880091

  4. Targeted Nanotechnology in Glioblastoma Multiforme

    Science.gov (United States)

    Glaser, Talita; Han, Inbo; Wu, Liquan; Zeng, Xiang

    2017-01-01

    Gliomas, and in particular glioblastoma multiforme, are aggressive brain tumors characterized by a poor prognosis and high rates of recurrence. Current treatment strategies are based on open surgery, chemotherapy (temozolomide) and radiotherapy. However, none of these treatments, alone or in combination, are considered effective in managing this devastating disease, resulting in a median survival time of less than 15 months. The efficiency of chemotherapy is mainly compromised by the blood-brain barrier (BBB) that selectively inhibits drugs from infiltrating into the tumor mass. Cancer stem cells (CSCs), with their unique biology and their resistance to both radio- and chemotherapy, compound tumor aggressiveness and increase the chances of treatment failure. Therefore, more effective targeted therapeutic regimens are urgently required. In this article, some well-recognized biological features and biomarkers of this specific subgroup of tumor cells are profiled and new strategies and technologies in nanomedicine that explicitly target CSCs, after circumventing the BBB, are detailed. Major achievements in the development of nanotherapies, such as organic poly(propylene glycol) and poly(ethylene glycol) or inorganic (iron and gold) nanoparticles that can be conjugated to metal ions, liposomes, dendrimers and polymeric micelles, form the main scope of this summary. Moreover, novel biological strategies focused on manipulating gene expression (small interfering RNA and clustered regularly interspaced short palindromic repeats [CRISPR]/CRISPR associated protein 9 [Cas 9] technologies) for cancer therapy are also analyzed. The aim of this review is to analyze the gap between CSC biology and the development of targeted therapies. A better understanding of CSC properties could result in the development of precise nanotherapies to fulfill unmet clinical needs.

  5. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma.

    Science.gov (United States)

    Kessler, Tobias; Sahm, Felix; Blaes, Jonas; Osswald, Matthias; Rübmann, Petra; Milford, David; Urban, Severino; Jestaedt, Leonie; Heiland, Sabine; Bendszus, Martin; Hertenstein, Anne; Pfenning, Philipp-Niclas; Ruiz de Almodóvar, Carmen; Wick, Antje; Winkler, Frank; von Deimling, Andreas; Platten, Michael; Wick, Wolfgang; Weiler, Markus

    2015-10-13

    Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.

  6. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Hayley Patricia Ellis

    2014-03-01

    Full Text Available Glioblastoma Multiforme (GBM is the most common primary intrinsic CNS tumour and has an extremely poor overall survival, despite advances in neurosurgery, chemotherapy and radiation therapy. There has been interesting preliminary evidence suggesting that patients receiving the group of anti-diabetic drugs known as PPARγ (Peroxisome proliferator-activated receptor gamma agonists have a lower incidence of glioma. The nuclear hormone receptor PPARγ has been found to be expressed in high grade gliomas, and its activation has been shown to have several antineoplastic effects on human and rat glioma cell lines, and in some instances an additional protective increase in antioxidant enzymes has been observed in normal astrocytes. At present, no clinical trials are underway with regards to treating glioma patients using PPARγ agonists, as Pioglitazone and Rosiglitazone are only FDA-approved for use in treatment of type-2 diabetes. This review presents the case for evaluating the potential of PPARγ agonists as novel adjuvants in the treatment of high grade glioma. We introduce the PPARγ pathway, PPARγ gene and its products and examine recent research in glioblastoma.

  7. Small cell glioblastoma or small cell carcinoma

    DEFF Research Database (Denmark)

    Hilbrandt, Christine; Sathyadas, Sathya; Dahlrot, Rikke H

    2013-01-01

    was admitted to the hospital with left-sided loss of motor function. A MRI revealed a 6 cm tumor in the right temporoparietal area. The histology was consistent with both glioblastoma multiforme (GBM) and small cell lung carcinoma (SCLC) but IHC was suggestive of a SCLC metastasis. PET-CT revealed...

  8. Stereotactic radiosurgery for glioblastoma: retrospective analysis

    Directory of Open Access Journals (Sweden)

    Walter Kevin A

    2009-03-01

    Full Text Available Abstract Purpose This retrospective study was done to better understand the conditions for which stereotactic radiosurgery (SRS for glioblastoma may be efficacious. Methods Between 2000 and 2007, 33 patients with a pathological diagnosis of glioblastoma received SRS with the Novalis® Shaped Beam Radiosurgery system. Eighteen patients (54% underwent salvage SRS for recurrence while 15 (45% patients received upfront SRS following standard fractionated RT for newly diagnosed glioblastoma. Results There were no RTOG grade >2 acute side effects. The median survival after SRS was 6.7 months (range 1.4 – 74.7. There was no significant difference in overall survival (from the time of initial diagnosis with respect to the timing of SRS (p = 0.2. There was significantly better progression free survival in patients treated with SRS as consolidation versus at the time of recurrence (p = 0.04. The majority of patients failed within or at the margin of the SRS treatment volume (21/26 evaluable for recurrence. Conclusion SRS is well tolerated in the treatment of glioblastoma. As there was no difference in survival whether SRS is delivered upfront or at recurrence, the treatment for each patient should be individualized. Future studies are needed to identify patients most likely to respond to SRS.

  9. Multiple glioblastomas: CT and MR features

    Energy Technology Data Exchange (ETDEWEB)

    Lafitte, F.; Morel-Precetti, S.; Martin-Duverneuil, N.; Guermazi, A.; Brunet, E.; Chiras, J. [Hopital de la Salpetriere, Paris (France). Service de Neuroradiologie Charcot; Heran, F. [Service de Radiologie, Fondation Rothschild, Paris (France)

    2001-01-01

    The aim of this study was to analyze the CT and MR features of multiple glioblastomas, and to determine the best imaging modality for the initial diagnosis. The CT (four exams) and MR imaging (eight exams) of eight patients with proven multiple glioblastomas were reviewed by two neuroradiologists. The lesions were always hypo- or isodense on CT and hyperintense on T2-weighted images (100%). They were usually hypo- or isointense on T1-weighted images (90%). Edema and mass effect were very variable. After contrast media administration, the enhancement was mostly strong (71% on CT and 70% on MR), often either heterogeneous or ring-like. The different lesions of a patient often had a different pattern on MR (75% of cases). Meningeal or ventricular enhancement, suggestive of a possible way of dissemination, was rare. In case of multiple cerebral masses, multiple glioblastomas should be considered as a possible diagnosis in addition to the better known diagnosis of brain metastases, abscesses, or multifocal lymphomas. Moderate edema and mass effect on MR associated with strong and heterogeneous enhancement are suggestive of feature of multiple glioblastomas. Magnetic resonance allows rarely the visualization of a dissemination route. (orig.)

  10. Telomere profiling: toward glioblastoma personalized medicine.

    Science.gov (United States)

    Ferrandon, Sylvain; Saultier, Paul; Carras, Julien; Battiston-Montagne, Priscillia; Alphonse, Gersende; Beuve, Michael; Malleval, Céline; Honnorat, Jérôme; Slatter, Tania; Hung, Noelyn; Royds, Janice; Rodriguez-Lafrasse, Claire; Poncet, Delphine

    2013-02-01

    Despite a standard of care combining surgery, radiotherapy (RT), and temozolomide chemotherapy, the average overall survival (OS) of glioblastoma patients is only 15 months, and even far lower when the patient cannot benefit from this combination. Therefore, there is a strong need for new treatments, such as new irradiation techniques. Against this background, carbon ion hadrontherapy, a new kind of irradiation, leads to a greater biological response of the tumor, while minimizing adverse effects on healthy tissues in comparison with RT. As carbon ion hadrontherapy is restricted to RT-resistant patients, photon irradiation resistance biomarkers are needed. Long telomeres and high telomerase activity have been widely associated with photon radioresistance in other cancers. Moreover, telomere protection, telomere function, and telomere length (TL) also depend on the shelterin protein complex (TRF1, TRF2, TPP1, POT1, TIN2, and hRAP1). We thus decided to evaluate an enlarged telomeric status (TL, telomerase catalytic subunit, and the shelterin component expression level) as a potential radioresistance biomarker in vitro using cellular models and ex vivo using patient tumor biopsies. In addition, nothing was known about the role of telomeres in carbon ion response. We thus evaluated telomeric status after both types of irradiation. We report here a significant correlation between TL and the basal POT1 expression level and photon radioresistance, in vitro, and a significant increase in the OS of patients with long telomeres or a high POT1 level, in vivo. POT1 expression was predictive of patient response irrespective of the TL. Strikingly, these correlations were lost, in vitro, when considering carbon irradiation. We thus propose (1) a model of the implications of telomeric damage in the cell response to both types of irradiation and (2) assessment of the POT1 expression level and TL using patient tumor biopsies to identify radioresistant patients who could benefit from

  11. Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration

    Energy Technology Data Exchange (ETDEWEB)

    Michaud-Levesque, Jonathan; Bousquet-Gagnon, Nathalie; Beliveau, Richard, E-mail: oncomol@nobel.si.uqam.ca

    2012-05-01

    Evidence has suggested that STAT3 functions as an oncogene in gliomagenesis. As a consequence, changes in the inflammatory microenvironment are thought to promote tumor development. Regardless of its origin, cancer-related inflammation has many tumor-promoting effects, such as the promotion of cell cycle progression, cell proliferation, cell migration and cell survival. Given that IL-6, a major cancer-related inflammatory cytokine, regulates STAT3 activation and is upregulated in glioblastoma, we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by IL-6, and to determine the underlying mechanisms of action. In this study, we show that quercetin is a potent inhibitor of the IL-6-induced STAT3 signaling pathway in T98G and U87 glioblastoma cells. Exposure to quercetin resulted in the reduction of GP130, JAK1 and STAT3 activation by IL-6, as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6. Interestingly, quercetin also modulated the expression of two target genes regulated by STAT3, i.e. cyclin D1 and matrix metalloproteinase-2 (MMP-2). Moreover, quercetin reduced the recruitment of STAT3 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of IL-6. Overall, these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6, with a potential role in the prevention and treatment of glioblastoma.

  12. Cisgenic barley with improved phytase activity

    DEFF Research Database (Denmark)

    Holme, Inger; Dionisio, Giuseppe; Brinch-Pedersen, Henrik

    2012-01-01

    The cisgenesis concept implies that plants are transformed only with their own genetic materials or genetic materials from closely related species capable of sexual hybridization. Furthermore, foreign sequences such as selection genes and vector-backbone sequences should be absent. We used a barley...... phytase gene (HvPAPhy_a) expressed during grain filling to evaluate the cisgenesis concept in barley. The marker gene elimination method was used to obtain marker-free plant lines. Here, the gene of interest and the selection gene are flanked by their own T-DNA borders to allow unlinked integration...... of the two genes. We analysed the transformants for co-transformation efficiency, increased phytase activities in the grain, integration of the kanamycin resistance gene of the vector-backbone and segregation between the HvPAPhy_a insert and the hygromycin resistance gene. The frequencies of the four...

  13. Salinomycin induced ROS results in abortive autophagy and leads to regulated necrosis in glioblastoma

    Science.gov (United States)

    Xipell, Enric; Gonzalez-Huarriz, Marisol; de Irujo, Juan Jose Martinez; García-Garzón, Antonia; Lang, Fred F.; Jiang, Hong; Fueyo, Juan; Gomez-Manzano, Candelaria; Alonso, Marta M.

    2016-01-01

    Glioblastoma is the most frequent malignant brain tumor. Even with aggressive treatment, prognosis for patients is poor. One characteristic of glioblastoma cells is its intrinsic resistance to apoptosis. Therefore, drugs that induce alternative cell deaths could be interesting to evaluate as alternative therapeutic candidates for glioblastoma. Salinomycin (SLM) was identified through a chemical screening as a promising anticancer drug, but its mechanism of cell death remains unclear. In the present work we set out to elucidate how SLM causes cell death in glioblastoma cell lines (both established cell lines and brain tumor stem cell lines), aiming to find a potential antitumor candidate. In addition, we sought to determine the mechanism of action of SLM so that this mechanism can be can be exploited in the fight against cancer. Our data showed that SLM induces a potent endoplasmic reticulum (ER) stress followed by the trigger of the unfolded protein response (UPR) and an aberrant autophagic flux that culminated in necrosis due to mitochondria and lysosomal alterations. Of importance, the aberrant autophagic flux was orchestrated by the production of Reactive Oxygen Species (ROS). Alleviation of ROS production restored the autophagic flux. Altogether our data suggest that in our system the oxidative stress blocks the autophagic flux through lipid oxidation. Importantly, oxidative stress could be instructing the type of cell death in SLM-treated cells, suggesting that cell death modality is a dynamic concept which depends on the cellular stresses and the cellular mechanism activated. PMID:27121320

  14. Inhibition of Indoleamine-2,3-dioxygenase (IDO in Glioblastoma Cells by Oncolytic Herpes Simplex Virus

    Directory of Open Access Journals (Sweden)

    Bonnie Reinhart

    2012-01-01

    Full Text Available Successful oncolytic virus treatment of malignant glioblastoma multiforme depends on widespread tumor-specific lytic virus replication and escape from mitigating innate immune responses to infection. Here we characterize a new HSV vector, JD0G, that is deleted for ICP0 and the joint sequences separating the unique long and short elements of the viral genome. We observed that JD0G replication was enhanced in certain glioblastoma cell lines compared to HEL cells, suggesting that a vector backbone deleted for ICP0 may be useful for treatment of glioblastoma. The innate immune response to virus infection can potentially impede oncolytic vector replication in human tumors. Indoleamine-2,3-dioxygenase (IDO is expressed in response to interferon γ (IFNγ and has been linked to both antiviral functions and to the immune escape of tumor cells. We observed that IFNγ treatment of human glioblastoma cells induced the expression of IDO and that this expression was quelled by infection with both wild-type and JD0G viruses. The role of IDO in inhibiting virus replication and the connection of this protein to the escape of tumor cells from immune surveillance suggest that IDO downregulation by HSV infection may enhance the oncolytic activity of vectors such as JD0G.

  15. Effects of Flavonoids from Food and Dietary Supplements on Glial and Glioblastoma Multiforme Cells.

    Science.gov (United States)

    Vidak, Marko; Rozman, Damjana; Komel, Radovan

    2015-10-23

    Quercetin, catechins and proanthocyanidins are flavonoids that are prominently featured in foodstuffs and dietary supplements, and may possess anti-carcinogenic activity. Glioblastoma multiforme is the most dangerous form of glioma, a malignancy of the brain connective tissue. This review assesses molecular structures of these flavonoids, their importance as components of diet and dietary supplements, their bioavailability and ability to cross the blood-brain barrier, their reported beneficial health effects, and their effects on non-malignant glial as well as glioblastoma tumor cells. The reviewed flavonoids appear to protect glial cells via reduction of oxidative stress, while some also attenuate glutamate-induced excitotoxicity and reduce neuroinflammation. Most of the reviewed flavonoids inhibit proliferation of glioblastoma cells and induce their death. Moreover, some of them inhibit pro-oncogene signaling pathways and intensify the effect of conventional anti-cancer therapies. However, most of these anti-glioblastoma effects have only been observed in vitro or in animal models. Due to limited ability of the reviewed flavonoids to access the brain, their normal dietary intake is likely insufficient to produce significant anti-cancer effects in this organ, and supplementation is needed.

  16. Improving active eigenvector assignment through passive modifications

    Science.gov (United States)

    Belotti, R.; Richiedei, D.

    2016-09-01

    Specifications on the dynamic behavior of feedback-controlled vibrating systems are often expressed in terms of its eigenstructure, i.e. eigenvalues and eigenvectors. The notion of controllability establishes the possibility to assign eigenvalues through state feedback, but it is not adequate to assure the assignment of arbitrary eigenvectors. Indeed, assignable eigenvectors are just those belonging to the allowable vector subspace, which depends on the physical properties of the vibrating system (mass, damping and stiffness matrices) and of the actuators. To overcome this limitation, this paper proposes a hybrid approach that exploits passive modification of the system physical parameters to modify the allowable subspace in such a way that it spans (or closely approximates) the desired eigenvectors. Then, once that the system modifications have been computed, standard techniques for control synthesis can be employed to compute the gains assigning the desired poles and the eigenvectors. The modification of the allowable subspace is cast in this work as a rank minimization problem, which can be efficiently tackled through semi-definite programming. The proposed method is numerically validated on a lumped parameter system, by proving that the assignment of eigenvectors by hybrid control is significantly enhanced compared with sole active control.

  17. Molecular heterogeneity in glioblastoma: therapeutic opportunities and challenges.

    Science.gov (United States)

    Nicholas, M Kelly; Lukas, Rimas V; Chmura, Steven; Yamini, Bakhtihar; Lesniak, Maciej; Pytel, Peter

    2011-04-01

    Glioblastoma (GBM) has been recognized as a clinical and pathologic entity for more than a century. Throughout its history, its cells of origin have been in question. Its behavior is aggressive and despite decades of effort, median survival is just beginning to improve. Surgical techniques and radiotherapy schemas continue to be refined, but the most recent progress has been achieved through improved medical therapies. These are the result of both pharmacological advances and a deeper understanding of the biological characteristics of GBM. Due to a combination of its complex phenotype and organ-specific clinical manifestations, efforts to refine GBM treatment with targeted therapies largely have been frustrated. In this review, we discuss recent attempts to exploit new molecular insights, consider the reasons for slow progress in developing better treatments, and examine future therapeutic options.

  18. Genetic variations in EGF and EGFR and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, Sara; Andersson, Ulrika; Liu, Yanhong;

    2010-01-01

    Few prognostic factors have been associated with glioblastoma survival. We analyzed a complete tagging of the epidermal growth factor (EGF) and EGF receptor (EGFR) gene polymorphisms as potential prognostic factors. Thirty tagging single-nucleotide polymorphisms (SNPs) in EGF and 89 tagging SNPs...... in EGFR were analyzed for association with survival in 176 glioblastoma cases. Validation analyses were performed for 4 SNPs in a set of 638 glioblastoma patients recruited at The University of Texas M. D. Anderson Cancer Center (MDACC). Three hundred and seventy-four glioblastoma patients aged 50 years...... or older at diagnosis were subanalyzed to enrich for de novo arising glioblastoma. We found 7 SNPs in haplotype 4 in EGF that were associated with prognosis in glioblastoma patients. In EGFR, 4 of 89 SNPs were significantly associated with prognosis but judged as false positives. Four of the significantly...

  19. Hyaluronic acid-conjugated liposome nanoparticles for targeted delivery to CD44 overexpressing glioblastoma cells

    Science.gov (United States)

    Hayward, Stephen L.; Wilson, Christina L.; Kidambi, Srivatsan

    2016-01-01

    Glioblastoma Multiforme (GBM) is a highly prevalent and deadly brain malignancy characterized by poor prognosis and restricted disease management potential. Despite the success of nanocarrier systems to improve drug/gene therapy for cancer, active targeting specificity remains a major hurdle for GBM. Additionally, since the brain is a multi-cell type organ, there is a critical need to develop an approach to distinguish between GBM cells and healthy brain cells for safe and successful treatment. In this report, we have incorporated hyaluronic acid (HA) as an active targeting ligand for GBM. To do so, we employed HA conjugated liposomes (HALNPs) to study the uptake pathway in key cells in the brain including primary astrocytes, microglia, and human GBM cells. We observed that the HALNPs specifically target GBM cells over other brain cells due to higher expression of CD44 in tumor cells. Furthermore, CD44 driven HALNP uptake into GBM cells resulted in lysosomal evasion and increased efficacy of Doxorubicin, a model anti-neoplastic agent, while the astrocytes and microglia cells exhibited extensive HALNP-lysosome co-localization and decreased antineoplastic potency. In summary, novel CD44 targeted lipid based nanocarriers appear to be proficient in mediating site-specific delivery of drugs via CD44 receptors in GBM cells, with an improved therapeutic margin and safety. PMID:27120809

  20. Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Lin YL

    2015-09-01

    Full Text Available Yu-Ling Lin,1,2,* Kai-Fu Chang,3,* Xiao-Fan Huang,3 Che-Lun Hung,4 Shyh-Chang Chen,5 Wan-Ru Chao,6,7 Kuang-Wen Liao,1,8 Nu-Man Tsai3,9 1College of Biological Science and Technology, 2Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, 3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, 4Department of Computer Science and Communication Engineering, Providence University, 5Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, 6Institute of Medicine, Chung Shan Medical University, 7Department of Pathology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, 8Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 9Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan *These authors contributed equally to this work Background: The natural compound n-butylidenephthalide (BP can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.Objective: The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.Methods: To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC. Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.Results: When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than

  1. Association between RAD 51 rs1801320 and susceptibility to glioblastoma.

    Science.gov (United States)

    Franceschi, S; Tomei, S; Mazzanti, C M; Lessi, F; Aretini, P; La Ferla, M; De Gregorio, V; Pasqualetti, F; Zavaglia, K; Bevilacqua, G; Naccarato, A G

    2016-01-01

    Glioblastoma is the most common and aggressive malignant primary brain tumor. Despite decades of research and the advent of new therapies, patients with glioblastoma continue to have a very poor prognosis. Radiation therapy has a major role as adjuvant treatment for glioblastoma following surgical resection. Many studies have shown that polymorphisms of genes involved in pathways of DNA repair may affect the sensitivity of the cells to treatment. Although the role of these polymorphisms has been investigated in relation to response to radiotherapy, their role as predisposing factors to glioblastoma has not been clarified yet. In the present study, we evaluated the association between polymorphisms in DNA repair genes, namely: XRCC1 rs25487, XRCC3 rs861539 and RAD51 rs1801320, with the susceptibility to develop glioblastoma. Eighty-five glioblastoma patients and 70 matched controls were recruited for this study. Data from the 1000 Genomes Project (98 Tuscans) were also downloaded and used for the association analysis. Subjects carrying RAD51 rs1801320 GC genotype showed an increased risk of glioblastoma (GC vs GG, χ(2) = 10.75; OR 3.0087; p = 0.0010). The C allele was also significantly associated to glioblastoma (χ(2) = 8.66; OR 2.5674; p = 0.0032). Moreover, RAD51 rs1801320 C allele increased the risk to develop glioblastoma also when combined to XRCC1 rs25487 G allele and XRCC3 rs861539 C allele (χ(2) = 6.558; p = 0.0053).

  2. PCDH10 is required for the tumorigenicity of glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Echizen, Kanae [Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Nakada, Mitsutoshi, E-mail: mnakada@med.kanazawa-u.ac.jp [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1, Takara-machi, Kanazawa 920-8641 (Japan); Hayashi, Tomoatsu [Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Sabit, Hemragul; Furuta, Takuya [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1, Takara-machi, Kanazawa 920-8641 (Japan); Nakai, Miyuki; Koyama-Nasu, Ryo; Nishimura, Yukiko; Taniue, Kenzui [Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Morishita, Yasuyuki [Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Hirano, Shinji [Department of Neurobiology and Anatomy, Kochi Medical School, Kochi University, Okoh-cho, Nangoku-City, Kochi 783-8505 (Japan); Terai, Kenta [Laboratory of Function and Morphology, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Todo, Tomoki; Ino, Yasushi; Mukasa, Akitake; Takayanagi, Shunsaku; Ohtani, Ryohei; Saito, Nobuhito [Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan); Akiyama, Tetsu, E-mail: akiyama@iam.u-tokyo.ac.jp [Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan)

    2014-01-31

    Highlights: • PCDH10 is required for the proliferation, survival and self-renewal of glioblastoma cells. • PCDH10 is required for glioblastoma cell migration and invasion. • PCDH10 is required for the tumorigenicity of glioblastoma cells. • PCDH10 may be a promising target for the therapy of glioblastoma. - Abstract: Protocadherin10 (PCDH10)/OL-protocadherin is a cadherin-related transmembrane protein that has multiple roles in the brain, including facilitating specific cell–cell connections, cell migration and axon guidance. It has recently been reported that PCDH10 functions as a tumor suppressor and that its overexpression inhibits proliferation or invasion of multiple tumor cells. However, the function of PCDH10 in glioblastoma cells has not been elucidated. In contrast to previous reports on other tumors, we show here that suppression of the expression of PCDH10 by RNA interference (RNAi) induces the growth arrest and apoptosis of glioblastoma cells in vitro. Furthermore, we demonstrate that knockdown of PCDH10 inhibits the growth of glioblastoma cells xenografted into immunocompromised mice. These results suggest that PCDH10 is required for the proliferation and tumorigenicity of glioblastoma cells. We speculate that PCDH10 may be a promising target for the therapy of glioblastoma.

  3. Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival

    Directory of Open Access Journals (Sweden)

    Southey Bruce R

    2011-06-01

    . Biological processes associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death. Conclusions Known biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme.

  4. Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Bernhart, Eva; Damm, Sabine; Wintersperger, Andrea [Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz (Austria); DeVaney, Trevor [Institute of Biophysics, Medical University of Graz (Austria); Zimmer, Andreas [Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, Karl-Franzens University, Graz (Austria); Raynham, Tony; Ireson, Christopher [Cancer Research Technology Ltd, London (United Kingdom); Sattler, Wolfgang, E-mail: wolfgang.sattler@medunigraz.at [Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz (Austria)

    2013-08-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which, despite combined modality treatment, reoccurs and is invariably fatal for affected patients. Recently, a member of the serine/threonine protein kinase D (PRKD) family, PRKD2, was shown to be a potent mediator of glioblastoma growth. Here we studied the role of PRKD2 in U87MG glioblastoma cell migration and invasion in response to sphingosine-1-phosphate (S1P), an activator of PRKD2 and a GBM mitogen. Time-lapse microscopy demonstrated that random cell migration was significantly diminished in response to PRKD2 silencing. The pharmacological PRKD family inhibitor CRT0066101 decreased chemotactic migration and invasion across uncoated or matrigel-coated Transwell inserts. Silencing of PRKD2 attenuated migration and invasion of U87MG cells even more effectively. In terms of downstream signaling, CRT0066101 prevented PRKD2 autophosphorylation and inhibited p44/42 MAPK and to a smaller extent p54/46 JNK and p38 MAPK activation. PRKD2 silencing impaired activation of p44/42 MAPK and p54/46 JNK, downregulated nuclear c-Jun protein levels and decreased c-Jun{sup S73} phosphorylation without affecting the NFκB pathway. Finally, qPCR array analyses revealed that silencing of PRKD2 downregulates mRNA levels of integrin alpha-2 and -4 (ITGA2 and -4), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and matrix metallopeptidase 1 (MMP1). Findings of the present study identify PRKD2 as a potential target to interfere with glioblastoma cell migration and invasion, two major determinants contributing to recurrence of glioblastoma after multimodality treatment. Highlights: • Sphingosine-1-phosphate induces glioma cell migration and invasion. • Part of the effects is mediated by protein kinase D2 (PRKD2) activation. • Inactivation of PRKD2 attenuates glioblastoma cell migration and invasion. • Both, RNAi and pharmacological inhibition of PRKD2 inhibits MAPK

  5. Immobilization of activated sludge using improved polyvinyl alcohol (PVA) gel

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The microbial immobilization method using polyvinyl alcohol (PVA) gel as an immobilizing material was improved and used for entrapment of activated sludge. The OUR (oxygen uptake rate) was used to characterize the biological activity of immobilized activated sludge. Three kinds of PVA-immobilized particles of activated sludge, that is, PVA-boric acid beads, PVA-sodium nitrate beads and PVA-orthophosphate beads was prepared, and their biological activity was compared by measuring the OUR value. The bioactivity of both autotrophic and heterotrophic microorganisms of activated sludge was determined using different synthetic wastewater media (containing 250 mg/L COD and 25 mg/L NH4+-N). The experimental results showed that the bioactivity and stability of the three kinds of immobilized activated sludge was greatly improved after activation. With respect of the bioactivity and the mechanical stability, the PVA-orthophosphate method may be a promising and economical technique for microbial immobilization.

  6. Overview of Cellular Immunotherapy for Patients with Glioblastoma

    Directory of Open Access Journals (Sweden)

    Elodie Vauleon

    2010-01-01

    Full Text Available High grade gliomas (HGG including glioblastomas (GBM are the most common and devastating primary brain tumours. Despite important progresses in GBM treatment that currently includes surgery combined to radio- and chemotherapy, GBM patients' prognosis remains very poor. Immunotherapy is one of the new promising therapeutic approaches that can specifically target tumour cells. Such an approach could also maintain long term antitumour responses without inducing neurologic defects. Since the past 25 years, adoptive and active immunotherapies using lymphokine-activated killer cells, cytotoxic T cells, tumour-infiltrating lymphocytes, autologous tumour cells, and dendritic cells have been tested in phase I/II clinical trials with HGG patients. This paper inventories these cellular immunotherapeutic strategies and discusses their efficacy, limits, and future perspectives for optimizing the treatment to achieve clinical benefits for GBM patients.

  7. Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma.

    Science.gov (United States)

    Chang, Liang; Zhao, Dan; Liu, Hui-Bin; Wang, Qiu-Shi; Zhang, Ping; Li, Chen-Long; Du, Wen-Zhong; Wang, Hong-Jun; Liu, Xing; Zhang, Zhi-Ren; Jiang, Chuan-Lu

    2015-11-01

    Aberrant hedgehog signaling contributes to the development of various malignancies, including glioblastoma (GBM). However, the potential mechanism of hedgehog signaling in GBM migration and invasion has remained to be elucidated. The present study showed that enhanced hedgehog signaling by recombinant human sonic hedgehog N‑terminal peptide (rhSHH) promoted the adhesion, invasion and migration of GBM cells, accompanied by increases in mRNA and protein levels of matrix metalloproteinase‑2 (MMP‑2) and MMP‑9. However, inhibition of hedgehog signaling with cyclopamine suppressed the adhesion, invasion and migration of GBM cells, accompanied by decreases in mRNA and protein levels of MMP‑2 and ‑9. Furthermore, it was found that MMP‑2- and MMP‑9-neutralizing antibodies or GAM6001 reversed the inductive effects of rhSHH on cell migration and invasion. In addition, enhanced hedgehog signaling by rhSHH increased AKT phosphorylation, whereas blockade of hedgehog signaling decreased AKT phosphorylations. Further experiments showed that LY294002, an inhibitor of phosphoinositide-3 kinase (PI3K), decreased rhSHH‑induced upregulation of MMP‑2 and ‑9. Finally, the protein expression of glioblastoma-associated oncogene 1 was positively correlated with levels of phosphorylated AKT as well as protein expressions of MMP‑2 and ‑9 in GBM tissue samples. In conclusion, the present study indicated that the hedgehog pathway regulates GBM-cell migration and invasion by increasing MMP-2 and MMP-9 production via the PI3K/AKT pathway.

  8. Nutrient activation of Trichoderma fungal spores for improved biocontrol activity

    Institute of Scientific and Technical Information of China (English)

    Linda Gordon Hjeljord; Arne Tronsmo

    2004-01-01

    @@ The effect of preliminary nutrient activation on the ability of conidia of the antagonist Trichoderma harzianum P1 (ThP1) to suppress Botrytis cinerea was investigated in laboratory, greenhouse and field trials. Preliminary nutrient activation at 21 ℃ accelerated subsequent germination of the antagonist at temperatures from 9 ℃ to 21 ℃; at ≥ 18 ℃ the germination time of preactivated ThP1conidia did not differ significantly from that of B. cinerea. When coinoculated with B. cinerea,concentrated inocula of preactivated but ungerminated ThP1 conidia reduced in vitro germination of the pathogen by ≥ 87 % at 12 ℃ to 25 ℃; initially-quiescent conidia achieved this level of suppression only at 25 ℃. Application of quiescent ThP1 conidia to detached strawberry flowers in moist chambers reduced infection by B. cinerea by ≥85 % at 24 ℃ , but only by 35 % at 12 ℃. Preactivated conidia reduced infection by ≥60% at 12 ℃. Both quiescent and preactivated conidia significantly reduced latent infection in greenhouse-grown strawberries at a mean temperture of 19 ℃, while only preactivated conidia were effective in the field at a mean temperature of 14 ℃ on the day of treatment application.

  9. MicroRNA biomarkers in glioblastoma

    DEFF Research Database (Denmark)

    Hermansen, Simon Kjær; Kristensen, Bjarne Winther

    2013-01-01

    Recent research suggests that deregulation of microRNAs (miRNAs) is involved in initiation and progression of many cancers, including gliomas and that miRNAs hold great potential as future diagnostic and therapeutic tools in cancer. MiRNAs are a class of short non-coding RNA sequences (18......-24 nucleotides), which base-pair to target messenger RNA (mRNA) and thereby cause translational repression or mRNA degradation based on the level of complementarity between strands. Profiling miRNAs in clinical glioblastoma samples has shown aberrant expression of numerous miRNAs when compared to normal brain...... tissues. Understanding these alterations is key to developing new biomarkers and intelligent treatment strategies. This review presents an overview of current knowledge about miRNA alterations in glioblastoma while focusing on the clinical future of miRNAs as biomarkers and discussing the strengths...

  10. Glioblastoma multiforme after radiotherapy for acromegaly

    Energy Technology Data Exchange (ETDEWEB)

    Piatt, J.H. Jr.; Blue, J.M.; Schold, S.C. Jr.; Burger, P.C.

    1983-07-01

    A case of glioblastoma multiforme that occurred 14 years after radiotherapy for acromegaly is presented. The striking correspondence between the anatomy of the tumor and the geometry of the radiation ports is suggestive of a causal relationship. Previously reported cases of radiation-associated glioma are reviewed, and a brief appraisal of the evidence for induction of these lesions by radiation is presented. The differentiation of radiation-associated neoplasms from radionecrosis is also discussed.

  11. Glioblastoma multiforme associated with klinefelter syndrome.

    Science.gov (United States)

    Sasayama, Takashi; Mizukawa, Katsu; Sakagami, Yoshio; Mizowaki, Takashi; Tanaka, Kazuhiro; Ohbayashi, Chiho; Mori, Kiyoshi; Kitazawa, Sohei; Kohmura, Eiji

    2009-11-01

    A 54-year-old man with Klinefelter syndrome presented with glioblastoma multiforme manifesting as a 2-week history of motor weakness of the bilateral extremities. Magnetic resonance imaging showed multiple heterogeneously enhanced tumors in the bilateral frontal lobes. Angiography showed no tumor stain or arteriovenous shunt. The tumor was partially removed through a right craniotomy. The histological diagnosis was glioblastoma. Immunohistochemical examination showed no O(6)-methylguanine-deoxyribonucleic acid methyltransferase protein expression. Postoperative local radiotherapy (60 Gy/30 fractions) combined with temozolomide (75 mg/m(2) x 42 days) and interferon-beta (3,000,000 U, 3 times/week) was performed. The patient's clinical status rapidly deteriorated during chemoradiotherapy, and he died of tumor progression 3.5 months after the surgery. Postmortem examination revealed widespread glioblastoma infiltrating the basal ganglia and thalamus. Klinefelter syndrome is associated with increased cancer predisposition, especially for male breast cancer and germ cell tumors, but glioma is extremely rare. The abnormal genetic constitution of this patient may have been directly responsible for the poor outcome.

  12. Do Active-Learning Strategies Improve Students' Critical Thinking?

    Science.gov (United States)

    Nelson, Larry P.; Crow, Mary L.

    2014-01-01

    Improving students' ability to recognize work-related problems and apply effective strategies and solutions to fundamental challenges in the field is at the crux of a good college preparation. This paper attempts to investigate if active-learning strategies improve students' critical thinking ability in this regard. Participants were pre-service…

  13. Development of targeted therapies in treatment of glioblastoma

    Institute of Scientific and Technical Information of China (English)

    Yuan-Yuan Xu; Pei Gao; Ying Sun; You-Rong Duan

    2015-01-01

    Glioblastoma (GBM) is a type of tumor that is highly lethal despite maximal therapy. Standard therapeutic approaches provide modest improvement in progression-free and overall survival, necessitating the investigation of novel therapies. Oncologic therapy has recently experienced a rapid evolution toward “targeted therapy”, with drugs directed against speciifc targets which play essential roles in the proliferation, survival, and invasiveness of GBM cells, including numerous molecules involved in signal transduction pathways. Inhibitors of these molecules have already entered or are undergoing clinical trials. However, signiifcant challenges in their development remain because several preclinical and clinical studies present conlficting results. In this article, we will provide an up-to-date review of the current targeted therapies in GBM.

  14. Notch signaling in glioblastoma: a developmental drug target?

    Directory of Open Access Journals (Sweden)

    Boulay Jean-Louis

    2010-11-01

    Full Text Available Abstract Malignant gliomas are among the most devastating tumors for which conventional therapies have not significantly improved patient outcome. Despite advances in imaging, surgery, chemotherapy and radiotherapy, survival is still less than 2 years from diagnosis and more targeted therapies are urgently needed. Notch signaling is central to the normal and neoplastic development of the central nervous system, playing important roles in proliferation, differentiation, apoptosis and cancer stem cell regulation. Notch is also involved in the regulation response to hypoxia and angiogenesis, which are typical tumor and more specifically glioblastoma multiforme (GBM features. Targeting Notch signaling is therefore a promising strategy for developing future therapies for the treatment of GBM. In this review we give an overview of the mechanisms of Notch signaling, its networking pathways in gliomas, and discuss its potential for designing novel therapeutic approaches.

  15. Nanotechnology to augment immunotherapy for the treatment of glioblastoma multiforme.

    Science.gov (United States)

    Ung, Nolan; Yang, Isaac

    2015-07-01

    Glioblastoma multiforme (GBM) is characterized as one of the most common and most deadly malignant primary brain tumors. Current treatment modalities include the use of surgical resection and adjuvant chemotherapy and radiation therapy, though survival is still limited. Because of this, new treatment strategies are needed to improve overall survival. Immunotherapy has emerged as a potential treatment, but still possesses certain limitations to have a substantial clinical effect. In addition, nanotechnology has emerged as potent treatment effectors that have been shown to augment the effects of therapies including chemotherapy, gene therapy, and more. Nanoparticles possess a novel approach due to the myriad of functional groups that can create targeted treatments, though further optimization is still required. In this review, the authors will present the current uses and abilities of nanotechnology and its implication for use with immunotherapy in the treatment of GBM.

  16. Standards of care and novel approaches in the management of glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    Andreas F. Hottinger; Roger Stupp; Krisztian Homicsko

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Standard therapeutic approaches provide modest improvement in the progression-free and overall survival, necessitating the investigation of novel therapies. We review the standard treatment options for GBM and evaluate the results obtained in clinical trials for promising novel approaches, including the inhibition of angiogenesis, targeted approaches against molecular pathways, immunotherapies, and local treatment with low voltage electric fields.

  17. Glioblastoma extracellular vesicles: reservoirs of potential biomarkers

    Directory of Open Access Journals (Sweden)

    Redzic JS

    2014-02-01

    Full Text Available Jasmina S Redzic,1 Timothy H Ung,2 Michael W Graner2 1Skaggs School of Pharmacy and Pharmaceutical Sciences, 2Department of Neurosurgery, School of Medicine, University of Colorado Denver, Aurora, CO, USA Abstract: Glioblastoma multiforme (GBM is the most frequent and most devastating of the primary central nervous system tumors, with few patients living beyond 2 years postdiagnosis. The damage caused by the disease and our treatments for the patients often leave them physically and cognitively debilitated. Generally, GBMs appear after very short clinical histories and are discovered by imaging (using magnetic resonance imaging [MRI], and the diagnosis is validated by pathology, following surgical resection. The treatment response and diagnosis of tumor recurrence are also tracked by MRI, but there are numerous problems encountered with these monitoring modalities, such as ambiguous interpretation and forms of pseudoprogression. Diagnostic, prognostic, and predictive biomarkers would be an immense boon in following treatment schemes and in determining recurrence, which often requires an invasive intracranial biopsy to verify imaging data. Extracellular vesicles (EVs are stable, membrane-enclosed, virus-sized particles released from either the cell surface or from endosomal pathways that lead to the systemic release of EVs into accessible biofluids, such as serum/plasma, urine, cerebrospinal fluid, and saliva. EVs carry a wide variety of proteins, nucleic acids, lipids, and other metabolites, with many common features but with enough individuality to be able to identify the cell of origin of the vesicles. These components, if properly interrogated, could allow for the identification of tumor-derived EVs in biofluids, indicating tumor progression, relapse, or treatment failure. That knowledge would allow clinicians to continue with treatment regimens that were actually effective or to change course if the therapies were failing. Here, we review

  18. An Improved Production Activity Control Architecture for Shop Floor Control

    Institute of Scientific and Technical Information of China (English)

    SHAHIDIkramullahButt; SUNHou-fang; HAMIDUllahKhanNiazi

    2005-01-01

    This paper presents a further improved Production Activity Control Architecture to deal with the complexity of information by creating Sub-Producers and Sub-Movers which will not only give a better control at workstation level but also reduce load on the Dispatcher. It also makes an analysis of the basic and improved PAC (Production Activity Control) Architecture in the Control System for Integrated Manufacturing. The PAC Architecture and the improvement will further enhance the flexibility and adaptability of the architecture in the ever changing environment of the Shop Floor Control (SFC) Systems.

  19. Improving hospital cost accounting with activity-based costing.

    Science.gov (United States)

    Chan, Y C

    1993-01-01

    In this article, activity-based costing, an approach that has proved to be an improvement over the conventional costing system in product costing, is introduced. By combining activity-based costing with standard costing, health care administrators can better plan and control the costs of health services provided while ensuring that the organization's bottom line is healthy.

  20. A role for the transcription factor HEY1 in glioblastoma

    DEFF Research Database (Denmark)

    Hulleman, Esther; Quarto, Micaela; Vernell, Richard

    2009-01-01

    Glioblastoma multiforme (GBM), the highest-grade glioma, is the most frequent tumour of the brain with a very poor prognosis and limited therapeutic options. Although little is known about the molecular mechanisms that underlie glioblastoma formation, a number of signal transduction routes, such ...

  1. DNA-repair gene variants are associated with glioblastoma survival

    DEFF Research Database (Denmark)

    Wibom, Carl; Sjöström, Sara; Henriksson, Roger

    2012-01-01

    genes, in 138 glioblastoma samples from Sweden and Denmark. We confirmed our findings in an independent cohort of 121 glioblastoma patients from the UK. Our analysis revealed nine SNPs annotating MSH2, RAD51L1 and RECQL4 that were significantly (p

  2. Active Listening Improve Your Ability to Listen and Lead

    CERN Document Server

    (CCL), Center for Creative Leadership

    2011-01-01

    Active listening is a person's willingness and ability to hear and understand. At its core, active listening is a state of mind that involves paying full and careful attention to the other person, avoiding premature judgment, reflecting understanding, clarifying information, summarizing, and sharing. By learning and committing to the skills and behaviors of active listening, leaders can become more effective listeners and, over time, improve their ability to lead.

  3. Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.

    Science.gov (United States)

    Kang, Sang Soo; Han, Kyung-Seok; Ku, Bo Mi; Lee, Yeon Kyung; Hong, Jinpyo; Shin, Hye Young; Almonte, Antoine G; Woo, Dong Ho; Brat, Daniel J; Hwang, Eun Mi; Yoo, Seung Hyun; Chung, Chun Kee; Park, Sung-Hye; Paek, Sun Ha; Roh, Eun Joo; Lee, Sung Joong; Park, Jae-Yong; Traynelis, Stephen F; Lee, C Justin

    2010-02-01

    Calcium signaling is important in many signaling processes in cancer cell proliferation and motility including in deadly glioblastomas of the brain that aggressively invade neighboring tissue. We hypothesized that disturbing Ca(2+) signaling pathways might decrease the invasive behavior of giloblastoma, extending survival. Evaluating a panel of small-molecule modulators of Ca(2+) signaling, we identified caffeine as an inhibitor of glioblastoma cell motility. Caffeine, which is known to activate ryanodine receptors, paradoxically inhibits Ca(2+) increase by inositol 1,4,5-trisphospate receptor subtype 3 (IP(3)R3), the expression of which is increased in glioblastoma cells. Consequently, by inhibiting IP(3)R3-mediated Ca(2+) release, caffeine inhibited migration of glioblastoma cells in various in vitro assays. Consistent with these effects, caffeine greatly increased mean survival in a mouse xenograft model of glioblastoma. These findings suggest IP(3)R3 as a novel therapeutic target and identify caffeine as a possible adjunct therapy to slow invasive growth of glioblastoma.

  4. Fyn and Src are Effectors of Oncogenic EGFR Signaling in Glioblastoma Patients

    Science.gov (United States)

    Lu, Kan V.; Zhu, Shaojun; Cvrljevic, Anna; Huang, Tiffany T.; Sarkaria, Shawn; Ahkavan, David; Dang, Julie; Dinca, Eduard B.; Plaisier, Seema B.; Oderberg, Isaac; Lee, Yohan; Chen, Zugen; Caldwell, Jeremy S.; Xie, Yongmin; Loo, Joseph A.; Seligson, David; Chakravari, Arnab; Lee, Francis Y.; Weinmann, Roberto; Cloughesy, Timothy F.; Nelson, Stanley F.; Bergers, Gabriele; Graeber, Thomas; Furnari, Frank B.; James, C. David; Cavenee, Webster K.; Johns, Terrance G.; Mischel, Paul S.

    2009-01-01

    Activating EGFR mutations are common in many cancers including glioblastoma. However, clinical responses to EGFR inhibitors are infrequent and short-lived. We demonstrate that the Src family kinases (SFKs) Fyn and Src are effectors of oncogenic EGFR signaling, enhancing invasion and tumor cell survival in vivo. Expression of a constitutively active EGFR mutant, EGFRvIII, resulted in activating phosphorylation and physical association with Src and Fyn, promoting tumor growth and motility. Gene silencing of Fyn and Src limited EGFR and EGFRvIII-dependent tumor cell motility. The SFK inhibitor dasatinib inhibited invasion, promoted tumor regression and induced apoptosis in vivo, significantly prolonging survival of an orthotopic glioblastoma model expressing endogenous EGFRvIII. Dasatinib enhanced the efficacy of an anti-EGFR monoclonal antibody (mAb 806) in vivo, further limiting tumor growth and extending survival. Examination of a large cohort of clinical samples demonstrated frequent coactivation of EGFR and SFKs in glioblastoma patients. These results establish a mechanism linking EGFR signaling with Fyn and Src activation to promote tumor progression and invasion in vivo and provide rationale for combined anti-EGFR and anti-SFK targeted therapies. PMID:19690143

  5. Performance in physiology evaluation: possible improvement by active learning strategies.

    Science.gov (United States)

    Montrezor, Luís H

    2016-12-01

    The evaluation process is complex and extremely important in the teaching/learning process. Evaluations are constantly employed in the classroom to assist students in the learning process and to help teachers improve the teaching process. The use of active methodologies encourages students to participate in the learning process, encourages interaction with their peers, and stimulates thinking about physiological mechanisms. This study examined the performance of medical students on physiology over four semesters with and without active engagement methodologies. Four activities were used: a puzzle, a board game, a debate, and a video. The results show that engaging in activities with active methodologies before a physiology cognitive monitoring test significantly improved student performance compared with not performing the activities. We integrate the use of these methodologies with classic lectures, and this integration appears to improve the teaching/learning process in the discipline of physiology and improves the integration of physiology with cardiology and neurology. In addition, students enjoy the activities and perform better on their evaluations when they use them.

  6. Resveratrol Inhibits the Invasion of Glioblastoma-Initiating Cells via Down-Regulation of the PI3K/Akt/NF-κB Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yuming Jiao

    2015-06-01

    Full Text Available Invasion and metastasis of glioblastoma-initiating cells (GICs are thought to be responsible for the progression and recurrence of glioblastoma multiforme (GBM. A safe drug that can be applied during the rest period of temozolomide (TMZ maintenance cycles would greatly improve the prognosis of GBM patients by inhibiting GIC invasion. Resveratrol (RES is a natural compound that exhibits anti-invasion properties in multiple tumor cell lines. The current study aimed to evaluate whether RES can inhibit GIC invasion in vitro and in vivo. GICs were identified using CD133 and Nestin immunofluorescence staining and tumorigenesis in non-obese diabetic severe combined immunodeficient (NOD/SCID mice. Invasive behaviors, including the adhesion, invasion and migration of GICs, were determined by tumor invasive assays in vitro and in vivo. The activity of matrix metalloproteinases (MMPs was measured by the gelatin zymography assay. Western blotting analysis and immunofluorescence staining were used to determine the expression of signaling effectors in GICs. We demonstrated that RES suppressed the adhesion, invasion and migration of GICs in vitro and in vivo. Moreover, we proved that RES inhibited the invasion of GICs via the inhibition of PI3K/Akt/NF-κB signal transduction and the subsequent suppression of MMP-2 expression.

  7. Established and emerging variants of glioblastoma multiforme: review of morphological and molecular features.

    Science.gov (United States)

    Karsy, Michael; Gelbman, Marshall; Shah, Paarth; Balumbu, Odessa; Moy, Fred; Arslan, Erol

    2012-01-01

    Since the recent publication of the World Health Organization brain tumour classification guidelines in 2007, a significant expansion in the molecular understanding of glioblastoma multiforme (GBM) and its pathological as well as genomic variants has been evident. The purpose of this review article is to evaluate the histopathological, molecular and clinical features surrounding emerging and currently established GBM variants. The tumours discussed include classic glioblastoma multiforme and its four genomic variants, proneural, neural, mesenchymal, classical, as well as gliosarcoma (GS), and giant cell GBM (gcGBM). Furthermore, the emerging variants include fibrillary/epithelial GBM, small cell astrocytoma (SCA), GBM with oligodendroglial component (GBMO), GBM with primitive neuroectodermal features (GBM-PNET), gemistocytic astrocytoma (GA), granular cell astrocytoma (GCA), and paediatric high-grade glioma (HGG) as well as diffuse intrinsic pontine glioma (DIPG). Better understanding of the heterogeneous nature of GBM may provide improved treatment paradigms, prognostic classification, and approaches towards molecularly targeted treatments.

  8. Apparent diffusion coefficient parametric response mapping MRI for follow-up of glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Ra Gyoung [Catholic Kwandong University International St. Mary' s Hospital, Catholic Kwandong University College of Medicine, Department of Radiology, Seo-gu, Incheon (Korea, Republic of); Kim, Ho Sung; Hong, Gil Sun; Kim, Sang Joon [Asan Medical Center, University of Ulsan College of Medicine, Department of Radiology and Research Institute of Radiology, Songpa-Gu, Seoul (Korea, Republic of); Kim, Dae Yoon [Bundang Jesaeng Hospital, Department of Radiology, Seongnam-si, Gyeonggi-do (Korea, Republic of)

    2016-04-15

    To determine the diagnostic superiority of parametric response mapping of apparent diffusion coefficient (ADCPR) for predicting glioblastoma treatment response, compared to single time point measurement. Fifty post-treatment glioblastoma patients were enrolled. ADCPR was calculated from serial apparent diffusion coefficient (ADC) maps acquired before and at the time of first detection of an enlarged contrast-enhancing lesion on voxel-by-voxel basis. The percentage-decrease in ADCPR and tenth percentile histogram cutoff value of ADC (ADC10) were compared at subsequent 3-month and 1-year follow-ups. The percentage-decrease in ADCPR was significantly higher in the progression group (mean = 33.2-38.3 %) than in the stable-response group (mean = 9.7 %) at 3 months follow-up (corrected p < 0.001 for both readers). ADCPR significantly improved area under the receiver operating characteristic curve from 0.67 to 0.88 (corrected p = 0.037) and from 0.70 to 0.92 (corrected p = 0.020) for both readers, respectively, compared to ADC10 at 3-month follow-up, but did not significantly improve at 1-year follow-up. The inter-reader agreement was higher for ADCPR than ADC10 (intraclass correlation coefficient, 0.93 versus 0.86). Voxel-based ADCPR appears to be a superior imaging biomarker than ADC, particularly for predicting early tumour progression in patients with glioblastoma. (orig.)

  9. Leveraging Human Brain Activity to Improve Object Classification

    OpenAIRE

    Fong, Ruth Catherine

    2015-01-01

    Today, most object detection algorithms differ drastically from how humans tackle visual problems. In this thesis, I present a new paradigm for improving machine vision algorithms by designing them to better mimic how humans approach these tasks. Specifically, I demonstrate how human brain activity from functional magnetic resonance imaging (fMRI) can be leveraged to improve object classification. Inspired by the graduated manner in which humans learn, I present a novel algorithm that sim...

  10. BIS-mediated STAT3 stabilization regulates glioblastoma stem cell-like phenotypes

    Science.gov (United States)

    Im, Chang-Nim; Yun, Hye Hyeon; Song, Byunghoo; Youn, Dong-Ye; Cui, Mei Nu; Kim, Hong Sug; Park, Gyeong Sin; Lee, Jeong-Hwa

    2016-01-01

    Glioblastoma stem cells (GSCs) are a subpopulation of highly tumorigenic and stem-like cells that are responsible for resistance to conventional therapy. Bcl-2-intreacting cell death suppressor (BIS; also known as BAG3) is an anti-apoptotic protein that is highly expressed in human cancers with various origins, including glioblastoma. In the present study, to investigate the role of BIS in GSC subpopulation, we examined the expression profile of BIS in A172 and U87-MG glioblastoma cell lines under specific in vitro culture conditions that enrich GSC-like cells in spheres. Both BIS mRNA and protein levels significantly increased under the sphere-forming condition as compared with standard culture conditions. BIS depletion resulted in notable decreases in sphere-forming activity and was accompanied with decreases in SOX-2 expression. The expression of STAT3, a master regulator of stemness, also decreased following BIS depletion concomitant with decreases in the nuclear levels of active phosphorylated STAT3, while ectopic STAT3 overexpression resulted in recovery of sphere-forming activity in BIS-knockdown glioblastoma cells. Additionally, immunoprecipitation and confocal microscopy revealed that BIS physically interacts with STAT3. Furthermore, BIS depletion increased STAT3 ubiquitination, suggesting that BIS is necessary for STAT3 stabilization in GSC-like cells. BIS depletion also affected epithelial-to-mesenchymal transition-related genes as evidenced by decrease in SNAIL and MMP-2 expression and increase in E-cadherin expression in GSC-like cells. Our findings suggest that high levels of BIS expression might confer stem-cell-like properties on cancer cells through STAT3 stabilization, indicating that BIS is a potential target in cancer therapy. PMID:27145367

  11. RNOP-09: Pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma - a phase II study

    Directory of Open Access Journals (Sweden)

    Proescholdt Martin

    2009-09-01

    Full Text Available Abstract Background Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for. Methods In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx™, PEG-Dox and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression. Results The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12 was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison. Conclusion Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data Trial registration clinicaltrials.gov NCT00944801.

  12. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma.

    Science.gov (United States)

    Rieger, Johannes; Bähr, Oliver; Maurer, Gabriele D; Hattingen, Elke; Franz, Kea; Brucker, Daniel; Walenta, Stefan; Kämmerer, Ulrike; Coy, Johannes F; Weller, Michael; Steinbach, Joachim P

    2014-06-01

    Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3-13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12-124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (pketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet.

  13. Cross inhibition improves activity selection when switching incurs time costs

    Institute of Scientific and Technical Information of China (English)

    James A.R.MARSHALL; Angélique FAVREAU-PEIGN(E); Lutz FROMHAGE; John M.MCNAMARA; Lianne F.S.MEAH; Alasdair I.HOUSTON

    2015-01-01

    We consider a behavioural model of an animal choosing between two activities,based on positive feedback,and examine the effect of introducing cross inhibition between the motivations for the two activities.While cross-inhibition has previously been included in models of decision making,the question of what benefit it may provide to an animal's activity selection behaviour has not previously been studied.In neuroscience and in collective behaviour cross-inhibition,and other equivalent means of coupling evidence-accumulating pathways,have been shown to approximate statistically-optimal decision-making and to adaptively break deadlock,thereby improving decision performance.Switching between activities is an ongoing decision process yet here we also find that cross-inhibition robustly improves its efficiency,by reducing the frequency of costly switches between behaviours [Current Zoology 61 (2):242-250,2015].

  14. Synthetic analogs of anoplin show improved antimicrobial activities

    DEFF Research Database (Denmark)

    Munk, Jens; Uggerhøj, Lars Erik; Poulsen, Tanja Juul;

    2013-01-01

    We present the antimicrobial and hemolytic activities of the decapeptide anoplin and 19 analogs thereof tested against methicillin-resistant Staphylococcus aureus ATCC 33591 (MRSA), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), vancomycin-resistant Enterococcus faecium (ATCC...... 700221) (VRE), and Candida albicans (ATCC 200955). The anoplin analogs contain substitutions in amino acid positions 2, 3, 5, 6, 8, 9, and 10. We use these peptides to study the effect of altering the charge and hydrophobicity of anoplin on activity against red blood cells and microorganisms. We find...... that increasing the charge and/or hydrophobicity improves antimicrobial activity and increases hemolytic activity. For each strain tested, we identify at least six anoplin analogs with an improved therapeutic index compared with anoplin, the only exception being Enterococcus faecium, against which only few...

  15. Nanomedicine to overcome radioresistance in glioblastoma stem-like cells and surviving clones.

    Science.gov (United States)

    Séhédic, Delphine; Cikankowitz, Annabelle; Hindré, François; Davodeau, François; Garcion, Emmanuel

    2015-04-01

    Radiotherapy is one of the standard treatments for glioblastoma, but its effectiveness often encounters the phenomenon of radioresistance. This resistance was recently attributed to distinct cell contingents known as glioblastoma stem-like cells (GSCs) and dominant clones. It is characterized in particular by the activation of signaling pathways and DNA repair mechanisms. Recent advances in the field of nanomedicine offer new possibilities for radiosensitizing these cell populations. Several strategies have been developed in this direction, the first consisting of encapsulating a contrast agent or synthesizing metal-based nanocarriers to concentrate the dose gradient at the level of the target tissue. In the second strategy the physicochemical properties of the vectors are used to encapsulate a wide range of pharmacological agents which act in synergy with the ionizing radiation to destroy the cancerous cells. This review reports on the various molecular anomalies present in GSCs and the predominant role of nanomedicines in the development of radiosensitization strategies.

  16. Tumor suppressor WWOX and p53 alterations and drug resistance in glioblastomas

    Directory of Open Access Journals (Sweden)

    Ming-Fu eChiang

    2013-03-01

    Full Text Available Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs and appears to contribute, in part, to resistance to temozolomide and therapeutic drugs. WW domain-containing oxidoreductase WWOX (FOR or WOX1 is a proapoptotic protein and is considered as a tumor suppressor. Loss of WWOX gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade. Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. WWOX is known to physically bind and stabilize wild type p53. Here, we provide an overview for the updated knowledge in p53 and WWOX, and postulate a potential scenarios that wild type and mutant p53, or isoforms, modulate the apoptotic function of WWOX. We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death.

  17. Is There Pseudoprogression in Secondary Glioblastomas?

    Energy Technology Data Exchange (ETDEWEB)

    Juratli, Tareq A., E-mail: Tareq.Juratli@uniklinikum-dresden.de [Department of Neurosurgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden (Germany); Engellandt, Kay [Institute of Neuroradiology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden (Germany); Lautenschlaeger, Tim [Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center/Arthur G. James Cancer Hospital and Richard L. Solove Research Institute, The Ohio State University College of Medicine Columbus, Ohio (United States); Geiger, Kathrin D. [Institute of Neuropathology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden (Germany); Kummer, Rüdiger von; Cerhova, Jana [Institute of Neuroradiology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden (Germany); Chakravarti, Arnab [Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center/Arthur G. James Cancer Hospital and Richard L. Solove Research Institute, The Ohio State University College of Medicine Columbus, Ohio (United States); Krex, Dietmar; Schackert, Gabriele [Department of Neurosurgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden (Germany)

    2013-12-01

    Purpose: Pseudoprogression (PP) during adjuvant treatment of glioblastoma (GBM) is frequent and is a clinically and radiologically challenging problem. While there are several reports of the frequency of PP in GBM cohorts including mainly patients with primary GBM, there are few data on the incidence of PP in patients with secondary glioblastomas (sGBM). Therefore, the goal of this study was to evaluate the frequency of PP in sGBM. Methods and Materials: We retrospectively evaluated the incidence of PP in adult patients with sGBM treated with chemoradiation therapy (CRTx) using temozolomide (TMZ) and sought to assess if there was an association between PP and MGMT promoter methylation status, IDH mutations status, or 1p/19q codeletion. The definition of PP according to the Response Assessment in Neuro-Oncology Working Group was used. Results: None of the evaluable 15 sGBM patients in our series demonstrated a PP. Of the 9 sGBM patients who received concomitant CRTx with TMZ, 6 patients had the methylated MGMT promoter, and 6 patients had IDH mutations. There also was no PP identified in sGBM patients who received sequential CRTx, irrespective of MGMT or IDH status. The median time of follow-up was 3.4 years after diagnosis of an sGBM, and the median overall survival was 18.2 months (range, 14.3-45.2 months). Three of 15 patients had previously received radiation therapy for their World Health Organization low-grade 2 glioma, while none of them had received chemotherapy at that stage. Conclusions: Based on this small series of sGBM patients treated with CRTx (concomitantly or sequentially) the frequency of PP appears to be very low in sGBM, even in those patients with methylated MGMT promoter or IDH mutations. Our results highlight the differences between primary glioblastomas and sGBM in particular as they relate to PP.

  18. METHODOLOGICAL ESSENTIAL PRINCIPLES OF REGIONAL INVESTMENT ACTIVITY FINANCEMENT MECHANIZM IMPROVEMENT

    OpenAIRE

    V.V. Morozov

    2005-01-01

    The strategy principles and main directions of regional investment activity financement mechanism improvement are formulated and worked out in the article. The contemporary conditions are analyzed, the factors are researched, the priority directions are defined, the suggestions on the better use of investment sources are worked out, and on this base the suggestions on the investment process activization in the territorial systems are worked out.

  19. Statin use and survival following glioblastoma multiforme

    DEFF Research Database (Denmark)

    Gaist, David; Hallas, Jesper; Friis, Søren;

    2014-01-01

    AIM: While some studies indicate a potential chemopreventive effect of statin use on the risk of glioma, the effect of statins on the prognosis of brain tumours has not yet been examined. We thus conducted a cohort study evaluating the influence of statin use on survival in patients...... with glioblastoma multiforme (GBM). METHODS: We identified 1562 patients diagnosed with GBM during 2000-2009 from the Danish Cancer Registry and linked this cohort to Danish nationwide demographic and health registries. Within the GBM cohort, each patient recorded as using statins prior to diagnosis (defined as ≥2...... redeemed prescriptions) was matched to two statin non-users (

  20. Performance in Physiology Evaluation: Possible Improvement by Active Learning Strategies

    Science.gov (United States)

    Montrezor, Luís H.

    2016-01-01

    The evaluation process is complex and extremely important in the teaching/learning process. Evaluations are constantly employed in the classroom to assist students in the learning process and to help teachers improve the teaching process. The use of active methodologies encourages students to participate in the learning process, encourages…

  1. Improving Listening Skills through the Use of Active Listening Strategies.

    Science.gov (United States)

    Engraffia, Margie; Graff, Nora; Jezuit, Sue; Schall, Leslie

    This report describes a program for improving active and critical listening skills for elementary age students. The targeted population consists of middle school children located near a large midwestern city. The problems of poor listening skills are documented through data revealing the need for attending interventions that have been put in…

  2. Active video gaming to improve balance in the elderly

    NARCIS (Netherlands)

    Lamoth, C.J.; Caljouw, S.R.; Postema, K.

    2011-01-01

    The combination of active video gaming and exercise (exergaming) is suggested to improve elderly people's balance, thereby decreasing fall risk. Exergaming has been shown to increase motivation during exercise therapy, due to the enjoyable and challenging nature, which could support long-term adhere

  3. Improving the Dynamics of Suspension Bridges using Active Control Systems

    DEFF Research Database (Denmark)

    Thoft-Christensen, Palle

    Improving the dynamics of suspension bridge using active control is discussed in this paper. The main dynamic problem with long suspension bridges is the aeroelastic phenomenon called flutter. Flutter oscillations of a bridge girder is a stability problem and the oscillations are perpendicular...

  4. In Vivo Magnetic Resonance Imaging of CD8+ T Lymphocytes Recruiting to Glioblastoma in Mice.

    Science.gov (United States)

    Li, Anning; Wu, Yue; Tang, Feng; Li, Wei; Feng, Xiaoyuan; Yao, Zhenwei

    2016-11-01

    Noninvasive in vivo tracking of adopted immune cells would help improve immunotherapy on glioblastoma. In this study, the authors tried to track adoptive CD8+ T lymphocytes in an in situ GL261 glioblastoma mouse model with magnetic resonance imaging (MRI). CD8+ T lymphocytes from spleen of preimmunized GL261 glioblastoma mice were labeled with superparamagnetic iron oxide, with polylysine as transfection agent. From Prussian blue staining, the labeling efficiency was 0.77% ± 0.06%, without altering cell viability and function. From anti-CD8, and anti-dextran staining, superparamagnetic iron oxide could be seen in the cytoplasm. In vitro imaging of agar gel mixtures with different concentrations of labeled CD8+ T lymphocytes was done with a 3.0T MR T2*WI sequence. Higher cell concentrations showed lower signal values. Twenty-four hours after tail vein injection of labeled and unlabeled CD8+ T lymphocytes, imaging of GL261 mice brain showed black spots at the periphery of the tumor in the labeled group only. Brain tumor pathology further verified infiltration of labeled CD8+ T lymphocytes in the tumor. Thus, preimmunized CD8+ T lymphocytes could be efficiently labeled with superparamagnetic iron oxide and tracked both in vitro and in vivo with 3.0T MRI.

  5. Isocitrate Dehydrogenase (IDH)1/2 Mutations as Prognostic Markers in Patients With Glioblastomas.

    Science.gov (United States)

    Chen, Jun-Rui; Yao, Yu; Xu, Hong-Zhi; Qin, Zhi-Yong

    2016-03-01

    The purpose of this study was to perform a meta-analysis examining the association of isocitrate dehydrogenase (IDH)1/2 mutations with overall survival (OS) and progression-free survival (PFS) in patients with glioblastomas. Medline, Cochrane, EMBASE, and Google Scholar were searched from inception to January 28, 2015, using combinations of the following keywords: IDH mutation, brain tumor, glioma, glioblastoma, oligodendroglioma, prognosis. Randomized controlled trials, and prospective and retrospective studies of patients with glioblastomas that provided IDH mutation and survival data were included. OS and PFS were used to evaluate the association of IDH1 and IDH1/2 mutations and prognosis. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for OS and PFS were calculated and compared between patients with and without mutations. Of 165 studies that were identified, 136 nonrelevant studies were excluded. Twenty-nine full-text articles were assessed, and of these, 5 were excluded as they did not provide a quantitative outcome. Therefore, 24 studies were included in the qualitative synthesis. The pooled HR of 0.358 (95% CI 0.264-0.487, P < 0.001) indicated that IDH mutations were associated with better OS. Similarly, the pooled HR of 0.322 (95% CI 0.24200.455, P < 0.001) indicated that IDH mutations were associated with better PFS. When patients were stratified by surgery versus no surgery or IDH1 versus IDH1/2 mutations, the results also indicated that the presence of IDH mutations was associated with better OS and PFS. The IDH mutations are associated with improved survival in patients with glioblastomas.

  6. Reduced-activation steels: Future development for improved creep strength

    Science.gov (United States)

    Klueh, R. L.

    2008-08-01

    Reduced-activation steels for fusion applications were developed in the 1980s to replace the elevated-temperature commercial steels first considered. The new steels were patterned after the commercial steels, with the objective that the new steels have yield stress and ultimate tensile strength and impact toughness in a Charpy test comparable to or better than the steels they replaced. That objective was achieved in reduced-activation steels developed in Japan, Europe, and the United States. Although tensile and impact toughness of the reduced-activation steels exceed those of the commercial steels they were patterned after, their creep-rupture properties are inferior to some commercial steels they replaced. They are even more inferior to commercial steels developed since the 1980s. In this paper, compositional differences between reduced-activation steels and new commercial steels are examined, and compositions are proposed for development of new-and-improved reduced-activation steels.

  7. Differentiation of radiation necrosis from glioblastoma recurrence after radiotherapy

    Institute of Scientific and Technical Information of China (English)

    Chrissa Sioka; Anastasia Zikou; Anna Goussia; Spyridon Tsiouris; Loucas G Astrakas; Athanassios P Kyritsis

    2016-01-01

    The standard treatment of glioblastoma, the most common type of primary-brain-tumor, involves radiotherapy with concomitant temozolomide chemotherapy. A patient with glioblastoma, post radiotherapy developed magnatic resonance imaging (MRI) changes consistent with either radiation-induced tumor necrosis or tumor recurrence. Perfusion MRI was suggestive of radiation necrosis, but magnetic resonance spectroscopy and99mTc-Tetrofosmin single photon emission computed tomography was indicative of tumor recurrence. Positron emission tomography scan was not available. Tumor recurrence was documented by biopsy. Several advanced imaging methods are available to differentiate tumor recurrence from radiation necrosis in glioblastoma patients. However, in inconclusive cases, brain biopsy should be performed for deifnite diagnosis.

  8. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, S; Wibom, C; Andersson, U

    2010-01-01

    Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are central components in the development and progression of glioblastoma. To investigate if genetic variation in VEGF and VEGFR2 is associated with glioblastoma prognosis, we examined blood samples from 154 glioblastoma cases...... collected in Sweden and Denmark between 2000 and 2004. Seventeen tagging single nucleotide polymorphisms (SNPs) in VEGF and 27 in VEGFR2 were genotyped and analysed, covering 90% of the genetic variability within the genes. In VEGF, we found no SNPs associated with survival. In VEGFR2, we found two SNPs...

  9. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, S; Wibom, C; Andersson, U

    2011-01-01

    Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are central components in the development and progression of glioblastoma. To investigate if genetic variation in VEGF and VEGFR2 is associated with glioblastoma prognosis, we examined blood samples from 154 glioblastoma cases...... collected in Sweden and Denmark between 2000 and 2004. Seventeen tagging single nucleotide polymorphisms (SNPs) in VEGF and 27 in VEGFR2 were genotyped and analysed, covering 90% of the genetic variability within the genes. In VEGF, we found no SNPs associated with survival. In VEGFR2, we found two SNPs...

  10. Glioblastoma Treatment: Bypassing the Toxicity of Platinum Compounds by Using Liposomal Formulation and Increasing Treatment Efficiency With Concomitant Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Charest, Gabriel; Sanche, Leon [Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Universite de Sherbrooke, Sherbrooke, Quebec (Canada); Fortin, David; Mathieu, David [Department of Surgery, Division of Neurosurgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec (Canada); Paquette, Benoit, E-mail: Benoit.Paquette@USherbrooke.ca [Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Universite de Sherbrooke, Sherbrooke, Quebec (Canada)

    2012-09-01

    Purpose: Treatments of glioblastoma with cisplatin or oxaliplatin only marginally improve the overall survival of patients and cause important side effects. To prevent adverse effects, improve delivery, and optimize the tumor response to treatment in combination with radiotherapy, a potential approach consists of incorporating the platinum agent in a liposome. Methods and Materials: In this study, cisplatin, oxaliplatin, carboplatin, Lipoplatin (the liposomal formulation of cisplatin), and Lipoxal (the liposomal formulation of oxaliplatin) were tested on F98 glioma orthotopically implanted in Fischer rats. The platinum compounds were administered by intracarotid infusion and were assessed for the ability to reduce toxicity, improve cancer cell uptake, and increase survival of animals when combined or not combined with radiotherapy. Results: The tumor uptake was 2.4-fold more important for Lipoxal than the liposome-free oxaliplatin. Lipoxal also improved the specificity of oxaliplatin as shown by a higher ratio of tumor to right hemisphere uptake. Surprisingly, Lipoplatin led to lower tumor uptake compared with cisplatin. However, Lipoplatin had the advantage of largely reducing the toxicity of cisplatin and allowed us to capitalize on the anticancer activity of this agent. Conclusion: Among the five platinum compounds tested, carboplatin showed the best increase in survival when combined with radiation for treatment of glioma implanted in Fischer rats.

  11. Glioblastoma Circulating Cells: Reality, Trap or Illusion?

    Directory of Open Access Journals (Sweden)

    A. Lombard

    2015-01-01

    Full Text Available Metastases are the hallmark of cancer. This event is in direct relationship with the ability of cancer cells to leave the tumor mass and travel long distances within the bloodstream and/or lymphatic vessels. Glioblastoma multiforme (GBM, the most frequent primary brain neoplasm, is mainly characterized by a dismal prognosis. The usual fatal issue for GBM patients is a consequence of local recurrence that is observed most of the time without any distant metastases. However, it has recently been documented that GBM cells could be isolated from the bloodstream in several studies. This observation raises the question of the possible involvement of glioblastoma-circulating cells in GBM deadly recurrence by a “homing metastasis” process. Therefore, we think it is important to review the already known molecular mechanisms underlying circulating tumor cells (CTC specific properties, emphasizing their epithelial to mesenchymal transition (EMT abilities and their possible involvement in tumor initiation. The idea is here to review these mechanisms and speculate on how relevant they could be applied in the forthcoming battles against GBM.

  12. Nuclear SMAD2 Restrains Proliferation of Glioblastoma

    Directory of Open Access Journals (Sweden)

    Yunhu Yu

    2015-03-01

    Full Text Available Aims: Although TGFβ receptor signaling has been shown to play a role in regulation of the growth and metastasis of glioblastoma multiforme (GBM, the downstream pathway through either SMAD2 or SMAD3 has not been elucidated. In this study, we investigate whether nuclear SMAD2 can restrain the proliferation of glioblastoma. Methods: A total of 23 resected specimens from GBM patients were collected for SMAD2 detection. Human GBM cell line A172, U87mg, D341m and Hs683 were maintained in Dulbecco's modified Eagle's medium and transfected with SMAD2 and SMAD3 shRNA plasmids. Gene expression was detected by RT-qPCR and Western and cell growth were detected by MTT assay. Results: Our results showed that the phosphorylated SMAD2 (pSMAD2, the nuclear and functional form of SMAD2 levels in GBM were significantly lower than the paired normal brain tissue in patients. Depletion of SMAD2, but not SMAD3, significantly abolished the inhibitory effects of TGFβ1 on the growth of GBM cells, possibly through pSMAD2-mediated increases in cell-cycle inhibitor, p27. Conclusion: Our data suggest that TGFβ/SMAD2 signaling cascades restrains growth of GBM.

  13. Improving aerobic capacity through active videogames: A randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Jorge Luiz de Brito-Gomes

    2015-09-01

    Full Text Available AbstractThe rate of peak workload improvement between different types of Active Video Games (AVG in young sedentary adults was investigated. Aerobic capacity improvement after a 6-week intervention between AVG types was also compared. Twenty participants, after baseline assessments, were randomized into one of three parallel groups: structured AVG (n= 6, unstructured AVG (n= 7 and a control group (n= 7. Participants played their respective AVG 3 times a week for 6-weeks (30 minutes-session. The control group maintained normal activities. Both structured and unstructured AVG improved peak workload after four weeks but only the structured group maintained this improvement through week five and six. Aerobic capacity improved in the unstructured (Pre: 36.0 ± 5.2ml.kg.min-¹,Post: 39.7 ± 4.9ml.kg.min-¹, p = .038 and structured AVG (Pre: 39.0 ± 5.9ml.kg.min-¹,Post: 47.8 ± 4.3ml.kg.min-¹, p = .006 groups. Structured AVG provide greater health benefits to aerobic capacity and peak workload in young sedentary but otherwise healthy males relative to unstructured AVG.

  14. IMPROVING QUALITY OF LIFE AT EDERLY PEOPLE, THROUGH GIMN ACTIVITIES

    Directory of Open Access Journals (Sweden)

    Ganciu Mihaela

    2015-10-01

    Full Text Available In light of permanent education, physical education and sports activities should be integrated throughout life. The objective of the research is to improve the quality of life of older people to the initiation of maintenance programs by simple methods, reliable and inexpensive. Therapeutic strategies will be adapted practitioners age, associated diseases, profession. The sample under investigation comprised 30 elderly people who participated in two gymnastics lessons a week and a society dance lesson. Inspection methods that I used: bibliographic study, experimental method, survey method and statistical method - mathematical and graphical representation. Quality of life assessment was done by assessing exercise capacity, the survey method and the call routed. Through a sustained program and rhythmic exercise improves cardiovascular activity, as evidenced by increased exercise capacity by lowering resting heart rate, a major component of cardiovascular disease prevention. Decrease abdominal fat and increased muscle tone abdominal favorable effects on biomechanics of the lumbar spine dynamics can thus be considered to be the prevention of back pain. In summary the study conducted, in order to highlight the benefits of the sport for optimal physical condition and fight aging, it can be concluded that physical activity has a beneficial role for the body, both physically and mentally. Survey conducted among people aged III revealed the following: Practicing the sport of gymnastics in a systematic, consistent results in improving health and fitness as well as comfort, good mood, optimism, improving intellectual activity. In short, we can say that these people the sport of gymnastics has improved quality of life.

  15. MicroRNA-7 regulates glioblastoma cell invasion via targeting focal adhesion kinase expression

    Institute of Scientific and Technical Information of China (English)

    WU De-gang; WANG Xi-rui; YOU Yong-ping; LIU Ning; WANG Ying-yi; FAN Li-gang; LUO Hui; HAN Bin; SUN Li-hua; WANG Xie-feng; ZHANG Jun-xia; CAO Lei

    2011-01-01

    Background Invasion growth is the most characteristic biological phenotype of glioblastoma,but the molecular mechanism in glioma cell invasion is poorly understood.Recent data have showed that microRNA plays an essential role in tumor invasion.Our study aimed to explore the mechanism of miR-7 involved in the control of glioblastoma cell invasion.Methods Glioma cell invasion was evaluated by transwell and scratch assays after up-regulation of miR-7 using miR-7 mimics in U87 and U251 cells.Luciferase reporter assay was used to determine focal adhesion kinase (FAK) as a target of miR-7.The levels of miR-7,matrix metalloproteinases (MMP)-2 and MMP-9 mRNA were detected by PCR assay,and the levels of FAK,MMP-2,MMP-9,total and phosphorylation serine/threonine kinase (AKT),and extracellular signal-regulated kinase (ERK) 1/2 were measured by Western blotting analysis.Results Over-expression of miR-7 inhibited the invasion and migration activity of U87 and U251 cells.And up-regulation of miR-7 reduced FAK protein expression,Further,luciferase reporter assay showed that miR-7 modulated FAK expression directly by binding 3'UTR of FAK mRNA.In addition,miR-7 repressed p-ERK1/2 and p-AKT level,MMP-2 and MMP-9 expression.Finally,the inverse relationship between FAK and miR-7 expression was certificated in human glioma tissues.Conclusion To our knowledge,these data indicate for the first time that miR-7 directly regulates cell invasion by targeting FAK in glioblastoma and that miR-7 could be a potential therapeutic target for glioblastoma intervention.

  16. Positive-charged solid lipid nanoparticles as paclitaxel drug delivery system in glioblastoma treatment.

    Science.gov (United States)

    Chirio, Daniela; Gallarate, Marina; Peira, Elena; Battaglia, Luigi; Muntoni, Elisabetta; Riganti, Chiara; Biasibetti, Elena; Capucchio, Maria Teresa; Valazza, Alberto; Panciani, Pierpaolo; Lanotte, Michele; Annovazzi, Laura; Caldera, Valentina; Mellai, Marta; Filice, Gaetano; Corona, Silvia; Schiffer, Davide

    2014-11-01

    Paclitaxel loaded solid lipid nanoparticles (SLN) of behenic acid were prepared with the coacervation technique. Generally, spherical shaped SLN with mean diameters in the range 300–600 nm were obtained. The introduction of charged molecules, such as stearylamine and glycol chitosan into the formulation allowed to obtain positive SLN with Zeta potential in the 8-20 mV range and encapsulation efficiency in the 25–90% range.Blood–brain barrier (BBB) permeability, tested in vitro through hCMEC/D3 cells monolayer, showed a significantly increase in the permeation of Coumarin-6, used as model drug, when vehicled in SLN. Positive-charged SLN do not seem to enhance permeation although stearylamine-positive SLN resulted the best permeable formulation after 24 h.Cytotoxicity studies on NO3 glioblastoma cell line demonstrated the maintenance of cytotoxic activity of all paclitaxel-loaded SLN that was always unmodified or greater compared with free drug. No difference in cytotoxicity was noted between neutral and charged SLN.Co-culture experiments with hCMEC/D3 and different glioblastoma cells evidenced that, when delivered in SLN, paclitaxel increased its cytotoxicity towards glioblastoma cells.

  17. Circulating endothelial cells and procoagulant microparticles in patients with glioblastoma: prognostic value.

    Directory of Open Access Journals (Sweden)

    Gaspar Reynés

    Full Text Available AIM: Circulating endothelial cells and microparticles are prognostic factors in cancer. However, their prognostic and predictive value in patients with glioblastoma is unclear. The objective of this study was to investigate the potential prognostic value of circulating endothelial cells and microparticles in patients with newly diagnosed glioblastoma treated with standard radiotherapy and concomitant temozolomide. In addition, we have analyzed the methylation status of the MGMT promoter. METHODS: Peripheral blood samples were obtained before and at the end of the concomitant treatment. Blood samples from healthy volunteers were also obtained as controls. Endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Microparticles were quantified by flow cytometry. Microparticle-mediated procoagulant activity was measured by endogen thrombin generation and by phospholipid-dependent clotting time. Methylation status of MGMT promoter was determined by multiplex ligation-dependent probe amplification. RESULTS: Pretreatment levels of circulating endothelial cells and microparticles were higher in patients than in controls (p<0.001. After treatment, levels of microparticles and thrombin generation decreased, and phospholipid-dependent clotting time increased significantly. A high pretreatment endothelial cell count, corresponding to the 99(th percentile in controls, was associated with poor overall survival. MGMT promoter methylation was present in 27% of tumor samples and was associated to a higher overall survival (66 weeks vs 30 weeks, p<0.004. CONCLUSION: Levels of circulating endothelial cells may have prognostic value in patients with glioblastoma.

  18. Down-regulation of MicroRNA-126 in Glioblastoma and its Correlation with Patient Prognosis: A Pilot Study.

    Science.gov (United States)

    Han, In Bo; Kim, Minsoo; Lee, Soo Hong; Kim, Jin Kwon; Kim, Se Hoon; Chang, Jong Hee; Teng, Yang D

    2016-12-01

    Glioblastoma is the most common primary malignant tumor of the adult human brain. Although microRNA-126 (miR-126) has been reported to exhibit expression abnormalities in various types of cancer, to date very few studies have examined changes in miR-126 level in glioblastoma. In this pilot study, we investigated the changes in miR-126 expression in newly-dissected primary glioblastoma to explore possible roles of miR-126 in patient prognosis. Total RNA was extracted from tumoral and adjacent non-cancerous tissues from 14 patients' paired frozen specimens. Using an established quantitative reverse transcriptase-PCR protocol, the levels of miR-126 in glioblastoma and adjacent non-tumor brain tissues were compared against small nucleolar RNA U48 (RNU48) as a reference gene. The expression of miR-126 in glioblastoma samples was significantly lower than in paired non-tumoral controls (pglioblastoma patients with higher relative intratumoral miR-126 expression (i.e. 53-79% relative to that of the control tissue; n=7) had significantly improved survival duration than patients whose miR-126 levels were lower (i.e. 12-48%, n=7; stratified log-rank analysis p=0.011 when the dividing threshold was set at ≥51%; total: n=14, male: 8; female: 6). Thus, intraglioblastoma miR-126 may be down-regulated relative to normal tissue and patients with less down-regulation of intratumoral miR-126 expression could have improved postsurgical prognosis. Future clinical studies with larger sample sizes should be performed to validate this observation.

  19. APOPTOSIS INDUCED BY HYPERTHERMIA IN HUMAN GLIOBLASTOMA CELL LINE AND MURINE GLIOBLASTOMA

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To study the role of apoptosis in tumor cell of malignant glioma death following treatment with hyperthermia and calcium ionophore. Methods: The apoptosis induced by hyperthermia and calcium ionophore, A23187, in human glioblastoma cell line TJ905 and murine glioblastoma G422 was evaluated by characteristic findings in DNA agarose gel electrophresis, ultrastructural examination and flow cytometric analysis. Results: Apoptosis could be induced by moderate hyperthermia, but not by mild hyperthermia, calcium ionophore enhanced significantly the effect of mild hyperthermia on the induction of apoptosis. Conclusion: This result indicates that apoptotic cell death is one of the mechanisms of hyperthermic therapy for malignant glioma and taking measures to increase the cytolic calcium may enhance the effect of hyperthermia.

  20. Rhabdoid glioblastoma is distinguishable from classical glioblastoma by cytogenetics and molecular genetics.

    Science.gov (United States)

    Byeon, Sun-Ju; Cho, Hwa Jin; Baek, Hae Woon; Park, Chul-Kee; Choi, Seung-Hong; Kim, Se-Hoon; Kim, Hee Kyung; Park, Sung-Hye

    2014-03-01

    The clinicopathologic and molecular genetic features of 5 cases of rhabdoid glioblastoma, an extremely rare variant of glioblastoma that tends to affect patients at a young age, were investigated by immunohistochemical analysis and focused molecular genetic studies including array-based comparative genomic hybridization. All 5 cases had supratentorial tumors that immunohistochemical analysis revealed to be robustly positive for epithelial membrane antigen, vimentin, p53, and PDGFRα (platelet-derived growth factor receptor, alpha polypeptide) but only focally positive for glial fibrillary acidic protein. Although complete retention of SMARCB1 (INI1) was observed in all 5 cases, epidermal growth factor receptor (EGFR) amplification, PTEN (phosphatase and tensin homolog) loss, homozygous deletion of cyclin-dependent kinase inhibitor 2A, 1p/19q codeletion, and isocitrate dehydrogenase 1 R132/IDH2 R172 mutation were not observed in any case, although a high level of EGFR polysomy was detected in 1 recurrent tumor. Although c-MET (MET protein) expression was focal but robustly positive in 3 cases, met proto-oncogene (MET) fluorescence in situ hybridization revealed low polysomy but not MET amplification. MGMT (O-6-methylguanine-DNA methyl-40 transferase) methylation-specific polymerase chain reaction revealed MGMT methylation in only 1 case. Furthermore, array-based comparative genomic hybridization revealed gain of chromosome 7 and loss of 1p, 6, 8p, 11, 13q, and 18q but no deletion of chromosome 22. In contrast to the classical subtype of primary glioblastoma, the cases studied here were characterized by the absence of EGFR amplification, PTEN loss, and 9p homozygous deletion and overexpression of p53, PDGFRα, and c-MET, suggesting that they can be classified as the proneural or mesenchymal subtype of glioblastoma and benefit from intensive therapy that includes temozolomide.

  1. Anticancer potential and mechanism of action of mango ginger (Curcuma amada Roxb.) supercritical CO₂ extract in human glioblastoma cells.

    Science.gov (United States)

    Ramachandran, Cheppail; Lollett, Ivonne V; Escalon, Enrique; Quirin, Karl-Werner; Melnick, Steven J

    2015-04-01

    Mango ginger (Curcuma amada Roxb.) is among the less-investigated species of Curcuma for anticancer properties. We have investigated the anticancer potential and the mechanism of action of a supercritical CO2 extract of mango ginger (CA) in the U-87MG human glioblastoma cell line. CA demonstrated higher cytotoxicity than temozolomide, etoposide, curcumin, and turmeric force with IC50, IC75, and IC90 values of 4.92 μg/mL, 12.87 μg/mL, and 21.30 μg/mL, respectively. Inhibitory concentration values of CA for normal embryonic mouse hypothalamus cell line (mHypoE-N1) is significantly higher than glioblastoma cell line, indicating the specificity of CA against brain tumor cells. CompuSyn analysis indicates that CA acts synergistically with temozolomide and etoposide for the cytotoxicity with combination index values of <1. CA treatment also induces apoptosis in glioblastoma cells in a dose-dependent manner and downregulates genes associated with apoptosis, cell proliferation, telomerase activity, oncogenesis, and drug resistance in glioblastoma cells.

  2. TCGA Workshop: Genomics and Biology of Glioblastoma Multiforme (GBM) - TCGA

    Science.gov (United States)

    The National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI) held a workshop entitled, “Genomics and Biology of Glioblastoma Multiforme (GBM),” to review the initial GBM data from the TCGA pilot project.

  3. Glioblastoma multiforme in a child with tuberous sclerosis complex.

    Science.gov (United States)

    Vignoli, Aglaia; Lesma, Elena; Alfano, Rosa Maria; Peron, Angela; Scornavacca, Giulia Federica; Massimino, Maura; Schiavello, Elisabetta; Ancona, Silvia; Cerati, Michele; Bulfamante, Gaetano; Gorio, Alfredo; Canevini, Maria Paola

    2015-10-01

    Tuberous Sclerosis Complex (TSC) is characterized by the presence of benign tumors in the brain, kidneys, heart, eyes, lungs, and skin. The typical brain lesions are cortical tubers, subependimal nodules and subependymal giant-cell astrocytomas. The occurrence of malignant astrocytomas such as glioblastoma is rare. We report on a child with a clinical diagnosis of TSC and a rapidly evolving glioblastoma multiforme. Genetic analysis identified a de novo mutation in TSC2. Molecular characterization of the tumor was performed and discussed, as well as a review of the literature where cases of TSC and glioblastoma multiforme are described. Although the co-occurrence of TSC and glioblastoma multiforme seems to be rare, this possible association should be kept in mind, and proper clinical and radiological follow up should be recommended in these patients.

  4. Prognostic relevance of epilepsy at presentation in glioblastoma patients

    NARCIS (Netherlands)

    Berendsen, Sharon; Varkila, Meri; Kroonen, Jérôme; Seute, Tatjana; Snijders, Tom J; Kauw, Frans; Spliet, Wim G M; Willems, Marie; Poulet, Christophe; Broekman, Marike L; Bours, Vincent; Robe, Pierre A

    2016-01-01

    BACKGROUND: Epileptogenic glioblastomas are thought to convey a favorable prognosis, either due to early diagnosis or potential antitumor effects of antiepileptic drugs. We investigated the relationship between survival and epilepsy at presentation, early diagnosis, and antiepileptic drug therapy in

  5. A prospective PET study of patients with glioblastoma multiforme

    DEFF Research Database (Denmark)

    Andersen, Preben B.; Blinkenberg, M; Lassen, U;

    2006-01-01

    OBJECTIVE: To study the post-surgical metabolic and structural cerebral changes in patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: We examined ten patients prospectively with newly diagnosed GBM. All patients were primarily treated with surgery, followed by chemotherapy...

  6. Glioblastoma multiforme no cerebelo: registro de um caso

    Directory of Open Access Journals (Sweden)

    Roberto Aidar Aun

    1981-09-01

    Full Text Available O glioblastoma multiforme no cerebelo é raro. Foram publicados cêrca de 38 casos na literatura. Os autores relatam um caso, parecendo tratar-se da primeira referência na literatura brasileira.

  7. Perceiving active listening activates the reward system and improves the impression of relevant experiences

    OpenAIRE

    Kawamichi, Hiroaki; Yoshihara, Kazufumi; Sasaki, Akihiro T.; Sugawara, Sho K.; Hiroki C Tanabe; Shinohara, Ryoji; Sugisawa, Yuka; Tokutake, Kentaro; Mochizuki, Yukiko; Anme, Tokie; Sadato, Norihiro

    2014-01-01

    Although active listening is an influential behavior, which can affect the social responses of others, the neural correlates underlying its perception have remained unclear. Sensing active listening in social interactions is accompanied by an improvement in the recollected impressions of relevant experiences and is thought to arouse positive feelings. We therefore hypothesized that the recognition of active listening activates the reward system, and that the emotional appraisal of experiences...

  8. Pine (Pinus morrisonicola Hayata) needle extracts sensitize GBM8901 human glioblastoma cells to temozolomide by downregulating autophagy and O(6)-methylguanine-DNA methyltransferase expression.

    Science.gov (United States)

    Liao, Chia-Leng; Chen, Chien-Min; Chang, Yan-Zin; Liu, Guang-Yaw; Hung, Hui-Chih; Hsieh, Tung-Ying; Lin, Chih-Li

    2014-10-29

    Pine needle extracts of Pinus morrisonicola (Hayata) are commonly used as a functional health beverage. However, it remains unclear what the mechanism is underlying the antitumor activity of pine needle extract. The aims of present study were to investigate the anti-glioblastoma effects of pine needle extracts as well as its bioactive compounds. From three different solvent extracts of pine needles, the water extract displayed the strongest cytotoxicity effects on GBM8901 glioblastoma cells. The isolated compounds were identified as pinocembrin, chrysin, and tiliroside. Chrysin was the most active ingredient of pine needle extract for the induction of apoptosis and suppression of migration and invasion. It also markedly inhibited temozolomide (TMZ)-induced autophagy and O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Because both autophagy and MGMT overexpression have been implicated to TMZ-induced drug resistance in glioblastoma, our results showed that pine needle extract and chrysin may serve as a potential anticancer agent against glioblastoma, especially with regard to sensitizing glioblastoma cells resistant to TMZ.

  9. Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma.

    Science.gov (United States)

    Mieczkowski, Jakub; Kocyk, Marta; Nauman, Pawel; Gabrusiewicz, Konrad; Sielska, Małgorzata; Przanowski, Piotr; Maleszewska, Marta; Rajan, Wenson D; Pszczolkowska, Dominika; Tykocki, Tomasz; Grajkowska, Wieslawa; Kotulska, Katarzyna; Roszkowski, Marcin; Kostkiewicz, Boguslaw; Kaminska, Bozena

    2015-10-20

    Glioblastoma (GBM) is an aggressive malignancy associated with profound host immunosuppression. Microglia and macrophages infiltrating GBM acquire the pro-tumorigenic, M2 phenotype and support tumor invasion, proliferation, survival, angiogenesis and block immune responses both locally and systematically. Mechanisms responsible for immunological deficits in GBM patients are poorly understood. We analyzed immune/inflammatory gene expression in five datasets of low and high grade gliomas, and performed Gene Ontology and signaling pathway analyses to identify defective transcriptional responses. The expression of many immune/inflammatory response and TLR signaling pathway genes was reduced in high grade gliomas compared to low grade gliomas. In particular, we found the reduced expression of the IKBKB, a gene coding for IKKβ, which phosphorylates IκB proteins and represents a convergence point for most signal transduction pathways leading to NFκB activation. The reduced IKBKB expression and IKKβ levels in GBM tissues were demonstrated by qPCR, Western blotting and immunohistochemistry. The IKKβ expression was down-regulated in microglia/macrophages infiltrating glioblastoma. NFκB activation, prominent in microglia/macrophages infiltrating low grade gliomas, was reduced in microglia/macrophages in glioblastoma tissues. Down-regulation of IKBKB expression and NFκB signaling in microglia/macrophages infiltrating glioblastoma correlates with defective expression of immune/inflammatory genes and M2 polarization that may result in the global impairment of anti-tumor immune responses in glioblastoma.

  10. Active robotic training improves locomotor function in a stroke survivor

    Directory of Open Access Journals (Sweden)

    Krishnan Chandramouli

    2012-08-01

    Full Text Available Abstract Background Clinical outcomes after robotic training are often not superior to conventional therapy. One key factor responsible for this is the use of control strategies that provide substantial guidance. This strategy not only leads to a reduction in volitional physical effort, but also interferes with motor relearning. Methods We tested the feasibility of a novel training approach (active robotic training using a powered gait orthosis (Lokomat in mitigating post-stroke gait impairments of a 52-year-old male stroke survivor. This gait training paradigm combined patient-cooperative robot-aided walking with a target-tracking task. The training lasted for 4-weeks (12 visits, 3 × per week. The subject’s neuromotor performance and recovery were evaluated using biomechanical, neuromuscular and clinical measures recorded at various time-points (pre-training, post-training, and 6-weeks after training. Results Active robotic training resulted in considerable increase in target-tracking accuracy and reduction in the kinematic variability of ankle trajectory during robot-aided treadmill walking. These improvements also transferred to overground walking as characterized by larger propulsive forces and more symmetric ground reaction forces (GRFs. Training also resulted in improvements in muscle coordination, which resembled patterns observed in healthy controls. These changes were accompanied by a reduction in motor cortical excitability (MCE of the vastus medialis, medial hamstrings, and gluteus medius muscles during treadmill walking. Importantly, active robotic training resulted in substantial improvements in several standard clinical and functional parameters. These improvements persisted during the follow-up evaluation at 6 weeks. Conclusions The results indicate that active robotic training appears to be a promising way of facilitating gait and physical function in moderately impaired stroke survivors.

  11. Differentiation of glioblastoma multiforme stem-like cells leads to downregulation of EGFR and EGFRvIII and decreased tumorigenic and stem-like cell potential

    DEFF Research Database (Denmark)

    Stockhausen, Marie-Thérése; Kristoffersen, Karina; Stobbe Olsen, Marie-Louise;

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and devastating primary brain tumor among adults. Despite recent treatment progress, most patients succumb to their disease within 2 years of diagnosis. Current research has highlighted the importance of a subpopulation of cells, assigned brain...... cancer stem-like cells (bCSC), to play a pivotal role in GBM malignancy. bCSC are identified by their resemblance to normal neural stem cells (NSC), and it is speculated that the bCSC have to be targeted in order to improve treatment outcome for GBM patients. One hallmark of GBM is aberrant expression...... and activation of the epidermal growth factor receptor (EGFR) and expression of a deletion variant EGFRvIII. In the normal brain, EGFR is expressed in neurogenic areas where also NSC are located and it has been shown that EGFR is involved in regulation of NSC proliferation, migration, and differentiation...

  12. Perceiving active listening activates the reward system and improves the impression of relevant experiences.

    Science.gov (United States)

    Kawamichi, Hiroaki; Yoshihara, Kazufumi; Sasaki, Akihiro T; Sugawara, Sho K; Tanabe, Hiroki C; Shinohara, Ryoji; Sugisawa, Yuka; Tokutake, Kentaro; Mochizuki, Yukiko; Anme, Tokie; Sadato, Norihiro

    2015-01-01

    Although active listening is an influential behavior, which can affect the social responses of others, the neural correlates underlying its perception have remained unclear. Sensing active listening in social interactions is accompanied by an improvement in the recollected impressions of relevant experiences and is thought to arouse positive feelings. We therefore hypothesized that the recognition of active listening activates the reward system, and that the emotional appraisal of experiences that had been subject to active listening would be improved. To test these hypotheses, we conducted functional magnetic resonance imaging (fMRI) on participants viewing assessments of their own personal experiences made by evaluators with or without active listening attitude. Subjects rated evaluators who showed active listening more positively. Furthermore, they rated episodes more positively when they were evaluated by individuals showing active listening. Neural activation in the ventral striatum was enhanced by perceiving active listening, suggesting that this was processed as rewarding. It also activated the right anterior insula, representing positive emotional reappraisal processes. Furthermore, the mentalizing network was activated when participants were being evaluated, irrespective of active listening behavior. Therefore, perceiving active listening appeared to result in positive emotional appraisal and to invoke mental state attribution to the active listener.

  13. Active video gaming to improve balance in the elderly.

    Science.gov (United States)

    Lamoth, Claudine J C; Caljouw, Simone R; Postema, Klaas

    2011-01-01

    The combination of active video gaming and exercise (exergaming) is suggested to improve elderly people's balance, thereby decreasing fall risk. Exergaming has been shown to increase motivation during exercise therapy, due to the enjoyable and challenging nature, which could support long-term adherence for exercising balance. However, scarce evidence is available of the direct effects of exergaming on postural control. Therefore, the aim of the study was to assess the effect of a six-week videogame-based exercise program aimed at improving balance in elderly people. Task performance and postural control were examined using an interrupted time series design. Results of multilevel analyses showed that performance on the dot task improved within the first two weeks of training. Postural control improved during the intervention. After the intervention period task performance and balance were better than before the intervention. Results of this study show that healthy elderly can benefit from a videogame-based exercise program to improve balance and that all subjects were highly motivated to exercise balance because they found gaming challenging and enjoyable.

  14. Rubisco activity and regulation as targets for crop improvement.

    Science.gov (United States)

    Parry, Martin A J; Andralojc, P John; Scales, Joanna C; Salvucci, Michael E; Carmo-Silva, A Elizabete; Alonso, Hernan; Whitney, Spencer M

    2013-01-01

    Rubisco (ribulose-1,5-bisphosphate (RuBP) carboxylase/oxygenase) enables net carbon fixation through the carboxylation of RuBP. However, some characteristics of Rubisco make it surprisingly inefficient and compromise photosynthetic productivity. For example, Rubisco catalyses a wasteful reaction with oxygen that leads to the release of previously fixed CO(2) and NH(3) and the consumption of energy during photorespiration. Furthermore, Rubisco is slow and large amounts are needed to support adequate photosynthetic rates. Consequently, Rubisco has been studied intensively as a prime target for manipulations to 'supercharge' photosynthesis and improve both productivity and resource use efficiency. The catalytic properties of Rubiscos from diverse sources vary considerably, suggesting that changes in turnover rate, affinity, or specificity for CO(2) can be introduced to improve Rubisco performance in specific crops and environments. While attempts to manipulate plant Rubisco by nuclear transformation have had limited success, modifying its catalysis by targeted changes to its catalytic large subunit via chloroplast transformation have been much more successful. However, this technique is still in need of development for most major food crops including maize, wheat, and rice. Other bioengineering approaches for improving Rubisco performance include improving the activity of its ancillary protein, Rubisco activase, in addition to modulating the synthesis and degradation of Rubisco's inhibitory sugar phosphate ligands. As the rate-limiting step in carbon assimilation, even modest improvements in the overall performance of Rubisco pose a viable pathway for obtaining significant gains in plant yield, particularly under stressful environmental conditions.

  15. Glioblastoma multiforme: State of the art and future therapeutics

    Directory of Open Access Journals (Sweden)

    Taylor A Wilson

    2014-01-01

    Full Text Available Background: Glioblastoma multiforme (GBM is the most common and lethal primary malignancy of the central nervous system (CNS. Despite the proven benefit of surgical resection and aggressive treatment with chemo- and radiotherapy, the prognosis remains very poor. Recent advances of our understanding of the biology and pathophysiology of GBM have allowed the development of a wide array of novel therapeutic approaches, which have been developed. These novel approaches include molecularly targeted therapies, immunotherapies, and gene therapy. Methods: We offer a brief review of the current standard of care, and a survey of novel therapeutic approaches for treatment of GBM. Results: Despite promising results in preclinical trials, many of these therapies have demonstrated limited therapeutic efficacy in human clinical trials. Thus, although survival of patients with GBM continues to slowly improve, treatment of GBM remains extremely challenging. Conclusion: Continued research and development of targeted therapies, based on a detailed understanding of molecular pathogenesis can reasonably be expected to yield improved outcomes for patients with GBM.

  16. Zinc Pyrithione Improves the Antibacterial Activity of Silver Sulfadiazine Ointment

    Science.gov (United States)

    Blanchard, Catlyn; Brooks, Lauren; Ebsworth-Mojica, Katherine; Didione, Louis; Wucher, Benjamin; Dewhurst, Stephen; Krysan, Damian

    2016-01-01

    ABSTRACT Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus are commonly associated with biofilm-associated wound infections that are recalcitrant to conventional antibiotics. As an initial means to identify agents that may have a greater propensity to improve clearance of wound-associated bacterial pathogens, we screened a Food and Drug Administration-approved drug library for members that display bactericidal activity toward 72-h-established P. aeruginosa biofilms using an adenylate kinase reporter assay for bacterial cell death. A total of 34 compounds displayed antibiofilm activity. Among these, zinc pyrithione was also shown to reduce levels of A. baumannii and S. aureus biofilm-associated bacteria and exhibited an additive effect in combination with silver sulfadiazine, a leading topical therapeutic for wound site infections. The improved antimicrobial activity of zinc pyrithione and silver sulfadiazine was maintained in an ointment formulation and led to improved clearance of P. aeruginosa, A. baumannii, and S. aureus in a murine model of wound infection. Taken together, these results suggest that topical zinc pyrithione and silver sulfadiazine combination formulations may mitigate wound-associated bacterial infections and disease progression. IMPORTANCE Topical antimicrobial ointments ostensibly mitigate bacterial wound disease and reliance on systemic antibiotics. Yet studies have called into question the therapeutic benefits of several traditional topical antibacterials, accentuating the need for improved next-generation antimicrobial ointments. Yet the development of such agents consisting of a new chemical entity is a time-consuming and expensive proposition. Considering that drug combinations are a mainstay therapeutic strategy for the treatment of other therapeutic indications, one alternative approach is to improve the performance of conventional antimicrobial ointments by the addition of a well-characterized and FDA

  17. HOW A WRITING ACTIVITY IMPROVED MY ENGLISH CLASS

    Institute of Scientific and Technical Information of China (English)

    1994-01-01

    Introduction In this article, I’d like to describe a writing activity I use to improve my students’ writing ability. The activity is a type of journal-keeping for college-English students. I ask the students to write something at regular intervals. It can be of any length. If they don’t have anything specific to write about, they can write summaries or discussions about texts from their English class. They then submit the assignment by a fixed deadline. The results have been satisfactory. Most students handed in some sort of work on time, covering a wide range of topics from personal matters (such as worries and ambitions), interests (such as hobbies, friends and hometowns) to something related to their English class (summaries, discussions or even transcriptions of model paragraphs). Stimulated by immediate feedback from the teacher, the activity has continued through the whole college-English learning period.

  18. Prioritising Investments in Marketing Activities to Improve Business Performance

    DEFF Research Database (Denmark)

    Martensen, Anne; Mouritsen, Jan

    2014-01-01

    dimensions: (1) Small m: marketing strategy and marketing implementation and (2) big M: cross-functional coordination and innovation. Big M and small m interact and influence BP similarly. When considering investing in marketing activities to improve financial performance, the first priority is to recruit...... and retain competent employees and the second, to collect, disseminate and act upon market insight in the form of measurement of effectiveness and production of intelligence. These provide resources for the development of a customer-oriented marketing strategy that in turn helps innovation and cross......The purpose of this study is to prioritise investments in marketing activities based on their effect on business performance (BP). On the basis of the European Foundation for Quality Management (EFQM) model adapted to a marketing context, four generic marketing activities are structured in two...

  19. Long-term survival in glioblastoma: methyl guanine methyl transferase (MGMT) promoter methylation as independent favourable prognostic factor

    Science.gov (United States)

    Smrdel, Uros; Zwitter, Matjaz; Bostjancic, Emanuela; Zupan, Andrej; Kovac, Viljem; Glavac, Damjan; Bokal, Drago; Jerebic, Janja

    2016-01-01

    Abstract Background In spite of significant improvement after multi-modality treatment, prognosis of most patients with glioblastoma remains poor. Standard clinical prognostic factors (age, gender, extent of surgery and performance status) do not clearly predict long-term survival. The aim of this case-control study was to evaluate immuno-histochemical and genetic characteristics of the tumour as additional prognostic factors in glioblastoma. Patients and methods Long-term survivor group were 40 patients with glioblastoma with survival longer than 30 months. Control group were 40 patients with shorter survival and matched to the long-term survivor group according to the clinical prognostic factors. All patients underwent multimodality treatment with surgery, postoperative conformal radiotherapy and temozolomide during and after radiotherapy. Biopsy samples were tested for the methylation of MGMT promoter (with methylation specific polymerase chain reaction), IDH1 (with immunohistochemistry), IDH2, CDKN2A and CDKN2B (with multiplex ligation-dependent probe amplification), and 1p and 19q mutations (with fluorescent in situ hybridization). Results Methylation of MGMT promoter was found in 95% and in 36% in the long-term survivor and control groups, respectively (p < 0.001). IDH1 R132H mutated patients had a non-significant lower risk of dying from glioblastoma (p = 0.437), in comparison to patients without this mutation. Other mutations were rare, with no significant difference between the two groups. Conclusions Molecular and genetic testing offers additional prognostic and predictive information for patients with glioblastoma. The most important finding of our analysis is that in the absence of MGMT promoter methylation, longterm survival is very rare. For patients without this mutation, alternative treatments should be explored. PMID:27904447

  20. Characterization of radioresistant variant from U251 human glioblastoma cell line and the role of antioxdant enzymes in its radioresistancy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hyung Chahn; Park, In Chul; Park, Myung Jin; Woo, Sang Hyeok; Rhee, Chang Hum; Hong, Seok-II [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2004-07-01

    To investigate the radioresistant mechanism in glioblastoma multiforme(GBM), we isolated the radioresistant clone (RRC) from U251 human glioblastoma cell line by exposing to repeated fractions of 3 Gy {gamma}-radiation for six months. RRC had higher radioresistance than the parent cell line as measured by clonogenic survival assay. FACS analysis showed that RRC had a delayed G2 arrest after radiation. Antioxidant enzymes, such as SOD, catalase, glutathione peroxidase (GPX), glutathione reductase (GR), were activated up to 5 folds in RRC after radiation. Erk 1/2 activation was higher in RRC than in the parent cell. Therefore, radioresistancy in RRC might be due to the delayed cell cycle, the coordinated high activation of antioxidant enzyme rather than a single enzyme alone,and higher activation of Erk 1/2.

  1. The somatic genomic landscape of glioblastoma.

    Science.gov (United States)

    Brennan, Cameron W; Verhaak, Roel G W; McKenna, Aaron; Campos, Benito; Noushmehr, Houtan; Salama, Sofie R; Zheng, Siyuan; Chakravarty, Debyani; Sanborn, J Zachary; Berman, Samuel H; Beroukhim, Rameen; Bernard, Brady; Wu, Chang-Jiun; Genovese, Giannicola; Shmulevich, Ilya; Barnholtz-Sloan, Jill; Zou, Lihua; Vegesna, Rahulsimham; Shukla, Sachet A; Ciriello, Giovanni; Yung, W K; Zhang, Wei; Sougnez, Carrie; Mikkelsen, Tom; Aldape, Kenneth; Bigner, Darell D; Van Meir, Erwin G; Prados, Michael; Sloan, Andrew; Black, Keith L; Eschbacher, Jennifer; Finocchiaro, Gaetano; Friedman, William; Andrews, David W; Guha, Abhijit; Iacocca, Mary; O'Neill, Brian P; Foltz, Greg; Myers, Jerome; Weisenberger, Daniel J; Penny, Robert; Kucherlapati, Raju; Perou, Charles M; Hayes, D Neil; Gibbs, Richard; Marra, Marco; Mills, Gordon B; Lander, Eric; Spellman, Paul; Wilson, Richard; Sander, Chris; Weinstein, John; Meyerson, Matthew; Gabriel, Stacey; Laird, Peter W; Haussler, David; Getz, Gad; Chin, Lynda

    2013-10-10

    We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

  2. Current status of intratumoral therapy for glioblastoma.

    Science.gov (United States)

    Mehta, Ankit I; Linninger, Andreas; Lesniak, Maciej S; Engelhard, Herbert H

    2015-10-01

    With emerging drug delivery technologies becoming accessible, more options are expected to become available to patients with glioblastoma (GBM) in the near future. It is important for clinicians to be familiar with the underlying mechanisms and limitations of intratumoral drug delivery, and direction of recent research efforts. Tumor-adjacent brain is an extremely complex living matrix that creates challenges with normal tissue intertwining with tumor cells. For convection-enhanced delivery (CED), the role of tissue anisotropy for better predicting the biodistribution of the infusate has recently been studied. Computational predictive methods are now available to better plan CED therapy. Catheter design and placement—in addition to the agent being used—are critical components of any protocol. This paper overviews intratumoral therapies for GBM, highlighting key anatomic and physiologic perspectives, selected agents (especially immunotoxins), and some new developments such as the description of the glymphatic system.

  3. Citotoxic activity evaluation of essential oils and nanoemulsions of Drimys angustifolia and D. brasiliensis on human glioblastoma (U-138 MG and human bladder carcinoma (T24 cell lines in vitro

    Directory of Open Access Journals (Sweden)

    Madson R. F. Gomes

    2012-01-01

    Full Text Available The species Drimys angustifolia Miers and D. brasiliensis Miers, commonly known as "casca-de-anta", have in their leaves essential oils that can confer cytotoxic effects. In this study, we evaluated the citotoxic effects of the volatile oils from these two species. We also proposed a nanoemulsion formulation for each of the species and assessed the in vitro cytotoxicity on U-138 MG (human glioblastoma and T24 (human bladder carcinoma cell lines. The plant chemical composition was evaluated by gas chromatography coupled to mass spectrometer. Furthermore, the nanoemulsions were prepared and characterized. Our results showed that; bicyclogermacrene (19.6% and cyclocolorenone (18.2% were the most abundant for the D angustifolia oil and D brasiliensis oil, respectively. Both nanoemulsions, D angustifolia and D brasiliensis appeared macroscopically homogeneous and opalescent bluish liquids, with nanometric mean diameters of 168 nm for D brasiliensis and 181 nm for D angustifolia. The polydispersity indices were below 0.10, with an acid pH of 4.7-6.3, and negative zeta potentials about -34 mV. The results of transmission electron microscopy showed that droplets are present in the nanometer range. Only the D brasiliensis oil was efficient in reducing the cell viability of both U-138 MG (42.5%±7.0 and 67.8%±7.8 and T24 (33.2%±2.8, 60.3%±1.6 and 80.5%±8.8 cell lines, as assessed by MTT assay. Noteworthy, similar results were obtained with cell counting. Finally, D brasiliensis oil incubation caused an increase of annexin-V and propidium iodite population, according to evaluation by cytometry analysis, what is characteristic of late apoptosis. The results presented herein lead us to consider the potential therapeutic effects of the essential oils and nanoformulations as novel strategies to inhibit tumor growth.

  4. Induction of cytopathogenicity in human glioblastoma cells by chikungunya virus.

    Directory of Open Access Journals (Sweden)

    Rachy Abraham

    Full Text Available Chikungunya virus (CHIKV, an arthritogenic old-world alphavirus, has been implicated in the central nervous system (CNS infection in infants and elderly patients. Astrocytes are the major immune cells of the brain parenchyma that mediate inflammation. In the present study we found that a local isolate of CHIKV infect and activate U-87 MG cells, a glioblastoma cell line of human astrocyte origin. The infection kinetics were similar in infected U-87 MG cells and the human embryo kidney (HEK293 cells as indicated by immunofluorescence and plaque assays, 24h post-infection (p.i.. In infected U-87 MG cells, apoptosis was detectable from 48h p.i. evidenced by DNA fragmentation, PARP cleavage, loss of mitochondrial membrane potential, nuclear condensation and visible cytopathic effects in a dose and time-dependent manner. XBP1 mRNA splicing and eIF2α phosphorylation studies indicated the occurrence of endoplasmic reticulum stress in infected cells. In U-87 MG cells stably expressing a green fluorescent protein-tagged light chain-3 (GFP-LC3 protein, CHIKV infection showed increased autophagy response. The infection led to an enhanced expression of the mRNA transcripts of the pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and CXCL9 within 24h p.i. Significant up-regulation of the proteins of RIG-I like receptor (RLR pathway, such as RIG-I and TRAF-6, was observed indicating the activation of the cytoplasmic-cellular innate immune response. The overall results show that the U-87 MG cell line is a potential in vitro model for in depth study of these molecular pathways in response to CHIKV infection. The responses in these cells of CNS origin, which are inherently defective in Type I interferon response, could be analogous to that occurring in infants and very old patients who also have a compromised interferon-response. The results also point to the intriguing possibility of using this virus for studies to develop oncolytic virus therapy approaches

  5. Prognostic relevance of cytochrome C oxidase in primary glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Corinne E Griguer

    Full Text Available Patients with primary glioblastoma multiforme (GBM have one of the lowest overall survival rates among cancer patients, and reliable biomarkers are necessary to predict patient outcome. Cytochrome c oxidase (CcO promotes the switch from glycolytic to OXPHOS metabolism, and increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure. Thus, we investigated the relationship between tumor CcO activity and the survival of patients diagnosed with primary GBM. A total of 84 patients with grade IV glioma were evaluated in this retrospective cohort study. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test, and univariate and multivariate analyses were performed with the Cox regression model. Mitochondrial CcO activity was determined by spectrophotometrically measuring the oxidation of cytochrome c. High CcO activity was detected in a subset of glioma tumors (∼30%, and was an independent prognostic factor for shorter progression-free survival and overall survival [P = 0.0087 by the log-rank test, hazard ratio = 3.57 for progression-free survival; P<0.001 by the log-rank test, hazard ratio = 10.75 for overall survival]. The median survival time for patients with low tumor CcO activity was 14.3 months, compared with 6.3 months for patients with high tumor CcO activity. High CcO activity occurs in a significant subset of high-grade glioma patients and is an independent predictor of poor outcome. Thus, CcO activity may serve as a useful molecular marker for the categorization and targeted therapy of GBMs.

  6. Reverse engineering of modified genes by Bayesian network analysis defines molecular determinants critical to the development of glioblastoma.

    Directory of Open Access Journals (Sweden)

    Brian W Kunkle

    Full Text Available In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV, and 'key genes' within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated. These 10 genes were able to predict tumor status with 96-100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkβ, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential 'hubs of activity'. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several 'key genes' may be required for the development of glioblastoma. Further studies are needed to validate these 'key genes' as useful tools for early detection and novel therapeutic options for these tumors.

  7. Reverse engineering of modified genes by Bayesian network analysis defines molecular determinants critical to the development of glioblastoma.

    Science.gov (United States)

    Kunkle, Brian W; Yoo, Changwon; Roy, Deodutta

    2013-01-01

    In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV), and 'key genes' within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated). These 10 genes were able to predict tumor status with 96-100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkβ, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential 'hubs of activity'. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several 'key genes' may be required for the development of glioblastoma. Further studies are needed to validate these 'key genes' as useful tools for early detection and novel therapeutic options for these tumors.

  8. Improving Activity of Salt-Lyophilized Enzymes in Organic Media

    Science.gov (United States)

    Borole, Abhijeet P.; Davison, Brian H.

    Lyophilization with salts has been identified as an important method of activating enzymes in organic media. Using salt-activated enzymes to transform molecules tethered to solid surfaces in organic phase requires solubilization of enzymes in the solvents. Methods of improving performance of salt-lyophilized enzymes, further, via chemical modification, and use of surfactants and surfactants to create fine emulsions prior to lyophilization are investigated. The reaction system used is transesterification of N-acetyl phenylalanine ethyl ester with methanol or propanol. Initial rate of formation of amino acid esters by subtilisin Carlsberg (SC) was studied and found to increase two to sevenfold by either chemical modification or addition of surfactants in certain solvents, relative to the salt (only)-lyophilized enzyme. The method to prepare highly dispersed enzymes in a salt-surfactant milieu also improved activity by two to threefold. To test the effect of chemical modification on derivatization of drug molecules, acylation of bergenin was investigated using chemically modified SC.

  9. Improving Industrial Energy Quality by an Active Current Filter

    Directory of Open Access Journals (Sweden)

    Reyes–Trujillo E

    2010-10-01

    Full Text Available The growing number of non-linear loads on industrial applications has produced an important impact on the quality of electric power supply due to the increasing of the voltage and current harmonic distortion, and low power factor. In order to solve this, arrangements of capacitors and reactors, known as passive filters have been used. However these filters may produce resonance problems with network impedance, over compensation of reactive power at fundamental frequency, and poor flexibility for dynamic compensation of different frequency harmonic components. As a solution to the problems mentioned above, the active filters have been developed, whose features can be adapted in a dynamic and adjustable way on the requirements of the system to compensate. This paper presents the modelling and simulation results of an active current filter, used to reduce the harmonic distortion and to improve the power factor in an electric industrial system. A six-pulse diode converter has been used as non-linear passive load. During the analysis, it was observed that the total current harmonic distortion (THD was reduced from 16.47% to 0.46%, and the power factor in the distribution bus has improved from 0.5 to 0.95.The waveforms of a three-phase thyristor converter with a DC machine as active non-linear load are shown.

  10. IMPROVING VOICE ACTIVITY DETECTION VIA WEIGHTING LIKELIHOOD AND DIMENSION REDUCTION

    Institute of Scientific and Technical Information of China (English)

    Wang Huanliang; Han Jiqing; Li Haifeng; Zheng Tieran

    2008-01-01

    The performance of the traditional Voice Activity Detection (VAD) algorithms declines sharply in lower Signal-to-Noise Ratio (SNR) environments. In this paper, a feature weighting likelihood method is proposed for noise-robust VAD. The contribution of dynamic features to likelihood score can be increased via the method, which improves consequently the noise robustness of VAD.Divergence based dimension reduction method is proposed for saving computation, which reduces these feature dimensions with smaller divergence value at the cost of degrading the performance a little.Experimental results on Aurora Ⅱ database show that the detection performance in noise environments can remarkably be improved by the proposed method when the model trained in clean data is used to detect speech endpoints. Using weighting likelihood on the dimension-reduced features obtains comparable, even better, performance compared to original full-dimensional feature.

  11. Transforming fusions of FGFR and TACC genes in human glioblastoma.

    Science.gov (United States)

    Singh, Devendra; Chan, Joseph Minhow; Zoppoli, Pietro; Niola, Francesco; Sullivan, Ryan; Castano, Angelica; Liu, Eric Minwei; Reichel, Jonathan; Porrati, Paola; Pellegatta, Serena; Qiu, Kunlong; Gao, Zhibo; Ceccarelli, Michele; Riccardi, Riccardo; Brat, Daniel J; Guha, Abhijit; Aldape, Ken; Golfinos, John G; Zagzag, David; Mikkelsen, Tom; Finocchiaro, Gaetano; Lasorella, Anna; Rabadan, Raul; Iavarone, Antonio

    2012-09-07

    The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition.

  12. Genetic and Functional Diversity of Propagating Cells in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Sara G.M. Piccirillo

    2015-01-01

    Full Text Available Glioblastoma (GBM is a lethal malignancy whose clinical intransigence has been linked to extensive intraclonal genetic and phenotypic diversity and the common emergence of therapeutic resistance. This interpretation embodies the implicit assumption that cancer stem cells or tumor-propagating cells are themselves genetically and functionally diverse. To test this, we screened primary GBM tumors by SNP array to identify copy number alterations (a minimum of three that could be visualized in single cells by multicolor fluorescence in situ hybridization. Interrogation of neurosphere-derived cells (from four patients and cells derived from secondary transplants of these same cells in NOD-SCID mice allowed us to infer the clonal and phylogenetic architectures. Whole-exome sequencing and single-cell genetic analysis in one case revealed a more complex clonal structure. This proof-of-principle experiment revealed that subclones in each GBM had variable regenerative or stem cell activity, and highlighted genetic alterations associated with more competitive propagating activity in vivo.

  13. Volumetric and MGMT parameters in glioblastoma patients: Survival analysis

    Directory of Open Access Journals (Sweden)

    Iliadis Georgios

    2012-01-01

    Full Text Available Abstract Background In this study several tumor-related volumes were assessed by means of a computer-based application and a survival analysis was conducted to evaluate the prognostic significance of pre- and postoperative volumetric data in patients harboring glioblastomas. In addition, MGMT (O6-methylguanine methyltransferase related parameters were compared with those of volumetry in order to observe possible relevance of this molecule in tumor development. Methods We prospectively analyzed 65 patients suffering from glioblastoma (GBM who underwent radiotherapy with concomitant adjuvant temozolomide. For the purpose of volumetry T1 and T2-weighted magnetic resonance (MR sequences were used, acquired both pre- and postoperatively (pre-radiochemotherapy. The volumes measured on preoperative MR images were necrosis, enhancing tumor and edema (including the tumor and on postoperative ones, net-enhancing tumor. Age, sex, performance status (PS and type of operation were also included in the multivariate analysis. MGMT was assessed for promoter methylation with Multiplex Ligation-dependent Probe Amplification (MLPA, for RNA expression with real time PCR, and for protein expression with immunohistochemistry in a total of 44 cases with available histologic material. Results In the multivariate analysis a negative impact was shown for pre-radiochemotherapy net-enhancing tumor on the overall survival (OS (p = 0.023 and for preoperative necrosis on progression-free survival (PFS (p = 0.030. Furthermore, the multivariate analysis confirmed the importance of PS in PFS and OS of patients. MGMT promoter methylation was observed in 13/23 (43.5% evaluable tumors; complete methylation was observed in 3/13 methylated tumors only. High rate of MGMT protein positivity (> 20% positive neoplastic nuclei was inversely associated with pre-operative tumor necrosis (p = 0.021. Conclusions Our findings implicate that volumetric parameters may have a significant role in

  14. Cytoplasmic TRADD Confers a Worse Prognosis in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Sharmistha Chakraborty

    2013-08-01

    Full Text Available Tumor necrosis factor receptor 1 (TNFR1-associated death domain protein (TRADD is an important adaptor in TNFR1 signaling and has an essential role in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB activation and survival signaling. Increased expression of TRADD is sufficient to activate NF-κB. Recent studies have highlighted the importance of NF-κB activation as a key pathogenic mechanism in glioblastoma multiforme (GBM, the most common primary malignant brain tumor in adults.We examined the expression of TRADD by immunohistochemistry (IHC and find that TRADD is commonly expressed at high levels in GBM and is detected in both cytoplasmic and nuclear distribution. Cytoplasmic IHC TRADD scoring is significantly associated with worse progression-free survival (PFS both in univariate and multivariate analysis but is not associated with overall survival (n = 43 GBMs. PFS is a marker for responsiveness to treatment. We propose that TRADD-mediated NF-κB activation confers chemoresistance and thus a worse PFS in GBM. Consistent with the effect on PFS, silencing TRADD in glioma cells results in decreased NF-κB activity, decreased proliferation of cells, and increased sensitivity to temozolomide. TRADD expression is common in glioma-initiating cells. Importantly, silencing TRADD in GBM-initiating stem cell cultures results in decreased viability of stem cells, suggesting that TRADD may be required for maintenance of GBM stem cell populations. Thus, our study suggests that increased expression of cytoplasmic TRADD is both an important biomarker and a key driver of NF-κB activation in GBM and supports an oncogenic role for TRADD in GBM.

  15. Phosphatidylinositol 3-Kinase/AKT Pathway Inhibition by Doxazosin Promotes Glioblastoma Cells Death, Upregulation of p53 and Triggers Low Neurotoxicity.

    Directory of Open Access Journals (Sweden)

    Mariana Maier Gaelzer

    Full Text Available Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapy with temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide, as well as the human glioblastoma cell line U138-MG. We investigated doxazosin's (an antihypertensive drug activity against glioblastoma cells (C6 and U138-MG and its neurotoxicity on primary astrocytes and organoptypic hippocampal cultures. For this study, the following methods were used: citotoxicity assays, flow cytometry, western-blotting and confocal microscopy. We showed that doxazosin induces cell death on C6 and U138-MG cells. We observed that doxazosin's effects on the PI3K/Akt pathway were similar as LY294002 (PI3K specific inhibitor. In glioblastoma cells treated with doxasozin, Akt levels were greatly reduced. Upon examination of activities of proteins downstream of Akt we observed upregulation of GSK-3β and p53. This led to cell proliferation inhibition, cell death induction via caspase-3 activation and cell cycle arrest at G0/G1 phase in glioblastoma cells. We used in this study Lapatinib, a tyrosine kinase inhibitor, as a comparison with doxazosin because they present similar chemical structure. We also tested the neurocitotoxicity of doxazosin in primary astrocytes and organotypic cultures and observed that doxazosin induced cell death on a small percentage of non-tumor cells. Aggressiveness of glioblastoma tumors and dismal prognosis require development of new treatment agents. This includes less toxic drugs, more selective towards tumor cells, causing less damage to the patient. Therefore, our results confirm the potential of doxazosin as an attractive therapeutic antiglioma agent.

  16. Clinical implications of microRNAs in human glioblastoma

    Directory of Open Access Journals (Sweden)

    Masahiro eMizoguchi

    2013-02-01

    Full Text Available Glioblastoma (GBM is one of the most common and dismal brain tumors in adults. Further elucidation of the molecular pathogenesis of GBM is mandatory to improve the overall survival of patients. A novel small non-coding RNA molecule, microRNA (miRNA, appears to represent one of the most attractive target molecules contributing to the pathogenesis of various types of tumors. Recent global analyses have revealed that several miRNAs are clinically implicated in GBM, with some reports indicating the association of miRNA dysregulation with acquired temozolomide (TMZ resistance. More recent studies have revealed that miRNAs could play a role in cancer stem cell (CSC properties, contributing to treatment resistance. In addition, greater impact might be expected from miRNA-targeted therapies based on tumor-derived exosomes that contain numerous functional miRNAs, which could be transferred between tumor cells and surrounding structures. Tumor-derived miRNAs are now considered to be a novel molecular mechanism promoting the progression of GBM. Establishment of miRNA-targeted therapies based on miRNA dysregulation of CSCs could provide effective therapeutic strategies for TMZ-resistant GBM. Recent progress has revealed that miRNAs are not only putative biological markers for diagnosis, but also one of the most promising targets for GBM treatment. Herein, we summarize the translational aspects of miRNAs in the diagnosis and treatment of GBM.

  17. Current Trends in Targeted Therapies for Glioblastoma Multiforme

    Directory of Open Access Journals (Sweden)

    Fumiharu Ohka

    2012-01-01

    Full Text Available Glioblastoma multiforme (GBM is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas. Despite aggressive treatment including surgery, adjuvant TMZ-based chemotherapy, and radiotherapy, GBM still has a dismal prognosis: the median survival is 14.6 months from diagnosis. To date, many studies report several determinants of resistance to this aggressive therapy: (1 O6-methylguanine-DNA methyltransferase (MGMT, (2 the complexity of several altered signaling pathways in GBM, (3 the existence of glioma stem-like cells (GSCs, and (4 the blood-brain barrier. Many studies aim to overcome these determinants of resistance to conventional therapy by using various approaches to improve the dismal prognosis of GBM such as modifying TMZ administration and combining TMZ with other agents, developing novel molecular-targeting agents, and novel strategies targeting GSCs. In this paper, we review up-to-date clinical trials of GBM treatments in order to overcome these 4 hurdles and to aim at more therapeutical effect than conventional therapies that are ongoing or are about to launch in clinical settings and discuss future perspectives.

  18. Molecular mechanism of inositol hexaphosphate-mediated apoptosis in human malignant glioblastoma T98G cells.

    Science.gov (United States)

    Karmakar, Surajit; Banik, Naren L; Ray, Swapan K

    2007-12-01

    Glioblastoma is the deadliest brain tumor in humans. Current therapies are mostly ineffective and new agents need to be explored for controlling this devastating disease. Inositol hexaphosphate (IP6) is a phytochemical that is widely found in corns, cereals, nuts, and high fiber-content foods. Previous studies demonstrated anti-cancer properties of IP6 in several in vitro and in vivo tumor models. However, therapeutic efficacy of IP6 has not yet been evaluated in glioblastoma. Here, we explored the molecular mechanism of action of IP6 in human malignant glioblastoma T98G cells. The viability of T98G cells decreased following treatment with increasing doses of IP6. T98G cells exposed to 0.25, 0.5, and 1 mM IP6 for 24 h showed morphological and biochemical features of apoptosis. Western blotting indicated changes in expression of Bax and Bcl-2 proteins resulting in an increase in Bax:Bcl-2 ratio and upregulation of cytosolic levels of cytochrome c and Smac/Diablo, suggesting involvement of mitochondria-dependent caspase cascade in apoptosis. IP6 downregulated cell survival factors such as baculovirus inhibitor-of-apoptosis repeat containing-2 (BIRC-2) protein and telomerase to promote apoptosis. Upregulation of calpain and caspase-9 occurred in course of apoptosis. Increased activities of calpain and caspase-3 cleaved 270 kD alpha-spectrin at specific sites generating 145 kD spectrin break down product (SBDP) and 120 kD SBDP, respectively. Increased caspase-3 activity also cleaved inhibitor of caspase-3-activated DNase and poly(ADP-ribose) polymerase. Collectively, our results demonstrated that IP6 down regulated the survival factors BIRC-2 and telomerase and upregulated calpain and caspase-3 activities for apoptosis in T98G cells.

  19. Arsenic trioxide depletes cancer stem-like cells and inhibits repopulation of neurosphere derived from glioblastoma by downregulation of Notch pathway.

    Science.gov (United States)

    Wu, Jianing; Ji, Zhiyong; Liu, Huailei; Liu, Yaohua; Han, Dayong; Shi, Chen; Shi, Changbin; Wang, Chunlei; Yang, Guang; Chen, Xiaofeng; Shen, Chen; Li, Huadong; Bi, Yunke; Zhang, Dongzhi; Zhao, Shiguang

    2013-06-20

    Notch signaling has been demonstrated to have a central role in cancer stem-like cells (CSLCs) in glioblastoma multiforme (GBM). We have recently demonstrated the inhibitory effect of arsenic trioxide (ATO) on CSLCs in glioblastoma cell lines. In this study we used neurosphere recovery assay that measured neurosphere formation at three time points to assess the capacity of the culture to repopulate after ATO treatment. Our results provided strong evidence that ATO depleted CSLCs in GBM, and inhibited neurosphere recovery and secondary neurosphere formation. ATO inhibited the phosphorylation and activation of AKT and STAT3 through Notch signaling blockade. These data show that the ATO is a promising new approach to decrease glioblastoma proliferation and recurrence by downregulation of Notch pathway.

  20. Radiotherapy for glioblastoma: reorganization of genome maintenance mechanisms involved in the process of inhibiting cancer; Radioterapia de glioblastoma: reorganizacao das vias de manutencao do genoma

    Energy Technology Data Exchange (ETDEWEB)

    Ludwig, J.K.; Santos, C.L. dos [Centro Universitario Franciscano, Santa Maria, RS (Brazil). Curso de Fisica Medica; Simao, E.M., E-mail: edersimao@gmail.com [Centro Universitario Franciscano, Santa Maria, RS (Brazil). Programa de Pos-Graduacao em Nanociencias

    2014-11-01

    Glioblastoma is a very aggressive brain tumor, which occurs in Glial cells. The treatment consists in chemotherapy, surgery and radiotherapy. The radiotherapy is a treatment method that uses ionizing radiation to kill cancer cells. The cells have genome maintenance mechanisms (MMG) distributed in apoptosis, DNA damage response, and cell cycle pathways. These pathways are formed by sets of proteins and perform specific functions within the cell (example: induce cell death). The mutation of these proteins associated with the failure of the MMG can cause the activation of mutations and consequently induce the development of cancer. This work, objective has to identify pathways and proteins expressed in cancer treatment using free software of the statistical analysis, developed in Fortran and R platforms to show the effects caused by radiation in the proteins of cancerous tissues. The results, were fond to pathways of glioblastoma treated with radiotherapy, activation of apoptosis and response to DNA damage pathways, indicating that there is death of carcinogenic tissue caused by radiation and that some cells are triggering a process of DNA repair. (author)

  1. Limited advances in therapy of glioblastoma trigger re-consideration of research policy.

    Science.gov (United States)

    Frosina, Guido

    2015-11-01

    Glioblastoma (GB - WHO grade IV) is the most frequent and lethal primary brain tumour with median overall survival of 7-15 months after diagnosis. As in other cancer research areas, an overwhelming amount of pre-clinical research acquisitions in the GB field have not been translated to patients' benefit, potentially due to inappropriate treatment schedules and/or trial designs in the clinical setting. The recent failure of promising anti-VEGF bevacizumab to improve GB patients' overall survival recapitulates this sense of frustration. The following measures are proposed.

  2. Molten carbonate fuel cell cathodes. Improvement of the electrocatalytic activity

    Energy Technology Data Exchange (ETDEWEB)

    Escudero, M.J.; Daza, L. [Dpto. Energia, CIEMAT, Av. Complutense 22, 28040 Madrid (Spain); Rodrigo, T. [Instituto de Catalisis y Petroleoquimica, CSIC, Campus Cantoblanco, 28049 Madrid (Spain)

    2005-10-30

    The purpose of this work is to improve the electrocatalytic activity of Li-Ni mixed oxides by the addition of rare earth oxides (cerium or lanthanum). The influence of cerium and lanthanum on the electrocatalytic activity of these compounds was investigated by means of electrochemical impedance spectroscopy (EIS). The stability of these compounds was studied in a mixture of 62% lithium carbonate and 38% potassium carbonate at high temperature under an atmosphere rich in carbon dioxide to accelerate their dissolution. The morphology and the crystalline structure of the samples were not affected by the incorporation of cerium or lanthanum. The samples impregnated with CeO{sub 2} or La{sub 2}O{sub 3} showed lower resistance to charger-transfer processes than the sample without earth rare oxides. Both cerium and lanthanum improved the charger-transfer processes for oxygen reduction in an atmosphere rich in carbon dioxide. The reason may be due to cerium oxide acting as oxygen donor, and lanthanum oxide capturing CO{sub 2}, and the partial pressure of carbon dioxide on the surface of electrode.

  3. File list: InP.Neu.50.AllAg.Glioblastoma [Chip-atlas[Archive

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  13. Combining NK cells and mAb9.2.27 to combat NG2-dependent and anti-inflammatory signals in glioblastoma.

    Science.gov (United States)

    Kmiecik, Justyna; Gras Navarro, Andrea; Poli, Aurelie; Planagumà, Jesús Planagumà; Zimmer, Jacques; Chekenya, Martha

    2014-01-01

    Glioblastoma is a deadly brain cancer with limited treatment options. Targeting chondroitin sulfate proteoglycan 4 (CSPG4, best known as NG2) with the monoclonal antibody mAb9.2.27 and activated natural killer (NK) cells abrogated the tumor growth and prolonged the survival of glioblastoma-bearing animals by favoring the establishment of a pro-inflammatory microenvironment. The combination of NK cells and mAb9.2.27 recruited ED1(+)CCR2(low) macrophages that stimulated ED1(+)ED2(low)MHCII(high) microglial cells to exert robust cytotoxicity. Our findings demonstrate the therapeutic potential of targeting salient tumor associated-antigens.

  14. Exosome Proteome of U-87MG Glioblastoma Cells

    Directory of Open Access Journals (Sweden)

    Sohyun Chun

    2016-12-01

    Full Text Available Exosomes are small membrane vesicles between 30 and 100 nm in diameter secreted by many cell types, and are associated with a wide range of physiological and/or pathological processes. Exosomes containing proteins, lipids, mRNA, and microRNA contribute to cell-to-cell communication and cell-to-environment regulation, however, their biological functions are not yet fully understood. In this report, exosomes in the glioblastoma cell line, U-87MG, were isolated and the proteome was investigated. In addition, exosome proteome changes in U-87MG cells exposed to a low temperature were investigated to elucidate whether the exosome proteome could respond to an external stimulus. Cell culture medium was collected, and exosomes were isolated by continuous centrifugation eliminating cell debris, nucleic acids, and other particles. The morphology of exosomes was observed by cryo-tunneling electron microscopy. According to 2-dimensional electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry, certain proteins including collagen type VI alpha 1, putative RNA-binding protein 15B chain A, substrate induced remodeling of the active site regulates HTRA1, coatomer protein complex-subunit beta 2, myosin-heavy chain 1, and keratin-type I cytoskeletal 9 showed differences between the control proteome and the low temperature-exposed proteome.

  15. Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

    Energy Technology Data Exchange (ETDEWEB)

    Jhanwar-Uniyal, Meena, E-mail: meena_jhanwar@nymc.edu; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj [Department of Neurosurgery, New York Medical College, Valhalla, NY 10595 (United States)

    2015-03-25

    Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM.

  16. Phenotypic characterization of glioblastoma identified through shape descriptors

    Science.gov (United States)

    Chaddad, Ahmad; Desrosiers, Christian; Toews, Matthew

    2016-03-01

    This paper proposes quantitatively describing the shape of glioblastoma (GBM) tissue phenotypes as a set of shape features derived from segmentations, for the purposes of discriminating between GBM phenotypes and monitoring tumor progression. GBM patients were identified from the Cancer Genome Atlas, and quantitative MR imaging data were obtained from the Cancer Imaging Archive. Three GBM tissue phenotypes are considered including necrosis, active tumor and edema/invasion. Volumetric tissue segmentations are obtained from registered T1˗weighted (T1˗WI) postcontrast and fluid-attenuated inversion recovery (FLAIR) MRI modalities. Shape features are computed from respective tissue phenotype segmentations, and a Kruskal-Wallis test was employed to select features capable of classification with a significance level of p < 0.05. Several classifier models are employed to distinguish phenotypes, where a leave-one-out cross-validation was performed. Eight features were found statistically significant for classifying GBM phenotypes with p <0.05, orientation is uninformative. Quantitative evaluations show the SVM results in the highest classification accuracy of 87.50%, sensitivity of 94.59% and specificity of 92.77%. In summary, the shape descriptors proposed in this work show high performance in predicting GBM tissue phenotypes. They are thus closely linked to morphological characteristics of GBM phenotypes and could potentially be used in a computer assisted labeling system.

  17. A comprehensive characterization of mitochondrial DNA mutations in glioblastoma multiforme.

    Science.gov (United States)

    Vidone, Michele; Clima, Rosanna; Santorsola, Mariangela; Calabrese, Claudia; Girolimetti, Giulia; Kurelac, Ivana; Amato, Laura Benedetta; Iommarini, Luisa; Trevisan, Elisa; Leone, Marco; Soffietti, Riccardo; Morra, Isabella; Faccani, Giuliano; Attimonelli, Marcella; Porcelli, Anna Maria; Gasparre, Giuseppe

    2015-06-01

    Glioblastoma multiforme (GBM) is the most malignant brain cancer in adults, with a poor prognosis, whose molecular stratification still represents a challenge in pathology and clinics. On the other hand, mitochondrial DNA (mtDNA) mutations have been found in most tumors as modifiers of the bioenergetics state, albeit in GBM a characterization of the mtDNA status is lacking to date. Here, a characterization of the burden of mtDNA mutations in GBM samples was performed. First, investigation of tumor-specific vs. non tumor-specific mutations was carried out with the MToolBox bioinformatics pipeline by analyzing 45 matched tumor/blood samples, from whole genome or whole exome sequencing datasets obtained from The Cancer Genome Atlas (TCGA) consortium. Additionally, the entire mtDNA sequence was obtained in a dataset of 104 fresh-frozen GBM samples. Mitochondrial mutations with potential pathogenic interest were prioritized based on heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. A preliminary biochemical analysis of the activity of mitochondrial respiratory complexes was also performed on fresh-frozen GBM samples. Although a high number of mutations was detected, we report that the large majority of them does not pass the prioritization filters. Therefore, a relatively limited burden of pathogenic mutations is indeed carried by GBM, which did not appear to determine a general impairment of the respiratory chain. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.

  18. Decitabine nanoconjugate sensitizes human glioblastoma cells to temozolomide.

    Science.gov (United States)

    Cui, Yi; Naz, Asia; Thompson, David H; Irudayaraj, Joseph

    2015-04-01

    In this study, we developed and characterized a delivery system for the epigenetic demethylating drug, decitabine, to sensitize temozolomide-resistant human glioblastoma multiforme (GBM) cells to alkylating chemotherapy. A poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) based nanoconjugate was fabricated to encapsulate decitabine and achieved a better therapeutic response in GBM cells than that with the free drug. After synthesis, the highly efficient uptake process and intracellular dynamics of this nanoconjugate were monitored by single-molecule fluorescence tools. Our experiments demonstrated that, under an acidic pH due to active glycolysis in cancer cells, the PLGA-PEG nanovector could release the conjugated decitabine at a faster rate, after which the hydrolyzed lactic acid and glycolic acid would further acidify the intracellular microenvironment, thus providing positive feedback to increase the effective drug concentration and realize growth inhibition. In temozolomide-resistant GBM cells, decitabine can potentiate the cytotoxic DNA alkylation by counteracting cytosine methylation and reactivating tumor suppressor genes, such as p53 and p21. Owing to the excellent internalization and endolysosomal escape enabled by the PLGA-PEG backbone, the encapsulated decitabine exhibited a better anti-GBM potential than that of free drug molecules. Hence, the synthesized nanoconjugate and temozolomide could act in synergy to deliver a more potent and long-term antiproliferative effect against malignant GBM cells.

  19. Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma.

    Science.gov (United States)

    Ahmad, F; Dixit, D; Sharma, V; Kumar, A; Joshi, S D; Sarkar, C; Sen, E

    2016-05-05

    Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) - two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the in vitro findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells.

  20. Nanocarriers for the treatment of glioblastoma multiforme: Current state-of-the-art.

    Science.gov (United States)

    Karim, Reatul; Palazzo, Claudio; Evrard, Brigitte; Piel, Geraldine

    2016-04-10

    Glioblastoma multiforme, a grade IV glioma, is the most frequently occurring and invasive primary tumor of the central nervous system, which causes about 4% of cancer-associated-deaths, making it one of the most fatal cancers. With present treatments, using state-of-the-art technologies, the median survival is about 14 months and 2 year survival rate is merely 3-5%. Hence, novel therapeutic approaches are urgently necessary. However, most drug molecules are not able to cross the blood-brain barrier, which is one of the major difficulties in glioblastoma treatment. This review describes the features of blood-brain barrier, and its anatomical changes with different stages of tumor growth. Moreover, various strategies to improve brain drug delivery i.e. tight junction opening, chemical modification of the drug, efflux transporter inhibition, convection-enhanced delivery, craniotomy-based drug delivery and drug delivery nanosystems are discussed. Nanocarriers are one of the highly potential drug transport systems that have gained huge research focus over the last few decades for site specific drug delivery, including drug delivery to the brain. Properly designed nanocolloids are capable to cross the blood-brain barrier and specifically deliver the drug in the brain tumor tissue. They can carry both hydrophilic and hydrophobic drugs, protect them from degradation, release the drug for sustained period, significantly improve the plasma circulation half-life and reduce toxic effects. Among various nanocarriers, liposomes, polymeric nanoparticles and lipid nanocapsules are the most widely studied, and are discussed in this review. For each type of nanocarrier, a general discussion describing their composition, characteristics, types and various uses is followed by their specific application to glioblastoma treatment. Moreover, some of the main challenges regarding toxicity and standardized evaluation techniques are narrated in brief.

  1. Novel anti-apoptotic microRNAs 582-5p and 363 promote human glioblastoma stem cell survival via direct inhibition of caspase 3, caspase 9, and Bim.

    Directory of Open Access Journals (Sweden)

    Desiree Hunt Floyd

    Full Text Available Glioblastoma is the most common and lethal primary brain tumor. Tumor initiation and recurrence are likely caused by a sub-population of glioblastoma stem cells, which may derive from mutated neural stem and precursor cells. Since CD133 is a stem cell marker for both normal brain and glioblastoma, and to better understand glioblastoma formation and recurrence, we looked for dys-regulated microRNAs in human CD133+ glioblastoma stem cells as opposed to CD133+ neural stem cells isolated from normal human brain. Using FACS sorting of low-passage cell samples followed by microRNA microarray analysis, we found 43 microRNAs that were dys-regulated in common in three separate CD133+ human glioblastomas compared to CD133+ normal neural stem cells. Among these were several microRNAs not previously associated with cancer. We then verified the microRNAs dys-regulated in glioblastoma using quantitative real time PCR and Taqman analysis of the original samples, as well as human GBM stem cell and established cell lines and many human specimens. We show that two candidate oncogenic microRNAs, miR-363 and miR-582-5p, can positively influence glioblastoma survival, as shown by forced expression of the microRNAs and their inhibitors followed by cell number assay, Caspase 3/7 assay, Annexin V apoptosis/fluorescence activated cell sorting, siRNA rescue of microRNA inhibitor treatment, as well as 3'UTR mutagenesis to show luciferase reporter rescue of the most successful targets. miR-582-5p and miR-363 are shown to directly target Caspase 3, Caspase 9, and Bim.

  2. Inhibition of neutrophil activity improves cardiac function after cardiopulmonary bypass

    Directory of Open Access Journals (Sweden)

    Grünwald Frank

    2007-10-01

    Full Text Available Abstract Background The arterial in line application of the leukocyte inhibition module (LIM in the cardiopulmonary bypass (CPB limits overshooting leukocyte activity during cardiac surgery. We studied in a porcine model whether LIM may have beneficial effects on cardiac function after CPB. Methods German landrace pigs underwent CPB (60 min myocardial ischemia; 30 min reperfusion without (group I; n = 6 or with LIM (group II; n = 6. The cardiac indices (CI and cardiac function were analyzed pre and post CPB with a Swan-Ganz catheter and the cardiac function analyzer. Neutrophil labeling with technetium, scintigraphy, and histological analyses were done to track activated neutrophils within the organs. Results LIM prevented CPB-associated increase of neutrophil counts in peripheral blood. In group I, the CI significantly declined post CPB (post: 3.26 ± 0.31; pre: 4.05 ± 0.45 l/min/m2; p 2; p = 0.23. Post CPB, the intergroup difference showed significantly higher CI values in the LIM group (p Conclusion Our data provides strong evidence that LIM improves perioperative hemodynamics and cardiac function after CPB by limiting neutrophil activity and inducing accelerated sequestration of neutrophils in the spleen.

  3. Improvements of anticoagulant activities of silk fibroin films with fucoidan

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Fucoidan (FC),an effective anticoagulant constituent extracted from brown algae,was introduced into silk fibroin (SF) for improving its blood compatibility.The SF and SF/FC blend films were characterized by attenuated total reflectance Fourier-transform infrared (ATR-FTIR),X-ray photoelectron spectroscopy (XPS),scanning electron microscopy (SEM) and dynamic contact angle determinator (CA).The in vitro anticoagulant activities of the films were evaluated by activated partial thromboplastin time (APTT),thrombin time (TT) and prothrombin time (PT) measurements.The endothelial cell attachment and proliferation viability on the film were assessed by micropipette aspiration technique and MTT assay,respectively.The testing results indicated that the introduction of FC increased the roughness,hydrophilicity and sulfate component of the film surface without impeding the formation of β-sheet conformation in SF.More important,FC brought excellent anticoagulant activity and better endothelial cell affinity to SF.The SF/FC blend film was hopeful to be used as blood-contacting biomaterials.

  4. Improving active space telescope wavefront control using predictive thermal modeling

    Science.gov (United States)

    Gersh-Range, Jessica; Perrin, Marshall D.

    2015-01-01

    Active control algorithms for space telescopes are less mature than those for large ground telescopes due to differences in the wavefront control problems. Active wavefront control for space telescopes at L2, such as the James Webb Space Telescope (JWST), requires weighing control costs against the benefits of correcting wavefront perturbations that are a predictable byproduct of the observing schedule, which is known and determined in advance. To improve the control algorithms for these telescopes, we have developed a model that calculates the temperature and wavefront evolution during a hypothetical mission, assuming the dominant wavefront perturbations are due to changes in the spacecraft attitude with respect to the sun. Using this model, we show that the wavefront can be controlled passively by introducing scheduling constraints that limit the allowable attitudes for an observation based on the observation duration and the mean telescope temperature. We also describe the implementation of a predictive controller designed to prevent the wavefront error (WFE) from exceeding a desired threshold. This controller outperforms simpler algorithms even with substantial model error, achieving a lower WFE without requiring significantly more corrections. Consequently, predictive wavefront control based on known spacecraft attitude plans is a promising approach for JWST and other future active space observatories.

  5. Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma.

    Science.gov (United States)

    Johansson, Erik; Zhai, Qiwei; Zeng, Zhao-Jun; Yoshida, Takeshi; Funa, Keiko

    2016-05-01

    TLX (also called NR2E1) is an orphan nuclear receptor that maintains stemness of neuronal stem cells. TLX is highly expressed in the most malignant form of glioma, glioblastoma multiforme (GBM), and is important for the proliferation and maintenance of the stem/progenitor cells of the tumor. Transforming Growth Factor-β (TGF-β) is a cytokine regulating many different cellular processes such as differentiation, migration, adhesion, cell death and proliferation. TGF-β has an important function in cancer where it can work as either a tumor suppressor or oncogene, depending on the cancer type and stage of tumor development. Since glioblastoma often have dysfunctional TGF-β signaling we wanted to find out if there is any interaction between TLX and TGF-β in glioblastoma cells. We demonstrate that knockdown of TLX enhances the canonical TGF-β signaling response in glioblastoma cell lines. TLX physically interacts with and stabilizes Smurf1, which can ubiquitinate and target TGF-β receptor II for degradation, whereas knockdown of TLX leads to stabilization of TGF-β receptor II, increased nuclear translocation of Smad2/3 and enhanced expression of TGF-β target genes. The interaction between TLX and TGF-β may play an important role in the regulation of proliferation and tumor-initiating properties of glioblastoma cells.

  6. Endocannabinoid metabolism in human glioblastomas and meningiomas compared to human non-tumour brain tissue

    DEFF Research Database (Denmark)

    Petersen, G.; Moesgaard, B.; Hansen, Harald S.

    2005-01-01

    The endogenous levels of the two cannabinoid receptor ligands 2-arachidonoyl glycerol and anandamide, and their respective congeners, monoacyl glycerols and N-acylethanolamines, as well as the phospholipid precursors of N-acylethanolamines, were measured by gas chromatography-mass spectrometry in...... in glioblastoma (WHO grade IV) tissue and meningioma (WHO grade I) tissue and compared with human non-tumour brain tissue. Furthermore, the metabolic turnover of N-acylethanolamines was compared by measurements of the enzymatic activity of N-acyltransferase, N...

  7. Evaluation of blood-brain barrier-stealth nanocomposites for in situ glioblastoma theranostics applications

    Science.gov (United States)

    Su, Chia-Hao; Tsai, Ching-Yi; Tomanek, Boguslaw; Chen, Wei-Yu; Cheng, Fong-Yu

    2016-04-01

    The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy.The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy. Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c6nr00280c

  8. Locomotion and proliferation of glioblastoma cells in vitro statistical evaluation of videomicroscopic observations

    CERN Document Server

    Hegedus, B; Fazekas, I; Babel, T; Madarasz, E; Vicsek, T

    1999-01-01

    Long-term videomicroscopy and computer-aided statistical analysis were used to determine some characteristic parameters of in vitro cell motility and proliferation in three established cell lines derived from human glioblastoma tumors. Migration and proliferation activities were compared among the three cell lines since these are two features of tumor cells that strongly influence the progression of cancer. The results on these dynamical parameters of cell locomotion were compared to pathological data obtained by traditional methods. The data indicate that the analysis of cell motility provides more specific information and is potentially useful in diagnosis.

  9. Assessment of temozolomide action encapsulated in chitosan and polymer nanostructures on glioblastoma cell lines

    Directory of Open Access Journals (Sweden)

    Abrudan C.

    2014-03-01

    Full Text Available Purpose : Glioblastoma multiforme (GBM remains one of the most devastating diseases known to mankind and affects more than 17,000 patients in the United States alone every year. This malignancy infiltrates the brain early in its course and makes complete neurosurgical resection almost impossible. Recent years have brought significant advances in tumor biology. Many cancers, including gliomas, appear to be supported by cells with stemlike properties. Nanoparticles are excellent candidates to serve as delivery vectors of drugs or biologically active molecules because of their unique chemical and physical properties that result in specific transportation and deposition of such agents in specific organs and tissues..

  10. The c-Met receptor tyrosine kinase inhibitor MP470 radiosensitizes glioblastoma cells

    Directory of Open Access Journals (Sweden)

    Bearss David

    2009-12-01

    Full Text Available Abstract Purpose Glioblastoma multiforme (GBM is resistant to current cytotoxic therapies, in part because of enhanced DNA repair. Activation of the receptor tyrosine kinase c-Met has been shown to protect cancer cells from DNA damage. We hypothesized that inhibiting c-Met would decrease this protection and thus sensitize resistant tumor cells to the effects of radiation therapy. Materials and methods Eight human GBM cell lines were screened for radiosensitivity to the small-molecule c-Met inhibitor MP470 with colony-count assays. Double-strand (ds DNA breaks was quantified by using antibodies to gamma H2AX. Western blotting demonstrate expression of RAD51, glycogen synthase kinase (GSK-3β, and other proteins. A murine xenograft tumor flank model was used for in vivo radiosensitization studies. Results MP470 reduced c-Met phosphorylation and enhanced radiation-induced cell kill by 0.4 logs in SF767 cells. Cells pretreated with MP470 had more ds DNA damage than cells treated with radiation alone. Mechanistically, MP470 was shown to inhibit dsDNA break repair and increase apoptosis. MP470 influences various survival and DNA repair related proteins such as pAKT, RAD51 and GSK3β. In vivo, the addition of MP470 to radiation resulted in a tumor-growth-delay enhancement ratio of 2.9 over radiation alone and extended survival time. Conclusions GBM is a disease site where radiation is often used to address both macroscopic and microscopic disease. Despite attempts at dose escalation outcomes remain poor. MP470, a potent small-molecule tyrosine kinase inhibitor of c-Met, radiosensitized several GBM cell lines both in vitro and in vivo, and may help to improve outcomes for patients with GBM.

  11. An Update in the Use of Antibodies to Treat Glioblastoma Multiforme

    Directory of Open Access Journals (Sweden)

    Norma Y. Hernández-Pedro

    2013-01-01

    Full Text Available Glioblastoma is a deadly brain disease and modest improvement in survival has been made. At initial diagnosis, treatment consists of maximum safe surgical resection, followed by temozolomide and chemoirradiation or adjuvant temozolomide alone. However, these treatments do not improve the prognosis and survival of patients. New treatment strategies are being sought according to the biology of tumors. The epidermal growth factor receptor has been considered as the hallmark in glioma tumors; thereby, some antibodies have been designed to bind to this receptor and block the downstream signaling pathways. Also, it is known that vascularization plays an important role in supplying new vessels to the tumor; therefore, new therapy has been guided to inhibit angiogenic growth factors in order to limit tumor growth. An innovative strategy in the treatment of glial tumors is the use of toxins produced by bacteria, which may be coupled to specific carrier-ligands and used for tumoral targeting. These carrier-ligands provide tumor-selective properties by the recognition of a cell-surface receptor on the tumor cells and promote their binding of the toxin-carrier complex prior to entry into the cell. Here, we reviewed some strategies to improve the management and treatment of glioblastoma and focused on the use of antibodies.

  12. An update in the use of antibodies to treat glioblastoma multiforme.

    Science.gov (United States)

    Hernández-Pedro, Norma Y; Rangel-López, Edgar; Vargas Félix, Gustavo; Pineda, Benjamín; Sotelo, Julio

    2013-01-01

    Glioblastoma is a deadly brain disease and modest improvement in survival has been made. At initial diagnosis, treatment consists of maximum safe surgical resection, followed by temozolomide and chemoirradiation or adjuvant temozolomide alone. However, these treatments do not improve the prognosis and survival of patients. New treatment strategies are being sought according to the biology of tumors. The epidermal growth factor receptor has been considered as the hallmark in glioma tumors; thereby, some antibodies have been designed to bind to this receptor and block the downstream signaling pathways. Also, it is known that vascularization plays an important role in supplying new vessels to the tumor; therefore, new therapy has been guided to inhibit angiogenic growth factors in order to limit tumor growth. An innovative strategy in the treatment of glial tumors is the use of toxins produced by bacteria, which may be coupled to specific carrier-ligands and used for tumoral targeting. These carrier-ligands provide tumor-selective properties by the recognition of a cell-surface receptor on the tumor cells and promote their binding of the toxin-carrier complex prior to entry into the cell. Here, we reviewed some strategies to improve the management and treatment of glioblastoma and focused on the use of antibodies.

  13. Improved Isotherm Data for Adsorption of Methane on Activated Carbons

    KAUST Repository

    Loh, Wai Soong

    2010-08-12

    This article presents the adsorption isotherms of methane onto two different types of activated carbons, namely, Maxsorb III and ACF (A-20) at temperatures from (5 to 75) °C and pressures up to 2.5 MPa. The volumetric technique has been employed to measure the adsorption isotherms. The experimental results presented herein demonstrate the improved accuracy of the uptake values compared with previous measurement techniques for similar adsorbate-adsorbent combinations. The results are analyzed with various adsorption isotherm models. The heat of adsorption, which is concentration and temperature dependent, has been calculated from the measured isotherm data. Henry\\'s law coefficients for these adsorbent-methane pairs are also evaluated at various temperatures. © 2010 American Chemical Society.

  14. An Improved Force Feedback Control Algorithm for Active Tendons

    Directory of Open Access Journals (Sweden)

    Ligang Cai

    2012-08-01

    Full Text Available An active tendon, consisting of a displacement actuator and a co-located force sensor, has been adopted by many studies to suppress the vibration of large space flexible structures. The damping, provided by the force feedback control algorithm in these studies, is small and can increase, especially for tendons with low axial stiffness. This study introduces an improved force feedback algorithm, which is based on the idea of velocity feedback. The algorithm provides a large damping ratio for space flexible structures and does not require a structure model. The effectiveness of the algorithm is demonstrated on a structure similar to JPL-MPI. The results show that large damping can be achieved for the vibration control of large space structures.

  15. Motor Skill Improvement in Preschoolers: How Effective Are Activity Cards?

    Directory of Open Access Journals (Sweden)

    Lars Donath

    2014-12-01

    Full Text Available Strategies to early develop and implement motor skill promotion in preschoolers are lacking. Thus, we examined the effects of a card-based exercise promotion program in a kindergarten setting. 214 preschool children (5.5 ± 0.6 y, range 4.2–6.7 y were examined in the present intervention study. Body mass index (BMI and waist circumference were measured. Children were randomly assigned to the KIDZ-Box® physical activity intervention program (INT: n = 107 or the control group (CON: n = 107. Children were trained daily for 15 min over 7 month at the preschool for agility, balance, endurance and jump performance, employing the card-based KIDZ-Box® media package. At pre- and post-testing, dynamic balance, jump and agility performance were tested. Cross-sectionally, agility testing differed between sexes (p = 0.01 and BMI (p = 0.02. Trends towards a significant association were found between BMI and side-to-side jumping (p = 0.1 and beam balancing (p = 0.05. Relevant interventional effects favoring the intervention group were slightly found for agility (p = 0.04, ηp2 = 0.02 and moderately for side-to-side jumping (p < 0.001, ηp2 = 0.08. Balance performance did not relevantly improve. As jumping cards have been used frequently by the teachers, jumping improvements are plausible. The activity cards are feasibly applicable but should be employed with more structure during longer training sessions.

  16. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.

    Science.gov (United States)

    Reardon, David A; Gokhale, Prafulla C; Klein, Sarah R; Ligon, Keith L; Rodig, Scott J; Ramkissoon, Shakti H; Jones, Kristen L; Conway, Amy Saur; Liao, Xiaoyun; Zhou, Jun; Wen, Patrick Y; Van Den Abbeele, Annick D; Hodi, F Stephen; Qin, Lei; Kohl, Nancy E; Sharpe, Arlene H; Dranoff, Glenn; Freeman, Gordon J

    2016-02-01

    Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8(+) and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma.

  17. Estimation of Tumor Volumes by 11C-MeAIB and 18F-FDG PET in an Orthotopic Glioblastoma Rat Model

    DEFF Research Database (Denmark)

    Halle, Bo; Thisgaard, Helge; Hvidsten, Svend

    2015-01-01

    UNLABELLED: Brain tumor volume assessment is a major challenge. Molecular imaging using PET may be a promising option because it reflects the biologically active cells. We compared the agreement between PET- and histology-derived tumor volumes in an orthotopic glioblastoma rat model with a noninf...

  18. Glioblastoma in the setting of tuberous sclerosis.

    Science.gov (United States)

    Reyes, Dennys; Prayson, Richard

    2015-05-01

    Tuberous sclerosis is an autosomal dominant condition commonly manifesting with seizures, mental retardation, cortical tubers and hamartomas. Neoplasms may occasionally arise in this setting with the majority of these tumors being subependymal giant cell astrocytomas (World Health Organization [WHO] grade I). Reports of high grade astrocytic neoplasms arising in patients with tuberous sclerosis are rare. We report a left fronto-parietal mass presenting in a 33-year-old woman with altered mental status and slurred speech. The tumor demonstrated areas of enhancement and was associated with mass effect on CT imaging. The tumor was marked by prominent cellularity, easily identifiable mitotic figures, vascular proliferative changes, necrosis and multinucleated giant cells. A Ki-67 labeling index of greater than 30% was noted. The findings were interpreted as being consistent with a glioblastoma (WHO grade IV). The limited literature on similar cases of malignant gliomas arising in the setting of tuberous sclerosis are reviewed. Few reports of similar tumors have been described in the literature. Presentation appears to depend on where the tumor is situated; locations have been variable in previous reports. For those cases in which survival data were included, the prognosis is poor.

  19. Vascular Distribution of Glioblastoma Multiforme at Diagnosis

    Science.gov (United States)

    Yohay, K.; Wolf, D.S.; Aronson, L.J.; Duus, M.; Melhem, E.R.; Cohen, K.J.

    2013-01-01

    Summary Treatment of high-grade gliomas with selective intra-arterial (IA) administration of chemotherapies has been proposed, and utilized as a therapeutic modality. This approach offers the conceptual benefit of providing maximal delivery of the agent to the tumor bed, while potentially reducing systemic exposure to the agent. This retrospective study was designed to determine the vascular distribution of glioblastoma multiforme (GBM) at the time of diagnosis in an effort to determine what proportion of patients would likely be candidates for this approach. The preoperative MRI scans of 50 patients with GBM were analyzed and compared to published normative data of intracranial vascular distribution. Vascular distribution was determined by analyzing post-gadolinium axial and coronal T1 images, axial T2 images, and axial T2 images with an additional 1 cm margin (T2 + 1 cm) added in all dimensions. T1 analysis demonstrated 60% of tumors in a single vascular distribution. T2 analysis of these tumors reduced that number to 34%. When the T2 + 1 cm margin was utilized, only 6% of tumors were in a single vascular distribution. 66% of tumors were limited to the anterior circulation on T1 imaging but only 34% on T2 + 1 cm imaging. 30% of tumors were also within the distribution of the anterior choroidal artery. These findings suggest that the use of selective IA administration of agents is necessarily limited to a fraction of presenting patients or will require administration via multiple cerebral arteries. PMID:23472735

  20. Improved Active Harmonic Current Elimination Based on Voltage Detection.

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    Tianyuan Tan

    Full Text Available With the increasing penetration of power electronic equipment in modern residential distribution systems, harmonics mitigation through the distributed generation (DG interfacing converters has received significant attention. Among recently proposed methods, the so-called active resonance damper (ARD and harmonic voltage compensator (HVC based on voltage detection can effectively reduce the harmonic distortions in selected areas of distribution systems. However, it is found out that when traditional ARD algorithm is used to eliminate harmonic current injected by non-linear loads, its performance is constrained by stability problems and can at most eliminate half of the load harmonic currents. Thus, inspired by the duality between ARD and HVC, this paper presents a novel improved resistive active power filter (R-APF algorithm based on integral-decoupling control. The design guideline for its parameters is then investigated through carefully analyzing the closed-loop poles' trajectory. Computer studies demonstrate that the proposed algorithm can effectively mitigate the load harmonic currents and its performance is much better than traditional ARD based on proportional control.

  1. Glioblastoma and the significance of MGMT gene methylation

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    Payam Izadpanahi

    2014-08-01

    Full Text Available In this research Glioblastoma has been studied as one of the most common brain tumors and a short review of the available therapeutic methods have presented including surgery, radiotherapy, chemotherapy and particularly adjuvant chemotherapy with temozolomide, as the most effective developed treatment. Moreover, MGMT gene promoter methylation has been introduced as an important predictive factor of treatment response to temozolamide. The different mechanisms of methylation and the availableliterature on its association with patient survival and disease recurrence have been summarized. Taken together, Glioblastoma is a tumor in which the MGMT gene expression can potentially deliver the highest amount of data in comparison to other tumors; as almost every related study has emphasized on the direct association between MGMT methylation and patient survival. Regarding this debate, the pseudoprogression pattern in Glioblastoma patients and the laboratory methods studying MGMT gene methylation have been examined. At the end of this review, the obstacles to its development have been briefly mentioned.

  2. Imaging modalities to assess oxygen status in glioblastoma

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    Aurélien eCorroyer-Dulmont

    2015-08-01

    Full Text Available Hypoxia, the result of an inadequacy between a disorganized and functionally impaired vasculature and the metabolic demand of tumor cells is a feature of glioblastoma. Hypoxia promotes the aggressiveness of these tumors and, equally, negatively correlates with a decrease in outcome. Tools to characterize oxygen status are essential for the therapeutic management of patients with glioblastoma: i to refine prognosis; ii to adapt the treatment regimen; iii and to assess the therapeutic efficacy. While methods that are focal and invasive in nature are of limited use, non-invasive imaging technologies have been developed. Each of these technologies is characterized by its singular advantages and limitations in terms of oxygenation status in glioblastoma. The aim of this short review is, first, to focus on the interest to characterize hypoxia for a better therapeutic management of patients and, second, to discuss recent and pertinent approaches for the assessment of oxygenation/hypoxia and their direct implication for patient care.

  3. Improving fold activation of small transcription activating RNAs (STARs) with rational RNA engineering strategies.

    Science.gov (United States)

    Meyer, Sarai; Chappell, James; Sankar, Sitara; Chew, Rebecca; Lucks, Julius B

    2016-01-01

    Regulatory RNAs have become integral components of the synthetic biology and bioengineering toolbox for controlling gene expression. We recently expanded this toolbox by creating small transcription activating RNAs (STARs) that act by disrupting the formation of a target transcriptional terminator hairpin placed upstream of a gene. While STARs are a promising addition to the repertoire of RNA regulators, much work remains to be done to optimize the fold activation of these systems. Here we apply rational RNA engineering strategies to improve the fold activation of two STAR regulators. We demonstrate that a combination of promoter strength tuning and multiple RNA engineering strategies can improve fold activation from 5.4-fold to 13.4-fold for a STAR regulator derived from the pbuE riboswitch terminator. We then validate the generality of our approach and show that these same strategies improve fold activation from 2.1-fold to 14.6-fold for an unrelated STAR regulator, opening the door to creating a range of additional STARs to use in a broad array of biotechnologies. We also establish that the optimizations preserve the orthogonality of these STARs between themselves and a set of RNA transcriptional repressors, enabling these optimized STARs to be used in sophisticated circuits.

  4. Protein Phosphatase 2A Inhibition with LB100 Enhances Radiation-Induced Mitotic Catastrophe and Tumor Growth Delay in Glioblastoma.

    Science.gov (United States)

    Gordon, Ira K; Lu, Jie; Graves, Christian A; Huntoon, Kristin; Frerich, Jason M; Hanson, Ryan H; Wang, Xiaoping; Hong, Christopher S; Ho, Winson; Feldman, Michael J; Ikejiri, Barbara; Bisht, Kheem; Chen, Xiaoyuan S; Tandle, Anita; Yang, Chunzhang; Arscott, W Tristram; Ye, Donald; Heiss, John D; Lonser, Russell R; Camphausen, Kevin; Zhuang, Zhengping

    2015-07-01

    Protein phosphatase 2A (PP2A) is a tumor suppressor whose function is lost in many cancers. An emerging, though counterintuitive, therapeutic approach is inhibition of PP2A to drive damaged cells through the cell cycle, sensitizing them to radiotherapy. We investigated the effects of PP2A inhibition on U251 glioblastoma cells following radiation treatment in vitro and in a xenograft mouse model in vivo. Radiotherapy alone augmented PP2A activity, though this was significantly attenuated with combination LB100 treatment. LB100 treatment yielded a radiation dose enhancement factor of 1.45 and increased the rate of postradiation mitotic catastrophe at 72 and 96 hours. Glioblastoma cells treated with combination LB100 and radiotherapy maintained increased γ-H2AX expression at 24 hours, diminishing cellular repair of radiation-induced DNA double-strand breaks. Combination therapy significantly enhanced tumor growth delay and mouse survival and decreased p53 expression 3.68-fold, compared with radiotherapy alone. LB100 treatment effectively inhibited PP2A activity and enhanced U251 glioblastoma radiosensitivity in vitro and in vivo. Combination treatment with LB100 and radiation significantly delayed tumor growth, prolonging survival. The mechanism of radiosensitization appears to be related to increased mitotic catastrophe, decreased capacity for repair of DNA double-strand breaks, and diminished p53 DNA-damage response pathway activity.

  5. Effect and Mechanism of Total Flavonoids Extracted from Cotinus coggygria against Glioblastoma Cancer In Vitro and In Vivo.

    Science.gov (United States)

    Wang, Gang; Wang, JunJie; Du, Li; Li, Fei

    2015-01-01

    Flavonoids, a major constituent of Cotinus coggygria (CC), have been reported to possess diverse biological activities, including antigenotoxic and hepatoprotective effects; however, few studies have investigated the biological activity of the total flavonoids of Cotinus coggygria, especially in terms of its cytotoxicity in cancer cells. In the present study, the Cotinus coggygria flavonoids (CCF) were extracted from Cotinus coggygria and characterized by HPLC. These results indicated that CCF extracts could inhibit cell proliferation, with IC50 values of 128.49 µg/mL (U87), 107.62 µg/mL (U251), and 93.57 µg/mL (DBTRG-05MG). The current investigation also revealed that CCF induced apoptosis in highly malignant glioblastoma cells, a process that apparently involved the inhibition of Akt coupled with ERK protein expression. This finding suggests that the PI3K/Akt-ERK signaling pathway is regulated by CCF and leads to the inhibition of the glioblastoma cancer cells. Furthermore, a significant antitumor effect of CCF was observed in xenograft animal models of glioblastoma multiforme in vivo. Taken together, these data suggest that CCF is the active component in the Cotinus coggygria plant that offers potential therapeutic modality in the abrogation of cancer cell proliferation, including the induction of apoptosis.

  6. Attitudes to Improving Speaking Skills by Guided Individual Activities

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    Galina Kavaliauskienė

    2014-06-01

    Full Text Available Students’ perceptions of difficulties in speaking on professional issues are in the focus of the present article. It is generally assumed that the skill of speaking a foreign language is very difficult to master, while speaking on professional topics involves such difficulties as the usage of specific vocabulary and ability to deal with listeners’ oncoming arguments. The aims of the current research are to investigate learners’ attitudes to the level of difficulty in speaking activi - ties on a subject matter at university and apply an innovative approach to improving their speaking skills. The methodology applied was focused on guided individual learning (GIL, with gradually increasing amount of spontaneity in public talks on the subject matter, starting with prepared short talks on an ESP issue leading to group discussions; moving on to Power Point presentations, involving spontaneous deviations from the subject and followed by question time; further, adding some complex subject matter, such as a discussion on a problematic professional subject suggested by learning materials; and, eventually, speaking impromptu on an issue, with a high level of control of one’s speaking skills. The research method of the learners’ attitudes employed the survey on learner attitudes to four different speaking activities in the classroom, which included short talks, Power Point Presentations, discussions and speaking impromptu. The questionnaire was administered to students of two different specializations by the end of the semester. The respondents were students who studied Psychology and Social Work at the Faculty of Social Policy, at Mykolas Romeris University in Vilnius, Lithuania. The respondents were asked to indicate the degree of difficulty they had with the various speaking activities on the Likert’s scale ranging from “very difficult” (1 to “very easy” (5. The results indicated that perceptions of difficulties to developing speaking

  7. Sulfasalazine and temozolomide with radiation therapy for newly diagnosed glioblastoma

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    Satoru Takeuchi

    2014-01-01

    Full Text Available Background: A recent phase 1/2 clinical trial argued for caution for the use of sulfasalazine in progressive glioblastoma (GBM. However, the study enrolled patients with recurrent or progressive high-grade glioma indicating that patients recruited probably had severe disease. Thus, the study may not accurately reflect the effectiveness of sulfasalazine for GBM and we hypothesized that earlier sulfasalazine administration may lead to anticancer effects. Aim: The aim of this study was to investigate whether sulfasalazine can improve the outcomes of patients with newly diagnosed GBM. Subjects and Methods: A total of 12 patients were treated with temozolomide and sulfasalazine with radiation therapy after surgery. Twelve patients with primary GBM treated with temozolomide and radiation therapy formed the control group. Progression-free survival (PFS, overall survival (OS and seizure-free survival (SFS curves were obtained using the Kaplan-Meier method. The survival curves were compared using the log-rank test. Results: The median OS, PFS and SFS did not differ between the groups. Grade 3 or 4 adverse events occurred over the duration of the study in nine (75% patients. The median SFS was 12 months in nine patients who received sulfasalazine administration for more than 21 days, which was strongly but not significantly longer than the 3 months observed in the control group (P = 0.078. Conclusions: Sulfasalazine treatment with temozolomide plus radiotherapy for newly diagnosed primary GBM is associated with a high rate of discontinuation due to hematologic toxic effects. This treatment may have no effect on OS or PFS, although it may improve seizure control if an adequate dose can be administered.

  8. Effect of 7-hydroxystaurosporine on glioblastoma cell invasion and migration

    Institute of Scientific and Technical Information of China (English)

    Qing-hui MENG; Li-xin ZHOU; Jia-lin LUO; Jian-ping CAO; Jian TONG; Sai-jun FAN

    2005-01-01

    Aim: To investigate the effect of 7-hydroxystaurosporine (UCN-01), a selective protein kinase C (PKC) inhibitor, on cell growth, migration, and invasion in inva sive human glioblastoma U-87MG cells. Methods: PKC activity was determined based on the PKC-catalyzed transfer of the 32p-phosphate group from [g-32p]ATP into a PKC-specific peptide substrate. Cell viability was measured by MTT assay.Cell invasion and migration were evaluated by a Boyden chamber assay and scratch wound assay, respectively. Protein expression was analyzed using Western blot assay. The formation of 3-dimensional cellular aggregates was examined by a cell-cell aggregation assay. Results: UCN-01 treatment resulted in concentration- and time-dependent inhibition of U-87MG cell growth at higher doses (> 100 nmol/L), and reduced cell invasion and migration capability at less cytotoxic doses (<100 nmol/L). UCN-01 significantly repressed PKC activity. Consistent with this result, UCN-01 blocked cell invasion stimulated by phorbel 12-myristate13-acetate (PMA) and ethanol (EtOH), 2 PKC activators. Enforced expression of the tumor suppressor genes BRCA1 and PTEN increased the anti-invasion potential of UCN-01. Exposure to UCN-01 caused a dose-dependent increase in cell adhesion molecule E-cadherin. The effect of UCN-01 on the formation of cell-cell aggregation was significantly reduced by the addition of an anti-E-cadherin antibody. Conclusion: UCN-01 inhibits the invasion and migration of human glioma cells. Accordingly, UCN-01 can have potential clinical applications for the treatment of human glioma metastasis.

  9. Pluronic-based micelle encapsulation potentiates myricetin-induced cytotoxicity in human glioblastoma cells.

    Science.gov (United States)

    Tang, Xiang-Jun; Huang, Kuan-Ming; Gui, Hui; Wang, Jun-Jie; Lu, Jun-Ti; Dai, Long-Jun; Zhang, Li; Wang, Gang

    As one of the natural herbal flavonoids, myricetin has attracted much research interest, mainly owing to its remarkable anticancer properties and negligible side effects. It holds great potential to be developed as an ideal anticancer drug through improving its bioavailability. This study was performed to investigate the effects of Pluronic-based micelle encapsulation on myricetin-induced cytotoxicity and the mechanisms underlying its anticancer properties in human glioblastoma cells. Cell viability was assessed using a methylthiazol tetrazolium assay and a real-time cell analyzer. Immunoblotting and quantitative reverse transcriptase polymerase chain reaction techniques were used for determining the expression levels of related molecules in protein and mRNA. The results indicated that myricetin-induced cytotoxicity was highly potentiated by the encapsulation of myricetin. Mitochondrial apoptotic pathway was demonstrated to be involved in myricetin-induced glioblastoma cell death. The epidermal growth factor receptor (EGFR)/PI3K/Akt pathway located in the plasma membrane and cytosol and the RAS-ERK pathway located in mitochondria served as upstream and downstream targets, respectively, in myricetin-induced apoptosis. MiR-21 inhibitors interrupted the expression of EGFR, p-Akt, and K-Ras in the same fashion as myricetin-loaded mixed micelles (MYR-MCs) and miR-21 expression were dose-dependently inhibited by MYR-MCs, indicating the interaction of miR-21 with MYR-MCs. This study provided evidence supportive of further development of MYR-MC formulation for preferentially targeting mitochondria of glioblastoma cells.

  10. AT-33A PHASE II STUDY OF CONCURRENT RADIATION THERAPY, TEMOZOLOMIDE AND THE HISTONE DEACETYLASE INHIBITOR VALPROIC ACID FOR PATIENTS WITH GLIOBLASTOMA MULTIFORME

    Science.gov (United States)

    Krauze, Andra V.; Myrehaug, Sten D.; Chang, Michael G.; Holdford, Diane J.; Smith, Sharon; Shih, Joanna; Tofilon, Peter; Fine, Howard; Camphausen, Kevin A.

    2014-01-01

    BACKGROUND: Glioblastoma (GBM) remains an aggressive brain tumor with poor prognosis. Valproic acid (VPA) is an antiepileptic agent that has been shown to have HDACi activity and to radiosensitize GBM cells in preclinical models. This phase II study aimed to determine if the addition of VPA to standard radiation therapy and temozolomide would improve OS and PFS. METHODS: We prospectively assessed survival, radiological and clinical progression in 37 newly diagnosed glioblastoma patients with the administration of VPA at 25 mg/kg orally BID concurrent with radiation therapy (RT) and temozolomide (TMZ). The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently tapered up to 25 mg/kg/day over the week prior to radiation. RESULTS: 81% of patients took VPA according to protocol. Median OS was 29.6 months (21- 63.8), median PFS was 10.5 (6.8 - 51.2). OS at 6, 12, 24 months was 97%, 86%, 56% respectively. PFS at 6, 12, 24 months was 70%, 43%, 38% respectively. The most common grade 3 or 4 toxicities of VPA in conjunction with TMZ were blood/ bone marrow toxicity (32%), neurological (11%), metabolic/laboratory (8%). At the end of the study 26 (70%) patients were dead, 7 were live without disease, 4 alive with disease. Younger age (<= 50 years) compared to older age and class V RPA were significant for both OS and PFS. Using a landmark analysis, an early progression was related to a shorter interval between progression and death, whereas, a later progression was related to a longer interval between progression and death (p = 0.0002) HR 4.7. CONCLUSION: The addition of VPA to concurrent RT and TMZ in the treatment of newly diagnosed GBM may result in superior outcomes as compared to contemporary and historical data and merits further study.

  11. 3-Bromopyruvate treatment induces alterations of metabolic and stress-related pathways in glioblastoma cells.

    Science.gov (United States)

    Chiasserini, Davide; Davidescu, Magdalena; Orvietani, Pier Luigi; Susta, Federica; Macchioni, Lara; Petricciuolo, Maya; Castigli, Emilia; Roberti, Rita; Binaglia, Luciano; Corazzi, Lanfranco

    2017-01-30

    Glioblastoma (GBM) is the most common and aggressive brain tumour of adults. The metabolic phenotype of GBM cells is highly dependent on glycolysis; therefore, therapeutic strategies aimed at interfering with glycolytic pathways are under consideration. 3-Bromopyruvate (3BP) is a potent antiglycolytic agent, with a variety of targets and possible effects on global cell metabolism. Here we analyzed the changes in protein expression on a GBM cell line (GL15 cells) caused by 3BP treatment using a global proteomic approach. Validation of differential protein expression was performed with immunoblotting and enzyme activity assays in GL15 and U251 cell lines. The results show that treatment of GL15 cells with 3BP leads to extensive changes in the expression of glycolytic enzymes and stress related proteins. Importantly, other metabolisms were also affected, including pentose phosphate pathway, aminoacid synthesis, and glucose derivatives production. 3BP elicited the activation of stress response proteins, as shown by the phosphorylation of HSPB1 at serine 82, caused by the concomitant activation of the p38 pathway. Our results show that inhibition of glycolysis in GL15 cells by 3BP influences different but interconnected pathways. Proteome analysis may help in the molecular characterization of the glioblastoma response induced by pharmacological treatment with antiglycolytic agents.

  12. Bioactive form of resveratrol in glioblastoma cells and its safety for normal brain cells

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    Xiao-Hong Shu

    2013-05-01

    Full Text Available ABSTRACTBackground: Resveratrol, a plant polyphenol existing in grapes and many other natural foods, possesses a wide range of biological activities including cancer prevention. It has been recognized that resveratrol is intracellularly biotransformed to different metabolites, but no direct evidence has been available to ascertain its bioactive form because of the difficulty to maintain resveratrol unmetabolized in vivo or in vitro. It would be therefore worthwhile to elucidate the potential therapeutic implications of resveratrol metabolism using a reliable resveratrol-sensitive cancer cells.Objective: To identify the real biological form of trans-resveratrol and to evaluate the safety of the effective anticancer dose of resveratrol for the normal brain cells.Methods: The samples were prepared from the condition media and cell lysates of human glioblastoma U251 cells, and were purified by solid phase extraction (SPE. The samples were subjected to high performance liquid chromatography (HPLC and liquid chromatography/tandem mass spectrometry (LC/MS analysis. According to the metabolite(s, trans-resveratrol was biotransformed in vitro by the method described elsewhere, and the resulting solution was used to treat U251 cells. Meanwhile, the responses of U251 and primarily cultured rat normal brain cells (glial cells and neurons to 100μM trans-resveratrol were evaluated by multiple experimental methods.Results: The results revealed that resveratrol monosulfate was the major metabolite in U251 cells. About half fraction of resveratrol monosulfate was prepared in vitro and this trans-resveratrol and resveratrol monosulfate mixture showed little inhibitory effect on U251 cells. It is also found that rat primary brain cells (PBCs not only resist 100μM but also tolerate as high as 200μM resveratrol treatment.Conclusions: Our study thus demonstrated that trans-resveratrol was the bioactive form in glioblastoma cells and, therefore, the biotransforming

  13. Molecular characterization of EGFR and EGFRvIII signaling networks in human glioblastoma tumor xenografts.

    Science.gov (United States)

    Johnson, Hannah; Del Rosario, Amanda M; Bryson, Bryan D; Schroeder, Mark A; Sarkaria, Jann N; White, Forest M

    2012-12-01

    Glioblastoma multiforme (GBM) is a malignant primary brain tumor with a mean survival of 15 months with the current standard of care. Genetic profiling efforts have identified the amplification, overexpression, and mutation of the wild-type (wt) epidermal growth factor receptor tyrosine kinase (EGFR) in ≈ 50% of GBM patients. The genetic aberration of wtEGFR is frequently accompanied by the overexpression of a mutant EGFR known as EGFR variant III (EGFRvIII, de2-7EGFR, ΔEGFR), which is expressed in 30% of GBM tumors. The molecular mechanisms of tumorigenesis driven by EGFRvIII overexpression in human tumors have not been fully elucidated. To identify specific therapeutic targets for EGFRvIII driven tumors, it is important to gather a broad understanding of EGFRvIII specific signaling. Here, we have characterized signaling through the quantitative analysis of protein expression and tyrosine phosphorylation across a panel of glioblastoma tumor xenografts established from patient surgical specimens expressing wtEGFR or overexpressing wtEGFR (wtEGFR+) or EGFRvIII (EGFRvIII+). S100A10 (p11), major vault protein, guanylate-binding protein 1(GBP1), and carbonic anhydrase III (CAIII) were identified to have significantly increased expression in EGFRvIII expressing xenograft tumors relative to wtEGFR xenograft tumors. Increased expression of these four individual proteins was found to be correlated with poor survival in patients with GBM; the combination of these four proteins represents a prognostic signature for poor survival in gliomas. Integration of protein expression and phosphorylation data has uncovered significant heterogeneity among the various tumors and has highlighted several novel pathways, related to EGFR trafficking, activated in glioblastoma. The pathways and proteins identified in these tumor xenografts represent potential therapeutic targets for this disease.

  14. Study on Apoptosis-Inducing Effect of XIAP Antisense Oligonucleotides on Glioblastoma Cells in Vitro

    Institute of Scientific and Technical Information of China (English)

    Zhongwei Zhao; Zhengchun Sun; Yunhan Zhang; Ming Zhang; Xudong Ma

    2009-01-01

    OBJECTIVE To investigate the apoptosis-inducing effect of XIAP antisense oligonucleotides on glioblastoma cells in vitro.METHODS There were 4 groups in our experiment. Group A,as a cell control group, had normal cell culture and no treatment applied. Group B, as a blank control group, had normal cell culture and no liposome control of ASODN. Group C was N-ODN.Group D was the ASODN group. RT-PCR and Western blot assay were conducted to detect the expression of XIAP in all A-172cell groups after treatment with XIAP antisense oligonucleotides (ASODN). MTT assay and flow-cytometry (FCM) detection were used to detect the ability of cell anchoring growth and apoptotic rates of all groups. The processing time was 72 h.RESULTS The expression of XIAP in the A-172 cells was greatly down-regulated, after treated with XIAP-ASODN. Among different concentrations of ASODN, the 300nM was the most optimal one. The down-regulation of XIAP obviously inhibited the succinate dehydrogenase (SDH) activity of the A-172 cells and the increased apoptotic rate of A-172 cells (87.45%) was significantly higher than that of the A-172 in the control groups. There was a statistically significant difference between the treatment and control groups (P < 0.01).CONCLUSION The XIAP-ASODN can effectively regulate the expression of the XIAP down, as a result, inhibit the growth of the glioblastoma cells (A-172) and obviously increase the apoptotic rate of the A-172 cells. The results of the study manifest an overt killing role of XIAP-ASODN to the glioblastoma cells.

  15. Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma

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    Koji eYoshimoto

    2012-12-01

    Full Text Available Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma. Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT has been described as the main modulator to determine the sensitivity of glioblastoma to TMZ, a subset of glioblastoma does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR, and the base-excision repair (BER pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break (SSB repair and double-strand break (DSB repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.

  16. Improved Fission Neutron Data Base for Active Interrogation of Actinides

    Energy Technology Data Exchange (ETDEWEB)

    Pozzi, Sara; Czirr, J. Bart; Haight, Robert; Kovash, Michael; Tsvetkov, Pavel

    2013-11-06

    This project will develop an innovative neutron detection system for active interrogation measurements. Many active interrogation methods to detect fissionable material are based on the detection of neutrons from fission induced by fast neutrons or high-energy gamma rays. The energy spectrum of the fission neutrons provides data to identify the fissionable isotopes and materials such as shielding between the fissionable material and the detector. The proposed path for the project is as follows. First, the team will develop new neutron detection systems and algorithms by Monte Carlo simulations and bench-top experiments. Next, They will characterize and calibrate detection systems both with monoenergetic and white neutron sources. Finally, high-fidelity measurements of neutron emission from fissions induced by fast neutrons will be performed. Several existing fission chambers containing U-235, Pu-239, U-238, or Th-232 will be used to measure the neutron-induced fission neutron emission spectra. The challenge for making confident measurements is the detection of neutrons in the energy ranges of 0.01 – 1 MeV and above 8 MeV, regions where the basic data on the neutron energy spectrum emitted from fission is least well known. In addition, improvements in the specificity of neutron detectors are required throughout the complete energy range: they must be able to clearly distinguish neutrons from other radiations, in particular gamma rays and cosmic rays. The team believes that all of these challenges can be addressed successfully with emerging technologies under development by this collaboration. In particular, the collaboration will address the area of fission neutron emission spectra for isotopes of interest in the advanced fuel cycle initiative (AFCI).

  17. Neuropeptides of the VIP family inhibit glioblastoma cell invasion.

    Science.gov (United States)

    Cochaud, Stéphanie; Meunier, Annie-Claire; Monvoisin, Arnaud; Bensalma, Souheyla; Muller, Jean-Marc; Chadéneau, Corinne

    2015-03-01

    Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides acting through VPAC1, VPAC2 and PAC1 receptors (referred here as the VIP-receptor system). In the central nervous system, VIP and PACAP are involved in neurogenesis, cell differentiation and migration, suggesting that they could be implicated in the development of glioblastoma (GBM). The infiltrative nature of GBM remains a major problem for the therapy of these tumors. We previously demonstrated that the VIP-receptor system regulated cell migration of the human cell lines M059J and M059K, derived from a single human GBM. Here, we evaluated the involvement of the VIP-receptor system in GBM cell invasion. In Matrigel invasion assays, M059K cells that express more the VIP-receptor system than M059J cells were less invasive. Invasion assays performed in the presence of agonists, antagonists or anti-PACAP antibodies as well as experiments with transfected M059J cells overexpressing the VPAC1 receptor indicated that the more the VIP-receptor system was expressed and activated, the less the cells were able to invade. Western immunoblotting experiments revealed that the VIP-receptor system inactivated the signaling protein AKT. Invasion assays carried out in the presence of an AKT inhibitor demonstrated the involvement of this signaling kinase in the regulation of cell invasion by the VIP-receptor system in M059K cells. The inhibition by VIP of invasion and AKT was also observed in U87 cells. In conclusion, VIP and PACAP act as anti-invasive factors in different GBM cell lines, a function mediated by VPAC1 inhibition of AKT signaling in M059K cells.

  18. Pluronic-based micelle encapsulation potentiates myricetin-induced cytotoxicity in human glioblastoma cells

    Directory of Open Access Journals (Sweden)

    Tang XJ

    2016-10-01

    Full Text Available Xiang-Jun Tang,1,* Kuan-Ming Huang,1,* Hui Gui,1,* Jun-Jie Wang,2 Jun-Ti Lu,1 Long-Jun Dai,1,3 Li Zhang,1 Gang Wang2 1Department of Neurosurgery, TaiHe Hospital, Hubei University of Medicine, Shiyan, 2Department of Pharmaceutics, Shanghai Eighth People’s Hospital, Jiangsu University, Shanghai, People’s Republic of China; 3Department of Surgery, University of British Columbia, Vancouver, BC, Canada *These authors contributed equally to this work Abstract: As one of the natural herbal flavonoids, myricetin has attracted much research interest, mainly owing to its remarkable anticancer properties and negligible side effects. It holds great potential to be developed as an ideal anticancer drug through improving its bioavailability. This study was performed to investigate the effects of Pluronic-based micelle encapsulation on myricetin-induced cytotoxicity and the mechanisms underlying its anticancer properties in human glioblastoma cells. Cell viability was assessed using a methylthiazol tetrazolium assay and a real-time cell analyzer. Immunoblotting and quantitative reverse transcriptase polymerase chain reaction techniques were used for determining the expression levels of related molecules in protein and mRNA. The results indicated that myricetin-induced cytotoxicity was highly potentiated by the encapsulation of myricetin. Mitochondrial apoptotic pathway was demonstrated to be involved in myricetin-induced glioblastoma cell death. The epidermal growth factor receptor (EGFR/PI3K/Akt pathway located in the plasma membrane and cytosol and the RAS-ERK pathway located in mitochondria served as upstream and downstream targets, respectively, in myricetin-induced apoptosis. MiR-21 inhibitors interrupted the expression of EGFR, p-Akt, and K-Ras in the same fashion as myricetin-loaded mixed micelles (MYR-MCs and miR-21 expression were dose-dependently inhibited by MYR-MCs, indicating the interaction of miR-21 with MYR-MCs. This study provided evidence

  19. Information-Theoretic Active SOM for Improving Generalization Performance

    Directory of Open Access Journals (Sweden)

    Ryotaro Kamimura

    2016-10-01

    Full Text Available In this paper, we introduce a new type of information-theoretic method called “information-theoretic active SOM”, based on the self-organizing maps (SOM for training multi-layered neural networks. The SOM is one of the most important techniques in unsupervised learning. However, SOM knowledge is sometimes ambiguous and cannot be easily interpreted. Thus, we introduce the information-theoretic method to produce clearer and interpretable representations. The present method extends this information-theoretic approach into supervised learning. The main contribution can be summarized by three points. First, it is shown that clear representations by the information-theoretic method can be effective in training supervised learning. Second, the method is sufficiently simple where there are two separated components, namely, information maximization and error minimization component. Usually, two components are mixed in one framework, and it is difficult to compromise between them. In addition, the knowledge obtained by this information-theoretic SOM can be used to solve the shortage of unlabeled data, because the information maximization component is unsupervised and can process all input data with and without labels. The method was applied to the well-known image segmentation datasets. Experimental results showed that clear weights were produced and generalization performance was improved by using the information-theoretic SOM. In addition, the final results were stable, almost independent of the parameter values.

  20. Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging.

    Science.gov (United States)

    Umanskaya, Alisa; Santulli, Gaetano; Xie, Wenjun; Andersson, Daniel C; Reiken, Steven R; Marks, Andrew R

    2014-10-21

    Age-related skeletal muscle dysfunction is a leading cause of morbidity that affects up to half the population aged 80 or greater. Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca(2+) transients, decreased intracellular Ca(2+) leak and increased sarcoplasmic reticulum (SR) Ca(2+) load compared with age-matched wild type (WT) littermates. Furthermore, ryanodine receptor 1 (the sarcoplasmic reticulum Ca(2+) release channel required for skeletal muscle contraction; RyR1) from aged MCat mice was less oxidized, depleted of the channel stabilizing subunit, calstabin1, and displayed increased single channel open probability (Po). Overall, these data indicate a direct role for mitochondrial free radicals in promoting the pathological intracellular Ca(2+) leak that underlies age-dependent loss of skeletal muscle function. This study harbors implications for the development of novel therapeutic strategies, including mitochondria-targeted antioxidants for treatment of mitochondrial myopathies and other healthspan-limiting disorders.

  1. Morphometic analysis of TCGA glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Chang Hang

    2011-12-01

    Full Text Available Abstract Background Our goals are to develop a computational histopathology pipeline for characterizing tumor types that are being generated by The Cancer Genome Atlas (TCGA for genomic association. TCGA is a national collaborative program where different tumor types are being collected, and each tumor is being characterized using a variety of genome-wide platforms. Here, we have developed a tumor-centric analytical pipeline to process tissue sections stained with hematoxylin and eosin (H&E for visualization and cell-by-cell quantitative analysis. Thus far, analysis is limited to Glioblastoma Multiforme (GBM and kidney renal clear cell carcinoma tissue sections. The final results are being distributed for subtyping and linking the histology sections to the genomic data. Results A computational pipeline has been designed to continuously update a local image database, with limited clinical information, from an NIH repository. Each image is partitioned into blocks, where each cell in the block is characterized through a multidimensional representation (e.g., nuclear size, cellularity. A subset of morphometric indices, representing potential underlying biological processes, can then be selected for subtyping and genomic association. Simultaneously, these subtypes can also be predictive of the outcome as a result of clinical treatments. Using the cellularity index and nuclear size, the computational pipeline has revealed five subtypes, and one subtype, corresponding to the extreme high cellularity, has shown to be a predictor of survival as a result of a more aggressive therapeutic regime. Further association of this subtype with the corresponding gene expression data has identified enrichment of (i the immune response and AP-1 signaling pathways, and (ii IFNG, TGFB1, PKC, Cytokine, and MAPK14 hubs. Conclusion While subtyping is often performed with genome-wide molecular data, we have shown that it can also be applied to categorizing histology

  2. A simplified approach for the molecular classification of glioblastomas.

    Directory of Open Access Journals (Sweden)

    Marie Le Mercier

    Full Text Available Glioblastoma (GBM is the most common malignant primary brain tumors in adults and exhibit striking aggressiveness. Although GBM constitute a single histological entity, they exhibit considerable variability in biological behavior, resulting in significant differences in terms of prognosis and response to treatment. In an attempt to better understand the biology of GBM, many groups have performed high-scale profiling studies based on gene or protein expression. These studies have revealed the existence of several GBM subtypes. Although there remains to be a clear consensus, two to four major subtypes have been identified. Interestingly, these different subtypes are associated with both differential prognoses and responses to therapy. In the present study, we investigated an alternative immunohistochemistry (IHC-based approach to achieve a molecular classification for GBM. For this purpose, a cohort of 100 surgical GBM samples was retrospectively evaluated by immunohistochemical analysis of EGFR, PDGFRA and p53. The quantitative analysis of these immunostainings allowed us to identify the following two GBM subtypes: the "Classical-like" (CL subtype, characterized by EGFR-positive and p53- and PDGFRA-negative staining and the "Proneural-like" (PNL subtype, characterized by p53- and/or PDGFRA-positive staining. This classification represents an independent prognostic factor in terms of overall survival compared to age, extent of resection and adjuvant treatment, with a significantly longer survival associated with the PNL subtype. Moreover, these two GBM subtypes exhibited different responses to chemotherapy. The addition of temozolomide to conventional radiotherapy significantly improved the survival of patients belonging to the CL subtype, but it did not affect the survival of patients belonging to the PNL subtype. We have thus shown that it is possible to differentiate between different clinically relevant subtypes of GBM by using IHC

  3. Different diagnostic values of imaging parameters to predict pseudoprogression in glioblastoma subgroups stratified by MGMT promoter methylation

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Ra Gyoung [Catholic Kwandong University International St. Mary' s Hospital, Department of Radiology, Catholic Kwandong University College of Medicine, Incheon (Korea, Republic of); Kim, Ho Sung; Shim, Woo Hyun; Kim, Sang Joon [University of Ulsan College of Medicine, Asan Medical Center, Department of Radiology and Research Institute of Radiology, Seoul (Korea, Republic of); Paik, Wooyul [Dankook Unversity Hospital, Department of Radiology, Cheonan-si, Chungcheongnam-do (Korea, Republic of); Kim, Jeong Hoon [University of Ulsan College of Medicine, Asan Medical Center, Department of Neurosurgery, Seoul (Korea, Republic of)

    2017-01-15

    The aim of this study was to determine whether diffusion and perfusion imaging parameters demonstrate different diagnostic values for predicting pseudoprogression between glioblastoma subgroups stratified by O{sup 6}-mythylguanine-DNA methyltransferase (MGMT) promoter methylation status. We enrolled seventy-five glioblastoma patients that had presented with enlarged contrast-enhanced lesions on magnetic resonance imaging (MRI) one month after completing concurrent chemoradiotherapy and undergoing MGMT promoter methylation testing. The imaging parameters included 10 or 90 % histogram cutoffs of apparent diffusion coefficient (ADC10), normalized cerebral blood volume (nCBV90), and initial area under the time signal-intensity curve (IAUC90). The results of the areas under the receiver operating characteristic curve (AUCs) with cross-validation were compared between MGMT methylation and unmethylation groups. MR imaging parameters demonstrated a trend toward higher accuracy in the MGMT promoter methylation group than in the unmethylation group (cross-validated AUCs = 0.70-0.95 and 0.56-0.87, respectively). The combination of MGMT methylation status with imaging parameters improved the AUCs from 0.70 to 0.75-0.90 for both readers in comparison with MGMT methylation status alone. The probability of pseudoprogression was highest (95.7 %) when nCBV90 was below 4.02 in the MGMT promoter methylation group. MR imaging parameters could be stronger predictors of pseudoprogression in glioblastoma patients with the methylated MGMT promoter than in patients with the unmethylated MGMT promoter. (orig.)

  4. Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells.

    Directory of Open Access Journals (Sweden)

    Maria Zeniou

    Full Text Available Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM, the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication.

  5. Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells.

    Science.gov (United States)

    Zeniou, Maria; Fève, Marie; Mameri, Samir; Dong, Jihu; Salomé, Christophe; Chen, Wanyin; El-Habr, Elias A; Bousson, Fanny; Sy, Mohamadou; Obszynski, Julie; Boh, Alexandre; Villa, Pascal; Assad Kahn, Suzana; Didier, Bruno; Bagnard, Dominique; Junier, Marie-Pierre; Chneiweiss, Hervé; Haiech, Jacques; Hibert, Marcel; Kilhoffer, Marie-Claude

    2015-01-01

    Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication.

  6. Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery.

    Science.gov (United States)

    Gilbert, Mark R; Kuhn, John; Lamborn, Kathleen R; Lieberman, Frank; Wen, Patrick Y; Mehta, Minesh; Cloughesy, Timothy; Lassman, Andrew B; Deangelis, Lisa M; Chang, Susan; Prados, Michael

    2012-01-01

    Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvβ3 and αvβ5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.

  7. BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53

    Science.gov (United States)

    Nie, Er; Jin, Xin; Wu, Weining; Yu, Tianfu; Zhou, Xu; Zhi, Tongle; Shi, Zhumei; Zhang, Junxia; Liu, Ning; You, Yongping

    2016-01-01

    The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo. Further investigation revealed that BACH1 activation significantly enhanced the expression of MGMT, and depletion of p53 disrupted the effects of BACH1 on MGMT and temozolomide resistance. P53 sequesters SP1 to prevent its binding to the MGMT promoter region and thus inhibits MGMT expression. Moreover, BACH1 overexpression impaired the association between p53 and SP1 via competitive binding p53, and antagonized the impact of p53 on MGMT expression. Finally, we found that BACH1 low expression correlated with better prognosis in GBM patients undergoing temozolomide therapy, especially in patients with wild-type TP53. Collectively, our findings identify a potential mechanism by which wild-type TP53 GBM cells develop resistance to temozolomide and suggest that targeting this pathway may be beneficial for overcoming resistance. PMID:28000777

  8. Salinomycin potentiates the cytotoxic effects of TRAIL on glioblastoma cell lines.

    Directory of Open Access Journals (Sweden)

    Alessia Calzolari

    Full Text Available Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL has been reported to exhibit therapeutic activity in cancer. However, many tumors remain resistant to treatment with TRAIL. Therefore, small molecules that potentiate the cytotoxic effects of TRAIL could be used for combinatorial therapy. Here we found that the ionophore antibiotic salinomycin acts in synergism with TRAIL, enhancing TRAIL-induced apoptosis in glioma cells. Treatment with low doses of salinomycin in combination with TRAIL augmented the activation of caspase-3 and increased TRAIL-R2 cell surface expression. TRAIL-R2 upmodulation was required for mediating the stimulatory effect of salinomycin on TRAIL-mediated apoptosis, since it was abrogated by siRNA-mediated TRAIL-R2 knockdown. Salinomycin in synergism with TRAIL exerts a marked anti-tumor effect in nude mice xenografted with human glioblastoma cells. Our results suggest that the combination of TRAIL and salinomycin may be a useful tool to overcome TRAIL resistance in glioma cells and may represent a potential drug for treatment of these tumors. Importantly, salinomycin+TRAIL were able to induce cell death of well-defined glioblastoma stem-like lines.

  9. Salinomycin potentiates the cytotoxic effects of TRAIL on glioblastoma cell lines.

    Science.gov (United States)

    Calzolari, Alessia; Saulle, Ernestina; De Angelis, Maria Laura; Pasquini, Luca; Boe, Alessandra; Pelacchi, Federica; Ricci-Vitiani, Lucia; Baiocchi, Marta; Testa, Ugo

    2014-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to exhibit therapeutic activity in cancer. However, many tumors remain resistant to treatment with TRAIL. Therefore, small molecules that potentiate the cytotoxic effects of TRAIL could be used for combinatorial therapy. Here we found that the ionophore antibiotic salinomycin acts in synergism with TRAIL, enhancing TRAIL-induced apoptosis in glioma cells. Treatment with low doses of salinomycin in combination with TRAIL augmented the activation of caspase-3 and increased TRAIL-R2 cell surface expression. TRAIL-R2 upmodulation was required for mediating the stimulatory effect of salinomycin on TRAIL-mediated apoptosis, since it was abrogated by siRNA-mediated TRAIL-R2 knockdown. Salinomycin in synergism with TRAIL exerts a marked anti-tumor effect in nude mice xenografted with human glioblastoma cells. Our results suggest that the combination of TRAIL and salinomycin may be a useful tool to overcome TRAIL resistance in glioma cells and may represent a potential drug for treatment of these tumors. Importantly, salinomycin+TRAIL were able to induce cell death of well-defined glioblastoma stem-like lines.

  10. Alkylphospholipids deregulate cholesterol metabolism and induce cell-cycle arrest and autophagy in U-87 MG glioblastoma cells.

    Science.gov (United States)

    Ríos-Marco, Pablo; Martín-Fernández, Mario; Soria-Bretones, Isabel; Ríos, Antonio; Carrasco, María P; Marco, Carmen

    2013-08-01

    Glioblastoma is the most common malignant primary brain tumour in adults and one of the most lethal of all cancers. Growing evidence suggests that human tumours undergo abnormal lipid metabolism, characterised by an alteration in the mechanisms that regulate cholesterol homeostasis. We have investigated the effect that different antitumoural alkylphospholipids (APLs) exert upon cholesterol metabolism in the U-87 MG glioblastoma cell line. APLs altered cholesterol homeostasis by interfering with its transport from the plasma membrane to the endoplasmic reticulum (ER), thus hindering its esterification. At the same time they stimulated the synthesis of cholesterol from radiolabelled acetate and its internalisation from low-density lipoproteins (LDLs), inducing both 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and LDL receptor (LDLR) genes. Fluorescent microscopy revealed that these effects promoted the accumulation of intracellular cholesterol. Filipin staining demonstrated that this accumulation was not confined to the late endosome/lysosome (LE/LY) compartment since it did not colocalise with LAMP2 lysosomal marker. Furthermore, APLs inhibited cell growth, producing arrest at the G2/M phase. We also used transmission electron microscopy (TEM) to investigate ultrastructural alterations induced by APLs and found an abundant presence of autophagic vesicles and autolysosomes in treated cells, indicating the induction of autophagy. Thus our findings clearly demonstrate that antitumoural APLs interfere with the proliferation of the glioblastoma cell line via a complex mechanism involving cholesterol metabolism, cell-cycle arrest or autophagy. Knowledge of the interrelationship between these processes is fundamental to our understanding of tumoural response and may facilitate the development of novel therapeutics to improve treatment of glioblastoma and other types of cancer.

  11. Virtual mutagenesis of isocitrate dehydrogenase 1 involved in glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    WANG Ming-dong; SHI Yan-fang; WANG Hong; WANG Jia-liang; MA Wen-bin; WANG Ren-zhi

    2011-01-01

    Background Site A132Arg mutations potentially impair the affinity of isocitrate dehydrogenase 1 (IDH1) for its substrate isocitrate (ICT),consequently reducing the production of α-ketoglutarate and leading to tumor growth through the induction of the hypoxia-inducible factor-1 (HIF-1) pathway.However,given that the roles of other active sites in IDH1 substrate binding remain unclear,we aimed to investigate IDH1 mutation pattern and its influence on enzyme function.Methods Fifteen IDH1 catalytic active site candidates were selected for in silico mutagenesis and protein homology modeling.Binding free energy of the IDH1/ICT complexes with single-site mutations was compared with that of the wild type.The affinity of 10 IDH1 catalytic active sites for the ICT substrate was further calculated.Results The IDH1 active site included seven residues from chain A (A77Thr,A94Ser,A100Arg,A132Arg,A1O9Arg,A275Asp,and A279Asp) and three residues from chain B (B214Thr,B212Lys,and B252Asp) that constituted the substrate ICT-binding site.These residues were located within 0.5 nm of ICT,indicating a potential interaction with the substrate.IDH1 changes of binding free energy (△E) suggested that the A132Arg residue from chain A contributes three hydrogen bonds to the ICT α-carboxyl and β-carboxyl groups,while the other nine residues involved in ICT binding form only one or two hydrogen bonds.Amino acid substitutes at A132Arg,A109Arg,and B212Lys sites,had the greatest effect on enzyme affinity for its substrate.Conclusions Mutations at sites A132Arg,A109Arg,and B212Lys reduced IDH1 affinity for ICT,indicating these active sites may play a central role in substrate binding.Mutations at sites A77Thr,A94Ser,and A275Asp increased the affinity of IDH1 for ICT,which may enhance IDN1 catalytic activity.Mutant IDH1 proteins with higher catalytic activity than the wild-type IDH1 could potentially be used as a novel gene therapy for glioblastoma multiforme.

  12. Glioblastoma stem-like cells give rise to tumour endothelium

    NARCIS (Netherlands)

    R. Wang; K. Chadalavada; J. Wilshire; U. Kowalik; K.E. Hovinga; A. Geber; B. Fligelman; M. Leversha; C. Brennan; V. Tabar

    2010-01-01

    Glioblastoma (GBM) is among the most aggressive of human cancers(1). A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia(2). Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poo

  13. Recent advances in the molecular understanding of glioblastoma

    NARCIS (Netherlands)

    F.E. Bleeker (Fonnet); R.J. Molenaar (Remco); S. Leenstra (Sieger)

    2012-01-01

    textabstractGlioblastoma is the most common and most aggressive primary brain tumor. Despite maximum treatment, patients only have a median survival time of 15 months, because of the tumor's resistance to current therapeutic approaches. Thus far, methylation of the O 6-methylguanine-DNA methyltransf

  14. Genetic variations in EGF and EGFR and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, Sara; Andersson, Ulrika; Liu, Yanhong

    2010-01-01

    Few prognostic factors have been associated with glioblastoma survival. We analyzed a complete tagging of the epidermal growth factor (EGF) and EGF receptor (EGFR) gene polymorphisms as potential prognostic factors. Thirty tagging single-nucleotide polymorphisms (SNPs) in EGF and 89 tagging SNPs ...

  15. MGMT gene silencing and benefit from temozolomide in glioblastoma

    NARCIS (Netherlands)

    Hegi, ME; Diserens, A; Gorlia, T; Hamou, M; de Tribolet, N; Weller, M; Kros, JM; Hainfellner, JA; Mason, W; Mariani, L; Bromberg, JEC; Hau, P; Mirimanoff, RO; Cairncross, JG; Janzer, RC; Stupp, R

    2005-01-01

    BACKGROUND: Epigenetic silencing of the MGMT (O(sup 6)-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship bet

  16. Nanoparticles of carbon allotropes inhibit glioblastoma multiforme angiogenesis in ovo

    DEFF Research Database (Denmark)

    Grodzik, Marta; Sawosz, Ewa; Wierzbicki, Mateusz

    2011-01-01

    The objective of the study was to determine the effect of carbon nanoparticles produced by different methods on the growth of brain tumor and the development of blood vessels. Glioblastoma multiforme cells were cultured on the chrioallantoic membrane of chicken embryo and after 7 days of incubati...

  17. Detection of MGMT promoter methylation in glioblastoma using pyrosequencing.

    Science.gov (United States)

    Xie, Hao; Tubbs, Raymond; Yang, Bin

    2015-01-01

    Recent clinical trials on patients with glioblastoma revealed that O6-Methylguanine-DNA methyltransferase (MGMT) methylation status significantly predicts patient's response to alkylating agents. In this study, we sought to develop and validate a quantitative MGMT methylation assay using pyrosequencing on glioblastoma. We quantified promoter methylation of MGMT using pyrosequencing on paraffin-embedded fine needle aspiration biopsy tissues from 43 glioblastoma. Using a 10% cutoff, MGMT methylation was identified in 37% cases of glioblastoma and 0% of the non-neoplastic epileptic tissue. Methylation of any individual CpG island in MGMT promoter ranged between 33% and 95%, with a mean of 65%. By a serial dilution of genomic DNA of a homogenously methylated cancer cell line with an unmethylated cell line, the analytical sensitivity is at 5% for pyrosequencing to detect MGMT methylation. The minimal amount of genomic DNA required is 100 ng (approximately 3,000 cells) in small fine needle biopsy specimens. Compared with methylation-specific PCR, pyrosequencing is comparably sensitive, relatively specific, and also provides quantitative information for each CpG methylation.

  18. The Dynamics of Interactions Among Immune and Glioblastoma Cells.

    Science.gov (United States)

    Eder, Katalin; Kalman, Bernadette

    2015-12-01

    Glioblastoma is the most common intracranial malignancy that constitutes about 50 % of all gliomas. Despite aggressive, multimodal therapy consisting of surgery, radiation, and chemotherapy, the outcome of patients with glioblastoma remains poor with 5-year survival rates of immune mediators may represent a critical contributor to this resistance. The tumor microenvironment contains innate and adaptive immune cells in addition to the cancer cells and their surrounding stroma. These various cells communicate with each other by means of direct cell-cell contact or by soluble factors including cytokines and chemokines, and act in autocrine and paracrine manners to modulate tumor growth. There are dynamic interactions among the local immune elements and the tumor cells, where primarily the protective immune cells attempt to overcome the malignant cells. However, by developing somatic mutations and epigenetic modifications, the glioblastoma tumor cells acquire the capability of counteracting the local immune responses, and even exploit the immune cells and products for their own growth benefits. In this review, we survey those immune mechanisms that likely contribute to glioblastoma pathogenesis and may serve as a basis for novel treatment strategies.

  19. High CD133 Expression Is Associated with Worse Prognosis in Patients with Glioblastoma.

    Science.gov (United States)

    Zhang, Wei; Chen, Huanran; Lv, Shengqing; Yang, Hui

    2016-05-01

    The CD133 antigen has been identified as a putative stem cell marker in gliomas. However, the prognostic significance of CD133 expression in glioblastoma patients remained controversial. A meta-analysis of published data was performed to comprehensively assess the prognostic role of CD133 expression in glioblastoma patients. Publications assessing the prognostic significance of CD133 expression in glioblastoma patients were identified in PubMed, Embase, and Web of Science up to November 2014. The pooled hazard ratio (HR) with 95% confidence interval (95% CI) was calculated using meta-analysis to evaluate the prognostic significance of CD133 expression in glioblastoma. Ten studies with a total of 715 glioblastoma patients were included into the meta-analysis. Overall, high CD133 expression was associated with poorer overall survival in patients with glioblastoma (HR = 1.96, 95% CI 1.46-2.64, P glioblastoma (HR = 2.03, 95% CI 1.43-2.88, P glioblastoma. Meta-analysis of studies with adjusted estimates further showed that high CD133 expression was an independent prognostic factor of glioblastoma. High CD133 expression is associated with worse prognosis in patients with glioblastoma. More prospective studies with well-design are needed to confirm this finding.

  20. Puerarin Synergizes with Arsenic Trioxide for the Apoptosis of Human Glioblastoma Cells through the Protein Kinase/p38 Mitogen-activated Protein Kinases Pathway%葛根素与三氧化二砷协同作用通过Akt/p38途径促进人胶质瘤细胞凋亡

    Institute of Scientific and Technical Information of China (English)

    羊轶驹; 孙振球

    2012-01-01

    目的:研究葛根素(PRN)是否通过Akt/p38途径协同三氧化二砷(As2O3)促进人胶质瘤细胞的凋亡.方法:MTT检测细胞的存活率,流式细胞仪(FCM)技术检测细胞的凋亡状态,蛋白免疫印迹(Immunoblotting)检测细胞phosphorylated Akt和p38-MAPK,Cleaved Caspase-3蛋白的表达,PCR检测Caspase-3的mRNA的表达.结果:PRN协同As2O3降低人胶质瘤细胞U87的存活.与对照组相比,PRN(16μM)组,As2O3(2μM)组显著增加细胞内钙水平(1.13±0.015),(1.18±0.33).此外,PRN能够协同As2O3增加细胞内钙(1.34±0.72),下调蛋白phosphorylated Akt,上调phosphorylated p38-MAPK和Cleaved Caspase-3蛋白及Cleaved Caspase-3 mRNA表达水平.结论:PRN协同As2O3增加胶质瘤细胞内钙水平,抑制细胞存活.此外,PRN联合As2O3下调phosphorylated Akt,增强phosphorylated p38-MAPK和Cleaved Caspase-3的表达,进而促进肿瘤细胞凋亡.PRN可能成为临床上辅助As2O3治疗肿瘤中的潜在的辅助治疗药物.%Objective: To investigate whether puerarin (PRN) synergizes with arsenic trioxide (As2O3) in facilitating the apoptosis of human glioblastoma cell line U87 through the protein kinase (Akt)/p 38 mitogen-activated protein kinases (p38-MAPK) pathway. Methods: The 3-(4,5-deimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide technique was performed to detect cell survival. Flow cytometry was applied to calculate cell apoptosis, and immunoblot technique was used to verify the protein expressions of phosphorylated Akt, p38-MAPK, and cleaved caspase-3. In addition, caspase-3 mRNA levels were detected by real-time polymerase chain reaction. Results: PRN synergized with As2O3 to decrease the survival of human glioblastoma cell line U87. A single dosage each of PRN (16 μM; 1.13±0.015) and As2O3 (2 μM; 1.18±0.33) significantly increased the intracellular calcium concentration. Moreover, PRN synergized with As2O3 to increase the in-tracellular calcium concentration (1.34±0.72) compared with the findings in

  1. The involvement of hematopoietic pre-B cell leukemia transcription factor-interacting protein in regulating epithelial-mesenchymal transition of human spinal glioblastoma.

    Science.gov (United States)

    Wang, Deliang; Wang, Li; Zhou, Yi; Zhao, Xinjun; Xiong, Hui

    2016-05-01

    To date, hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP), a co-repressor for the transcription factor PBX, has been involved into the initiation and onset in a wide variety of cancers. However, the molecular mechanisms underlying HPIP-induced epithelial-mesenchymal transition (EMT) in the spinal glioblastoma have been under investigation. In the present study, spinal glioblastoma tissues, U87, and U251 cell lines were used and subjected to in vitro assays, such as RT-PCR, and Western blot. Here, in vitro assays revealed that HPIP mRNA and protein were highly expressed in five cases of spinal glioblastoma tissues, compared with non-tumor tissues. Subsequently, in vitro experiments demonstrated HPIP promoted the U87 and U251 cell growth and regulated the G1/S phase transitions in U87 and U251 cell cycle, respectively, accompanied by the increased expression of cyclin A2, cyclin B1, and cyclin D1. Furthermore, HPIP increased the expression of N-cadherin, Slug, and MMP2, and decreased the expression of E-cadherin. By contrast, knockdown of HPIP reversed HPIP-induced EMT biomarkers, migration, and invasion in U87 and U251 cells. In conclusion, our findings identified HPIP plays an important role in the progression and EMT of spinal glioblastoma, by which cell growth is improved. Thus, HPIP gene or protein could act as a useful target in the clinical practice.

  2. Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis.

    Science.gov (United States)

    Lamborn, Kathleen R; Chang, Susan M; Prados, Michael D

    2004-07-01

    Survival for patients with glioblastoma multiforme is short, and current treatments provide limited benefit. Therefore, there is interest in conducting phase 2 trials of experimental treatments in newly diagnosed patients. However, this requires historical data with which to compare the experimental therapies. Knowledge of prognostic markers would also allow stratification into risk groups for phase 3 randomized trials. In this retrospective study of 832 glioblastoma multiforme patients enrolled into prospective clinical trials at the time of initial diagnosis, we evaluated several potential prognostic markers for survival to establish risk groups. Analyses were done using both Cox proportional hazards modeling and recursive partitioning analyses. Initially, patients from 8 clinical trials, 6 of which included adjuvant chemotherapy, were included. Subsequent analyses excluded trials with interstitial brachytherapy, and finally included only nonbrachytherapy trials with planned adjuvant chemotherapy. The initial analysis defined 4 risk groups. The 2 lower risk groups included patients under the age of 40, the lowest risk group being young patients with tumor in the frontal lobe only. An intermediate-risk group included patients with Karnofsky performance status (KPS) >70, subtotal or total resection, and age between 40 and 65. The highest risk group included all patients over 65 and patients between 40 and 65 with either KPS<80 or biopsy only. Subgroup analyses indicated that inclusion of adjuvant chemotherapy provides an increase in survival, although that improvement tends to be minimal for patients over age 65, for patients over age 40 with KPS less than 80, and for those treated with brachytherapy.

  3. NT113, a pan-ERBB inhibitor with high brain penetrance, inhibits the growth of glioblastoma xenografts with EGFR amplification.

    Science.gov (United States)

    Yoshida, Yasuyuki; Ozawa, Tomoko; Yao, Tsun-Wen; Shen, Wang; Brown, Dennis; Parsa, Andrew T; Raizer, Jeffrey J; Cheng, Shi-Yuan; Stegh, Alexander H; Mazar, Andrew P; Giles, Francis J; Sarkaria, Jann N; Butowski, Nicholas; Nicolaides, Theodore; James, C David

    2014-12-01

    This report describes results from our analysis of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; determination of survival benefit from treatment; analysis of tumor IHC reactivity for indication of treatment effect on proliferation and apoptotic response; Western blot analysis for determination of effects of treatment on ERBB and ERBB signaling mediator activation; and high-performance liquid chromatography for determination of NT113 concentration in tissue extracts from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In experiments including lapatinib and/or erlotinib, NT113 treatment was associated with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot analysis results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the analysis of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clinical investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM.

  4. Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain

    OpenAIRE

    Charest, Gabriel; Sanche, Léon; Fortin, David; Mathieu, David; Paquette, Benoit

    2013-01-01

    Treatment of glioblastoma with platinum compounds modestly improves progression-free survival and may cause toxic effects which prevent use at higher dose that would otherwise improve the antineoplastic effect. To reduce toxicity, we propose to encapsulate the platinum drug in a liposome. We have also tested three methods of drug administration (intra-venous, intra-arterial and intra-arterial combined with blood brain barrier disruption) to determine which one optimizes the tumor cell uptake,...

  5. Glioblastoma primário de cone medula: relato de caso Primary connus medullaris glioblastoma: case report

    Directory of Open Access Journals (Sweden)

    Rodrigo Mendonça

    2005-06-01

    Full Text Available O glioblastoma, um tumor anaplásico de linhagem astrocitária, é o mais freqüente tumor cerebral. Localiza-se preferencialmente nos hemisférios cerebrais; seu crescimento primário no cone medular é muito raro, e o manejo e prognóstico deste tipo de lesão são distintos dos outros tumores observados nesta localização. Apresentamos o caso de um homem de 39 anos com tumor intramedular com diagnóstico histo-patológico de glioblastoma.Glioblastomas are the most common type of brain tumors; astrocytic in their origin, they are anaplastic tumors, and are located mainly in the cerebral hemispheres. Primary growth in the conus medullaris is very rare, and the assessment and prognosis of this kind of tumor are distinct and unique. We present here the case of a 39 years-old man with an intramedullary tumor of the spinal cord, with an histo pathological diagnosis of glioblastoma, along with some therapeutic considerations.

  6. Underlying mechanisms of improving physical activity behavior after rehabilitation

    NARCIS (Netherlands)

    van der Ploeg, Hidde P; Streppel, Kitty R M; van der Beek, Allard J; van der Woude, Luc H V; van Harten, Wim H; van Mechelen, Willem; van der Woude, Lucas

    2008-01-01

    BACKGROUND: Regular physical activity is beneficial for the health and functioning of people with a disability. Effective components of successful physical activity promotion interventions should be identified and disseminated. PURPOSE: To study the underlying mechanisms of the combined sport stimul

  7. Underlying mechanisms of improving physical activity behavior after rehabilitation

    NARCIS (Netherlands)

    Ploeg, van der Hidde P.; Streppel, Kitty R.M.; Beek, van der Allard J.; Woude, Luc H.V.; Harten, van Wim H.; Mechelen, van Willem

    2008-01-01

    Background: Regular physical activity is beneficial for the health and functioning of people with a disability. Effective components of successful physical activity promotion interventions should be identified and disseminated. Purpose: To study the underlying mechanisms of the combined sport stimul

  8. Intracranial elimination of human glioblastoma brain tumors in nude rats using the bispecific ligand-directed toxin, DTEGF13 and convection enhanced delivery.

    Science.gov (United States)

    Oh, Seunguk; Ohlfest, John R; Todhunter, Deborah A; Vallera, Vincent D; Hall, Walter A; Chen, Hua; Vallera, Daniel A

    2009-12-01

    A bispecific ligand-directed toxin (BLT) consisting of human interleukin-13, epithelial growth factor, and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma. In vitro, DTEGF13 selectively killed the human glioblastoma cell line U87-luc as well as other human glioblastomas. DTEGF13 fulfilled the requirement of a successful BLT by having greater activity than either of its monospecific counterparts or their mixture proving it necessary to have both ligands on the same single chain molecule. Aggressive brain tumors established intracranially (IC) in nude rats with U87 glioma genetically marked with a firefly luciferase reporter gene were treated with two injections of DTEGF13 using convection enhanced delivery resulting in tumor eradication in 50% of the rats which survived with tumor free status at least 110 days post tumor inoculation. An irrelevant BLT control did not protect establishing specificity. The bispecific DTEGF13 MTD dose was measured at 2 microg/injection or 0.5 microg/kg and toxicity studies indicated safety in this dose. Combination of monospecific DTEGF and DTIL13 did not inhibit tumor growth. ELISA assay indicated that anti-DT antibodies were not generated in normal immunocompetent rats given identical intracranial DTEGF13 therapy. Thus, DTEGF13 is safe and efficacious as an alternative drug for glioblastoma therapy and warrants further study.

  9. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide.

    Science.gov (United States)

    Kast, Richard E; Karpel-Massler, Georg; Halatsch, Marc-Eric

    2014-09-30

    CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs--aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

  10. Immunotherapy of intracranial G422 glioblastoma with dendritic cells pulsed with tumor extract or RNA

    Institute of Scientific and Technical Information of China (English)

    张哲; 汤灵玲; 詹仁雅; 童鹰; 姚航平; 杜理安

    2004-01-01

    Objective: To investigate the anti-tumor efficacy of dendritic cell (DC)-based vaccines pulsed with tumor extracts or RNA in a mouse model of intracranial G422 glioblastoma. Methods: Bone marrow-derived DCs were pulsed ex vivo with tumor extracts or RNA. Ninety female mice harboring 4-day-old intracranial G422 glioblastomas and 126 normal mice were treated with three spaced one week apart subcutaneous injections either with PBS, unpulsed DCs, G422 tumor extracts, RNA, DCs pulsed with G422 tumor extracts (DC/extract) or with RNA (DC/RNA). Seven days after the third immunization of normal mice, the spleens of 36 of them were harvested for cytotoxic T lyphocyte (CTL) assays and the others were challenged in the brain with G422 tumor cells. All the treated mice were followed for survival. Some mice brains were removed and examined pathologically when they died. Results: Immunization using DC/extract or DC/RNA significantly induced G422-specific CTL responses compared with control groups (P<0.01). Vaccination with DC/extract or DC/RNA, either prior to G422 tumor challenge or in tumor-harboring mice, significantly prolonged survival compared with other control groups (P<0.01). Conclusion: DCs pulsed with tumor extracts or RNA derived from autologous tumors has potential antitumor effects via activation of cell-mediated immunity. Our results suggest a useful therapeutic strategy against gliomas.

  11. Immunotherapy of intracranial G422 glioblastoma with dendritic cells pulsed with tumor extract or RNA

    Institute of Scientific and Technical Information of China (English)

    张哲; 汤灵玲; 詹仁雅; 童鹰; 姚航平; 杜理安

    2004-01-01

    Objective: To investigate the anti-tumor efficacy of dendritic cell (DC)-based vaccines pulsed with tumor extracts or RNA in a mouse model of intracranial G422 glioblastoma. Methods: Bone marrow-derived DCs were pulsed ex vivo with tumor extracts or RNA. Ninety female mice harboring 4-day-old intracranial G422 glioblastomas and 126 normal mice were treated with three spaced one week apart subcutaneous injections either with PBS, unpulsed DCs, G422 tumor extracts, RNA, DCs pulsed with G422 tumor extracts (DC/extract) or with RNA (DC/RNA). Seven days after the third immunization of normal mice, the spleens of 36 of them were harvested for cytotoxic T lyphocyte (CTL) assays and the others were challenged in the brain with G422 tumor cells. All the treated mice were followed for survival. Some mice brains were removed and examined pathologically when they died. Results: Immunization using DC/extract or DC/RNA significantly induced G422-specific CTL responses compared with control groups (P<0.01). Vaccination with DC/extract or DC/RNA, either prior to G422 tumor challenge or in tumor-harboring mice, significantly prolonged survival compared with other control groups (P<0.01). Conclusion: DCs pulsed with tumor extracts or RNA derived from autologous tumors has potential antitumor effects via activation of cell-mediated immunity. Our results suggest a useful therapeutic strategy against gliomas.

  12. Comparing predictive models of glioblastoma multiforme built using multi-institutional and local data sources.

    Science.gov (United States)

    Singleton, Kyle W; Hsu, William; Bui, Alex A T

    2012-01-01

    The growing amount of electronic data collected from patient care and clinical trials is motivating the creation of national repositories where multiple institutions share data about their patient cohorts. Such efforts aim to provide sufficient sample sizes for data mining and predictive modeling, ultimately improving treatment recommendations and patient outcome prediction. While these repositories offer the potential to improve our understanding of a disease, potential issues need to be addressed to ensure that multi-site data and resultant predictive models are useful to non-contributing institutions. In this paper we examine the challenges of utilizing National Cancer Institute datasets for modeling glioblastoma multiforme. We created several types of prognostic models and compared their results against models generated using data solely from our institution. While overall model performance between the data sources was similar, different variables were selected during model generation, suggesting that mapping data resources between models is not a straightforward issue.

  13. The improved physical activity index for measuring physical activity in EPIC Germany.

    Directory of Open Access Journals (Sweden)

    Angelika Wientzek

    Full Text Available In the European Investigation into Cancer and Nutrition study (EPIC, physical activity (PA has been indexed as a cross-tabulation between PA at work and recreational activity. As the proportion of non-working participants increases, other categorization strategies are needed. Therefore, our aim was to develop a valid PA index for this population, which will also be able to express PA continuously. In the German EPIC centers Potsdam and Heidelberg, a clustered sample of 3,766 participants was re-invited to the study center. 1,615 participants agreed to participate and 1,344 participants were finally included in this study. PA was measured by questionnaires on defined activities and a 7-day combined heart rate and acceleration sensor. In a training sample of 433 participants, the Improved Physical Activity Index (IPAI was developed. Its performance was evaluated in a validation sample of 911 participants and compared with the Cambridge Index and the Total PA Index. The IPAI consists of items covering five areas including PA at work, sport, cycling, television viewing, and computer use. The correlations of the IPAI with accelerometer counts in the training and validation sample ranged r = 0.40-0.43 and with physical activity energy expenditure (PAEE r = 0.33-0.40 and were higher than for the Cambridge Index and the Total PA Index previously applied in EPIC. In non-working participants the IPAI showed higher correlations than the Cambridge Index and the Total PA Index, with r = 0.34 for accelerometer counts and r = 0.29 for PAEE. In conclusion, we developed a valid physical activity index which is able to express PA continuously as well as to categorize participants according to their PA level. In populations with increasing rates of non-working people the performance of the IPAI is better than the established indices used in EPIC.

  14. Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth

    Institute of Scientific and Technical Information of China (English)

    Qi QI; Xia LIU; Shiyong LI; Harish C JOSHI; Keqiang YE

    2013-01-01

    Aim:Noscapine (NOS) is a non-narcotic opium alkaloid with anti-tumor activity.The aim of this study was to investigate the effects of the combination of NOS with conventional chemotherapeutics temozolamide (TMZ),bis-chloroethylnitrosourea (BCNU),or cisplatin (ClS)on human glioblastoma cells.Methods:U87MG human glioblastoma cells were examined.Cell proliferation was quantified using MTT assay.Western blotting and flow cytometry were used to examine apoptosis and the expression of active caspase-3 and cleaved PARP.Mouse tumor xenograft model bearing U87MG cells was treated with TMZ (2 mg·kg1~-1,ip) or ClS (2 mg/kg,ip 3 times a week) alone or in combination with NOS (200 mg·kg-l·d-1,ig) for 3 weeks.Immunohistochemistry was used to investigate the expression of active caspase-3 and Ki67 following treatment in vivo.The safety of the combined treatments was evaluated based on the body weight and histological studies of the animal's organs.Results:NOS (10 or 20 mol/L) markedly increased the anti-proliferation effects of TMZ,BCNU,and ClS on U87MG cells in vitro.The calculated combination index (Cl) values of NOS-ClS,NOS-TMZ,and NOS-BCNU (20 μmoVL) were 0.45,0.51,and 0.57,respectively,demonstrating synergistic inhibition of the drug combinations.In tumor xenograft models,combined treatment with NOS robustly augmented the anti-cancer actions of TMZ and ClS,and showed no detectable toxicity.The combined treatments significantly enhanced the apoptosis,the activated caspase-3 and PARP levels in U87MG cells in vitro,and reduced Ki67 staining and increased the activated caspase-3 level in the shrinking xenografts in vivo.Conclusion:NOS synergistically potentiated the efficacy of FDA-approved anti-cancer drugs against human glioblastoma cells,thereby allowing them to be used at lower doses and hence minimizing their toxic side effects.

  15. Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2.

    Directory of Open Access Journals (Sweden)

    Julie Dwyer

    Full Text Available Glioblastoma constitutes the most aggressive and deadly of brain tumors. As yet, both conventional and molecular-based therapies have met with limited success in treatment of this cancer. Among other explanations, the heterogeneity of glioblastoma and the associated microenvironment contribute to its development, as well as resistance and recurrence in response to treatments. Increased vascularity suggests that tumor angiogenesis plays an important role in glioblastoma progression. However, the molecular crosstalk between endothelial and glioblastoma cells requires further investigation. To examine the effects of glioblastoma-derived signals on endothelial homeostasis, glioblastoma cell secretions were collected and used to treat brain endothelial cells. Here, we present evidence that the glioblastoma secretome provides pro-angiogenic signals sufficient to disrupt VE-cadherin-mediated cell-cell junctions and promote endothelial permeability in brain microvascular endothelial cells. An unbiased angiogenesis-specific antibody array screen identified the chemokine, interleukin-8, which was further demonstrated to function as a key factor involved in glioblastoma-induced permeability, mediated through its receptor CXCR2 on brain endothelia. This underappreciated interface between glioblastoma cells and associated endothelium may inspire the development of novel therapeutic strategies to induce tumor regression by preventing vascular permeability and inhibiting angiogenesis.

  16. JNK contributes to temozolomide resistance of stem-like glioblastoma cells via regulation of MGMT expression.

    Science.gov (United States)

    Okada, Masashi; Sato, Atsushi; Shibuya, Keita; Watanabe, Eriko; Seino, Shizuka; Suzuki, Shuhei; Seino, Manabu; Narita, Yoshitaka; Shibui, Soichiro; Kayama, Takamasa; Kitanaka, Chifumi

    2014-02-01

    While elimination of the cancer stem cell population is increasingly recognized as a key to successful treatment of cancer, the high resistance of cancer stem cells to conventional chemoradiotherapy remains a therapeutic challenge. O6-methylguanine DNA methyltransferase (MGMT), which is frequently expressed in cancer stem cells of glioblastoma, has been implicated in their resistance to temozolomide, the first-line chemotherapeutic agent against newly diagnosed glioblastoma. However, much remains unknown about the molecular regulation that underlies MGMT expression and temozolomide resistance of glioblastoma cancer stem cells. Here, we identified JNK as a novel player in the control of MGMT expression and temozolomide resistance of glioblastoma cancer stem cells. We showed that inhibition of JNK, either pharmacologically or by RNA interference, in stem-like glioblastoma cells derived directly from glioblastoma tissues reduces their MGMT expression and temozolomide resistance. Importantly, sensitization of stem-like glioblastoma cells to temozolomide by JNK inhibition was dependent on MGMT expression, implying that JNK controls temozolomide resistance of stem-like glioblastoma cells through MGMT expression. Our findings suggest that concurrent use of JNK inhibitors with temozolomide may be a rational therapeutic approach to effectively target the cancer stem cell population in the treatment of glioblastoma.

  17. Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment

    NARCIS (Netherlands)

    Angevaren, Maaike; Aufdemkampe, Geert; Verhaar, H. J. J.; Aleman, A.; Vanhees, Luc

    2008-01-01

    Background Physical activity is beneficial for healthy ageing. It may also help maintain good cognitive function in older age. Aerobic activity improves cardiovascular fitness, but it is not known whether this sort of fitness is necessary for improved cognitive function. Studies in which activity, f

  18. Targeting the unfolded protein response in glioblastoma cells with the fusion protein EGF-SubA.

    Directory of Open Access Journals (Sweden)

    Antony Prabhu

    Full Text Available Rapidly growing tumors require efficient means to allow them to adapt to fluctuating microenvironments consisting of hypoxia, nutrient deprivation, and acidosis. The unfolded protein response (UPR represents a defense mechanism allowing cells to respond to these adverse conditions. The chaperone protein GRP78 serves as a master UPR regulator that is aberrantly expressed in a variety of cancers, including glioma. Therefore, cancer cells may be particularly reliant upon the adaptive mechanisms offered by the UPR and targeting GRP78 may represent a unique therapeutic strategy. Here we report that diffuse expression of GRP78 protein is present in Grade III-IV, but not Grade I-II glioma. To determine the role GRP78 plays in glioblastoma tumorigenesis, we explored the anti-tumor activity of the novel fusion protein EGF-SubA, which combines EGF with the cytotoxin SubA that has been recently shown to selectively cleave GRP78. EGF-SubA demonstrated potent tumor-specific proteolytic activity and cytotoxicity in glioblastoma lines and potentiated the anti-tumor activity of both temozolomide and ionizing radiation. To determine if the tumor microenvironment influences EGF-SubA activity, we maintained cells in acidic conditions that led to both UPR activation and increased EGF-SubA induced cytotoxicity. EGF-SubA was well tolerated in mice and led to a significant tumor growth delay in a glioma xenograft mouse model. The UPR is emerging as an important adaptive pathway contributing to glioma tumorigenesis. Targeting its primary mediator, the chaperone protein GRP78, through specific, proteolytic cleavage with the immunotoxin EGF-SubA represents a novel and promising multi-targeted approach to cancer therapy.

  19. FASB Proposes Improved Disclosures for Derivatives and Hedging Activities

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ The Financial Accounting Standards Board (FASB) today issued a proposal that would provide investors and others with better information about the effects of derivative and hedging activities on a company's financial statements.

  20. Performance improvement clarification for refrigeration system using active system monitoring

    DEFF Research Database (Denmark)

    Green, Torben; Niemann, Hans Henrik; Izadi-Zamanabadi, Roozbeh

    2011-01-01

    This paper addresses the problem of determining whether a refrigeration plant has the possibility of delivering a better performance of the operation. The controllers are wellknown but detailed knowledge about the underlying dynamics of the refrigeration plant is not available. Thus, the question...... is if it is possible to achieve a better performance by changing the controller parameter. An approach to active system monitoring, based on active fault diagnosis techniques, is employed in order to evaluate changes in the system performance under operation....

  1. Improvement of an electrical activation protocol for porcine oocytes.

    Science.gov (United States)

    Zhu, Jie; Telfer, Evelyn E; Fletcher, Judy; Springbett, Anthea; Dobrinsky, John R; De Sousa, Paul A; Wilmut, Ian

    2002-03-01

    Factors influencing pig oocyte activation by electrical stimulation were evaluated by their effect on the development of parthenogenetic embryos to the blastocyst stage to establish an effective activation protocol for pig nuclear transfer. This evaluation included 1) a comparison of the effect of epidermal growth factor and amino acids in maturation medium, 2) an investigation of interactions among oocyte age, applied voltage field strength, electrical pulse number, and pulse duration, and 3) a karyotype analysis of the parthenogenetic blastocysts yielded by an optimized protocol based on an in vitro system of oocyte maturation and embryo culture. In the first study, addition of amino acids in maturation medium was beneficial for the developmental competence of activated oocytes. In the second study, the developmental response of activated oocytes was dependent on interactions between oocyte age at activation and applied voltage field strength, voltage field strength and pulse number, and pulse number and duration. The formation of parthenogenetic blastocysts was optimal when activation was at 44 h of maturation using three 80-microsec consecutive pulses of 1.0 kV/cm DC. Approximately 84% of parthenogenetic blastocysts yielded by this protocol were diploid, implying a potential for further in vivo development.

  2. Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Carrasco-Garcia, Estefania; Saceda, Miguel [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad de Investigacion, Hospital General Universitario de Elche, 03203 Elche (Alicante) (Spain); Grasso, Silvina; Rocamora-Reverte, Lourdes; Conde, Mariano; Gomez-Martinez, Angeles [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Garcia-Morales, Pilar [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad de Investigacion, Hospital General Universitario de Elche, 03203 Elche (Alicante) (Spain); Ferragut, Jose A. [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Martinez-Lacaci, Isabel, E-mail: imlacaci@umh.es [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad AECC de Investigacion Traslacional en Cancer, Hospital Universitario Virgen de la Arrixaca, 30120 Murcia (Spain)

    2011-06-10

    Signaling through the epidermal growth factor receptor (EGFR) is relevant in glioblastoma. We have determined the effects of the EGFR inhibitor AG1478 in glioblastoma cell lines and found that U87 and LN-229 cells were very sensitive to this drug, since their proliferation diminished and underwent a marked G{sub 1} arrest. T98 cells were a little more refractory to growth inhibition and A172 cells did not undergo a G{sub 1} arrest. This G{sub 1} arrest was associated with up-regulation of p27{sup kip1}, whose protein turnover was stabilized. EGFR autophosphorylation was blocked with AG1478 to the same extent in all the cell lines. Other small-molecule EGFR tyrosine kinase inhibitors employed in the clinic, such as gefitinib, erlotinib and lapatinib, were able to abrogate proliferation of glioblastoma cell lines, which underwent a G{sub 1} arrest. However, the EGFR monoclonal antibody, cetuximab had no effect on cell proliferation and consistently, had no effect on cell cycle either. Similarly, cetuximab did not inhibit proliferation of U87 {Delta}EGFR cells or primary glioblastoma cell cultures, whereas small-molecule EGFR inhibitors did. Activity of downstream signaling molecules of EGFR such as Akt and especially ERK1/2 was interrupted with EGFR tyrosine kinase inhibitors, whereas cetuximab treatment could not sustain this blockade over time. Small-molecule EGFR inhibitors were able to prevent phosphorylation of erbB3 and erbB4, whereas cetuximab only hindered EGFR phosphorylation, suggesting that EGFR tyrosine kinase inhibitors may mediate their anti-proliferative effects through other erbB family members. We can conclude that small-molecule EGFR inhibitors may be a therapeutic approach for the treatment of glioblastoma patients.

  3. Genome-wide transcriptional profiling of human glioblastoma cells in response to ITE treatment.

    Science.gov (United States)

    Kang, Bo; Zhou, Yanwen; Zheng, Min; Wang, Ying-Jie

    2015-09-01

    A ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is recently revealed to play a key role in embryogenesis and tumorigenesis (Feng et al. [1], Safe et al. [2]) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) (Song et al. [3]) is an endogenous AhR ligand that possesses anti-tumor activity. In order to gain insights into how ITE acts via the AhR in embryogenesis and tumorigenesis, we analyzed the genome-wide transcriptional profiles of the following three groups of cells: the human glioblastoma U87 parental cells, U87 tumor sphere cells treated with vehicle (DMSO) and U87 tumor sphere cells treated with ITE. Here, we provide the details of the sample gathering strategy and show the quality controls and the analyses associated with our gene array data deposited into the Gene Expression Omnibus (GEO) under the accession code of GSE67986.

  4. Activation Cross Sections Improvements needed for IFE Power Reactors Designs

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez, A; Cabellos, O; Sanz, J; FalQuina, R; Latkowski, J; Reyes, S

    2003-10-02

    Uncertainties in the prediction of the neutron induced long-lived activity in the natural elements from H to Bi due to activation cross section uncertainties are estimated assuming as neutron environment those of the HYLIFE-II and Sombrero vessel structures. The latest available activation cross section data are employed. The random variables used in the uncertainty analysis have been the concentration limits (CL's) corresponding to hands-on recycling, remote recycling and shallow land burial, quantities typically considered in ranking elements under waste management considerations. The CL standard value (CL{sub nom}), i.e. without uncertainties, is compared with the 95th percentile CL value (CL95). The results of the analysis are very helpful in assessing the quality of the current activation data for IFE applications, providing a rational basis for programmatic priority assignments for new cross sections measurements or evaluations. The HYLIFE-II results shown that a significant error is estimated in predicting the activation of several elements. The estimated errors in the Sombrero case are much less important.

  5. Multicentric glioblastoma arising in two unusual sites: cerebellum and thalamus

    Directory of Open Access Journals (Sweden)

    Eduardo Cambruzzi

    2013-04-01

    Full Text Available Multicentric glioblastomas (MGBM arising in infra/supratentorial regions are uncommon lesions. The authors report a case of MGBM in a 61 year-old female patient, who presented a sudden onset of left hemiplegia. The magnetic resonance imaging (MRI showed two expansive large lesions affecting cerebellum and thalamus, with strong contrast enhancement. The patient underwent resection of the cerebellar lesion. Microscopy revealed a high grade glial neoplasm exhibiting high mitotic index, areas of necrosis and microvascular proliferation. The neoplastic cells showed positive immunoexpression for glial fibrillary acidic protein (GFAP. The morphological findings were consistent with glioblastoma (GBM. The patient was referred to radiotherapy, with discrete signs of tumor regression after a 60-day clinical follow-up.

  6. Isocitrate dehydrogenase status and molecular subclasses of glioma and glioblastoma.

    Science.gov (United States)

    Agnihotri, Sameer; Aldape, Kenneth D; Zadeh, Gelareh

    2014-12-01

    Diffuse gliomas and secondary glioblastomas (GBMs) that develop from low-grade gliomas are a common and incurable class of brain tumor. Mutations in the metabolic enzyme glioblastomas (IDH1) represent a distinguishing feature of low-grade gliomas and secondary GBMs. IDH1 mutations are one of the most common and earliest detectable genetic alterations in low-grade diffuse gliomas, and evidence supports this mutation as a driver of gliomagenesis. Here, the authors highlight the biological consequences of IDH1 mutations in gliomas, the clinical and therapeutic/diagnostic implications, and the molecular subtypes of these tumors. They also explore, in brief, the non-IDH1-mutated gliomas, including primary GBMs, and the molecular subtypes and drivers of these tumors. A fundamental understanding of the diversity of GBMs and lower-grade gliomas will ultimately allow for more effective treatments and predictors of survival.

  7. On the road to improved scheduling - fitting activities to capacity

    DEFF Research Database (Denmark)

    Lindhard, Søren Munch; Wandahl, Søren

    2012-01-01

    process proceeds in a pace which ensures that enough activities are made ready to the Weekly Work Plans. Experiences from case studies are included. It is observed that site-mangers tend to either include at risk activities or to adjust the manning in order to mach work with capacity. Several different......Last Planner System has through the sounding process increased the reliability of the schedule. The sound activities are moved to a buffer and afterwards selected to the Weekly Work Plans to match capacity. Therefore, in order to maximise productivity it is essential to ensure that the sounding...... solutions to the problem are suggested and discussed. It is proposed to simplify the production by decreasing the number of trades and tasks completed at site. This can be achieved by increasing...

  8. Improved Control Strategy for Active Bouncers used in Klystron Modulators

    CERN Document Server

    Aguglia, D; Benedetti, M; Garcia Retegui, R; Maestri, S; Nisbet, D

    2012-01-01

    This paper introduces a closed-loop control system for klystron modulators. The system is based on the discharge of a capacitor into a step-up voltage transformer and an active bouncer implemented with a multiphase buck converter. In order to obtain a constant Klystron voltage at the at-top, the active bouncer must compensate both the capacitor discharge and the pulse transformer characteristic. The proposed control includes an inner voltage regulation loop that controls the active bouncer output voltage and an outer one that controls the klystron voltage. The primary side current and main capacitor voltage are included in the regulation loops to simplify the controllers. Simulations demonstrate that the strategy adopted allows to obtain a precision better than 0:1% on a 110 kV klystron. Experimental tests have shown that the multiphase converter is able to track a high dynamics reference even under variable output voltage conditions.

  9. Combination of Endothelial-Monocyte-Activating Polypeptide-II with Temozolomide Suppress Malignant Biological Behaviors of Human Glioblastoma Stem Cells via miR-590-3p/MACC1 Inhibiting PI3K/AKT/mTOR Signal Pathway

    Science.gov (United States)

    Zhou, Wei; Liu, Libo; Xue, Yixue; Zheng, Jian; Liu, Xiaobai; Ma, Jun; Li, Zhen; Liu, Yunhui

    2017-01-01

    This study aims to investigate the effect of Endothelial-Monocyte-Activating Polypeptide-II (EMAP-II) combined with temozolomide (TMZ) upon glioblastoma stem cells (GSCs) and its possible molecular mechanisms. In this study, combination of EMAP-II with TMZ inhibited cell viability, migration and invasion in GSCs, and autophagy inhibitor 3-methyl adenine (3-MA) and chloroquine (CQ) partly reverse the anti-proliferative effect of the combination treatment. Autophagic vacuoles were formed in GSCs after the combination therapy, accompanied with the up-regulation of LC3-II and Beclin-1 as well as the down-regulation of p62/SQSTM1. Further, miR-590-3p was up-regulated and Metastasis-associated in colon cancer 1 (MACC1) was down-regulated by the combination treatment in GSCs; MiR-590-3p overexpression and MACC1 knockdown up-regulated LC3-II and Beclin-1 as well as down-regulated p62/SQSTM1 in GSCs; MACC1 was identified as a direct target of miR-590-3p, mediating the effects of miR-590-3p in the combination treatment. Furthermore, the combination treatment and MACC1 knockdown decreased p-PI3K, p-Akt, p-mTOR, p-S6 and p-4EBP in GSCs; PI3K/Akt agonist insulin-like growth factor-1(IGF-1) partly blocked the effect of the combination treatment. Moreover, in vivo xenograft models, the mice given stable overexpressed miR-590-3p cells and treated with EMAP-II and TMZ had the smallest tumor sizes, besides, miR-590-3p + EMAP-II + TMZ up-regulated the expression level of miR-590-3p, LC3-II and Beclin-1 as well as down-regulated p62/SQSTM1. In conclusion, these results elucidated anovel molecular mechanism of EMAP-II in combination with TMZ suppressed malignant biological behaviors of GSCs via miR-590-3p/MACC1 inhibiting PI3K/AKT/mTOR signaling pathway, and might provide potential therapeutic approaches for human GSCs.

  10. PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma.

    Science.gov (United States)

    Restall, Ian J; Parolin, Doris A E; Daneshmand, Manijeh; Hanson, Jennifer E L; Simard, Manon A; Fitzpatrick, Megan E; Kumar, Ritesh; Lavictoire, Sylvie J; Lorimer, Ian A J

    2015-01-01

    Cellular senescence is a tumor suppressor mechanism where cells enter a permanent growth arrest following cellular stress. Oncogene-induced senescence (OIS) is induced in non-malignant cells following the expression of an oncogene or inactivation of a tumor suppressor. Previously, we have shown that protein kinase C iota (PKCι) depletion induces cellular senescence in glioblastoma cells in the absence of a detectable DNA damage response. Here we demonstrate that senescent glioblastoma cells exhibit an aberrant centrosome morphology. This was observed in basal levels of senescence, in p21-induced senescence, and in PKCι depletion-induced senescence. In addition, senescent glioblastoma cells are polyploid, Ki-67 negative and arrest at the G1/S checkpoint, as determined by expression of cell cycle regulatory proteins. These markers are all consistent with cells that have undergone mitotic slippage. Failure of the spindle assembly checkpoint to function properly can lead to mitotic slippage, resulting in the premature exit of mitotic cells into the G1 phase of the cell cycle. Although in G1, these cells have the replicated DNA and centrosomal phenotype of a cell that has entered mitosis and failed to divide. Overall, we demonstrate that PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma cells. To our knowledge, this is the first evidence of markers of mitotic slippage directly in senescent cells by co-staining for senescence-associated β-galactosidase and immunofluorescence markers in the same cell population. We suggest that markers of mitotic slippage be assessed in future studies of senescence to determine the extent of mitotic slippage in the induction of cellular senescence.

  11. Brain Cancer Stem Cells: Current Status on Glioblastoma Multiforme

    OpenAIRE

    2011-01-01

    Glioblastoma multiforme (GBM), an aggressive brain tumor of astrocytic/neural stem cell origin, represents one of the most incurable cancers. GBM tumors are highly heterogeneous. However, most tumors contain a subpopulation of cells that display neural stem cell characteristics in vitro and that can generate a new brain tumor upon transplantation in mice. Hence, previously identified molecular pathways regulating neural stem cell biology were found to represent the cornerstone of GBM stem cel...

  12. BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors

    Directory of Open Access Journals (Sweden)

    Pinsker Marcus O

    2010-02-01

    Full Text Available Abstract Background The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU, one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare. Methods We performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m2 BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS, tumor burden, pretreatment with temozolomide (TMZ, type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model. Results The median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15, median overall survival 22 weeks (95% CI: 18-27. The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression. No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off. Conclusion In summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are

  13. Radiotherapy with and without temozolomide in elderly patients with glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Niyazi, M.; Schwarz, S.B.; Belka, C. [Ludwig-Maximilian-Univ. Munich, Muenchen (Germany). Dept. of Radiation Oncology; Suchorska, B. [Ludwig-Maximilian-Univ. Munich, Muenchen (Germany). Dept. of Neurosurgery

    2012-02-15

    The optimal treatment for elderly patients (age {>=} 70 years) with glioblastoma (GBM) remains controversial. We conducted a retrospective analysis in 43 consecutive elderly patients with glioblastoma who either underwent radiotherapy (RT) or radiotherapy plus concomitant temozolomide (TMZ). A total of 43 patients ({>=} 70 years of age, median age 75.8 years) with newly diagnosed glioblastoma and a Karnofsky performance status (KPS) {>=} 70 were treated with RT alone (median 60 Gy in 2 Gy single fractions) or RT plus TMZ at a dose of 75 mg/m{sup 2} per day. The two groups were well-balanced; univariate (log-rank test) and multivariate Cox proportional hazards analysis were used to identify relevant prognostic factors. The median overall survival (mOS) of the entire patient cohort was 264 days (8.8 months) and the median progression-free survival (PFS) was 192 days (6.4 months). The factors age, sex, previous surgery, KPS, and concomitant use of TMZ had no significant influence on OS/PFS; multivariate analysis was performed to obtain adjusted hazard ratios. TMZ use resulted in a trend toward poorer overall survival when applied concomitantly (314 days compared to 192 days within the TMZ group, p = 0.106). The subgroup analysis revealed that TMZ use resulted in significantly worse survival rates in patients with KPS70 (p = 0.027), but for patients with KPS80 this difference was not detectable. TMZ should only be used carefully in elderly patients with unfavorable KPS. In this patient cohort, radiotherapy alone is a reasonable option. Standard RT plus concomitant TMZ may be an advantageous treatment option for elderly patients with newly diagnosed glioblastoma who present with good prognostic factors. (orig.)

  14. Multicentric glioblastoma arising in two unusual sites : cerebellum and thalamus

    OpenAIRE

    Cambruzzi, Eduardo; Pêgas,Karla Lais; Simão,Mariana Fernandez; Stüker, Guilherme

    2013-01-01

    Multicentric glioblastomas (MGBM) arising in infra/supratentorial regions are uncommon lesions. The authors report a case of MGBM in a 61 year-old female patient, who presented a sudden onset of left hemiplegia. The magnetic resonance imaging (MRI) showed two expansive large lesions affecting cerebellum and thalamus, with strong contrast enhancement. The patient underwent resection of the cerebellar lesion. Microscopy revealed a high grade glial neoplasm exhibiting high mitotic index, areas o...

  15. Improving health through policies that promote active travel

    DEFF Research Database (Denmark)

    de Nazelle, Audrey; Nieuwenhuijsen, Mark J; Antó, Josep M;

    2011-01-01

    Substantial policy changes to control obesity, limit chronic disease, and reduce air pollution emissions, including greenhouse gasses, have been recommended. Transportation and planning policies that promote active travel by walking and cycling can contribute to these goals, potentially yielding...... further co-benefits. Little is known, however, about the interconnections among effects of policies considered, including potential unintended consequences....

  16. Mid-level Features Improve Recognition of Interactive Activities

    Science.gov (United States)

    2012-11-14

    Recognizing action as clouds of space-time interest points. In CVPR, 2009. [5] W. Brendel, A. Fern , and S. Todorovic. Probabilistic event logic for interval...context. In CVPR, 2009. [27] R. Messing, C. Pal, and H. Kautz. Activity recognition using the velocity histories of tracked keypoints. In ICCV, 2009

  17. Glioblastoma multiforme of the pineal region: case report

    Directory of Open Access Journals (Sweden)

    Gasparetto Emerson Leandro

    2003-01-01

    Full Text Available PURPOSE: pineal region tumors are uncommon, and comprise more frequently three categories: germ cell, parenchymal cell and glial tumors. Most pineal gliomas are low-grade astrocytomas. Glioblastoma multiforme, the most aggressive and common brain tumor, is extremely rare at this location with only few cases reported. CASE DESCRIPTION: a 29-year-old woman with a two month history of headache, nuchal pain, fever, nausea and seizures and physical examination showing nuchal rigidity, generalized hypotony, hypotrophy and hyper-reflexia, Babinski sign and left VI cranial par palsy. CT scan examination revealed a ill-defined hypodense lesion at the pineal region with heterogeneous contrast enhancement. MRI showed a lesion at the pineal region infiltrating the right thalamic region. The patient underwent a right craniotomy with partial resection of the mass. The histological examination of paraffin-embedded material defined the diagnosis of glioblastoma multiforme. Post-operative radiotherapy was indicated but the patient refused the treatment and died two months afterwards. CONCLUSION: in spite of its rarity at this location, glioblastoma multiforme should be considered in the differential diagnosis of aggressive lesions at the pineal region.

  18. Outcome in unresectable glioblastoma: MGMT promoter methylation makes the difference.

    Science.gov (United States)

    Thon, Niklas; Thorsteinsdottir, Jun; Eigenbrod, Sabina; Schüller, Ulrich; Lutz, Jürgen; Kreth, Simone; Belka, Claus; Tonn, Jörg-Christian; Niyazi, Maximilian; Kreth, Friedrich Wilhelm

    2017-02-01

    In 2011, we reported a predominant prognostic/predictive role of MGMT promoter methylation status on progression-free survival (PFS) in unresectable glioblastoma patients undergoing upfront radiotherapy plus concomitant and maintenance temozolomide (RTX/TMZ → TMZ). We, here, present the final results of this prospective study focussing on the prognostic/predictive value of MGMT promoter methylation status for death risk stratification. Overall, 56 adult patients with unresectable, biopsy proven glioblastoma were prospectively assigned to upfront RTX/TMZ → TMZ treatment between March 2006 and August 2008. Last follow-up was performed in June 2016. MGMT promoter methylation was determined using methylation-specific PCR (MSP) and sodium bisulfite sequencing. Analyses were done by intention to treat. Prognostic factors were obtained from proportional hazard models. At the time of the final analysis 55 patients showed progressive disease and 53 patients had died. MGMT promoter was methylated (unmethylated) in 30 (26) patients. Methylation of the MGMT promoter was the strongest favorable predictor for overall survival (OS, median: 20.3 vs. 7.3 months, p MGMT promoter methylation status is essential for patients' counseling, prognostic evaluation, and for the design of future trials dealing with unresectable glioblastomas.

  19. Arrested neural and advanced mesenchymal differentiation of glioblastoma cells-comparative study with neural progenitors

    Directory of Open Access Journals (Sweden)

    Biernat Wojciech

    2009-02-01

    Full Text Available Abstract Background Although features of variable differentiation in glioblastoma cell cultures have been reported, a comparative analysis of differentiation properties of normal neural GFAP positive progenitors, and those shown by glioblastoma cells, has not been performed. Methods Following methods were used to compare glioblastoma cells and GFAP+NNP (NHA: exposure to neural differentiation medium, exposure to adipogenic and osteogenic medium, western blot analysis, immunocytochemistry, single cell assay, BrdU incorporation assay. To characterize glioblastoma cells EGFR amplification analysis, LOH/MSI analysis, and P53 nucleotide sequence analysis were performed. Results In vitro differentiation of cancer cells derived from eight glioblastomas was compared with GFAP-positive normal neural progenitors (GFAP+NNP. Prior to exposure to differentiation medium, both types of cells showed similar multilineage phenotype (CD44+/MAP2+/GFAP+/Vimentin+/Beta III-tubulin+/Fibronectin+ and were positive for SOX-2 and Nestin. In contrast to GFAP+NNP, an efficient differentiation arrest was observed in all cell lines isolated from glioblastomas. Nevertheless, a subpopulation of cells isolated from four glioblastomas differentiated after serum-starvation with varying efficiency into derivatives indistinguishable from the neural derivatives of GFAP+NNP. Moreover, the cells derived from a majority of glioblastomas (7 out of 8, as well as GFAP+NNP, showed features of mesenchymal differentiation when exposed to medium with serum. Conclusion Our results showed that stable co-expression of multilineage markers by glioblastoma cells resulted from differentiation arrest. According to our data up to 95% of glioblastoma cells can present in vitro multilineage phenotype. The mesenchymal differentiation of glioblastoma cells is advanced and similar to mesenchymal differentiation of normal neural progenitors GFAP+NNP.

  20. Current challenges in glioblastoma: intratumour heterogeneity, residual disease and models to predict disease recurrence

    Directory of Open Access Journals (Sweden)

    Hayley Patricia Ellis

    2015-11-01

    Full Text Available Glioblastoma (GB is the most common malignant primary brain tumour, and despite the availability of chemotherapy and radiotherapy to combat the disease, overall survival remains low with a high incidence of tumour recurrence. Technological advances are continually improving our understanding of the disease and in particular our knowledge of clonal evolution, intratumour heterogeneity and possible reservoirs of residual disease. These may inform how we approach clinical treatment and recurrence in GB. Mathematical modelling (including neural networks, and strategies such as multiple-sampling during tumour resection and genetic analysis of circulating cancer cells, may be of great future benefit to help predict the nature of residual disease and resistance to standard and molecular therapies in GB.

  1. Pharmacokinetics and tolerance of nicotinamide combined with radiation therapy in patients with glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Cartei, F. [Cattedra di Radioterapia, Pisa Univ. (Italy); Danesi, R. [Scuola Superiore di Studi Universitari e di Perfezionamento S. Anna (Italy); Ducci, F. [Cattedra di Radioterapia, Pisa Univ. (Italy); Fatigante, L. [Cattedra di Radioterapia, Pisa Univ. (Italy); Caciagli, P.G. [Ist. di Neurochirurgia, Pisa Univ. (Italy); Del Tacca, M. [Ist. di Farmacologia, Pisa Univ. (Italy); Laddaga, M. [Cattedra di Radioterapia, Pisa Univ. (Italy)

    1994-12-31

    The pharmacokinetic properties of nicotinamide and its tolerance were studied in seven patients affected by glioblastoma multiforme and treated with two fractions per day of radiation therapy. Nicotinamide was given orally at two daily doses of 4 g and then 2 g separated by a 6-h-interval. The treatment was well tolerated in almost all patients and had no effect on blood pressure, cardiac rhythm or body temperature. Pharmacokinetic analysis showed peak plasma levels (C{sub max}) above 100 mg/l 45 minutes after the administration of both doses. This was followed by a biexponential decay of plasma concentrations with a thermal half life of 9.4 h. Tumours were irradiated 1 hour after each drug dose to match with drug C{sub max} in plasma, and although it is too early to evaluate the tumour response, the drug levels achieved should be sufficient to improve radiation therapy. (orig.).

  2. External beam re-irradiation, combination chemoradiotherapy, and particle therapy for the treatment of recurrent glioblastoma

    Science.gov (United States)

    Taunk, Neil K.; Moraes, Fabio Y.; Escorcia, Freddy E.; Mendez, Lucas Castro; Beal, Kathryn; Marta, Gustavo N.

    2016-01-01

    SUMMARY Glioblastoma is a common aggressive primary malignant brain tumor, and is nearly universal in progression and mortality after initial treatment. Re-irradiation presents a promising treatment option for progressive disease, both palliating symptoms and potentially extending survival. Highly conformal radiation techniques such as stereotactic radiosurgery and hypofractionated radiosurgery are effective short courses of treatment that allow delivery of high doses of therapeutic radiation with steep dose gradients to protect normal tissue. Patients with higher performance status, younger age, and longer interval between primary treatment and progression represent the best candidates for re-irradiation. Multiple studies are also underway involving combinations of radiation and systemic therapy to bend the survival curve and improve the therapeutic index. In the multimodal treatment of recurrent high-grade glioma, the use of surgery, radiation, and systemic therapy should be highly individualized. Here we comprehensively review radiation therapy and techniques, along with discussion of combination treatment and novel strategies. PMID:26781426

  3. Using an Improved Clustering Method to Detect Anomaly Activities

    Institute of Scientific and Technical Information of China (English)

    LI Han; ZHANG Nan; BAO Lihui

    2006-01-01

    In this paper, an improved k-means based clustering method (IKCM) is proposed. By refining the initial cluster centers and adjusting the number of clusters by splitting and merging procedures, it can avoid the algorithm resulting in the situation of locally optimal solution and reduce the number of clusters dependency. The IKCM has been implemented and tested. We perform experiments on KDD-99 data set. The comparison experiments with H-means+also have been conducted. The results obtained in this study are very encouraging.

  4. Muscular activity may improve in edentulous patients after implant treatment.

    Science.gov (United States)

    Afrashtehfar, Kelvin I; Schimmel, Martin

    2016-12-01

    Data sourcesMedline via Pubmed and the Cochrane Library were searched from January 1980 to September 2013. This was complemented by a manual search of the magazines Deutsche Zahnaerztliche Zeitung, Quintessenz, Zeitschrift für Zahnärztliche Implantologie, Schweizerische Monatszeitschrift and Implantologie. Additionally, the list of reference s of all selected full-text articles and related reviews were further scrutinised for potential included studies in English or German.Study selectionThree review authors independently searched for clinical trials that assessed the muscular activity in the intervention groups: edentulous patients treated with implant-overdentures (IODs) and implant-supported fixed dental prostheses (ISFDPs) and the comparison groups: dentates and edentulous patients treated with mucosa-borne complete removable dental prostheses (CRDPs).Data extraction and synthesisThe primary outcome was the muscular activity (measured by electromyography [EMG]) in masseter or temporalis muscle of the participants during clenching and chewing. The data extraction of each included study consisted of author, year, age range, treatment, number of participants, number of implants inserted, arch treated, opposite jaw, kind and side of the muscles that were measured. EMG gain or loss (unit measured: volt) was considered by using the effect size. For the meta-analyses only the studies that included masseter muscle measured separately from temporalis were considered. Concerning the side of measurement (right and left side measured together or right and left side measured separately), only the dominant type in each category was included.ResultsSixteen articles, out of the initial 646 retrieved abstracts, were analysed. The muscular activity of edentulous subjects increased after implant support therapy during clenching (effect size [ES]: 2.18 [95% confidence interval [CI]: 1.14, 3.23]) and during chewing (ES: 1.45 [95 % CI: 1.21, 1.69]). In addition, the pooled EMG

  5. Ontology-based improvement to human activity recognition

    Science.gov (United States)

    Tahmoush, David; Bonial, Claire

    2016-05-01

    Human activity recognition has often prioritized low-level features extracted from imagery or video over higher-level class attributes and ontologies because they have traditionally been more effective on small datasets. However, by including knowledge-driven associations between actions and attributes while recognizing the lower-level attributes with their temporal relationships, we can attempt a hybrid approach that is more easily extensible to much larger datasets. We demonstrate a combination of hard and soft features with a comparison factor that prioritizes one approach over the other with a relative weight. We then exhaustively search over the comparison factor to evaluate the performance of a hybrid human activity recognition approach in comparison to the base hard approach at 84% accuracy and the current state-of-the-art.

  6. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.

    NARCIS (Netherlands)

    Stupp, R.; Hegi, M.E.; Mason, W.P.; Bent, M.J. van den; Taphoorn, M.J.B.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; Hau, P.; Brandes, A.A.; Gijtenbeek, J.M.M.; Marosi, C.; Vecht, C.J.; Mokhtari, K.; Wesseling, P.; Villa, S.; Eisenhauer, E.; Gorlia, T.; Weller, M.; Lacombe, D.; Cairncross, J.G.; Mirimanoff, R.O.

    2009-01-01

    BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and ad

  7. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study : 5-year analysis of the EORTC-NCIC trial

    NARCIS (Netherlands)

    Stupp, Roger; Hegi, Monika E.; Mason, Warren P.; van den Bent, Martin J.; Taphoorn, Martin J. B.; Janzer, Robert C.; Ludwin, Samuel K.; Allgeier, Anouk; Fisher, Barbara; Belanger, Karl; Hau, Peter; Brandes, Alba A.; Gijtenbeek, Johanna; Marosi, Christine; Vecht, Charles J.; Mokhtari, Karima; Wesseling, Pieter; Villa, Salvador; Eisenhauer, Elizabeth; Gorlia, Thierry; Weller, Michael; Lacombe, Denis; Cairncross, J. Gregory; Mirimanoff, Rene-Olivier

    2009-01-01

    Background In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adj

  8. Improvement of photodynamic activity of aluminium sulphophthalocyanine due to biotinylation

    Science.gov (United States)

    Meerovich, Irina G.; Jerdeva, Victoria V.; Derkacheva, Valentina M.; Meerovich, Gennadii A.; Lukyanets, Eugeny A.; Kogan, Eugenia A.; Savitsky, Alexander P.

    2003-09-01

    The photodynamic activity of dibiotinylated aluminium sulphophthalocyanine in vitro and in vivo were studied. It was obtained that in vitro dibiotinylated aluminium sulphophthalocyanine provides the effective damage of small cell lung carcinoma OAT-75. In vivo dibiotinylated aluminium sulphophthalocyanine causes destruction of tumor (Erlich carcinoma), results in total necrosis of tumor tissue and expresses vascular damage (trombosis and destruction of vascular walls) even in concentration 0.25 mg/kg of a body weight.

  9. Pharmacological blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide

    Science.gov (United States)

    Golubovskaya, Vita M.; Huang, Grace; Ho, Baotran; Yemma, Michael; Morrison, Carl D.; Lee, Jisook; Eliceiri, Brian P.; Cance, William G.

    2012-01-01

    Malignant gliomas are characterized by aggressive tumor growth with a mean survival of 15–18 months and frequently developed resistance to temozolomide. Therefore, strategies that sensitize glioma cells to temozolomide have a high translational impact. We have studied focal adhesion kinase (FAK), a tyrosine kinase and emerging therapeutic target that is known to be highly expressed and activated in glioma. In this report we tested the FAK autophosphorylation inhibitor, Y15 in DBTRG and U87 glioblastoma cells. Y15 significantly decreased viability and clonogenicity in a dose-dependent manner, increased detachment in a dose and time-dependent manner, caused apoptosis and inhibited cell invasion in both cell lines. In addition, Y15 treatment decreased autophosphorylation of FAK in a dose-dependent manner and changed cell morphology by causing cell rounding in DBTRG and U87 cells. Administration of Y15 significantly decreased subcutaneous DBTRG tumor growth with decreased Y397-FAK autophosphorylation, activated caspase-3 and PARP. Y15 was administered in an orthotopic glioma model, leading to an increase in mouse survival. The combination of Y15 with temozolomide was more effective than either agent alone in decreasing viability and activating caspase-8 in DBTRG and U87 cells in vitro. In addition, the combination of Y15 and temozolomide synergistically blocked U87 brain tumor growth in vivo. Thus, pharmacologic blockade of FAK autophosphorylation with the oral administration of a small molecule inhibitor Y15 has a potential to be an effective therapy approach for glioblastoma either alone or in combination with chemotherapy agents such as temozolomide. PMID:23243059

  10. Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide.

    Science.gov (United States)

    Golubovskaya, Vita M; Huang, Grace; Ho, Baotran; Yemma, Michael; Morrison, Carl D; Lee, Jisook; Eliceiri, Brian P; Cance, William G

    2013-02-01

    Malignant gliomas are characterized by aggressive tumor growth with a mean survival of 15 to 18 months and frequently developed resistance to temozolomide. Therefore, strategies that sensitize glioma cells to temozolomide have a high translational impact. We have studied focal adhesion kinase (FAK), a tyrosine kinase and emerging therapeutic target that is known to be highly expressed and activated in glioma. In this report, we tested the FAK autophosphorylation inhibitor, Y15, in DBTRG and U87 glioblastoma cells. Y15 significantly decreased viability and clonogenicity in a dose-dependent manner, increased detachment in a dose- and time-dependent manner, caused apoptosis, and inhibited cell invasion in both cell lines. In addition, Y15 treatment decreased autophosphorylation of FAK in a dose-dependent manner and changed cell morphology by causing cell rounding in DBTRG and U87 cells. Administration of Y15 significantly decreased subcutaneous DBTRG tumor growth with decreased Y397-FAK autophosphorylation, activated caspase-3 and PARP. Y15 was administered in an orthotopic glioma model, leading to an increase in mouse survival. The combination of Y15 with temozolomide was more effective than either agent alone in decreasing viability and activating caspase-8 in DBTRG and U87 cells in vitro. In addition, the combination of Y15 and temozolomide synergistically blocked U87 brain tumor growth in vivo. Thus, pharmacologic blockade of FAK autophosphorylation with the oral administration of a small-molecule inhibitor Y15 has a potential to be an effective therapy approach for glioblastoma either alone or in combination with chemotherapy agents such as temozolomide.

  11. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

    Energy Technology Data Exchange (ETDEWEB)

    Parra, N. Andres [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Maudsley, Andrew A. [Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida (United States); Gupta, Rakesh K. [Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, Haryana (India); Ishkanian, Fazilat; Huang, Kris [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Walker, Gail R. [Biostatistics and Bioinformatics Core Resource, Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (United States); Padgett, Kyle [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida (United States); Roy, Bhaswati [Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, Haryana (India); Panoff, Joseph; Markoe, Arnold [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Stoyanova, Radka, E-mail: RStoyanova@med.miami.edu [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States)

    2014-10-01

    Purpose: Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials: Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV{sub 46} and CTV{sub 60}, respectively). MTV{sub Cho} and MTV{sub NAA} were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results: The MRSI coverage of the brain was between 70% and 76%. The MTV{sub NAA} were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTV{sub Cho} was outside of the edema (median, 33%) and for some patients it was also outside of the CTV{sub 46} and CTV{sub 60}. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTV{sub Cho} for these patients were outside of CTV{sub 60}. Conclusions: This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on

  12. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells.

    Science.gov (United States)

    Zhu, Thant S; Costello, Mark A; Talsma, Caroline E; Flack, Callie G; Crowley, Jessica G; Hamm, Lisa L; He, Xiaobing; Hervey-Jumper, Shawn L; Heth, Jason A; Muraszko, Karin M; DiMeco, Francesco; Vescovi, Angelo L; Fan, Xing

    2011-09-15

    One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.

  13. Information systems as a tool to improve legal metrology activities

    Science.gov (United States)

    Rodrigues Filho, B. A.; Soratto, A. N. R.; Gonçalves, R. F.

    2016-07-01

    This study explores the importance of information systems applied to legal metrology as a tool to improve the control of measuring instruments used in trade. The information system implanted in Brazil has also helped to understand and appraise the control of the measurements due to the behavior of the errors and deviations of instruments used in trade, allowing the allocation of resources wisely, leading to a more effective planning and control on the legal metrology field. A study case analyzing the fuel sector is carried out in order to show the conformity of fuel dispersers according to maximum permissible errors. The statistics of measurement errors of 167,310 fuel dispensers of gasoline, ethanol and diesel used in the field were analyzed demonstrating the accordance of the fuel market in Brazil to the legal requirements.

  14. Research activities to improve the utilization of antibiotics in Africa.

    Science.gov (United States)

    Massele, Amos; Tiroyakgosi, Celda; Matome, Matshediso; Desta, Abayneh; Muller, Arno; Paramadhas, Bene D Anand; Malone, Brighid; Kurusa, Gobuiwang; Didimalang, Thatayaone; Moyo, Mosana; Godman, Brian

    2017-02-01

    There is a need to improve the rational use of antibiotics across continents including Africa. This has resulted in initiatives in Botswana including treatment guidelines and the instigation of Antibiotic Stewardship Programs (ASPs). The next steps involve a greater understanding of current antibiotic utilization and resistance patterns (AMR). This resulted in a 2-day meeting involving key stakeholders principally from Botswana to discuss key issues including AMR rates as well as ASPs in both the public and private sectors. Following this, the findings will be used to plan future studies across Africa including point prevalence studies. The findings will be presented in July 2016 at the next Medicines Utilization Research in Africa meeting will ideally serve as a basis for planning future pertinent interventional studies to enhance the rational use of antibiotics in Botswana and wider.

  15. Improving Decision-Making Activities for Meningitis and Malaria

    Science.gov (United States)

    Ceccato, Pietro; Trzaska, Sylwia; Garcia-Pando, Carlos Perez; Kalashnikova, Olga; del Corral, John; Cousin, Remi; Blumenthal, M. Benno; Bell, Michael; Connor, Stephen J.; Thomson, Madeleine C.

    2013-01-01

    Public health professionals are increasingly concerned about the potential impact that climate variability and change can have on infectious disease. The International Research Institute for Climate and Society (IRI) is developing new products to increase the public health community's capacity to understand, use and demand the appropriate climate data and climate information to mitigate the public health impacts of climate on infectious disease, in particular meningitis and malaria. In this paper, we present the new and improved products that have been developed for: (i) estimating dust aerosol for forecasting risks of meningitis and (ii) for monitoring temperature and rainfall and integrating them into a vectorial capacity model for forecasting risks of malaria epidemics. We also present how the products have been integrated into a knowledge system (IRI Data Library Map Room, SERVIR) to support the use of climate and environmental information in climate-sensitive health decision-making.

  16. Improving Decision-Making Activities for Meningitis and Malaria

    Science.gov (United States)

    Ceccato, P.; Trzaska, S.; Perez, C.; Kalashnikova, O. V.; del Corral, J.; Cousin, R.; Blumenthal, M. B.; Connor, S.; Thomson, M. C.

    2012-12-01

    Public health professionals are increasingly concerned about the potential impact that climate variability and change can have on infectious disease. The International Research Institute for Climate and Society (IRI) is developing new products to increase the public health community's capacity to understand, use, and demand the appropriate climate data and climate information to mitigate the public health impacts of climate on infectious disease, in particular Meningitis and Malaria. In this paper we present the new and improved products that have been developed for monitoring dust, temperature, rainfall and vectorial capacity model for monitoring and forecasting risks of Meningitis and Malaria epidemics. We also present how the products have been integrated into a knowledge system (IRI Data Library Map room, SERVIR) to support the use of climate and environmental information in climate-sensitive health decision-making.

  17. A designer bleomycin with significantly improved DNA cleavage activity.

    Science.gov (United States)

    Huang, Sheng-Xiong; Feng, Zhiyang; Wang, Liyan; Galm, Ute; Wendt-Pienkowski, Evelyn; Yang, Dong; Tao, Meifeng; Coughlin, Jane M; Duan, Yanwen; Shen, Ben

    2012-08-15

    The bleomycins (BLMs) are used clinically in combination with a number of other agents for the treatment of several types of tumors, and the BLM, etoposide, and cisplatin treatment regimen cures 90-95% of metastatic testicular cancer patients. BLM-induced pneumonitis is the most feared, dose-limiting side effect of BLM in chemotherapy, which can progress into lung fibrosis and affect up to 46% of the total patient population. There have been continued efforts to develop new BLM analogues in the search for anticancer drugs with better clinical efficacy and lower lung toxicity. We have previously cloned and characterized the biosynthetic gene clusters for BLMs from Streptomyces verticillus ATCC15003, tallysomycins from Streptoalloteichus hindustanus E465-94 ATCC31158, and zorbamycin (ZBM) from Streptomyces flavoviridis SB9001. Comparative analysis of the three biosynthetic machineries provided the molecular basis for the formulation of hypotheses to engineer novel analogues. We now report engineered production of three new analogues, 6'-hydroxy-ZBM, BLM Z, and 6'-deoxy-BLM Z and the evaluation of their DNA cleavage activities as a measurement for their potential anticancer activity. Our findings unveiled: (i) the disaccharide moiety plays an important role in the DNA cleavage activity of BLMs and ZBMs, (ii) the ZBM disaccharide significantly enhances the potency of BLM, and (iii) 6'-deoxy-BLM Z represents the most potent BLM analogue known to date. The fact that 6'-deoxy-BLM Z can be produced in reasonable quantities by microbial fermentation should greatly facilitate follow-up mechanistic and preclinical studies to potentially advance this analogue into a clinical drug.

  18. Initiation and characterization of a glioblastoma multiforme derived cell line.

    Directory of Open Access Journals (Sweden)

    Carmen Lucía Roa

    2009-11-01

    Full Text Available Introducción: Las líneas celulares y los cultivos primarios son una excelente herramienta para el estudio de la biología, desarrollo y respuesta a la terapia en tumores cerebrales. Objetivo: Establecer y caracterizar una línea celular derivada de un glioblastoma multiforme como un modelo de estudio in vitro para la extrapolación y aplicación futura en terapia génica. Material y métodos: Se obtuvo una muestra de un paciente con diagnóstico clínico e histopatológico de glioblastoma multiforme, se caracterizó mediante inmunohistoquímica en cortes de tejido y por inmunocitoquímica sobre células cultivadas a partir del tumor desde el inicio del cultivo y durante los seis primeros pases, con dos tipos de marcadores específicos para glía: GFAP (glial fibrillary acidic protein y S-100 (proteína de unión a calcio. Además, se evaluó la expresión de p53 y Bcl-2, como moduladores de apoptosis. Por último se hizo la caracterización citogenética. Resultados: Histopatológicamente, se confirmó el diagnóstico de glioblastoma multiforme. En los cultivos primarios se encontraron características citomorfológicas propias de un glioblastoma: células fibroblastoides planas, células con escaso citoplasma con 3 ó más procesos y por último bipolares o unipolares. Se encontró una expresión diferencial con los cuatro marcadores, con un patrón de marcaciones a nivel citoplasmático y nuclear a través de los pases estudiados. La línea celular se caracterizó por ser en su mayoría aneuploide con un número modal cromosómico entre 43 y 45, con un gran número de poliploidías (55-102 , XXYY y endo-reduplicaciones (end 45, X, -Y. Conclusión: Se estableció una línea celular derivada de un glioblastoma multiforme con un fenotipo estable, con un notable mantenimiento del perfil glial y citogenético.

  19. Mining bipartite graphs to improve semantic pedophile activity detection

    OpenAIRE

    Fournier, Raphaël; Danisch, Maximilien

    2014-01-01

    International audience; Peer-to-peer (P2P) networks are popular to exchange large volumes of data through the Internet. Paedophile activity is a very important topic for our society and some works have recently attempted to gauge the extent of paedophile exchanges on P2P networks. A key issue is to obtain an efficient detection tool, which may decide if a sequence of keywords is related to the topic or not. We propose to use social network analysis in a large dataset from a P2P network to imp...

  20. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma

    Directory of Open Access Journals (Sweden)

    Lu Lizhi

    2006-12-01

    Full Text Available Abstract Background Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. Results In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol and etoposide (VP16 compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors. Conclusion Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in

  1. Glioblastomas with Oligodendroglial Component – Common Origin of the Different Histological Parts and Genetic Subclassification

    Directory of Open Access Journals (Sweden)

    Barbara Klink

    2010-01-01

    Full Text Available Background: Glioblastomas are the most common and most malignant brain tumors in adults. A small subgroup of glioblastomas contains areas with histological features of oligodendroglial differentiation (GBMO. Our objective was to genetically characterize the oligodendroglial and the astrocytic parts of GBMOs and correlate morphologic and genetic features with clinical data.

  2. miR-577 inhibits glioblastoma tumor growth via the Wnt signaling pathway.

    Science.gov (United States)

    Zhang, Weiguang; Shen, Chen; Li, Chenguang; Yang, Guang; Liu, Huailei; Chen, Xin; Zhu, Dan; Zou, Huichao; Zhen, Yunbo; Zhang, Daming; Zhao, Shiguang

    2016-05-01

    microRNAs (miRNAs) are commonly altered in glioblastoma. Publicly available algorithms suggest the Wnt pathway is a potential target of miR-577 and the Wnt pathway is commonly altered in glioblastoma. Glioblastoma has not been previously evaluated for miR-577 expression. Glioblastoma tumors and cell lines were evaluated for their expression of miR-577. Cell lines were transfected with miR-577, miR-577-mutant, or control mimics to evaluate the effect of miR-577 expression on cell proliferation in vitro and in an animal model. Wnt pathway markers were also evaluated for their association with miR-577 expression. miR-577 expression was decreased in 33 of 40 (82.5%) glioblastoma tumors and 5 of 6 glioblastoma cell lines. miR-577 expression correlated negatively with cell growth and cell viability. miR-577 down-regulation was associated with increased expression of the Wnt signaling pathway genes lipoprotein receptor-related protein (LRP) 6 (LRP6) and β-catenin. Western blot analysis confirmed decreased expression of the Wnt signaling pathway genes Axin2, c-myc, and cyclin D1 in miR-577 transfected cells. miR-577 expression is down-regulated in glioblastoma. miR-577 directly targets Wnt signaling pathway components LRP6 and β-catenin. miR-577 suppresses glioblastoma multiforme (GBM) growth by regulating the Wnt signaling pathway.

  3. DIETARY ISOTHIOCYANATE IBERIN INHIBITS GROWTH AND INDUCES APOPTOSIS IN HUMAN GLIOBLASTOMA CELLS

    Science.gov (United States)

    In this study, we evaluated the antiproliferative and proapoptotic effects of the isothiocyanate iberin, a bioactive agent in Brassicaceae species, in human glioblastoma cells. The human glioblastoma cell cultures were treated with different concentrations of iberin and tested for growth inhibition...

  4. Presentation of Two Cases with Early Extracranial Metastases from Glioblastoma and Review of the Literature

    DEFF Research Database (Denmark)

    Johansen, Maria Dinche; Rochat, Per; Law, Ian;

    2016-01-01

    Extracranial metastases from glioblastoma are rare. We report two patients with extracranial metastases from glioblastoma. Case 1 concerns a 59-year-old woman with multiple metastases that spread early in the course of disease. What makes this case unusual is that the tumor had grown into the falx...

  5. Necrosis de médula espinal, edema cerebral y glioblastoma

    OpenAIRE

    Iglesias Rozas, José Rafael, 1942-

    1987-01-01

    Cinco imágenes de una necrosis de la médula espinal, un edema cerebral y un glioblastoma en una paciente de 76 años. Five pictures of a spinal cord necrosis, a cerebral edema and a glioblastoma in a 76-year-old female patient.

  6. The Effect of Z-Ligustilide on the Mobility of Human Glioblastoma T98G Cells.

    Directory of Open Access Journals (Sweden)

    Jun Yin

    Full Text Available Z-ligustilide (LIG, an essential oil extract from Radix Angelica sinensis, has broad pharmaceutical applications in treating cardio-vascular diseases and ischemic brain injury. Recently, LIG has been connected to Glioblastoma multiforme (GBM because of its structural similarity to 3-n-alkyphthalide (NBP, which is specifically cytotoxic to GBM cells. Hence, we investigated LIG's effect on GBM T98G cells. The study shows that LIG can significantly reduce T98G cells' migration in a dose-dependent manner. Furthermore, the attenuation of cellular mobility can be linked to the activity of the Rho GTPases (RhoA, Rac1 and Cdc42, the three critical molecular switches governing cytoskeleton remodeling; thus, regulating cell migration. LIG significantly reduces the expression of RhoA and affects in a milder manner the expression of Cdc42 and Rac1.

  7. 45 CFR 98.51 - Activities to improve the quality of child care.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Activities to improve the quality of child care... the quality of child care. (a) No less than four percent of the aggregate funds expended by the Lead...) Activities to improve the quality of child care services may include, but are not limited to: (i)...

  8. Interacting Patients: The construction of active patientship in quality improvement initiatives

    NARCIS (Netherlands)

    F.D. Vennik (Femke)

    2016-01-01

    markdownabstractThe promotion of active patient participation in healthcare quality improvement projects is an important policy goal in the Netherlands and other Western countries. Healthcare quality improvement is no longer perceived to be an exclusive professional activity; patients, who may be ab

  9. Using NLP meta, Milton, metaphor models, for improving the activity of the organization

    Directory of Open Access Journals (Sweden)

    Cornel Marian IOSIF

    2010-12-01

    Full Text Available The objective of this paper is the improving of the three methods from the neuro- linguistic programming – metaphor, Milton model and the meta-model, so by using this in daily activities by an organization to improve the activities witch, are performed and to have a more efficient allocation of the available resources.

  10. GROWTH OF MANAGERIAL PERFORMANCE BY IMPROVING AUDITING ACTIVITY

    Directory of Open Access Journals (Sweden)

    Daniel DĂNECI-PĂTRĂU

    2014-04-01

    Full Text Available To reflect the place and role of internal audit in the economic entity and its function as assistant manager in this paper we followed the presentation of the preliminary assumptions of a model for measuring the quality of internal audit. Also, we presented a possible model of research regarding managerial effectiveness. Questions that sought answer in this research are: How can we streamline internal audit? What is meant by effective internal audit? What is the relationship between internal audit efficiency and performance management? Recording a high level of performance of internal audit provide a high level of performance of the whole economic entity. Of course, responsible for the implementation of recommendations made by the Internal Auditor is the manager, but in our opinion, as long as the internal audit department conducts activities / tasks with maximum seriousness, conscientiousness and professionalism, the manager will be to some extent forced to implement the recommendations, having a high confidence in those.

  11. Does inhibition of proteolytic activity improve adhesive luting?

    Science.gov (United States)

    Lührs, Anne-Katrin; De Munck, Jan; Geurtsen, Werner; Van Meerbeek, Bart

    2013-04-01

    Endogenous enzymes may be involved in the biodegradation of adhesive restoration-tooth interfaces. Inhibitors of matrix metalloproteinases (MMPs) have been suggested to retard the bond-degradation process. Limited data are available on whether composite cements may also benefit from MMP inhibitors. Therefore, the aim of this study was to determine the effect of two MMP inhibitors--chlorhexidine digluconate (CHX) and galardin--on the microtensile bond strength (μTBS) of two self-adhesive composite cements to dentin. Ceramic specimens were cemented to bur-cut dentin surfaces using the self-adhesive composite cements RelyX Unicem 2 (3M ESPE) or Clearfil SA (Kuraray), or the etch-and-rinse composite cement Nexus 3 (Kerr) that served as the control. The surfaces were left untreated or were pretreated with MMP inhibitors (2% CHX or 0.2 mM galardin). The μTBS was determined 'immediately' and upon ageing (water storage for 6 months). Statistical analysis revealed a significant effect of the factors 'composite cement' and 'storage', as well as all interactions, but no effect of the MMP inhibitors. After 6 months of ageing, the μTBS decreased for all cements, except for the multistep etch-and-rinse luting composite when it was applied without MMP inhibitors. The MMP inhibitors could not prevent the decrease in μTBS upon ageing and therefore do not improve the luting durability of the composite cements tested.

  12. TENDENCY OF IMPROVEMENT ANALYSIS OF VENTURE ACTIVITY FOR MANAGEMENT DECISIONS

    Directory of Open Access Journals (Sweden)

    G.Yu. Iakovetс

    2015-03-01

    Full Text Available The questions concerning the definition of current trends and prospects of venture financing new innovative enterprises as one of the most effective and alternative, but with a high degree of risk financing sources of the entity. The features of venture financing that is different from other sources of business financing, as well as income from investments of venture capital can greatly exceed the volume of investments, but at the same time such financing risks are significant, so it all makes it necessary to build an effective system of venture capital investments in the workplace. In the course of the study also revealed problems of analysis and minimization of risks in the performance of venture financing of innovative enterprises. Defining characteristics analysis and risk assessment of venture financing helps to find ways to minimize and systematization, avoidance and prevention of risks in the performance of venture capital. The study also identified the major areas of improvement analysis of venture capital for management decisions.

  13. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy†

    Science.gov (United States)

    Raizer, Jeffrey J.; Abrey, Lauren E.; Lassman, Andrew B.; Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Yung, W.K. Alfred; Gilbert, Mark R.; Aldape, Kenneth A.; Wen, Patrick Y.; Fine, Howard A.; Mehta, Minesh; DeAngelis, Lisa M.; Lieberman, Frank; Cloughesy, Timothy F.; Robins, H. Ian; Dancey, Janet; Prados, Michael D.

    2010-01-01

    Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was not allowed. Patients received 150 mg/day erlotinib. Patients requiring surgery were treated 7 days prior to tumor removal for PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) and intracellular signaling pathways. Ninety-six patients were evaluable (53 recurrent MG and 43 NP GBM); 5 patients were not evaluable for response. PFS-6 in recurrent GBM was 3% with a median PFS of 2 months; PFS-6 in recurrent AG was 27% with a median PFS of 2 months. Twelve-month survival was 57% in NP GBMs post-RT. Primary toxicity was dermatologic. The tissue-to-plasma ratio normalized to nanograms per gram dry weight for erlotinib and OSI-420 ranged from 25% to 44% and 30% to 59%, respectively, for pretreated surgical patients. No effect on EGFR or intratumoral signaling was seen. Patients with NP GBM post-RT who developed rash in cycle 1 had improved survival (P < .001). Single-agent activity of erlotinib is minimal for recurrent MGs and marginally beneficial following RT for NP GBM patients. Development of rash in cycle 1 correlates with survival in patients with NP GBM after RT. PMID:20150372

  14. Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice

    Science.gov (United States)

    Ferrer-Font, Laura; Villamañan, Lucia; Arias-Ramos, Nuria; Vilardell, Jordi; Plana, Maria; Ruzzene, Maria; Pinna, Lorenzo A.; Itarte, Emilio; Arús, Carles; Candiota, Ana Paula

    2017-01-01

    Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response. PMID:28208677

  15. Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice

    Directory of Open Access Journals (Sweden)

    Laura Ferrer-Font

    2017-02-01

    Full Text Available Glioblastoma (GBM causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2 contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129 phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05 was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6 when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6 and controls (22.5 ± 1.2, n = 6. Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response.

  16. Infratentorial congenital glioblastoma multiforme. A rare tumour with a still unknown biology.

    Science.gov (United States)

    Salas, S; Agut, T; Rovira, C; Canizo, D; Lavarino, C; Garcia-Alix, A

    2016-11-01

    Introduccion. El glioblastoma multiforme congenito representa solo el 3% de los tumores congenitos del sistema nervioso central, y su ubicacion infrantentorial es excepcional. Caso clinico. Recien nacido con un glioblastoma multiforme congenito sin mutacion en el gen TP53 ni inmunorreactividad nuclear p53, que infiltraba practicamente todo el tronco cerebral e invadia tambien estructuras supratentoriales. Conclusiones. Hasta donde sabemos, solo se han referido previamente cuatro casos de localizacion infratentorial, tres en el cerebelo y uno en el tronco del encefalo. La biologia del glioblastoma multiforme congenito no se conoce bien y, a diferencia del glioblastoma multiforme en la edad adulta, las mutaciones en el gen TP53 son poco frecuentes, sin que eso parezca implicar un mejor pronostico. Estas observaciones sugieren que el glioblastoma multiforme con origen en la vida fetal tiene una biologia diferente del que se presenta en otras etapas de la vida.

  17. Low expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in glioblastoma predicts longer patient survival

    DEFF Research Database (Denmark)

    Aaberg-Jessen, Charlotte; Christensen, Karina; Offenberg, Hanne Kjær;

    2009-01-01

    immunoreactivity of both tumour cells and blood vessels. Moreover, TIMP-1 in situ hybridisation was performed on ten of the glioblastomas. In the vast majority of the tumours TIMP-1 protein was expressed in both tumour cells and blood vessels. In situ hybridisation for TIMP-1 mRNA on glioblastomas confirmed...... the immunohistochemical expression of TIMP-1. The percentage of TIMP-1 positive tumour cells and blood vessels as well as the staining intensity varied between tumours of the same grade, but the total staining score increased with tumour grade. The multivariate Cox regression test showed that glioblastoma patients...... in glioblastoma patients, suggesting a role for TIMP-1 as a biomarker in glioblastoma....

  18. An Internet-Based Physical Activity Intervention to Improve Quality of Life of Inactive Older Adults

    DEFF Research Database (Denmark)

    Broekhuizen, Karen; de Gelder, Jelle; Wijsman, Carolien A

    2016-01-01

    BACKGROUND: Increasing physical activity is a viable strategy for improving both the health and quality of life of older adults. OBJECTIVE: The aim of this study was to assess if an Internet-based intervention aimed to increase physical activity was effective in improving quality of life of inact......-based physical activity program was effective in improving quality of life in 60-70-year-olds after 3 months, particularly in participants that reached their individually targeted increase in daily physical activity. TRIAL REGISTRATION: Nederlands Trial Register: NTR 3045; http...

  19. Improved installation prototype for measurement of low argon-37 activity

    Science.gov (United States)

    Pakhomov, Sergei; Dubasov, Yuri

    2015-04-01

    On-site Inspection (OSI) is a key element of verification of State Parties' compliance with the Comprehensive Nuclear-Test-Ban Treaty (CTBT). An on-site inspection is launched to establish whether or not a nuclear explosion has been carried out. One of the most significant evidence of n underground nuclear explosion (UNE) is detection above background concentrations of argon-37 in near surface air. Argon-37 is formed in large amounts at interaction of neutrons of UNE with the potassium which is a part of the majority of rocks. Its estimated contents for the 100th days after explosion with a energy of 1000 t of TNT near a surface can vary from 1 to 1000 mBq/m3. The background concentrations of argon-37 in subsoil air vary 1 do100 mBq/m3. Traditionally, for argon-37 activity measurement the gas-proportional counters are used. But at Khlopin Radium institute the developments of the new type of highly sensitive and low-background installation capable to provide the required range of measurements of the argon-37 concentration are conducted. The liquid scintillation method of the registration of the low-energetic argon-37 electrons is the basic installation principle and as scintillator, the itself condensed air argon sample is used. Registration of scintillations of liquid argon is made by means of system from 3 PMT which cathodes are cooled near to the temperature of liquid nitrogen together with the measuring chamber in which placed the quartz glass ampule, containing the measured sample of the liquefied argon. For converse the short wavelength photons (λ = 127 nm) of liquid argon scintillations to more long-wave, corresponding to the range of PMT sensitivity, the polymer film with tetra-phenyl-butadiene (TPB) is provided. Even the insignificant impurities of nitrogen, oxygen and others gaseous in the liquid argon samples can to cause the quenching of scintillation, especially their slow components. To account this effect and it influence on change of registration

  20. MGMT-INDEPENDENT TEMOZOLOMIDE RESISTANCE IN PAEDIATRIC GLIOBLASTOMA CELLS ASSOCIATED WITH A PI3-KINASE-MEDIATED HOX / STEM CELL GENE SIGNATURE

    OpenAIRE

    Gaspar, Nathalie; Marshall, Lynley; Perryman, Lara; Bax, Dorine A; Little, Suzanne E.; Viana-Pereira, Marta; Swee Y Sharp; Vassal, Gilles; Pearson, Andrew D. J.; Rui M. Reis; Hargrave, Darren; Workman, Paul; Jones, Chris

    2010-01-01

    Sensitivity to temozolomide (TMZ) is restricted to a subset of glioblastoma patients, with the major determinant of resistance being a lack of promoter methylation of the gene encoding the repair protein DNA methyltransferase MGMT, although other mechanisms are thought to be active. There are, however, limited preclinical data in model systems derived from paediatric glioma patients. We have screened a series of cell lines for TMZ efficacy in vitro, and have investigated the differential mech...

  1. Mesoporous Metal-Containing Carbon Nitrides for Improved Photocatalytic Activities

    Directory of Open Access Journals (Sweden)

    Jie Luo

    2013-01-01

    Full Text Available Graphitic carbon nitrides (g-C3N4 have attracted increasing interest due to their unusual properties and promising applications in water splitting, heterogeneous catalysis, and organic contaminant degradation. In this study, a new method was developed for the synthesis of mesoporous Fe contained g-C3N4 (m-Fe-C3N4 photocatalyst by using SiO2 nanoparticles as hard template and dicyandiamide as precursor. The physicochemical properties of m-Fe-C3N4 were thoroughly investigated. The XRD and XPS results indicated that Fe was strongly coordinated with the g-C3N4 matrix and that the doping and mesoporous structure partially deteriorated its crystalline structure. The UV-visible absorption spectra revealed that m-Fe-C3N4 with a unique electronic structure displays an increased band gap in combination with a slightly reduced absorbance, implying that mesoporous structure modified the electronic properties of g-Fe-C3N4. The photocatalytic activity of m-Fe-C3N4 for photodegradation of Rhodamine B (RhB was much higher than that of g-Fe-C3N4, clearly demonstrating porous structure positive effect.

  2. Activities of CEZ Inc. and improvement of the environment

    Energy Technology Data Exchange (ETDEWEB)

    Kindl, I.V. [Czech Power Co. (CEZ), Prague (Czechoslovakia)

    1995-12-01

    All highly developed nations round the world have gradually assumed the responsibility for the quality of the environment at their respective territories by creating the preconditions (by setting forth concepts, and the legislative, economic and institutional framework as well as the educational information and resources systems) stimulating both individuals and corporate bodies to take care of the environment. Damaging the environment is punished. The approach has been successful in most of the countries. Companies and individuals have begun to recognize the correlations existing between their production and consumption activities and the environment and their direct responsibility for the environmental conditions, realizing that to remove a source of environmental damage or to minimis the damage caused by it in both necessary and more beneficial than being penalized (up to ban of operation) both economically and in broader social terms for failing to comply with the relevant laws. Since 1990 a number of the so-called {open_quotes}ecological{close_quotes} laws, formerly sorely lacking, have been enacted, such as the Environment Act, the Environmental Effects Assessment Act, and the Wastes Act, and the Clean Air Act has been fundamentally amended so that to meet again the requirements of effective protection of the atmosphere from pollutants. In the area of economic tools, the duty of the waste producer to pay for the waste produced was introduced, the fines for air pollution were raised significantly and the polluted waste water discharge fines were amended to keep pace with the devaluation of the local currency.

  3. Improved Chemical Structure-Activity Modeling Through Data Augmentation.

    Science.gov (United States)

    Cortes-Ciriano, Isidro; Bender, Andreas

    2015-12-28

    Extending the original training data with simulated unobserved data points has proven powerful to increase both the generalization ability of predictive models and their robustness against changes in the structure of data (e.g., systematic drifts in the response variable) in diverse areas such as the analysis of spectroscopic data or the detection of conserved domains in protein sequences. In this contribution, we explore the effect of data augmentation in the predictive power of QSAR models, quantified by the RMSE values on the test set. We collected 8 diverse data sets from the literature and ChEMBL version 19 reporting compound activity as pIC50 values. The original training data were replicated (i.e., augmented) N times (N ∈ 0, 1, 2, 4, 6, 8, 10), and these replications were perturbed with Gaussian noise (μ = 0, σ = σnoise) on either (i) the pIC50 values, (ii) the compound descriptors, (iii) both the compound descriptors and the pIC50 values, or (iv) none of them. The effect of data augmentation was evaluated across three different algorithms (RF, GBM, and SVM radial) and two descriptor types (Morgan fingerprints and physicochemical-property-based descriptors). The influence of all factor levels was analyzed with a balanced fixed-effect full-factorial experiment. Overall, data augmentation constantly led to increased predictive power on the test set by 10-15%. Injecting noise on (i) compound descriptors or on (ii) both compound descriptors and pIC50 values led to the highest drop of RMSEtest values (from 0.67-0.72 to 0.60-0.63 pIC50 units). The maximum increase in predictive power provided by data augmentation is reached when the training data is replicated one time. Therefore, extending the original training data with one perturbed repetition thereof represents a reasonable trade-off between the increased performance of the models and the computational cost of data augmentation, namely increase of (i) model complexity due to the need for optimizing

  4. The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals

    Science.gov (United States)

    Wang, Yahua; Ying, Xue; Xu, Haolun; Yan, Helu; Li, Xia; Tang, Hui

    2017-01-01

    Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood–brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposomes in order to improve the drug delivery system onto the glioma cells and induce the apoptosis of glioma stem cells afterward. In this experiment, curcumin was chosen to kill gliomas, while quinacrine was used to induce apoptosis of the glioma stem cells. Also, p-aminophenyl-α-D-mannopyranoside could facilitate the transport of liposomes across the blood–brain barrier and finally target the brain glioma cells. The cell experiments in vitro indicated that the targeted liposomes could significantly improve the anti-tumor effects of the drugs, while enhancing the uptake effects, apoptosis effects, and endocytic effects of C6 glioma cells and C6 glioma stem cells. Given the animal experiments in vivo, we discovered that the targeted liposomes could obviously increase the survival period of brain glioma-bearing mice and inhibit the growth of gliomas. In summary, curcumin and quinacrine liposomes modified with p-aminophenyl-α-D-mannopyranoside is a potential preparation to treat brain glioma cells and brain glioma stem cells. PMID:28260885

  5. Correlation of microvascular fractal dimension with positron emission tomography [(11)C]-methionine uptake in glioblastoma multiforme: preliminary findings.

    Science.gov (United States)

    Di Ieva, Antonio; Grizzi, Fabio; Tschabitscher, Manfred; Colombo, Piergiuseppe; Casali, Massimiliano; Simonelli, Matteo; Widhalm, Georg; Muzzio, Pier Carlo; Matula, Christian; Chiti, Arturo; Rodriguez y Baena, Riccardo

    2010-09-01

    Neuroradiological and metabolic imaging is a fundamental diagnostic procedure in the assessment of patients with primary and metastatic brain tumors. The correlation between objective parameters capable of quantifying the neoplastic angioarchitecture and imaging data may improve our understanding of the underlying physiopathology and make it possible to evaluate treatment efficacy in brain tumors. Only a few studies have so far correlated the quantitative parameters measuring the neovascularity of brain tumors with the metabolic profiles measured by means of amino acid uptake in positron emission tomography (PET) scans. Fractal geometry offers new mathematical tools for the description and quantification of complex anatomical systems, including microvascularity. In this study, we evaluated the microvascular network complexity of six cases of human glioblastoma multiforme quantifying the surface fractal dimension on CD34 immunostained specimens. The microvascular fractal dimension was estimated by applying the box-counting algorithm. As the fractal dimension depends on the density, size and shape of the vessels, and their distribution pattern, we defined it as an index of the whole complexity of microvascular architecture and compared it with the uptake of (11)C-methionine (MET) assessed by PET. The different fractal dimension values observed showed that the same histological category of brain tumor had different microvascular network architectures. Fractal dimension ranged between 1.19 and 1.77 (mean: 1.415+/-0.225), and the uptake of (11)C-methionine ranged between 1.30 and 5.30. A statistically significant direct correlation between the microvascular fractal dimension and the uptake of (11)C-methionine (p=0.02) was found. Our preliminary findings indicate that that vascularity (estimated on the histologic specimens by means of the fractal dimension) and (11)C-methionine uptake (assessed by PET) closely correlate in glioblastoma multiforme and that microvascular

  6. Improved activity and thermostability of Bacillus pumilus lipase by directed evolution

    NARCIS (Netherlands)

    Akbulut, Nagihan; Ozturk, Merve Tuzlakoglu; Pijning, Tjaard; Ozturk, Saliha Issever; Gumusel, Fusun

    2013-01-01

    To improve enzymatic activity of Bacillus pumilus lipases, DNA shuffling was applied to two lipase genes from local B. pumilus isolates. Using a high-throughput activity assay, the mutant with highest activity was selected. This chimeric mutant (L3-3), carrying two crossover positions and three poin

  7. Physical Activity: A Tool for Improving Health (Part 3--Recommended Amounts of Physical Activity for Optimal Health)

    Science.gov (United States)

    Gallaway, Patrick J.; Hongu, Nobuko

    2016-01-01

    By promoting physical activities and incorporating them into their community-based programs, Extension professionals are improving the health of individuals, particularly those with limited resources. This article is the third in a three-part series describing the benefits of physical activity for human health: (1) biological health benefits of…

  8. How do Australian Small and Medium Enterprises Communicate their Environmental Improvement Activities Online?

    Directory of Open Access Journals (Sweden)

    Craig Parker

    2011-03-01

    Full Text Available There have been calls in the IS/eBusiness literature for research on "green" IS/IT in a Small and Medium Enterprises (SMEs context. The Corporate Social Responsibility (CSR literature has neglected the issue of how SMEs can use websites to communicate their environmental improvement activities. This paper links these two previously separate disciplines by reporting on a content analysis of 443 Australian SME websites from four industry sectors to identify if and how they use websites to communicate their environmental improvement activities. The study found that 47 websites were communicating such activities in some form. A detailed analysis was undertaken of these 47 websites to identify emergent themes relating to how these SMEs were communicating their environmental improvement activities. These themes resulted in a reconceptualisation of the traditional "4 Ps" of marketing for online communication of environmental improvement activities by SMEs: profile; product; process and prominence.

  9. Canadian recommendations for the treatment of glioblastoma multiforme.

    Science.gov (United States)

    Mason, W P; Maestro, R Del; Eisenstat, D; Forsyth, P; Fulton, D; Laperrière, N; Macdonald, D; Perry, J; Thiessen, B

    2007-06-01

    RECOMMENDATION 1: Management of patients with glioblastoma multiforme (GBM) should be highly individualized and should take a multidisciplinary approach involving neuro-oncology, neurosurgery, radiation oncology, and pathology, to optimize treatment outcomes. Patients and caregivers should be kept informed of the progress of treatment at every stage. RECOMMENDATION 2: Sufficient tissue should be obtained during surgery for cytogenetic analysis and, whenever feasible, for tumour banking. RECOMMENDATION 3: Surgery is an integral part of the treatment plan, to establish a histopathologic diagnosis and to achieve safe, maximal, and feasible tumour resection, which may improve clinical signs and symptoms. RECOMMENDATION 4: The preoperative imaging modality of choice is magnetic resonance imaging (MRI) with gadolinium as the contrast agent. Other imaging modalities, such as positron emission tomography with [(18)F]-fluoro-deoxy-d-glucose, may also be considered in selected cases. Postoperative imaging (mri or computed tomography) is recommended within 72 hours of surgery to evaluate the extent of resection. RECOMMENDATION 5: Postoperative external-beam radiotherapy is recommended as standard therapy for patients with gbm. The recommended dose is 60 Gy in 2-Gy fractions. The recommended clinical target volume should be identified with gadolinium-enhanced T1-weighted mri, with a margin in the order of 2-3 cm. Target volumes should be determined based on a postsurgical planning MRI. A shorter course of radiation may be considered for older patients with poor performance status. RECOMMENDATION 6: During RT, temozolomide 75 mg/m(2) should be administered concurrently for the full duration of radio-therapy, typically 42 days. Temozolomide should be given approximately 1 hour before radiation therapy, and at the same time on the days that no radiotherapy is scheduled. RECOMMENDATION 7: Adjuvant temozolomide 150 mg/m(2), in a 5/28-day schedule, is recommended for cycle 1

  10. Cordyceps militaris and mycelial fermentation induced apoptosis and autophagy of human glioblastoma cells

    Science.gov (United States)

    Yang, C-H; Kao, Y-H; Huang, K-S; Wang, C-Y; Lin, L-W

    2012-01-01

    This study is the first report that investigated the apoptosis-inducing effects of Cordyceps militaris (CM) and its mycelial fermentation in human glioblastoma cells. Both fractions arrested the GBM8401 cells in the G0/G1 phase, whereas the U-87MG cells were arrested at the G2/M transitional stage. Western blot data suggested that upregulation of p53 and p21 might be involved in the disruption of cell cycle progression. Induction of chromosomal condensation and the appearance of a sub-G1 hypodipoid population further supported the proapoptogenicity, possibly through the activation of caspase-3 and caspase-8, and the downregulation of antiapoptotic Bcl-2 and the upregulation of proapoptotic Bax protein expression. Downregulation of mammalian target of rapamycin and upregulation of Atg5 and LC3 II levels in GBM8401 cells implicated the involvement of autophagy. The signaling profiles with mycelial fermentation treatment indicated that mycelial fermentation triggered rapid phosphorylation of Akt, p38 MAPK, and JNK, but suppressed constitutively high levels of ERK1/2 in GBM8401 cells. Mycelial fermentation treatment only significantly increased p38 MAPK phosphorylation, but decreased constitutively high levels of Akt, ERK1/2, and JNK phosphorylation in U-87MG cells. Pretreatment with PI3K inhibitor wortmannin and MEK1 inhibitor PD98059 prevented the mycelial fermentation-induced cytotoxicity in GBM8401 and U-87MG cells, suggesting the involvement of PI3K/Akt and MEK1 pathways in mycelial fermentation-driven glioblastoma cell apoptosis and autophagy. PMID:23190603

  11. Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells

    Science.gov (United States)

    Spina, Raffaella; Voss, Dillon M.; Asnaghi, Laura; Sloan, Andrew; Bar, Eli E.

    2016-01-01

    Glioblastoma multiforme (GBM) are the most common primary malignant brain tumor in adults, with a median survival of about one year. This poor prognosis is attributed primarily to therapeutic resistance and tumor recurrence after surgical removal, with the root cause suggested to be found in glioblastoma stem cells (GSCs). Using glial fibrillary acidic protein (GFAP) as a reporter of astrocytic differentiation, we isolated multiple clones from three independent GSC lines which express GFAP in a remarkably stable fashion. We next show that elevated expression of GFAP is associated with reduced clonogenicity in vitro and tumorigenicity in vivo. Utilizing this in vitro cell-based differentiation reporter system we screened chemical libraries and identified the non-depolarizing neuromuscular blocker (NNMB), Atracurium Besylate, as a small molecule which effectively induces astroglial but not neuronal differentiation of GSCs. Functionally, Atracurium Besylate treatment significantly inhibited the clonogenic capacity of several independent patient-derived GSC neurosphere lines, a phenomenon which was largely irreversible. A second NNMB, Vecuronium, also induced GSC astrocytic differentiation while Dimethylphenylpiperazinium (DMPP), a nicotinic acetylcholine receptor (nAChR) agonist, significantly blocked Atracurium Besylate pro-differentiation activity. To investigate the clinical importance of nAChRs in gliomas, we examined clinical outcomes and found that glioma patients with tumors overexpressing CHRNA1 or CHRNA9 (encoding for the AChR-α1 or AChR-α9) exhibit significant shorter overall survival. Finally, we found that ex-vivo pre-treatment of GSCs, expressing CHRNA1 and CHRNA9, with Atracurium Besylate significantly increased the survival of mice xenotransplanted with these cells, therefore suggesting that tumor initiating subpopulations have been reduced. PMID:26575950

  12. Tumor regrowth between surgery and initiation of adjuvant therapy in patients with newly diagnosed glioblastoma

    Science.gov (United States)

    Pirzkall, Andrea; McGue, Colleen; Saraswathy, Suja; Cha, Soonmee; Liu, Raymond; Vandenberg, Scott; Lamborn, Kathleen R.; Berger, Mitchel S.; Chang, Susan M.; Nelson, Sarah J.

    2009-01-01

    To assess incidence and degree of regrowth in glioblastoma between surgery and radiation therapy (RT) and to correlate regrowth with presurgical imaging and survival, we examined images of 32 patients with newly diagnosed glioblastoma who underwent MR spectroscopic imaging (MRSI), perfusion-weighted imaging (PWI), and diffusion-weighted imaging (DWI) prior to surgery, after surgery, and prior to RT/temozolomide. Contrast enhancement (CE) in the pre-RT MR image was compared with postsurgical DWI to differentiate tumor growth from postsurgical infarct. MRSI and PWI parameters were analyzed prior to surgery and pre-RT. Postsurgical MRI indicated that 18 patients had gross total and 14 subtotal resections. Twenty-one patients showed reduced diffusion, and 25 patients showed new or increased CE. In eight patients (25%), the new CE was confined to areas of postsurgical reduced diffusion. In the other 17 patients (53%), new CE was found to be indicative of tumor growth or a combination of tumor growth and surgical injury. Higher perfusion and creatine within nonenhancing tumor in the presurgery MR were associated with subsequent tumor growth. High levels of choline and reduced diffusion in pre-RT CE suggested active metabolism and tumor cell proliferation. Median survival was 14.6 months in patients with interim tumor growth and 24 months in patients with no growth. Increased volume or new onset of CE between surgery and RT was attributed to tumor growth in 53% of patients and was associated with shorter survival. This suggests that reducing the time between surgery and adjuvant therapy may be important. The acquisition of metabolic and physiologic imaging data prior to adjuvant therapy may also be valuable in assessing regions of new CE and nonenhancing tumor. PMID:19229057

  13. The involvement of mitochondrial apoptotic pathway in eugenol-induced cell death in human glioblastoma cells.

    Science.gov (United States)

    Liang, Wei-Zhe; Chou, Chiang-Ting; Hsu, Shu-Shong; Liao, Wei-Chuan; Shieh, Pochuen; Kuo, Daih-Huang; Tseng, Hui-Wen; Kuo, Chun-Chi; Jan, Chung-Ren

    2015-01-05

    Eugenol, a natural phenolic constituent of clove oil, has a wide range of applications in medicine as a local antiseptic and anesthetic. However, the effect of eugenol on human glioblastoma is unclear. This study examined whether eugenol elevated intracellular free Ca(2+) levels ([Ca(2+)]i) and induced apoptosis in DBTRG-05MG human glioblastoma cells. Eugenol evoked [Ca(2+)]i rises which were reduced by removing extracellular Ca(2+). Eugenol-induced [Ca(2+)]i rises were not altered by store-operated Ca(2+) channel blockers but were inhibited by the PKC inhibitor GF109203X and the transient receptor potential channel melastatin 8 (TRPM8) antagonist capsazepine. In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) or 2,5-di-tert-butylhydroquinone (BHQ) abolished eugenol-induced [Ca(2+)]i rises. The phospholipase C (PLC) inhibitor U73122 significantly inhibited eugenol-induced [Ca(2+)]i rises. Eugenol killed cells which were not reversed by prechelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). Eugenol induced apoptosis through increasing reactive oxygen species (ROS) production, decreasing mitochondrial membrane potential, releasing cytochrome c and activating caspase-9/caspase-3. Together, in DBTRG-05MG cells, eugenol evoked [Ca(2+)]i rises by inducing PLC-dependent release of Ca(2+) from the endoplasmic reticulum and caused Ca(2+) influx possibly through TRPM8 or PKC-sensitive channels. Furthermore, eugenol induced the mitochondrial apoptotic pathway.

  14. Glioblastoma research 2006-2010: pattern of citation and systematic review of highly cited articles.

    Science.gov (United States)

    Nieder, Carsten; Astner, Sabrina T; Grosu, Anca L

    2012-11-01

    High and continuously increasing research activity related to different aspects of pathogenesis, epidemiology, diagnosis and treatment of glioblastoma has been performed between 2006 and 2010. Different measures of impact, visibility and quality of published research are available, each with its own pros and cons. For this review, article citation rate was chosen. Articles were identified through systematic search of the abstract database PubMed followed by analyses of total number of citations and proportion of highly cited articles, arbitrarily defined as those with ≥100, 50-99, and 25-49 citations, respectively (citation database Scopus). Overall 5831 scientific articles on the subject were published during this time period. 1.5% of all articles accumulated at least 100 citations, 3.2% were cited between 50 and 99 times, and 7.5% were cited between 25 and 49 times. Among the 10 most cited articles, 7 reported on genomic analyses, molecular subclasses of glioblastoma and/or stem cells. Overall, 18 randomized clinical trials were published between 2006 and 2010, including those with phase II design. Thirty-nine percent of them accumulated at least 50 citations and 72% were cited at least 25 times. In general, annual citation rate appeared to gradually increase during the first 2-3 years after publication before reaching high levels. A large variety of preclinical and clinical topics achieved at least 25 citations. However, areas such as quality of life, side effects, and end-of-life care were underrepresented. Efforts to increase their visibility might be warranted.

  15. Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future direction

    Directory of Open Access Journals (Sweden)

    Supriya Mallick

    2015-01-01

    Full Text Available Glioblastoma multiforme (GBM is the most aggressive form of primary brain tumor. Maximal safe surgical resection followed by adjuvant partial brain radiation with concurrent and adjuvant temozolomide (TMZ (oral alkylating agent is the standard of care. Five years survival in TMZ treated patient reaches 9.8%. We aimed to summarize the changes in the management of GBM beyond conventional temozolomide based adjuvant treatment. We searched the PUBMED with the following key words: Glioblastoma, phase III trial, Phase II trial, adjuvant treatment in GBM. Clinical research has found a wide range of molecular aberrations in GBM and attempts are being made to further improve survival with the addition of different classes of drugs. Angiogenesis inhibitors, oncolytic vaccines, dose dense TMZ, and anti-epidermal growth factor receptor monoclonal antibody in phase III trials have failed to improve survival. Recent studies have also shown that the management strategies might be different and needs to be customized as per the age of patients such as pediatric and elderly patients. In addition, treatments should be personalized depending on the molecular aberrations. We reviewed all published phase III trials for newly diagnosed GBM as well as also looked into possible future directions in this review. Limited progress has happed beyond conventional TMZ in the adjuvant treatment of GBM. Newer insights are emerging about treatment intensification and introduction of newer molecular targeted drugs with more information about molecular aberrations.

  16. Methotrexate-loaded biodegradable nanoparticles: preparation, characterization and evaluation of its cytotoxic potential against U-343 MGa human neuronal glioblastoma cells

    Indian Academy of Sciences (India)

    Kranti P Musmade; Praful B Deshpande; Prashant B Musmade; M Naseer Maliyakkal; A Ranjith Kumar; M Sreenivasa Reddy; N Udupa

    2014-06-01

    Nanoparticles represent one of the attractive alternatives in the effective treatment of cancer chemotherapy. In the present work, formulation and development of a novel methotrexate (MTX)-loaded biodegradable nanoparticles using poly(D,L-lactide-co-glycolide) (PLGA) was carried out. The prepared nanoparticles were evaluated for physicochemical properties such as particle size, zeta potential, release studies, etc and also evaluated for its in vitro cytotoxic potential against U-343 MGa human neuronal glioblastoma cells. Particle size of optimized formulation was < 200 nm. There was a considerable decrease in cell viability and enhancement in cytotoxic activity of MTX-loaded nanoparticles compared to MTX alone when tested against U-343 MGa human neuronal glioblastoma cells.

  17. Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations.

    Directory of Open Access Journals (Sweden)

    Jo Meagan Garner

    Full Text Available Malignant glioblastoma (GBM is a highly aggressive brain tumor with a dismal prognosis and limited therapeutic options. Genomic profiling of GBM samples has identified four molecular subtypes (Proneural, Neural, Classical and Mesenchymal, which may arise from different glioblastoma stem-like cell (GSC populations. We previously showed that adherent cultures of GSCs grown on laminin-coated plates (Ad-GSCs and spheroid cultures of GSCs (Sp-GSCs had high expression of stem cell markers (CD133, Sox2 and Nestin, but low expression of differentiation markers (βIII-tubulin and glial fibrillary acid protein. In the present study, we characterized GBM tumors produced by subcutaneous and intracranial injection of Ad-GSCs and Sp-GSCs isolated from a patient-derived xenoline. Although they formed tumors with identical histological features, gene expression analysis revealed that xenografts of Sp-GSCs had a Classical molecular subtype similar to that of bulk tumor cells. In contrast xenografts of Ad-GSCs expressed a Mesenchymal gene signature. Adherent GSC-derived xenografts had high STAT3 and ANGPTL4 expression, and enrichment for stem cell markers, transcriptional networks and pro-angiogenic markers characteristic of the Mesenchymal subtype. Examination of clinical samples from GBM patients showed that STAT3 expression was directly correlated with ANGPTL4 expression, and that increased expression of these genes correlated with poor patient survival and performance. A pharmacological STAT3 inhibitor abrogated STAT3 binding to the ANGPTL4 promoter and exhibited anticancer activity in vivo. Therefore, Ad-GSCs and Sp-GSCs produced histologically identical tumors with different gene expression patterns, and a STAT3/ANGPTL4 pathway is identified in glioblastoma that may serve as a target for therapeutic intervention.

  18. Applicable advances in the molecular pathology of glioblastoma.

    Science.gov (United States)

    Ranjit, Melissa; Motomura, Kazuya; Ohka, Fumiharu; Wakabayashi, Toshihiko; Natsume, Atsushi

    2015-07-01

    Comprising more than 80% of malignant brain tumors, glioma has proven to be a daunting cause of mortality in a vast majority of the human population. Progressive and extensive research on malignant glioma has substantially enhanced our understanding of glioma cell biology and molecular pathology. Subtypes of glioma such as astrocytoma and oligodendroglioma are currently grouped together into one pathological class, where they show many differences in histology and molecular etiology. This indicates that it may be beneficial to consider a new and radical subclassification. Thus, we summarize recent developments in glioblastoma multiforme (GBM) subtypes, immunohistochemical analyses useful for diagnoses and the biological evaluation and therapeutic implications of gliomas in this review.

  19. Oncogene addiction and non-oncogene addiction in glioblastoma therapy

    Institute of Scientific and Technical Information of China (English)

    Kimberly Ng; Clark C.Chen

    2011-01-01

    @@ INTRODUCTION Glioblastoma is the most common form of primary brain tumor.The incidence of this tumor is fairly low,with 2-3 cases per 100 000 people in Europe and North America.1It is one of the most aggressive forms of cancer.2 Without treatment,the median survival is approximately 3 months.3 The current standard of treatment involves maximal surgical resection followed by concurrent radiation therapy and chemotherapy with the DNA alkylating agent,temozolomide.4,5 With this regimen,the median survival is approximately 14 months.For nearly all affected,the treatments available remain palliative.

  20. Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, Arnulf; Vaupel, Peter; Stockinger, Marcus; Schmidberger, Heinz [University Medical Center, Department of Radiooncology and Radiotherapy, Mainz (Germany); Struss, Hans-Garlich [University Medical Center, Department of Laboratory Medicine, Mainz (Germany); Giese, Alf [University Medical Center, Department of Neurosurgery, Mainz (Germany)

    2014-10-15

    In comparison to normal brain tissue, glioblastomas exhibit significantly increased glucose uptake. Brain edema is a common complication during adjuvant chemoradiotherapy, leading to a requirement for glucocorticoid treatment. Glucocorticoid treatment frequently causes considerable deregulation of blood glucose levels. Therefore, episodes of hyperglycemia may contribute to radio- and/or chemoresistance. This study comprises a retrospective analysis of the influence of hyperglycemic episodes (HEs) during adjuvant therapy on the overall survival of 106 glioblastoma multiforme patients. The occurrence of one or more deregulated blood glucose value(s) > 10 mM is associated with a reduction in median overall survival from 16.7 to 8.8 months. A significantly poorer overall survival of patients with hyperglycemia could also be detected in subgroup analyses of patients with complete tumor resection and complete treatment according to the EORTC 22891/26891 trial protocol, as well as in a multivariate Cox proportional hazards analysis. A history of diabetes mellitus had no influence on prognosis. Our data suggest that the observed negative impact of elevated blood glucose levels on overall survival may not solely be explained by the patients' poorer general condition; the elevated blood glucose concentration itself may play a pathogenetic role. This could be due to increased activity of antioxidant systems, elevated expression of DNA damage response proteins and protection of hypoxic tumor cells against apoptosis combined with hypoxia-mediated radioresistance. A possible prognostic impact of elevated blood glucose levels during the period of adjuvant (chemo-) radiotherapy of glioblastoma should be evaluated in a prospective clinical trial. (orig.) [German] Glioblastome zeigen im Vergleich mit normalem Gehirngewebe eine deutlich vermehrte Glukoseaufnahme. Im Rahmen der adjuvanten Radio(chemo)therapie von Glioblastomen treten vielfach Hirnoedeme auf, die eine

  1. Irinotecan and bevacizumab in recurrent glioblastoma multiforme

    DEFF Research Database (Denmark)

    Jakobsen, Jan Nyrop; Hasselbalch, Benedikte; Stockhausen, Marie-Thérése;

    2011-01-01

    . In the present paper the authors discuss selected key aspects of this treatment modality. A literature search was performed using PubMed in February 2011. EXPERT OPINION: BVZ + irinotecan leads to high RR and to an increased 6-month progression-free survival. However, no improvement in median overall survival...

  2. A novel PPAR alpha/gamma dual agonist inhibits cell growth and induces apoptosis in human glioblastoma T98G cells

    Institute of Scientific and Technical Information of China (English)

    Da-chuan LIU; Chuan-bing ZANG; Hong-yu LIU; Kurt POSSINGER; Shao-guang FAN; Elena ELSTNER

    2004-01-01

    AIM: To examine the effect of a novel peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist TZD 18 on cell proliferation and apoptosis in human glioblastoma T98G cells and its possible mechanism. METHODS: RTPCR, MTT, TUNEL, Flow cytometry, and Western blot analysis were employed. RESULTS: TZD18 inhibited the growth of T98G cells in a concentration-dependent manner, which was associated with a G1 to S cell cycle arrest.Besides, significant apoptosis was induced after treatment with a non-toxic dose of TZD 18. During the process,the expression of Bcl-2 protein was down-regulated, while that of Bax and p27kip proteins was up-regulated, and the activity of caspase-3 was elevated. However, this effect appeared to be PPARα and PPARγ independent since their antagonists could not reverse this effect. CONCLUSIONS: TZD18, a novel PPARα/γ dual agonist, inhibited cell growth and induce apoptosis in human glioblastoma T98G cells in vitro, indicating a therapeutic potential for TZD 18 in the treatment of glioblastoma.

  3. STAT6 expression in glioblastoma promotes invasive growth

    Directory of Open Access Journals (Sweden)

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