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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.

  2. CD166/activated leukocyte cell adhesion molecule is expressed on glioblastoma progenitor cells and involved in the regulation of tumor cell invasion.

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    Kijima, Noriyuki; Hosen, Naoki; Kagawa, Naoki; Hashimoto, Naoya; Nakano, Akiko; Fujimoto, Yasunori; Kinoshita, Manabu; Sugiyama, Haruo; Yoshimine, Toshiki

    2012-10-01

    For improvement of prognosis for glioblastoma patients, which remains poor, identification and targeting of glioblastoma progenitor cells are crucial. In this study, we found that the cluster of differentiation (CD)166/activated leukocyte cell adhesion molecule (ALCAM) was highly expressed on CD133+ glioblastoma progenitor cells. ALCAM+ CD133+ cells were highly enriched with tumor sphere-initiating cells in vitro. Among gliomas with isocitrate dehydrogenase-1/R132H mutation, the frequencies of ALCAM+ cells were significantly higher for glioblastomas than for World Health Organization grade II or III gliomas. The function of ALCAM in glioblastoma was then investigated. An in vitro invasion assay showed that transfection of ALCAM small interfering RNA or small hairpin RNA into glioblastoma cells significantly increased cell invasion without affecting cell proliferation. A soluble isoform of ALCAM (sALCAM) was also expressed in all glioblastoma samples and at levels that correlated well with ALCAM expression levels. In vitro invasion of glioblastoma cells was significantly enhanced by administration of purified sALCAM. Furthermore, overexpression of sALCAM in U87MG glioblastoma cells promoted tumor progression in i.c. transplants into immune-deficient mice. In summary, we were able to show that ALCAM constitutes a novel glioblastoma progenitor cell marker. We could also demonstrate that ALCAM and its soluble isoform are involved in the regulation of glioblastoma invasion and progression.

  3. 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.

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

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    Bleeker, Fonnet E.; Atai, Nadia A.; Lamba, Simona; Jonker, Ard; Rijkeboer, Denise; Bosch, Klazien S.; Tigchelaar, Wikky; Troost, Dirk; Vandertop, W. Peter; Bardelli, Alberto; van Noorden, Cornelis 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,

  5. Do Increased Doses to Stem-Cell Niches during Radiation Therapy Improve Glioblastoma Survival?

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    Sebastian Adeberg

    2016-01-01

    Full Text Available Background and Purpose. The reasons for the inevitable glioblastoma recurrence are yet understood. However, recent data suggest that tumor cancer stem cells (CSCs in the stem-cell niches, with self-renewing capacities, might be responsible for tumor initiation, propagation, and recurrence. We aimed to analyze the effect of higher radiation doses to the stem-cell niches on progression-free survival (PFS and overall survival (OS in glioblastoma patients. Materials and Methods. Sixty-five patients with primary glioblastoma treated with radiation therapy were included in this retrospective analysis. The SVZ and DG were segmented on treatment planning magnetic resonance imaging, and the dose distributions to the structures were calculated. The relationship of dosimetry data and survival was evaluated using the Cox regression analysis. Results. Conventionally fractionated patients (n=54 who received higher doses (Dmean ≥ 40 Gy to the IL SVZ showed improved PFS (8.5 versus 5.2 months; p=0.013. Furthermore, higher doses (Dmean ≥ 30 Gy to the CL SVZ were associated with increased PFS (10.1 versus 6.9 months; p=0.025. Conclusion. Moderate higher IL SVZ doses (≥40 Gy and CL SVZ doses (≥30 Gy are associated with improved PFS. Higher doses to the DG, the second stem-cell niche, did not influence the survival. Targeting the potential cancer stem cells in the SVZ might be a promising treatment approach for glioblastoma and should be addressed in a prospective randomized trial.

  6. 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 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.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.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.

  7. 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.

  8. Mitotic activity of multinucleated giant cells with glial fibrillary acidic protein immunoreactivity in glioblastomas: an immunohistochemical double labeling study.

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    Takeuchi, Hiroaki; Sato, Kazufumi; Ido, Kazunori; Kubota, Toshihiko

    2006-05-01

    To investigate the mitotic activity of multinucleated giant cells (MNGCs) with glial fibrillary acidic protein (GFAP) in glioblastomas, double immunohistochemical staining for GFAP and Ki67 was performed in formalin-fixed and paraffin-embedded specimens obtained from 12 primary glioblastomas with MNGCs including three giant cell glioblastomas. The Ki67 labeling index (LI:%) of GFAP+ tumor cells ranged from 0 to 5.6 (2.5+/-1.7, mean+/-standard deviation). The Ki67 LI of GFAP- tumor cells ranged from 18.6 to 35.9 (24.7+/-6.6). The Ki67 LI of GFAP+ cells was significantly lower than that of GFAP- cells (Pglioblastomas. MNGCs identified in glioblastomas may develop via not only the proliferation of abnormal nuclei in a single tumor cell but also other processes.

  9. Lipoprotein internalisation induced by oncogenic AMPK activation is essential to maintain glioblastoma cell growth.

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    Ríos, M; Foretz, M; Viollet, B; Prieto, A; Fraga, M; García-Caballero, T; Costoya, J A; Señarís, R

    2014-12-01

    Metabolic adaptations are essential during tumour growth to maintain the high proliferation levels exhibited by cancer cells. In this study, we examined the transformations that occurred in the lipid metabolism in astrocytic tumours, and the possible role of the fuel-sensing enzyme AMPK. Metabolic targets might help design new and effective drugs for cancer. To accomplish this objective, we studied both mice and human astrocytic tumours. We first used a mouse model of astrocytoma driven by oncogenic H-RasV12 and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We then confirmed the results in human glioblastoma cell lines and in glioblastoma tissue samples from patients. We show that the high levels of activated AMPK, observed in astrocytic tumours, increase extracellular lipid internalisation and reduce energy expenditure by inhibiting 'de novo' fatty acid (FA) synthesis, which allows tumour cells to obtain building blocks and energy to be able to create new organelles and new cells. Our findings demonstrate that AMPK plays a crucial role in glioblastoma cell growth and suggest that blocking lipoprotein receptors could potentially be used as a plausible therapeutic approach for these and other type of tumours with high levels of AMPK. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

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    Huang, Jia-Lin; Jiang, Gan; Song, Qing-Xiang; Gu, Xiao; Hu, Meng; Wang, Xiao-Lin; Song, Hua-Hua; Chen, Le-Pei; Lin, Ying-Ying; Jiang, Di; Chen, Jun; Feng, Jun-Feng; Qiu, Yong-Ming; Jiang, Ji-Yao; Jiang, Xin-Guo; Chen, Hong-Zhuan; Gao, Xiao-Ling

    2017-05-01

    Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to `drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood-brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.

  11. 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.

  12. Telomerase inhibition improves tumor response to radiotherapy in a murine orthotopic model of human glioblastoma.

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    Ferrandon, Sylvain; Malleval, Céline; El Hamdani, Badia; Battiston-Montagne, Priscillia; Bolbos, Radu; Langlois, Jean-Baptiste; Manas, Patrick; Gryaznov, Sergei M; Alphonse, Gersende; Honnorat, Jérôme; Rodriguez-Lafrasse, Claire; Poncet, Delphine

    2015-07-17

    Glioblastoma (GBM) is the most frequent and aggressive type of adult brain tumor. Most GBMs express telomerase; a high level of intra-tumoral telomerase activity (TA) is predictive of poor prognosis. Thus, telomerase inhibitors are promising options to treat GBM. These inhibitors increase the response to radiotherapy (RT), in vitro as well as in vivo. Since typical treatments for GBM include RT, our objective was to evaluate the efficiency of Imetelstat (TA inhibitor) combined with RT. We used a murine orthotopic model of human GBM (N = 8 to11 mice per group) and μMRI imaging to evaluate the efficacy of Imetelstat (delivered by intra-peritoneal injection) alone and combined with RT. Using a clinically established protocol, we demonstrated that Imetelstat significantly: (i) inhibited the TA in the very center of the tumor, (ii) reduced tumor volume as a proportion of TA inhibition, and (iii) increased the response to RT, in terms of tumor volume regression and survival increase. Imetelstat is currently evaluated in refractory brain tumors in young patients (without RT). Our results support its clinical evaluation combined with RT to treat GBM.

  13. 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.

  14. Propolis changes the anticancer activity of temozolomide in U87MG human glioblastoma cell line.

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    Markiewicz-Żukowska, Renata; Borawska, Maria H; Fiedorowicz, Anna; Naliwajko, Sylwia K; Sawicka, Diana; Car, Halina

    2013-02-27

    Propolis is a honey bee product which contains many active compounds, such as CAPE or chrysin, and has many beneficial activities. Recently, its anti-tumor properties have been discussed. We have tested whether the ethanolic extract of propolis (EEP) interferes with temozolomide (TMZ) to inhibit U87MG cell line growth. The U87MG glioblastoma cell line was exposed to TMZ (10-100 μM), EEP (10-100 μg/ml) or a mixture of TMZ and EEP during 24, 48 or 72 hours. The cell division was examined by the H3-thymidine incorporation, while the western blot method was used for detection of p65 subunit of NF-κB and ELISA test to measure the concentration of its p50 subunit in the nucleus. We have found that both, TMZ and EEP administrated alone, had a dose- and time-dependent inhibitory effect on the U87MG cell line growth, which was manifested by gradual reduction of cell viability and alterations in proliferation rate. The anti-tumor effect of TMZ (20 μM) was enhanced by EEP, which was especially well observed after a short time of exposition, where simultaneous usage of TMZ and EEP resulted in a higher degree of growth inhibition than each biological factor used separately. In addition, cells treated with TMZ presented no changes in NF-κB activity in prolonged time of treatment and EEP only slightly reduced the nuclear translocation of this transcription factor. In turn, the combined incubation with TMZ and EEP led to an approximately double reduction of NF-κB nuclear localization. We conclude that EEP presents cytotoxic properties and may cooperate with TMZ synergistically enhancing its growth inhibiting activity against glioblastoma U87MG cell line. This phenomenon may be at least partially mediated by a reduced activity of NF-κB.

  15. 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.

  16. Activity of irofulven (6-hydroxymethylacylfulvene) in the treatment of glioblastoma multiforme-derived xenografts in athymic mice.

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    Friedman, H S; Keir, S T; Houghton, P J; Lawless, A A; Bigner, D D; Waters, S J

    2001-11-01

    This study was conducted to define the activity of irofulven in the treatment of a series of xenografts derived from human glioblastoma multiforme growing subcutaneously and intracranially in athymic nude mice. Athymic mice bearing subcutaneous or intracranial tumors were treated with irofulven at a 10% lethal dose with responses compared to tumor-bearing mice treated with drug vehicle. Irofulven was active against all tumor lines tested with growth delays ranging from 5.6 to 81.6 days (all values statistically significant, P Irofulven also produced a statistically significant (P Irofulven is active in a spectrum of human glioblastoma multiforme-derived xenografts and evaluation in patients with this neoplasm is warranted.

  17. Epi-reevesioside F inhibits Na+/K+-ATPase, causing cytosolic acidification, Bak activation and apoptosis in glioblastoma.

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    Hsu, Jui-Ling; Liu, Fan-Lun; Hsu, Lih-Ching; Chang, Hsun-Shuo; Leu, Wohn-Jenn; Yu, Chia-Chun; Chang, Wei-Ling; Chen, Ih-Sheng; Kung, Fan-Lu; Guh, Jih-Hwa

    2015-09-15

    Epi-reevesioside F, a new cardiac glycoside isolated from the root of Reevesia formosana, displayed potent activity against glioblastoma cells. Epi-reevesioside F was more potent than ouabain with IC50 values of 27.3±1.7 vs. 48.7±1.8 nM (P Epi-reevesioside F and ouabain were ineffective in A172 cells, a glioblastoma cell line with low Na+/K+-ATPase α3 subunit expression. Epi-reevesioside F induced cell cycle arrest at S and G2 phases and apoptosis. It also induced an increase of intracellular concentration of Na+ but not Ca2+, cleavage and exposure of N-terminus of Bak, loss of mitochondrial membrane potential, inhibition of Akt activity and induction of caspase cascades. Potassium supplements significantly inhibited Epi-reevesioside F-induced effects. Notably, Epi-reevesioside F caused cytosolic acidification that was highly correlated with the anti-proliferative activity. In summary, the data suggest that Epi-reevesioside F inhibits Na+/K+-ATPase, leading to overload of intracellular Na+ and cytosolic acidification, Bak activation and loss of mitochondrial membrane potential. The PI3-kinase/Akt pathway is inhibited and caspase-dependent apoptosis is ultimately triggered in Epi-reevesioside F-treated glioblastoma cells.

  18. Radioresistance of mesenchymal glioblastoma initiating cells correlates with patient outcome and is associated with activation of inflammatory program.

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    Stanzani, Elisabetta; Martínez-Soler, Fina; Mateos, Teresa Martín; Vidal, Noemi; Villanueva, Alberto; Pujana, Miquel Angel; Serra-Musach, Jordi; de la Iglesia, Núria; Giménez-Bonafé, Pepita; Tortosa, Avelina

    2017-09-26

    Glioblastoma (GBM) still remains an incurable disease being radiotherapy (RT) the mainstay treatment. Glioblastoma intra-tumoral heterogeneity and Glioblastoma-Initiating Cells (GICs) challenge the design of effective therapies. We investigated GICs and non-GICs response to RT in a paired in-vitro model and addressed molecular programs activated in GICs after RT. Established GICs heterogeneously expressed several GICs markers and displayed a mesenchymal signature. Upon fractionated RT, GICs reported higher radioresistance compared to non-GICs and showed lower α- and β-values, according to the Linear Quadratic Model interpretation of the survival curves. Moreover, a significant correlation was observed between GICs radiosensitivity and patient disease-free survival. Transcriptome analysis of GICs after acquisition of a radioresistant phenotype reported significant activation of Proneural-to-Mesenchymal transition (PMT) and pro-inflammatory pathways, being STAT3 and IL6 the major players. Our findings support a leading role of mesenchymal GICs in defining patient response to RT and provide the grounds for targeted therapies based on the blockade of inflammatory pathways to overcome GBM radioresistance.

  19. Regulation of HGF Expression by ΔEGFR-Mediated c-Met Activation in Glioblastoma Cells

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    Jeannine Garnett

    2013-01-01

    Full Text Available The hepatocyte growth factor receptor (c-Met and a constitutively active mutant of the epidermal growth factor receptor (ΔEGFR/EGFRvIII are frequently overexpressed in glioblastoma (GBM and promote tumorigenesis. The mechanisms underlying elevated hepatocyte growth factor (HGF production in GBM are not understood. We found higher, coordinated mRNA expression levels of HGF and c-Met in mesenchymal (Mes GBMs, a subtype associated with poor treatment response and shorter overall survival. In an HGF/c-Met–dependent GBM cell line, HGF expression declined upon silencing of c-Met using RNAi or by inhibiting its activity with SU11274. Silencing c-Met decreased anchorage-independent colony formation and increased the survival of mice bearing intracranial GBM xenografts. Consistent with these findings, c-Met activation by ΔEGFR also elevated HGF expression, and the inhibition of ΔEGFR with AG1478 reduced HGF levels. Interestingly, c-Met expression was required for ΔEGFR-mediated HGF production, anchorage-independent growth, and in vivo tumorigenicity, suggesting that these pathways are coupled. Using an unbiased mass spectrometry–based screen, we show that signal transducer and activator of transcription 3 (STAT3 Y705 is a downstream target of c-Met signaling. Suppression of STAT3 phosphorylation with WP1193 reduced HGF expression in ΔEGFR-expressing GBM cells, whereas constitutively active STAT3 partially rescued HGF expression and colony formation in c-Met knockdown cells expressing ΔEGFR. These results suggest that the c-Met/HGF signaling axis is enhanced by ΔEGFR through increased STAT3-dependent HGF expression and that targeting c-Met in Mes GBMs may be an important strategy for therapy.

  20. Intracranial AAV-IFN-β gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model.

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    GuhaSarkar, Dwijit; Neiswender, James; Su, Qin; Gao, Guangping; Sena-Esteves, Miguel

    2017-02-01

    The highly invasive property of glioblastoma (GBM) cells and genetic heterogeneity are largely responsible for tumor recurrence after the current standard-of-care treatment and thus a direct cause of death. Previously, we have shown that intracranial interferon-beta (IFN-β) gene therapy by locally administered adeno-associated viral vectors (AAV) successfully treats noninvasive orthotopic glioblastoma models. Here, we extend these findings by testing this approach in invasive human GBM xenograft and syngeneic mouse models. First, we show that a single intracranial injection of AAV encoding human IFN-β eliminates invasive human GBM8 tumors and promotes long-term survival. Next, we screened five AAV-IFN-β vectors with different promoters to drive safe expression of mouse IFN-β in the brain in the context of syngeneic GL261 tumors. Two AAV-IFN-β vectors were excluded due to safety concerns, but therapeutic studies with the other three vectors showed extensive tumor cell death, activation of microglia surrounding the tumors, and a 56% increase in median survival of the animals treated with AAV/P2-Int-mIFN-β vector. We also assessed the therapeutic effect of combining AAV-IFN-β therapy with temozolomide (TMZ). As TMZ affects DNA replication, an event that is crucial for second-strand DNA synthesis of single-stranded AAV vectors before active transcription, we tested two TMZ treatment regimens. Treatment with TMZ prior to AAV-IFN-β abrogated any benefit from the latter, while the reverse order of treatment doubled the median survival compared to controls. These studies demonstrate the therapeutic potential of intracranial AAV-IFN-β therapy in a highly migratory GBM model as well as in a syngeneic mouse model and that combination with TMZ is likely to enhance its antitumor potency. © 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

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

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    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...

  2. Apoptosis activation by TRAIL receptor selective variants in glioblastoma (stem) cells

    NARCIS (Netherlands)

    van Roosmalen, Ingrid A. M.; Joseph, Justin Vareecal; Balasubramaniyan, V.; Yuvaraj, Saravanan; Quax, Wim J.; Kruyt, Frank A. E.

    2011-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumour in humans. The 5-year survival rate of patients is <10%. GBM has a very high rate of recurrence after treatment, which is thought to involve a subpopulation of cells in the tumour, called cancer stem cells

  3. Caffeine inhibits the growth of glioblastomas through activating the caspase-3 signaling pathway in vitro.

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    Liu, J-D; Song, L-J; Yan, D-J; Feng, Y-Y; Zang, Y-G; Yang, Y

    2015-08-01

    To study the effects and associated mechanisms of caffeine on cell viability, cycle dynamics, proliferation and apoptosis both in glioblastoma C6 and U87MG cells. Cell livability in presence or absence of caffeine was detected by the methyl thiazolyl tetrazolium (MTT) colorimetric assay. Flow cytometric analysis was conducted to investigate the cell cycle dynamics and Cell Counting Kit-8 (CCK-8) was used to further study the proliferation of C6 and U87MG glioblastoma cells after treated with caffeine or DMSO. To study the influence of caffeine on apoptosis of glioblastoma C6 and U87MG cells, the value of apoptosis ratio (AR) was calculated by flow cytometry detection. Western blot analysis was used to detect the expression of apoptosis-related factors, including Caspase-3, Cyt-C, Bax and Bcl-2. Caffeine at 1 mM reduced the cell viability of the both rat C6 and human U87MG glioblastoma cells to less than 70%. Flow cytometry detection found that caffeine remarkably arrested the C6 and U87MG cells in G0/G1 phase (C6, U87MG: pcells in S phase obviously decreased in the caffeine-treated group, when comparing to that of the normal control (C6, U87MG: pcells were observed in caffeine treatment group, when comparing to that of the normal control (C6, U87MG: pcaffeine induced much higher apoptosis of glioblastoma cells, compared with the normal control (C6, U87MG: pcaffeine markedly reduced the expression of Bcl-2 (C6, U87MG: pCaffeine inhibits proliferation and induces apoptosis of C6 and U87MG cells, leading to an imbalance in the ratio of proliferation and apoptosis. The apoptosis might be promoted by the motivation of the caspase-3 signaling pathway, which is induced by the release of Cyt-C as well as the elevated rate of Bax/Bcl-2.

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

    Science.gov (United States)

    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.

    2015-01-01

    The development of drugs to inhibit glioblastoma (GBM) growth requires reliable preclinical 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 (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. The 20 PDGXs belonged to three of four TCGA subtypes: 8 classical, 8 mesenchymal, and 4 proneural; none neural. Amplification of EGFR gene was observed in 9 out 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 preclinical 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. PMID:25598002

  5. Bevacizumab for Patients with Recurrent Multifocal Glioblastomas

    Science.gov (United States)

    Breuer, Stella; Cieplik, Hans C.; Harter, Patrick N.; Franz, Kea; Bähr, Oliver; Steinbach, Joachim P.

    2017-01-01

    In patients with glioblastoma, antiangiogenic therapy with bevacizumab (BEV) has been shown to improve progression-free survival (PFS), but not overall survival (OS). Especially in patients with an unusual infiltrative phenotype as seen in multifocal glioblastoma, the use of BEV therapy is still more controversial. Therefore, we prepared a retrospective case series with 16 patients suffering from a multifocal glioblastoma treated with BEV. We compared these patients to a matched control cohort of 16 patients suffering from glioblastoma with a single lesion treated with BEV. The objective of this study was to evaluate whether the course of disease differs in glioblastoma patients with a multifocal disease pattern compared to those with a single lesion only. Patients were treated with BEV monotherapy or BEV in combination with irinotecan or lomustine (CCNU). Response rates and PFS were similar in both groups. There was a trend for an unfavorable OS in the patient group with multifocal glioblastoma, which was expected due to the generally worse prognosis of multifocal glioblastoma. We investigated whether BEV therapy affects the invasive growth pattern as measured by the appearance of new lesions on magnetic resonance imaging (MRI). Under BEV therapy, there was a trend for a lower frequency of new lesions both in multifocal and solitary glioblastoma. Based on these results, BEV therapy at relapse appears to be justified to no lesser extent in multifocal glioblastoma than in solitary glioblastoma. PMID:29156610

  6. Bevacizumab for Patients with Recurrent Multifocal Glioblastomas

    Directory of Open Access Journals (Sweden)

    Michael C. Burger

    2017-11-01

    Full Text Available In patients with glioblastoma, antiangiogenic therapy with bevacizumab (BEV has been shown to improve progression-free survival (PFS, but not overall survival (OS. Especially in patients with an unusual infiltrative phenotype as seen in multifocal glioblastoma, the use of BEV therapy is still more controversial. Therefore, we prepared a retrospective case series with 16 patients suffering from a multifocal glioblastoma treated with BEV. We compared these patients to a matched control cohort of 16 patients suffering from glioblastoma with a single lesion treated with BEV. The objective of this study was to evaluate whether the course of disease differs in glioblastoma patients with a multifocal disease pattern compared to those with a single lesion only. Patients were treated with BEV monotherapy or BEV in combination with irinotecan or lomustine (CCNU. Response rates and PFS were similar in both groups. There was a trend for an unfavorable OS in the patient group with multifocal glioblastoma, which was expected due to the generally worse prognosis of multifocal glioblastoma. We investigated whether BEV therapy affects the invasive growth pattern as measured by the appearance of new lesions on magnetic resonance imaging (MRI. Under BEV therapy, there was a trend for a lower frequency of new lesions both in multifocal and solitary glioblastoma. Based on these results, BEV therapy at relapse appears to be justified to no lesser extent in multifocal glioblastoma than in solitary glioblastoma.

  7. Dexamethasone-Mediated Activation of Fibronectin Matrix Assembly Reduces Dispersal of Primary Human Glioblastoma Cells.

    Directory of Open Access Journals (Sweden)

    Stephen Shannon

    Full Text Available Despite resection and adjuvant therapy, the 5-year survival for patients with Glioblastoma multiforme (GBM is less than 10%. This poor outcome is largely attributed to rapid tumor growth and early dispersal of cells, factors that contribute to a high recurrence rate and poor prognosis. An understanding of the cellular and molecular machinery that drive growth and dispersal is essential if we are to impact long-term survival. Our previous studies utilizing a series of immortalized GBM cell lines established a functional causation between activation of fibronectin matrix assembly (FNMA, increased tumor cohesion, and decreased dispersal. Activation of FNMA was accomplished by treatment with Dexamethasone (Dex, a drug routinely used to treat brain tumor related edema. Here, we utilize a broad range of qualitative and quantitative assays and the use of a human GBM tissue microarray and freshly-isolated primary human GBM cells grown both as conventional 2D cultures and as 3D spheroids to explore the role of Dex and FNMA in modulating various parameters that can significantly influence tumor cell dispersal. We show that the expression and processing of fibronectin in a human GBM tissue-microarray is variable, with 90% of tumors displaying some abnormality or lack in capacity to secrete fibronectin or assemble it into a matrix. We also show that low-passage primary GBM cells vary in their capacity for FNMA and that Dex treatment reactivates this process. Activation of FNMA effectively "glues" cells together and prevents cells from detaching from the primary mass. Dex treatment also significantly increases the strength of cell-ECM adhesion and decreases motility. The combination of increased cohesion and decreased motility discourages in vitro and ex vivo dispersal. By increasing cell-cell cohesion, Dex also decreases growth rate of 3D spheroids. These effects could all be reversed by an inhibitor of FNMA and by the glucocorticoid receptor antagonist, RU

  8. ET-17TRANSIENT FASTING ENHANCES REPLICATION AND THERAPEUTIC ACTIVITY OF ONCOLYTIC HSV IN GLIOBLASTOMA THERAPY

    OpenAIRE

    Esaki, Shinichi; Rabkin, Samuel D; Martuza, Robert L; Wakimoto, Hiroaki

    2014-01-01

    BACKGROUND AND OBJECTIVE: Short term fasting has been shown to enhance efficacy of chemotherapy by sensitizing tumor cells and protecting normal cells in a variety of cancer models including glioblastoma (GBM). Malignant cells, unlike normal cells, respond to fasting by promoting oncogenic signaling and protein synthesis, which could in turn sensitize them to anti-cancer agents, broadening therapeutic window. We hypothesize that fasting increases replication of oncolytic herpes simplex virus ...

  9. 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

  10. 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.

  11. 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...

  12. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.

    Directory of Open Access Journals (Sweden)

    Tim F Cloughesy

    2008-01-01

    Full Text Available There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population.Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR, we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation varied substantially. Tumor cell proliferation (measured by Ki-67 staining was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test

  13. Methyl gallate isolated from Spondias pinnata exhibits anticancer activity against human glioblastoma by induction of apoptosis and sustained extracellular signal-regulated kinase 1/2 activation.

    Science.gov (United States)

    Chaudhuri, Dipankar; Ghate, Nikhil Baban; Singh, Sudhir Shankar; Mandal, Nripendranath

    2015-01-01

    Spondias pinnata has been reported for its efficient anticancer effects, but the studies were mostly focused on its extract. Since its bioactive compounds are largely unknown, this study was designed to characterize the lead components present in it and their anticancer activity against human glioblastoma cell line (U87). Major compounds from the ethyl acetate fraction were isolated by column chromatography and their anticancer potentials against U87 cells were evaluated. Furthermore, flow cytometric and immunoblotting analyses were performed to demonstrate the mechanism of apoptosis inducing activity of methyl gallate (MG) against U87 cell line. Four major compounds were isolated from the ethyl acetate fraction. Amongst these, two compounds showed promising activities and with the help of different spectroscopic methods they were identified as gallic acid and MG. Flow cytometric studies revealed that MG-induced apoptosis in U87 cells dose-dependently; the same was confirmed by activation of caspases through cleavage of endogenous substrate poly (adenosine diphosphate-ribose) polymerase. MG treatment also induced the expression of p53 and B-cell lymphoma-2-associated X and cleavage of BH3 interacting-domain with a concomitant decrease in B-cell lymphoma-2 expression. Moreover, MG-induced sustained phosphorylation of extracellular signal-regulated kinase (ERK1/2) in U87 cells with no change in the phosphorylation of other mitogen-activated protein kinases (c-Jun N-terminal of stress-activated protein kinases, p38). MG is a potent antioxidant and it induces sustained ERK1/2 activation and apoptosis in human glioblastoma U87, and provide a rationale for evaluation of MG for other brain carcinoma cell lines for the advancement of glioblastoma therapy.

  14. Complement activation in Glioblastoma Multiforme pathophysiology: Evidence from serum levels and presence of complement activation products in tumor tissue

    NARCIS (Netherlands)

    T.A.M. Bouwens; L.A. Trouw (L.); R. Veerhuis; C.M.F. Dirven (Clemens); M.L.M. Lamfers (Martine); H. Al-Khawaja

    2015-01-01

    textabstractInflammation plays a key role in the pathophysiology of Glioblastoma Multiforme (GBM). Here we focus on the contribution of the so far largely ignored complement system.ELISA and immunohistochemistry were combined to assess levels and localization of critical components of the

  15. 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.

  16. Mesenchymal Migration as a Therapeutic Target in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Jessie Zhong

    2010-01-01

    Full Text Available Extensive infiltration of the surrounding healthy brain tissue is a cardinal feature of glioblastomas, highly lethal brain tumors. Deep infiltration by the glioblastoma cells renders complete surgical excision difficult and contemporary adjuvant therapies have had little impact on long-term survival. Thus, deep infiltration and resistance to irradiation and chemotherapy remain a major cause of patient mortality. Modern therapies specifically targeted to this unique aspect of glioblastoma cell biology hold significant promise to substantially improve survival rates for glioblastoma patients. In the present paper, we focus on the role of adhesion signaling molecules and the actin cytoskeleton in the mesenchymal mode of motility that characterizes invading glioblastoma cells. We then review current approaches to targeting these elements of the glioblastoma cell migration machinery and discuss other aspects of cell migration that may improve the treatment of infiltrating glioblastoma.

  17. Sulforaphane inhibits invasion via activating ERK1/2 signaling in human glioblastoma U87MG and U373MG cells.

    Directory of Open Access Journals (Sweden)

    Chunliu Li

    Full Text Available Glioblastoma has highly invasive potential, which might result in poor prognosis and therapeutic failure. Hence, the key we study is to find effective therapies to repress migration and invasion. Sulforaphane (SFN was demonstrated to inhibit cell growth in a variety of tumors. Here, we will further investigate whether SFN inhibits migration and invasion and find the possible mechanisms in human glioblastoma U87MG and U373MG cells.First, the optimal time and dose of SFN for migration and invasion study were determined via cell viability and cell morphological assay. Further, scratch assay and transwell invasion assay were employed to investigate the effect of SFN on migration and invasion. Meanwhile, Western blots were used to detect the molecular linkage among invasion related proteins phosphorylated ERK1/2, matrix metalloproteinase-2 (MMP-2 and CD44v6. Furthermore, Gelatin zymography was performed to detect the inhibition of MMP-2 activation. In addition, ERK1/2 blocker PD98059 (25 µM was integrated to find the link between activated ERK1/2 and invasion, MMP-2 and CD44v6.The results showed that SFN (20 µM remarkably reduced the formation of cell pseudopodia, indicating that SFN might inhibit cell motility. As expected, scratch assay and transwell invasion assay showed that SFN inhibited glioblastoma cell migration and invasion. Western blot and Gelatin zymography showed that SFN phosphorylated ERK1/2 in a sustained way, which contributed to the downregulated MMP-2 expression and activity, and the upregulated CD44v6 expression. These molecular interactions resulted in the inhibition of cell invasion.SFN inhibited migration and invasion processes. Furthermore, SFN inhibited invasion via activating ERK1/2 in a sustained way. The accumulated ERK1/2 activation downregulated MMP-2 expression and decreased its activity and upregulated CD44v6. SFN might be a potential therapeutic agent by activating ERK1/2 signaling against human glioblastoma.

  18. Inhibition of glioblastoma malignancy by Lgl1.

    Science.gov (United States)

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

    2014-11-30

    lethal giant larvae (lgl) was first identified as a tumor suppressor in Drosophila, where its loss repressed the differentiation and promoted the invasion of neuroblasts, the Drosophila equivalent of the neural stem cell. Recently we have shown that a human homolog of Lgl, Lgl1 (LLGL1), is constitutively phosphorylated and inactivated in glioblastoma cells; this occurs as a downstream consequence of PTEN loss, one of the most frequent genetic events in glioblastoma. Here we have investigated the consequences of this loss of functional Lgl1 in glioblastoma in vivo. We used a doxycycline-inducible system to express a non-phosphorylatable, constitutively active version of Lgl1 (Lgl3SA) in either a glioblastoma cell line or primary glioblastoma cells isolated under neural stem cell culture conditions from patients. In both types of cells, expression of Lgl3SA, but not wild type Lgl1, inhibited cell motility in vitro. Induction of Lgl3SA in intracerebral xenografts markedly reduced the in vivo invasion of primary glioblastoma cells. Lgl3SA expression also induced the differentiation of glioblastoma cells in vitro and in vivo along the neuronal lineage. Thus the central features of Lgl function as a tumor suppressor in Drosophila are conserved in human glioblastoma.

  19. The Initial Area Under the Curve Derived from Dynamic Contrast-Enhanced MRI Improves Prognosis Prediction in Glioblastoma with Unmethylated MGMT Promoter.

    Science.gov (United States)

    Choi, Y S; Ahn, S S; Lee, H-J; Chang, J H; Kang, S-G; Kim, E H; Kim, S H; Lee, S-K

    2017-08-01

    Although perfusion and permeability MR parameters have known to have prognostic value, they have reproducibility issues. Our aim was to evaluate whether the initial area under the time-to-signal intensity curve (IAUC) derived from dynamic contrast-enhanced MR imaging can improve prognosis prediction in patients with glioblastoma with known MGMT status. We retrospectively examined 88 patients with glioblastoma who underwent preoperative dynamic contrast-enhanced MR imaging. The means of IAUC values at 30 and 60 seconds (IAUC30mean and IAUC60mean) were extracted from enhancing tumors. The prognostic values of IAUC parameters for overall survival and progression-free survival were assessed with log-rank tests, according to the MGMT status. Multivariate overall survival and progression-free survival models before and after adding the IAUC parameters as covariates were explored by net reclassification improvement after receiver operating characteristic analysis for 1.5-year overall survival and 1-year progression-free survival and by random survival forest. High IAUC parameters were associated with worse overall survival and progression-free survival in the unmethylated MGMT group, but not in the methylated group. In the unmethylated MGMT group, 1.5-year overall survival and 1-year progression-free survival prediction improved significantly after adding IAUC parameters (overall survival area under the receiver operating characteristic curve, 0.86; progression-free survival area under the receiver operating characteristic curve, 0.74-0.76) to the model with other prognostic factors (overall survival area under the receiver operating characteristic curve, 0.81; progression-free survival area under the receiver operating characteristic curve, 0.69; P < .05 for all) except in the case of IAUC60mean for 1-year progression-free survival prediction (P = .059). Random survival forest models indicated that the IAUC parameters were the second or most important predictors in the

  20. TGFβ Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response.

    Science.gov (United States)

    Han, Jianfeng; Chen, Xilin; Chu, Jianhong; Xu, Bo; Meisen, Walter H; Chen, Lichao; Zhang, Lingling; Zhang, Jianying; He, Xiaoming; Wang, Qi-En; Chiocca, E Antonio; Kaur, Balveen; Caligiuri, Michael A; Yu, Jianhua

    2015-12-15

    Oncolytic viruses, including oncolytic herpes simplex virus (oHSV), have produced provocative therapeutic responses in patients with glioblastoma, the most aggressive brain tumor. Paradoxically, innate immune responses mediated by natural killer (NK) cells and macrophages/microglia appear to limit oHSV efficacy. Therefore, we investigated whether pretreatment with an immunosuppressive cytokine, TGFβ, might reverse these effects and thereby potentiate oHSV efficacy. TGFβ treatment of NK cells rendered them less cytolytic against oHSV-infected glioblastoma cells and stem-like cells in vitro. Furthermore, TGFβ treatment of NK cells, macrophages, or microglia increased viral titers of oHSV in cocultures with glioblastoma cells. In a syngeneic mouse model of glioblastoma, administering TGFβ prior to oHSV injection inhibited intracranial infiltration and activation of NK cells and macrophages. Notably, a single administration of TGFβ prior to oHSV therapy was sufficient to phenocopy NK-cell depletion and suppress tumor growth and prolong survival in both xenograft and syngeneic models of glioblastoma. Collectively, our findings show how administering a single dose of TGFβ prior to oncolytic virus treatment of glioblastoma can transiently inhibit innate immune cells that limit efficacy, thereby improving therapeutic responses and survival outcomes. ©2015 American Association for Cancer Research.

  1. Combination of measles virus virotherapy and radiation therapy has synergistic activity in the treatment of glioblastoma multiforme.

    Science.gov (United States)

    Liu, Chunsheng; Sarkaria, Jann N; Petell, Cory A; Paraskevakou, Georgia; Zollman, Paula J; Schroeder, Mark; Carlson, Brett; Decker, Paul A; Wu, Wenting; James, C David; Russell, Stephen J; Galanis, Evanthia

    2007-12-01

    Glioblastoma multiforme is the most frequent primary brain tumor in adults and represents one of the most lethal malignancies with a median survival of 12-16 months. We have previously shown that an oncolytic measles virus derivative expressing soluble human carcinoembryonic antigen (MV-CEA) has significant antitumor activity against glioblastoma multiforme cell lines and xenografts. Radiation therapy (RT) represents one of the mainstays of glioma treatment. Here we tested the hypothesis that the combination of RT with MV-CEA would have synergistic activity against gliomas. 3-(4,5-Dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and clonogenic assays were used to test cytoxicity of the combination treatment in vivo. To examine the mechanism of synergy, one-step viral growth curves, terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays, and Western blot analyses were performed. In vivo assessment of synergistic antitumor activity was conducted in a U87 glioma model. MTS and clonogenic assays showed a strong synergistic interaction between MV-CEA and RT in glioblastoma multiforme cells including both primary and established glioma lines. Furthermore, significant antitumor efficacy was observed in vivo in a subcuteneous U87 xenograph model. There was significant prolongation of survival (P = 0.001) in the combination treatment group as compared with single modality- or control-treated animals. One-step viral growth curves showed increased viral burst size by up to 2 log in MV/RT combination-treated cells, as compared with single agent MV-CEA-treated glioma cells. Changes in CEA levels and expression of viral N and H protein were also consistent with increased viral production. Furthermore, TUNEL assays and Western blot analysis showed increase in apoptosis in MV/RT combination-treated cells. The pan-caspase inhibitor Z-VAD-FMK and the caspase-8 inhibitor Z-IETD-FMK, but not the caspase-9

  2. Antitumor effect of aspirin in glioblastoma cells by modulation of β-catenin/T-cell factor-mediated transcriptional activity.

    Science.gov (United States)

    Lan, Fengming; Yue, Xiao; Han, Lei; Yuan, Xubo; Shi, Zhendong; Huang, Kai; Yang, Yang; Zou, Jian; Zhang, Junxia; Jiang, Tao; Pu, Peiyu; Kang, Chunsheng

    2011-10-01

    The goal in this study was to investigate the antitumor effect of aspirin in glioblastoma cells and the molecular mechanism involved in its antineoplastic activities. The authors used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, flow cytometry, the annexin V method, and Transwell cell invasion test to detect the proliferation and invasive activity of U87 and A172 glioma cells before and after being treated with aspirin. To determine the effects of aspirin on β-catenin/T-cell factor (TCF) transcription activity, reporter constructs containing 3 repeats of the wild-type (TOPflash) or mutant (FOPflash) TCF-binding sites were used. Reverse transcriptase polymerase chain reaction and Western blot analyses were used to detect the expression of multiple β-catenin/TCF target genes following aspirin treatment. The transcriptional activity of the β-catenin/TCF complex was strongly inhibited by aspirin. Increasing the concentration of aspirin resulted in decreased expression of c-myc, cyclin D1, and fra-1 mRNA and protein in U87 and A172 cells in a dose-dependent manner. Aspirin inhibited glioma cell proliferation and invasive ability, and induced apoptotic cell death. The results suggest that aspirin is a potent antitumor agent, and that it exerts its antineoplastic action by inhibition of the β-catenin/TCF signaling pathway in glioma cells.

  3. 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

    2015-01-01

    L-Glutamine (Gln) functions physiologically to balance tissue requirements of carbon and nitrogen. 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 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, 13C-glucose tracing showed that GS produces Gln from TCA cycle-derived carbons. Finally, while it is contributed only marginally by the circulation, the Gln required for the growth of GBM tumours is either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes. PMID:26595383

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

    Directory of Open Access Journals (Sweden)

    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.

  5. 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.

  6. 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. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  7. Inhibition of Farnesyltransferase Potentiates NOTCH-Targeted Therapy against Glioblastoma Stem Cells

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    Yufang Ma

    2017-12-01

    Full Text Available Summary: Accumulating evidence suggests that cancer cells with stem cell-like phenotypes drive disease progression and therapeutic resistance in glioblastoma (GBM. NOTCH regulates self-renewal and resistance to chemoradiotherapy in GBM stem cells. However, NOTCH-targeted γ-secretase inhibitors (GSIs exhibited limited efficacy in GBM patients. We found that farnesyltransferase inhibitors (FTIs significantly improved sensitivity to GSIs. This combination showed significant antineoplastic and radiosensitizing activities in GBM stem cells, whereas non-stem GBM cells were resistant. These combinatorial effects were mediated, at least partially, through inhibition of AKT and cell-cycle progression. Using subcutaneous and orthotopic GBM models, we showed that the combination of FTIs and GSIs, but not either agent alone, significantly reduced tumor growth. With concurrent radiation, this combination induced a durable response in a subset of orthotopic tumors. These findings collectively suggest that the combination of FTIs and GSIs is a promising therapeutic strategy for GBM through selectively targeting the cancer stem cell subpopulation. : NOTCH-targeted agents may selectively compromise glioblastoma stem cells. In this article, Wang and colleagues demonstrate that farnesyltransferase inhibitors significantly augmented the sensitivity of glioblastoma stem cells to γ-secretase inhibitors and improved tumor growth control in xenograft models. This combination therapy also promoted radiosensitivity and resulted in a durable response in orthotopic glioblastoma models with concurrent radiation. Keywords: Notch, glioblastoma stem cells, γ-secretase inhibitors, farnesyltransferase inhibitors

  8. Primary cerebellar glioblastoma multiforme.

    Science.gov (United States)

    Demir, Mustafa Kemal; Hakan, Tayfun; Akinci, Okan; Berkman, Zafer

    2005-06-01

    Primary glioblastoma multiforme of cerebellar hemispheres in adults is a rare condition. Most of them result from dedifferentiation of astrocytoma to glioblastoma. We present two cases of unusual de novo cerebellar glioblastomas, one of which is the giant-cell variant. We review their clinical behaviour with conventional MR imaging features and discuss the key findings that can lead to the correct diagnosis in sight of new MR imaging technologies.

  9. Endothelial-Monocyte Activating Polypeptide II Suppresses the In Vitro Glioblastoma-Induced Angiogenesis by Inducing Autophagy

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    Zhiqing Li

    2017-06-01

    Full Text Available The obstacle in delivering therapeutics to glioblastoma (GBM is tumor-induced angiogenesis which leads to the formation of abnormal vessels and a dysfunctional blood-tumor barrier. Here, we elucidated the effect of endothelial-monocyte activating polypeptide II (EMAP II on the GBM-induced angiogenesis as well as its potential mechanisms. Our results proved that EMAP II inhibited the viability, mitochondrial membrane potential, migration and tube formation of GBM-induced endothelial cells (GECs by inducing cell autophagy, demonstrated by cell viability assay, JC-1 staining assay, transwell assay and tube formation assay, respectively. Cell autophagy was induced by EMAP II through the observation of autophagic vacuoles formation and the up-regulation of microtubule-associated protein-1 light chain-3 (LC3-II and p62/SQSTM1 expression, demonstrated by transmission electron microscopy analysis, immunofluorescence assay and Western blot assay. The activity of PI3K/AKT/mTOR signal pathway could be inhibited by the EMAP II treatment. Furthermore, unfolded protein response (UPR-related proteins (GRP78, eIF2α, and CHOP were up-regulated by EMAP II, which suggest that GECs exposed to EMAP II experienced endoplasmic reticulum stress. Further, mechanistic investigations found that EMAP II reduced the miR-96 expression which could directly target the 3′-UTR of these UPR-related proteins, and over-expression of miR-96 inhibited LC3 and p62/SQSTM1 expression by down-regulating these UPR-related proteins in GECs. Moreover, the combination of EMAP II with miR-96 inhibitor showed the inhibitory effect on the viability, migration, and in vitro tube formation of GECs, which are critical for angiogenesis. Taken together, we have demonstrated the fact that EMAP II resulted in the decreased GBM-induced angiogenesis by inducing autophagy, which might contribute to establishing potential strategies for human GBM treatment.

  10. Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG-Expressing Glioblastoma Patients.

    Science.gov (United States)

    Pointer, Kelli B; Clark, Paul A; Eliceiri, Kevin W; Salamat, M Shahriar; Robertson, Gail A; Kuo, John S

    2017-01-01

    Glioblastoma is the most malignant primary brain tumor, with a median survival of less than 2 years. More effective therapeutic approaches are needed to improve clinical outcomes. Glioblastoma patient-derived cells (GPDC) were isolated from patient glioblastomas and implanted in mice to form xenografts. IHC was performed for human Ether-à-go-go-Related Gene (hERG) expression and tumor proliferation. Sphere-forming assays with the hERG blocker E-4031 were performed on a high and low hERG-expressing lines. A glioblastoma tissue microarray (TMA; 115 patients) was used to correlate hERG expression with patient survival. Clinical data were analyzed to determine whether patient survival was affected by incidental administration of hERG inhibitory drugs and the correlative effect of patient glioblastoma hERG expression levels. hERG expression was upregulated in glioblastoma xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared with low hERG-expressing GPDCs. Glioblastoma TMA analysis showed worse survival for glioblastoma patients with high hERG expression versus low expression-43.5 weeks versus 60.9 weeks, respectively (P = 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared with patients who did not (P = 0.0015). Subgroup analysis showed that glioblastoma patients with high hERG expression who received hERG blockers had improved survival (P = 0.0458). There was no difference in survival for low hERG-expressing glioblastoma patients who received hERG blockers (P = 0.4136). Our findings suggest that hERG is a potential glioblastoma survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be repurposed as adjuvant glioblastoma therapy in high hERG-expressing glioblastoma patients. Clin Cancer Res; 23(1); 73-80. ©2016 AACRSee related commentary by Arcangeli and

  11. Activation of Aurora A kinase through the FGF1/FGFR signaling axis sustains the stem cell characteristics of glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Yi-Chao [Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (China); Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan (China); Kao, Chien-Yu [Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (China); Graduate Program of Biotechnology in Medicine, Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan (China); Chung, Yu-Fen; Lee, Don-Ching [Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (China); Liu, Jen-Wei [Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (China); Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan (China); Chiu, Ing-Ming, E-mail: ingming@nhri.org.tw [Division of Regenerative Medicine, Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (China); Graduate Program of Biotechnology in Medicine, Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan (China); Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan (China)

    2016-06-10

    Fibroblast growth factor 1 (FGF1) binds and activates FGF receptors, thereby regulating cell proliferation and neurogenesis. Human FGF1 gene 1B promoter (−540 to +31)-driven SV40 T antigen has been shown to result in tumorigenesis in the brains of transgenic mice. FGF1B promoter (−540 to +31)-driven green fluorescent protein (F1BGFP) has also been used in isolating neural stem cells (NSCs) with self-renewal and multipotency from developing and adult mouse brains. In this study, we provide six lines of evidence to demonstrate that FGF1/FGFR signaling is implicated in the expression of Aurora A (AurA) and the activation of its kinase domain (Thr288 phosphorylation) in the maintenance of glioblastoma (GBM) cells and NSCs. First, treatment of FGF1 increases AurA expression in human GBM cell lines. Second, using fluorescence-activated cell sorting, we observed that F1BGFP reporter facilitates the isolation of F1BGFP(+) GBM cells with higher expression levels of FGFR and AurA. Third, both FGFR inhibitor (SU5402) and AurA inhibitor (VX680) could down-regulate F1BGFP-dependent AurA activity. Fourth, inhibition of AurA activity by two different AurA inhibitors (VX680 and valproic acid) not only reduced neurosphere formation but also induced neuronal differentiation of F1BGFP(+) GBM cells. Fifth, flow cytometric analyses demonstrated that F1BGFP(+) GBM cells possessed different NSC cell surface markers. Finally, inhibition of AurA by VX680 reduced the neurosphere formation of different types of NSCs. Our results show that activation of AurA kinase through FGF1/FGFR signaling axis sustains the stem cell characteristics of GBM cells. Implications: This study identified a novel mechanism for the malignancy of GBM, which could be a potential therapeutic target for GBM. - Highlights: • We report that FGF1 treatment can stimulate AurA kinase expression in human GBM cells. • FGF1/FGFR signaling is involved in the activation of AurA kinase. • FGF1 sustains the self

  12. 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...

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

    Directory of Open Access Journals (Sweden)

    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.

  14. 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

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

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    Maria Teresa Gentile

    Full Text Available 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.

  16. 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.

  17. Antiproliferative effects of Tubi-bee propolis in glioblastoma cell lines

    Directory of Open Access Journals (Sweden)

    Kleiton Silva Borges

    2011-01-01

    Full Text Available Propolis is a resin formed by a complex chemical composition of substances that bees collect from plants. Since ancient times, propolis has been used in folk medicine, due to its biological properties, that include antimicrobial, anti-inflammatory, antitumoral and immunomodulatory activities. Glioblastoma is the most common human brain tumor. Despite the improvements in GBM standard treatment, patients' prognosis is still very poor. The aim of this work was to evaluate in vitro the Tubi-bee propolis effects on human glioblastoma (U251 and U343 and fibroblast (MRC-5 cell lines. Proliferation, clonogenic capacity and apoptosis were analyzed after treatment with 1 mg/mL and 2 mg/mL propolis concentrations for different time periods. Additionally, glioblastoma cell lines were submitted to treatment with propolis combined with temozolomide (TMZ. Data showed an antiproliferative effect of tubi-bee propolis against glioblastoma and fibroblast cell lines. Combination of propolis with TMZ had a synergic antiproliferative effect. Moreover, propolis caused decrease in colony formation in glioblastoma cell lines. Propolis treatment had no effects on apoptosis, demonstrating a cytostatic action. Further investigations are needed to elucidate the molecular mechanism of the antitumor effect of propolis, and the study of its individual components may reveal specific molecules with antiproliferative capacity.

  18. Simulation predicts IGFBP2-HIF1α interaction drives glioblastoma growth.

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    Ka Wai Lin

    2015-04-01

    Full Text Available Tremendous strides have been made in improving patients' survival from cancer with one glaring exception: brain cancer. Glioblastoma is the most common, aggressive and highly malignant type of primary brain tumor. The average overall survival remains less than 1 year. Notably, cancer patients with obesity and diabetes have worse outcomes and accelerated progression of glioblastoma. The root cause of this accelerated progression has been hypothesized to involve the insulin signaling pathway. However, while the process of invasive glioblastoma progression has been extensively studied macroscopically, it has not yet been well characterized with regards to intracellular insulin signaling. In this study we connect for the first time microscale insulin signaling activity with macroscale glioblastoma growth through the use of computational modeling. Results of the model suggest a novel observation: feedback from IGFBP2 to HIF1α is integral to the sustained growth of glioblastoma. Our study suggests that downstream signaling from IGFI to HIF1α, which has been the target of many insulin signaling drugs in clinical trials, plays a smaller role in overall tumor growth. These predictions strongly suggest redirecting the focus of glioma drug candidates on controlling the feedback between IGFBP2 and HIF1α.

  19. PKC signaling in glioblastoma

    Science.gov (United States)

    do Carmo, Anália; Balça-Silva, Joana; Matias, Diana; Lopes, Maria Celeste

    2013-01-01

    Glioblastoma Multiforme (GBM) is the most aggressive brain tumor characterized by intratumoral heterogeneity at cytopathological, genomic and transcriptional levels. Despite the efforts to develop new therapeutic strategies the median survival of GBM patients is 12−14 months. Results from large-scale gene expression profile studies confirmed that the genetic alterations in GBM affect pathways controlling cell cycle progression, cellular proliferation and survival and invasion ability, which may explain the difficulty to treat GBM patients. One of the signaling pathways that contribute to the aggressive behavior of glioma cells is the protein kinase C (PKC) pathway. PKC is a family of serine/threonine-specific protein kinases organized into three groups according the activating domains. Due to the variability of actions controlled by PKC isoforms, its contribution to the development of GBM is poorly understood. This review intends to highlight the contribution of PKC isoforms to proliferation, survival and invasive ability of glioma cells. PMID:23358475

  20. miR-133a Promotes TRAIL Resistance in Glioblastoma via Suppressing Death Receptor 5 and Activating NF-κB Signaling

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    Shan-shan Wang

    2017-09-01

    Full Text Available Recombinant tumor necrosis factor (TNF-related apoptosis-inducing ligand (TRAIL, as a novel cancer therapeutic, is being tested in phase II and III clinical trials; however, TRAIL resistance remains a big obstacle preventing its clinical application. Considering that TRAIL-induced apoptosis through death receptors DR4 and DR5, their activation may be an alternative pathway to suppress TRAIL resistance. In this study, a negative correlation between DR5 expression and TRAIL resistance was observed, and miR-133a was predicted to be the most promising candidate to suppress DR5 expression. Further investigation demonstrated that miR-133a knockdown dramatically suppressed TRAIL resistance in glioblastoma in vitro and in vivo. An NF-κB family member, phosphorylated IκBα (P-IκBα, was shown to be stimulated by miR-133a, leading to the activation of this signaling. Finally, miR-133a was found to be inversely correlated with DR5 expression in human clinical specimens. In conclusion, our data demonstrate that miR-133a promotes TRAIL resistance in glioblastoma by suppressing DR5 expression and activating NF-κB signaling.

  1. Phosphoinositide 5-phosphatase activities control cell motility in glioblastoma: Two phosphoinositides PI(4,5)P2 and PI(3,4)P2 are involved.

    Science.gov (United States)

    Ramos, Ana Raquel; Elong Edimo, William's; Erneux, Christophe

    2017-09-05

    Inositol polyphosphate 5-phosphatases or phosphoinositide 5-phosphatases (PI 5-phosphatases) are enzymes that can act on soluble inositol phosphates and/or phosphoinositides (PIs). Several PI 5-phosphatases have been linked to human genetic diseases, in particular the Lowe protein or OCRL which is mutated in the Lowe syndrome. There are 10 different members of this family and 9 of them can use PIs as substrate. One of these substrates, PI(3,4,5)P3 binds to specific PH domains and recruits as effectors specific proteins to signaling complexes. Protein kinase B is one target protein and activation of the kinase will have a major impact on cell proliferation, survival and cell metabolism. Two other PIs, PI(4,5)P2 and PI(3,4)P2, are produced or used as substrates of PI 5-phosphatases (OCRL, INPP5B, SHIP1/2, SYNJ1/2, INPP5K, INPP5J, INPP5E). The inositol lipids may influence many aspects of cytoskeletal organization, lamellipodia formation and F-actin polymerization. PI 5-phosphatases have been reported to control cell migration, adhesion, polarity and cell invasion particularly in cancer cells. In glioblastoma, reducing SHIP2 expression can positively or negatively affect the speed of cell migration depending on the glioblastoma cell type. The two PI 5-phosphatases SHIP2 or SKIP could be localized at the plasma membrane and can reduce either PI(3,4,5)P3 or PI(4,5)P2 abundance. In the glioblastoma 1321 N1 cells, SHIP2 controls plasma membrane PI(4,5)P2 thereby participating in the control of cell migration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Bacterial Carriers for Glioblastoma Therapy

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    Nalini Mehta

    2017-03-01

    Full Text Available Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro-apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals. Histological and proteomic analyses were performed to elucidate the safety and efficacy of these carriers, showing an absence of systemic toxicity and a restored neural environment in treated responders. In the treated non-responders, proteomic analysis revealed competing mechanisms of pro-apoptotic and drug-resistant activity. This bacterial carrier opens a versatile avenue to overcome diffusion barriers in glioblastoma by virtue of its active motility in extracellular space and can lead to tailored therapies via tumor-specific expression of tumoricidal proteins.

  3. microRNA-100 targets SMRT/NCOR2, reduces proliferation, and improves survival in glioblastoma animal models.

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    Bahauddeen M Alrfaei

    Full Text Available Glioblastoma (GBM is the most frequently diagnosed malignant human glioma, and current median patient survival is less than two years despite maximal surgery followed by temozolomide chemoradiation therapies. Novel microRNA-related therapies are now being developed for cancers such as GBM. Differential microRNA expression profiling revealed that miR-100 expression is down-regulated in GBM compared to normal controls. We report that miR-100 expression reduces GBM tumorigenicity. In vitro, four GBM lines (U87, U251, 22T, and 33T demonstrated reduced proliferation 24 hours after transient miR100 overexpression via transfection. miR-100 triggered cell death an average 70% more than scrambled miR controls 24 hours after transient transfection (p < 0.01. miR-100 targeted inhibition of the "silencing mediator of retinoid or thyroid hormone receptor-2" (SMRT/NCOR2 gene was confirmed via reporter assays. Ki67 proliferation index was decreased 40% in tumor xenografts generated from stable miR-100 transfected GBM lines versus controls (p < 0.01. Furthermore, treatment of tumor xenografts with a single pre-mir-100 injection (60 pmol significantly extended survival of mice bearing intracranial GBM xenografts 25% more than scrambled controls (p < 0.01; n=8. These studies establish miR-100's effect on tumor GBM growth, and suggest clinical potential for microRNA-related GBM therapy.

  4. microRNA-100 Targets SMRT/NCOR2, Reduces Proliferation, and Improves Survival in Glioblastoma Animal Models

    Science.gov (United States)

    Alrfaei, Bahauddeen M.; Vemuganti, Raghu; Kuo, John S.

    2013-01-01

    Glioblastoma (GBM) is the most frequently diagnosed malignant human glioma, and current median patient survival is less than two years despite maximal surgery followed by temozolomide chemoradiation therapies. Novel microRNA-related therapies are now being developed for cancers such as GBM. Differential microRNA expression profiling revealed that miR-100 expression is down-regulated in GBM compared to normal controls. We report that miR-100 expression reduces GBM tumorigenicity. In vitro, four GBM lines (U87, U251, 22T, and 33T) demonstrated reduced proliferation 24 hours after transient miR100 overexpression via transfection. miR-100 triggered cell death an average 70% more than scrambled miR controls 24 hours after transient transfection (p SMRT/NCOR2) gene was confirmed via reporter assays. Ki67 proliferation index was decreased 40% in tumor xenografts generated from stable miR-100 transfected GBM lines versus controls (p < 0.01). Furthermore, treatment of tumor xenografts with a single pre-mir-100 injection (60 pmol) significantly extended survival of mice bearing intracranial GBM xenografts 25% more than scrambled controls (p < 0.01; n=8). These studies establish miR-100’s effect on tumor GBM growth, and suggest clinical potential for microRNA-related GBM therapy. PMID:24244722

  5. Isolated third ventricle glioblastoma.

    Science.gov (United States)

    Yılmaz, Baran; Ekşi, Murat Şakir; Demir, Mustafa Kemal; Akakın, Akın; Toktaş, Zafer Orkun; Yapıcıer, Özlem; Kılıç, Türker

    2016-01-01

    Glioblastoma is the most common and the most malignant type of gliomas. Cerebral hemispheres are usual locations for gliomas. Isolated third ventricular presentation is very rare for glioblastomas. A new case of isolated third ventricular glioblastoma has been presented in this report. A 36-year-old woman was admitted to outpatient clinic with headache, blurred vision and confusion. A head CT scan and MRI had showed third ventricular mass lesion with obstructive hydrocephalus. Previous to her admission to our clinic, a ventriculo-peritoneal shunt had been inserted and her hydrocephalus had been relieved to some extent in acute settings. In our clinic, stereotactic biopsy was performed and a second ventriculoperitoneal shunt was inserted from the opposite site. Histopathological diagnosis was glioblastoma. Radiotherapy and chemotherapy were started immediately after the surgery. Patient's hydrocephalus has resolved and she was well at post-operative 6th month. In differential diagnosis list of the tumors presenting in the third ventricle, there are plenty of tumors such as colloid cyst, meningioma, germinoma, craniopharyngioma, lymphoma, choroid plexus papilloma, subependymal giant cell astrocytoma, chiasmatic and hypothalamic benign astrocytoma. Ring enhancement of this region pathology is a peculiar sign for glioblastoma, yet not pathognomonic. Tumor histology is crucial to yield the final diagnosis. Management of obstructive hydrocephalus, making histopathological diagnosis, starting adjuvant radiotherapy and chemotherapy in isolated third ventricular glioblastomas is a safe and effective approach when we consider malignant nature and intractable progress of glioblastomas.

  6. [Morphological classification of glioblastomas].

    Science.gov (United States)

    Figarella-Branger, D; Bouvier, C; Moroch, J; Michalak, S; F Burel-Vandenbos

    2010-12-01

    In the 2007 WHO classification, glioblastomas are classified among the group of astrocytic tumors. They are highly malignant (grade IV). This group of tumors is morphologically heterogeneous. The WHO distinguishes between clinico-pathological entities, variants of entities and histological pattern. Variants are defined as being reliably indentified histologically and having some relevance for clinical outcome but as still being part of a previously defined overarching entity. Patterns of differentiation are identifiable by histological appearances but without clinical or pathological significance. The description of the histological and immunohistochemical features is based on the 2007 WHO classification. In addition to the classic form of glioblastoma, two variants exist: the giant cell GBM and the gliosarcoma. The first but not the second would have a better outcome than the classic glioblastoma. The WHO classification also distinguishes several patterns of differentiation: small cells glioblastoma; glioblastoma with lipidized cells; glioblastoma with oligodendroglioma component; glioblastoma with heterologous differentiation. These patterns have to be recognized because they represent sometimes a diagnostic challenge. GFAP, Olig2 and Mib1/Ki67 are the most relevant immunohistochemical markers. Diagnostic value of neuronal markers is still controversial. EGFR or p53 expression can be detected and their prognosis value is discussed in this chapter. A systematic analysis of some markers in routine, for example IDH1 or internexin-a, could help to define more homogeneous groups of patients. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  7. 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.

  8. Nanotechnology applications for glioblastoma.

    Science.gov (United States)

    Nduom, Edjah K; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G

    2012-07-01

    Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. Although conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds promise in the use of multifunctional nanoparticles for imaging and targeted therapy of glioblastoma. This article examines the current state of nanotechnology in the treatment of glioblastoma and directions of further study. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Phosphoinositide 3-Kinases Upregulate System xc− via Eukaryotic Initiation Factor 2α and Activating Transcription Factor 4 – A Pathway Active in Glioblastomas and Epilepsy

    Science.gov (United States)

    Baxter, Paul; Kassubek, Rebecca; Albrecht, Philipp; Van Liefferinge, Joeri; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Karpel-Massler, Georg; Meakin, Paul J.; Hayes, John D.; Aronica, Eleonora; Smolders, Ilse; Ludolph, Albert C.; Methner, Axel; Conrad, Marcus; Massie, Ann; Hardingham, Giles E.

    2014-01-01

    Abstract Aims: Phosphoinositide 3-kinases (PI3Ks) relay growth factor signaling and mediate cytoprotection and cell growth. The cystine/glutamate antiporter system xc− imports cystine while exporting glutamate, thereby promoting glutathione synthesis while increasing extracellular cerebral glutamate. The aim of this study was to analyze the pathway through which growth factor and PI3K signaling induce the cystine/glutamate antiporter system xc− and to demonstrate its biological significance for neuroprotection, cell growth, and epilepsy. Results: PI3Ks induce system xc− through glycogen synthase kinase 3β (GSK-3β) inhibition, general control non-derepressible-2-mediated eukaryotic initiation factor 2α phosphorylation, and the subsequent translational up-regulation of activating transcription factor 4. This pathway is essential for PI3Ks to modulate oxidative stress resistance of nerve cells and insulin-induced growth in fibroblasts. Moreover, the pathway is active in human glioblastoma cells. In addition, it is induced in primary cortical neurons in response to robust neuronal activity and in hippocampi from patients with temporal lobe epilepsy. Innovation: Our findings further extend the concepts of how growth factors and PI3Ks induce neuroprotection and cell growth by adding a new branch to the signaling network downstream of GSK-3β, which, ultimately, leads to the induction of the cystine/glutamate antiporter system xc−. Importantly, the induction of this pathway by neuronal activity and in epileptic hippocampi points to a potential role in epilepsy. Conclusion: PI3K-regulated system xc− activity is not only involved in the stress resistance of neuronal cells and in cell growth by increasing the cysteine supply and glutathione synthesis, but also plays a role in the pathophysiology of tumor- and non-tumor-associated epilepsy by up-regulating extracellular cerebral glutamate. Antioxid. Redox Signal. 20: 2907–2922. PMID:24219064

  10. Therapeutic Advances using Combinational Therapy in the Treatment of Glioblastoma

    DEFF Research Database (Denmark)

    Staberg, Mikkel

    2017-01-01

    Glioblastoma is the most malignant brain tumor in adults. Median survival is only about 15 months despite aggressive treatment, consisting of surgery followed by radio- and chemotherapy, stressing the need for new therapies. Development of glioblastoma is thought to be a result of both genetic...... of glioblastoma cells, an effect that is even more pronounced when combined with traditional chemotherapeutic agents. The EGFR and Notch pathways are shown to be of great importance for glioblastoma cell survival and for the formation of new blood vessels, a process known as angiogenesis. Results presented herein...... suggests that targeting redundant signaling pathways can overcome required or initial treatment resistance, thus leading to improved tumor cell elimination. We hypothesize that future therapies will likely be a result of combination therapies for glioblastoma patients based on their molecular tumor profile...

  11. New perspectives in glioblastoma antiangiogenic therapy

    Directory of Open Access Journals (Sweden)

    Alisa Madalina Popescu

    2015-12-01

    Full Text Available Glioblastoma (GB is highly vascularised tumour, known to exhibit enhanced infiltrative potential. One of the characteristics of glioblastoma is microvascular proliferation surrounding necrotic areas, as a response to a hypoxic environment, which in turn increases the expression of angiogenic factors and their signalling pathways (RAS/RAF/ERK/MAPK pathway, PI3K/Akt signalling pathway and WTN signalling cascade. Currently, a small number of anti-angiogenic drugs, extending glioblastoma patients survival, are available for clinical use. Most medications are ineffective in clinical therapy of glioblastoma due to acquired malignant cells or intrinsic resistance, angiogenic receptors cross-activation and redundant intracellular signalling, or the inability of the drug to cross the blood-brain barrier and to reach its target in vivo . Researchers have also observed that GB tumours are different in many aspects, even when they derive from the same tissue, which is the reason for personalised therapy. An understanding of the molecular mechanisms regulating glioblastoma angiogenesis and invasion may be important in the future development of curative therapeutic approaches for the treatment of this devastating disease.

  12. Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma.

    Science.gov (United States)

    Tateishi, Kensuke; Iafrate, A John; Ho, Quan; Curry, William T; Batchelor, Tracy T; Flaherty, Keith T; Onozato, Maristela L; Lelic, Nina; Sundaram, Sudhandra; Cahill, Daniel P; Chi, Andrew S; Wakimoto, Hiroaki

    2016-09-01

    Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma. The glycolytic dependency of Myc-driven glioblastoma was tested using (13)C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD(+) salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models. Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN-amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts. Myc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452-65. ©2016 AACR

  13. [Giant cell glioblastoma. Case report].

    Science.gov (United States)

    Alvarez-Betancourt, Leonardo; López-Ortega, Salvador; Caldera-Duarte, Agustín

    2004-01-01

    Glioblastomas (World Health Organization, (WHO), grade IV) are the most frequent and malignant neoplasms of the human nervous system. Giant cells glioblastomas, a subtype of these, account for less than 1% of all brain toumors and up to 5% of glioblastomas. We present the case of a female who was diagnosed and treated for a right intra and paraventricular giant cell glioblastoma. We enfatize the importance of histological features of this toumor related to its prognosis.

  14. Prognostic implications of epilepsy in glioblastomas.

    Science.gov (United States)

    Toledo, Manuel; Sarria-Estrada, Silvana; Quintana, Manuel; Maldonado, Xavier; Martinez-Ricarte, Francisco; Rodon, Jordi; Auger, Cristina; Salas-Puig, Javier; Santamarina, Estevo; Martinez-Saez, Elena

    2015-12-01

    The role of seizures and antiepileptic treatments associated with glioblastoma is a current topic of discussion. The objective of this study is to characterize and establish implications of epilepsy associated with glioblastoma. We retrospectively analyzed the medical history, focused on epileptic features of 134 histologically diagnosed glioblastoma over a period of 4 years. The sample group had an average age of 56 years and 66% were male. Complete tumor resection was performed in 66% and 64.2% received further radio-oncologic treatment. The average survival rate was 12.4 months and 11.5% survived to 5 years. Epileptic seizures were the presentation symptom in 27% of cases and 51% suffered seizures during the disease, 26% become drug-resistant. Focal evolving to a bilateral convulsive seizures were the most frequent type. Epileptic seizures at presentation independently predicted longer survival (pepilepsy or seizures during disease improved survival. Late onset seizures, recurrences or status epilepticus during the course of the disease indicated tumor progression or the final stages of life. Prophylactic antiepileptic drugs did not prevent seizures. Similarly, there was no difference in survival between patients who did not use antiepileptic drugs and those using valproate or levetiracetam. Patients under 60 years, full oncologic treatment and secondary glioblastomas were factors that improved survival (pepilepsy or the onset of seizures as a presentation symptom in glioblastomas predict longer survival. Half of patients have seizures during the course of the disease. Antiepileptic drugs alone do not increase survival in glioblastoma patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Emerging Biomarkers in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Warren P. Mason

    2013-08-01

    Full Text Available 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.

  16. 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.

  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. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. [Glioblastoma and nursing care in neurosurgery].

    Science.gov (United States)

    Lefort, Mathilde

    2017-02-01

    Nurses in neurosurgical departments play a critical role as they are involved in the first stages of the care pathway of patients with glioblastoma. Indeed, surgery enables a definitive histopathological diagnosis to be established and the size of the tumour to be significantly reduced, thereby improving the prognosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  19. Eosinophils in glioblastoma biology

    Directory of Open Access Journals (Sweden)

    Curran Colleen S

    2012-01-01

    Full Text Available Abstract Glioblastoma multiforme (GBM is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review.

  20. Flavopiridol's antiproliferative effects in glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Gozde Cobanoglu

    2016-01-01

    Conclusion: The present study demonstrated that flavopiridol did not induce caspase-3/7 activation, BIM, and BAX pro-apoptotic proteins but it leads to the expression changes of various proteins that inhibit proliferation and eternity in glioblastoma cell lines which have different genetic alterations.

  1. 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

  2. CD34 expression in glioblastoma and giant cell glioblastoma.

    Science.gov (United States)

    Galloway, M

    2010-01-01

    This study aimed to determine whether CD34 is expressed in glioblastomas and giant cell glioblastomas, as this information may be of value when attempting to differentiate between giant cell glioblastomas and other relevant differential diagnoses such as pleomorphic xanthoastrocytomas with anaplastic features and anaplastic gangliogliomas. 11 giant cell glioblastomas and 16 non-giant cell glioblastomas were assessed with immunocytochemical staining for CD34. Standard immunocytochemical techniques were used, to reflect the staining patterns likely to be seen in routine diagnostic practice. Positive staining refers to staining of neoplastic cells. 73% of giant cell glioblastomas showed some degree of staining for CD34, and 55% showed strong widespread staining. 56% of non-giant cell glioblastomas showed some degree of CD34 staining, and 25% showed strong widespread staining. Both giant cell and non-giant cell glioblastomas frequently show CD34 expression by neoplastic cells, which may in some cases be strong and diffuse. Strong widespread staining of neoplastic cells for CD34 was more frequent in giant cell than non-giant cell glioblastomas, however this difference was not statistically significant. CD34 staining in isolation is unlikely to be of assistance in differentiating between giant cell glioblastoma and pleomorphic xanthoastrocytomas with anaplastic features or anaplastic gangliogliomas.

  3. Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells

    Directory of Open Access Journals (Sweden)

    Chengbin Qu

    2017-09-01

    Full Text Available Glioblastoma (GBM is the most advanced and aggressive form of gliomas. Dihydroartemisinin (DHA has been shown to exhibit anti-tumor activity in various cancer cells. However, the effect and molecular mechanisms underlying its anti-tumor activity in human GBM cells remain to be elucidated. Our results proved that DHA treatment significantly reduced cell viability in a dose- and time-dependent manner by CCK-8 assay. Further investigation identified that the cell viability was rescued by pretreatment either with Z-VAD-FMK, 3-methyladenine (3-MA or in combination. Moreover, DHA induced apoptosis of GBM cells through mitochondrial membrane depolarization, release of cytochrome c and activation of caspases-9. Enhanced expression of GRP78, CHOP and eIF2α and activation of caspase 12 were additionally confirmed that endoplasmic reticulum (ER stress pathway of apoptosis was involved in the cytotoxicity of DHA. DHA-treated GBM cells exhibited the morphological and biochemical changes typical of autophagy. Co-treatment with chloroquine (CQ significantly induced the above effects. Furthermore, ER stress and mitochondrial dysfunction were involved in the DHA-induced autophagy. Further study revealed that accumulation of reactive oxygen species (ROS was attributed to the DHA induction of apoptosis and autophagy. The illustration of these molecular mechanisms will present a novel insight for the treatment of human GBM.

  4. Cotard's syndrome with glioblastoma multiforme.

    Science.gov (United States)

    Reich, Michel; Comet, Benedicte; Le Rhun, Emilie; Ramirez, Carole

    2012-06-01

    Brain tumors are classically associated with neurological and/or psychiatric symptomatology. Behavioral or cognitive disorders can underlie delirium, personality changes, psychotic reactions, and mood disorders. To illustrate this, we report the case of a 60-year-old male patient confronted with an inoperable glioblastoma multiforme on the splenium of the corpus callosum, of poor prognosis, treated by concomitant radiochemotherapy with temozolomide, who developed psychotic depression with Cotard's syndrome. Clinical manifestations of this syndrome with untoward consequences in terms of prognosis are classically characterized by intense moral suffering, indignity and pessimistic fixations, suicidal ideations, and a nihilistic delusion relating to one's own body. Nevertheless, this association between Cotard's syndrome and glioblastoma has been seldom described. To our knowledge, this is the first time that this has been described as a complication of this particular tumor location. Some neuropsychopathological hypotheses are proposed, which involve medical, iatrogenic, and psychogenesis issues. This case report points to the necessary collaboration between psychiatrists, neuro-oncologists and radiation oncologists in improving the patient's management and quality of life.

  5. 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)

  6. Nanomedicine based curcumin and doxorubicin combination treatment of glioblastoma with scFv-targeted micelles: In vitro evaluation on 2D and 3D tumor models.

    Science.gov (United States)

    Sarisozen, Can; Dhokai, Shekhar; Tsikudo, Edcar G; Luther, Ed; Rachman, Ilya M; Torchilin, Vladimir P

    2016-11-01

    NF-κB is strongly associated with poor prognosis of different cancer types and an important factor responsible for the malignant phenotype of glioblastoma. Overcoming chemotherapy-induced resistance caused by activation of PI3K/Akt and NF-κB pathways is crucial for successful glioblastoma therapy. We developed an all-in-one nanomedicine formulation for co-delivery of a chemotherapeutic agent (topoisomerase II inhibitor, doxorubicin) and a multidrug resistance modulator (NF-κB inhibitor, curcumin) for treatment of glioblastoma due to their synergism. Both agents were incorporated into PEG-PE-based polymeric micelles. The glucose transporter-1 (GLUT1) is overexpressed in many tumors including glioblastoma. The micellar system was decorated with GLUT1 antibody single chain fragment variable (scFv) as the ligand to promote blood brain barrier transport and glioblastoma targeting. The combination treatment was synergistic (combination index, CI of 0.73) against U87MG glioblastoma cells. This synergism was improved by micellar encapsulation (CI: 0.63) and further so with GLUT1 targeting (CI: 0.46). Compared to non-targeted micelles, GLUT1 scFv surface modification increased the association of micelles (>20%, P<0.01) and the nuclear localization of doxorubicin (∼3-fold) in U87MGcells, which also translated into enhanced cytotoxicity. The increased caspase 3/7 activation by targeted micelles indicates successful apoptosis enhancement by combinatory treatment. Moreover, GLUT1 targeted micelles resulted in deeper penetration into the 3D spheroid model. The increased efficacy of combination nanoformulations on the spheroids compared to a single agent loaded, or to non-targeted formulations, reinforces the rationale for selection of this combination and successful utilization of GLUT1 scFv as a targeting agent for glioblastoma treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. 11C-Methionine Positron Emission Tomographic Imaging of Biologic Activity of a Recurrent Glioblastoma Treated with Stereotaxy-Guided Laser-Induced Interstitial Thermotherapy

    Directory of Open Access Journals (Sweden)

    Norbert Galldiks

    2012-07-01

    Full Text Available In patients with recurrent glioblastoma multiforme (GBM, local minimally invasive treatment modalities have gained increasing interest recently because they are associated with fewer side effects than open surgery. For example, local tumor coagulation by laser-induced interstitial thermotherapy (LITT is such a minimally invasive technique. We monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent GBM using amino acid positron emission tomography (PET. Serial 11C-methyl-L-methionine positron emission tomography (MET-PET and contrast-enhanced computed tomography (CT were performed using a hybrid PET/CT system in a patient with recurrent GBM before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3 was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value.

  8. Glioblastoma: molecular analysis and its clinical implications

    OpenAIRE

    Castañeda, Carlos A.; Instituto Nacional de Enfermedades Neoplásicas. Lima, Perú.; Casavilca, Sandro; Instituto Nacional de Enfermedades Neoplásicas. Lima, Perú.; Orrego, Enrique; Instituto Nacional de Enfermedades Neoplásicas. Lima, Perú.; García-Corrochano, Pamela; Instituto Nacional de Enfermedades Neoplásicas. Lima, Perú.; Deza, Pedro; Instituto Nacional de Enfermedades Neoplásicas. Lima, Perú.; Heinike, Hugo; Instituto Nacional de Enfermedades Neoplásicas. Lima, Perú.; Castillo, Miluska; Instituto Nacional de Enfermedades Neoplásicas. Lima, Perú.; Belmar-Lopez, Carolina; Instituto Nacional de Enfermedades Neoplásicas. Lima, Perú.; Ojeda, Luis; Instituto Nacional de Enfermedades Neoplásicas. Lima, Perú.

    2015-01-01

    Glioblastoma (GB) is the most common and most lethal primary brain tumor. Epidemiologic information indicatethat its incidence is lower in Hispanic race. Surgery is the only curative strategy and has recently introduced newstrategies that increase resection rates. The use of concurrent chemotherapy with radiotherapy improves survival ofpatients but is associated with toxicity. Improved understanding of molecular biology of GB allows the identification ofpredictive biomarkers of response and p...

  9. Overexpression of Large-Conductance Calcium-Activated Potassium Channels in Human Glioblastoma Stem-Like Cells and Their Role in Cell Migration.

    Science.gov (United States)

    Rosa, Paolo; Sforna, Luigi; Carlomagno, Silvia; Mangino, Giorgio; Miscusi, Massimo; Pessia, Mauro; Franciolini, Fabio; Calogero, Antonella; Catacuzzeno, Luigi

    2017-09-01

    Glioblastomas (GBMs) are brain tumors characterized by diffuse invasion of cancer cells into the healthy brain parenchyma, and establishment of secondary foci. GBM cells abundantly express large-conductance, calcium-activated potassium (BK) channels that are thought to promote cell invasion. Recent evidence suggests that the GBM high invasive potential mainly originates from a pool of stem-like cells, but the expression and function of BK channels in this cell subpopulation have not been studied. We investigated the expression of BK channels in GBM stem-like cells using electrophysiological and immunochemical techniques, and assessed their involvement in the migratory process of this important cell subpopulation. In U87-MG cells, BK channel expression and function were markedly upregulated by growth conditions that enriched the culture in GBM stem-like cells (U87-NS). Cytofluorimetric analysis further confirmed the appearance of a cell subpopulation that co-expressed high levels of BK channels and CD133, as well as other stem cell markers. A similar association was also found in cells derived from freshly resected GBM biopsies. Finally, transwell migration tests showed that U87-NS cells migration was much more sensitive to BK channel block than U87-MG cells. Our data show that BK channels are highly expressed in GBM stem-like cells, and participate to their high migratory activity. J. Cell. Physiol. 232: 2478-2488, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. Motor Activity Improves Temporal Expectancy

    Science.gov (United States)

    Fautrelle, Lilian; Mareschal, Denis; French, Robert; Addyman, Caspar; Thomas, Elizabeth

    2015-01-01

    Certain brain areas involved in interval timing are also important in motor activity. This raises the possibility that motor activity might influence interval timing. To test this hypothesis, we assessed interval timing in healthy adults following different types of training. The pre- and post-training tasks consisted of a button press in response to the presentation of a rhythmic visual stimulus. Alterations in temporal expectancy were evaluated by measuring response times. Training consisted of responding to the visual presentation of regularly appearing stimuli by either: (1) pointing with a whole-body movement, (2) pointing only with the arm, (3) imagining pointing with a whole-body movement, (4) simply watching the stimulus presentation, (5) pointing with a whole-body movement in response to a target that appeared at irregular intervals (6) reading a newspaper. Participants performing a motor activity in response to the regular target showed significant improvements in judgment times compared to individuals with no associated motor activity. Individuals who only imagined pointing with a whole-body movement also showed significant improvements. No improvements were observed in the group that trained with a motor response to an irregular stimulus, hence eliminating the explanation that the improved temporal expectations of the other motor training groups was purely due to an improved motor capacity to press the response button. All groups performed a secondary task equally well, hence indicating that our results could not simply be attributed to differences in attention between the groups. Our results show that motor activity, even when it does not play a causal or corrective role, can lead to improved interval timing judgments. PMID:25806813

  11. Immunological Evasion in Glioblastoma

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    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.

  12. Nanotechnology Applications for Glioblastoma

    Science.gov (United States)

    Nduom, Edjah; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G.

    2012-01-01

    Synopsis Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. While conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting the residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds much promise in the use of multifunctional nanoparticles for the imaging and targeted therapy of GBM.. Nanoparticles have emerged as potential “theranostic” agents that can permit the diagnosis and therapeutic treatment of GBM tumors. A recent human clinical trial with magnetic nanoparticles has provided feasibility and efficacy data for potential treatment of GBM patients with thermotherapy. Here we examine the current state of nanotechnology in the treatment of glioblastoma and interesting directions of further study. PMID:22748656

  13. RGD peptide conjugation results in enhanced antitumor activity of PD0325901 against glioblastoma by both tumor-targeting delivery and combination therapy.

    Science.gov (United States)

    Hou, Jianjun; Diao, Yiping; Li, Wei; Yang, Zhenjun; Zhang, Lihe; Chen, Zili; Wu, Yun

    2016-05-30

    Glioblastoma (GBM) is the most aggressive tumor type in the central nervous system. Both tumor-targeting drug delivery and combination therapy of multiple therapeutic agents with distinct mechanisms are important for GBM treatment. We combined these two strategies and developed a new platform of peptide-drug conjugate (RGD-PEG-Suc-PD0325901, W22) for tumor-targeting delivery using a combination of PD0325901 (a MEK1/2 inhibitor) and RGD peptide. In the present study, the combination of PD0325901 and RGD peptide strongly inhibited U87MG model in vitro and in vivo. This inhibition contributed to synergistic suppression of cell proliferation by blocking ERK pathway activity and cell migration. Modified by conjugation strategy, their conjugate W22 enhanced PD0325901 delivery to GBM cells by receptor mediated cellular internalization. W22 showed great superiority in targeting to U87MG xenografted tumors and strong anti-tumor efficacy based on ERK pathway inhibition and tumor-targeted delivery in vitro and in vivo. Moreover, W22 was stable in serum and able to release PD0325901 in the enzymatic environment. These data indicated that the RGD-PEG-Suc-PD0325901 conjugate provided a strategy for effective delivery of PD0325901 and RGD peptide into the GBM cells and inhibition of tumor growth in a synergistic manner. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. CD47 activation-induced UHRF1 over-expression is associated with silencing of tumor suppressor gene p16INK4A in glioblastoma cells.

    Science.gov (United States)

    Boukhari, Abdelaziz; Alhosin, Mahmoud; Bronner, Christian; Sagini, Krizia; Truchot, Cécile; Sick, Emilie; Schini-Kerth, Valerie B; André, Philippe; Mély, Yves; Mousli, Marc; Gies, Jean-Pierre

    2015-01-01

    CD47, an integrin-associated protein is over-expressed in several tumors including glioblastomas. Activation of CD47 induces proliferation of human astrocytoma cells but not normal astrocytes via an Akt-dependent way. However, the pathways mediating this process are still unknown. The epigenetic integrator UHRF1 (Ubiquitin-like containing PHD and RING Finger 1) is over-expressed in various cancers and plays a vital role in the silencing of numerous tumor suppressor genes including p16(INK4A), thereby promoting cell proliferation. The aim of the present study was to investigate the role of UHRF1 and p16(INK4A) in CD47-induced effects. Herein we showed that activation of CD47 in human astrocytoma cell lines U87 and CCF- STTG1 (Grade IV), up-regulated the expression of UHRF1 with subsequent down-regulation of p16(INK4A), thus promoting cell proliferation. Blockage of CD47 using a blocking antibody down-regulated UHRF1 expression, accompanied by a re-expression of p16(INK4A), conducting to decreased cell proliferation in both cancer cell lines. Neither CD47 activation nor its blocking has any effect on UHRF1/p16(INK4A) expression in normal human astrocytes. Depletion of CD47 in the U87 cell line resulted in down-regulation of UHRF1. We also found that CD47 activated the inflammatory genes IL-6, IL-7 and MCP-1 by a NF-κB-dependent mechanism in human astrocytoma but not in normal astrocytes. In conclusion, the present findings indicate that CD47 activation increases expression of UHRF1 and suggest, for the first time, that CD47 regulates the epigenetic code by targeting UHRF1. This could represent a new pathway towards cell proliferation and metastasis. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Inhibition of the Autophagy Pathway Synergistically Potentiates the Cytotoxic Activity of Givinostat(ITF2357on Human Glioblastoma Cancer Stem Cells

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    Francesca Angeletti

    2016-10-01

    Full Text Available Increasing evidence highlighted the role of cancer stem cells (CSCs in the development of tumor resistance to therapy, particularly in glioblastoma (GBM. Therefore, the development of new therapies, specifically directed against GBM CSCs, constitutes an important research avenue. Considering the extended range of cancer-related pathways modulated by histone acetylation/deacetylation processes, we studied the anti-proliferative and pro-apoptotic efficacy of givinostat (GVS, a pan-histone deacetylase inhibitor, on cell cultures enriched in CSCs, isolated from nine human GBMs. We report that GVS induced a significant reduction of viability and self-renewal ability in all GBM CSC cultures; conversely, GVS exposure did not cause a significant cytotoxic activity toward differentiated GBM cells and normal mesenchymal human stem cells.Analysing the cellular and molecular mechanisms involved, we demonstrated that GVS affected CSC viability through the activation of programmed cell death pathways. In particular, a marked stimulation of macroautophagy was observed after GVS treatment. To understand the functional link between GVS treatment and autophagy activation, different genetic and pharmacological interfering strategies were used. We show that the up-regulation of the autophagy process, obtained by deprivation of growth factors, induced a reduction of CSC sensitivity to GVS, while the pharmacological inhibition of the autophagy pathway and the silencing of the key autophagy gene ATG7, increased the cell death rate induced by GVS. Altogether these findings suggest that autophagy represents a pro-survival mechanism activated by GBM CSCs to counteract the efficacy of the anti-proliferative activity of GVS. In conclusion, we demonstrate that GVS is a novel pharmacological tool able to target GBM CSC viability and its efficacy can be enhanced by autophagy inhibitory strategies.

  16. 4G/5G and A-844G Polymorphisms of Plasminogen Activator Inhibitor-1 Associated with Glioblastoma in Iran--a Case-Control Study.

    Science.gov (United States)

    Pooyan, Honari; Ahmad, Ebrahimi; Azadeh, Rakhshan

    2015-01-01

    Glioblastoma is a highly aggressive and malignant brain tumor. Risk factors are largely unknown however, although several biomarkers have been identified which may support development, angiogenesis and invasion of tumor cells. One of these biomarkers is PAI-1. 4G/5G and A-844G are two common polymorphisms in the gene promotor of PAI 1 that may be related to high transcription and expression of this gene. Studies have shown that the prevalence of the 4G and 844G allele is significantly higher in patients with some cancers and genetic disorders. We here assessed the association of 4G/5G and A-844G polymorphisms with glioblastoma cancer risk in Iranians in a case-control study. All 71 patients with clinically confirmed and 140 volunteers with no history and symptoms of glioblastoma as control group were screened for 4G/5G and A-844G polymorphisms of PAI-1, using ARMS-PCR. Genotype and allele frequencies of case and control groups were analyzed using the DeFinetti program. Our results showed significant associations between 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms of the PAI-1 gene with glioblastoma cancer risk in our Iranian population. The results of this study supporting an association of the PAI-1 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms with increasing glioblastoma cancer risk in Iranian patients.

  17. Tumor hypoxia: Impact on gene amplification in glioblastoma.

    Science.gov (United States)

    Fischer, Ulrike; Radermacher, Jens; Mayer, Jens; Mehraein, Yasmin; Meese, Eckart

    2008-09-01

    Gene amplification is frequently found in human glioblastoma but the mechanisms driving amplifications remain to be elucidated. Hypoxia as hallmark of glioblastoma is known to be involved in the induction of fragile sites that are central to gene amplification. We analyzed the potential of hypoxia (pO2 0%) and mini hypoxia (pO2 5%) to induce fragile sites within a homogeneously staining region (HSR) at 12q14-15 in a glioblastoma cell line (TX3868). Treatment of cells by hypoxia or by mini hypoxia induced double minutes (DMs) and caused breakage of the HSR structure at 12q14-15, suggesting a novel hypoxia inducible fragile site on 12q. Treatment with aphidicolin, a known fragile site inducer, indicates that the hypoxia inducible fragile site is a common fragile site. Reintegration of amplified sequences and occurrence of anaphase-bridge-like structures shows that mini hypoxia and hypoxia are able to initiate amplification processes in human glioblastoma cells. Hypoxia as known tumor microenvironment factor is crucial for the development of amplifications in glioblastoma. The identification and characterization of novel common fragile sites induced by hypoxia will improve the understanding of mechanisms underlying amplifications in glioblastoma.

  18. Curcumin potentiates the potent antitumor activity of ACNU against glioblastoma by suppressing the PI3K/AKT and NF-κB/COX-2 signaling pathways

    Directory of Open Access Journals (Sweden)

    Zhao J

    2017-11-01

    Full Text Available Jun Zhao,1,* Jiabin Zhu,2,* Xiaoshu Lv,3 Jinshan Xing,4 Shuang Liu,5 Chen Chen,6 Yinghui Xu1 1Department of Neurosurgery, 2Department of Urology, First Affiliated Hospital of Dalian Medical University, 3Department of Endocrinology, 4Department of Neurosurgery, 5Department of Gastroenterology, Second Affiliated Hospital of Dalian Medical University, 6Department of Cardiovascular, First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China *These authors contributed equally to this work Abstract: Glioblastoma (GBM is a highly invasive and challenging primary tumor of the central nervous system (CNS, and currently available treatments provide limited benefits to patients with this disease. Therefore, the development of novel therapeutic targets and effective treatment strategies is essential. Nimustine hydrochloride (ACNU is widely used as the standard chemotherapeutic agent and is frequently administered together with other chemotherapeutic agents in clinical studies. Curcumin, a natural polyphenolic compound, could potentially be combined with chemotherapeutics for cancer treatment; however, there are no reports of studies where ACNU and curcumin were combined for GBM treatment, and the mechanisms underlying their activity remain poorly understood. In the present study, we investigated the effects of combined treatment with curcumin and ACNU on GBM cells and found that it significantly enhanced the inhibition of cell proliferation, colony formation, migration, and invasion. In addition, co-treatment with curcumin increased ACNU-induced apoptosis through enhancing the release of cytochrome c from the mitochondrial intermembrane space into the cytosol. Further, curcumin and ACNU acted synergistically in their antitumor effects by targeting N-cadherin/MMP2/9, PI3K/AKT, and NF-κB/COX-2 signaling. These results indicate that curcumin can enhance the anti-proliferation, anti-migration, and proapoptotic activities of

  19. 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

  20. Differential Activity of NADPH-Producing Dehydrogenases Renders Rodents Unsuitable Models to Study IDH1(R132) Mutation Effects in Human Glioblastoma

    NARCIS (Netherlands)

    Atai, Nadia A.; Renkema-Mills, Nynke A.; Bosman, Joost; Schmidt, Nadja; Rijkeboer, Denise; Tigchelaar, Wikky; Bosch, Klazien S.; Troost, Dirk; Jonker, Ard; Bleeker, Fonnet E.; Miletic, Hrvoje; Bjerkvig, Rolf; de Witt Hamer, Philip C.; van Noorden, Cornelis J. F.

    2011-01-01

    The somatic IDH1(R132) mutation in the isocitrate dehydrogenase 1 gene occurs in high frequency in glioma and in lower frequency in acute myeloid leukemia and thyroid cancer but not in other types of cancer. The mutation causes reduced NADPH production capacity in glioblastoma by 40% and is

  1. 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.

  2. Harnessing nanomedicine for therapeutic intervention in glioblastoma.

    Science.gov (United States)

    Gutkin, Anna; Cohen, Zvi R; Peer, Dan

    2016-11-01

    Glioblastoma is a type of brain cancer arises from glial cells. Glioblastoma multiforme (GBM), a subtype of glioblastoma, is the most common and most aggressive primary brain tumor. Currently, GBM therapy includes surgery and post-operative high-doses of radiation and chemotherapy. This therapeutic strategy has a limited contribution in extending the survival rate of GBM patients. Areas covered: Herein, we focus on harnessing nanoscale drug delivery strategies to treat brain malignancies. Specifically, we briefly discuss the challenges facing GBM therapy such as restricted passage across the blood-brain barrier (BBB) and low enhanced permeability and retention effect. Next, we describe different pathways to address these challenges. Finally, we discuss the field of nanomedicine, which emerged as a promising platform for drug delivery to brain malignancies. Expert opinion: Countless strategies have been applied in preclinical and clinical settings to treat GBM. Among them is the use of different types of nanoparticles (NPs) and viruses with different approaches to cross or bypass the BBB. We suggest here a paradigm shift in thinking about crossing the BBB and tumor penetration as fundamental issues that need to be address in order to improve the therapeutic outcome in GBM.

  3. STAT-1 expression in human glioblastoma and peritumoral tissue.

    Science.gov (United States)

    Haybaeck, J; Obrist, P; Schindler, C U; Spizzo, G; Doppler, W

    2007-01-01

    Glioblastoma is a very aggressive brain tumour with poor prognosis despite radical surgery or radiotherapy. Signal transducers and activators of transcription (STAT) proteins are important elements in intracellular signalling and part of the JAK-STAT pathway. They are activated by growth factors and cytokines and translocate into the nucleus upon activation to exert their function as transcription factors. STAT-1 can be induced by interferons and has also been found to be important in sensitizing tumours to chemotherapeutic drugs. Forty-six glioblastoma samples have been analysed for the expression of STAT-1 by immunohistochemistry. In our study performed by immunohistochemistry, 22 out of 46 glioblastomas (48%) were strongly positive for staining with a STAT-1 antibody, 9 (20%) showed an intermediate reactivity, 8 (17%) low immunoreactivity, and 7 (15%) were completely negative. In the tumour tissue, STAT-1 expression was mostly localized in the cytoplasm. This location of STAT-1 suggests the predominant presence of an inactive form of STAT-1. Tumour giant cells were frequently strongly stained. Part of the peritumoral brain tissue showed strongly positively reactive glial cells. Interestingly, within the infiltration area strong STAT-1 expression was found in reactive astrocytes, glia, and particularly in microglial components. The expression of STAT-1 in the majority of glioblastomas, together with its documented role in apoptosis and in the action of chemotherapeutic drugs on tumour cell lines point to a possible function of this protein in the response of glioblastomas to chemotherapy.

  4. Physical Activity Improves Quality of Life

    Science.gov (United States)

    ... It Works Healthy Workplace Food and Beverage Toolkit Physical activity improves quality of life Updated:Mar 2,2015 ... proven to improve both mental and physical health. Physical activity boosts mental wellness. Regular physical activity can relieve ...

  5. Immunotherapy with subcutaneous immunogenic autologous tumor lysate increases murine glioblastoma survival.

    Science.gov (United States)

    Belmans, Jochen; Van Woensel, Matthias; Creyns, Brecht; Dejaegher, Joost; Bullens, Dominique M; Van Gool, Stefaan W

    2017-10-24

    Immunotherapeutic strategies for glioblastoma, the most frequent malignant primary brain tumor, aim to improve its disastrous consequences. On top of the standard treatment, one strategy uses T cell activation by autologous dendritic cells (DC) ex vivo loaded with tumor lysate to attack remaining cancer cells. Wondering whether 'targeting' in vivo DCs could replace these ex vivo ones, immunogenic autologous tumor lysate was used to treat glioma-inoculated mice in the absence of ex vivo loaded DCs. Potential immune mechanisms were studied in two orthotopic, immunocompetent murine glioma models. Pre-tumoral subcutaneous lysate treatment resulted in a survival benefit comparable to subcutaneous DC therapy. Focussing on the immune response, glioma T cell infiltration was observed in parallel with decreased amounts of regulatory T cells. Moreover, these results were accompanied by the presence of strong tumor-specific immunological memory, shown by complete survival of a second glioblastoma tumor, inoculated 100 days after the first one. Finally, in combination with temozolomide, survival of established glioma in mice could be increased. Our results show the potential of immunogenic autologous tumor lysate used to treat murine glioblastoma, which will be worthwhile to study in clinical trials as it has potential as a cost-efficient adjuvant treatment strategy for gliomas.

  6. Dendritic cell vaccination in glioblastoma after fluorescence-guided resection

    Science.gov (United States)

    Valle, Ricardo Diez; de Cerio, Ascension Lopez-Diaz; Inoges, Susana; Tejada, Sonia; Pastor, Fernando; Villanueva, Helena; Gallego, Jaime; Espinos, Jaime; Aristu, Javier; Idoate, Miguel Angel; Andreu, Enrique; Bendandi, Maurizio

    2012-01-01

    AIM: To assess whether the addition of a customized, active immunotherapy to standard of care including fluorescence-guided surgery, may provide hints of an improved survival for patients with poor-prognosis, incurable glioblastoma multiform. METHODS: Preliminary to our ongoing, phase-II clinical trial, we conducted a small pilot study enrolling five consecutive patients with resectable glioblastoma. In terms of Recursive Partitioning Analysis, four patients were class V and one was class IV. In all five cases, fluorescence-guided surgery was employed, followed by rapid steroid discontinuation. Patients were then treated with a combination of standard radio-chemotherapy with temozolomide and tumor lysate-pulsed, mature dendritic cell-based vaccinations. RESULTS: Though all five patients ultimately progressed, with any further treatment left to the sole decision of the treating oncologist, active immunotherapy was very well tolerated and induced specific immune responses in all three patients for whom enough material was available for such an assessment. Median progression-free survival was 16.1 mo. Even more important, median and mean overall survival were 27 mo and 26 mo, respectively. Three patients have died with an overall survival of 9 mo, 27 mo and 27.4 mo, while the other two are still alive at 32 mo and 36 mo, the former receiving treatment with bevacizumab, while the latter has now been off therapy for 12 mo. Four of five patients were alive at two years. CONCLUSION: Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-II study is ongoing to possibly improve further on our very encouraging clinical results. PMID:23293753

  7. RT-21Mre11-Rad50-Nbs1 COMPLEX INHIBITOR MIRIN ENHANCES RADIOSENSITIVITY IN HUMAN GLIOBLASTOMA CELLS

    OpenAIRE

    Mishima, Kazuhiko; Mishima-Kaneko, Masayo; Saya, Hideyuki; Ishimaru, Naozumi; Yamada, Kouichi; Fukada, Junichi; Nishikawa, Ryo; Kawata, Tetsuya

    2014-01-01

    PURPOSE: Radiation therapy plays a central part in the treatment of glioblastoma, however, it is not curative due to the high tumor radioresistance. Therefore, increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma. The Mre11, Rad 50 and Nbs1 proteins form a complex (MRN) that has a critical role in DNA damage detection and signaling. Because defects in MRN enhance radiosensitivity, it has been proposed that smal...

  8. Combination of RGD compound and low-dose paclitaxel induces apoptosis in human glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Ming-Wei Chang

    Full Text Available BACKGROUND: Integrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-αvβ3 is expressed on the surface of human glioblastoma cells, and can be further induced by chemical stress. The Arg-Gly-Asp (RGD motif-containing peptides are specifically bound to integrin-αvβ3, and to inhibit neovasculature underlying competition to normal extracellular matrix proteins. This study employed two types of RGD peptides, cyclic RGD (c(RGDyK and bi-cyclic RGD (E[c(RGDyK](2 peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis. PRINCIPAL FINDINGS: Human glioblastoma U87MG cells were treated with RGD peptides in the absence or presence of initial exposure to low-dose 10 nM PTX. Results showed that integrin-αvβ3 expressing on the surface of U87MG cells was induced by 10 nM PTX pre-treatment for 12 hrs. Additionally, the U87MG cells pre-treated with PTX and followed by RGD peptides exhibited greater expression of caspases-3, -8 and -9 than those merely treated with single agent of PTX or RGD peptide. Furthermore, the caspase-3, -8 and -9 inhibitor presented significant protection against E[c(RGDyK](2 peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvβ3 was correlated with the enhanced apoptosis in U87MG cells. CONCLUSIONS: This study provides a novel concept of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve efficiency in human glioblastoma treatment.

  9. Combination of RGD Compound and Low-Dose Paclitaxel Induces Apoptosis in Human Glioblastoma Cells

    Science.gov (United States)

    Chang, Ming-Wei; Lo, Jem-Mau; Juan, Hsueh-Fen; Chang, Hsin-Yi; Chuang, Chun-Yu

    2012-01-01

    Background Integrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-αvβ3 is expressed on the surface of human glioblastoma cells, and can be further induced by chemical stress. The Arg-Gly-Asp (RGD) motif-containing peptides are specifically bound to integrin-αvβ3, and to inhibit neovasculature underlying competition to normal extracellular matrix proteins. This study employed two types of RGD peptides, cyclic RGD (c(RGDyK)) and bi-cyclic RGD (E[c(RGDyK)]2) peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX) pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis. Principal Findings Human glioblastoma U87MG cells were treated with RGD peptides in the absence or presence of initial exposure to low-dose 10 nM PTX. Results showed that integrin-αvβ3 expressing on the surface of U87MG cells was induced by 10 nM PTX pre-treatment for 12 hrs. Additionally, the U87MG cells pre-treated with PTX and followed by RGD peptides exhibited greater expression of caspases-3, -8 and -9 than those merely treated with single agent of PTX or RGD peptide. Furthermore, the caspase-3, -8 and -9 inhibitor presented significant protection against E[c(RGDyK)]2 peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvβ3 was correlated with the enhanced apoptosis in U87MG cells. Conclusions This study provides a novel concept of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve efficiency in human glioblastoma treatment. PMID:22655084

  10. Rosmarinic Acid and Melissa officinalis Extracts Differently Affect Glioblastoma Cells

    OpenAIRE

    Kristina Ramanauskiene; Raimondas Raudonis; Daiva Majiene

    2016-01-01

    Lemon balm (Melissa officinalis L.) has many biological effects but especially important is its neuroprotective activity. The aim of the study is to produce different extracts of Melissa officinalis and analyse their chemical composition and biological properties on rat glioblastoma C6 cells. Results revealed that rosmarinic acid (RA) is the predominant compound of lemon balm extracts. RA has cytotoxic effect on glioblastoma cells (LC50 290.5 μM after the incubation of 24 h and LC50 171.3 μM ...

  11. 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.

  12. Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme

    NARCIS (Netherlands)

    Verhoeff, J.J.C.; van Tellingen, O.; Claes, A.; Stalpers, L.J.A.; van Linde, M.E.; Richel, D.J.; Leenders, W.P.J.; van Furth, W.R.

    2009-01-01

    BACKGROUND: The relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours. Although patients benefit greatly from reduced cerebral oedema and intracranial pressure, this important clinical improvement

  13. 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

  14. 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

  15. 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.)

  16. Rosmarinic Acid and Melissa officinalis Extracts Differently Affect Glioblastoma Cells.

    Science.gov (United States)

    Ramanauskiene, Kristina; Raudonis, Raimondas; Majiene, Daiva

    Lemon balm (Melissa officinalis L.) has many biological effects but especially important is its neuroprotective activity. The aim of the study is to produce different extracts of Melissa officinalis and analyse their chemical composition and biological properties on rat glioblastoma C6 cells. Results revealed that rosmarinic acid (RA) is the predominant compound of lemon balm extracts. RA has cytotoxic effect on glioblastoma cells (LC50 290.5 μM after the incubation of 24 h and LC50 171.3 μM after 48 h). RA at concentration 80-130 μM suppresses the cell proliferation and has an antioxidant effect. 200 μM and higher concentrations of RA have a prooxidant effect and initiate cell death through necrosis. The aqueous extract of lemon balm is also enriched in phenolic compounds: protocatechuic, caftaric, caffeic, ferulic, and cichoric acids and flavonoid luteolin-7-glucoside. This extract at concentrations 50 μM-200 μM RA has cytotoxic activity and initiates cell death through apoptosis. Extracts prepared with 70% ethanol contain the biggest amount of active compounds. These extracts have the highest cytotoxic activity on glioblastoma cells. They initiate generation of intracellular ROS and cell death through apoptosis and necrosis. Our data suggest that differently prepared lemon balm extracts differently affect glioblastoma cells and can be used as neuroprotective agents in several therapeutic strategies.

  17. Rosmarinic Acid and Melissa officinalis Extracts Differently Affect Glioblastoma Cells

    Directory of Open Access Journals (Sweden)

    Kristina Ramanauskiene

    2016-01-01

    Full Text Available Lemon balm (Melissa officinalis L. has many biological effects but especially important is its neuroprotective activity. The aim of the study is to produce different extracts of Melissa officinalis and analyse their chemical composition and biological properties on rat glioblastoma C6 cells. Results revealed that rosmarinic acid (RA is the predominant compound of lemon balm extracts. RA has cytotoxic effect on glioblastoma cells (LC50 290.5 μM after the incubation of 24 h and LC50 171.3 μM after 48 h. RA at concentration 80–130 μM suppresses the cell proliferation and has an antioxidant effect. 200 μM and higher concentrations of RA have a prooxidant effect and initiate cell death through necrosis. The aqueous extract of lemon balm is also enriched in phenolic compounds: protocatechuic, caftaric, caffeic, ferulic, and cichoric acids and flavonoid luteolin-7-glucoside. This extract at concentrations 50 μM–200 μM RA has cytotoxic activity and initiates cell death through apoptosis. Extracts prepared with 70% ethanol contain the biggest amount of active compounds. These extracts have the highest cytotoxic activity on glioblastoma cells. They initiate generation of intracellular ROS and cell death through apoptosis and necrosis. Our data suggest that differently prepared lemon balm extracts differently affect glioblastoma cells and can be used as neuroprotective agents in several therapeutic strategies.

  18. IDH mutation and MGMT promoter methylation are associated with the pseudoprogression and improved prognosis of glioblastoma multiforme patients who have undergone concurrent and adjuvant temozolomide-based chemoradiotherapy.

    Science.gov (United States)

    Li, Hailong; Li, Jiye; Cheng, Gang; Zhang, Jianning; Li, Xuezhen

    2016-12-01

    This study aimed to investigate the potential association between IDH mutation and O 6 -methyl-guanine methyl transferase (MGMT) gene promoter methylation and pseudoprogression disease (psPD) in glioblastoma multiforme (GBM) patients after concurrent temozolomide (TMZ)-based chemoradiotherapy. A total of 157 GBM patients who received concurrent TMZ-based chemoradiotherapy were included in this retrospective study. The association between psPD and a number of demographic and genetic factors, including IDH mutation and MGMT promoter methylation, were analyzed based on logistic regression, Cox regression, and multivariate analysis. Of the 157 GBM patients, 145 (92.36%) patients, including 38 patients with psPD, 38 patients with early progression (ePD), and 69 patients with non-progression (non-PD), were followed up for six to 56 months. We identified a higher rate of MGMT promoter methylation and IDH1 mutation in psPD patients compared with ePD patients (P=0.002). In addition, MGMT promoter methylation and IDH1 mutation predicted a high probability of psPD development in GBM patients (P=0.001 and PIDH1 mutation, Karnofsky performance score (KPS) ≥70, and psPD were associated with a significantly longer overall survival of GBM patients (P=0.001, 0.001, 0.002, and PIDH mutation had a cumulative effect on the OS of GBM patients. GBM patients with psPD (39.2±2.1months, PIDH1 mutation were associated with PsPD and predicted a longer median survival in GBM patients after TMZ-based chemoradiotherapy. Genetic analyses of the MGMT promoter and IDH1 may allow us to effectively treat GBM patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression

    Directory of Open Access Journals (Sweden)

    Nienke A. de Vries

    2015-01-01

    Full Text Available EZH2 is frequently overexpressed in glioblastoma (GBM, suggesting an oncogenic function that could be a target for therapeutic intervention. However, reduced EZH2 activity can also promote tumorigenesis, leading to concerns about the use of EZH2 inhibitors. Here, we provide further insight about the effects of prolonged Ezh2 inhibition in glioblastoma using preclinical mouse models and primary tumor-derived human GBM cell lines. Using doxycycline-inducible shRNAs that mimic the effects of a selective EZH2 inhibitor, we demonstrate that prolonged Ezh2 depletion causes a robust switch in cell fate, including significantly enhanced proliferation, DNA damage repair, and activation of part of the pluripotency network, resulting in altered tumor cell identity and tumor progression. Short-term Ezh2 depletion significantly improved survival without the tumor progression observed upon prolonged Ezh2 depletion, suggesting that precise dosing regiments are very important. These results could be of high clinical relevance with regard to how glioblastomas should be treated with epigenetic therapies.

  20. Effects of single or combined treatments with radiation and chemotherapy on survival and danger signals expression in glioblastoma cell lines.

    Science.gov (United States)

    Pasi, Francesca; Paolini, Alessandro; Nano, Rosanna; Di Liberto, Riccardo; Capelli, Enrica

    2014-01-01

    The success of chemo- and radiotherapy in glioblastoma multiforme, the most common and lethal primary brain tumour, could rely on the induction of immunogenic tumour cell death and on the induction of anticancer immune response. In this study we investigated cell survival to single treatments or combination of X-rays and temozolomide in glioblastoma cell lines (T98G and U251MG) and we attempted to identify danger signals (HMGB1 and HSP70) released by dying cells in the microenvironment that could activate antitumour immunity contributing to the therapeutic efficacy of conventional treatments. Our data suggest that HSP70 translocates from cytoplasm to extracellular environment after an increase in radiation dose and HMGB1 translocates from the nucleus to the cytoplasm and subsequently is released into the extracellular space, confirming a role of these proteins as signals released after radiation-induced damage in glioblastoma cells. We also could state that TMZ had limited effectiveness in activating HMGB1 and HSP70 signalling and, instead, an adjuvant effect was observed in some combined treatments, depending on schedule, cell line, and timing. A big challenge in tumour therapy is, therefore, to identify the most beneficial combination and chronology of multiple treatment options to contribute to the improvement of the therapeutic outcome.

  1. Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression.

    Science.gov (United States)

    Perazzoli, Gloria; Prados, Jose; Ortiz, Raul; Caba, Octavio; Cabeza, Laura; Berdasco, Maria; Gónzalez, Beatriz; Melguizo, Consolación

    2015-01-01

    The use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated. Four nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2'-deoxycytidine was used to demethylate the MGMT promoter and O(6)-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed. Our results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229) and high (SF268 and SK-N-SH) basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC50 showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC50 did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC50, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines. These results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma multiforme patients.

  2. 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...

  3. 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...

  4. 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...

  5. Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme.

    Science.gov (United States)

    Hakin-Smith, V; Jellinek, D A; Levy, D; Carroll, T; Teo, M; Timperley, W R; McKay, M J; Reddel, R R; Royds, J A

    2003-03-08

    Despite advances in the molecular pathogenesis of glioblastoma multiforme, no reliable prognostic markers have been identified. We analysed telomerase activity and telomere lengths in glioblastoma multiformes from 77 patients. 19 patients (25%) had tumours with the alternative-lengthening-of-telomere (ALT) phenotype. Median survival for patients with this phenotype was 542 days (95% CI 114-970) compared with 247 days (224-270) for glioblastoma multiformes with normal telomeres (p=0.0003). Cox's regression analysis showed that this association is independent of age. In patients with non-ALT tumours, telomerase activity did not affect survival (median 287 [199-375] vs 236 [230-242] days, p=0.275). We conclude that ALT is a prognostic indicator for patients with glioblastoma multiforme.

  6. 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

  7. 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.

  8. RT-21Mre11-Rad50-Nbs1 COMPLEX INHIBITOR MIRIN ENHANCES RADIOSENSITIVITY IN HUMAN GLIOBLASTOMA CELLS

    Science.gov (United States)

    Mishima, Kazuhiko; Mishima-Kaneko, Masayo; Saya, Hideyuki; Ishimaru, Naozumi; Yamada, Kouichi; Fukada, Junichi; Nishikawa, Ryo; Kawata, Tetsuya

    2014-01-01

    PURPOSE: Radiation therapy plays a central part in the treatment of glioblastoma, however, it is not curative due to the high tumor radioresistance. Therefore, increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma. The Mre11, Rad 50 and Nbs1 proteins form a complex (MRN) that has a critical role in DNA damage detection and signaling. Because defects in MRN enhance radiosensitivity, it has been proposed that small molecule inhibitors targeted to these proteins might be used as radiosensitizers. Here, we investigated the effects of the MRN complex inhibitor, Mirin, on radiation response of human glioma cells. MATERIALS AND METHODS: Glioma cell lines (U251, LN229 and LN428) were irradiated with and without Mirin and then clonogenicity, apoptosis, and cell cycle change were examined. Western blot analysis was performed to determine the relative potency of Mirin to inhibit the radioresistance, through the signaling activity of AKT. We also examined the levels of H2AX phosphorylation (γH2AX), which is a marker of DNA double-strand breaks (DSBs) using Western blot. RESULTS: Glioblastoma cells pretreated with Mirin demonstrated an enhanced sensitivity to radiation. FACS analysis revealed that Mirin and radiation caused the glioma cells to accumulate in the G2/M-phase of the cell cycle and the combination of these two treatments further increased the G2/M fraction of the glioma cells. Mirin significantly enhanced radiation-induced apoptotic cell death. Also, Mirin blocked the basal and increase of radiation-induced AKT phosphorylation. We observed that the combination of Mirin and radiation increased persistence of γH2AX at 24 h suggesting the inhibition of DNA DSBs repair. CONCLUSION: These results indicate that Mirin can effectively enhance glioma cell radiosensitivity. It suggests that Mirin is a potent radiosensitizer for treating glioma cells.

  9. Stereotactic radiosurgery for glioblastoma: retrospective analysis

    OpenAIRE

    Walter Kevin A; Vates G Edward; Bakos Robert S; Pilcher Webster H; Smudzin Therese; Schell Michael C; Okunieff Paul; Biswas Tithi; Wensel Andrew; Korones David N; Milano Michael T

    2009-01-01

    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. Res...

  10. 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.

  11. Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity

    Directory of Open Access Journals (Sweden)

    Assia L. Angelova

    2017-12-01

    Full Text Available Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV, show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01, H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood–brain (tumor barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO synthase (iNOS expression in tumor-associated microglia/macrophages (TAM, and accumulation of activated TAM in cluster of differentiation (CD 40 ligand (CD40L-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (preclinical testing.

  12. Glioblastoma: A Method for Predicting Response to Antiangiogenic Chemotherapy by Using MR Perfusion Imaging—Pilot Study1

    OpenAIRE

    Sawlani, Rahul N.; Raizer, Jeffrey; Horowitz, Sandra W.; Shin, Wanyong; Grimm, Sean A.; Chandler, James P.; Levy, Robert; Getch, Christopher; Carroll, Timothy J

    2010-01-01

    In this pilot study, we have derived an imaging metric (hyperperfusion volume) that reflects local perfusion changes in glioblastomas and have found that this metric has significantly improved correlation to time to progression as compared with more commonly used metrics.

  13. AMG 595, an Anti-EGFRvIII Antibody-Drug Conjugate, Induces Potent Antitumor Activity against EGFRvIII-Expressing Glioblastoma.

    Science.gov (United States)

    Hamblett, Kevin J; Kozlosky, Carl J; Siu, Sophia; Chang, Wesley S; Liu, Hua; Foltz, Ian N; Trueblood, Esther S; Meininger, David; Arora, Taruna; Twomey, Brian; Vonderfecht, Steven L; Chen, Qing; Hill, John S; Fanslow, William C

    2015-07-01

    Epidermal growth factor receptor variant III (EGFRvIII) is a cancer-specific deletion mutant observed in approximately 25% to 50% of glioblastoma multiforme (GBM) patients. An antibody drug conjugate, AMG 595, composed of the maytansinoid DM1 attached to a highly selective anti-EGFRvIII antibody via a noncleavable linker, was developed to treat EGFRvIII-positive GBM patients. AMG 595 binds to the cell surface and internalizes into the endo-lysosomal pathway of EGFRvIII-expressing cells. Incubation of AMG 595 with U251 cells expressing EGFRvIII led to potent growth inhibition. AMG 595 treatment induced significant tumor mitotic arrest, as measured by phospho-histone H3, in GBM subcutaneous xenografts expressing EGFRvIII. A single intravenous injection of AMG 595 at 17 mg/kg (250 μg DM1/kg) generated complete tumor regression in the U251vIII subcutaneous xenograft model. AMG 595 mediated tumor regression in the D317 subcutaneous xenograft model that endogenously expresses EGFRvIII. Finally, AMG 595 treatment inhibited the growth of D317 xenografts orthotopically implanted into the brain as determined by magnetic resonance imaging. These results demonstrate that AMG 595 is a promising candidate to evaluate in EGFRvIII-expressing GBM patients. ©2015 American Association for Cancer Research.

  14. Genetic profile of the giant cell glioblastoma.

    Science.gov (United States)

    Peraud, A; Watanabe, K; Schwechheimer, K; Yonekawa, Y; Kleihues, P; Ohgaki, H

    1999-02-01

    Giant cell glioblastoma is a rare glioblastoma variant characterized by the presence of large, bizarre, multinucleated giant cells. This glioblastoma subtype develops clinically de novo after a short clinical history and contains a high frequency of p53 mutations. In this study, we screened a series of 18 giant cell glioblastomas for additional genetic alterations. PCR-SSCP followed by DNA sequencing revealed PTEN mutations in 5 of 15 tumors (33%). Of these, two mutations were located in exon 5, two mutations in exon 6, and one mutation each in exons 1 and 9. Four mutations were point mutations and two mutations were deletions. One neoplasm contained two PTEN mutations (exons 5 and 6). None of the giant cell glioblastomas showed a homozygous deletion of PTEN orp16, or amplification of MDM2. Immunohistochemically, MDM2 overexpression was either not observed or detected in only a minor fraction of tumor cells. Differential PCR revealed EGFR amplification in only one of 17 tumors (6%). These results indicate that giant cell glioblastomas occupy a hybrid position, sharing with primary (de novo) glioblastomas a short clinical history, the absence of a less malignant precursor lesion and a 30% frequency of PTEN mutations. With secondary glioblastomas that develop through progression from low-grade astrocytomas, they have in common a younger patient age at manifestation and a high frequency (>70%) of p53 mutations.

  15. Epilepsy in Adults with Supratentorial Glioblastoma: Incidence and Influence Factors and Prophylaxis in 184 Patients.

    Science.gov (United States)

    Liang, Shuli; Zhang, Junchen; Zhang, Shaohui; Fu, Xiangping

    2016-01-01

    To analyze the incidence of epilepsy in adult patients with supratentorial glioblastoma, assess the factors influencing the development of epilepsy in these cases, and evaluate patients' response to antiepileptic drugs (AEDs) in a series of 184 patients. We retrospectively analyzed the 184 adult patients diagnosed with supratentorial glioblastoma. All subjects were treated within our hospital and subsequently died between 2003 and 2013. The incidence of epilepsy was assessed before and after initial resection and reexamined every 2 months thereafter. We evaluated the efficacy of prophylactic AEDs in this patient population based on the gathered incidence data. Of 184 patients, 43 (23.37%) were diagnosed with epilepsy before their initial resection. The total incidence of epilepsy (both pre- and postoperative) was 68.48%. The prevalence of active epilepsy reached over 80% in patients with epilepsy and survival of greater than 13 months postoperatively. Patients with glioblastoma in the frontal and/or temporal lobes had a higher prevalence of epilepsy. In the 43 patients with preoperative epilepsy, total resection of glioblastoma resulted in significantly lower seizure frequency. Patients who received epilepsy prophylaxis with AEDs for at least 6 months had significantly fewer seizures and higher Karnofsky scores than those receiving AEDs for less than one month or not at all. The incidence of epilepsy in adult patients with glioblastoma was high and responded poorly to AEDs in the short term. However, when taken for longer periods, AEDs can reduce the frequency of seizures in patients with glioblastoma.

  16. Activating clinical trials: a process improvement approach.

    Science.gov (United States)

    Martinez, Diego A; Tsalatsanis, Athanasios; Yalcin, Ali; Zayas-Castro, José L; Djulbegovic, Benjamin

    2016-02-24

    The administrative process associated with clinical trial activation has been criticized as costly, complex, and time-consuming. Prior research has concentrated on identifying administrative barriers and proposing various solutions to reduce activation time, and consequently associated costs. Here, we expand on previous research by incorporating social network analysis and discrete-event simulation to support process improvement decision-making. We searched for all operational data associated with the administrative process of activating industry-sponsored clinical trials at the Office of Clinical Research of the University of South Florida in Tampa, Florida. We limited the search to those trials initiated and activated between July 2011 and June 2012. We described the process using value stream mapping, studied the interactions of the various process participants using social network analysis, and modeled potential process modifications using discrete-event simulation. The administrative process comprised 5 sub-processes, 30 activities, 11 decision points, 5 loops, and 8 participants. The mean activation time was 76.6 days. Rate-limiting sub-processes were those of contract and budget development. Key participants during contract and budget development were the Office of Clinical Research, sponsors, and the principal investigator. Simulation results indicate that slight increments on the number of trials, arriving to the Office of Clinical Research, would increase activation time by 11 %. Also, incrementing the efficiency of contract and budget development would reduce the activation time by 28 %. Finally, better synchronization between contract and budget development would reduce time spent on batching documentation; however, no improvements would be attained in total activation time. The presented process improvement analytic framework not only identifies administrative barriers, but also helps to devise and evaluate potential improvement scenarios. The strength

  17. 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

  18. Adipose tissue mesenchymal stromal cells as therapeutic vehicles against glioblastoma

    OpenAIRE

    Krasheninnikova, Maria Alieva

    2012-01-01

    Lately adipose tissue mesenchymal stem cells (hAMSCs) have emerged as cellular vehicles for therapy of solid tumors, due to their ease of isolation and manipulation, and wound/tumor homing capacity. HAMSCs have been successfully used in suicide gene therapy, employing the prodrug activating system based on Herpes simplex virus type I thymidine kinase (HSV-TK)/ganciclovir (GCV). In the current study we demonstrate an effective model of glioblastoma therapy based on the use of genetically modif...

  19. 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.

  20. Immune phenotypes predict survival in patients with glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    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.

  1. A tree shrew glioblastoma model recapitulates features of human glioblastoma.

    Science.gov (United States)

    Tong, Yaohui; Hao, Junjun; Tu, Qiu; Yu, Hualin; Yan, Lanzhen; Li, Yuan; Lv, Longbao; Wang, Fei; Iavarone, Antonio; Zhao, Xudong

    2017-03-14

    Tupaia belangeri (tree shrew), an animal species whose genome has significantly higher similarity to primates than rodents, has been used in biomedical research. To generate animal models that reproduce the human tumors more faithfully than rodents, we present the first report of a cancer model mimicking human tumor genetics in tree shrew. By engineering a lentiviral system for the transduction of mutant H-Ras and a shRNA against tree shrew p53, we successfully generated malignant glioma in tree shrew. The tree shrew glioma exhibited aggressive behavior and a relatively short latency, and markedly reduced animal survival. Remarkably, the biological features of human high-grade glioma (necrosis, microvascular proliferation, pseudopalisading) were all present in tree shrew glioma. Furthermore, genetic analysis of tree shrew glioma revealed that the tumors were clustered within the mesenchymal subgroup of human glioblastoma multiforme. Compared with the corresponding mouse glioma, tree shrew gliomas were markedly more similar to human glioblastoma at gene expression profile. The tree shrew glioma model provides colleagues working in the field of gliomas and cancer in general with a more accurate animal model.

  2. 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.

  3. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling.

    Science.gov (United States)

    Jahani-Asl, Arezu; Yin, Hang; Soleimani, Vahab D; Haque, Takrima; Luchman, H Artee; Chang, Natasha C; Sincennes, Marie-Claude; Puram, Sidharth V; Scott, Andrew M; Lorimer, Ian A J; Perkins, Theodore J; Ligon, Keith L; Weiss, Samuel; Rudnicki, Michael A; Bonni, Azad

    2016-06-01

    EGFRvIII-STAT3 signaling is important in glioblastoma pathogenesis. Here, we identified the cytokine receptor OSMR as a direct target gene of the transcription factor STAT3 in mouse astrocytes and human brain tumor stem cells (BTSCs). We found that OSMR functioned as an essential co-receptor for EGFRvIII. OSMR formed a physical complex with EGFRvIII, and depletion of OSMR impaired EGFRvIII-STAT3 signaling. Conversely, pharmacological inhibition of EGFRvIII phosphorylation inhibited the EGFRvIII-OSMR interaction and activation of STAT3. EGFRvIII-OSMR signaling in tumors operated constitutively, whereas EGFR-OSMR signaling in nontumor cells was synergistically activated by the ligands EGF and OSM. Finally, knockdown of OSMR strongly suppressed cell proliferation and tumor growth of mouse glioblastoma cells and human BTSC xenografts in mice, and prolonged the lifespan of these mice. Our findings identify OSMR as a critical regulator of glioblastoma tumor growth that orchestrates a feed-forward signaling mechanism with EGFRvIII and STAT3 to drive tumorigenesis.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Unsupervised deep learning reveals prognostically relevant subtypes of glioblastoma.

    Science.gov (United States)

    Young, Jonathan D; Cai, Chunhui; Lu, Xinghua

    2017-10-03

    One approach to improving the personalized treatment of cancer is to understand the cellular signaling transduction pathways that cause cancer at the level of the individual patient. In this study, we used unsupervised deep learning to learn the hierarchical structure within cancer gene expression data. Deep learning is a group of machine learning algorithms that use multiple layers of hidden units to capture hierarchically related, alternative representations of the input data. We hypothesize that this hierarchical structure learned by deep learning will be related to the cellular signaling system. Robust deep learning model selection identified a network architecture that is biologically plausible. Our model selection results indicated that the 1st hidden layer of our deep learning model should contain about 1300 hidden units to most effectively capture the covariance structure of the input data. This agrees with the estimated number of human transcription factors, which is approximately 1400. This result lends support to our hypothesis that the 1st hidden layer of a deep learning model trained on gene expression data may represent signals related to transcription factor activation. Using the 3rd hidden layer representation of each tumor as learned by our unsupervised deep learning model, we performed consensus clustering on all tumor samples-leading to the discovery of clusters of glioblastoma multiforme with differential survival. One of these clusters contained all of the glioblastoma samples with G-CIMP, a known methylation phenotype driven by the IDH1 mutation and associated with favorable prognosis, suggesting that the hidden units in the 3rd hidden layer representations captured a methylation signal without explicitly using methylation data as input. We also found differentially expressed genes and well-known mutations (NF1, IDH1, EGFR) that were uniquely correlated with each of these clusters. Exploring these unique genes and mutations will allow us to

  6. Improving physical activity in daycare interventions.

    Science.gov (United States)

    Bonis, Marc; Loftin, Mark; Ward, Dianne; Tseng, Tung Sung; Clesi, Ann; Sothern, Melinda

    2014-08-01

    The aim of the study was to objectively determine whether the Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC) program improved physical activity levels during the school day. The study compared the physical activity levels of subjects from 26 daycare centers, randomized into treatment (N=13) and control (N=13) groups. The subjects were 3 to 5 year olds (N=209, 104 males and 105 females; age [years]=3.85±0.8 [mean±standard deviation]), and accelerometry was used to determine the subjects' physical activity levels. Accelerometers were attached to each subject for 2 days before and immediately after a 6-month intervention. Height, mass, and waist were also measured. Regression analyses indicated that the treatment group demonstrated significant increases in moderate and vigorous physical activity, as compared to the control group (F(1, 207)=6.3, pdaycare facilities resulted in significant increases in objectively measured physical activity levels, compared to the control group, demonstrating physical activity improvement in the treatment daycare centers.

  7. Rare clinical form of glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    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. Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma.

    Science.gov (United States)

    Oh, Ji Eun; Ohta, Takashi; Nonoguchi, Naosuke; Satomi, Kaishi; Capper, David; Pierscianek, Daniela; Sure, Ulrich; Vital, Anne; Paulus, Werner; Mittelbronn, Michel; Antonelli, Manila; Kleihues, Paul; Giangaspero, Felice; Ohgaki, Hiroko

    2016-07-01

    The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas. © 2015 International Society of Neuropathology.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Improving activation cross section data with TALYS

    Science.gov (United States)

    Dzysiuk, Nataliia; Koning, Arjan

    2017-09-01

    Needs for accurate (n,x) activation cross sections for fusion technology have been considered with reference to the current status of the TENDL library. The current work is focused on improving activation cross section data for nuclear reactions relevant mainly for fusion and astrophysical needs. The fits have been performed with the TALYS-1.8 code by means of nuclear model parameter variation, mostly for the optical model and level densities, followed by comparison to recent experimental data taken from EXFOR and other evaluated nuclear databases. The updated cross section data are going to be adopted into the new version of TENDL. The improvements have been performed both for differential as well as integral data sets.

  11. MicroRNA involvement in glioblastoma pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Novakova, Jana [University Cell Immunotherapy Center, Faculty of Medicine, Masaryk University, Brno (Czech Republic); Department of Biochemistry, Faculty of Science, Masaryk University, Brno (Czech Republic); Slaby, Ondrej, E-mail: slaby@mou.cz [University Cell Immunotherapy Center, Faculty of Medicine, Masaryk University, Brno (Czech Republic); Masaryk Memorial Cancer Institute, Department of Laboratory Medicine, Zluty kopec 7, 656 53 Brno (Czech Republic); Vyzula, Rostislav [Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Brno (Czech Republic); Michalek, Jaroslav [University Cell Immunotherapy Center, Faculty of Medicine, Masaryk University, Brno (Czech Republic)

    2009-08-14

    MicroRNAs are endogenously expressed regulatory noncoding RNAs. Altered expression levels of several microRNAs have been observed in glioblastomas. Functions and direct mRNA targets for these microRNAs have been relatively well studied over the last years. According to these data, it is now evident, that impairment of microRNA regulatory network is one of the key mechanisms in glioblastoma pathogenesis. MicroRNA deregulation is involved in processes such as cell proliferation, apoptosis, cell cycle regulation, invasion, glioma stem cell behavior, and angiogenesis. In this review, we summarize the current knowledge of miRNA functions in glioblastoma with an emphasis on its significance in glioblastoma oncogenic signaling and its potential to serve as a disease biomarker and a novel therapeutic target in oncology.

  12. Glioblastoma after radiotherapy for pituitary adenoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Young; Park, Kyung Ran; KIm, Jun Joo; Lee, Chong In; Kim, Myung Soon; Jung, Soon Hee [Wonju College of Medicine, Yonsei Univ., Wonju (Korea, Republic of)

    1999-12-01

    A 39-year-old woman developed a glioblastoma about 7 years and 10 months after local radiotherapy (45 Gy) for pituitary adenoma. Clinical and histopathological details are presented, and previously reported cases of radiation-induced glioma are reviewed.

  13. Combining Immunotherapy with Standard Glioblastoma Therapy

    Science.gov (United States)

    This clinical trial is testing standard therapy (surgery, radiation and temozolomide) plus immunotherapy with pembrolizumab with or without a cancer treatment vaccine for patients with newly diagnosed glioblastoma, a common and deadly type of brain tumor.

  14. Inhibition of glioblastoma malignancy by Lgl1

    OpenAIRE

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

    2014-01-01

    lethal giant larvae (lgl) was first identified as a tumor suppressor in Drosophila, where its loss repressed the differentiation and promoted the invasion of neuroblasts, the Drosophila equivalent of the neural stem cell. Recently we have shown that a human homolog of Lgl, Lgl1 (LLGL1), is constitutively phosphorylated and inactivated in glioblastoma cells; this occurs as a downstream consequence of PTEN loss, one of the most frequent genetic events in glioblastoma. Here we have investigated ...

  15. Immunotherapy for the Treatment of Glioblastoma

    Science.gov (United States)

    Thomas, Alissa A.; Ernstoff, Marc S.; Fadul, Camilo E.

    2012-01-01

    Glioblastoma, the most aggressive primary brain tumor, thrives in a microenvironment of relative immunosuppression within the relatively immune-privileged central nervous system. Despite treatments with surgery, radiation therapy, and chemotherapy, prognosis remains poor. The recent success of immunotherapy in the treatment of other cancers has renewed interest in vaccine therapy for the treatment of gliomas. In this article, we outline various immunotherapeutic strategies, review recent clinical trials data, and discuss the future of vaccine therapy for glioblastoma. PMID:22290259

  16. Current Studies of Immunotherapy on Glioblastoma

    OpenAIRE

    Agrawal, Neena Stephanie; Miller, Rickey; Lal, Richa; Mahanti, Harshini; Dixon-Mah, Yaenette N.; Decandio, Michele L.; Vandergrift, W Alex; Varma, Abhay K.; Patel, Sunil J.; Banik, Naren L.; Lindhorst, Scott M.; Giglio, Pierre; Das, Arabinda

    2014-01-01

    Glioblastoma is a form of brain tumor with a very high morbidity and mortality. Despite decades of research, the best treatments currently in clinical practice only extend survival by a number of months. A promising alternative to conventional treatment for glioblastomas is immunotherapy. Although proposed over a century ago, the field of cancer immunotherapy has historically struggled to translate it into effective clinical treatments. Better understanding is needed of the various regulatory...

  17. Improving Accuracy of Processing Through Active Control

    Directory of Open Access Journals (Sweden)

    N. N. Barbashov

    2016-01-01

    Full Text Available An important task of modern mathematical statistics with its methods based on the theory of probability is a scientific estimate of measurement results. There are certain costs under control, and under ineffective control when a customer has got defective products these costs are significantly higher because of parts recall.When machining the parts, under the influence of errors a range scatter of part dimensions is offset towards the tolerance limit. To improve a processing accuracy and avoid defective products involves reducing components of error in machining, i.e. to improve the accuracy of machine and tool, tool life, rigidity of the system, accuracy of the adjustment. In a given time it is also necessary to adapt machine.To improve an accuracy and a machining rate there, currently  become extensively popular various the in-process gaging devices and controlled machining that uses adaptive control systems for the process monitoring. Improving the accuracy in this case is compensation of a majority of technological errors. The in-cycle measuring sensors (sensors of active control allow processing accuracy improvement by one or two quality and provide a capability for simultaneous operation of several machines.Efficient use of in-cycle measuring sensors requires development of methods to control the accuracy through providing the appropriate adjustments. Methods based on the moving average, appear to be the most promising for accuracy control since they include data on the change in some last measured values of the parameter under control.

  18. Giant cell glioblastoma: a glioblastoma subtype with distinct epidemiology and superior prognosis.

    Science.gov (United States)

    Kozak, Kevin R; Moody, John S

    2009-12-01

    Giant cell glioblastoma (GC) is an uncommon subtype of glioblastoma multiforme (GBM). Consequently, the epidemiology, natural history, and factors associated with outcome are not well defined. Patients diagnosed with GC from 1988 through 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Outcomes were examined with Kaplan-Meier survival analysis and Cox models. For comparison, similar analyses were conducted for patients diagnosed with GBM. GC was identified in 1% of 16,430 patients diagnosed with either GC or GBM. Compared with GBM, GC showed similar gender and racial distributions. Likewise, tumor size and location were not significantly different between the two histologies. GC tended to occur in younger patients with a median age at diagnosis of 51 years, compared with 62 years for GBM. Additionally, patients with GC were more likely to undergo complete resection compared with patients with GBM. For both histologies, young age, tumor size, extent of resection, and the use of adjuvant radiation therapy (RT) were associated with improved survival. Cox modeling suggests the prognosis for GC is significantly superior to that for GBM (hazard ratio = 0.76; 95% confidence interval, 0.59-0.97) even after adjustment for factors affecting survival. GC is an uncommon GBM subtype that tends to occur in younger patients. Prospective data defining optimal treatment for GC are unavailable; however, these retrospective findings suggest that resection, as opposed to biopsy only, and adjuvant RT may improve survival. The prognosis of GC is superior to that of GBM, and long-term survival is possible, suggesting aggressive therapy is warranted.

  19. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

    DEFF Research Database (Denmark)

    Sehested, Astrid Marie

    2016-01-01

    fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET......Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET...

  20. Strategies in Gene Therapy for Glioblastoma

    Science.gov (United States)

    Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S.

    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 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. PMID:24202446

  1. Strategies in Gene Therapy for Glioblastoma

    Directory of Open Access Journals (Sweden)

    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.

  2. 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.

  3. Detection of glioblastoma in biofluids.

    Science.gov (United States)

    Figueroa, Javier M; Carter, Bob S

    2017-10-20

    The detection of glioblastoma (GBM) in biofluids offers potential advantages over existing paradigms for the diagnosis and therapeutic monitoring of glial tumors. Biofluid-based detection of GBM focuses on detecting tumor-specific biomarkers in the blood and CSF. Current clinical research concentrates on studying 3 distinct tumor-related elements: extracellular macromolecules, extracellular vesicles, and circulating tumor cells. Investigations into these 3 biological classifications span the range of locales for tumor-specific biomarker discovery, and combined, have the potential to significantly impact GBM diagnosis, monitoring for treatment response, and surveillance for recurrence. This review highlights the recent advancements in the development of biomarkers and their efficacy for the detection of GBM.

  4. Suppression of the Eag1 potassium channel sensitizes glioblastoma cells to injury caused by temozolomide.

    Science.gov (United States)

    Sales, Thais Torquato; Resende, Fernando Francisco Borges; Chaves, Natália Lemos; Titze-De-Almeida, Simoneide Souza; Báo, Sônia Nair; Brettas, Marcella Lemos; Titze-De-Almeida, Ricardo

    2016-10-01

    Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma.

  5. Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship

    Science.gov (United States)

    Kim, Hyunsoo; Huang, Wei; Jiang, Xiuli; Pennicooke, Brenton; Park, Peter J.; Johnson, Mark D.

    2010-01-01

    Using a multidimensional genomic data set on glioblastoma from The Cancer Genome Atlas, we identified hsa-miR-26a as a cooperating component of a frequently occurring amplicon that also contains CDK4 and CENTG1, two oncogenes that regulate the RB1 and PI3 kinase/AKT pathways, respectively. By integrating DNA copy number, mRNA, microRNA, and DNA methylation data, we identified functionally relevant targets of miR-26a in glioblastoma, including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate that miR-26a alone can transform cells and it promotes glioblastoma cell growth in vitro and in the mouse brain by decreasing PTEN, RB1, and MAP3K2/MEKK2 protein expression, thereby increasing AKT activation, promoting proliferation, and decreasing c-JUN N-terminal kinase-dependent apoptosis. Overexpression of miR-26a in PTEN-competent and PTEN-deficient glioblastoma cells promoted tumor growth in vivo, and it further increased growth in cells overexpressing CDK4 or CENTG1. Importantly, glioblastoma patients harboring this amplification displayed markedly decreased survival. Thus, hsa-miR-26a, CDK4, and CENTG1 comprise a functionally integrated oncomir/oncogene DNA cluster that promotes aggressiveness in human cancers by cooperatively targeting the RB1, PI3K/AKT, and JNK pathways. PMID:20080666

  6. Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Resham Lal Gurung

    Full Text Available BACKGROUND: A major concern of cancer chemotherapy is the side effects caused by the non-specific targeting of both normal and cancerous cells by therapeutic drugs. Much emphasis has been placed on discovering new compounds that target tumour cells more efficiently and selectively with minimal toxic effects on normal cells. METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxic effect of thymoquinone, a component derived from the plant Nigella sativa, was tested on human glioblastoma and normal cells. Our findings demonstrated that glioblastoma cells were more sensitive to thymoquinone-induced antiproliferative effects. Thymoquinone induced DNA damage, cell cycle arrest and apoptosis in the glioblastoma cells. It was also observed that thymoquinone facilitated telomere attrition by inhibiting the activity of telomerase. In addition to these, we investigated the role of DNA-PKcs on thymoquinone mediated changes in telomere length. Telomeres in glioblastoma cells with DNA-PKcs were more sensitive to thymoquinone mediated effects as compared to those cells deficient in DNA-PKcs. CONCLUSIONS/SIGNIFICANCE: Our results indicate that thymoquinone induces DNA damage, telomere attrition by inhibiting telomerase and cell death in glioblastoma cells. Telomere shortening was found to be dependent on the status of DNA-PKcs. Collectively, these data suggest that thymoquinone could be useful as a potential chemotherapeutic agent in the management for brain tumours.

  7. Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma

    Science.gov (United States)

    Arshad, Azeem; Yang, Bin; Bienemann, Alison S.; Barua, Neil U.; Wyatt, Marcella J.; Woolley, Max; Johnson, Dave E.; Edler, Karen J.; Gill, Steven S.

    2015-01-01

    We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas. PMID:26186224

  8. Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma.

    Science.gov (United States)

    Arshad, Azeem; Yang, Bin; Bienemann, Alison S; Barua, Neil U; Wyatt, Marcella J; Woolley, Max; Johnson, Dave E; Edler, Karen J; Gill, Steven S

    2015-01-01

    We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas.

  9. Glioblastoma

    Science.gov (United States)

    ... of Tumors Astrocytoma Atypical Teratoid Rhaboid Tumor (ATRT) Chondrosarcoma Choroid Plexus Craniopharyngioma Cysts Ependymoma Germ Cell Tumor ... of Tumors Astrocytoma Atypical Teratoid Rhaboid Tumor (ATRT) Chondrosarcoma Choroid Plexus Craniopharyngioma Cysts Ependymoma Germ Cell Tumor ...

  10. Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression.

    Directory of Open Access Journals (Sweden)

    Gloria Perazzoli

    Full Text Available The use of temozolomide (TMZ has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated.Four nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2'-deoxycytidine was used to demethylate the MGMT promoter and O(6-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed.Our results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229 and high (SF268 and SK-N-SH basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC50 showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC50 did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC50, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines.These results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma multiforme patients.

  11. Giant cell glioblastoma in a child: A rare case report.

    Science.gov (United States)

    Jain, S K; Sundar, I Vijay; Sinha, V D; Sharma, Vinod; Bhasme, Vishal; Goel, Ravishankar S

    2012-07-01

    Giant cell glioblastoma (GCG) is a subtype of Glioblastoma multiforme that is rare in incidence and distinct in features and histopathological examination. It is reported to have better prognosis than common glioblastomas. The incidence of GCG in children is even more rare. We report a case of GCG in a 10-year-old boy along with a review of the relevant literature focusing on the differentiating points from common glioblastoma.

  12. Giant cell glioblastoma in a child: A rare case report

    OpenAIRE

    Jain, S.K; Sundar, I. Vijay; V D Sinha; Sharma, Vinod; Bhasme, Vishal; Ravishankar S Goel

    2012-01-01

    Giant cell glioblastoma (GCG) is a subtype of Glioblastoma multiforme that is rare in incidence and distinct in features and histopathological examination. It is reported to have better prognosis than common glioblastomas. The incidence of GCG in children is even more rare. We report a case of GCG in a 10-year-old boy along with a review of the relevant literature focusing on the differentiating points from common glioblastoma.

  13. Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies.

    Directory of Open Access Journals (Sweden)

    Michael Preukschas

    Full Text Available Glioblastomas are highly aggressive brain tumors of adults with poor clinical outcome. Despite a broad range of new and more specific treatment strategies, therapy of glioblastomas remains challenging and tumors relapse in all cases. Recent work demonstrated that the posttranslational hypusine modification of the eukaryotic initiation factor 5A (eIF-5A is a crucial regulator of cell proliferation, differentiation and an important factor in tumor formation, progression and maintenance. Here we report that eIF-5A as well as the hypusine-forming enzymes deoxyhypusine synthase (DHS and deoxyhypusine hydroxylase (DOHH are highly overexpressed in glioblastoma patient samples. Importantly, targeting eIF-5A and its hypusine modification with GC7, a specific DHS-inhibitor, showed a strong antiproliferative effect in glioblastoma cell lines in vitro, while normal human astrocytes were not affected. Furthermore, we identified p53 dependent premature senescence, a permanent cell cycle arrest, as the primary outcome in U87-MG cells after treatment with GC7. Strikingly, combined treatment with clinically relevant alkylating agents and GC7 had an additive antiproliferative effect in glioblastoma cell lines. In addition, stable knockdown of eIF-5A and DHS by short hairpin RNA (shRNA could mimic the antiproliferative effects of GC7. These findings suggest that pharmacological inhibition of eIF-5A may represent a novel concept to treat glioblastomas and may help to substantially improve the clinical course of this tumor entity.

  14. 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...

  15. Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma

    National Research Council Canada - National Science Library

    Penas-Prado, Marta; Hess, Kenneth R; Fisch, Michael J; Lagrone, Lore W; Groves, Morris D; Levin, Victor A; De Groot, John F; Puduvalli, Vinay K; Colman, Howard; Volas-Redd, Gena; Giglio, Pierre; Conrad, Charles A; Salacz, Michael E; Floyd, Justin D; Loghin, Monica E; Hsu, Sigmund H; Gonzalez, Javier; Chang, Eric L; Woo, Shiao Y; Mahajan, Anita; Aldape, Kenneth D; Yung, W K Alfred; Gilbert, Mark R

    2015-01-01

    ...) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide...

  16. Delivery of hypoxia and glioma dual-specific suicide gene using dexamethasone conjugated polyethylenimine for glioblastoma-specific gene therapy.

    Science.gov (United States)

    Kim, Hyun Ah; Park, Jin Hyeong; Yi, Na; Lee, Minhyung

    2014-03-03

    Gene therapy has been considered a promising approach for glioblastoma therapy. To avoid side effects and increase the specificity of gene expression, gene expression should be tightly regulated. In this study, glioma and hypoxia dual-specific plasmids (pEpo-NI2-SV-Luc and pEpo-NI2-SV-HSVtk) were developed by combining the erythropoietin (Epo) enhancer and nestin intron 2 (NI2). In the in vitro studies, pEpo-NI2-SV-Luc showed higher gene expression under hypoxia than normoxia in a glioblastoma-specific manner. The MTT and caspase assays demonstrated that pEpo-NI2-SV-HSVtk specifically induced caspase activity and cell death in hypoxic glioblastoma cells. For in vivo evaluation, subcutaneous and intracranial glioblastoma models were established. Dexamethasone-conjugated-polyethylenimine (PEI-Dexa) was used as a gene carrier, since PEI-Dexa efficiently delivers plasmid to glioblastoma cells and also has an antitumor effect due to the effect of dexamethasone. In the in vivo study in the subcutaneous and intracranial glioblastoma models, the tumor size was reduced more effectively in the pEpo-NI2-SV-HSVtk group than in the control and pSV-HSVtk groups. In addition, higher levels of HSVtk gene expression and TUNEL-positive cells were observed in the pEpo-NI2-SV-HSVtk group compared with the control and pSV-HSVtk groups, suggesting that pEpo-NI2-SV-HSVtk increased the therapeutic efficacy in hypoxic glioblastoma. Therefore, pEpo-NI2-SV-HSVtk/PEI-Dexa complex may be useful for glioblastoma-specific gene therapy.

  17. Pharmacometabolomics Informs Quantitative Radiomics for Glioblastoma Diagnostic Innovation.

    Science.gov (United States)

    Katsila, Theodora; Matsoukas, Minos-Timotheos; Patrinos, George P; Kardamakis, Dimitrios

    2017-08-01

    Applications of omics systems biology technologies have enormous promise for radiology and diagnostics in surgical fields. In this context, the emerging fields of radiomics (a systems scale approach to radiology using a host of technologies, including omics) and pharmacometabolomics (use of metabolomics for patient and disease stratification and guiding precision medicine) offer much synergy for diagnostic innovation in surgery, particularly in neurosurgery. This synthesis of omics fields and applications is timely because diagnostic accuracy in central nervous system tumors still challenges decision-making. Considering the vast heterogeneity in brain tumors, disease phenotypes, and interindividual variability in surgical and chemotherapy outcomes, we believe that diagnostic accuracy can be markedly improved by quantitative radiomics coupled to pharmacometabolomics and related health information technologies while optimizing economic costs of traditional diagnostics. In this expert review, we present an innovation analysis on a systems-level multi-omics approach toward diagnostic accuracy in central nervous system tumors. For this, we suggest that glioblastomas serve as a useful application paradigm. We performed a literature search on PubMed for articles published in English between 2006 and 2016. We used the search terms "radiomics," "glioblastoma," "biomarkers," "pharmacogenomics," "pharmacometabolomics," "pharmacometabonomics/pharmacometabolomics," "collaborative informatics," and "precision medicine." A list of the top 4 insights we derived from this literature analysis is presented in this study. For example, we found that (i) tumor grading needs to be better refined, (ii) diagnostic precision should be improved, (iii) standardization in radiomics is lacking, and (iv) quantitative radiomics needs to prove clinical implementation. We conclude with an interdisciplinary call to the metabolomics, pharmacy/pharmacology, radiology, and surgery communities that

  18. 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.

  19. The NFL-TBS.40-63 anti-glioblastoma peptide enters selectively in glioma cells by endocytosis.

    Science.gov (United States)

    Lépinoux-Chambaud, Claire; Eyer, Joël

    2013-10-01

    Glioblastoma are the most frequent and aggressive tumour of the nervous system despite surgical resection associated with chemotherapy and radiotherapy. Recently, we showed that the NFL-TBS.40-63 peptide corresponding to the sequence of a tubulin-binding site of neurofilaments, enters selectively in glioblastoma cells where it blocks microtubule polymerization, inhibits their proliferation, and reduces tumour development in rats bearing glioblastoma (Bocquet et al., 2009; Berges et al., 2012a). Here, we characterized the molecular mechanism responsible for the uptake of NFL-TBS.40-63 peptide by glioblastoma cells. Unlike other cell penetrating peptides (CPPs), which use a balance between endocytosis and direct translocation, the NFL-TBS.40-63 peptide is unable to translocate directly through the membrane when incubated with giant plasma membrane vesicles. Then, using a panel of markers and inhibitors, flow cytometry and confocal microscopy investigations showed that the uptake occurs mainly through endocytosis. Moreover, glycosaminoglycans and αVβ3 integrins are not involved in the NFL-TBS.40-63 peptide recognition and internalization by glioblastoma cells. Finally, the signalling of tyrosine kinase receptors is involved in the peptide uptake, especially via EGFR overexpressed in tumour cells, indicating that the uptake of NFL-TBS.40-63 peptide by glioblastoma cells is related to their abnormally high proliferative activity. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma.

    Science.gov (United States)

    De Bonis, Pasquale; Anile, Carmelo; Pompucci, Angelo; Fiorentino, Alba; Balducci, Mario; Chiesa, Silvia; Maira, Giulio; Mangiola, Annunziato

    2012-08-01

    Combining Gliadel wafers and radiochemotherapy with TMZ may carry the risk of increased adverse events (AE). We analyzed the efficacy and safety in patients with glioblastoma who underwent multimodal treatment with implantation of Gliadel wafers. One hundred sixty-five consecutive patients with newly diagnosed (77 patients) or recurrent (88 patients) glioblastoma were studied. Forty-seven patients underwent surgery + Gliadel. The impact of age (≥65 vs. <65), resection extent (gross total vs. partial), use of Gliadel and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on overall survival (OS, for patients with newly diagnosed glioblastoma) and on recurrence-survival (for patients with recurrent glioblastoma) was analyzed with Cox regression. The impact of age, history (newly diagnosed vs. recurrent glioblastoma), number of Gliadel wafers implanted (0 vs. <8 vs. 8), resection extent (gross-total vs. partial) and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on the occurrence of AE and on the occurrence of implantation site-related AE (ISAE) was analyzed with the logistic regression model. Significance was set at p < 0.05. Multivariate analysis showed the only factor associated with longer survival, both for newly diagnosed and for recurrent GBM, was resection extent. Both patients with a higher number of wafers implanted and patients with recurrent tumors were significantly at risk for AE and ISAE. Patients with eight Gliadel wafers implanted had a 3-fold increased risk of AE and a 5.6-fold increased risk of ISAE, and patients with recurrent tumor had a 2.8-fold increased risk of AE and a 9.3-fold increased risk of ISAE. Adding Gliadel to standard treatment did not significantly improve the outcome. The toxicity after Gliadel use was significantly higher, both for patients with newly diagnosed and patients with recurrent glioblastoma.

  1. USING FUN ACTIVITIES TO IMPROVE LISTENING SKILL

    Directory of Open Access Journals (Sweden)

    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

  2. Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme

    DEFF Research Database (Denmark)

    Lassen, Ulrik; Sorensen, Morten; Gaziel, Tine Bernhardtsen

    2013-01-01

    Bevacizumab combined with chemotherapy has recently shown promising efficacy in recurrent high-grade glioma. Phosphatase and tensin homolog (PTEN) mutation in glioblastoma multiforme (GBM) patients causes abnormally high activity of the pathways of Phosphatidylinositide 3-kinases (PI3K), Protein...

  3. Analysis of the cytotoxicity of hierarchical nanoporous graphenic carbon against human glioblastoma grade IV cells

    DEFF Research Database (Denmark)

    Jaworski, Sławomir; Biniecka, Paulina; Bugajska, Żaneta

    2017-01-01

    with the U87 cells can also lead to the excessive generation of reactive oxygen species (ROS) and activate apoptotic mechanisms in cancer cells. The investigation was performed using U87 human glioblastoma and PCS-201–010 normal fibroblast cell lines, where cell morphology and ultrastructure, viability, ROS...... pathway, without inducing necrosis. Our research indicates the potential applicability of HNC in cancer therapy....

  4. Effect of epithermal neutrons on viability of glioblastoma tumor cells in vitro.

    Science.gov (United States)

    Mostovich, L A; Gubanova, N V; Kutsenko, O S; Aleinik, V I; Kuznetsov, A S; Makarov, A N; Sorokin, I N; Taskaev, S Yu; Nepomnyashchikh, G I; Grigor'eva, E V

    2011-06-01

    We studied in vitro effect of epithermal neutrons in various doses on viability of glioblastoma U87 tumor cells. Increasing the dose from 1.9 to 4.1 Sv promoted cell death. Cytofluorimetric analysis revealed no activation of apoptosis in the irradiated cells, which attested to necrotic death of the tumor cells exposed to epithermal neutron radiation.

  5. Giant cell glioblastoma in the pediatric age group: Report of two cases

    OpenAIRE

    Sachin Anil Borkar; Lakshmiprasad, G.; Kiran Chikkanahalli Subbarao; Mehar Chand Sharma; Ashok K Mahapatra

    2013-01-01

    Giant cell glioblastoma multiforme is a rare subgroup of glioblastoma multiforme. It constitutes about 5% of all glioblastoma cases. Pediatric giant cell glioblastoma is extremely rare. We report two such cases of giant cell glioblastoma in pediatric age group (≤18 years). The pertinent literature is reviewed regarding this uncommon entity.

  6. Giant cell glioblastoma in the pediatric age group: Report of two cases.

    Science.gov (United States)

    Borkar, Sachin Anil; Lakshmiprasad, G; Subbarao, Kiran Chikkanahalli; Sharma, Mehar Chand; Mahapatra, Ashok K

    2013-01-01

    Giant cell glioblastoma multiforme is a rare subgroup of glioblastoma multiforme. It constitutes about 5% of all glioblastoma cases. Pediatric giant cell glioblastoma is extremely rare. We report two such cases of giant cell glioblastoma in pediatric age group (≤18 years). The pertinent literature is reviewed regarding this uncommon entity.

  7. Toward a noncytotoxic glioblastoma therapy: blocking MCP-1 with the MTZ Regimen

    Directory of Open Access Journals (Sweden)

    Salacz ME

    2016-04-01

    Full Text Available Michael E Salacz,1,2 Richard E Kast,3 Najmaldin Saki,4 Ansgar Brüning,5 Georg Karpel-Massler,6 Marc-Eric Halatsch6 1Department of Internal Medicine, 2Department of Neurosurgery, University of Kansas, Kansas City, KS, USA; 3IIAIGC Study Center, Burlington, VT, USA; 4Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 5Molecular Biology Laboratory, University Hospital Munich, Munich, Germany; 6Department of Neurosurgery, University of Ulm, Ulm, Germany Abstract: To improve the prognosis of glioblastoma, we developed an adjuvant treatment directed to a neglected aspect of glioblastoma growth, the contribution of nonmalignant monocyte lineage cells (MLCs (monocyte, macrophage, microglia, dendritic cells that infiltrated a main tumor mass. These nonmalignant cells contribute to glioblastoma growth and tumor homeostasis. MLCs comprise of approximately 10%–30% of glioblastoma by volume. After integration into the tumor mass, these become polarized toward an M2 immunosuppressive, pro-angiogenic phenotype that promotes continued tumor growth. Glioblastoma cells initiate and promote this process by synthesizing 13 kDa MCP-1 that attracts circulating monocytes to the tumor. Infiltrating monocytes, after polarizing toward an M2 phenotype, synthesize more MCP-1, forming an amplification loop. Three noncytotoxic drugs, an antibiotic – minocycline, an antihypertensive drug – telmisartan, and a bisphosphonate – zoledronic acid, have ancillary attributes of MCP-1 synthesis inhibition and could be re-purposed, singly or in combination, to inhibit or reverse MLC-mediated immunosuppression, angiogenesis, and other growth-enhancing aspects. Minocycline, telmisartan, and zoledronic acid – the MTZ Regimen – have low-toxicity profiles and could be added to standard radiotherapy and temozolomide. Re-purposing older drugs has advantages of established safety and low

  8. Physical activity improves cognition: possible explanations.

    Science.gov (United States)

    Koščak Tivadar, Blanka

    2017-08-01

    Good cognitive abilities (CA) enable autonomy, improve social inclusion and act preventively. Regular physical activity (PA) reduces the risk of developing Alzheimer's disease (AD) and, at the same time, it reduces the decline of CA and stimulates neurogenesis. So PA in connection with cognitive training, nutrition and social interaction has a positive effect on general CA and the central nervous system, the central executor, memory and attention, and reduces the likelihood of developing dementia. Our objective was to examine which sort and intensity of PA is preferred. We did a review, restricted only to human studies, of transparent scientific articles and sample surveys carried out and published in the period between 2001 and 2016 based on the keywords: age, aging, physical activity, physical abilities, cognitive abilities, memory and Alzheimer's disease. According to results CA and PA interact, as an increasing PA of only 10% reduces the risk of dementia and AD significantly. However, there is a question of appropriate intensity of exercise. Low-intensity aerobic exercise has a positive effect on the visual spatial perception and attention, whereas moderate PA has a positive impact on general CA, working memory and attention, verbal memory and attention and vice versa. While the majority of experts recommends vigorous or moderate exercise, many of them warn that higher intensity requires more attention to PA and less to cognitive processes, particularly in terms of reducing reactions, selective attention and flexibility to tasks. There is also a further question what PA should be like. Although some experts believe that the best combination is aerobic PA and exercises against resistance, it is not entirely clear whether the improvement in CA is a result of cardiac vascular fitness. On the other hand, for most elderly it is more suitable to perform an alternative form (not anaerobic) of PA due to comorbidity and actual fragility. We can conclude that PA has a

  9. Advances in the treatment of glioblastoma multiforme

    OpenAIRE

    Jaramillo, Sonia; Pontificia Universidad Javerian; Osorio, Walter; Pontificia Universidad Javeriana; Espitia, Juan Carlos; Pontificia Universidad Javeriana

    2010-01-01

    Glioblastoma multiforme is the most common central nervous system (CNS) primary tumor in men. Its incidence in Europe lies between 3 to 4 cases per 100,000 inhabitants and it represents 25% of all the CNS tumors and 50% of the primary tumors. Less than 3% of all patients diagnosed with glioblastoma multiforme survive more than 4 years and the average survival is of 6 months. Studies aiming to increase the survival rate, as well as to achieve longer asymptomatic periods are being carried out a...

  10. Mikrosatelitna nestabilnost i gubitak heterozigotnosti u glioblastoma

    OpenAIRE

    Gunčić, Ivana

    2016-01-01

    U ovom radu govorit ću o dvije genske promjene u glioblastoma i njihovom utjecaju na proces kancerogeneze. Riječ je o gubitku heterozigotnosti (LOH) i mikrosatelitnoj nestabilnosti (MSI). Cilj je iznijeti teorijsku pozadinu i sumirati neka od dosadašnjih istraživanja u području glioblastoma za navedene nestabilnosti. Naime, njihova pojava i učestalost varira u promatranim istraživanjima, no svakako doprinose genomskoj nestabilnosti. Daju uvid u genske promjene uključene u razvoj (i vraćanje) ...

  11. Overcoming Temozolomide Resistance in Glioblastoma Multiforme with MGMT-Targeting Spherical Nucleic Acids

    Science.gov (United States)

    Sita, Timothy L.

    Glioblastoma multiforme (GBM) is the most prevalent primary central nervous system malignancy. Due to the aggressive nature of these tumors and our inability to adequately treat them, only 3-5% of patients survive longer than 3 years post-diagnosis. The standard of care for newly diagnosed GBM is surgical resection followed by concomitant and adjuvant radiotherapy and temozolomide (TMZ) chemotherapy. TMZ cytotoxicity is mediated primarily through methylation of the O 6 -position of guanine. In the majority of patients, this methyl group is rapidly removed by the enzyme O6 -methylguanine-DNA methyltransferase (MGMT), conferring resistance to the chemotherapy. However, in a small subset of GBM patients, the promoter region for MGMT is methylated over the course of tumor development. This epigenetic silencing of MGMT activity allows TMZ to induce apoptosis in glioblastoma cells and drastically increases survival in GBM patients. The following work seeks to recapitulate this improved survival phenotype by combining TMZ with a novel nanoconstruct capable of silencing MGMT expression. The nanoconstruct consists of gold nanoparticles densely conjugated with either an MGMT-targeting ribozyme (ribozyme-Spherical Nucleic Acids (SNAs)), or small interfering RNA (siRNA) duplexes designed against MGMT (siMGMT-SNAs), and has been found to have unique characteristics, including (1) the rapid internalization by all glioma cell types studied including glioma initiating cells (GICs), (2) the capacity to potently silence MGMT expression, (3) increased apoptotic response in GBM cells, (4) the ability to cross the blood-brain barrier (BBB), blood-tumor barrier (BTB), and accumulate in GBM xenografts, and (5) no observable acute toxicity at high doses in animal models. In summary, preliminary data suggest ribozyme-SNA and siMGMT-SNAs sensitize GBM cells in vitro and in vivo, enhancing the therapeutic response to TMZ.

  12. Cancer Stem Cells in Glioblastoma Multiforme

    Directory of Open Access Journals (Sweden)

    Amy Ruth Bradshaw

    2016-08-01

    Full Text Available Aim To identify and characterize cancer stem cells (CSC in glioblastoma multiforme (GBM.Methods 4μm-thick formalin-fixed paraffin-embedded GBM samples from six patients underwent 3,3-diaminobenzidine (DAB and immunofluorescent (IF immunohistochemical (IHC staining for the embryonic stem cell (ESC markers NANOG, OCT4, SALL4, SOX2 and pSTAT3. IF IHC staining was performed to demonstrate co-expression of these markers with GFAP. The protein expression and the transcriptional activities of the genes encoding NANOG, OCT4, SOX2, SALL4 and STAT3 were investigated using Western blotting (WB and NanoString gene expression analysis, respectively. Results DAB and IF IHC staining demonstrated the presence of a CSC population expressing NANOG, OCT4, SOX2, SALL4 and STAT3 with the almost ubiquitous presence of SOX2 and a relatively low abundance of OCT4, within GBM. The expression of NANOG, SOX2 and pSTAT3 but, not OCT and SALL4, was confirmed by WB. NanoString gene analysis demonstrated transcriptional activation of NANOG, OCT4, SALL4, STAT3 and SOX2 in GBM. Conclusion This study demonstrated a population of CSCs within GBM characterized by the expression of the CSC markers NANOG, SALL4, SOX2, pSTAT3 and OCT4 at the protein and mRNA levels. The almost ubiquitous presence of SOX2 and a relatively low abundance of OCT4 would support the putative existence of a stem cell hierarchy within GBM.

  13. Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma.

    Science.gov (United States)

    Penas-Prado, Marta; Hess, Kenneth R; Fisch, Michael J; Lagrone, Lore W; Groves, Morris D; Levin, Victor A; De Groot, John F; Puduvalli, Vinay K; Colman, Howard; Volas-Redd, Gena; Giglio, Pierre; Conrad, Charles A; Salacz, Michael E; Floyd, Justin D; Loghin, Monica E; Hsu, Sigmund H; Gonzalez, Javier; Chang, Eric L; Woo, Shiao Y; Mahajan, Anita; Aldape, Kenneth D; Yung, W K Alfred; Gilbert, Mark R

    2015-02-01

    Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy. The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide. The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia. The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma. NCT00112502. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. 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.

  15. 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.

  16. MicroRNA biomarkers in glioblastoma

    DEFF Research Database (Denmark)

    Hermansen, Simon Kjær; Kristensen, Bjarne Winther

    2013-01-01

    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...

  17. PICTORIAL REVIEW Glioblastoma multiforme has many faces

    African Journals Online (AJOL)

    in both its pathological and radiological appearance.3 We present a series of 5 patients with histologically proven glioblastoma multiforme with atypical MRI findings. Case 1: Gliosarcoma. A 64-year-old man was initially admitted for pneumonia. On further inquiry, relatives reported that he had suffered from mild confusion,.

  18. Irinotecan and bevacizumab in recurrent glioblastoma multiforme

    DEFF Research Database (Denmark)

    Jakobsen, Jan Nyrop; Hasselbalch, Benedikte; Stockhausen, Marie-Thérése

    2011-01-01

    INTRODUCTION: Glioblastoma multiforme (GBM) is the most common high grade primary brain tumor in adults. Despite significant advances in treatment, the prognosis remains poor. Bevacizumab (BVZ) and irinotecan (CPT-11) are currently being investigated in the treatment of GBM patients. Although...

  19. Current Studies of Immunotherapy on Glioblastoma.

    Science.gov (United States)

    Agrawal, Neena Stephanie; Miller, Rickey; Lal, Richa; Mahanti, Harshini; Dixon-Mah, Yaenette N; DeCandio, Michele L; Vandergrift, W Alex; Varma, Abhay K; Patel, Sunil J; Banik, Naren L; Lindhorst, Scott M; Giglio, Pierre; Das, Arabinda

    2014-04-05

    Glioblastoma is a form of brain tumor with a very high morbidity and mortality. Despite decades of research, the best treatments currently in clinical practice only extend survival by a number of months. A promising alternative to conventional treatment for glioblastomas is immunotherapy. Although proposed over a century ago, the field of cancer immunotherapy has historically struggled to translate it into effective clinical treatments. Better understanding is needed of the various regulatory and co-stimulatory factors in the glioblastoma patient for more efficient immunotherapy treatments. The tumor microenvironment is anatomically shielded from normal immune-surveillance by the blood-brain barrier, irregular lymphatic drainage system, and it's in a potently immunosuppressive environment. Immunotherapy can potentially manipulate these forces effectively to enhance anti-tumor immune response and clinical benefit. New treatments utilizing the immune system show promise in terms of targeting and efficacy. This review article attempts to discuss current practices in glioblastoma treatment, the theory behind immunotherapy, and current research into various clinical trials.

  20. 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...

  1. Stereotactic radiosurgery for glioblastoma: retrospective analysis.

    Science.gov (United States)

    Biswas, Tithi; Okunieff, Paul; Schell, Michael C; Smudzin, Therese; Pilcher, Webster H; Bakos, Robert S; Vates, G Edward; Walter, Kevin A; Wensel, Andrew; Korones, David N; Milano, Michael T

    2009-03-17

    This retrospective study was done to better understand the conditions for which stereotactic radiosurgery (SRS) for glioblastoma may be efficacious. 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. 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). 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.

  2. Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma.

    Science.gov (United States)

    Mandel, Jacob J; Yust-Katz, Shlomit; Patel, Akash J; Cachia, David; Liu, Diane; Park, Minjeong; Yuan, Ying; Kent, Thomas A; de Groot, John F

    2018-01-10

    Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials. A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative. Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care. The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.

  3. Successfully Improving Physical Activity Behavior After Rehabilitation

    NARCIS (Netherlands)

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

    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 randomized

  4. 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.

  5. Imatinib mesylate radiosensitizes human glioblastoma cells through inhibition of platelet-derived growth factor receptor.

    Science.gov (United States)

    Holdhoff, Matthias; Kreuzer, Karl-Anton; Appelt, Christine; Scholz, Regina; Na, Il-Kang; Hildebrandt, Bert; Riess, Hanno; Jordan, Andreas; Schmidt, Christian A; Van Etten, Richard A; Dörken, Bernd; le Coutre, Philipp

    2005-01-01

    Imatinib mesylate is a small molecule inhibitor of the c-Abl, platelet-derived growth factor (PDGF) receptor and c-Kit tyrosine kinases that is approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Glioblastoma multiforme is a highly malignant primary brain tumor that is usually treated with surgery and/or radiotherapy. Previous studies implicate an autocrine loop caused by high expression of PDGF and its receptor, PDGFR, in the proliferation of some glioblastomas. Here, we demonstrate that pretreatment of a human glioblastoma cell line, RuSi RS1, with imatinib significantly enhanced the cytotoxic effect of ionizing radiation. This effect was not seen in human breast cancer (BT20) and colon cancer (WiDr) cell lines. Whereas c-Abl and c-Kit were expressed about equally in the three cell lines, RuSi RS1 cells showed significantly higher expression of PDGFR-beta protein in comparison to BT20 and WiDr. Imatinib treatment of RuSi RS1 cells decreased overall levels of cellular tyrosine phosphorylation and specifically inhibited phosphorylation of PDGFR-beta, while c-Abl was not prominently activated in these cells. These results suggest that imatinib may have clinical utility as a radiosensitizer in the treatment of human glioblastoma, possibly through disruption of an autocrine PDGF/PDGFR loop.

  6. 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.

  7. Intracellular cholesterol level regulates sensitivity of glioblastoma cells against temozolomide-induced cell death by modulation of caspase-8 activation via death receptor 5-accumulation and activation in the plasma membrane lipid raft.

    Science.gov (United States)

    Yamamoto, Yutaro; Tomiyama, Arata; Sasaki, Nobuyoshi; Yamaguchi, Hideki; Shirakihara, Takuya; Nakashima, Katsuhiko; Kumagai, Kosuke; Takeuchi, Satoru; Toyooka, Terushige; Otani, Naoki; Wada, Kojiro; Narita, Yoshitaka; Ichimura, Koichi; Sakai, Ryuichi; Namba, Hiroki; Mori, Kentaro

    2018-01-01

    Development of resistance against temozolomide (TMZ) in glioblastoma (GBM) after continuous treatment with TMZ is one of the critical problems in clinical GBM therapy. Intracellular cholesterol regulates cancer cell biology, but whether intracellular cholesterol is involved in TMZ resistance of GBM cells remains unclear. The involvement of intracellular cholesterol in acquired resistance against TMZ in GBM cells was investigated. Intracellular cholesterol levels were measured in human U251 MG cells with acquired TMZ resistance (U251-R cells) and TMZ-sensitive control U251 MG cells (U251-Con cells), and found that the intracellular cholesterol level was significantly lower in U251-R cells than in U251-Con cells. In addition, treatment by intracellular cholesterol remover, methyl-beta cyclodextrin (MβCD), or intracellular cholesterol inducer, soluble cholesterol (Chol), regulated TMZ-induced U251-Con cell death in line with changes in intracellular cholesterol level. Involvement of death receptor 5 (DR5), a death receptor localized in the plasma membrane, was evaluated. TMZ without or with MβCD and/or Chol caused accumulation of DR5 into the plasma membrane lipid raft and formed a complex with caspase-8, an extrinsic caspase cascade inducer, reflected in the induction of cell death. In addition, treatment with caspase-8 inhibitor or knockdown of DR5 dramatically suppressed U251-Con cell death induced by combination treatment with TMZ, MβCD, and Chol. Combined treatment of Chol with TMZ reversed the TMZ resistance of U251-R cells and another GBM cell model with acquired TMZ resistance, whereas clinical antihypercholesterolemia agents at physiological concentrations suppressed TMZ-induced cell death of U251-Con cells. These findings suggest that intracellular cholesterol level affects TMZ treatment of GBM mediated via a DR5-caspase-8 mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. The importance of genomic copy number changes in the prognosis of glioblastoma multiforme.

    Science.gov (United States)

    Arslantas, Ali; Artan, Sevilhan; Oner, Ulkü; Müslümanoğlu, Hamza; Durmaz, Ramazan; Cosan, Erhan; Atasoy, Metin Ant; Başaran, Nurettin; Tel, Eşref

    2004-01-01

    Glial tumors are the most common tumors of the nervous system, affecting individuals at any age. Since understanding of the molecular pathologies underlying human gliomas is still very poor, the treatment and therefore prognosis of this malignancy could not yet be improved. In order to determine whether different glioblastoma-associated genomic aberrations may serve as prognostic markers in combination with histopathological findings, 20 primary glioblastoma multiforme tumors were screened by comparative genomic hybridization, and the results were compared with histopathological and clinical features. All tumors showed genomic copy aberrations detected by comparative genomic hybridization. Regional and numerical increases in chromosome 7 copy number were the most frequently seen abnormality (10/20 tumors), followed by loss of chromosome 10 (8/20). Both of these aberrations were associated with shorter surveillance time. Chromosome 12q amplification was detected in seven tumors. Loss of 17p, 1p, and 19q in combination was seen in three cases. One of them was a giant cell GBM, whereas the remaining two cases were still alive. Combination of chromosome 1p and 19q deletions was also seen in a case with long surveillance. According to the preliminary findings of this study, in addition to the EGFR gene, amplification of other genes on chromosome 7 and the deletion of PTEN gene and other cancer-related genes on chromosome 10 appeared important to the development of glioblastoma multiforme and were associated with poor prognosis, whereas the combination of chromosome 1p and 19q deletions seems to be an informative molecular marker for better prognosis. The clinical features and genetic alterations of primary and secondary glioblastoma multiforme should be compared in large series to clarify the effective prognostic markers; and further molecular analyses focused on chromosomes 7 and 10 will be very helpful for understanding the molecular mechanisms underlying the

  9. 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.

  10. Harnessing glycosylation to improve cellulase activity

    Energy Technology Data Exchange (ETDEWEB)

    Beckham, Gregg T.; Dai, Ziyu; Mattews, James F.; Momany, Michelle; Payne, Christina M.; Adney, William S.; Baker, Scott E.; Himmel, Michael E.

    2012-06-11

    Cellulases and hemicellulases are responsible for the turnover of plant cell wall polysaccharides in the biosphere, and thus form the foundation of enzyme engineering efforts in biofuels research. Many of these carbohydrate-active enzymes from filamentous fungi contain both N-linked and O-linked glycosylation, the extent and heterogeneity of which depends on growth conditions, expression host, and the presence of glycan trimming enzymes in the secretome, all of which in turn impacts enzyme activity. As the roles of glycosylation in enzyme function have not been fully elucidated, here we discuss the potential roles of glycosylation on glycoside hydrolase enzyme structure and function after secretion. We posit that glycosylation, instead of hindering cellulase engineering, can be used as an additional tool to enhance enzyme activity, given deeper understanding of its molecular-level role in biomass deconstruction.

  11. Harnessing Glycosylation to Improve Cellulase Activity

    Energy Technology Data Exchange (ETDEWEB)

    Beckham, G. T.; Dai, Z.; Matthews, J. F.; Momany, M.; Payne, C. M.; Adney, W. S.; Baker, S. E.; Himmel, M. E.

    2012-06-01

    Cellulases and hemicellulases are responsible for the turnover of plant cell wall polysaccharides in the biosphere, and thus form the foundation of enzyme engineering efforts in biofuels research. Many of these carbohydrate-active enzymes from filamentous fungi contain both N-linked and O-linked glycosylation, the extent and heterogeneity of which depends on growth conditions, expression host, and the presence of glycan trimming enzymes in the secretome, all of which in turn impact enzyme activity. As the roles of glycosylation in enzyme function have not been fully elucidated, here we discuss the potential roles of glycosylation on glycoside hydrolase enzyme structure and function after secretion. We posit that glycosylation, instead of hindering cellulase engineering, can be used as an additional tool to enhance enzyme activity, given deeper understanding of its molecular-level role in biomass deconstruction.

  12. 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

  13. Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme

    DEFF Research Database (Denmark)

    Lassen, Ulrik; Sorensen, Morten; Gaziel, Tine Bernhardtsen

    2013-01-01

    BACKGROUND: Bevacizumab combined with chemotherapy has recently shown promising efficacy in recurrent high-grade glioma. Phosphatase and tensin homolog (PTEN) mutation in glioblastoma multiforme (GBM) patients causes abnormally high activity of the pathways of Phosphatidylinositide 3-kinases (PI3K....../10), infection (1/10), hypertension (1/10), and hyperglycemia (1/10). CONCLUSION: Temsirolimus can be safely administered in combination with bevacizumab. This study failed to detect activity of such a combination in patients with progressive GBM beyond bevacizumab therapy....

  14. 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.

  15. Immune Checkpoint in Glioblastoma: Promising and Challenging

    Directory of Open Access Journals (Sweden)

    Jing Huang

    2017-05-01

    Full Text Available Glioblastoma (GBM is a severe malignant brain cancer with poor overall survival. Conventional intervention remains dismal to prevent recurrence and deterioration of GBM cell. Recent years have witnessed exciting breakthroughs in novel immune strategies, especially checkpoint inhibitors, some of which have become adjuvant setting after standard of care in melanoma. Several clinical trials of checkpoint inhibitors are ongoing in glioblastoma and other brain carcinomas. Plus, synergistic combinations of checkpoint inhibitors with conventional therapy strategies—radiotherapy, temozolomide, bevacizumab, and corticosteroids are now being exploited and applied in clinical settings. This review highlights the recent developments of checkpoints in GBM immunotherapy to provide a brief and comprehensive review of current treatment options. Furthermore, we will discuss challenges remained, such as unique immune system of central nervous system (CNS, immune-related toxicities, synergies, and adverse interactions of combination therapies.

  16. Diffuse glioblastoma resembling acute hemorrhagic leukoencephalitis.

    Science.gov (United States)

    Schettino, Carla; Caranci, Ferdinando; Lus, Giacomo; Signoriello, Elisabetta; Eoli, Marica; Anghileri, Elena; Pollo, Bianca; Melone, Mariarosa A B; Di Iorio, Giuseppe; Finocchiaro, Gaetano; Ugga, Lorenzo; Tedeschi, Enrico

    2017-10-01

    We report the case of a young man with sudden onset of diplopia after an upper respiratory tract infection. Based on the first radiological findings acute hemorrhagic leukoencephalitis, a variant of acute disseminated encephalomyelitis, was suspected and treatment with high dose intravenous dexamethasone was started but it was stopped for intolerance. The patient clinically worsened, developing gait instability, ataxia and ophthalmoplegia; brain MRI performed 20 days later showed severe progression of the disease with subependymal dissemination. After brain biopsy of the right temporal lesion the histological diagnosis was glioblastoma. These findings suggest that MRI features of acute hemorrhagic leukoencephalitis may dissimulate the diagnosis of diffuse glioma/glioblastoma. This case underscores the importance of considering diffuse glioma in the differential diagnosis of atypical signs and symptoms of acute hemorrhagic leukoencephalitis and underlines the relevant role of integrating neuroradiologic findings with neuropathology.

  17. Hypoxic glucose metabolism in glioblastoma as a potential prognostic factor

    Energy Technology Data Exchange (ETDEWEB)

    Toyonaga, Takuya; Hirata, Kenji; Kobayashi, Kentaro; Manabe, Osamu; Watanabe, Shiro; Hattori, Naoya; Shiga, Tohru; Tamaki, Nagara [Hokkaido University Graduate School of Medicine, Department of Nuclear Medicine, Sapporo, Hokkaido (Japan); Yamaguchi, Shigeru [Hokkaido University Graduate School of Medicine, Department of Nuclear Medicine, Sapporo, Hokkaido (Japan); Hokkaido University Graduate School of Medicine, Department of Neurosurgery, Sapporo (Japan); Terasaka, Shunsuke; Kobayashi, Hiroyuki [Hokkaido University Graduate School of Medicine, Department of Neurosurgery, Sapporo (Japan); Kuge, Yuji [Hokkaido University, Central Institute of Isotope Science, Sapporo (Japan); Tanaka, Shinya [Hokkaido University Graduate School of Medicine, Department of Cancer Pathology, Sapporo (Japan); Ito, Yoichi M. [Hokkaido University Graduate School of Medicine, Department of Biostatistics, Sapporo (Japan)

    2017-04-15

    Metabolic activity and hypoxia are both important factors characterizing tumor aggressiveness. Here, we used F-18 fluoromisonidazole (FMISO) and F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) to define metabolically active hypoxic volume, and investigate its clinical significance in relation to progression free survival (PFS) and overall survival (OS) in glioblastoma patients. Glioblastoma patients (n = 32) underwent FMISO PET, FDG PET, and magnetic resonance imaging (MRI) before surgical intervention. FDG and FMISO PET images were coregistered with gadolinium-enhanced T1-weighted MR images. Volume of interest (VOI) of gross tumor volume (GTV) was manually created to enclose the entire gadolinium-positive areas. The FMISO tumor-to-normal region ratio (TNR) and FDG TNR were calculated in a voxel-by-voxel manner. For calculating TNR, standardized uptake value (SUV) was divided by averaged SUV of normal references. Contralateral frontal and parietal cortices were used as the reference region for FDG, whereas the cerebellar cortex was used as the reference region for FMISO. FDG-positive was defined as the FDG TNR ≥1.0, and FMISO-positive was defined as FMISO TNR ≥1.3. Hypoxia volume (HV) was defined as the volume of FMISO-positive and metabolic tumor volume in hypoxia (hMTV) was the volume of FMISO/FDG double-positive. The total lesion glycolysis in hypoxia (hTLG) was hMTV x FDG SUVmean. The extent of resection (EOR) involving cytoreduction surgery was volumetric change based on planimetry methods using MRI. These factors were tested for correlation with patient prognosis. All tumor lesions were FMISO-positive and FDG-positive. Univariate analysis indicated that hMTV, hTLG, and EOR were significantly correlated with PFS (p = 0.007, p = 0.04, and p = 0.01, respectively) and that hMTV, hTLG, and EOR were also significantly correlated with OS (p = 0.0028, p = 0.037, and p = 0.014, respectively). In contrast, none of FDG TNR, FMISO TNR, GTV, HV

  18. Combination of palbociclib and radiotherapy for glioblastoma

    OpenAIRE

    Whittaker, Shane; Madani, Daniel; Joshi, Swapna; Chung, Sylvia A; Johns, Terrance; Day, Bryan; Khasraw, Mustafa; McDonald, Kerrie L.

    2017-01-01

    The cyclin-dependent kinase inhibitor, palbociclib has shown compelling efficacy in breast cancer patients. Several pre-clinical studies of glioblastoma (GBM) have also shown palbociclib to be efficacious. In this study, we investigated palbociclib in combination with radiation therapy (RT) for treating GBM. We tested palbociclib (with and without RT) on four patient-derived cell lines (PDCLs; RB1 retained; CDKN2A loss). We investigated the impact of therapy on the cell cycle and apoptosis us...

  19. Orphan drugs in glioblastoma multiforme: a review

    Directory of Open Access Journals (Sweden)

    Lassen U

    2014-11-01

    Full Text Available Ulrik Lassen, Morten Mau-Sørensen, Hans Skovgaard Poulsen Department of Oncology, Rigshospitalet, Copenhagen, DenmarkAbstract: Glioblastoma multiforme (GBM is the most common and deadly brain tumor in adults. The incidence of GBM in the USA and Europe is 2–3 per 100,000. By definition, an orphan disease affects up to 200,000 persons in the USA (one in every 1,500. A search was made in the US Food and Drug Administration orphan drug listing. In addition, a PubMed search of orphan drugs designated for GBM or high-grade glioma was performed, followed by a search for clinical studies in GBM with orphan drugs designated for other indications. This included cytotoxic chemotherapy and targeted agents. Thirteen drugs with orphan designation for the treatment of glioblastoma, high-grade glioma, or primary malignant brain tumors were identified. In addition, 16 drugs with orphan designation for other indications were identified to have been evaluated in clinical studies of GBM. The efficacy data from the clinical studies is presented. A few agents have been approved by the US Food and Drug Administration for the treatment of high-grade gliomas following orphan drug designation, but most have failed to reach the market. However, a few patients may have benefited from receiving developmental agents within clinical trials. Biomarkers for selection of these patients may result in more success in the field of personalized medicine. Keywords: orphan drugs, glioblastoma multiforme, brain tumor, targeted therapy, cytotoxic therapy

  20. Novel multifunctional acyloxyalkyl ester prodrugs of 5-aminolevulinic acid display improved anticancer activity dependent on photoactivation

    Science.gov (United States)

    Berkovitch, G.; Nudelman, A.; Ehenberg, B.; Rephaeli, A.; Malik, Z.

    2009-06-01

    New approaches to PDT using multifunctional 5-aminolevulinic acid (ALA) based prodrugs activating mutual routes of toxicity are described. We investigated the mutual anti-cancer activity of ALA prodrugs which upon metabolic hydrolysis by unspecific esterases release ALA, formaldehyde or acetaldehye and the histone deacetylase inhibitor (HDACI) butyric acid. The most potent prodrug in this study was butyryloxyethyl 5-amino-4-oxopentanoate (AN-233) that stimulated a rapid biosynthesis of protoporphyrin IX (PpIX) in human glioblastoma U-251 cells and generated an efficient photodynamic destruction. AN-233 induced a considerable high level of intracellular ROS in the cells following light irradiation, reduction of mitochondrial activity, dissipation of the mitochondrial membrane potential resulting in necrotic and apoptotic cell death. The main advantage of AN-233 over ALA stems from its ability to induce photodamage at a significantly lower dose than ALA.

  1. Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

    Directory of Open Access Journals (Sweden)

    Gutin Philip H

    2011-01-01

    Full Text Available Abstract Surgical resection followed by radiotherapy and temozolomide in newly diagnosed glioblastoma can prolong survival, but it is not curative. For patients with disease progression after frontline therapy, there is no standard of care, although further surgery, chemotherapy, and radiotherapy may be used. Antiangiogenic therapies may be appropriate for treating glioblastomas because angiogenesis is critical to tumor growth. In a large, noncomparative phase II trial, bevacizumab was evaluated alone and with irinotecan in patients with recurrent glioblastoma; combination treatment was associated with an estimated 6-month progression-free survival (PFS rate of 50.3%, a median overall survival of 8.9 months, and a response rate of 37.8%. Single-agent bevacizumab also exceeded the predetermined threshold of activity for salvage chemotherapy (6-month PFS rate, 15%, achieving a 6-month PFS rate of 42.6% (p

  2. 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.

  3. On-Demand Drug Release from Dual-Targeting Small Nanoparticles Triggered by High-Intensity Focused Ultrasound Enhanced Glioblastoma-Targeting Therapy.

    Science.gov (United States)

    Luo, Zimiao; Jin, Kai; Pang, Qiang; Shen, Shun; Yan, Zhiqiang; Jiang, Ting; Zhu, Xiaoyan; Yu, Lei; Pang, Zhiqing; Jiang, Xinguo

    2017-09-20

    Glioblastoma is one of the most challenging and intractable tumors with the difficult treatment and poor prognosis. Unsatisfactory traditional systemic chemotherapies for glioblastoma are mainly attributed to the insufficient and nonspecific drug delivery into the brain tumors as well as the incomplete drug release at the tumor sites. Inspired by the facts that angiopep-2 peptide is an acknowledged dual-targeting moiety for brain tumor-targeting delivery and high-intensity focused ultrasound (HIFU) is an ideal trigger for drug release with an ultrahigh energy and millimeter-sized focus ability, in the present study, a novel HIFU-responsive angiopep-2-modified small poly(lactic-co-glycolic acid) (PLGA) hybrid nanoparticle (NP) drug delivery system holding doxorubicin/perfluorooctyl bromide (ANP-D/P) was designed to increase the intratumoral drug accumulation, further trigger on-demand drug release at the glioblastoma sites, and enhance glioblastoma therapy. It was shown that the ANP-D/P was stable and had a small size of 41 nm. The angiopep-2 modification endowed the ANP-D/P with improved blood-brain barrier transportation and specific accumulation in glioblastoma tissues by 17 folds and 13.4 folds compared with unmodified NPs, respectively. Under HIFU irradiation, the ANP-D/P could release 47% of the drug within 2 min and induce the apoptosis of most tumor cells. HIFU-triggered instantaneous drug release at the glioblastoma sites eventually enabled the ANP-D/P to achieve the strongest antiglioblastoma efficacy with the longest median survival time (56 days) of glioblastoma-bearing mice and the minimum vestiges of tumor cells in the pathological slices among all groups. In conclusion, the HIFU-responsive ANP-D/P in this study provided a new way for glioblastoma therapy with a great potential for clinical applications.

  4. Forms and Methods of Agricultural Sector Innovative Activity Improvement

    Directory of Open Access Journals (Sweden)

    Aisha S. Ablyaeva

    2013-01-01

    Full Text Available The article is focused on basic forms and methods to improve the efficiency of innovative activity in the agricultural sector of Ukraine. It was determined that the development of agriculture in Ukraine is affected by a number of factors that must be considered to design innovative models of entrepreneurship development and ways to improve the efficiency of innovative entrepreneurship activity.

  5. 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

  6. Toxicity and tropism of oncolytic VSV vectors in glioblastoma gene therapy

    OpenAIRE

    Zehtab Jahedi, Roza

    2012-01-01

    Glioblastoma multiforme is the most common and most fatal primary brain tumor in adults. Despite using advanced conventional therapeutic approaches like surgical resection, radiotherapy and chemotherapy only marginal improvement with a median survival of about 14 months is observed. Thus, finding urgent novel therapeutic strategies to target and kill GBM cells are desperately needed. In this respect, gene therapy provides new perspectives for treating cancer, although the safet...

  7. Migration of mesenchymal stem cells towards glioblastoma cells depends on hepatocyte-growth factor and is enhanced by aminolaevulinic acid-mediated photodynamic treatment.

    Science.gov (United States)

    Vogel, Sebastian; Peters, Corinna; Etminan, Nima; Börger, Verena; Schimanski, Adrian; Sabel, Michael C; Sorg, Rüdiger V

    2013-02-15

    Hepatocyte-growth factor (HGF) is expressed by glioblastomas and contributes to their growth, migration and invasion. HGF also mediates migration of mesenchymal stem cells (MSC) to sites of apoptotic cell death. Moreover, MSC show tropism for glioblastomas, which is exploited in gene therapy to deliver the therapeutics to the tumor cells. Here, we have studied whether HGF contributes to the recruitment of MSC by glioblastoma cells and whether aminolaevulinic acid-mediated photodynamic therapy (ALA/PDT), a novel therapeutic approach that induces apoptosis in glioblastoma cells, affects HGF release and this migratory response. MSC expressed the HGF receptor MET and migrated towards U87 and U251 glioblastoma spheroids. Migration increased significantly when spheroids were subjected to ALA/PDT, which was associated with induction of apoptosis and up-regulation of HGF. Neutralizing HGF resulted in significant inhibition of MSC migration towards untreated as well as ALA/PDT-treated spheroids. Thus, glioblastoma cells express HGF, which contributes to the attraction of MSC. ALA/PDT induces apoptosis and augments HGF release causing enhanced MSC migration towards the tumor cells. ALA/PDT may therefore be exploited to improve targeting of MSC delivered gene therapy, but it may also constitute a risk in terms of beneficial effects for the tumor. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme

    NARCIS (Netherlands)

    Kuijlen, Jos M. A.; Mooij, Jan Jakob A.; Platteel, Inge; Hoving, Eelco W.; van der Graaf, Winette T. A.; Span, Mark M.; Hollema, Harry; den Dunnen, Wilfred F. A.

    Purpose: In order to improve the survival of patients with a glioblastoma multiforme tumor (GBM), new therapeutic strategies must be developed. The use of a death inducing ligand such as TRAIL (TNF Related Apoptosis Inducing Ligand) seems a promising innovative therapy. The aim of this study was to

  9. Target-specific delivery of doxorubicin to human glioblastoma cell ...

    Indian Academy of Sciences (India)

    Abdullah Tahir Bayraç

    2018-01-29

    Jan 29, 2018 ... nano-sized targeted drug delivery approach adorned with A-172 glioblastoma cell-line-specific single stranded DNA. (ssDNA) ... GMT-3 aptamer-mediated therapeutic drug transportation in the treatment of gliomas specifically. ..... Nanomedicine to overcome radioresistance in glioblastoma stem-like cells ...

  10. Amnesia due to bilateral hippocampal glioblastoma. MRI finding

    Energy Technology Data Exchange (ETDEWEB)

    Shimauchi, M.; Wakisaka, S.; Kinoshita, K. (Miyazaki Medical Coll., Kiyotake (Japan). Dept. of Neurosurgery)

    1989-11-01

    The authors report a unique case of glioblastoma which caused permanent amnesia. Magnetic resonance imaging showed the lesion to be limited to the hippocampal formation bilaterally. Although glioblastoma extends frequently into fiber pathways and expands into the opposite cerebral hemisphere, making a 'butterfly' lesion, it is unusual for it to invade the limbic system selectively to this extent. (orig.).

  11. Subventricular Zone Involvement Characterized by Diffusion Tensor Imaging in Glioblastoma

    NARCIS (Netherlands)

    van Dijken, Bart Rj; Yan, Jiun-Lin; Boonzaier, Natalie R; Li, Chao; van Laar, Peter Jan; van der Hoorn, Anouk; Price, Stephen J

    BACKGROUND: Glioblastomas have a poor prognosis, possibly because of a subpopulation of therapy-resistant stem cells within the heterogeneous glioblastoma. Because the subventricular zone is the main source of neural stem cells, we aimed at characterizing the subventricular zone using diffusion

  12. 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...... 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...

  13. Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants.

    Science.gov (United States)

    Krenciute, Giedre; Prinzing, Brooke L; Yi, Zhongzhen; Wu, Meng-Fen; Liu, Hao; Dotti, Gianpietro; Balyasnikova, Irina V; Gottschalk, Stephen

    2017-07-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Rα2-positive glioma model in which limited IL13Rα2-CAR T-cell persistence results in recurrence of antigen-positive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Rα2-CARs or IL15 (IL13Rα2-CAR.IL15 T cells). IL13Rα2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity, and produced more cytokines after repeated stimulations in comparison with IL13Rα2-CAR T cells. No autonomous IL13Rα2-CAR.IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen. In vivo, IL13Rα2-CAR.IL15 T cells persisted longer and had greater antiglioma activity than IL13Rα2-CAR T cells, resulting in a survival advantage. Gliomas recurring after 40 days after T-cell injection had downregulated IL13Rα2 expression, indicating that antigen loss variants occur in the setting of improved T-cell persistence. Thus, CAR T cells for GBM should not only be genetically modified to improve their proliferation and persistence, but also to target multiple antigens.Summary: Glioblastoma responds imperfectly to immunotherapy. Transgenic expression of IL15 in T cells expressing CARs improved their proliferative capacity, persistence, and cytokine production. The emergence of antigen loss

  14. Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current

    Science.gov (United States)

    Barbieri, Federica; Peretti, Marta; Pizzi, Erika; Pattarozzi, Alessandra; Carra, Elisa; Sirito, Rodolfo; Daga, Antonio; Curmi, Paul M.G.; Mazzanti, Michele; Florio, Tullio

    2014-01-01

    Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown. Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity. The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin's antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment. PMID:25361004

  15. The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures

    NARCIS (Netherlands)

    Narayan, Ravi S.; Fedrigo, Carlos A.; Brands, Eelke; Dik, Rogier; Stalpers, Lukas J. A.; Baumert, Brigitta G.; Slotman, Ben J.; Westerman, Bart A.; Peters, Godefridus J.; Sminia, Peter

    2017-01-01

    Background: Glioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has been associated with increased survival and resistance to therapy. The aim of this study

  16. Global targeting of subcellular heat shock protein-90 networks for therapy of glioblastoma.

    Science.gov (United States)

    Siegelin, Markus D; Plescia, Janet; Raskett, Christopher M; Gilbert, Candace A; Ross, Alonzo H; Altieri, Dario C

    2010-06-01

    Drug discovery for complex and heterogeneous tumors now aims at dismantling global networks of disease maintenance, but the subcellular requirements of this approach are not understood. Here, we simultaneously targeted the multiple subcellular compartments of the molecular chaperone heat shock protein-90 (Hsp90) in a model of glioblastoma, a highly lethal human malignancy in urgent need of fresh therapeutic strategies. Treatment of cultured or patient-derived glioblastoma cells with Shepherdin, a dual peptidomimetic inhibitor of mitochondrial and cytosolic Hsp90, caused irreversible collapse of mitochondria, degradation of Hsp90 client proteins in the cytosol, and tumor cell killing by apoptosis and autophagy. Stereotactic or systemic delivery of Shepherdin was well tolerated and suppressed intracranial glioma growth via inhibition of cell proliferation, induction of apoptosis, and reduction of angiogenesis in vivo. These data show that disabling Hsp90 cancer networks in their multiple subcellular compartments improves strategies for drug discovery and may provide novel molecular therapy for highly recalcitrant human tumors.

  17. 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.

  18. 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

    .0009) and high expression of a HLA class II gene (2-fold increase in HLA-DQA1; OR = 1.22; 95% CI: 1.01-1.47; P = 0.04). These two genes were included in a model that is able predict response to bevacizumab combination therapy in clinical practice. When stratified for a validated prognostic index, the predictive...... model for response was significantly associated with improved overall survival. Conclusion: Two genes (low angiotensinogen and high HLA-class II expression) were predictive for bevacizumab response and were included in a predictive model for response. This model can be used in clinical practice...... 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...

  19. Frequency of NFKBIA deletions is low in glioblastomas and skewed in glioblastoma neurospheres.

    Science.gov (United States)

    Patanè, Monica; Porrati, Paola; Bottega, Elisa; Morosini, Sara; Cantini, Gabriele; Girgenti, Vita; Rizzo, Ambra; Eoli, Marica; Pollo, Bianca; Sciacca, Francesca L; Pellegatta, Serena; Finocchiaro, Gaetano

    2013-12-11

    The NF-kB family of transcription factors is up-regulated in inflammation and different cancers. Recent data described heterozygous deletions of the NF-kB Inhibitor alpha gene (NFKBIA) in about 20% of glioblastomas (GBM): deletions were mutually exclusive with epidermal growth factor receptor (EGFR) amplification, a frequent event in GBM. We assessed the status of NFKBIA and EGFR in 69 primary GBMs and in corresponding neurospheres (NS). NFKBIA deletion was investigated by the copy number variation assay (CNV); EGFR amplification by CNV ratio with HGF; expression of EGFR and EGFRvIII by quantitative PCR or ReverseTranscriptase PCR. Heterozygous deletions of NFKBIA were present in 3 of 69 primary GBMs and, surprisingly, in 30 of 69 NS. EGFR amplification was detected in 36 GBMs: in corresponding NS, amplification was lost in 13 cases and reduced in 23 (10 vs 47 folds in NS vs primary tumors; p < 0.001). The CNV assay was validated investigating HPRT1 on chromosome X in females and males. Results of array-CGH performed on 3 primary GBMs and 1 NS line were compatible with the CNV assay. NS cells with NFKBIA deletion had increased nuclear activity of p65 (RelA) and increased expression of the NF-kB target IL-6. In absence of EGF in the medium, EGFR amplification was more conserved and NFKBIA deletion less frequent point to a low frequency of NFKBIA deletions in GBM and suggest that EGF in the culture medium of NS may affect frequency not only of EGFR amplifications but also of NFKBIA deletions.

  20. 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.

  1. Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic.

    Science.gov (United States)

    Volpin, F; Casaos, J; Sesen, J; Mangraviti, A; Choi, J; Gorelick, N; Frikeche, J; Lott, T; Felder, R; Scotland, S J; Eisinger-Mathason, T S K; Brem, H; Tyler, B; Skuli, N

    2017-05-25

    The median survival for glioblastoma patients is ~15 months despite aggressive surgery and radio-chemotherapy approaches. Thus, developing new therapeutics is necessary to improve the treatment of these invasive brain tumors, which are known to show high levels of the eukaryotic initiation factor, eIF4E, a potent oncogene. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C treatment. Here, we report the effect of ribavirin on proliferation, cell cycle, cell death and migration of several human and murine glioma cell lines, as well as human glioblastoma stem-like cells, in vitro. In addition, we tested ribavirin efficacy in vivo, alone and in combination with temozolomide and radiation. Our work showed that ribavirin inhibits glioma cell growth and migration, and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E, EZH2 and ERK pathways. We also demonstrate that ribavirin treatment in combination with temozolomide or irradiation increases cell death in glioma cells. Finally and most importantly, ribavirin treatment in vivo significantly enhances chemo-radiotherapy efficacy and improves survival of rats and mice orthotopically implanted with gliosarcoma tumors or glioma stem-like cells, respectively. On the basis of these results, we propose that ribavirin represents a new therapeutic option for glioblastoma patients as an enhancer of the cytotoxic effects of temozolomide and radiotherapy.

  2. 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.)

  3. Expression of the zinc importer protein ZIP9/SLC39A9 in glioblastoma cells affects phosphorylation states of p53 and GSK-3β and causes increased cell migration.

    Science.gov (United States)

    Münnich, Nico; Wernhart, Simon; Hogstrand, Christer; Schlomann, Uwe; Nimsky, Christopher; Bartsch, Jörg W

    2016-12-01

    Zinc importer proteins (ZIPs) have been proven as important molecular regulators in different cancers. As a member of the solute carrier family, ZIP9/SLC39A9 is overexpressed in prostate and breast cancer and affects B-cell receptor signaling. Here, we present data indicating that changes in intracellular zinc levels in glioblastoma cells can cause enhanced cell survival and cell migration, both hallmarks of the disease process. In particular, treatment of human glioblastoma cells with sublethal doses of cell-permeable heavy metal (Zn2+ > Fe2+ > Mn2+) chelator (N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN)) induced ZIP9 expression. Either TPEN treatment or expression of ZIP9 cDNA causes enhanced migration behavior of glioblastoma cells. Compared to untreated glioblastoma cells TPEN treatment or expression of ZIP9 results in activation of the tumor suppressor p53 by phosphorylation at serine residue 46 (Ser46) and in inactivation of the migration relevant glycogen synthase kinase 3 beta (GSK-3β) by phosphorylation at serine residue 9 (Ser9). Whilst p53 activation affects cell survival in response to TPEN, GSK-3β inactivation directly affects glioblastoma cell migration. Therefore, ZIP9 expression could regulate the migratory behavior of glioblastoma cells, so that ZIP9 may be of biological, but not of clinical relevance for glioblastomas, since in GBM tumor tissues, ZIP9 expression is not significantly increased compared to normal brain.

  4. Are students' impressions of improved learning through active learning methods reflected by improved test scores?

    Science.gov (United States)

    Everly, Marcee C

    2013-02-01

    To report the transformation from lecture to more active learning methods in a maternity nursing course and to evaluate whether student perception of improved learning through active-learning methods is supported by improved test scores. The process of transforming a course into an active-learning model of teaching is described. A voluntary mid-semester survey for student acceptance of the new teaching method was conducted. Course examination results, from both a standardized exam and a cumulative final exam, among students who received lecture in the classroom and students who had active learning activities in the classroom were compared. Active learning activities were very acceptable to students. The majority of students reported learning more from having active-learning activities in the classroom rather than lecture-only and this belief was supported by improved test scores. Students who had active learning activities in the classroom scored significantly higher on a standardized assessment test than students who received lecture only. The findings support the use of student reflection to evaluate the effectiveness of active-learning methods and help validate the use of student reflection of improved learning in other research projects. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. 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.

  6. 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.

  7. 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 (

  8. Glioblastoma: Part I. Current state of affairs.

    Science.gov (United States)

    Salacz, Michael E; Watson, Kenneth R; Schomas, David A

    2011-01-01

    Although uncommon, "brain cancer" is one of the most feared diseases that afflict human beings. While still regarded as one of the most deadly forms of primary brain neoplasm, recent advances in the treatment of glioblastoma (GBM) have offered new hope for patients, families, and clinicians. In the first part of this two-part review, we will focus on the multidisciplinary advances that have established the current treatment approach in the management of GBM. In the second part of this review, ongoing research will be presented including current clinical trials as well as some of the newer technologies that are forming the promise of the future.

  9. Design of a PKCδ-specific small peptide as a theragnostic agent for glioblastoma.

    Science.gov (United States)

    Cho, Jun-Haeng; Ha, Na-Reum; Koh, Seong-Ho; Yoon, Moon-Young

    2016-03-01

    Glioblastoma is an aggressive malignant brain tumor that starts in the brain or spine and frequently recurs after anticancer treatment. The development of an accurate diagnostic system combined with effective cancer therapy is essential to improve prognosis of glioma patients. Peptides, produced from phage display, are attractive biomolecules for glioma treatment because of their biostability, nontoxicity, and small size. In this study, we employed phage display methodology to screen for peptides that specifically recognize the target PKCδ as a novel biomarker for glioma. The phage library screening yielded four different peptides displayed on phages with a 20- to 200-pM Kd value for the recombinant PKCδ catalytic domain. Among these four phage peptides, we selected one to synthesize and tagged it with fluorescein isothiocyanate (FITC) based on the sequence of the PKCδ-binding phage clone. The synthetic peptide showed a relative binding affinity for antibody and localization in the U373 glioma cell. The kinase activity of PKCδ was inhibited by FITC-labeled peptide with an IC50 of 1.4 μM in vitro. Consequently, the peptide found in this study might be a promising therapeutic agent against malignant brain tumor. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Prevention Research Matters-Communities Working to Improve Physical Activity

    Centers for Disease Control (CDC) Podcasts

    2018-02-15

    We know that children who are physically active every day are less likely to develop chronic diseases as adults, including obesity. Dr. Sandy Slater, a researcher with the University of Illinois, Chicago Prevention Research Center, discusses how a park improvement project in Chicago helped engage communities to improve areas for play and activity.  Created: 2/15/2018 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 2/15/2018.

  11. Highly efficient eradication of intracranial glioblastoma using Eg5 siRNA combined with HVJ envelope.

    Science.gov (United States)

    Matsuda, M; Yamamoto, T; Matsumura, A; Kaneda, Y

    2009-12-01

    Hemagglutinating virus of Japan envelope (HVJ-E) vector with inactivated replication-defective Sendai virus was originally developed as a versatile drug delivery system. Recently, we have shown the direct tumor-killing activity of HVJ-E itself without therapeutic molecules in prostate cancer cells. Although human glioblastoma cells were also sensitive to HVJ-E treatment, complete eradication was not achieved using HVJ-E alone. Here, to develop more effective therapeutic strategy of glioblastoma, we enhanced the anti-tumor activity by incorporating Short interfering RNA (siRNA) of mitotic motor protein Eg5 into HVJ-E. Treatment with HVJ-E-containing Eg5 siRNA induced monopolar spindle formation and resulted in cell-cycle arrest and apoptosis. When HVJ-E-containing Eg5 siRNA was directly injected into an intradermal tumor xenograft, all mice became tumor-free. Similar results were observed in the intracranial tumor xenografts. The survival time of treated mice was significantly prolonged when HVJ-E was used. Histological examination showed that tumors remained in the brain after treatment with HVJ-E-containing negative control siRNA, but no tumors were detected after treatment with HVJ-E-containing Eg5 siRNA. This remarkable anti-tumor response was likely due to a synergistic effect of Eg5 siRNA and HVJ-E. Thus, this combination shows promise as an attractive novel therapy for glioblastoma.

  12. Why dapsone stops seizures and may stop neutrophils' delivery of VEGF to glioblastoma.

    Science.gov (United States)

    Kast, R E; Lefranc, F; Karpel-Massler, G; Halatsch, M-E

    2012-12-01

    Lopez-Gomez et al. recently published remarkable but mechanistically unexplained empirical evidence that the old antibiotic dapsone has antiepileptic activity. We addressed the question "Why should a sulfone antibiotic reduce seizures?". We report here our conclusions based on data from past studies that seizures are associated with elevated interleukin-8 (IL-8) and that dapsone inhibits IL-8 release and function in several different clinical and experimental contexts. Diverse CNS insults cause an increase in CNS IL-8. Thus, the pro-inflammatory environment generated by increase IL-8 leads to a lower seizure threshold. Together this evidence indicates dapsone exerts anti-seizure activity by diminishing IL-8 signalling. Since IL-8 is clearly upregulated in glioblastoma and contributes to the florid angiogenesis of that disease, and since interference with IL-8 function has been shown to inhibit glioblastoma invasion and growth in several experimental models, and dapsone has been repeatedly been shown to clinically inhibit IL-8 function when used to treat human neutrophilic dermatoses, we believe that dapsone thereby reduces seizures by countering IL-8 function and may similarly retard glioblastoma growth by such anti-IL-8 function.

  13. HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway

    Directory of Open Access Journals (Sweden)

    Xin Deng

    2017-12-01

    Full Text Available Glioblastoma is the most common malignant tumor in central nervous system (CNS, and it is still insurmountable and has a poor prognosis. The proliferation and survival mechanism of glioma cells needs to be explored further for the development of glioma treatment. Hematopoietic-substrate-1 associated protein X-1 (HAX-1 has been reported as an anti-apoptosis protein that plays an important role in several malignant tumors. However, the effect and mechanism of HAX-1 in glioblastomas remains unknown. This study aimed to investigate the effect of HAX-1 in glioblastoma cells and explore the mechanism. The results of clone formation and Edu proliferation assay showed slower multiplication in HAX-1 knock-out cells. Flow cytometry showed cell cycle arrest mainly in G0/G1 phase. Apoptosis due to oxidative stress was increased after HAX-1 was knocked out. Western-blot assay exhibited that the levels of p21, Bax, and p53 proteins were significantly raised, and that the activation of the caspase cascade was enhanced in the absence of HAX-1. The degradation rate and ubiquitination of p53 declined because of the decrease in phosphorylation of proteins MDM2 and Akt1. Co-immunoprecipitation (Co-IP and immunefluorescent co-localization assays were performed to test the influence of HAX-1 on the interaction between Akt1 and Hsp90, which is crucial for the activity of Akt1. In conclusion, this novel study suggested that HAX-1 could affect the Akt1 pathway through Hsp90. The knock-out of HAX-1 leads to the inactivity of the Ak1t/MDM2 axis, which leads to increased levels of p53, and finally generates cell cycle arrest and results in the apoptosis of glioblastoma cells.

  14. From glioblastoma to endothelial cells through extracellular vesicles: messages for angiogenesis.

    Science.gov (United States)

    Giusti, Ilaria; Delle Monache, Simona; Di Francesco, Marianna; Sanità, Patrizia; D'Ascenzo, Sandra; Gravina, Giovanni Luca; Festuccia, Claudio; Dolo, Vincenza

    2016-09-01

    Glioblastoma has one of the highest mortality rates among cancers, and it is the most common and malignant form of brain cancer. Among the typical features of glioblastoma tumors, there is an aberrant vascularization: all gliomas are among the most vascularized/angiogenic tumors. In recent years, it has become clear that glioblastoma cells can secrete extracellular vesicles which are spherical and membrane-enclosed particles released, in vitro or in vivo, by both normal and tumor cells; they are involved in the regulation of both physiological and pathological processes; among the latter, cancer is the most widely studied. Extracellular vesicles from tumor cells convey messages to other tumor cells, but also to normal stromal cells in order to create a microenvironment that supports cancer growth and progression and are implicated in drug resistance, escape from immunosurveillance and from apoptosis, as well as in metastasis formation; they are also involved in angiogenesis stimulation, inducing endothelial cells proliferation, and other pro-angiogenic activities. To this aim, the present paper assesses in detail the extracellular vesicles phenomenon in the human glioblastoma cell line U251 and evaluates extracellular vesicles ability to promote the processes required to achieve the formation of new blood vessels in human brain microvascular endothelial cells, highlighting that they stimulate proliferation, motility, and tube formation in a dose-response manner. Moreover, a molecular characterization shows that extracellular vesicles are fully equipped for angiogenesis stimulation in terms of proteolytic enzymes (gelatinases and plasminogen activators), pro-angiogenic growth factors (VEGF and TGFβ), and the promoting-angiogenic CXCR4 chemokine receptor.

  15. Enhanced Antitumorigenic Effects in Glioblastoma on Double Targeting of Pleiotrophin and Its Receptor ALK

    Directory of Open Access Journals (Sweden)

    Marius Grzelinski

    2009-02-01

    Full Text Available In adults, glioblastomas are the most lethal and most frequent malignant brain tumors, and the poor prognosis despite aggressive treatment indicates the need to establish novel targets for molecular intervention. The secreted growth factor pleiotrophin (PTN, HB-GAM, HBNF, OSF-1 shows mitogenic, chemotactic, and transforming activity. Whereas PTN expression is tightly regulated during embryogenesis and is very limited in normal adult tissues, a marked PTN up-regulation is seen in tumors including glioblastomas. Likewise, the PTN receptor anaplastic lymphoma kinase (ALK has been shown previously to be upregulated and functionally relevant in glioblastoma. In this study, we explore the antitumorigenic effects of the simultaneous ribozyme-mediated knockdown of both receptor and ligand. Various glioblastoma cell lines are analyzed for PTN and ALK expression. Beyond the individual efficacies of several specific ribozymes against PTN or ALK, respectively, antiproliferative and proapoptotic effects of a single gene targeting approach are strongly enhanced on double knockdown of both genes in vitro. More importantly, this results in the abolishment of tumor growth in an in vivo subcutaneous tumor xenograft model. Finally, the analysis of various downstream signaling pathways by antibody arrays reveals a distinct pattern of changes in the activation of signal transduction molecules on PTN/ALK double knockdown. Beyond the already known ones, it identifies additional pathways relevant for PTN/ALK signaling. We conclude that double targeting of PTN and ALK leads to enhanced antitumorigenic effects over single knockdown approaches, which offers novel therapeutic options owing to increased efficacy also after prolonged knockdown.

  16. Photodynamic process induced by chloro-aluminum phthalocyanine nanoemulsion in glioblastoma.

    Science.gov (United States)

    Castilho-Fernandes, Andrielle; Lopes, Tácila G; Primo, Fernando L; Pinto, Marcelo R; Tedesco, Antonio C

    2017-09-01

    Glioblastoma multiforme (GBM) is a tumor characterized by rapid cell proliferation and migration. GBM constitutes the most aggressive and deadly type of brain tumor and is classified into several subtypes that show high resistance to conventional therapies. There are currently no curative treatments for malignant glioma despite the numerous advances in surgical techniques, radiotherapy, and chemotherapy. Therefore, alternative approaches are required to improve GBM treatment. Our study proposes the use of photodynamic therapy (PDT) for GBM treatment, which uses chloro-aluminum phthalocyanine (AlClPc) encapsulated in a new drug delivery system (DDS) and designed as a nanoemulsion (AlClPc/NE). The optimal dark non-cytotoxic AlClPc/NE concentration for the U87 MG glioma cell model and the most suitable laser light intensity for irradiation were determined. Experimental U87 MG cancer cells were analyzed via MTT cell viability assay. Cellular localization of AlClPc, morphological changes, and cell death via the necrotic and apoptotic pathways were also evaluated. AlClPc remained in the cytoplasmic region at 24h after administration. Additionally, treatment with 1.0μmol/L AlClPc under light irradiation at doses lower than 140mJ/cm resulted in morphological changes with 50±6% cell death (p<0.05). Moreover, 20±2% of U87 MG cells underwent cell death via the necrotic pathway. Measurement of Caspase-9 and -3 activities also suggested that cells underwent apoptosis. Taken together, these results indicate that AlClPc/NE-PDT can be used in the treatment of glioblastoma by inducing necrotic and apoptotic cell death. Our findings suggest that AlClPc/NE-PDT induces cell death in U87 MG cells in a dose-dependent manner and could thus serve as an effective adjuvant treatment for malignant glioma. AlClPc/NE-PDT utilizes a low dose of visible light and can be used in combination with other classic GBM treatment approaches, such as a combination of chemotherapy and surgery

  17. The influence of corporate structure and quality improvement activities on outcome improvement in residential care homes.

    Science.gov (United States)

    Winters, S; Kool, R B; Klazinga, N S; Huijsman, R

    2014-08-01

    To examine the impact of corporate structure and quality improvement (QI) activities on improvements in client-reported and professional indicators between 2007 and 2009. A cross-sectional study using organizational survey and indicator multilevel modelling to test relationships between corporate structure, QI activities and performance improvements on indicators. In total, 169 residential care homes for the elderly in the Netherlands. Change between 2007 and 2009 in client-reported and professional indicators. A middle-size corporate structure was associated with QI. The QI activity 'multidisciplinary team meetings' was positively correlated with the indicator 'safety environment' for somatic and psycho-geriatric care. The QI activities 'educational material' and 'direct work instructions' were associated negatively with the indicator 'availability of personnel' for somatic clients, but positively for psycho-geriatric clients. QI activities such as 'health plan activities', 'clinical lessons' and 'financial activities' had no relationship to improved performance. For psycho-geriatric clients mainly organizational QI activities were positively associated with QI. The mediating role of the corporate structure for performing QI activities appeared stronger for the change in client-reported than for professional indicators. This study reveals associations between QI activities and corporate structure and changes in indicator performance. A corporate structure was associated with improvement in client-reported indicators, but less on professional indicators, which assumes a central policy at corporate level with impact on client-reported indicators, in contrast to a more local level approach towards activities that result in QI on professional indicators. Tailoring QI activities at the right managerial level may be important to achieve improvement. © The Author 2014. Published by Oxford University Press in association with the International Society for Quality in

  18. A Novel Molecular Diagnostic of Glioblastomas: Detection of an Extracellular Fragment of Protein Tyrosine Phosphatase μ

    Directory of Open Access Journals (Sweden)

    Susan M. Burden-Gulley

    2010-04-01

    Full Text Available We recently found that normal human brain and low-grade astrocytomas express the receptor protein tyrosine phosphatase mu (PTPμ and that the more invasive astrocytomas, glioblastoma multiforme (GBM, downregulate full-length PTPμ expression. Loss of PTPμ expression in GBMs is due to proteolytic cleavage that generates an intracellular and potentially a cleaved and released extracellular fragment of PTPμ. Here, we identify that a cleaved extracellular fragment containing the domains required for PTPμ-mediated adhesion remains associated with GBM tumor tissue. We hypothesized that detection of this fragment would make an excellent diagnostic tool for the localization of tumor tissue within the brain. To this end, we generated a series of fluorescently tagged peptide probes that bind the PTPμ fragment. The peptide probes specifically recognize GBM cells in tissue sections of surgically resected human tumors. To test whether the peptide probes are able to detect GBM tumors in vivo, the PTPμ peptide probes were tested in both mouse flank and intracranial xenograft human glioblastoma tumor model systems. The glial tumors were molecularly labeled with the PTPμ peptide probes within minutes of tail vein injection using the Maestro FLEX In Vivo Imaging System. The label was stable for at least 3 hours. Together, these results indicate that peptide recognition of the PTPμ extracellular fragment provides a novel molecular diagnostic tool for detection of human glioblastomas. Such a tool has clear translational applications and may lead to improved surgical resections and prognosis for patients with this devastating disease.

  19. 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 IDH mutations were associated with better OS. Similarly, the pooled HR of 0.322 (95% CI 0.24200.455, P 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.

  20. 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.

  1. Lipidized giant-cell glioblastoma of cerebellum.

    Science.gov (United States)

    Queiroz, L S; Faria, A V; Zanardi, V A; Netto, J R Menezes

    2005-01-01

    Glioblastoma multiforme is recognized rarely in the cerebellum. We describe a peculiar case with lipid accumulation in giant tumor cells, possibly the second example so far reported in this unusual location. A 46-year-old man with a 5-month history of headache, vomiting, dizziness and instability of gait, was found to have on magnetic resonance imaging an expanding mass situated deep in the left cerebellar hemisphere. The lesion was hypointense in T 1- and hyperintense in T2-weighted images, had poorly defined borders, peripheral edema and annular foci of contrast enhancement. Eight months after subtotal removal and radiotherapy, control MRI showed tumor recurrence with aggressive features. The patient was alive 15 months after operation but follow-up was eventually lost. Histologically, the tumor showed marked pleomorphism, with many giant cells characterized by finely vacuolated cytoplasm strongly suggestive of lipid accumulation. There were few, sometimes atypical mitotic figures and foci of endothelial proliferation. The tumor cells were strongly positive for GFAP, vimentin and S100 protein, all of which stressed the foamy appearance of the giant cells. About 15% of nuclei were positive for Ki-67. We considered the case to be a so-called lipidized glioblastoma, first recognized as a subtype by Kepes and Rubinstein [1981]. Differential diagnosis with anaplastic pleomorphic xanthoastrocytoma is discussed.

  2. 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.

  3. 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.

  4. State public health laboratory system quality improvement activities.

    Science.gov (United States)

    Su, Bertina; Vagnone, Paula Snippes

    2013-01-01

    The Association of Public Health Laboratories (APHL) and the APHL Laboratory Systems and Standards Committee manage the Laboratory System Improvement Program (L-SIP). One component of L-SIP is an assessment that allows the members and stakeholders of a laboratory system to have an open and honest discussion about the laboratory system's strengths and weaknesses. From these facilitated discussions, gaps and opportunities for improvement are identified. In some cases, ideas for how to best address these gaps emerge, and workgroups are formed. Depending on resources, both monetary and personnel, laboratory staff will then prioritize the next component of L-SIP: which quality improvement activities to undertake. This article describes a sample of quality improvement activities initiated by several public health laboratories after they conducted L-SIP assessments. These projects can result in more robust linkages between system entities, which can translate into improvements in the way the system addresses the needs of stakeholders.

  5. The influence of corporate structure and quality improvement activities on outcome improvement in residential care homes

    NARCIS (Netherlands)

    Winters, S.; Kool, R. B.; Klazinga, N. S.; Huijsman, R.

    2014-01-01

    To examine the impact of corporate structure and quality improvement (QI) activities on improvements in client-reported and professional indicators between 2007 and 2009. A cross-sectional study using organizational survey and indicator multilevel modelling to test relationships between corporate

  6. The influence of corporate structure and quality improvement activities on outcome improvement in residential care homes

    NARCIS (Netherlands)

    Winters, S.; Kool, R.B.; Klazinga, N.S.; Huijsman, R.

    2014-01-01

    OBJECTIVE: To examine the impact of corporate structure and quality improvement (QI) activities on improvements in client-reported and professional indicators between 2007 and 2009. DESIGN: A cross-sectional study using organizational survey and indicator multilevel modelling to test relationships

  7. 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. Copyright © 2016 The American Physiological Society.

  8. The Role of Exergaming in Improving Physical Activity: A Review

    Science.gov (United States)

    Sween, Jennifer; Wallington, Sherrie Flynnt; Sheppard, Vanessa; Taylor, Teletia; Llanos, Adana A.; Adams-Campbell, Lucile Lauren

    2013-01-01

    Background The high prevalence of obesity in America can be attributed to inadequate energy expenditure as a result of high levels of physical inactivity. This review presents an overview of the current literature on physical activity, specifically through active videogame systems (exergaming) and how these systems can help to increase physical activity levels. Methods The search strategy for this review was to identify previous studies which investigated energy expenditure levels using a single active video game or a combination of active videogames. Results Based on data from 27 studies, a strong correlation exists between exergaming and increased energy expenditure (up to 300% above resting levels). The majority of active videogames tested were found to achieve physical activity levels of moderate intensity, which meet American College of Sports Medicine guidelines for health and fitness. Conclusions Exergaming is a new and exciting strategy to potentially improve physical activity levels and reduce obesity among Americans. PMID:25078529

  9. Quantitative assessment of intragenic receptor tyrosine kinase deletions in primary glioblastomas: their prevalence and molecular correlates.

    Science.gov (United States)

    Kastenhuber, Edward R; Huse, Jason T; Berman, Samuel H; Pedraza, Alicia; Zhang, Jianan; Suehara, Yoshiyuki; Viale, Agnes; Cavatore, Magali; Heguy, Adriana; Szerlip, Nicholas; Ladanyi, Marc; Brennan, Cameron W

    2014-05-01

    Intragenic deletion is the most common form of activating mutation among receptor tyrosine kinases (RTK) in glioblastoma. However, these events are not detected by conventional DNA sequencing methods commonly utilized for tumor genotyping. To comprehensively assess the frequency, distribution, and expression levels of common RTK deletion mutants in glioblastoma, we analyzed RNA from a set of 192 glioblastoma samples from The Cancer Genome Atlas for the expression of EGFRvIII, EGFRvII, EGFRvV (carboxyl-terminal deletion), and PDGFRAΔ8,9. These mutations were detected in 24, 1.6, 4.7, and 1.6 % of cases, respectively. Overall, 29 % (55/189) of glioblastomas expressed at least one RTK intragenic deletion transcript in this panel. For EGFRvIII, samples were analyzed by both quantitative real-time PCR (QRT-PCR) and single mRNA molecule counting on the Nanostring nCounter platform. Nanostring proved to be highly sensitive, specific, and linear, with sensitivity comparable or exceeding that of RNA seq. We evaluated the prognostic significance and molecular correlates of RTK rearrangements. EGFRvIII was only detectable in tumors with focal amplification of the gene. Moreover, we found that EGFRvIII expression was not prognostic of poor outcome and that neither recurrent copy number alterations nor global changes in gene expression differentiate EGFRvIII-positive tumors from tumors with amplification of wild-type EGFR. The wide range of expression of mutant alleles and co-expression of multiple EGFR variants suggests that quantitative RNA-based clinical assays will be important for assessing the relative expression of intragenic deletions as therapeutic targets and/or candidate biomarkers. To this end, we demonstrate the performance of the Nanostring assay in RNA derived from routinely collected formalin-fixed paraffin-embedded tissue.

  10. Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma.

    Science.gov (United States)

    Taylor, Jennie W; Dietrich, Jorg; Gerstner, Elizabeth R; Norden, Andrew D; Rinne, Mikael L; Cahill, Daniel P; Stemmer-Rachamimov, Anat; Wen, Patrick Y; Betensky, Rebecca A; Giorgio, Diana H; Snodgrass, Kellis; Randall, Alison E; Batchelor, Tracy T; Chi, Andrew S

    2015-02-01

    Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7-9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.

  11. 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.

  12. Nanoparticles for hyperthermic therapy: synthesis strategies and applications in glioblastoma

    NARCIS (Netherlands)

    Verma, Jyoti; Lal, Sumit; van Noorden, Cornelis J. F.

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Current GBM treatment includes surgery, radiation therapy, and chemotherapy, sometimes supplemented with novel therapies. Despite recent advances, survival of GBM patients remains poor.

  13. 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. © 2015 Wiley Periodicals, Inc.

  14. Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine

    DEFF Research Database (Denmark)

    Staberg, Mikkel; Michaelsen, Signe Regner; Rasmussen, Rikke Darling

    2017-01-01

    PURPOSE: Glioblastoma (GBM) ranks among the deadliest solid cancers worldwide and its prognosis has remained dismal, despite the use of aggressive chemo-irradiation treatment regimens. Limited drug delivery into the brain parenchyma and frequent resistance to currently available therapies...

  15. Systemic immune suppression in glioblastoma: the interplay between CD14+HLA-DRlo/neg monocytes, tumor factors, and dexamethasone

    OpenAIRE

    Gustafson, Michael P.; Lin, Yi; New, Kent C.; Bulur, Peggy A.; O'Neill, Brian Patrick; Gastineau, Dennis A.; Dietz, Allan B.

    2010-01-01

    Patients with glioblastoma (GBM) exhibit profound systemic immune defects that affect the success of conventional and immune-based treatments. A better understanding of the contribution of the tumor and/or therapy on systemic immune suppression is necessary for improved therapies, to monitor negative effects of novel treatments, to improve patient outcomes, and to increase understanding of this complex system. To characterize the immune profile of GBM patients, we phenotyped peripheral blood ...

  16. 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. © The Author(s) 2014.

  17. Correlation among pathology, genotype, and patient outcomes in glioblastoma.

    Science.gov (United States)

    Homma, Taku; Fukushima, Takao; Vaccarella, Salvatore; Yonekawa, Yasuhiro; Di Patre, Pier Luigi; Franceschi, Silvia; Ohgaki, Hiroko

    2006-09-01

    Glioblastomas are histologically and genetically heterogeneous. We have investigated to what extent histologic features reflect the genetic profile and whether they are predictive of clinical outcome. Key histologic characteristics, including major cell types (small cell, nonsmall cell), other components such as oligodendroglial components, gemistocytes, multinucleated giant cells, as well as necrosis and microvascular proliferation, of 420 cases of glioblastoma within a population-based study (1) were reassessed and correlated with patients' clinical outcome and key genetic alterations. EGFR amplification and p16 homozygous deletion were significantly more frequent in small cell glioblastomas than in nonsmall cell glioblastomas (EGFR, 46% vs 26%, p = 0.0002; p16 39% vs 25%, p = 0.0167). Multivariate analyses with adjustment for age and gender showed that small cell glioblastomas had frequent EGFR amplification and p16 deletion but infrequent PTEN mutations. An oligodendroglial component was detected in 20% of glioblastomas; these patients were significantly younger (54.4 +/- 13.6 vs 59.2 +/- 13.8 years; p = 0.0049) and survived longer (10.3 +/- 8.3 vs 8.2 +/- 8.4 months; p = 0.0647). However, multivariate analyses with adjustment for age and gender did not show the presence of an oligodendroglial component to be predictive of longer survival. After adjustment for age and gender, LOH 1p was associated with longer survival (hazard ratio, 0.7; 95% confidence interval [CI], 0.5-1.0), whereas LOH 10q was associated with shorter survival (hazard ratio, 1.4; 95% CI, 1.0-1.8) of patients with glioblastoma. Glioblastomas containing >or=5% multinucleated giant cells showed more frequent TP53 mutation and infrequent EGFR amplification than those containing giant cells (TP53, 45% vs 24%, p = 0.0001; EGFR, 24% vs 42%, p = 0.0005). Vascular proliferation was observed in all glioblastomas, whereas large ischemic and/or pseudopalisading necrosis was observed in 366 of 420 (87

  18. Giant cell glioblastoma: review of the literature and illustrated case

    OpenAIRE

    Valle-Folgueral, JM; Mascarenhas, L; Costa, JA; Vieira, F; Soares-Fernandes, J; Beleza, P; Alegria, C

    2009-01-01

    Giant cell glioblastoma is an infrequent variety of glioblastoma (5% of the cases). It has deserved a separate category in the World Health Organization classification of grade IV tumors. The clinical, imaging, histological and immunohistochemical characteristics, and the genetic alterations are reviewed. Treatment and prognosis are discussed and updated. The case of a patient that survived 19 months and died of spinal leptomeningeal metastases is illustrated.

  19. Giant cell glioblastoma: review of the literature and illustrated case.

    Science.gov (United States)

    Valle-Folgueral, J M; Mascarenhas, L; Costa, J A; Vieira, F; Soares-Fernandes, J; Beleza, P; Alegria, C

    2008-08-01

    Giant cell glioblastoma is an infrequent variety of glioblastoma (5% of the cases). It has deserved a separate category in the World Health Organization classification of grade IV tumors. The clinical, imaging, histological and immunohistochemical characteristics, and the genetic alterations are reviewed. Treatment and prognosis are discussed and updated. The case of a patient that survived 19 months and died of spinal leptomeningeal metastases is illustrated.

  20. A 16-gene signature distinguishes anaplastic astrocytoma from glioblastoma.

    Directory of Open Access Journals (Sweden)

    Soumya Alige Mahabala Rao

    Full Text Available Anaplastic astrocytoma (AA; Grade III and glioblastoma (GBM; Grade IV are diffusely infiltrating tumors and are called malignant astrocytomas. The treatment regimen and prognosis are distinctly different between anaplastic astrocytoma and glioblastoma patients. Although histopathology based current grading system is well accepted and largely reproducible, intratumoral histologic variations often lead to difficulties in classification of malignant astrocytoma samples. In order to obtain a more robust molecular classifier, we analysed RT-qPCR expression data of 175 differentially regulated genes across astrocytoma using Prediction Analysis of Microarrays (PAM and found the most discriminatory 16-gene expression signature for the classification of anaplastic astrocytoma and glioblastoma. The 16-gene signature obtained in the training set was validated in the test set with diagnostic accuracy of 89%. Additionally, validation of the 16-gene signature in multiple independent cohorts revealed that the signature predicted anaplastic astrocytoma and glioblastoma samples with accuracy rates of 99%, 88%, and 92% in TCGA, GSE1993 and GSE4422 datasets, respectively. The protein-protein interaction network and pathway analysis suggested that the 16-genes of the signature identified epithelial-mesenchymal transition (EMT pathway as the most differentially regulated pathway in glioblastoma compared to anaplastic astrocytoma. In addition to identifying 16 gene classification signature, we also demonstrated that genes involved in epithelial-mesenchymal transition may play an important role in distinguishing glioblastoma from anaplastic astrocytoma.

  1. Glioblastoma Multiforme Presenting as Spontaneous Intracerebral Hemorrhage

    Directory of Open Access Journals (Sweden)

    Cagatay Ozdol

    2014-06-01

    Full Text Available Brain tumors with concomitant intracerebral hemorrhage are rarely encountered. Hemorrhage as the initial presentation of a brain tumour may pose some diagnostic problems, especially if the tumour is small or the hemorrhage is abundant. We present a 47-year-old man who admitted to the emergency department with sudden onset headache, right blurred vision and gait disturbance. A non-contrast cranial computerized tomography scan performed immediately after his admission revealed a well circumscribed right occipitoparietal haematoma with intense peripheral edema causing compression of the ipsilateral ventricles. On 6th hour of his admission the patient%u2019s neurological status deteriorated and he subsequently underwent emergent craniotomy and microsurgical evacuation of the haematoma. The histopathological examination of the mass was consistent with a glioblastoma multiforme. Neoplasms may be hidden behind each case of spontaneous intracerebral hemorrhage. Histological sampling and investigation is mandatory in the presence of preoperative radiological features suggesting a neoplasm.

  2. Sinking skin flap syndrome in glioblastoma.

    Science.gov (United States)

    Kamiya-Matsuoka, Carlos; Shroff, Sheetal; Tatsui, Claudio E; Tremont-Lukats, Ivo W; Gilbert, Mark R

    2014-11-14

    Sinking skin flap syndrome (SSFS) is a rare neurological complication in patients with traumatic haemorrhage, stroke or cerebral oedema who undergo decompressive craniectomy to relieve increased intracranial pressure. Hallmark of SSFS is the sinking of the scalp to a plane lower than the edges of the skull defect in the setting of neurological deterioration. Our objective is to report that SSFS can present after small craniotomy without cerebral cortex compression and to share our diagnostic/therapeutic approach. A 62-year-old woman with a glioblastoma developed SSFS after a small craniectomy and tumour resection without cerebral cortex compression but a decrease in the surgical cavity volume. Brain MRI showed decreased size of the surgical cavity. Interestingly, the patient also developed posterior reversible encephalopathy syndrome (PRES). This case highlights an atypical presentation of SSFS and the possible association with PRES. It also illustrates how an early cranioplasty can successfully reverse SSFS. 2014 BMJ Publishing Group Ltd.

  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

    2012-11-01

    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. 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

    2013-04-01

    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.

  5. Active Learning Improves Student Performance in a Respiratory Physiology Lab

    Science.gov (United States)

    Wolf, Alex M.; Liachovitzky, Carlos; Abdullahi, Abass S.

    2015-01-01

    This study assessed the effectiveness of the introduction of active learning exercises into the anatomy and physiology curriculum in a community college setting. Specifically, the incorporation of a spirometry-based respiratory physiology lab resulted in improved student performance in two concepts (respiratory volumes and the hallmarks of…

  6. 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…

  7. Working Memory Training: Improving Intelligence--Changing Brain Activity

    Science.gov (United States)

    Jausovec, Norbert; Jausovec, Ksenija

    2012-01-01

    The main objectives of the study were: to investigate whether training on working memory (WM) could improve fluid intelligence, and to investigate the effects WM training had on neuroelectric (electroencephalography--EEG) and hemodynamic (near-infrared spectroscopy--NIRS) patterns of brain activity. In a parallel group experimental design,…

  8. 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

  9. 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...

  10. Improvement of nutritional quality and antioxidant activities of yeast ...

    African Journals Online (AJOL)

    This study evaluated the potential use and improves the health beneficial properties of the soybean waste manufacturing products by solid-state fermentation of six GRAS different yeast strains, including extractable antioxidant activities and bioavailable nutritional compositions. In comparison with nonfermented okara ...

  11. Heavily lipidized, calcified giant cell glioblastoma in an 8-year-old patient, associated with neurofibromatosis type 1 (NF1): report of a case with long-term survival.

    Science.gov (United States)

    Kroh, H; Matyja, E; Marchel, A; Bojarski, P

    2004-01-01

    Giant cell glioblastoma (GCG-BM) with predominance of bizarre, multinucleated giant cells is a rare subtype of glioblastoma, however, its clinical behavior and histological features are still not fully understood. We report an unusual case of a heavily lipidized form of giant cell glioma corresponding mostly to GCGBM in a young patient with neurofibromatosis 1 (NF1). Histologically, the tumor revealed numerous characteristic histopathological features of giant cell glioblastoma including cellular pleomorphism with numerous giant tumor cells, pseudopalisades around necrotic foci and mitotic activity, accompanied by additional unique morphological elements such as massive lipidization of the neoplastic cells, abundant microcalcifications and angiomatous pattern of vascularization. Such aberrant morphology might be associated with the unusually long survival period of 12 years without clinical evidence of tumor recurrence. The coexistence of intracerebral heavily lipidized, calcified giant cell glioblastoma with NF1 has not been previously reported in literature.

  12. FTY720 reduces migration and invasion of human glioblastoma cell lines via inhibiting the PI3K/AKT/mTOR/p70S6K signaling pathway.

    Science.gov (United States)

    Zhang, Li; Wang, Handong; Zhu, Jianhong; Ding, Ke; Xu, Jianguo

    2014-11-01

    2-Amino-2-[2-(4-octylphenyl)]-1,3-propanediol hydrochloride (FTY720), a synthetic compound from Isaria sinclairii, has been proven to possess various biological benefits including anti-cancer activity. However, the effects and related mechanisms of FTY720 on the migration and invasion of glioblastoma cells are still unclear. In the present study, we utilized U251MG and U87MG human glioblastoma cell lines to assess the effects of FTY720. We found that FTY720 significantly inhibited migration and invasion of glioblastoma cells. The anti-migration and invasion effects of FTY720 were associated with its down-regulation of matrix metalloproteinase-2 (MMP-2) and MMP-9 while up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Furthermore, FTY720 modulated the expression of roundabouts 1 (ROBO1), Rho-associated kinase-1 (ROCK1), and epithelial-to-mesenchymal transition (EMT)-related factors. In addition, the phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin/p70S6 kinase (PI3K/AKT/mTOR/p70S6K) signaling pathway participated in FTY720-mediated suppression of migration and invasion. Thus, our findings demonstrated that FTY720 reduced glioblastoma cells migration and invasion via multiple signaling pathways, suggesting that FTY720 is a potential therapeutic agent against glioblastoma.

  13. 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.

  14. 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.

  15. Desmopressin improves platelet activity in acute intracerebral hemorrhage.

    Science.gov (United States)

    Naidech, Andrew M; Maas, Matthew B; Levasseur-Franklin, Kimberly E; Liotta, Eric M; Guth, James C; Berman, Micheal; Rosenow, Joshua M; Lindholm, Paul F; Bendok, Bernard R; Prabhakaran, Shyam; Bernstein, Richard A; Kwaan, Hau C

    2014-08-01

    Minimizing hematoma growth in high-risk patients is an attractive strategy to improve outcomes after intracerebral hemorrhage. We tested the hypothesis that desmopressin (DDAVP), which improves hemostasis through the release of von Willebrand factor, improves platelet activity after intracerebral hemorrhage. Patients with reduced platelet activity on point-of-care testing alone (5), known aspirin use alone (1), or both (8) received desmopressin 0.4 μg/kg IV. We measured Platelet Function Analyzer-epinephrine (Siemens AG, Germany) and von Willebrand factor antigen from baseline to 1 hour after infusion start and hematoma volume from the diagnostic to a follow-up computed tomographic scan. We enrolled 14 patients with of mean age 66.8±14.6 years, 11 (85%) of whom were white and 8 (57%) were men. Mean Platelet Function Analyzer-epinephrine results shortened from 192±18 seconds pretreatment to 124±15 seconds (P=0.01) 1 hour later, indicating improved plate activity. von Willebrand factor antigen increased from 242±96% to 289±103% activity (P=0.004), indicating the expected increase in von Willebrand factor. Of 7 (50%) patients who received desmopressin within 12 hours of intracerebral hemorrhage symptom onset, changes in hematoma volume were modest, -0.5 (-1.4 to 8.4) mL and only 2 had hematoma growth. One patient had low blood pressure and another had a new fever within 6 hours of desmopressin administration. Intravenous desmopressin was well tolerated and improved platelet activity after acute intracerebral hemorrhage. Larger studies are needed to determine its potential effects on reducing hematoma growth versus platelet transfusion or placebo. http://www.clinicaltrials.gov. Unique identifier: NCT00961532. © 2014 American Heart Association, Inc.

  16. Combination therapies in a patient-derived glioblastoma model : A step towards precision medicine

    NARCIS (Netherlands)

    L.M.E. Berghauser Pont (Lotte)

    2015-01-01

    markdownabstract__Abstract__ Glioblastoma is the most malignant primary brain tumor. Glioblastoma is originating from the supportive tissue of the brain, the glial cells. Despite increased research, mortality rates have not decreased significantly. Standard therapy consists of surgical resection,

  17. 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.

  18. A novel 3D human glioblastoma cell culture system for modeling drug and radiation responses.

    Science.gov (United States)

    Gomez-Roman, Natividad; Stevenson, Katrina; Gilmour, Lesley; Hamilton, Graham; Chalmers, Anthony J

    2017-02-01

    Glioblastoma (GBM) is the most common primary brain tumor, with dismal prognosis. The failure of drug-radiation combinations with promising preclinical data to translate into effective clinical treatments may relate to the use of simplified 2-dimensional in vitro GBM cultures. We developed a customized 3D GBM culture system based on a polystyrene scaffold (Alvetex) that recapitulates key histological features of GBM and compared it with conventional 2D cultures with respect to their response to radiation and to molecular targeted agents for which clinical data are available. In 3 patient-derived GBM lines, no difference in radiation sensitivity was observed between 2D and 3D cultures, as measured by clonogenic survival. Three different molecular targeted agents, for which robust clinical data are available were evaluated in 2D and 3D conditions: (i) temozolomide, which improves overall survival and is standard of care for GBM, exhibited statistically significant effects on clonogenic survival in both patient-derived cell lines when evaluated in the 3D model compared with only one cell line in 2D cells; (ii) bevacizumab, which has been shown to increase progression-free survival when added to standard chemoradiation in phase III clinical trials, exhibited marked radiosensitizing activity in our 3D model but had no effect on 2D cells; and (iii) erlotinib, which had no efficacy in clinical trials, displayed no activity in our 3D GBM model, but radiosensitized 2D cells. Our 3D model reliably predicted clinical efficacy, strongly supporting its clinical relevance and potential value in preclinical evaluation of drug-radiation combinations for GBM.

  19. Synergistic Effects of Crizotinib and Temozolomide in Experimental FIG-ROS1 Fusion-Positive Glioblastoma

    Directory of Open Access Journals (Sweden)

    Arabinda Das

    2015-01-01

    Full Text Available Glioblastoma (GB is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs, including anaplastic lymphoma kinase (ALK, c-Met (hepatocyte growth factor receptor, and oncogenic c-ros oncogene1 (ROS1: RTK class orphan fusion kinase FIG (fused in GB-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for

  20. 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.

  1. Physical activity to improve strength and balance in old people

    Directory of Open Access Journals (Sweden)

    Luz Marina Chalapud Narváez

    2017-05-01

    Full Text Available Introduction: Old age encompasses a fairly broad age in a person’s life, and physical activity becomes the strategy to improve the elderly’s life quality. Objective: To determine the effectiveness of a physical activity program in improving strength to the lower limbs and balance for the elderly. Materials and methods: Semi-experimental longitudinal study with a sample of 57 elderly people to whom an initial and final assessment of balance and strength was performed, as well as a 4-week physical activity program with 2 training sessions each, comprising posture, proprioception, balance and muscle strength exercises. The program used for data analysis was SPSS v.24.0 for Windows. An univariate analysis was performed applying central trend measurements (mean, median, mode, standard deviation, range and a statistical analysis with non-parametric testing for two related Wilcoxon samples. Results: The following tests showed statistical significance: Functional extension (p=0,000, open eyes tandem (p=0,20, closed eyes tandem (p=0,002, closed eyes unipodal (p=0,012 and sitting/standing (p=0,000. Conclusion: This study determined that physical activity is effective to improve balance and muscle strength for lower limbs and a suitable tool to preserve senior’s functionality and Independence.

  2. Improvement of activity and stability of chloroperoxidase by chemical modification

    Directory of Open Access Journals (Sweden)

    Wang Min

    2007-05-01

    Full Text Available Abstract Background Enzymes show relative instability in solvents or at elevated temperature and lower activity in organic solvent than in water. These limit the industrial applications of enzymes. Results In order to improve the activity and stability of chloroperoxidase, chloroperoxidase was modified by citraconic anhydride, maleic anhydride or phthalic anhydride. The catalytic activities, thermostabilities and organic solvent tolerances of native and modified enzymes were compared. In aqueous buffer, modified chloroperoxidases showed similar Km values and greater catalytic efficiencies kcat/Km for both sulfoxidation and oxidation of phenol compared to native chloroperoxidase. Of these modified chloroperoxidases, citraconic anhydride-modified chloroperoxidase showed the greatest catalytic efficiency in aqueous buffer. These modifications of chloroperoxidase increased their catalytic efficiencies for sulfoxidation by 12%~26% and catalytic efficiencies for phenol oxidation by 7%~53% in aqueous buffer. However, in organic solvent (DMF, modified chloroperoxidases had lower Km values and higher catalytic efficiencies kcat/Km than native chloroperoxidase. These modifications also improved their thermostabilities by 1~2-fold and solvent tolerances of DMF. CD studies show that these modifications did not change the secondary structure of chloroperoxidase. Fluorescence spectra proved that these modifications changed the environment of tryptophan. Conclusion Chemical modification of epsilon-amino groups of lysine residues of chloroperoxidase using citraconic anhydride, maleic anhydride or phthalic anhydride is a simple and powerful method to enhance catalytic properties of enzyme. The improvements of the activity and stability of chloroperoxidase are related to side chain reorientations of aromatics upon both modifications.

  3. 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.

  4. Contribution of the Microenvironmental Niche to Glioblastoma Heterogeneity

    Directory of Open Access Journals (Sweden)

    Ivy A. W. Ho

    2017-01-01

    Full Text Available Glioblastoma is the most aggressive cancer of the brain. The dismal prognosis is largely attributed to the heterogeneous nature of the tumor, which in addition to intrinsic molecular and genetic changes is also influenced by the microenvironmental niche in which the glioma cells reside. The cancer stem cells (CSCs hypothesis suggests that all cancers arise from CSCs that possess the ability to self-renew and initiate tumor formation. CSCs reside in specialized niches where interaction with the microenvironment regulates their stem cell behavior. The reciprocal interaction between glioma stem cells (GSCs and cells from the microenvironment, such as endothelial cells, immune cells, and other parenchymal cells, may also promote angiogenesis, invasion, proliferation, and stemness of the GSCs and be likely to have an underappreciated role in their responsiveness to therapy. This crosstalk may also promote molecular transition of GSCs. Hence the inherent plasticity of GSCs can be seen as an adaptive response, changing according to the signaling cue from the niche. Given the association of GSCs with tumor recurrence and treatment sensitivity, understanding this bidirectional crosstalk between GSCs and its niche may provide a framework to identify more effective therapeutic targets and improve treatment outcome.

  5. 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)

  6. File list: Oth.Neu.05.AllAg.Glioblastoma [Chip-atlas[Archive

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  18. 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.

  19. Memory suppression is an active process that improves over childhood

    Directory of Open Access Journals (Sweden)

    Pedro M Paz-Alonso

    2009-09-01

    Full Text Available We all have memories that we prefer not to think about. The ability to suppress retrieval of unwanted memories has been documented in behavioral and neuroimaging research using the Think/No-Think (TNT paradigm with adults. Attempts to stop memory retrieval are associated with increased activation of lateral prefrontal cortex (PFC and concomitant reduced activation in medial temporal lobe (MTL structures. However, the extent to which children have the ability to actively suppress their memories is unknown. This study investigated memory suppression in middle childhood using the TNT paradigm. Forty children aged 8 to 12 and 30 young adults were instructed either to remember (Think or suppress (No-Think the memory of the second word of previously studied word-pairs, when presented with the first member as a reminder. They then performed two different cued recall tasks, testing their memory for the second word in each pair after the Think/No-Think phase using the same first studied word within the pair as a cue (intra-list cue and also an independent cue (extra-list cue. Children exhibited age-related improvements in memory suppression from age 8 to 12 in both memory tests, against a backdrop of overall improvements in declarative memory over this age range. These findings suggest that memory suppression is an active process that develops during late childhood, likely due to an age-related refinement in the ability to engage PFC to down-regulate activity in areas involved in episodic retrieval.

  20. Training to Support Standardization and Improvement of Configuration Management Activities

    Energy Technology Data Exchange (ETDEWEB)

    Dauber, V.; Scheffer, N.; Schoenfelder, C.

    2015-07-01

    In recent years AREVA has conducted several measures to enhance the effectiveness and efficiency of configuration management-related activities within a nuclear power plant (NPP) new build as well as modernization projects, thereby further strengthening its commitment to achieving the highest level of safety in nuclear facilities. This paper describes a new training course that shall support the standardization and improvement of configuration management activities. Recommendations will be given that should be considered when designing and developing comparable training programs to support change processes within engineering units. (Author)

  1. Anticancer activity of taraxerol acetate in human glioblastoma cells and a mouse xenograft model via induction of autophagy and apoptotic cell death, cell cycle arrest and inhibition of cell migration.

    Science.gov (United States)

    Hong, Jing-Fang; Song, Ying-Fang; Liu, Zheng; Zheng, Zhao-Cong; Chen, Hong-Jie; Wang, Shou-Sen

    2016-06-01

    The aim of the present study was to investigate the in vitro and in vivo anticancer and apoptotic effects of taraxerol acetate in U87 human glioblastoma cells. The effects on cell cycle phase distribution, cell cycle-associated proteins, autophagy, DNA fragmentation and cell migration were assessed. Cell viability was determined using the MTT assay, and phase contrast and fluorescence microscopy was utilized to determine the viability and apoptotic morphological features of the U87 cells. Flow cytometry using propidium iodide and Annexin V-fluorescein isothiocyanate demonstrated the effect of taraxerol acetate on the cell cycle phase distribution and apoptosis induction. Western blot analysis was performed to investigate the effect of the taraxerol acetate on cell cycle‑associated proteins and autophagy‑linked LC3B‑II proteins. The results demonstrated that taraxerol acetate induced dose‑ and time‑dependent cytotoxic effects in the U87 cells. Apoptotic induction following taraxerol acetate treatment was observed and the percentage of apoptotic cells increased from 7.3% in the control cells, to 16.1, 44.1 and 76.7% in the 10, 50 and 150 µM taraxerol acetate‑treated cells, respectively. Furthermore, taraxerol acetate treatment led to sub‑G1 cell cycle arrest with a corresponding decrease in the number of S‑phase cells. DNA fragments were observed as a result of the gel electrophoresis experiment following taraxerol acetate treatment. To investigate the inhibitory effects of taraxerol acetate on the migration of U87 cell, a wound healing assay was conducted. The number of cells that migrated to the scratched area decreased significantly following treatment with taraxerol acetate. In addition, taraxerol acetate inhibited tumor growth in a mouse xenograft model. Administration of 0.25 and 0.75 µg/g taraxerol acetate reduced the tumor weight from 1.2 g in the phosphate‑buffered saline (PBS)‑treated group (control) to 0.81 and 0.42

  2. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development.

    Science.gov (United States)

    Zhao, Hua-Fu; Wang, Jing; Shao, Wei; Wu, Chang-Peng; Chen, Zhong-Ping; To, Shing-Shun Tony; Li, Wei-Ping

    2017-06-07

    Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients' prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies.

  3. Effects of Dual Targeting of Tumor Cells and Stroma in Human Glioblastoma Xenografts with a Tyrosine Kinase Inhibitor against c-MET and VEGFR2

    NARCIS (Netherlands)

    Navis, A.C.; Bourgonje, A.M.; Wesseling, P.; Wright, A.; Hendriks, W.J.; Verrijp, K.; Laak, J.A.W.M. van der; Heerschap, A.; Leenders, W.P.J.

    2013-01-01

    Anti-angiogenic treatment of glioblastoma with Vascular Endothelial Growth Factor (VEGF)- or VEGF Receptor 2 (VEGFR2) inhibitors normalizes tumor vessels, resulting in a profound radiologic response and improved quality of life. This approach however does not halt tumor progression by diffuse

  4. 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.

  5. AKT pathway genes define 5 prognostic subgroups in glioblastoma.

    Directory of Open Access Journals (Sweden)

    Anna Joy

    Full Text Available Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Gene Ontology terms indicate a different cell of origin or dominant phenotype for each subgroup. Evidence suggests one subtype is very sensitive to BCNU or CCNU (median survival 5.8 vs. 1.5 years; BCNU/CCNU vs other treatments; respectively. AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subtyping may help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets.

  6. AKT Pathway Genes Define 5 Prognostic Subgroups in Glioblastoma

    Science.gov (United States)

    Smirnov, Ivan; Reiser, Mark; Misra, Anjan; Shapiro, William R.; Mills, Gordon B.; Kim, Seungchan; Feuerstein, Burt G.

    2014-01-01

    Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Gene Ontology terms indicate a different cell of origin or dominant phenotype for each subgroup. Evidence suggests one subtype is very sensitive to BCNU or CCNU (median survival 5.8 vs. 1.5 years; BCNU/CCNU vs other treatments; respectively). AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subtyping may help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets. PMID:24984002

  7. Epilepsy in glioblastoma multiforme: correlation with glutamine synthetase levels.

    Science.gov (United States)

    Rosati, Anna; Marconi, Silvia; Pollo, Bianca; Tomassini, Alessia; Lovato, Laura; Maderna, Emanuela; Maier, Klaus; Schwartz, Andreas; Rizzuto, Nicolò; Padovani, Alessandro; Bonetti, Bruno

    2009-07-01

    The hypothesis addressed by this study is that a glutamine synthetase (GS) deficiency in neoplastic astrocytes is a possible molecular basis associated with seizure generation in glioblastoma multiforme (GBM). Quantitative Western blot analysis of GS was performed in 20 individuals operated for malignant glioma. The levels of GS in patients with GBM and epilepsy were significantly lower (range 0.04-1.15; mean 0.35 +/- 0.36; median 0.25) than in non-epileptic GBM individuals (range 0.78-3.97; mean 1.64 +/- 0.99; median 1.25; P = 0.002). No relationship has been found between histological features (i.e. necrosis, gliosis, stroma, inflammatory cells, giant cells, and haemosiderine) and GS expression or epilepsy. Even though the epileptogenesis in glioma is multifactorial, it is conceivable that a down-regulation of GS may have an important pro-epileptogenic role in GBM, through the slowing of glutamate-glutamine cycle. This study suggests that seizures in GBM are coupled with a highly localized enzyme deficiency. The manipulation of GS activity might constitute a novel principle for inhibiting seizures in patients with glioma epilepsy.

  8. 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.

  9. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Engineering Chimeric Antigen Receptor T cells to Treat Glioblastoma.

    Science.gov (United States)

    Choi, Bryan D; O'Rourke, Donald M; Maus, Marcela V

    2017-08-01

    Immunotherapy has emerged as a promising strategy for glioblastoma (GBM), a disease that remains universally fatal despite currently available standard-of-care. Adoptive T cell therapy has been shown to produce potent antitumor immunity while obviating the need for traditional antigen presentation and primary immune responses. Chimeric antigen receptors (CARs) are specialized molecules that can be expressed on the surface of T cells allowing for redirected cytotoxicity against tumor antigens of interest. To date, the application of CAR T cells for GBM has been relatively limited, in large part due to a dearth of well-described tumor specific antigens that are both homogenously and frequently expressed. A mutated version of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase that is expressed on the surface of GBM and other common neoplasms, but completely absent from all normal tissues. We have recently generated CAR T cells directed against EGFRvIII and reported results from a Phase I clinical trial investigating this platform in patients with EGFRvIII-expressing GBM. Our study showed that despite conventional notions of central nervous system "immune-privilege," EGFRvIII CAR T cells trafficked to intracerebral tumors, leading to successful targeting and eradication of this antigen in the brain. Here, we review our experience with EGFRvIII CAR T cells and highlight important considerations for the clinical translation of this therapy in patients with GBM.

  11. Convection-enhanced delivery for the treatment of glioblastoma.

    Science.gov (United States)

    Vogelbaum, Michael A; Aghi, Manish K

    2015-03-01

    Effective treatment of glioblastoma (GBM) remains a formidable challenge. Survival rates remain poor despite decades of clinical trials of conventional and novel, biologically targeted therapeutics. There is considerable evidence that most of these therapeutics do not reach their targets in the brain when administered via conventional routes (intravenous or oral). Hence, direct delivery of therapeutics to the brain and to brain tumors is an active area of investigation. One of these techniques, convection-enhanced delivery (CED), involves the implantation of catheters through which conventional and novel therapeutic formulations can be delivered using continuous, low-positive-pressure bulk flow. Investigation in preclinical and clinical settings has demonstrated that CED can produce effective delivery of therapeutics to substantial volumes of brain and brain tumor. However, limitations in catheter technology and imaging of delivery have prevented this technique from being reliable and reproducible, and the only completed phase III study in GBM did not show a survival benefit for patients treated with an investigational therapeutic delivered via CED. Further development of CED is ongoing, with novel catheter designs and imaging approaches that may allow CED to become a more effective therapeutic delivery technique. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. AKT pathway genes define 5 prognostic subgroups in glioblastoma.

    Science.gov (United States)

    Joy, Anna; Ramesh, Archana; Smirnov, Ivan; Reiser, Mark; Misra, Anjan; Shapiro, William R; Mills, Gordon B; Kim, Seungchan; Feuerstein, Burt G

    2014-01-01

    Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Gene Ontology terms indicate a different cell of origin or dominant phenotype for each subgroup. Evidence suggests one subtype is very sensitive to BCNU or CCNU (median survival 5.8 vs. 1.5 years; BCNU/CCNU vs other treatments; respectively). AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subtyping may help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets.

  13. 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.

  14. Prioritization schema for immunotherapy clinical trials in glioblastoma.

    Science.gov (United States)

    Hodges, Tiffany R; Ferguson, Sherise D; Caruso, Hillary G; Kohanbash, Gary; Zhou, Shouhao; Cloughesy, Timothy F; Berger, Mitchel S; Poste, George H; Khasraw, Mustafa; Ba, Sujuan; Jiang, Tao; Mikkelson, Tom; Yung, W K Alfred; de Groot, John F; Fine, Howard; Cantley, Lewis C; Mellinghoff, Ingo K; Mitchell, Duane A; Okada, Hideho; Heimberger, Amy B

    2016-06-01

    Emerging immunotherapeutic strategies for the treatment of glioblastoma (GBM) such as dendritic cell (DC) vaccines, heat shock proteins, peptide vaccines, and adoptive T-cell therapeutics, to name a few, have transitioned from the bench to clinical trials. With upcoming strategies and developing therapeutics, it is challenging to critically evaluate the practical, clinical potential of individual approaches and to advise patients on the most promising clinical trials. The authors propose a system to prioritize such therapies in an organized and data-driven fashion. This schema is based on four categories of factors: antigenic target robustness, immune-activation and -effector responses, preclinical vetting, and early evidence of clinical response. Each of these categories is subdivided to focus on the most salient elements for developing a successful immunotherapeutic approach for GBM, and a numerical score is generated. The Score Card reveals therapeutics that have the most robust data to support their use, provides a reference prioritization score, and can be applied in a reiterative fashion with emerging data. The authors hope that this schema will give physicians an evidence-based and rational framework to make the best referral decisions to better guide and serve this patient population.

  15. Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants.

    Science.gov (United States)

    Joseph, Nancy M; Phillips, Joanna; Dahiya, Sonika; M Felicella, Michelle; Tihan, Tarik; Brat, Daniel J; Perry, Arie

    2013-03-01

    Recent work has demonstrated that nearly all diffuse gliomas display nuclear immunoreactivity for the bHLH transcription factor OLIG2, and the R132H mutant isocitrate dehydrogenase 1 (IDH1) protein is expressed in the majority of diffuse gliomas other than primary glioblastoma. However, these antibodies have not been widely applied to rarer glioblastoma variants, which can be diagnostically challenging when the astrocytic features are subtle. We therefore surveyed the expression patterns of OLIG2 and IDH1 in 167 non-conventional glioblastomas, including 45 small cell glioblastomas, 45 gliosarcomas, 34 glioblastomas with primitive neuroectodermal tumor-like foci (PNET-like foci), 23 with an oligodendroglial component, 11 granular cell glioblastomas, and 9 giant cell glioblastomas. OLIG2 was strongly expressed in all glioblastomas with oligodendroglial component, 98% of small cell glioblastomas, and all granular cell glioblastomas, the latter being particularly helpful in ruling out macrophage-rich lesions. In 74% of glioblastomas with PNET-like foci, OLIG2 expression was retained in the PNET-like foci, providing a useful distinction from central nervous system PNETs. The glial component of gliosarcomas was OLIG2 positive in 93% of cases, but only 14% retained focal expression in the sarcomatous component; as such this marker would not reliably distinguish these from pure sarcoma in most cases. OLIG2 was expressed in 67% of giant cell glioblastomas. IDH1 was expressed in 55% of glioblastomas with oligodendroglial component, 15% of glioblastomas with PNET-like foci, 7% of gliosarcomas, and none of the small cell, granular cell, or giant cell glioblastomas. This provides further support for the notion that most glioblastomas with oligodendroglial component are secondary, while small cell glioblastomas, granular cell glioblastomas, and giant cell glioblastomas are primary variants. Therefore, in one of the most challenging differential diagnoses, IDH1 positivity could

  16. 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.

  17. Incidence, survival, pathology, and genetics of adult Latino Americans with glioblastoma.

    Science.gov (United States)

    Shabihkhani, Maryam; Telesca, Donatello; Movassaghi, Masoud; Naeini, Yalda B; Naeini, Kourosh M; Hojat, Seyed Amin; Gupta, Diviya; Lucey, Gregory M; Ontiveros, Michael; Wang, Michael W; Hanna, Lauren S; Sanchez, Desiree E; Mareninov, Sergey; Khanlou, Negar; Vinters, Harry V; Bergsneider, Marvin; Nghiemphu, Phioanh Leia; Lai, Albert; Liau, Linda M; Cloughesy, Timothy F; Yong, William H

    2017-04-01

    Latino Americans are a rapidly growing ethnic group in the United States but studies of glioblastoma in this population are limited. We have evaluated characteristics of 21,184 glioblastoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. This SEER data from 2001 to 2011 draws from 28% of the U.S. Latinos have a lower incidence of GBM and present slightly younger than non-Latino Whites. Cubans present at an older age than other Latino sub-populations. Latinos have a higher incidence of giant cell glioblastoma than non-Latino Whites while the incidence of gliosarcoma is similar. Despite lower rates of radiation therapy and greater rates of sub-total resection than non-Latino Whites, Latinos have better 1 and 5 year survival rates. SEER does not record chemotherapy data. Survivals of Latino sub-populations are similar with each other. Age, extent of resection, and the use of radiation therapy are associated with improved survival but none of these variables are sufficient in a multivariate analysis to explain the improved survival of Latinos relative to non-Latino Whites. As molecular data is not available in SEER records, we studied the MGMT and IDH status of 571 patients from a UCLA database. MGMT methylation and IDH1 mutation rates are not statistically significantly different between non-Latino Whites and Latinos. For UCLA patients with available information, chemotherapy and radiation rates are similar for non-Latino White and Latino patients, but the latter have lower rates of gross total resection and present at a younger age.

  18. 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. Copyright © 2016 Elsevier B.V. All

  19. Exophytic giant cell glioblastoma of the medulla oblongata.

    Science.gov (United States)

    Luetjens, Goetz; Mirzayan, M Javad; Brandis, Almuth; Krauss, Joachim K

    2009-03-01

    Giant cell glioblastoma is a rare variant within the spectrum of glioblastoma multiforme (GBM) tumors. A giant cell glioblastoma may be associated with a better prognosis than the common type of GBM after combined treatment involving tumor resection and radiochemotherapy. A giant cell glioblastoma may occur at various sites in the brain and spinal cord. To the authors' knowledge, this type of tumor has not been previously reported as arising as an exophytic tumor from the medulla oblongata. The authors report on a 40-year-old man who presented with a large tumor located in the caudal fourth ventricle. The tumor was removed completely and the patient underwent percutaneous radiotherapy with 60 Gy and concomitant chemotherapy with temozolomide. Histopathological examination of the tumor revealed the typical features of a giant cell glioblastoma. At the 2-year follow-up the patient was doing well and showed no signs of tumor recurrence. It is important to identify variants of GBM because they may predict favorable long-term outcome, even when they arise from the caudal brainstem.

  20. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance.

    Science.gov (United States)

    Siebzehnrubl, Florian A; Silver, Daniel J; Tugertimur, Bugra; Deleyrolle, Loic P; Siebzehnrubl, Dorit; Sarkisian, Matthew R; Devers, Kelly G; Yachnis, Antony T; Kupper, Marius D; Neal, Daniel; Nabilsi, Nancy H; Kladde, Michael P; Suslov, Oleg; Brabletz, Simone; Brabletz, Thomas; Reynolds, Brent A; Steindler, Dennis A

    2013-08-01

    Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  1. Transferrin receptor 2 is frequently and highly expressed in glioblastomas.

    Science.gov (United States)

    Calzolari, Alessia; Larocca, Luigi Maria; Deaglio, Silvia; Finisguerra, Veronica; Boe, Alessandra; Raggi, Carla; Ricci-Vitani, Lucia; Pierconti, Francesco; Malavasi, Fabio; De Maria, Ruggero; Testa, Ugo; Pallini, Roberto

    2010-04-01

    Under physiological conditions, transferrin receptor 2 (TfR2) is expressed in the liver and its balance is related to the cell cycle rather than to intracellular iron levels. We recently showed that TfR2 is highly expressed in glioblastoma cell lines. Here, we demonstrate that, in these cells, TfR2 appears to localize in lipid rafts, induces extracellular signal-regulated kinase 1/2 phosphorylation after transferrin binding, and contributes to cell proliferation, as shown by RNA silencing experiments. In vitro hypoxic conditions induce a significant TfR2 up-regulation, suggesting a role in tumor angiogenesis. As assessed by immunohistochemistry, the level of TfR2 expression in astrocytic tumors is related to histologic grade, with the highest expression observed in glioblastomas. The level of TfR2 expression represents a favorable prognostic factor, which is associated with the higher sensitivity to temozolomide of TfR2-positive tumor cells in vitro. The endothelial cells of glioblastoma vasculature also stain for TfR2, whereas those of the normal brain vessels do not. Importantly, TfR2 is expressed by the subpopulation of glioblastoma cells with properties of cancer-initiating cells. TfR2-positive glioblastoma cells retain their TfR2 expression on xenografting in immunodeficient mice. In conclusion, our observations demonstrate that TfR2 is a neoantigen for astrocytomas that seems attractive for developing target therapies.

  2. 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

  3. MRE11-RAD50-NBS1 COMPLEX INHIBITOR MIRIN ENHANCES RADIOSENSITIVITY IN HUMAN GLIOBLASTOMA CELLS

    OpenAIRE

    Mishima, Kazuhiko; Mishima-Kaneko, Masayo; Kawata, Tetsuya; Saya, Hideyuki; Ishimaru, Naozumi; Yamada, Kouichi; Nishikawa, Ryo; Shigematsu, Naoyuki

    2014-01-01

    BACKGROUND: (blind field) METHODS: Glioma cell lines (U251, LN229 and LN428) were irradiated with and without Mirin and then clonogenicity, apoptosis, and cell cycle change were examined. Western blot analysis was performed to determine the relative potency of Mirin to inhibit the radioresistance, through the signaling activity of AKT. We also examined the levels of H2AX phosphorylation (γH2AX), which is a marker of DNA double-strand breaks (DSBs) using Western blot. RESULTS: Glioblastoma cel...

  4. 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.

  5. Favorable outcome of giant cell glioblastoma in a child. Report of an 11-year survival period.

    Science.gov (United States)

    Klein, R; Mölenkamp, G; Sörensen, N; Roggendorf, W

    1998-06-01

    Giant cell glioblastomas are defined as glioblastomas with a marked predominance of bizarre, multinucleated giant cells. They represent about 5% of all glioblastomas and can occur at any site of the central nervous system, but the temporal and frontal lobes are the sites of predilection. Overall, giant cell glioblastomas show a prolonged survival period compared with common glioblastoma multiforme, and survival periods of 7 and 9 years have been reported in adults. Here we report on a child aged 11 years at diagnosis, who has so far survived for 11 years since operation and adjunctive radio- and chemotherapy.

  6. Evaluation of cytotoxicity of propofol and its related mechanism in glioblastoma cells and astrocytes.

    Science.gov (United States)

    Hsu, Shu-Shong; Jan, Chung-Ren; Liang, Wei-Zhe

    2017-12-01

    Propofol (2,6-diisopropylphenol), one of the extensively and commonly used anesthetic agents, has been shown to affect the biological behavior of various models. Previous researches have shown that propofol-induced cytotoxicity might cause anticancer effect in different cells. However, the mechanisms underlying the effect of propofol on cytotoxicity is still elusive in human glioblastoma cells. The aims of this study were to evaluate effects of propofol on cytotoxicity, cell cycle distribution and ROS production, and establish the relationship between oxidative stress and cytotoxicity in GBM 8401 human glioblastoma cells and DI TNC1 rat astrocytes. Propofol (20-30 μM) concentration-dependently induced cytotoxicity, cell cycle arrest, and increased ROS production in GBM 8401 cells but not in DI TNC1 cells. In GBM 8401 cells, propofol induced G2/M phase cell arrest, which affected the CDK1, cyclin B1, p53, and p21 protein expression levels. Furthermore, propofol induced oxygen stresses by increasing O2- and H2 O2 levels but treatment with the antioxidant N-acetylcysteine (NAC) partially reversed propofol-regulated antioxidative enzyme levels (superoxide dismutase, catalase, and glutathione peroxidase). Most significantly, propofol induced apoptotic effects by decreasing Bcl-2 but increasing Bax, cleaved caspase-9/caspase-3 levels, which were partially reversed by NAC. Moreover, the pancaspase inhibitor Z-VAD-FMK also partially prevented propofol-induced apoptosis. Together, in GBM 8401 cells but not in DI TNC1 cells, propofol activated ROS-associated apoptosis that involved cell cycle arrest and caspase activation. These findings indicate that propofol not only can be an anesthetic agent which reduces pain but also has the potential to be used for the treatment of human glioblastoma. © 2017 Wiley Periodicals, Inc.

  7. CANINE BUTTERFLY GLIOBLASTOMAS: A NEURORADIOLOGICAL REVIEW

    Directory of Open Access Journals (Sweden)

    John Henry Rossmeisl

    2016-05-01

    Full Text Available In humans, high-grade gliomas may infiltrate across the corpus callosum resulting in bihemispheric lesions that may have symmetrical, winged-like appearances. This particular tumor manifestation has been coined a ‘butterfly’ glioma (BG. While canine and human gliomas share many neuroradiological and pathological features, the BG morphology has not been previously reported in dogs. Here we describe the magnetic resonance imaging (MRI characteristics of BG in three dogs, and review the potential differential diagnoses based on neuroimaging findings. All dogs presented with generalized seizures and interictal neurological deficits referable to multifocal or diffuse forebrain disease. MRI examinations revealed asymmetrical (2/3 or symmetrical (1/3, bihemispheric intra-axial mass lesions that predominantly affected the frontoparietal lobes and associated with extensive perilesional edema, and involvement of the corpus callosum. The masses displayed heterogeneous T1, T2, and FLAIR signal intensities, variable contrast enhancement (2/3, and mass effect. All tumors demonstrated classical histopathological features of glioblastoma (GBM including glial cell pseudopalisading, serpentine necrosis, microvascular proliferation, as well as invasion of the corpus callosum by neoplastic astrocytes. Although rare, GBM should be considered a differential diagnosis in dogs with MRI evidence of asymmetric or symmetric bilateral, intra-axial cerebral mass lesions with signal characteristics compatible with glioma.

  8. 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. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Methylation regulates HEY1 expression in glioblastoma.

    Science.gov (United States)

    Tsung, Andrew J; Guda, Maheedhara R; Asuthkar, Swapna; Labak, Collin M; Purvis, Ian J; Lu, Yining; Jain, Neha; Bach, Sarah E; Prasad, Durbaka V R; Velpula, Kiran K

    2017-07-04

    Glioblastoma (GBM) remains one of the most lethal and difficult-to-treat cancers of the central nervous system. The poor prognosis in GBM patients is due in part to its resistance to available treatments, which calls for identifying novel molecular therapeutic targets. In this study, we identified a mediator of Notch signaling, HEY1, whose methylation status contributes to the pathogenesis of GBM. Datamining studies, immunohistochemistry and immunoblot analysis showed that HEY1 is highly expressed in GBM patient specimens. Since methylation status of HEY1 may control its expression, we conducted bisulphite sequencing on patient samples and found that the HEY1 promoter region was hypermethylated in normal brain when compared to GBM specimens. Treatment on 4910 and 5310 xenograft cell lines with sodium butyrate (NaB) significantly decreased HEY1 expression with a concomitant increase in DNMT1 expression, confirming that promoter methylation may regulate HEY1 expression in GBM. NaB treatment also induced apoptosis of GBM cells as measured by flow cytometric analysis. Further, silencing of HEY1 reduced invasion, migration and proliferation in 4910 and 5310 cells. Furthermore, immunoblot and q-PCR analysis showed the existence of a potential positive regulatory loop between HEY1 and p53. Additionally, transcription factor interaction array with HEY1 recombinant protein predicted a correlation with p53 and provided various bonafide targets of HEY1. Collectively, these studies suggest HEY1 may be an important predictive marker for GBM and potential target for future GBM therapy.

  10. MicroRNA in Glioblastoma: An Overview

    Directory of Open Access Journals (Sweden)

    Barbara Banelli

    2017-01-01

    Full Text Available Glioblastoma is the most aggressive brain tumor and, even with the current multimodal therapy, is an invariably lethal cancer with a life expectancy that depends on the tumor subtype but, even in the most favorable cases, rarely exceeds 2 years. Epigenetic factors play an important role in gliomagenesis, are strong predictors of outcome, and are important determinants for the resistance to radio- and chemotherapy. The latest addition to the epigenetic machinery is the noncoding RNA (ncRNA, that is, RNA molecules that are not translated into a protein and that exert their function by base pairing with other nucleic acids in a reversible and nonmutational mode. MicroRNAs (miRNA are a class of ncRNA of about 22 bp that regulate gene expression by binding to complementary sequences in the mRNA and silence its translation into proteins. MicroRNAs reversibly regulate transcription through nonmutational mechanisms; accordingly, they can be considered as epigenetic effectors. In this review, we will discuss the role of miRNA in glioma focusing on their role in drug resistance and on their potential applications in the therapy of this tumor.

  11. Combination of palbociclib and radiotherapy for glioblastoma.

    Science.gov (United States)

    Whittaker, Shane; Madani, Daniel; Joshi, Swapna; Chung, Sylvia A; Johns, Terrance; Day, Bryan; Khasraw, Mustafa; McDonald, Kerrie L

    2017-01-01

    The cyclin-dependent kinase inhibitor, palbociclib has shown compelling efficacy in breast cancer patients. Several pre-clinical studies of glioblastoma (GBM) have also shown palbociclib to be efficacious. In this study, we investigated palbociclib in combination with radiation therapy (RT) for treating GBM. We tested palbociclib (with and without RT) on four patient-derived cell lines (PDCLs; RB1 retained; CDKN2A loss). We investigated the impact of therapy on the cell cycle and apoptosis using flow cytometry, in vitro. Balb/c nude mice were intracranially injected with the PDCL, GBM-L1 and treated orally with palbociclib (with and without RT). Overall survival was measured. Palbociclib treatment resulted in a significant increase in the percentage of cells in the G1 cell cycle phase. Apoptotic cell death, measured by Annexin V was induced. Palbociclib combined with RT acted synergistically with the significant impediment of colony formation. The oral treatment of mice with palbociclib did not show any significant survival advantage when compared to control mice, however when combined with RT, a survival advantage of 8 days was observed. Our results support the use of palbociclib as an adjuvant treatment to RT and warrant translation to the clinic.

  12. The Role of Hypoxia in Glioblastoma Invasion

    Directory of Open Access Journals (Sweden)

    Ana Rita Monteiro

    2017-11-01

    Full Text Available Glioblastoma multiforme (GBM, a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient’s median survival rate ranging from 15 to 17 months. The current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression.

  13. 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...... and that expression of HEY1 in GBM correlates with tumour-grade and survival. In addition, we show by chromatin immunoprecipitations, luciferase assays and Northern blot experiments that HEY1 is a bona fide target of the E2F family of transcription factors, connecting the Ras and Notch signalling pathways. Finally......, we show that ectopic expression of HEY1 induces cell proliferation in neural stem cells, while depletion of HEY1 by RNA interference reduces proliferation of glioblastoma cells in tissue culture. Together, these data imply a role for HEY1 in the progression of GBM, and therefore we propose that HEY1...

  14. 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.

  15. Improving activity of salt-lyophilized enzymes in organic media

    Energy Technology Data Exchange (ETDEWEB)

    Borole, Abhijeet P [ORNL; Davison, Brian H [ORNL

    2008-01-01

    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.

  16. In Vitro Effect of 8-Prenylnaringenin and Naringenin on Fibroblasts and Glioblastoma Cells-Cellular Accumulation and Cytotoxicity

    Directory of Open Access Journals (Sweden)

    Monika Stompor

    2017-06-01

    Full Text Available Gliomas are one of the most aggressive and treatment-resistant types of human brain cancer. Identification and evaluation of anticancer properties of compounds found in plants, such as naringenin (N and 8-prenylnaringenin (8PN, are among the most promising applications in glioma therapy. The prenyl group seems to be crucial to the anticancer activity of flavones, since it may lead to enhanced cell membrane targeting and thus increased intracellular activity. It should be noted that 8PN content in hop cones is 10 to 100 times lower compared to other flavonoids, such as xanthohumol. In the study presented, we used a simple method for the synthesis of 8PN from isoxanthohumol—O-demethylation, with a high yield of 97%. Cellular accumulation and cytotoxicity of naringenin and 8-prenylnaringenin in normal (BJ and cancer cells (U-118 MG was also examined. Obtained data indicated that 8-prenylnaringenin exhibited higher cytotoxicity against used cell lines than naringenin, and the effect of both flavones was stronger in U-118 MG cells than in normal fibroblasts. The anticancer properties of 8PN correlated with its significantly greater (37% accumulation in glioblastoma cells than in normal fibroblasts. Additionally, naringenin demonstrated higher selectivity for glioblastoma cells, as it was over six times more toxic for cancer than normal cells. Our results provide evidence that examined prenylated and non-prenylated flavanones have different biological activities against normal and cancer cell lines, and this property may be useful in designing new anticancer drugs for glioblastoma therapy.

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

    Energy Technology Data Exchange (ETDEWEB)

    Johansson, Erik; Zhai, Qiwei [Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, SE 405 30 Gothenburg (Sweden); Zeng, Zhao-jun [Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, SE 405 30 Gothenburg (Sweden); Molecular Biology Research Center, School of Life Sciences, Central South University, 110, Xiangya Road, Changsha, Hunan 410078 (China); Yoshida, Takeshi [Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, SE 405 30 Gothenburg (Sweden); Funa, Keiko, E-mail: keiko.funa@gu.se [Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, SE 405 30 Gothenburg (Sweden)

    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. - Highlights: • TLX knockdown enhances TGF-β dependent Smad signaling in glioblastoma cells • TLX knockdown increases the protein level of TGF-β receptor II. • TLX stabilizes and retains Smurf1 in the cytoplasm. • TLX enhances Smurf1-dependent ubiquitination and degradation of TGF-β receptor II.

  18. Development of induced glioblastoma by implantation of a human xenograft in Yucatan minipig as a large animal model.

    Science.gov (United States)

    Khoshnevis, Mehrdad; Carozzo, Claude; Bonnefont-Rebeix, Catherine; Belluco, Sara; Leveneur, Olivia; Chuzel, Thomas; Pillet-Michelland, Elodie; Dreyfus, Matthieu; Roger, Thierry; Berger, François; Ponce, Frédérique

    2017-04-15

    Glioblastoma is the most common and deadliest primary brain tumor for humans. Despite many efforts toward the improvement of therapeutic methods, prognosis is poor and the disease remains incurable with a median survival of 12-14.5 months after an optimal treatment. To develop novel treatment modalities for this fatal disease, new devices must be tested on an ideal animal model before performing clinical trials in humans. A new model of induced glioblastoma in Yucatan minipigs was developed. Nine immunosuppressed minipigs were implanted with the U87 human glioblastoma cell line in both the left and right hemispheres. Computed tomography (CT) acquisitions were performed once a week to monitor tumor growth. Among the 9 implanted animals, 8 minipigs showed significant macroscopic tumors on CT acquisitions. Histological examination of the brain after euthanasia confirmed the CT imaging findings with the presence of an undifferentiated glioma. Yucatan minipig, given its brain size and anatomy (gyrencephalic structure) which are comparable to humans, provides a reliable brain tumor model for preclinical studies of different therapeutic METHODS: in realistic conditions. Moreover, the short development time, the lower cyclosporine and caring cost and the compatibility with the size of commercialized stereotactic frames make it an affordable and practical animal model, especially in comparison with large breed pigs. This reproducible glioma model could simulate human anatomical conditions in preclinical studies and facilitate the improvement of novel therapeutic devices, designed at the human scale from the outset. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Physician Perceptions of Performance Feedback in a Quality Improvement Activity.

    Science.gov (United States)

    Eden, Aimee R; Hansen, Elizabeth; Hagen, Michael D; Peterson, Lars E

    2017-10-01

    Physician performance and peer comparison feedback can affect physician care quality and patient outcomes. This study aimed to understand family physician perspectives of the value of performance feedback in quality improvement (QI) activities. This study analyzed American Board of Family Medicine open-ended survey data collected between 2004 and 2014 from physicians who completed a QI module that provided pre- and post-QI project individual performance data and peer comparisons. Physicians made 3480 comments in response to a question about this performance feedback, which were generally positive in nature (86%). Main themes that emerged were importance of accurate feedback data, enhanced detail in the content of feedback, and ability to customize peer comparison groups to compare performance to peers with similar patient populations or practice characteristics. Meaningful and tailored performance feedback may be an important tool for physicians to improve their care quality and should be considered an integral part of QI project design.

  20. Survival Trends in Elderly Patients with Glioblastoma in the United States: a Population-based Study.

    Science.gov (United States)

    Shah, Binay Kumar; Bista, Amir; Sharma, Sandhya

    2016-09-01

    Concomitant and adjuvant temozolomide along with radiotherapy following surgery (the Stupp regimen) is the preferred therapy for young patients with glioblastoma as well as for elderly (>70 years) ones with favorable risk factors. This study investigated the survival trend since the introduction of the use of the Stupp regimen in elderly patients in a population-based setting. Surveillance, Epidemiology, and End Results 18 database was used to identify patients aged ≥70 years with glioblastoma as the first primary cancer diagnosed from 1999 to 2010. Chi-square test, Kaplan-Meier analysis with log-rank test and Cox proportional hazard method were used for analysis. A total of 5,575 patients were included in the survival analysis. Survival in Stupp era (year of diagnosis ≥2005) was significantly better compared to the pre-Stupp era with p<0.001 by log-rank test, with 1-, 2- and 3-year overall survival of 18.8% vs. 12.9%, 6.5% vs. 2.1% and 3.1% vs. 0.9% respectively, and hazard ratio for death in 3 years in the Stupp era was 0.87 (95% confidence interval=0.82-0.92; p<0.001) when compared with the pre-Stupp era. Factors such as younger age (<85 years), female sex, married status, Caucasian race and total resection favored better survival compared to their counterparts. This study shows that the survival of elderly patients with glioblastoma has improved since the introduction of the Stupp regimen. However, there are significant differences in survival rates among various cohorts. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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

  2. Improved thermal neutron activation sensor for detection of bulk explosives

    Science.gov (United States)

    McFee, John E.; Faust, Anthony A.; Andrews, H. Robert; Clifford, Edward T. H.; Mosquera, Cristian M.

    2012-06-01

    Defence R&D Canada - Suffield and Bubble Technology Industries have been developing thermal neutron activation (TNA) sensors for detection of buried bulk explosives since 1994. First generation sensors, employing an isotopic source and NaI(Tl) gamma ray detectors, were deployed by Canadian Forces in 2002 as confirmation sensors on the ILDS teleoperated, vehicle-mounted, multi-sensor anti-tank landmine detection systems. The first generation TNA could detect anti-tank mines buried 10 cm or less in no more than a minute, but deeper mines and those significantly displaced horizontally required considerably longer times. Mines as deep as 30 cm could be detected with long counting times (1000 s). The second generation TNA detector is being developed with a number of improvements aimed at increasing sensitivity and facilitating ease of operation. Among these are an electronic neutron generator to increase sensitivity for deeper and horizontally displaced explosives; LaBr3(Ce) scintillators, to improve time response and energy resolution; improved thermal and electronic stability; improved sensor head geometry to minimize spatial response nonuniformity; and more robust data processing. This improved sensitivity can translate to either decreased counting times, decreased minimum detectable explosive quantities, increased maximum sensor-to-target displacement, or a trade off among all three. Experiments to characterize the performance of the latest generation TNA in detecting buried landmines and IEDs hidden in culverts were conducted during 2011. This paper describes the second generation system. The experimental setup and methodology are detailed and preliminary comparisons between the performance of first and second generation systems are presented.

  3. Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

    Science.gov (United States)

    Liu, Kao-Hui; Yang, Shun-Tai; Lin, Yen-Kuang; Lin, Jia-Wei; Lee, Yi-Hsuan; Wang, Jia-Yi; Hu, Chaur-Jong; Lin, En-Yuan; Chen, Shu-Mei; Then, Chee-Kin; Shen, Shing-Chuan

    2015-01-01

    The efficacy of glioblastoma chemotherapy is not satisfactory; therefore, a new medication is expected to improve outcomes. As much evidence shows that antidepressants decrease cancer incidence and improve patients' quality of life, we therefore attempted to explore the potential for fluoxetine to be used to treat GBM and its possible underlying mechanism. The expression level of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was determined using immunohistochemical staining and PCR analysis. The mechanism of fluoxetine-induced apoptosis of gliomas was elucidated. Computer modeling and a binding assay were conducted to investigate the interaction of fluoxetine with the AMPAR. The therapeutic effect of fluoxetine was evaluated using an animal model. We found that fluoxetine directly bound to AMPAR, thus inducing transmembrane Ca2+ influx. The rise in the intracellular calcium concentration ([Ca2+]i) causes mitochondrial Ca2+ overload, thereby triggering apoptosis. AMPARs are excessively expressed in glioma tissues, suggesting that fluoxetine specifically executes glioma cells. Our in vivo study revealed that fluoxetine suppressed the growth of glioblastomas in brains of Nu/Nu mice, an effect similar to that produced by temozolomide. Our preclinical studies suggest fluoxetine, a commonly used antidepressant, might be selectively toxic to gliomas and could provide a new approach for managing this disease. PMID:25671301

  4. Topical Rosiglitazone Treatment Improves Ulcerative Colitis by Restoring Peroxisome Proliferator-Activated Receptor-gamma Activity

    DEFF Research Database (Denmark)

    Pedersen, G.; Brynskov, Jørn

    2010-01-01

    for 14 days. RESULTS: PPAR gamma expression was fourfold reduced in epithelial cells from inflamed compared with uninflamed mucosa and controls. Adipophillin levels were decreased in parallel. Rosiglitazone induced a concentration-dependent increase in adipophillin levels and restored PPAR gamma activity...... in epithelial cells from inflamed mucosa in vitro. Rosiglitazone enema treatment was well tolerated and reduced the Mayo ulcerative colitis score from 8.9 to 4.3 (P ... gamma activation in vivo. CONCLUSIONS: Roziglitasone enemas improve impaired PPAR gamma activity in inflamed colonic epithelium and have beneficial clinical effect in patients with active distal ulcerative colitis. These findings raise interest in further studies of PPAR gamma ligands that exhibit...

  5. Efficacy of systemic adoptive transfer immunotherapy targeting NY-ESO-1 for glioblastoma.

    Science.gov (United States)

    Everson, Richard G; Antonios, Joseph P; Lisiero, Dominique N; Soto, Horacio; Scharnweber, Rudi; Garrett, Matthew C; Yong, William H; Li, Ning; Li, Gang; Kruse, Carol A; Liau, Linda M; Prins, Robert M

    2016-03-01

    Immunotherapy is an ideal treatment modality to specifically target the diffusely infiltrative tumor cells of malignant gliomas while sparing the normal brain parenchyma. However, progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas. We utilized human glioblastoma cell cultures to induce expression of New York-esophageal squamous cell carcinoma (NY-ESO-1) following in vitro treatment with the demethylating agent decitabine. We then investigated the phenotype of lymphocytes specific for NY-ESO-1 using flow cytometry analysis and cytotoxicity against cells treated with decitabine using the xCelligence real-time cytotoxicity assay. Finally, we examined the in vivo application of this immune therapy using an intracranially implanted xenograft model for in situ T cell trafficking, survival, and tissue studies. Our studies showed that treatment of intracranial glioma-bearing mice with decitabine reliably and consistently induced the expression of an immunogenic tumor-rejection antigen, NY-ESO-1, specifically in glioma cells and not in normal brain tissue. The upregulation of NY-ESO-1 by intracranial gliomas was associated with the migration of adoptively transferred NY-ESO-1-specific lymphocytes along white matter tracts to these tumors in the brain. Similarly, NY-ESO-1-specific adoptive T cell therapy demonstrated antitumor activity after decitabine treatment and conferred a highly significant survival benefit to mice bearing established intracranial human glioma xenografts. Transfer of NY-ESO-1-specific T cells systemically was superior to intracranial administration and resulted in significantly extended and long-term survival of animals. These results reveal an innovative, clinically feasible strategy for the treatment of glioblastoma. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro

  6. Hemolytic anemia in two patients with glioblastoma multiforme: A possible interaction between vorinostat and dapsone.

    Science.gov (United States)

    Lewis, Jennifer A; Petty, William J; Harmon, Michele; Peacock, James E; Valente, Kari; Owen, John; Pirmohamed, Munir; Lesser, Glenn J

    2015-06-01

    Patients undergoing treatment for glioblastoma multiforme are routinely placed on prophylactic treatment for Pneumocystis jirovecii pneumonia because of significant therapy-induced lymphopenia. In patients with sulfa allergies, dapsone prophylaxis is often used due to its efficacy, long half-life, cost effectiveness, and general safety at low doses. However, dapsone may uncommonly induce a hemolytic anemia, particularly in patients deficient of glucose-6-phosphate dehydrogenase. This hemolysis is thought to be a result of oxidative stress on red blood cells induced by dapsone metabolites which produce reactive oxygen species that disrupt the red blood cell membrane and promote splenic sequestration. A single case report of dapsone-induced hemolytic anemia in a patient with glioblastoma multiforme has been reported. We present two patients with glioblastoma multiforme who developed severe hemolytic anemia shortly after initiating therapy with vorinostat, a pan-active histone deacetylase inhibitor, while on prophylactic dapsone. There are several potential mechanisms by which histone deacetylase inhibition may alter dapsone metabolism including changes in hepatic acetylation or N-glucuronidation leading to an increase in the bioavailability of dapsone's hematotoxic metabolites. In addition, vorinostat may lead to increased hemolysis through inhibition of heat shock protein-90, a chaperone protein that maintains the integrity of the red blood cell membrane cytoskeleton. The potential interaction between dapsone and vorinostat may have important clinical implications as more than 10 clinical trials evaluating drug combinations with vorinostat in patients with malignant glioma are either ongoing or planned in North America. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  7. P53-dependent antiproliferative and pro-apoptotic effects of trichostatin A (TSA) in glioblastoma cells.

    Science.gov (United States)

    Bajbouj, K; Mawrin, C; Hartig, R; Schulze-Luehrmann, J; Wilisch-Neumann, A; Roessner, A; Schneider-Stock, R

    2012-05-01

    Glioblastomas are known to be highly chemoresistant, but HDAC inhibitors (HDACi) have been shown to be of therapeutic relevance for this aggressive tumor type. We treated U87 glioblastoma cells with trichostatin A (TSA) to define potential epigenetic targets for HDACi-mediated antitumor effects. Using a cDNA array analysis covering 96 cell cycle genes, cyclin-dependent kinase inhibitor p21(WAF1) was identified as the major player in TSA-induced cell cycle arrest. TSA slightly inhibited proliferation and viability of U87 cells, cumulating in a G1/S cell cycle arrest. This effect was accompanied by a significant up-regulation of p53 and its transcriptional target p21(WAF1) and by down-regulation of key G1/S regulators, such as cdk4, cdk6, and cyclin D1. Nevertheless, TSA did not induce apoptosis in U87 cells. As expected, TSA promoted the accumulation of total acetylated histones H3 and H4 and a decrease in endogenous HDAC activity. Characterizing the chromatin modulation around the p21(WAF1) promoter after TSA treatment using chromatin immunoprecipitation, we found (1) a release of HDAC1, (2) an increase of acetylated H4 binding, and (3) enhanced recruitment of p53. p53-depleted U87 cells showed an abrogation of the G1/S arrest and re-entered the cell cycle. Immunofluorescence staining revealed that TSA induced the nuclear translocation of p21(WAF1) verifying a cell cycle arrest. On the other hand, a significant portion of p21(WAF1) was present in the cytoplasmic compartment causing apoptosis resistance. Furthermore, TSA-treated p53-mutant cell line U138 failed to show an induction in p21(WAF1), showed a deficient G2/M checkpoint, and underwent mitotic catastrophe. We suggest that HDAC inhibition in combination with other clinically used drugs may be considered an effective strategy to overcome chemoresistance in glioblastoma cells.

  8. Glioblastoma multiforme with long term survival.

    Science.gov (United States)

    Deb, Prabal; Sharma, Mehar Chand; Mahapatra, Ashok Kumar; Agarwal, Deepak; Sarkar, Chitra

    2005-09-01

    Glioblastoma multiforme (GBM) Patients generally have a dismal prognosis, with median survival of 10-12 months. GBM with long-term survival (LTS) of (3) > or = 5 years is rare, and no definite markers indicating better prognosis have been identified till date. The present study was undertaken to evaluate GBMs with LTS in order to identify additional correlates associated with favourable outcome. The cases were evaluated for relevant clinicopathological data, proliferation index and expression of tumortumour suppressor gene (p53 ), cyclin-dependant kinase-inhibitors (p27 and p16 ) and epidermal growth factor receptor (EGFR) proteins. Six cases of GBM with LTS with an average survival of 9 years (range 5-15 years) were identified. All were young patients with mean age of 27 years (range 8-45 years). Histology of three cases was consistent with conventional GBM, while two showed prominent oligodendroglial component admixed with GBM areas. One was a giant cell GBM, which progressed to gliosarcoma on recurrence. The mean MIB-1LI was 12% (range 6-20%). p53 was immunopositive in 4 out of 5 cases. EGFR and p27 were immunonegative in all, whereas p16 was immunonegative in 3 out of 5 cases. Currently, in the absence of specific molecular and genetic markers, GBM in young patients should be meticulously evaluated for foci of oligodendroglial component and/or giant cell elements, in addition to proliferative index and p53 expression, since these probably have prognostic connotations, as evident in this study. The role of p16 and p27 however needs better definition with study of more number of cases.

  9. 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.

  10. Significance of Epidermal Growth Factor Receptor in the Radiation Resistance of Glioblastoma Tumors

    Science.gov (United States)

    Petrás, Miklós; Lajtos, Tamás; Pintye, Éva; Feuerstein, Burt G.; Szöllősi, János; Vereb, György

    2008-12-01

    In the United States, a dramatically increased incidence and mortality of brain tumors have been observed over the past decades. Of the ˜44 thousand new cases of primary malignant and benign brain tumors diagnosed per year, high grade astrocytomas or multiform glioblastomas show particularly bad prognosis in spite of therapeutic developments. Current management of multiform glioblastoma includes the most extensive surgical resection possible, followed by adjuvant radio- and chemotherapy. However, treatment is frequently hampered by decreased radiosensitivity of the tumor. Recent studies revealed that subpopulations of glioblastoma cells show amplified checkpoint activation of the cell cycle upon ionizing radiation, which induces overactivation of DNA repair processes and leads to maintained proliferation rate as well as clinically observed radioresistance and recurrence of the tumor over time. In addition, overexpression of some transmembrane receptors has also been implicated in radioresistance. However, the role of the overexpressed proteins can only be interpreted reliably if their multi-faceted molecular interactions are properly characterized. Thus, based on recent evidence for the functional crosstalk between certain cell adhesion molecules and receptor tyrosine kinases, we have examined the molecular interactions of the receptor tyrosine kinase EGFR and the cell adhesion molecule β1-integrin using flow cytometric and microscopic fluorescence resosnance energy transfer (FRET) measurements on two cellular model systems showing similar expression patterns to low and high grade astrocytomas. On the one hand, U251 glioblastoma clones established by introducing varying amounts of extra chromosome 7 into the cells, and on the other hand stable, high and low EGFR expressing transfenctant U251 NCI sublines were investigated. The results revealed that increased EGFR and β1-integrin expression levels correlate with stronger EGFR—β1-integrin heteroassociation

  11. Assessment and treatment relevance in elderly glioblastoma patients.

    Science.gov (United States)

    Bauchet, Luc; Zouaoui, Sonia; Darlix, Amélie; Menjot de Champfleur, Nicolas; Ferreira, Ernestine; Fabbro, Michel; Kerr, Christine; Taillandier, Luc

    2014-11-01

    Glioblastoma (GBM) is the most common malignant primary brain tumor. Its incidence continues to increase in the elderly because the older segment of the population is growing faster than any other age group. Most clinical studies exclude elderly patients, and "standards of care" do not exist for GBM patients aged >70 years. We review epidemiology, tumor biology/molecular factors, prognostic factors (clinical, imaging data, therapeutics), and their assessments as well as classic and specific endpoints plus recent and ongoing clinical trials for elderly GBM patients. This work includes perspectives and personal opinions on this topic. Although there are no standards of care for elderly GBM patients, we can hypothesize that (i) Karnofsky performance status (KPS), probably after steroid treatment, is one of the most important clinical factors for determining our oncological strategy; (ii) resection is superior to biopsy, at least in selected patients (depending on location of the tumor and associated comorbidities); (iii) specific schedules of radiotherapy yield a modest but significant improvement; (iv) temozolomide has an acceptable tolerance, even when KPS patients; and (v) the addition of concomitant temozolomide to radiotherapy has not yet been validated but shows promising results in some studies, yet the optimal schedule of radiotherapy remains to be determined. In the future, specific assessments (geriatric, imaging, biology) and use of new endpoints (quality of life and toxicity measures) will aid clinicians in determining the balance of potential benefits and risks of each oncological strategy. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. 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

  13. 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.)

  14. Characterization and identification of glioblastoma progression on preoperative multimodal MRI

    NARCIS (Netherlands)

    Yan, Jiun-Lin; van der Hoorn, A.; Boonzaier, N. R.; Larkin, T. J.; Matys, T.; Price, Stephen J

    2016-01-01

    Introduction: The treatment failure of Glioblastoma (GBM) is mostly due to the inadequate identification of its invasive margin. We aimed to characterize the peri-tumoral area, the predominant site of tumor progression by using multi-modal MRI. Thereafter, a robust method to preoperatively identify

  15. Gemcitabine uptake in glioblastoma multiforme: potential as a radiosensitizer

    NARCIS (Netherlands)

    Sigmond, J.; Honeywell, R.J.; Postma, T.J.; Dirven, C.M.; Lange, de S.M.; Born, van der K.; Laan, A.; Baayen, J.C.; Groeningen, van C.J.; Bergman, A.M.; Giaccone, G.; Peters, G.J.

    2009-01-01

    Glioblastoma multiforme (GBM), the most frequent malignant brain tumor, has a poor prognosis, but is relatively sensitive to radiation. Both gemcitabine and its metabolite difluorodeoxyuridine (dFdU) are potent radiosensitizers. The aim of this phase 0 study was to investigate whether gemcitabine

  16. Oncogenic role of Merlin/NF2 in glioblastoma.

    Science.gov (United States)

    Guerrero, P A; Yin, W; Camacho, L; Marchetti, D

    2015-05-14

    Glioblastoma is the most common and aggressive primary brain tumor in adults, with a poor prognosis because of its resistance to radiotherapy and chemotherapy. Merlin/NF2 (moesin-ezrin-radixin-like protein/neurofibromatosis type 2) is a tumor suppressor found to be mutated in most nervous system tumors; however, it is not mutated in glioblastomas. Merlin associates with several transmembrane receptors and intracellular proteins serving as an anchoring molecule. Additionally, it acts as a key component of cell motility. By selecting sub-populations of U251 glioblastoma cells, we observed that high expression of phosphorylated Merlin at serine 518 (S518-Merlin), NOTCH1 and epidermal growth factor receptor (EGFR) correlated with increased cell proliferation and tumorigenesis. These cells were defective in cell-contact inhibition with changes in Merlin phosphorylation directly affecting NOTCH1 and EGFR expression, as well as downstream targets HES1 (hairy and enhancer of split-1) and CCND1 (cyclin D1). Of note, we identified a function for S518-Merlin, which is distinct from what has been reported when the expression of Merlin is diminished in relation to EGFR and NOTCH1 expression, providing first-time evidence that demonstrates that the phosphorylation of S518-Merlin in glioblastoma promotes oncogenic properties that are not only the result of inactivation of the tumor suppressor role of Merlin but also an independent process implicating a Merlin-driven regulation of NOTCH1 and EGFR.

  17. Glioblastoma multiforme has many faces | van Rensburg | SA ...

    African Journals Online (AJOL)

    Glioblastoma multiforme (GBM) is a class of devastating, highly aggressive central nervous system tumours. While the classical appearance is easily recognisable, several variations occur. We present 6 cases of confirmed GBM that illustrate the unusual findings in histological subtypes, early presentation and spread on ...

  18. 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 incubation...

  19. RARβ gene methylation is a candidate for primary glioblastoma ...

    African Journals Online (AJOL)

    Background: We screened RARβ methylation in primary glioblastoma multiforme (GBM) and the results were evaluated based on the clinical data and treatment type. Objective: The objective of this study was to find new areas for the usage of MS HRM applications in the determination of methylation levels in primary GBM ...

  20. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, S; Wibom, C; Andersson, U

    2011-01-01

    significantly associated to survival, namely rs2071559 and rs12502008. However, these results are likely to be false positives due to multiple testing and could not be confirmed in a separate dataset. Overall, this study provides little evidence that VEGF and VEGFR2 polymorphisms are important for glioblastoma...

  1. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, S; Wibom, C; Andersson, U

    2010-01-01

    significantly associated to survival, namely rs2071559 and rs12502008. However, these results are likely to be false positives due to multiple testing and could not be confirmed in a separate dataset. Overall, this study provides little evidence that VEGF and VEGFR2 polymorphisms are important for glioblastoma...

  2. Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells

    DEFF Research Database (Denmark)

    Schonberg, David L; Miller, Tyler E; Wu, Qiulian

    2015-01-01

    Glioblastomas display hierarchies with self-renewing cancer stem-like cells (CSCs). RNA sequencing and enhancer mapping revealed regulatory programs unique to CSCs causing upregulation of the iron transporter transferrin, the top differentially expressed gene compared with tissue-specific progeni...

  3. Short-term effects of radiation in glioblastoma spheroids

    DEFF Research Database (Denmark)

    Petterson, Stine Asferg; Jakobsen, Ida Pind; Jensen, Stine Skov

    2016-01-01

    Glioblastoma is the most frequent and malignant primary brain tumor. The standard treatment includes surgery, radiation and chemotherapy. The limited efficacy of the current treatment has been explained by the existence of treatment-resistant stem-like tumor cells. The aim of this study was to in......Glioblastoma is the most frequent and malignant primary brain tumor. The standard treatment includes surgery, radiation and chemotherapy. The limited efficacy of the current treatment has been explained by the existence of treatment-resistant stem-like tumor cells. The aim of this study...... was to investigate the short-term effects of radiation of spheroids containing tumor-initiating stem-like cells. We used a patient-derived glioblastoma stem cell enriched culture (T76) and the standard glioblastoma cell line U87. Primary spheroids were irradiated with doses between 2 and 50 Gy and assessed after two...... and five days. We found a small reduction in primary spheroid size after radiation and an associated small increase in uptake of the cell death marker propidium iodide. Using immunohistochemistry, P53 expression was found to be significantly increased, whereas the Ki-67 proliferation index...

  4. Clinical outcome of patients with glioblastoma multiforme: Single center experience

    Directory of Open Access Journals (Sweden)

    Özlem Yersal

    2017-12-01

    Full Text Available Glioblastoma multiforme (GBM is the most common and fatal brain tumor in adults. Prognosis remains dismal and median overall survival rarely exceeds 12 months. In this study, we evaluated the demographic and clinical features of Turkish glioblastoma patients from single institute to identify the important prognostic factors which might be related with patient outcomes in this population, retrospectively. Demographic data, clinicopathological data and treatment parameters (i.e. extent of surgical resection, radiotherapy and use of chemotherapy were obtained from medical records. SPSS version 22 was used for all statistical analyses. The median progression-free survival and overall survival was 9,9 and 13,7 months; respectively. The group of patients with the highest mean overall survival had a tumor at the fronto-temporal region, followed by frontal localization. In univariate analysis, age, concurrent chemoradiotherapy and adjuvant temozolomide use were all predictors for both PFS and OS. However, in multivariate analysis, age and concurrent radiotherapy were significant predictors of survival. Patients receiving cyberknife after recurrence had longer OS. We retrospectively evaluated glioblastoma patients from single institute, the results supported previously reported factors that influence survival time in glioblastoma.

  5. 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.

  6. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    Science.gov (United States)

    Karpel-Massler, Georg; Pareja, Fresia; Aimé, Pascaline; Shu, Chang; Chau, Lily; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Crary, John F.; Canoll, Peter; Siegelin, Markus D.

    2014-01-01

    Background Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID:25531448

  7. Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma.

    Science.gov (United States)

    Green, Adam L; Ramkissoon, Shakti H; McCauley, Dilara; Jones, Kristen; Perry, Jennifer A; Hsu, Jessie Hao-Ru; Ramkissoon, Lori A; Maire, Cecile L; Hubbell-Engler, Benjamin; Knoff, David S; Shacham, Sharon; Ligon, Keith L; Kung, Andrew L

    2015-05-01

    Glioblastoma (GBM) is poorly responsive to current chemotherapy. The nuclear transporter exportin 1 (XPO1, CRM1) is often highly expressed in GBM, which may portend a poor prognosis. Here, we determine the efficacy of novel selective inhibitors of nuclear export (SINE) specific to XPO1 in preclinical models of GBM. Seven patient-derived GBM lines were treated with 3 SINE compounds (KPT-251, KPT-276, and Selinexor) in neurosphere culture conditions. KPT-276 and Selinexor were also evaluated in a murine orthotopic patient-derived xenograft (PDX) model of GBM. Cell cycle effects were assayed by flow cytometry in vitro and immunohistochemistry in vivo. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase 3/7 activity assays. Treatment of GBM neurosphere cultures with KPT-276, Selinexor, and KPT-251 revealed dose-responsive growth inhibition in all 7 GBM lines [range of half-maximal inhibitory concentration (IC50), 6-354 nM]. In an orthotopic PDX model, treatment with KPT-276 and Selinexor demonstrated pharmacodynamic efficacy, significantly suppressed tumor growth, and prolonged animal survival. Cellular proliferation was not altered with SINE treatment. Instead, induction of apoptosis was apparent both in vitro and in vivo with SINE treatment, without overt evidence of neurotoxicity. SINE compounds show preclinical efficacy utilizing in vitro and in vivo models of GBM, with induction of apoptosis as the mechanism of action. Selinexor is now in early clinical trials in solid and hematological malignancies. Based on these preclinical data and excellent brain penetration, we have initiated clinical trials of Selinexor in patients with relapsed GBM. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. 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.

  9. Inhibition of AKT signaling by supercritical CO2 extract of mango ginger (Curcuma amada Roxb.) in human glioblastoma cells.

    Science.gov (United States)

    Ramachandran, Cheppail; Portalatin, Gilda; Quirin, Karl-W; Escalon, Enrique; Khatib, Ziad; Melnick, Steven J

    2015-12-01

    Mango ginger (Curcuma amada Roxb.) is a less-investigated herb for anticancer properties than other related Curcuma species. AKT (a serine/threonine protein kinase B, originally identified as an oncogene in the transforming retrovirus AKT8) plays a central role in the development and promotion of cancer. In this investigation, we have analyzed the effect of supercritical CO2 extract of mango ginger (CA) on the genetic pathways associated with AKT signaling in human glioblastoma cells. The inhibitory effect of supercritical CO2 extract of mango ginger (Curcuma amada) on AKT signaling was investigated in U-87MG glioblastoma cells. CA was highly cytotoxic to glioblastoma cell line (IC50=4.92±0.81 µg/mL) compared to mHypoE-N1 normal mouse hypothalamus cell line (IC50=40.57±0.06 µg/mL). CA inhibits AKT (protein Kinase B) and adenosine monophophate -activated protein kinase α (AMPKα) phosphorylation significantly in a dose-dependent manner. The cell migration which is necessary for invasion and metastasis was also inhibited by CA treatment, with about 43% reduction at 20 µg/mL concentration. Analysis of mRNA and protein expression of genes associated with apoptosis, cell proliferation and angiogenesis showed that CA modulates expression of genes associated with apoptosis (Bax, Bcl-2, Bcl-X, BNIP3, caspase-3, mutant p53 and p21), cell proliferation (Ki67) and angiogenesis vascular endothelial growth factor (VEGF). Additionally, heat shock protein 90 (HSP90) and AMPKα genes interacting with the AKT signaling pathway were also downregulated by CA treatment. These results indicate the molecular targets and mechanisms underlying the anticancer effect of CA in human glioblastoma cells.

  10. The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Sarah Ball

    Full Text Available Tumors of the central nervous system represent a major source of cancer-related deaths, with medulloblastoma and glioblastoma being the most common malignant brain tumors in children and adults respectively. While significant advances in treatment have been made, with the 5-year survival rate for medulloblastoma at 70-80%, treating patients under 3 years of age still poses a problem due to the deleterious effects of radiation on the developing brain, and the median survival for patients with glioblastoma is only 15 months. The transcription factor, STAT3, has been found constitutively activated in a wide variety of cancers and in recent years it has become an attractive therapeutic target. We designed a non-peptide small molecule STAT3 inhibitor, LLL12, using structure-based design. LLL12 was able to inhibit STAT3 phosphorylation, decrease cell viability and induce apoptosis in medulloblastoma and glioblastoma cell lines with elevated levels of p-STAT3 (Y705. IC(50 values for LLL12 were found to be between 1.07 µM and 5.98 µM in the five cell lines expressing phosphorylated STAT3. STAT3 target genes were found to be downregulated and a decrease in STAT3 DNA binding was observed following LLL12 treatment, indicating that LLL12 is an effective STAT3 inhibitor. LLL12 was also able to inhibit colony formation, wound healing and decreased IL-6 and LIF secretion. Our results suggest that LLL12 is a potent STAT3 inhibitor and that it may be a potential therapeutic treatment for medulloblastoma and glioblastoma.

  11. Nanomelatonin triggers superior anticancer functionality in a human malignant glioblastoma cell line

    Science.gov (United States)

    Yadav, Sanjeev Kumar; Srivastava, Anup Kumar; Dev, Atul; Kaundal, Babita; Choudhury, Subhasree Roy; Karmakar, Surajit

    2017-09-01

    Melatonin (MEL) has promising medicinal value as an anticancer agent in a variety of malignancies, but there are difficulties in achieving a therapeutic dose due to its short half-life, low bioavailability, poor solubility and extensive first-pass metabolism. In this study chitosan/tripolyphosphate (TPP) nanoparticles were prepared by an ionic gelation method to overcome the therapeutic challenges of melatonin and to improve its anticancer efficacy. Characterization of the melatonin-loaded chitosan (MEL-CS) nanoformulation was performed using transmission and scanning electron microscopies, dynamic light scattering, Fourier transform infrared spectroscopy, Raman spectroscopy and x-ray diffraction. In vitro release, cellular uptake and efficacy studies were tested for their enhanced anticancer potential in human U87MG glioblastoma cells. Confocal studies revealed higher cellular uptake of MEL-CS nanoparticles and enhanced anticancer efficacy in human malignant glioblastoma cancer cells than in healthy non-malignant human HEK293T cells in mono- and co-culture models. Our study has shown for the first time that MEL-CS nanocomposites are therapeutically more effective as compared to free MEL at inducing functional anticancer efficacy in the human brain tumour U87MG cell line.

  12. ROCK Inhibition Facilitates In Vitro Expansion of Glioblastoma Stem-Like Cells.

    Directory of Open Access Journals (Sweden)

    Samantha G Tilson

    Full Text Available Due to their stem-like characteristics and their resistance to existing chemo- and radiation therapies, there is a growing appreciation that cancer stem cells (CSCs are the root cause behind cancer metastasis and recurrence. However, these cells represent a small subpopulation of cancer cells and are difficult to propagate in vitro. Glioblastoma is an extremely deadly form of brain cancer that is hypothesized to have a subpopulation of CSCs called glioblastoma stem cells (GSCs; also called brain tumor initiating cells, BTICs. We propose the use of selective Rho-kinase (ROCK inhibitors, Y-27632 and fasudil, to promote GSC/BTIC-like cell survival and propagation in vitro. ROCK inhibitors have been implicated in suppressing apoptosis, and it was hypothesized that they would increase the number of GSC/BTIC-like cells grown in vitro and improve cloning efficiencies. Indeed, our data demonstrate that transient and continuous supplementation of non-toxic concentrations of Y-27632 and fasudil inhibited apoptosis, enhanced the cells' ability to form spheres, and increased stem cell marker expressing GSC/BTIC-like cell subpopulation. Our data indicated that pharmacological and genetic (siRNA inhibitions of the ROCK pathway facilitates in vitro expansion of GSC/BTIC-like cells. Thus, ROCK pathway inhibition shows promise for future optimization of CSC culture media.

  13. Reassessing the Role of Intra-Arterial Drug Delivery for Glioblastoma Multiforme Treatment

    Directory of Open Access Journals (Sweden)

    Jason A. Ellis

    2015-01-01

    Full Text Available Effective treatment for glioblastoma (GBM will likely require targeted delivery of several specific pharmacological agents simultaneously. Intra-arterial (IA delivery is one technique for targeting the tumor site with multiple agents. Although IA chemotherapy for glioblastoma (GBM has been attempted since the 1950s, the predicted benefits remain unproven in clinical practice. This review focuses on innovative approaches to IA drug delivery in treating GBM. Guided by novel in vitro and in vivo optical measurements, newer pharmacokinetic models promise to better define the complex relationship between background cerebral blood flow and drug injection parameters. Advanced optical technologies and tracers, unique nanoparticles designs, new cellular targets, and rational drug formulations are continuously modifying the therapeutic landscape for GBM. Personalized treatment approaches are emerging; however, such tailored approaches will largely depend on effective drug delivery techniques and on the ability to simultaneously deliver multidrug regimens. These new paradigms for tumor-selective drug delivery herald dramatic improvements in the effectiveness of IA chemotherapy for GBM. Therefore, within this context of so-called “precision medicine,” the role of IA delivery for GBM is thoroughly reassessed.

  14. 1, 3β-Glucan anchored, paclitaxel loaded chitosan nanocarrier endows enhanced hemocompatibility with efficient anti-glioblastoma stem cells therapy.

    Science.gov (United States)

    Singh, Pankaj K; Srivastava, Anup K; Dev, Atul; Kaundal, Babita; Choudhury, Subhasree Roy; Karmakar, Surajit

    2018-01-15

    Recurrence of glioblastoma is one of the major concerns due to its heterogeneous nature and association of Glioma Initiating stem-like Cells (GICs). Nanoparticles mediated delivery of chemotherapeutic agent targeting both cancer and glioma stem cells could provide a solution to recurrent malignancies of the glioblastoma tumor. The approach described here provides enhanced chemotherapeutic potency utilizing 1,3β-Glucan as an outer shell to the chitosan nanoparticles (Cs-NPs) loaded with paclitaxel to prevent hemolysis with, the core-shell nano-structure (Cs-PTX-NP) enabling effective chemotherapy against malignant glioblastoma. The prepared nanoparticles (1,3β-Cs-PTX-NPs) with sustained release of the paclitaxel provide a targeted therapeutic approach that overcome systemic toxicities with the 1,3β-Glucan shell and improve drug bioavailability. Hemolysis investigation indicated that 1,3β-Cs-PTX-NP was significantly less hemolytic than paclitaxel enabling intravenous delivery. Also, 1,3β-Cs-PTX-NPs were considerably more cytotoxic (IC50) against glioma cancer LN18 cells and C6 stem-like cells compared with the PTX. In conclusion, this study found that 1,3β-Cs-PTX-NP addressed serious limitation with systemic delivery of paclitaxel by preventing hemolysis and providing chemotherapeutic delivery with significant anti-cancer efficacy against recurrent glioblastoma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC.

    Science.gov (United States)

    Zhang, Ying; Guessous, Fadila; Kofman, Alex; Schiff, David; Abounader, Roger

    2010-02-01

    XL-184 (BMS-907351), under development by Exelixis Inc and Bristol-Myers Squibb Co, is a pan-tyrosine kinase inhibitor for the potential oral treatment of medullary thyroid cancer, glioblastoma multiforme and NSCLC. The prinicipal targets of XL-184 are MET, VEGFR-2 and RET, but the drug is also reported to display inhibitory activity against KIT, FLT3 and TEK. Preclinical studies demonstrated that XL-184 potently inhibited multiple receptor tyrosine kinases in various cancer cell lines and animal xenograft models, and that the drug exhibited significant oral bioavailability and blood-brain barrier penetration. A phase I clinical trial in patients with advanced solid malignancies indicated that XL-184 accumulated dose-dependently in the plasma and had a long terminal half-life. A phase II trial in patients with progressive or recurrent glioblastoma revealed modest but promising median progression-free survival. Toxicity and side effects for the drug have generally been of low-to-moderate severity. At the time of publication, three additional trials of XL-184 were recruiting patients, including a phase I trial in combination with standard of care in patients with glioblastoma, a phase I/II trial in combination with erlotinib in patients with NSCLC, and a phase III trial in patients with medullary thyroid cancer.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Improved Active Harmonic Current Elimination Based on Voltage Detection

    Science.gov (United States)

    Tan, Tianyuan; Dong, Shuan; Huang, Yingwei; Liu, Jian; Le, Jian; Liu, Kaipei

    2016-01-01

    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. PMID:27295213

  18. Attitudes to Improving Speaking Skills by Guided Individual Activities

    Directory of Open Access Journals (Sweden)

    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

  19. Inhibition of NF-κB Pathway and Modulation of MAPK Signaling Pathways in Glioblastoma and Implications for Lovastatin and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL Combination Therapy.

    Directory of Open Access Journals (Sweden)

    Pi Chu Liu

    Full Text Available Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5 in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-κB and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-κB inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.

  20. Inhibition of NF-κB Pathway and Modulation of MAPK Signaling Pathways in Glioblastoma and Implications for Lovastatin and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) Combination Therapy.

    Science.gov (United States)

    Liu, Pi Chu; Lu, Gang; Deng, Yi; Wang, Cheng Dong; Su, Xian Wei; Zhou, Jing Ye; Chan, Tat Ming; Hu, Xiang; Poon, Wai Sang

    2017-01-01

    Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5) in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-κB and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-κB inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.

  1. Improvement of innovative pedagogical activity in modern pedagogical science

    OpenAIRE

    Shamiyeva Aybakhor Ravshanovna; Umurzokov Dilmurod Kholmurodovich

    2015-01-01

    The article deals with the dual nature of pedagogical activities resulting in a new individual and new pedagogical knowledge development. If it is considered from the theory of activity, pedagogical activity is, in essence, innovative activity.

  2. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Post-mortem studies in glioblastoma patients treated with thermotherapy using magnetic nanoparticles.

    Science.gov (United States)

    van Landeghem, Frank K H; Maier-Hauff, K; Jordan, A; Hoffmann, Karl-Titus; Gneveckow, U; Scholz, R; Thiesen, B; Brück, W; von Deimling, A

    2009-01-01

    Patients with glioblastoma multiforme (GBM), the most common primary brain tumor in adults, have still a poor prognosis though new strategies of radio- and chemotherapy have been developed. Recently, our group demonstrated the feasibility, tolerability and anti-tumoral effects of a newly developed therapeutic approach, termed thermotherapy using magnetic nanoparticles or magnetic fluid hyperthermia (MFH), in a murine model of malignant glioma. Currently, the efficacy of MFH is being evaluated in a phase II study. Here, we report on post-mortem neuropathological findings of patients with GBM receiving MFH. In brain autopsies the installed magnetic nanoparticles were dispersed or distributed as aggregates within geographic tumor necroses, restricted in distribution to the sites of instillation. Therefore, our results underscore the need for multiple trajectories of instillation. The typical GBM necrosis with pseudopalisading was free of particles. Dispersed particles and particle aggregates were phagocytosed mainly by macrophages whereas glioblastoma cells showed an uptake to a minor extent. MFH therapy further promotes uptake of nanoparticles in macrophages, likely as a consequence of tumor inherent and therapy induced formation of necrosis with subsequent infiltration and activation of phagocytes. We did not observe bystander effects of MFH such as sarcomatous tumour formation, formation of a sterile abscess or foreign body giant cell reaction. Furthermore, all patients did not present any clinical symptoms related to possible adverse effects of MFH.

  4. Tenascin-C Orchestrates Glioblastoma Angiogenesis by Modulation of Pro- and Anti-angiogenic Signaling.

    Science.gov (United States)

    Rupp, Tristan; Langlois, Benoit; Koczorowska, Maria M; Radwanska, Agata; Sun, Zhen; Hussenet, Thomas; Lefebvre, Olivier; Murdamoothoo, Devadarssen; Arnold, Christiane; Klein, Annick; Biniossek, Martin L; Hyenne, Vincent; Naudin, Elise; Velazquez-Quesada, Ines; Schilling, Oliver; Van Obberghen-Schilling, Ellen; Orend, Gertraud

    2016-12-06

    High expression of the extracellular matrix component tenascin-C in the tumor microenvironment correlates with decreased patient survival. Tenascin-C promotes cancer progression and a disrupted tumor vasculature through an unclear mechanism. Here, we examine the angiomodulatory role of tenascin-C. We find that direct contact of endothelial cells with tenascin-C disrupts actin polymerization, resulting in cytoplasmic retention of the transcriptional coactivator YAP. Tenascin-C also downregulates YAP pro-angiogenic target genes, thus reducing endothelial cell survival, proliferation, and tubulogenesis. Glioblastoma cells exposed to tenascin-C secrete pro-angiogenic factors that promote endothelial cell survival and tubulogenesis. Proteomic analysis of their secretome reveals a signature, including ephrin-B2, that predicts decreased survival of glioma patients. We find that ephrin-B2 is an important pro-angiogenic tenascin-C effector. Thus, we demonstrate dual activities for tenascin-C in glioblastoma angiogenesis and uncover potential targeting and prediction opportunities. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. Monitoring of Radiochemotherapy in Patients with Glioblastoma Using O-(2-[18F]Fluoroethyl-L-Tyrosine Positron Emission Tomography: Is Dynamic Imaging Helpful?

    Directory of Open Access Journals (Sweden)

    Marc D. Piroth

    2013-09-01

    Full Text Available Monitoring of radiochemotherapy (RCX in patients with glioblastoma is difficult because unspecific alterations in magnetic resonance imaging with contrast enhancement can mimic tumor progression. Changes in tumor to brain ratios (TBRs in positron emission tomography (PET using O-(2-[18F]fluoroethyl-L-tyrosine (18F-FET after RCX with temozolomide of patients with glioblastoma have been shown to be valuable parameters to predict survival. The kinetic behavior of 18F-FET in the tumors is another promising parameter to analyze tumor metabolism. In this study, we investigated the predictive value of dynamic 18F-FET PET during RCX of glioblastoma. Time-activity curves (TACs of 18F-FET uptake of 25 patients with glioblastoma were evaluated after surgery (FET-1, early (7–10 days after completion of RCX (FET-2, and 6 to 8 weeks later (FET-3. Changes in the time to peak (TTP and the slope of the TAC (10–50 minutes postinjection were analyzed and related to survival. Changes in kinetic parameters of 18F-FET uptake after RCX showed no relationship with survival time. In contrast, the high predictive value of changes of TBR to predict survival was confirmed. We conclude that dynamic 18F-FET PET does not provide additional prognostic information during RCX. Static 18F-FET PET imaging (20–40 minutes postinjection appears to be sufficient for this purpose and reduces costs.

  6. Cytomorphology of giant cell glioblastoma: Report of a case and brief review of literature.

    Science.gov (United States)

    Jaiswal, Sushila; Vij, Mukul; Jaiswal, Awadhesh Kumar; Srivastava, Arun Kumar; Behari, Sanjay; Pandey, Rakesh

    2012-05-01

    Giant cell glioblastoma is a histological variant of glioblastoma that accounts for less than 1% of intracranial tumors and to 5% of glioblastoma. They occur at any age and are likely to affect the younger as well the older age group unlike the conventional glioblastoma multiforme (GBM). They are often located subcortically in the temporal and parietal lobes. Cytological descriptions of giant cell glioblastoma are extremely rare. We describe squash cytomorphology of giant cell glioblastoma of left posterior frontal region in 35-year-old male. The squash smears were moderately cellular displaying malignant astrocytic tumor cells disposed in cohesive clusters and dispersed population on a necrotic background. Most striking feature was numerous multinucleated giant cells. We also discuss the differential diagnosis in light of relevant literature. Copyright © 2011 Wiley-Liss, Inc.

  7. Negative control of the HGF/c-MET pathway by TGF-β: a new look at the regulation of stemness in glioblastoma.

    Science.gov (United States)

    Papa, Eleanna; Weller, Michael; Weiss, Tobias; Ventura, Elisa; Burghardt, Isabel; Szabó, Emese

    2017-12-13

    Multiple target inhibition has gained considerable interest in combating drug resistance in glioblastoma, however, understanding the molecular mechanisms of crosstalk between signaling pathways and predicting responses of cancer cells to targeted interventions has remained challenging. Despite the significant role attributed to transforming growth factor (TGF)-β family and hepatocyte growth factor (HGF)/c-MET signaling in glioblastoma pathogenesis, their functional interactions have not been well characterized. Using genetic and pharmacological approaches to stimulate or antagonize the TGF-β pathway in human glioma-initiating cells (GIC), we observed that TGF-β exerts an inhibitory effect on c-MET phosphorylation. Inhibition of either mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway attenuated this effect. A comparison of c-MET-driven and c-MET independent GIC models revealed that TGF-β inhibits stemness in GIC at least in part via its negative regulation of c-MET activity, suggesting that stem cell (SC) maintenance may be controlled by the balance between these two oncogenic pathways. Importantly, immunohistochemical analyses of human glioblastoma and ex vivo single-cell gene expression profiling of TGF-β and HGF confirm the negative interaction between both pathways. These novel insights into the crosstalk of two major pathogenic pathways in glioblastoma may explain some of the disappointing results when targeting either pathway alone in human glioblastoma patients and inform on potential future designs on targeted pharmacological or genetic intervention.

  8. Psychometric analyses to improve the Dutch ICF Activity Inventory.

    Science.gov (United States)

    Bruijning, Janna E; van Rens, Ger; Knol, Dirk; van Nispen, Ruth

    2013-08-01

    In the past, rehabilitation centers for the visually impaired used unstructured or semistructured methods to assess rehabilitation needs of their patients. Recently, an extensive instrument, the Dutch ICF Activity Inventory (D-AI), was developed to systematically investigate rehabilitation needs of visually impaired adults and to evaluate rehabilitation outcomes. The purpose of this study was to investigate the underlying factor structure and other psychometric properties to shorten and improve the D-AI. The D-AI was administered to 241 visually impaired persons who recently enrolled in a multidisciplinary rehabilitation center. The D-AI uses graded scores to assess the importance and difficulty of 65 rehabilitation goals. For high-priority goals (e.g., daily meal preparation), the difficulty of underlying tasks (e.g., read recipes, cut vegetables) was assessed. To reduce underlying task items (>950), descriptive statistics were investigated and factor analyses were performed for several goals. The internal consistency reliability and test-retest reliability of the D-AI were investigated by calculating Cronbach α and Cohen (weighted) κ. Finally, consensus-based discussions were used to shorten and improve the D-AI. Except for one goal, factor analysis model parameters were at least reasonable. Internal consistency reliability was satisfactory (range, 0.74 to 0.93). In total, 60% of the 65 goal importance items and 84.4% of the goal difficulty items showed moderate to almost perfect κ values (≥0.40). After consensus-based discussions, a new D-AI was produced, containing 48 goals and less than 500 tasks. The analyses were an important step in the validation process of the D-AI and to develop a more feasible assessment tool to investigate rehabilitation needs of visually impaired persons in a systematic way. The D-AI is currently implemented in all Dutch rehabilitation centers serving all visually impaired adults with various rehabilitation needs.

  9. Realizing the therapeutic potential of rare earth elements in designing nanoparticles to target and treat glioblastoma.

    Science.gov (United States)

    Lu, Victor M; McDonald, Kerrie L; Townley, Helen E

    2017-10-01

    The prognosis of brain cancer glioblastoma (GBM) is poor, and despite intense research, there have been no significant improvements within the last decade. This stasis implicates the need for more novel therapeutic investigation. One such option is the use of nanoparticles (NPs), which can be beneficial due to their ability to penetrate the brain, overcome the blood-brain barrier and take advantage of the enhanced permeation and retention effect of GBM to improve specificity. Rare earth elements possess a number of interesting natural properties due to their unique electronic configuration, which may prove therapeutically advantageous in an NP formulation. The underexplored exciting potential for rare earth elements to augment the therapeutic potential of NPs in GBM treatment is discussed in this review.

  10. Bioaugmentation to improve nitrification in activated sludge treatment.

    Science.gov (United States)

    Leu, Shao-Yuan; Stenstrom, Michael K

    2010-06-01

    Bioaugmentation is a proposed technique to improve nutrient removal in municipal wastewater treatment. Compared with commonly used nitrification/denitrification (NDN) processes, bioaugmentation may be able to reduce tankage or land requirements. Many approaches for bioaugmentation have been developed, but few studies have compared the benefits among different approaches. This paper quantifies the effectiveness of bioaugmentation processes and investigates three major "onsite" bioaugmentation alternatives: 1) the parallel-plants approach, which uses acclimated biomass grown in a nitrifying "long-SRT" (sludge retention time) plant to augment a low-SRT treatment plant; 2) the enricher-reactor approach, which uses an offline reactor to produce the augmentation cultures; and 3) the enricher-reactor/return activated sludge (ER-RAS) approach, which grows enrichment culture in a reaeration reactor that receives a portion of the recycle activated sludge. Kinetic models were developed to simulate each approach, and the benefits of various approaches are presented on the same basis with controllable parameters, such as bioaugmentation levels, aeration tank volume, and temperatures. Examples were given to illustrate the potential benefits of bioaugmentation by upgrading a "carbon-only" wastewater treatment plant to nitrification. Simulation results suggested that all bioaugmentation approaches can decrease the minimum SRT for nitrification. The parallel-plants approach creates the highest concentration of biomass but may fail at too low temperature. The ER-RAS approach likely would be more useful at lower temperature and required less reactor volume; enricher-reactor approach would likely be more advantageous in the presence of inhibitory compound(s).

  11. 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).

  12. Malignant melanoma mimicking giant cell variant of glioblastoma multiforme: A case report and review of literature

    OpenAIRE

    Arcega, R; Yong, WH; Xu, H

    2015-01-01

    We present a case of metastatic malignant melanoma in a patient initially diagnosed with glioblastoma multiforme, giant cell variant. A forty year old female presented to our institution for a re-resection of a recurrent right parietal lobe mass, presumed to be recurrent glioblastoma multiforme. PET scan during preoperative evaluation revealed a 3 cm left lower lobe lung mass. Metastatic glioblastoma to lung was considered in the differential diagnosis. Resection of the brain mass revealed a ...

  13. Physical activity interventions to improve daily walking activity in cancer survivors

    Directory of Open Access Journals (Sweden)

    Uebelhart Daniel

    2010-08-01

    Full Text Available Abstract Background Cancer patients may benefit from physical exercise programs. It is unclear, however, how sustained levels of physical activity are best achieved in this population. A systematic review was performed to summarize the current evidence of the effect of physical activity interventions on daily walking activity enhancement in cancer survivors, and to review the literature for its methodological quality. Methods A search in Medline, PEDro and the Cochrane databases was performed for English literature citations (randomized controlled trials; 'RCTs'. In a first step, one reviewer abstracted data from the included studies on patients, physical activity interventions and outcomes. Two independent reviewers reviewed the methodological quality of these studies. Data were pooled using random-effects calculations. Results Our search identified 201 citations. Five RCTs that reported changes in daily step activity over time were identified, and were reviewed for methodological quality and substantive results. The median score across studies for methodological quality based on the PEDro criteria was 8. These 5 RCTs evaluated 660 participants with a mean age of 53.6 (SD 4.2 years. The mean change in daily step activity for patients with a physical exercise intervention was 526 daily steps (SD 537, with a range from -92 to 1299 daily steps. The data of three studies reporting the effect of combined physical activity and counseling on daily walking activity in breast cancer survivors were pooled, however; the I2 was 79%, indicating statistical heterogeneity between the three trials. Conclusion The 5 RCTs reviewed were of good methodological quality. Together they suggest that combined physical activity and counseling improves daily step activity in (breast cancer survivors. Studies that define a step goal appear to be more effective in improving daily walking activity than studies that do not do so. However, the current results should be

  14. Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial.

    Science.gov (United States)

    Beije, N; Kraan, J; Taal, W; van der Holt, B; Oosterkamp, H M; Walenkamp, A M; Beerepoot, L; Hanse, M; van Linde, M E; Otten, A; Vernhout, R M; de Vos, F Y F; Gratama, J W; Sleijfer, S; van den Bent, M J

    2015-07-14

    Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma. In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated. The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log₁₀CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log₁₀CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS. CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.

  15. Using RF Smart Points for the Improvement of Metrological Activities

    Directory of Open Access Journals (Sweden)

    Claudio de Capua

    2007-03-01

    Full Text Available This work describes the realization of a “radio-frequency identification system” for the improvement of the activities of a metrological laboratory. Some radio-frequency modules, called by the authors RF Smart Points (“radio-frequency smart points”, have been designed to store into their memories all data which are necessary for the instruments tracking (the type of instruments, their identification numbers or serial numbers, the manufacturer, the date when they have been admitted to the installed base of the laboratory, their working state, the elapsed time from the last calibration procedure. The insertion of the data and the inquiry of the instruments are executed by the technical staff of the laboratory through a PDA (Personal Digital Assistant or a PC, which manage the radio-frequency communication by using the RS 232 interface for sending messages to a RF Transceiver. The executable software for managing the communication between the Smart Points and the “PDA/PC-Controllers” is realized in LabVIEW graphical programming environment.

  16. Glioblastoma in neurofibromatosis 1 patients without IDH1, BRAF V600E, and TERT promoter mutations.

    Science.gov (United States)

    Shibahara, Ichiyo; Sonoda, Yukihiko; Suzuki, Hiroyoshi; Mayama, Akifumi; Kanamori, Masayuki; Saito, Ryuta; Suzuki, Yasuhiro; Mashiyama, Shoji; Uenohara, Hiroshi; Watanabe, Mika; Kumabe, Toshihiro; Tominaga, Teiji

    2017-11-14

    Pilocytic astrocytomas and low-grade gliomas are more common compared with glioblastomas in patients with neurofibromatosis 1 (NF1). A recent genome-wide analysis has shown frequent NF1 gene alterations in the mesenchymal subtype of a glioblastoma; however, little is known about clinicopathological features of glioblastomas in NF1 patients (NF1 glioblastomas). We analyzed four NF1 glioblastomas. Radiographical and intraoperative findings showed well-circumscribed tumors from surrounding brain. Pathological analysis presented a paucity of processes with an eosinophilic cytoplasm, bizarre nuclei, xanthomatous-like appearance, multinucleated giant cells, and histiocytoid appearance. During the follow-up period, one patient died at 49 months and others remained alive for 60, 87, and 106 months; thus, patients with NF1 glioblastoma presented a relatively favorable survival. None of the NF1 glioblastomas harbored isocitrate dehydrogenase 1 (IDH1) gene mutation, v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene mutation, and telomerase reverse transcriptase (TERT) gene promoter mutation. We identified that NF1 glioblastoma is a unique subset of glioblastoma.

  17. Serum alpha 2-HS glycoprotein predicts survival in patients with glioblastoma.

    Science.gov (United States)

    Petrik, Vladimir; Saadoun, Samira; Loosemore, Alison; Hobbs, Josie; Opstad, Kirstie S; Sheldon, Joanna; Tarelli, Edward; Howe, Franklyn A; Bell, B Anthony; Papadopoulos, Marios C

    2008-04-01

    Glioblastoma, the most common primary brain tumor, has variable prognosis. We aimed to identify serum biomarkers that predict survival of patients with glioblastoma. In phase 1 (biomarker discovery), SELDI-TOF mass spectra were studied in 200 serum samples from 58 control subjects and 36 patients with grade II astrocytoma, 15 with anaplastic astrocytoma, and 91 with glioblastoma. To identify potential biomarkers, we searched for peptide peaks that changed progressively in size with increasing malignancy. One peak, identified as the B-chain of alpha 2-Heremans-Schmid glycoprotein (AHSG), was less prominent with increasing tumor grade. We therefore investigated AHSG as a survival predictor in glioblastoma. We measured serum AHSG by turbidimetry and determined indices of malignancy, including tumor proliferation (Ki67 immunolabel) and necrosis (tumor lipids on magnetic resonance spectroscopy). In phase 2 (biomarker validation), the prognostic power of AHSG was validated in an independent group of 72 glioblastoma patients. Median survival was longer (51 vs 29 weeks) in glioblastoma patients with normal vs low serum AHSG concentrations (hazard ratio 2.7, 95% CI 1.5-5.0, P AHSG inversely correlated with Ki-67 immunolabeling and tumor lipids. A prognostic index combining serum AHSG with patient age and Karnofsky score separated glioblastoma patients with short (2 years) median survival. The prognostic value of serum AHSG was validated in a different cohort of glioblastoma patients. We conclude that serum AHSG concentration, measured before starting treatment, predicts survival in patients with glioblastoma.

  18. 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.

  19. 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.

  20. Rapid progression of gliomatosis cerebri to secondary glioblastoma, factors that affects the progression rate: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hee Kyung; Yu, In Kyu; Kim, Seung Min; Kim, Joo Heon; Lee, Seung Hoon; Lee, Seung Yeon [Eulji University Hospital, Daejeon (Korea, Republic of)

    2017-03-15

    Glioblastomas may develop de novo or through progression from low-grade or anaplastic astrocytomas. The term 'primary glioblastoma' refers to a glioblastoma that lacks a precursor lesion and has a clinical history of less than three months. On the other hand, the term 'secondary glioblastoma' indicates that the glioblastoma has progressed from a low-grade tumor after a long latency period and often manifests in younger patients. These subtypes of glioblastoma develop via different genetic pathways, and they differ in prognosis and response to therapy. Thus, differential diagnosis of these subtypes and prediction of the factors that affect the progression from low-grade diffuse astrocytoma to secondary glioblastoma would be clinically very important. We present a rare case of secondary glioblastoma, which developed only three months after the follow up imaging evaluations, with a history of low grade glioma, and present the factors that cause rapid progression.

  1. Advanced case of glioblastoma multiforme and pregnancy. An ethical dilemma.

    Science.gov (United States)

    Al-Rasheedy, Intisar M; Al-Hameed, Fahad M

    2015-10-01

    Glioblastoma multiforme (GBM) is the most common and malignant form of the glial tumors. Advanced and treated GBM is rarely associated with pregnancy for many reasons. Glioblastoma multiforme presenting during pregnancy carries unique challenges to the patient, baby, family, and health care providers. We describe an unusual case of advanced GBM that was treated with maximum doses of chemotherapy and radiations, and she became pregnant and presented at eighteenth weeks of gestation. Her medical management was associated with a significant ethical dilemma. We managed to deliver the baby safely through cesarean section at week 28 despite the critical condition of the mother. Unfortunately, the mother died 2 weeks post delivery. We concluded that although recurrent and treated GBM is rarely associated with pregnancy and carries dismal prognosis, but if it occurs, it can still be carried, and a multidisciplinary team work is the key for successful outcome.

  2. Improving synthetic efficiency using the computational prediction of biological activity.

    Science.gov (United States)

    Broglé, K C; Gund, T; Kyle, D J

    2006-02-01

    A process has been developed whereby libraries of compounds for lead optimization can be synthesized and screened with greater efficiency using computational tools. In this method, analogues of a lead chemical structure are considered in the form of a virtual library. Less than 1/3 of the library is selected as a training set by clustering the compounds and choosing the centroid of each cluster. This training set is then used to generate a model using PLS regression upon the experimental values from that assay using 1D/2D descriptors. The model is applied to the remaining compounds (the test set) for which assay values are predicted and a rank ordering established. An example of this was a set of 169 PDE4 inhibitors. A predictive model was achieved using a training set of 52 compounds. When applied to the remaining 117 compounds this model allowed a rank ordering of these compounds for synthesis and testing. Selecting the top 33 compounds of the test set gives 78% of the compounds with the desired activity (hits) by synthesizing only 50% of the library, including the training set. Selecting the top 59 of the test set gives 97% of the hits from only 67% of the library. This process succeeds by avoiding two principal weaknesses of 2D descriptors: lack of interpretation and lack of extrapolation. Two principal assumptions of QSAR are shown to be unnecessary; removing descriptor redundancy does not improve fit and a predictive r2 greater than 0.5 is not necessary if rank-ordering is desired.

  3. Indirect costs associated with glioblastoma: Experience at one hospital.

    Science.gov (United States)

    Undabeitia, J; Torres-Bayona, S; Samprón, N; Arrázola, M; Bollar, A; Armendariz, M; Torres, P; Ruiz, I; Caballero, M C; Egaña, L; Querejeta, A; Villanua, J; Pardo, E; Etxegoien, I; Liceaga, G; Urtasun, M; Michan, M; Emparanza, J I; Aldaz, P; Matheu, A; Úrculo, E

    2016-07-20

    Glioblastoma is the most common primary brain tumour. Despite advances in treatment, its prognosis remains dismal, with a mean survival time of about 14 months. Many articles have addressed direct costs, those associated with the diagnosis and treatment of the disease. Indirect costs, those associated with loss of productivity due to the disease, have seldom been described. We conducted a retrospective study in patients diagnosed with glioblastoma at Hospital Universitario Donostia between January 1, 2010 and December 31, 2013. We collected demographics, data regarding the treatment received, and survival times. We calculated the indirect costs with the human capital approach, adjusting the mean salaries of comparable individuals by sex and age and obtaining mortality data for the general population from the Spanish National Statistics Institute. Past salaries were updated to 2015 euros according to the annual inflation rate and we applied a discount of 3.5% compounded yearly to future salaries. We reviewed the records of 99 patients: 46 women (mean age 63.53) and 53 men (mean age 59.94); 29 patients underwent a biopsy and the remaining 70 underwent excisional surgery. Mean survival was 18.092 months for the whole series. The total indirect cost for the series was €11 080 762 (2015). Mean indirect cost per patient was €111 926 (2015). Although glioblastoma is a relatively uncommon type of tumour, accounting for only 4% of all cancers, its poor prognosis and potential sequelae generate disproportionately large morbidity and mortality rates which translate to high indirect costs. Clinicians should be aware of the societal impact of glioblastoma and indirect costs should be taken into account when cost effectiveness studies are performed to better illustrate the overall consequences of this disease. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Cerebellar giant cell glioblastoma multiforme in an adult

    OpenAIRE

    Sudhansu Sekhar Mishra; Sanjay Kumar Behera; Manmath Kumar Dhir; Satya Bhusan Senapati

    2014-01-01

    Cerebellar glioblastoma multiforme (GBM) is a rare tumor that accounts for only 1% of all cases of GBM and its giant cell variant is even much rarely encountered in adults. A case of cerebellar giant cell GBM managed at our institution reporting its clinical presentation, radiological and histological findings, and treatment instituted is described. In conjunction, a literature review, including particular issues, clinical data, advances in imaging studies, pathological characteristics, treat...

  5. Genetic Characteristics of Glioblastoma: Clinical Implications of Heterogeneity

    Directory of Open Access Journals (Sweden)

    Qian Li

    2015-01-01

    Full Text Available Glioblastoma multiforme (GBM is a heterogeneous group of tumors, each with its own distinct molecular and genetic signatures. This heterogeneity is a major clinical hurdle for classifying tumors and for devising effective personalized therapies targeting the disease pathways. Herein, the primary genetic and epigenetic alterations in GBM that have been used as therapeutic targets in clinical settings nowadays, with or without clinical benefits for patients, as well as the future directions for developing novel strategies were discussed.

  6. A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced delivery of carboplatin for recurrent glioblastoma.

    Science.gov (United States)

    Barua, Neil U; Hopkins, Kirsten; Woolley, Max; O'Sullivan, Stephen; Harrison, Rob; Edwards, Richard J; Bienemann, Alison S; Wyatt, Marcella J; Arshad, Azeem; Gill, Steven S

    2016-01-01

    Inadequate penetration of the blood-brain barrier (BBB) by systemically administered chemotherapies including carboplatin is implicated in their failure to improve prognosis for patients with glioblastoma. Convection-enhanced delivery (CED) of carboplatin has the potential to improve outcomes by facilitating bypass of the BBB. We report the first use of an implantable CED system incorporating a novel transcutaneous bone-anchored port (TBAP) for intermittent CED of carboplatin in a patient with recurrent glioblastoma. The CED catheter system was implanted using a robot-assisted surgical method. Catheter targeting accuracy was verified by performing intra-operative O-arm imaging. The TBAP was implanted using a skin-flap dermatome technique modeled on bone-anchored hearing aid surgery. Repeated infusions were performed by attaching a needle administration set to the TBAP. Drug distribution was monitored with serial real-time T2-weighted magnetic resonance imaging (MRI). All catheters were implanted to within 1.5 mm of their planned target. Intermittent infusions of carboplatin were performed on three consecutive days and repeated after one month without the need for further surgical intervention. Infused volumes of 27.9 ml per day were well tolerated, with the exception of a single seizure episode. Follow-up MRI at eight weeks demonstrated a significant reduction in the volume of tumor enhancement from 42.6 ml to 24.6 ml, and was associated with stability of the patient's clinical condition. Reduction in the volume of tumor enhancement indicates that intermittent CED of carboplatin has the potential to improve outcomes in glioblastoma. The novel technology described in this report make intermittent CED infusion regimes an achievable treatment strategy.

  7. Adult classical glioblastoma with a BRAF V600E mutation.

    Science.gov (United States)

    Takahashi, Yoshinobu; Akahane, Toshiaki; Sawada, Takahiro; Ikeda, Hidetoshi; Tempaku, Akira; Yamauchi, Shigeru; Nishihara, Hiroshi; Tanaka, Shinya; Nitta, Kazumi; Ide, Wataru; Hashimoto, Ikuo; Kamada, Hajime

    2015-03-11

    The B-Raf proto-oncogene serine/threonine kinase (B-Raf) is a member of the Raf kinase family. The BRAF V600E mutation occurs frequently in certain brain tumors such as pleomorphic xanthoastrocytoma, ganglioglioma, and pilocytic astrocytoma, and less frequently in epithelioid and giant cell glioblastoma. BRAF V600E mutation in these cases has been canonically detected using Sanger sequencing or immunohistochemistry but not with next-generation sequencing (NGS). Moreover, to our knowledge, there is no detailed report of the BRAF V600E mutation in an adult glioblastoma with classical histologic features (c-GBM). Therefore, we performed NGS analysis to determine the mutational status of BRAF of 13 glioblastomas (GBMs) (11 primary and 2 secondary cases) and detected one tumor harboring the BRAF V600E mutation. We report here the detection of the BRAF V600E mutation in a patient with c-GBM and describe the patient's clinical course as well as the results of histopathological analysis.

  8. CAR-T cell Therapies in Glioblastoma: a first look.

    Science.gov (United States)

    Migliorini, Denis; Dietrich, Pierre-Yves; Stupp, Roger; Linette, Gerald P; Posey, Avery D; June, Carl H

    2017-11-20

    Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, immunosuppressive microenvironment and partially permissive anatomical blood brain barrier (BBB). Results from three first-in-man CAR-T cell trials targeting IL13Rα2, Her2/CMV and EGFRvIII have recently been reported. Each one of these trials addresses important questions, such as T cell trafficking to CNS, engraftment and persistence, tumor microenvironment (TME) remodeling, and monitoring of glioma response to chimeric antigen receptor (CAR) T cells. Objective radiological responses have been reported. Here, we discuss and summarize the results of these trials and suggest opportunities for the field. Copyright ©2017, American Association for Cancer Research.

  9. Comorbidity assessment and adjuvant radiochemotherapy in elderly affected by glioblastoma.

    Science.gov (United States)

    Fiorentino, Alba; Caivano, Rocchina; Chiumento, Costanza; Cozzolino, Mariella; Clemente, Stefania; Pedicini, Piernicola; Fusco, Vincenzo

    2012-12-01

    To assess the role of comorbidity on outcome in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant Temozolomide, patients over 65 years with glioblastoma, who underwent surgical resection or biopsy and radiochemotherapy, were evaluated. The Adjusted-Age Charlson Comorbidity Index and the Adult Comorbidity Evaluation-27 were used to assess comorbidity. From April 2005 to January 2011, 35 patients (median age 72 years) were treated in our Institution. Thirteen patients had a Charlson score more than 3, while, according to the Adult Comorbidity Evaluation-27, 21 patients had mild or severe comorbid conditions. Patients with low Charlson comorbidity score experienced a longer survival time than those with higher score (22 vs. 10 months, respectively). The Adjusted-Age Charlson Comorbidity Index influenced survival at univariate and multivariate analysis (p = 0.004, p = 0.001, respectively). No comorbidity index was a predictor for progression-free survival. Our data suggested that the association of radiotherapy with TMZ was safe and effective. Perhaps, the comorbidity assessment could be an appropriate tool in the treatment decision for elderly patients with glioblastoma.

  10. 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.; Woude, Luc H.V.; van Harten, Willem H.; Vollenbroek-Hutten, Miriam Marie Rosé; van Mechelen, 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

  11. Underlying mechanisms of improving physical activity behavior after rehabilitation

    NARCIS (Netherlands)

    van der Ploeg, H.P.; Streppel, K.R.; van der Beek, A.J.; van der Woude, L.H.V.; van Harten, W.H.; van Mechelen, W.

    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

  12. Improving activities of daily living ability in women with fibromyalgia

    DEFF Research Database (Denmark)

    von Bülow, Cecilie; Amris, Kirstine; Bandak, Elisabeth

    2017-01-01

    OBJECTIVE: To explore and compare the outcomes of adaptation and physical activity programmes regarding activities of daily living (ADL) ability following interdisciplinary rehabilitation in women with fibromyalgia. METHODS: Participants (n = 85) were quasi-randomized to 16-week adaptation (ADAPT...

  13. Protective properties of radio-chemoresistant glioblastoma stem cell clones are associated with metabolic adaptation to reduced glucose dependence.

    Directory of Open Access Journals (Sweden)

    Fei Ye

    Full Text Available Glioblastoma stem cells (GSC are a significant cell model for explaining brain tumor recurrence. However, mechanisms underlying their radiochemoresistance remain obscure. Here we show that most clonogenic cells in GSC cultures are sensitive to radiation treatment (RT with or without temozolomide (TMZ. Only a few single cells survive treatment and regain their self-repopulating capacity. Cells re-populated from treatment-resistant GSC clones contain more clonogenic cells compared to those grown from treatment-sensitive GSC clones, and repeated treatment cycles rapidly enriched clonogenic survival. When compared to sensitive clones, resistant clones exhibited slower tumor development in animals. Upregulated genes identified in resistant clones via comparative expression microarray analysis characterized cells under metabolic stress, including blocked glucose uptake, impaired insulin/Akt signaling, enhanced lipid catabolism and oxidative stress, and suppressed growth and inflammation. Moreover, many upregulated genes highlighted maintenance and repair activities, including detoxifying lipid peroxidation products, activating lysosomal autophagy/ubiquitin-proteasome pathways, and enhancing telomere maintenance and DNA repair, closely resembling the anti-aging effects of caloric/glucose restriction (CR/GR, a nutritional intervention that is known to increase lifespan and stress resistance in model organisms. Although treatment-introduced genetic mutations were detected in resistant clones, all resistant and sensitive clones were subclassified to either proneural (PN or mesenchymal (MES glioblastoma subtype based on their expression profiles. Functional assays demonstrated the association of treatment resistance with energy stress, including reduced glucose uptake, fatty acid oxidation (FAO-dependent ATP maintenance, elevated reactive oxygen species (ROS production and autophagic activity, and increased AMPK activity and NAD(+ levels accompanied by

  14. Suppression of TDO-mediated tryptophan catabolism in glioblastoma cells by a steroid-responsive FKBP52-dependent pathway.

    Science.gov (United States)

    Ott, Martina; Litzenburger, Ulrike M; Rauschenbach, Katharina J; Bunse, Lukas; Ochs, Katharina; Sahm, Felix; Pusch, Stefan; Opitz, Christiane A; Blaes, Jonas; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael

    2015-01-01

    Tryptophan catabolism is increasingly recognized as a key and druggable molecular mechanism active in cancer, immune, and glioneural cells and involved in the modulation of antitumor immunity, autoimmunity and glioneural function. In addition to the pivotal rate limiting enzyme indoleamine-2,3-dioxygenase, expression of tryptophan-2,3-dioxygenase (TDO) has recently been described as an alternative pathway responsible for constitutive tryptophan degradation in malignant gliomas and other types of cancer. In addition, TDO has been implicated as a key regulator of neurotoxicity involved in neurodegenerative diseases and ageing. The pathways regulating TDO expression, however, are largely unknown. Here, a siRNA-based transcription factor profiling in human glioblastoma cells revealed that the expression of human TDO is suppressed by endogenous glucocorticoid signaling. Similarly, treatment of glioblastoma cells with the synthetic glucocorticoid dexamethasone led to a reduction of TDO expression and activity in vitro and in vivo. TDO inhibition was dependent on the immunophilin FKBP52, whose FK1 domain physically interacted with the glucocorticoid receptor as demonstrated by bimolecular fluorescence complementation and in situ proximity ligation assays. Accordingly, gene expression profile analyses revealed negative correlation of FKBP52 and TDO in glial and neural tumors and in normal brain. Knockdown of FKBP52 and treatment with the FK-binding immunosuppressant FK506 enhanced TDO expression and activity in glioblastoma cells. In summary, we identify a novel steroid-responsive FKBP52-dependent pathway suppressing the expression and activity of TDO, a central and rate-limiting enzyme in tryptophan metabolism, in human gliomas. © 2014 Wiley Periodicals, Inc.

  15. ICT-mediated community coaching to improve physical activity

    NARCIS (Netherlands)

    Elloumi, Lamia; Meijerink, Margot; van Beijnum, Bernhard J.F.; Hermens, Hermanus J.; Gilbert, J.; Azhari, H.; Ali, H.; Quintão, C.; Sliwa, J.; Ruiz, C.; Fred, A.; Gamboa, H.

    It is commonly known that physical activity is important to maintain health and prevent diseases. Many physical activity interventions have been developed to motivate people to be more physically active. Existing ICT-based interventions provide system-to-human feedback as a motivational strategy to

  16. Improved Antitumoral Activity of Extracts Derived from Cultured ...

    African Journals Online (AJOL)

    Antiproliferative activity was assayed in four cancer cell lines (Hep-2, HeLa, SiHa, and KB) while cytotoxic activity was evaluated on a normal cell line (MDCK). Results: The 10-day cultivation organic extract exhibited increased antiproliferative activity compared with the control on human carcinoma nasopharynx (KB) and ...

  17. Giant cells glioblastoma: case report and pathological analysis from this uncommon subtype of glioma.

    Science.gov (United States)

    Belsuzarri, Telmo A B; Araujo, João F M; Catanoce, Aguinaldo P; Neves, Maick W F; Sola, Rodrigo A S; Navarro, Juliano N; Brito, Leandro G; Silva, Nilton R; Pontelli, Luis Otavio C; Mattos, Luiz Gustavo A; Gonçales, Tiago F; Zeviani, Wolnei M; Marques, Renata M B

    2015-02-11

    Glioblastoma multiforme (GBM) is the most common glial tumor of the brain system; nevertheless, the giant cell (GC) subtype is uncommon. Recent reviews report for an incidence of 1% in adults and 3% in children. The GCs usually have a better prognosis than GBM and also an increasing long-term survival rate. It is known that the diagnosis of this tumor is due to its histological findings and patterns, such as the unusual increased number of giant cells. Unfortunately, due to its rarity, the immunohistochemical and cytogenetical analysis of this tumor is not well known. Some authors also suggest that there are few subtypes of GCs and their patterns of aggressiveness could be due to cytogenetical markers. It is recognized that maximum safe resection treatment and adjuvant radiotherapy can improve survival rate (5-13 months) similar to GBM patients.

  18. Giant cells glioblastoma: case report and pathological analysis from this uncommon subtype of glioma

    Directory of Open Access Journals (Sweden)

    Telmo A.B. Belsuzarri

    2015-03-01

    Full Text Available Glioblastoma multiforme (GBM is the most common glial tumor of the brain system; nevertheless, the giant cell (GC subtype is uncommon. Recent reviews report for an incidence of 1% in adults and 3% in children. The GCs usually have a better prognosis than GBM and also an increasing long-term survival rate. It is known that the diagnosis of this tumor is due to its histological findings and patterns, such as the unusual increased number of giant cells. Unfortunately, due to its rarity, the immunohistochemical and cytogenetical analysis of this tumor is not well known. Some authors also suggest that there are few subtypes of GCs and their patterns of aggressiveness could be due to cytogenetical markers. It is recognized that maximum safe resection treatment and adjuvant radiotherapy can improve survival rate (5-13 months similar to GBM patients.

  19. 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.

  20. Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas

    NARCIS (Netherlands)

    Kaaijk, P.; Troost, D.; Sminia, P.; Hulshof, M. C.; van der Kracht, A. H.; Leenstra, S.; Bosch, D. A.

    1997-01-01

    The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the

  1. 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

  2. Physical activity stimulation program for children with cerebral palsy did not improve physical activity: a randomised trial

    NARCIS (Netherlands)

    van Wely, L.; Balemans, A.C.J.; Becher, J.G.; Dallmeijer, A.J.

    2014-01-01

    Question: In children with cerebral palsy, does a 6-month physical activity stimulation program improve physical activity, mobility capacity, fitness, fatigue and attitude towards sports more than usual paediatric physiotherapy? Design: Multicentre randomised controlled trial with concealed

  3. 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

    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

  4. Survival outcomes of giant cell glioblastoma: institutional experience in the management of 20 patients.

    Science.gov (United States)

    Oh, Taemin; Rutkowski, Martin J; Safaee, Michael; Sun, Matthew Z; Sayegh, Eli T; Bloch, Orin; Tihan, Tarik; Parsa, Andrew T

    2014-12-01

    Giant cell glioblastoma (GCG) is a rare subtype of glioblastoma (GBM) that is believed to carry an improved prognosis. However, given the rarity of this tumor, best management practices for GCG have yet to be ascertained. Here, we present our experience in managing GCG tumors at the University of California, San Francisco. Patients were retrospectively identified through chart review, and data pertaining to patient demographics, treatment plans, and follow-up were extracted from existing medical records. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints, respectively. In sum, we identified 22 patients who were managed or followed for GCG. Most patients (78%) initially underwent subtotal resection as primary treatment for their tumor, and most also received post-operative adjuvant therapy (90%), with radiation being the most frequently administered modality (85%). Within this institutional cohort, median OS and PFS were 15.4 months and 5.7 months, respectively. On multivariate survival analysis, age (p=0.84), sex (p=0.05), and adjuvant radiation plus temozolomide (p=0.12) were not associated with prolonged OS. However, adjuvant radiation plus temozolomide was associated with longer PFS (p=0.01), and patients receiving this therapy demonstrated a median PFS of 32.9 months versus 13.1 months. These findings confirm the comparatively improved prognosis of GCG over GBM. Moreover, they suggest that extent of resection may not significantly delay recurrence or extend survival, and that combination radiation with temozolomide may represent the optimum adjuvant paradigm to delay tumor progression. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. 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.

  6. Human glioblastoma-associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples.

    Science.gov (United States)

    Szulzewsky, Frank; Arora, Sonali; de Witte, Lot; Ulas, Thomas; Markovic, Darko; Schultze, Joachim L; Holland, Eric C; Synowitz, Michael; Wolf, Susanne A; Kettenmann, Helmut

    2016-08-01

    Glioblastoma (GBM) is the most aggressive brain tumor in adults. It is strongly infiltrated by microglia and peripheral monocytes that support tumor growth. In the present study we used RNA sequencing to compare the expression profile of CD11b(+) human glioblastoma-associated microglia/monocytes (hGAMs) to CD11b(+) microglia isolated from non-tumor samples. Hierarchical clustering and principal component analysis showed a clear separation of the two sample groups and we identified 334 significantly regulated genes in hGAMs. In comparison to human control microglia hGAMs upregulated genes associated with mitotic cell cycle, cell migration, cell adhesion, and extracellular matrix organization. We validated the expression of several genes associated with extracellular matrix organization in samples of human control microglia, hGAMs, and the hGAMs-depleted fraction via qPCR. The comparison to murine GAMs (mGAMs) showed that both cell populations share a significant fraction of upregulated transcripts compared with their respective controls. These genes were mostly related to mitotic cell cycle. However, in contrast to murine cells, human GAMs did not upregulate genes associated to immune activation. Comparison of human and murine GAMs expression data to several data sets of in vitro-activated human macrophages and murine microglia showed that, in contrast to mGAMs, hGAMs share a smaller overlap to these data sets in general and in particular to cells activated by proinflammatory stimulation with LPS + INFγ or TNFα. Our findings provide new insights into the biology of human glioblastoma-associated microglia/monocytes and give detailed information about the validity of murine experimental models. GLIA 2016 GLIA 2016;64:1416-1436. © 2016 Wiley Periodicals, Inc.

  7. 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

    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 NanoString...

  8. Glioblastoma following radiotherapy in a patient with tuberous sclerosis. Case report

    Energy Technology Data Exchange (ETDEWEB)

    Matsumura, Hirotaka; Takimoto, Hiroshi; Shimada, Nobumitsu; Hirata, Masayuki [Suita Municipal Hospital, Osaka (Japan); Ohnishi, Takanori; Hayakawa, Toru

    1998-05-01

    A 26-year-old male with tuberous sclerosis developed a glioblastoma in the right temporal lobe 8 years after surgical excision and irradiation of a subependymal giant cell astrocytoma. The glioblastoma was probably an irradiation-induced tumor. Irradiation should not be given routinely for subependymal giant cell astrocytoma. (author)

  9. Glioblastoma de células gigantes en puente de Varolio

    OpenAIRE

    Iglesias Rozas, José Rafael, 1942-

    1985-01-01

    Once imágenes de un glioblastoma de células gigantes situado en el puente de Varolio en un paciente de 4 años. Eleven pictures of a giant cell glioblastoma located in the pons of a 4-year-old male patient.

  10. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

    NARCIS (Netherlands)

    Bender, Sebastian; Gronych, Jan; Warnatz, Hans-Jörg; Hutter, Barbara; Gröbner, Susanne; Ryzhova, Marina; Pfaff, Elke; Hovestadt, Volker; Weinberg, Florian; Halbach, Sebastian; Kool, Marcel; Northcott, Paul A.; Sturm, Dominik; Bjerke, Lynn; Zichner, Thomas; Stütz, Adrian M.; Schramm, Kathrin; Huang, Bingding; Buchhalter, Ivo; Heinold, Michael; Risch, Thomas; Worst, Barbara C.; van Tilburg, Cornelis M.; Weber, Ursula D.; Zapatka, Marc; Raeder, Benjamin; Milford, David; Heiland, Sabine; von Kalle, Christof; Previti, Christopher; Lawerenz, Chris; Kulozik, Andreas E.; Unterberg, Andreas; Witt, Olaf; von Deimling, Andreas; Capper, David; Truffaux, Nathalène; Grill, Jacques; Jabado, Nada; Sehested, Astrid M.; Sumerauer, David; Brahim, Dorra Hmida-Ben; Trabelsi, Saoussen; Ng, Ho-Keung; Zagzag, David; Allen, Jeffrey C.; Karajannis, Matthias A.; Gottardo, Nicholas G.; Jones, Chris; Korbel, Jan O.; Schmidt, Sabine; Wolf, Stephan; Reifenberger, Guido; Felsberg, Jörg; Brors, Benedikt; Herold-Mende, Christel; Lehrach, Hans; Brummer, Tilman; Korshunov, Andrey; Eils, Roland; Yaspo, Marie-Laure; Pfister, Stefan M.; Lichter, Peter; Jones, David T. W.

    2016-01-01

    Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in similar to 10% of cases.

  11. CXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone

    NARCIS (Netherlands)

    Goffart, Nicolas; Lombard, Arnaud; Lallemand, François; Kroonen, Jérôme; Nassen, Jessica; Di Valentin, Emmanuel; Berendsen, Sharon; Dedobbeleer, Matthias; Willems, Estelle; Robe, Pierre; Bours, Vincent; Martin, Didier; Martinive, Philippe; Maquet, Pierre; Rogister, Bernard

    2017-01-01

    Background. Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line,

  12. 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

  13. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme

    DEFF Research Database (Denmark)

    Muhic, Aida; Poulsen, Hans Skovgaard; Mau-Sørensen, Paul Morten

    2013-01-01

    Nintedanib (BIBF 1120) is a small, orally available, triple angiokinase inhibitor in phase III development (various indications) that targets VEGFR 1-3, FGFR 1-3, and PDGFR-α/β. This open-label, uncontrolled, phase II study assessed the efficacy and safety of nintedanib in patients with recurrent....... Nintedanib had an acceptable safety profile, with no CTCAE grade 3-4 adverse events. Common adverse events were CTCAE grade 1-2 fatigue, loss of appetite, diarrhea, and nausea. Single-agent nintedanib (200 mg bid) demonstrated limited, but clinically non-relevant antitumor activity in patients with recurrent...... glioblastoma multiforme (GBM) who had previously failed radiotherapy plus temozolomide as first-line therapy (STUPP), or the same regimen with subsequent bevacizumab-based therapy as second-line treatment (BEV). Patients with a performance status of 0-1, histologically proven GBM, and measurable disease (by...

  14. 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.

  15. Improved Antitumoral Activity of Extracts Derived from Cultured ...

    African Journals Online (AJOL)

    Erah

    Purpose: Extracts of the green alga, Penicillus dumetosus, have shown antiproliferative activity against several cancer cell lines. The aim of this study was to evaluate if this activity is modified after cultivation. Methods: P. dumetosus was cultured under different light treatments. After 10, 20 and 30 days, alga samples were ...

  16. Physical Activity at Daycare: Childcare Providers' Perspectives for Improvements

    Science.gov (United States)

    Tucker, Patricia; van Zandvoort, Melissa M.; Burke, Shauna M.; Irwin, Jennifer D.

    2011-01-01

    In London, Ontario, approximately 45 percent of preschoolers are insufficiently active.With the large number of preschoolers who attend childcare (54%), and the low levels of physical activity among preschool-aged children, daycare centers may be an appropriate avenue to intervene. This study sought to collect childcare providers' suggestions for…

  17. Improving active Mealy machine learning for protocol conformance testing

    NARCIS (Netherlands)

    Aarts, F.; Kuppens, H.; Tretmans, J.; Vaandrager, F.; Verwer, S.

    2014-01-01

    Using a well-known industrial case study from the verification literature, the bounded retransmission protocol, we show how active learning can be used to establish the correctness of protocol implementation I relative to a given reference implementation R. Using active learning, we learn a model M

  18. Can dance exergaming contribute to improving physical activity ...

    African Journals Online (AJOL)

    Physically active video games that involve dancing are being marketed as possible forms of group physical activity (PA) in schools. However, the efficacy of a group video game dance intervention for reducing sedentary behaviour is unknown. The purpose of the present study was to compare before-school group video ...

  19. Improved Oxidase Mimetic Activity by Praseodymium Incorporation into Ceria Nanocubes.

    Science.gov (United States)

    Jiang, Lei; Fernandez-Garcia, Susana; Tinoco, Miguel; Yan, Zhaoxia; Xue, Qi; Blanco, Ginesa; Calvino, Jose J; Hungria, Ana B; Chen, Xiaowei

    2017-06-07

    Ceria nanocubes (NC) modified with increasing concentrations of praseodymium (5, 10, 15, and 20 mol %) have been successfully synthesized by a hydrothermal method. The as-synthesized Pr-modified ceria nanocubes exhibit an enhanced oxidase-like activity on the organic dye TMB within a wide range of concentrations and durations. The oxidase activity increases with increasing Pr amounts in Pr-modified ceria nanocubes within the investigated concentration range. Meanwhile, these Pr-modified ceria nanocubes also show higher reducibility than pure ceria nanocubes. The kinetics of their oxidase mimetic activity is fitted with the Michaelis-Menten equation. A mechanism has been proposed on how the Pr incorporation could affect the energy level of the bands in ceria and hence facilitate the TMB oxidation reaction. The presence of Pr(3+) species on the surface also contributes to the increasing activity of the Pr-modified ceria nanocubes present higher oxidase activity than pure ceria nanocubes.

  20. Dissecting inherent intratumor heterogeneity in patient-derived glioblastoma culture models.

    Science.gov (United States)

    Teng, Jian; Carla da Hora, Cintia; Kantar, Rami S; Nakano, Ichiro; Wakimoto, Hiroaki; Batchelor, Tracy T; Chiocca, E Antonio; Badr, Christian E; Tannous, Bakhos A

    2017-06-01

    Molecular profile of glioblastoma multiforme (GBM) revealed 4 subtypes, 2 of which, proneural and mesenchymal, have been predominantly observed, with the latter displaying a more aggressive phenotype and increased therapeutic resistance. Single-cell RNA sequencing revealed that multiple subtypes actually reside within the same tumor, suggesting cellular heterogeneity in GBM. Further, plasticity between these 2 subtypes is observed during tumor recurrence and in response to radiation therapy. Patient-derived GBM stemlike cells were cultured as neurospheres. These cells were differentiated in serum by attaching to the culture dishes. The "floating" cells that were not attached/differentiated were harvested from the conditioned medium. The characteristics of these cells were studied with limiting dilution assays and immunofluorescence staining. Cell growth and nuclear factor-kappaB (NFkB) activation were monitored using bioluminescent assays as well as quantitative polymerase chain reaction and western blotting. In vivo tumorigenesis was evaluated in orthotopic xenograft models using bioluminescence imaging. Patient-derived GBM stemlike cells undergo differentiation by attaching to the culture dish in serum-containing medium. We observed that a small subset of these cells escape this adhesion/differentiation and grow as floating cells. These cells displayed enhanced cancer stem cell properties with a molecular and phenotypic mesenchymal signature, including resistance to radiation and targeted therapies, a more aggressive tumor formation, and NFkB activation. Our results endorse inherent intratumor molecular subtype heterogeneity in glioblastoma and provide a valuable approach to study phenotypic plasticity, which could be applied to find novel therapeutic strategies to eradicate this aggressive tumor and can be extended to other cancer types.

  1. Active Learning to Improve Fifth Grade Mathematics Achievement in Banten

    Directory of Open Access Journals (Sweden)

    Andri Suherman

    2011-12-01

    Full Text Available Teaching for active learning is a pedagogical technique that has been actively promoted in Indonesian education through government reform efforts and international development assistance projects for decades. Recently, elementary schools in Banten province received training in active learning instructional strategies from the USAID-funded project, Decentralized Basic Education 2. Post-training evaluations conducted by lecturers from the University of Sultan Ageng Tirtayasa (UNTIRTA: Universitas Sultan Ageng Tirtayasa suggested that teachers were successfully employing active learning strategies in some subjects, but not mathematics. In order to understand the difficulties teachers were having in teaching for active learning in mathematics, and to assist them in using active learning strategies, a team of lecturers from UNTIRTA designed and carried out an action research project to train teachers in an elementary school in the city of Cilegon to use a technique called Magic Fingers in teaching Grade 5 multiplication. During the course of the project the research team discovered that teachers were having problems transferring knowledge gained from training in one context and subject to other school subjects and contexts. Key Words: Mathematics, Teaching for Active Learning, Indonesia, Banten

  2. Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization.

    Science.gov (United States)

    Stafford, Jason H; Hirai, Takahisa; Deng, Lei; Chernikova, Sophia B; Urata, Kimiko; West, Brian L; Brown, J Martin

    2016-06-01

    Glioblastoma (GBM) may initially respond to treatment with ionizing radiation (IR), but the prognosis remains extremely poor because the tumors invariably recur. Using animal models, we previously showed that inhibiting stromal cell-derived factor 1 signaling can prevent or delay GBM recurrence by blocking IR-induced recruitment of myeloid cells, specifically monocytes that give rise to tumor-associated macrophages. The present study was aimed at determining if inhibiting colony stimulating factor 1 (CSF-1) signaling could be used as an alternative strategy to target pro-tumorigenic myeloid cells recruited to irradiated GBM. To inhibit CSF-1 signaling in myeloid cells, we used PLX3397, a small molecule that potently inhibits the tyrosine kinase activity of the CSF-1 receptor (CSF-1R). Combined IR and PLX3397 therapy was compared with IR alone using 2 different human GBM intracranial xenograft models. GBM xenografts treated with IR upregulated CSF-1R ligand expression and increased the number of CD11b+ myeloid-derived cells in the tumors. Treatment with PLX3397 both depleted CD11b+ cells and potentiated the response of the intracranial tumors to IR. Median survival was significantly longer for mice receiving combined therapy versus IR alone. Analysis of myeloid cell differentiation markers indicated that CSF-1R inhibition prevented IR-recruited monocyte cells from differentiating into immunosuppressive, pro-angiogenic tumor-associated macrophages. CSF-1R inhibition may be a promising strategy to improve GBM response to radiotherapy. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. 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

  4. 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.

  5. 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,

  6. Active Experiencing Training Improves Episodic Memory Recall in Older Adults

    National Research Council Canada - National Science Library

    Sarah E. Banducci; Ana M. Daugherty; John R. Biggan; Gillian E. Cooke; Michelle Voss; Tony Noice; Helga Noice; Arthur F. Kramer

    2017-01-01

    Active experiencing (AE) is an intervention aimed at attenuating cognitive declines with mindfulness training via an immersive acting program, and has produced promising results in older adults with limited formal education...

  7. 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....

  8. Extramitochondrial domain rich in carbonic anhydrase activity improves myocardial energetics.

    Science.gov (United States)

    Schroeder, Marie A; Ali, Mohammad A; Hulikova, Alzbeta; Supuran, Claudiu T; Clarke, Kieran; Vaughan-Jones, Richard D; Tyler, Damian J; Swietach, Pawel

    2013-03-05

    CO2 is produced abundantly by cardiac mitochondria. Thus an efficient means for its venting is required to support metabolism. Carbonic anhydrase (CA) enzymes, expressed at various sites in ventricular myocytes, may affect mitochondrial CO2 clearance by catalyzing CO2 hydration (to H(+) and HCO3(-)), thereby changing the gradient for CO2 venting. Using fluorescent dyes to measure changes in pH arising from the intracellular hydration of extracellularly supplied CO2, overall CA activity in the cytoplasm of isolated ventricular myocytes was found to be modest (2.7-fold above spontaneous kinetics). Experiments on ventricular mitochondria demonstrated negligible intramitochondrial CA activity. CA activity was also investigated in intact hearts by (13)C magnetic resonance spectroscopy from the rate of H(13)CO3(-) production from (13)CO2 released specifically from mitochondria by pyruvate dehydrogenase-mediated metabolism of hyperpolarized [1-(13)C]pyruvate. CA activity measured upon [1-(13)C]pyruvate infusion was fourfold higher than the cytoplasm-averaged value. A fluorescent CA ligand colocalized with a mitochondrial marker, indicating that mitochondria are near a CA-rich domain. Based on immunoreactivity, this domain comprises the nominally cytoplasmic CA isoform CAII and sarcoplasmic reticulum-associated CAXIV. Inhibition of extramitochondrial CA activity acidified the matrix (as determined by fluorescence measurements in permeabilized myocytes and isolated mitochondria), impaired cardiac energetics (indexed by the phosphocreatine-to-ATP ratio measured by (31)P magnetic resonance spectroscopy of perfused hearts), and reduced contractility (as measured from the pressure developed in perfused hearts). These data provide evidence for a functional domain of high CA activity around mitochondria to support CO2 venting, particularly during elevated and fluctuating respiratory activity. Aberrant distribution of CA activity therefore may reduce the heart's energetic

  9. The suppression of manganese superoxide dismutase decreased the survival of human glioblastoma multiforme T98G cells

    Directory of Open Access Journals (Sweden)

    Novi S. Hardiany

    2017-05-01

    Full Text Available Background: Glioblastoma multiforme (GBM is a primary malignant brain tumor which has poor prognosis. High incidence of oxidative stress-based therapy resistance could be related to the high antioxidant status of GBM cells. Our previous study has reported that manganese superoxide dismutase (MnSOD antioxidant expression was significantly higher in high grade glioma than in low grade. The aim of this study was to analyze the impact of MnSOD suppression toward GBM cell survival.Methods: This study is an experimental study using human glioblastoma multiforme T98G cell line. Suppression of MnSOD expression was performed using in vitro transfection MnSOD-siRNA. The MnSOD expression was analyzed by measuring the mRNA using real time RT-PCR, protein using ELISA technique, and specific activity of enzyme using inhibition of xantine oxidase. Concentration of reactive oxygen species (ROS intracellular was determined by measuring superoxide radical and hydrogen peroxide. Cell survival was analyzed by measuring viability, proliferation, and cell apoptosis.Results: In vitro transfection of MnSOD-siRNA suppressed the mRNA, protein, and specific activity of MnSOD. This treatment significantly increased the concentration of superoxide radical; however, it did not influence the concentration of hydrogen peroxide. Moreover, viability MnSOD-suppressing cell significantly decreased, accompanied by increase of cell apoptosis without affecting cell proliferation.Conclusion: The suppression of MnSOD expression leads to decrease glioblastoma multiforme cell survival, which was associated to the increase of cell apoptotic.

  10. End-to-end workflow for finite element analysis of tumor treating fields in glioblastomas

    Science.gov (United States)

    Timmons, Joshua J.; Lok, Edwin; San, Pyay; Bui, Kevin; Wong, Eric T.

    2017-11-01

    Tumor Treating Fields (TTFields) therapy is an approved modality of treatment for glioblastoma. Patient anatomy-based finite element analysis (FEA) has the potential to reveal not only how these fields affect tumor control but also how to improve efficacy. While the automated tools for segmentation speed up the generation of FEA models, multi-step manual corrections are required, including removal of disconnected voxels, incorporation of unsegmented structures and the addition of 36 electrodes plus gel layers matching the TTFields transducers. Existing approaches are also not scalable for the high throughput analysis of large patient volumes. A semi-automated workflow was developed to prepare FEA models for TTFields mapping in the human brain. Magnetic resonance imaging (MRI) pre-processing, segmentation, electrode and gel placement, and post-processing were all automated. The material properties of each tissue were applied to their corresponding mask in silico using COMSOL Multiphysics (COMSOL, Burlington, MA, USA). The fidelity of the segmentations with and without post-processing was compared against the full semi-automated segmentation workflow approach using Dice coefficient analysis. The average relative differences for the electric fields generated by COMSOL were calculated in addition to observed differences in electric field-volume histograms. Furthermore, the mesh file formats in MPHTXT and NASTRAN were also compared using the differences in the electric field-volume histogram. The Dice coefficient was less for auto-segmentation without versus auto-segmentation with post-processing, indicating convergence on a manually corrected model. An existent but marginal relative difference of electric field maps from models with manual correction versus those without was identified, and a clear advantage of using the NASTRAN mesh file format was found. The software and workflow outlined in this article may be used to accelerate the investigation of TTFields in

  11. Looking for new active methods to improve the school performance: Physical activity!

    Directory of Open Access Journals (Sweden)

    Ruiz-Ariza Alberto

    2017-01-01

    Full Text Available The practice of physical activity (PA has recently been used as a stimulant to improve the cognitive performance in young people and to have positive repercussions on the academic performance [2]. The aims of this research were to conceptualize the relationship between PA and cognition, as well as to associate different physical qualities with better or worse school performance, and thus to be able to make decisions about the kind of PA more adequate to foment from the educative and familiar areas. Our findings are in line with previous literature, and show that a higher physical fitness is associated with better school performance. In conclusion, our study suggests that it is necessary to strengthen the daily PA practice within school context, as well as to raise awareness among families and society about PA promotion.

  12. Prioritising Investments in Marketing Activities to Improve Business Performance

    DEFF Research Database (Denmark)

    Martensen, Anne; Mouritsen, Jan

    2014-01-01

    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...... 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...

  13. 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.

  14. The Ras-related Protein, Rap1A, Mediates Thrombin-stimulated, Integrin-dependent Glioblastoma Cell Proliferation and Tumor Growth*

    Science.gov (United States)

    Sayyah, Jacqueline; Bartakova, Alena; Nogal, Nekeisha; Quilliam, Lawrence A.; Stupack, Dwayne G.; Brown, Joan Heller

    2014-01-01

    Rap1 is a Ras family GTPase with a well documented role in ERK/MAP kinase signaling and integrin activation. Stimulation of the G-protein-coupled receptor PAR-1 with thrombin in human 1321N1 glioblastoma cells led to a robust increase in Rap1 activation. This response was sustained for up to 6 h and mediated through RhoA and phospholipase D (PLD). Thrombin treatment also induced a 5-fold increase in cell adhesion to fibronectin, which was blocked by down-regulating PLD or Rap1A or by treatment with a β1 integrin neutralizing antibody. In addition, thrombin treatment led to increases in phospho-focal adhesion kinase (tyrosine 397), ERK1/2 phosphorylation and cell proliferation, which were significantly inhibited in cells treated with β1 integrin antibody or Rap1A siRNA. To assess the role of Rap1A in tumor formation in vivo, we compared growth of 1321N1 cells stably expressing control, Rap1A or Rap1B shRNA in a mouse xenograft model. Deletion of Rap1A, but not of Rap1B, reduced tumor mass by >70% relative to control. Similar observations were made with U373MG glioblastoma cells in which Rap1A was down-regulated. Collectively, these findings implicate a Rap1A/β1 integrin pathway, activated downstream of G-protein-coupled receptor stimulation and RhoA, in glioblastoma cell proliferation. Moreover, our data demonstrate a critical role for Rap1A in glioblastoma tumor growth in vivo. PMID:24790104

  15. The Ras-related protein, Rap1A, mediates thrombin-stimulated, integrin-dependent glioblastoma cell proliferation and tumor growth.

    Science.gov (United States)

    Sayyah, Jacqueline; Bartakova, Alena; Nogal, Nekeisha; Quilliam, Lawrence A; Stupack, Dwayne G; Brown, Joan Heller

    2014-06-20

    Rap1 is a Ras family GTPase with a well documented role in ERK/MAP kinase signaling and integrin activation. Stimulation of the G-protein-coupled receptor PAR-1 with thrombin in human 1321N1 glioblastoma cells led to a robust increase in Rap1 activation. This response was sustained for up to 6 h and mediated through RhoA and phospholipase D (PLD). Thrombin treatment also induced a 5-fold increase in cell adhesion to fibronectin, which was blocked by down-regulating PLD or Rap1A or by treatment with a β1 integrin neutralizing antibody. In addition, thrombin treatment led to increases in phospho-focal adhesion kinase (tyrosine 397), ERK1/2 phosphorylation and cell proliferation, which were significantly inhibited in cells treated with β1 integrin antibody or Rap1A siRNA. To assess the role of Rap1A in tumor formation in vivo, we compared growth of 1321N1 cells stably expressing control, Rap1A or Rap1B shRNA in a mouse xenograft model. Deletion of Rap1A, but not of Rap1B, reduced tumor mass by >70% relative to control. Similar observations were made with U373MG glioblastoma cells in which Rap1A was down-regulated. Collectively, these findings implicate a Rap1A/β1 integrin pathway, activated downstream of G-protein-coupled receptor stimulation and RhoA, in glioblastoma cell proliferation. Moreover, our data demonstrate a critical role for Rap1A in glioblastoma tumor growth in vivo. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Unlabelled iododeoxyuridine increases the rate of uptake of [{sup 125}I]iododeoxyuridine in human xenografted glioblastomas

    Energy Technology Data Exchange (ETDEWEB)

    Dupertuis, Yves M. [Division of Nuclear Medicine, University Hospital of Geneva (Switzerland); Clinical Nutrition, University Hospital of Geneva (Switzerland); Xiao, Wei-Hong; Slosman, Daniel O. [Division of Nuclear Medicine, University Hospital of Geneva (Switzerland); Tribolet, N. de [Division of Neurosurgery, University Hospital of Geneva (Switzerland); Pichard, Claude [Clinical Nutrition, University Hospital of Geneva (Switzerland); Bischof Delaloye, Angelika [Department of Nuclear Medicine, University Hospital of Lausanne (Switzerland); Buchegger, Franz [Division of Nuclear Medicine, University Hospital of Geneva (Switzerland); Department of Nuclear Medicine, University Hospital of Lausanne (Switzerland)

    2002-04-01

    5-Iodo-2'-deoxyuridine (IdUrd), a thymidine (TdR) analogue, can be radiolabelled with iodine-125, an Auger radiation emitter, to provoke double-strand breaks once incorporated into DNA of cancer cells. We have previously shown that co-incubation of [{sup 125}I]IdUrd with unlabelled IdUrd provided an additive cytotoxicity in two human glioblastoma cell lines. This observation was unexpectedly correlated with an increase in the rate of DNA incorporation of [{sup 125}I]IdUrd. Here, we further evaluated the effects of unlabelled IdUrd on the uptake of [{sup 125}I]IdUrd in vitro and in vivo in mice xenografted with three human glioblastoma lines. The results showed that, in these three glioblastoma lines, unlabelled IdUrd increased the rate of uptake of [{sup 125}I]IdUrd in vitro by 2- to 4.4-fold and in vivo by 1.5- to 2.8-fold. The rate of uptake of [{sup 125}I]IdUrd in normal rapidly dividing tissues was also increased by 1.3- to 2.8-fold. TdR completely blocked [{sup 125}I]IdUrd uptake in tumours and tissues. Analogues of IdUrd, such as deoxyuridine and 5-iodo-1,3-dimethyuracil, did not reproduce the effect of IdUrd on the uptake of [{sup 125}I]IdUrd, suggesting that it is not related to protection against [{sup 125}I]IdUrd degradation. It is concluded that combined administration of unlabelled IdUrd may improve the use of radiolabelled IdUrd for cancer diagnosis or therapy. (orig.)

  17. Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma.

    Directory of Open Access Journals (Sweden)

    Nicholas Brown

    Full Text Available Cediranib, an oral pan-vascular endothelial growth factor (VEGF receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR. This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma.This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS. Secondary outcome measures included overall survival (OS and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26. Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19. Eight subjects (42% had a partial response in the cediranib plus gefitinib arm versus five patients (26% in the cediranib plus placebo arm.Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted.ClinicalTrials.gov NCT01310855.

  18. Using Regulation Activities to Improve Undergraduate Collaborative Writing on Wikis

    Science.gov (United States)

    Cho, Moon-Heum; Lim, Seongmi

    2017-01-01

    Although wikis have been widely adopted to support collaborative writing in undergraduate classrooms, educators remain concerned about the level of student participation. Using regulation theories to design interventions in the form of activities, we examined their effects on collaborative writing on wikis. Results demonstrate that with the…

  19. Improving Preservice Chemistry Teachers' Content Knowledge through Intervention Activities

    Science.gov (United States)

    Wheeldon, Ruth

    2017-01-01

    The effect of intervention activities on the chemistry content knowledge of 92 preservice chemistry teachers (PSCT) was examined via a pre and post true/false with confidence level test focusing on ionisation energy values and the use of a common alternative conception (AC). Data were collected from three cohorts of PSCT each engaged in a one year…

  20. On the road to improved scheduling - fitting activities to capacity

    DEFF Research Database (Denmark)

    Lindhard, Søren Munch; Wandahl, Søren

    2012-01-01

    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 p...

  1. 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....

  2. Improvement in Activities of Daily Living among Danish Centenarians?

    DEFF Research Database (Denmark)

    Rasmussen, Signe Høi; Thinggaard, Mikael; Højgaard, Majken Boris

    2017-01-01

    at investigating if the later born cohort had better functioning in terms of activities of daily living (ADL). Methods: Identification, methodology and assessment instruments were identical in the 1895-West and 1915-West Birth Cohort Studies: All persons living in the western part of Denmark and turning 100 years...

  3. Targeting the epithelial to mesenchymal transition in glioblastoma: the emerging role of MET signaling

    Directory of Open Access Journals (Sweden)

    Lee JK

    2014-10-01

    Full Text Available Jin-Ku Lee,1,2,* Kyeung Min Joo,3 Jeongwu Lee,4 Yeup Yoon,5,* Do-Hyun Nam2,5 1Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea; 2Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 3Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 5Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea  *These authors contributed equally to this work Abstract: Glioblastoma multiforme (GBM is the most common human primary brain malignancy and has a dismal prognosis. Aggressive treatments using maximal surgical resection, radiotherapy, and temozolomide result in median survival of only 14.6 months in patients with GBM. Numerous clinical approaches using small molecule inhibitors have shown disappointing results because of the genetic heterogeneity of GBM. The epithelial to mesenchymal transition (EMT is a crucial biological process occurring in the early development stages of many species. However, cancer cells often obtain the ability to invade and metastasize through the EMT, which triggers the scattering of cells. The hepatocyte growth factor (HGF/MET signaling pathway is indicative of the EMT during both embryogenesis and the invasive growth of tumors, because HGF potently induces mesenchymal transition in epithelial-driven cells. Activation of MET signaling or co-overexpression of HGF and MET frequently represents aggressive growth and poor prognosis of various cancers, including GBM. Thus, efforts to treat cancers by inhibiting MET signaling using neutralizing antibodies or small molecule inhibitors have progressed during the last decade. In this review, we discuss HGF/MET signaling in the development of diseases

  4. 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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells.

    Science.gov (United States)

    Banelli, Barbara; Daga, Antonio; Forlani, Alessandra; Allemanni, Giorgio; Marubbi, Daniela; Pistillo, Maria Pia; Profumo, Aldo; Romani, Massimo

    2017-05-23

    In glioblastoma several histone demethylase genes (KDM) are overexpressed compared to normal brain tissue and the development of Temozolomide (TMZ) resistance is accompanied by the transient further increased expression of KDM5A and other KDMs following a mechanism that we defined as "epigenetic resilience". We hypothesized that targeting KDMs may kill the cells that survive the cytotoxic therapy.We determined the effect of JIB 04 and CPI-455, two KDM inhibitors, on glioblastoma cells and found that both molecules are more effective against TMZ-resistant rather than native cells.Because of its lower IC50, we focused on JIB 04 that targets KDM5A and other KDMs as well. We have shown that this molecule activates autophagic and apoptotic pathways, interferes with cell cycle progression, inhibits cell clonogenicity and dephosphorylates Akt thus inactivating a potent pro-survival pathway. We performed combination temozolomide/JIB 04 in vitro treatments showing that these two molecules, under certain conditions, have a strong synergic effect and we hypothesize that JIB 04 intercepts the cells that escape the G2 block exerted by TMZ. Finally we studied the permeability of JIB 04 across the blood-brain barrier and found that this molecule reaches bioactive concentration in the brain; furthermore a pilot in vivo experiment in an orthotopic GB xenograft model showed a trend toward longer survival in treated mice with an Hazard Ratio of 0.5.In conclusion we propose that the combination between cytotoxic drugs and molecules acting on the epigenetic landscape may offer the opportunity to develop new therapies for this invariably lethal disease.

  6. Automatic estimation of extent of resection and residual tumor volume of patients with glioblastoma.

    Science.gov (United States)

    Meier, Raphael; Porz, Nicole; Knecht, Urspeter; Loosli, Tina; Schucht, Philippe; Beck, Jürgen; Slotboom, Johannes; Wiest, Roland; Reyes, Mauricio

    2017-10-01

    OBJECTIVE In the treatment of glioblastoma, residual tumor burden is the only prognostic factor that can be actively influenced by therapy. Therefore, an accurate, reproducible, and objective measurement of residual tumor burden is necessary. This study aimed to evaluate the use of a fully automatic segmentation method-brain tumor image analysis (BraTumIA)-for estimating the extent of resection (EOR) and residual tumor volume (RTV) of contrast-enhancing tumor after surgery. METHODS The imaging data of 19 patients who underwent primary resection of histologically confirmed supratentorial glioblastoma were retrospectively reviewed. Contrast-enhancing tumors apparent on structural preoperative and immediate postoperative MR imaging in this patient cohort were segmented by 4 different raters and the automatic segmentation BraTumIA software. The manual and automatic results were quantitatively compared. RESULTS First, the interrater variabilities in the estimates of EOR and RTV were assessed for all human raters. Interrater agreement in terms of the coefficient of concordance (W) was higher for RTV (W = 0.812; p automatic estimates. BraTumIA showed a tendency to overestimate contrast-enhancing tumors, leading to moderate agreement with expert raters with respect to the literature-based, survival-relevant threshold values for EOR. CONCLUSIONS BraTumIA can generate volumetric estimates of EOR and RTV, in a fully automatic fashion, which are comparable to the estimates of human experts. However, automated analysis showed a tendency to overestimate the volume of a contrast-enhancing tumor, whereas manual analysis is prone to subjectivity, thereby causing considerable interrater variability.

  7. 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

    2012-11-29

    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.

  8. Using DSP technology to improve sound quality in active speakers

    OpenAIRE

    Magnusson, Mattias

    2010-01-01

    Aditus Science has developed a system to improve the sound quality in speaker systems, using DSP technology. Software developed in MATLAB is being used to make measurements of the speakers via microphones. Based on those results, the parameters for the signal processing in the DSP can be set. A prototype model of the system was used as hardware when the software was developed. The system has several analog and digital inputs and outputs over SPDIF, Ethernet, 3.5mm analog stereo plug etcetera....

  9. mTOR Promotes Survival and Astrocytic Characteristics Induced by Pten/Akt Signaling in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Xiaoyi Hu

    2005-04-01

    Full Text Available Combined activation of Ras and Akt leads to the formation of astrocytic glioblastoma multiforme (GBM in mice. In human GBMs, AKT is not mutated but is activated in approximately 70% of these tumors, in association with loss of PTEN and/or activation of receptor tyrosine kinases. Mechanistic justification for the therapeutic blockade of targets downstream of AKT, such as mTOR, in these cancers requires demonstration that the oncogenic effect of PTEN loss is through elevated AKT activity. We demonstrate here that loss of Pten is similar to Akt activation in the context of glioma formation in mice. We further delineate the role of mTOR activity downstream of Akt in the maintenance of Akt+KRas-induced GBMs. Blockade of mTOR results in regional apoptosis in these tumors and conversion in the character of surviving tumor cells from astrocytoma to oligodendroglioma. These data suggest that mTOR activity is required for the survival of some cells within these GBMs, and mTOR appears required for the maintenance of astrocytic character in the surviving cells. Furthermore, our study provides the first example of conversion between two distinct tumor types usually thought of as belonging to specific lineages, and provides evidence for signal transduction-mediated transdifferentiation between glioma subtypes.