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  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. A tree shrew glioblastoma model recapitulates features of human glioblastoma

    OpenAIRE

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

    2017-01-01

    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 t...

  3. Human cytomegalovirus-mediated immunomodulation: Effects on glioblastoma progression.

    Science.gov (United States)

    Foster, Haidn; Ulasov, Ilya V; Cobbs, Charles S

    2017-08-01

    The presence of human cytomegalovirus (HCMV) and glioblastoma multiforme (GBM), first established in 2002, has developed into an area of considerable interest and controversy. Numerous studies have found evidence of possible HCMV infection of GBM tumor cells as well as myriad onco- and immunomodulatory properties exhibited by HCMV antigens and transcripts, while recent reports have failed to detect HCMV particles in GBM and question the virus' role in tumor progression. This review highlights the known immunomodulatory properties of HCMV, independent of GBM infection status, that help drive the virus from peripheral blood into the vital tissues and subsequently dampen local immune response, assisting GBM tumors in evading immune surveillance and contributing to the disease's poor prognosis. Emerging antiviral approaches to treating GBM, including antiviral drugs and immunotherapies directed against HCMV, are also examined. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. 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 ...

  5. Infrasound sensitizes human glioblastoma cells to cisplatin-induced apoptosis.

    Science.gov (United States)

    Rachlin, Kenneth; Moore, Dan H; Yount, Garret

    2013-11-01

    The development of nontoxic agents that can selectively enhance the cytotoxicity of chemotherapy is an important aim in oncology. This study evaluates the ability of infrasound exposure to sensitize glioblastoma cells to cisplatin-induced apoptosis. The infrasound was delivered using a device designed to replicate the unique infrasound emissions measured during external Qigong treatments. Human glioblastoma cell lines harboring wild-type p53 (U87) or mutant p53 (U251, SF210, and SF188) were treated in culture with cisplatin, infrasound emissions, or the combination of the 2 agents. Induction of apoptosis was quantified after 24 hours by flow cytometry following annexin V/propidium iodide staining. Infrasound emissions alone, delivered at moderate levels (~10 mPa) with dynamic frequency content (7-13 Hz), did not induce apoptosis, yet combining infrasound with cisplatin augmented the induction of apoptosis by cisplatin in all the 4 cell lines (P < .05). Increased cellular uptake of the fluorophore calcein associated with infrasound exposure was quantified by fluorescence microscopy as well as flow cytometry, demonstrating increased cell membrane permeability. The 4 cell lines differed in the degree to which infrasound exposure increased calcein uptake, and these differences were predictive of the extent to which infrasound enhanced cisplatin-induced apoptosis. When exposed to specific frequencies, membrane permeabilization also appeared to be differentially responsive for each cell line, suggesting the potential for selective targeting of tissue types using isolated infrasonic frequencies. Additionally, the pressure amplitudes used in this study were several orders of magnitude less than those used in similar studies involving ultrasound and shock waves. The results of this study provide support for using infrasound to enhance the chemotherapeutic effects of cisplatin in a clinical setting.

  6. 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.

  7. Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215

    OpenAIRE

    Szereday, Z; Schally, A V; Nagy, A; Plonowski, A; Bajo, A M; Halmos, G; Szepeshazi, K; Groot, K

    2002-01-01

    Some brain tumours, such as glioblastomas express high levels of receptors for bombesin/gastrin releasing peptide. We investigated whether bombesin/gastrin releasing peptide receptors found in glioblastoma cell lines can be utilised for targeting of a cytotoxic bombesin analogue, AN-215 consisting of a potent derivative of doxorubicin, 2-pyrrolino-doxorubicin (AN-201) linked to a bombesin-like peptide carrier. This study reports the effect of AN-215 on the growth of U-87MG human glioblastomas...

  8. A reproducible brain tumour model established from human glioblastoma biopsies

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    Li Xingang

    2009-12-01

    Full Text Available Abstract Background Establishing clinically relevant animal models of glioblastoma multiforme (GBM remains a challenge, and many commonly used cell line-based models do not recapitulate the invasive growth patterns of patient GBMs. Previously, we have reported the formation of highly invasive tumour xenografts in nude rats from human GBMs. However, implementing tumour models based on primary tissue requires that these models can be sufficiently standardised with consistently high take rates. Methods In this work, we collected data on growth kinetics from a material of 29 biopsies xenografted in nude rats, and characterised this model with an emphasis on neuropathological and radiological features. Results The tumour take rate for xenografted GBM biopsies were 96% and remained close to 100% at subsequent passages in vivo, whereas only one of four lower grade tumours engrafted. Average time from transplantation to the onset of symptoms was 125 days ± 11.5 SEM. Histologically, the primary xenografts recapitulated the invasive features of the parent tumours while endothelial cell proliferations and necrosis were mostly absent. After 4-5 in vivo passages, the tumours became more vascular with necrotic areas, but also appeared more circumscribed. MRI typically revealed changes related to tumour growth, several months prior to the onset of symptoms. Conclusions In vivo passaging of patient GBM biopsies produced tumours representative of the patient tumours, with high take rates and a reproducible disease course. The model provides combinations of angiogenic and invasive phenotypes and represents a good alternative to in vitro propagated cell lines for dissecting mechanisms of brain tumour progression.

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

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    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.

  10. 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....

  11. 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.

  12. Bacoside A Induces Tumor Cell Death in Human Glioblastoma Cell Lines through Catastrophic Macropinocytosis

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    Sebastian John

    2017-06-01

    Full Text Available Glioblastoma multiforme (GBM is a highly aggressive type of brain tumor with an extremely poor prognosis. Recent evidences have shown that the “biomechanical imbalances” induced in GBM patient-derived glioblastoma cells (GC and in vivo via the administration of synthetic small molecules, may effectively inhibit disease progression and prolong survival of GBM animal models. This novel concept associated with de novo anti-GBM drug development has however suffered obstacles in adequate clinical utility due to the appearance of unrelated toxicity in the prolonged therapeutic windows. Here, we took a “drug repurposing approach” to trigger similar physico-chemical disturbances in the GBM tumor cells, wherein, the candidate therapeutic agent has been previously well established for its neuro-protective roles, safety, efficacy, prolonged tolerance and excellent brain bioavailability in human subjects and mouse models. In this study, we show that the extracts of an Indian traditional medicinal plant Bacopa monnieri (BM and its bioactive component Bacoside A can generate dosage associated tumor specific disturbances in the hydrostatic pressure balance of the cell via a mechanism involving excessive phosphorylation of calcium/calmodulin-dependent protein kinase IIA (CaMKIIA/CaMK2A enzyme that is further involved in the release of calcium from the smooth endoplasmic reticular networks. High intracellular calcium stimulated massive macropinocytotic extracellular fluid intake causing cell hypertrophy in the initial stages, excessive macropinosome enlargement and fluid accumulation associated organellar congestion, cell swelling, cell rounding and membrane rupture of glioblastoma cells; with all these events culminating into a non-apoptotic, physical non-homeostasis associated glioblastoma tumor cell death. These results identify glioblastoma tumor cells to be a specific target of the tested herbal medicine and therefore can be exploited as a safe anti

  13. Bacoside A Induces Tumor Cell Death in Human Glioblastoma Cell Lines through Catastrophic Macropinocytosis.

    Science.gov (United States)

    John, Sebastian; Sivakumar, K C; Mishra, Rashmi

    2017-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumor with an extremely poor prognosis. Recent evidences have shown that the "biomechanical imbalances" induced in GBM patient-derived glioblastoma cells (GC) and in vivo via the administration of synthetic small molecules, may effectively inhibit disease progression and prolong survival of GBM animal models. This novel concept associated with de novo anti-GBM drug development has however suffered obstacles in adequate clinical utility due to the appearance of unrelated toxicity in the prolonged therapeutic windows. Here, we took a "drug repurposing approach" to trigger similar physico-chemical disturbances in the GBM tumor cells, wherein, the candidate therapeutic agent has been previously well established for its neuro-protective roles, safety, efficacy, prolonged tolerance and excellent brain bioavailability in human subjects and mouse models. In this study, we show that the extracts of an Indian traditional medicinal plant Bacopa monnieri (BM) and its bioactive component Bacoside A can generate dosage associated tumor specific disturbances in the hydrostatic pressure balance of the cell via a mechanism involving excessive phosphorylation of calcium/calmodulin-dependent protein kinase IIA (CaMKIIA/CaMK2A) enzyme that is further involved in the release of calcium from the smooth endoplasmic reticular networks. High intracellular calcium stimulated massive macropinocytotic extracellular fluid intake causing cell hypertrophy in the initial stages, excessive macropinosome enlargement and fluid accumulation associated organellar congestion, cell swelling, cell rounding and membrane rupture of glioblastoma cells; with all these events culminating into a non-apoptotic, physical non-homeostasis associated glioblastoma tumor cell death. These results identify glioblastoma tumor cells to be a specific target of the tested herbal medicine and therefore can be exploited as a safe anti-GBM therapeutic.

  14. Overexpression of miR-100 inhibits cell proliferation, migration, and chemosensitivity in human glioblastoma through FGFR3

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    Luan YX

    2015-11-01

    Full Text Available Yongxin Luan,1 Shuyan Zhang,1 Ling Zuo,2 Lixiang Zhou1 1Department of Neurosurgery, First Bethune Hospital of Jilin University, 2Department of Ophthalmology, Second Bethune Hospital of Jilin University, Changchun, People’s Republic of China Background: Glioblastoma multiforme is one of the most deadly forms of brain cancer. We investigated the regulatory effects of microRNA-100 (miR-100 on cell proliferation, migration, and chemosensitivity in human glioblastoma. Methods: miR-100 expression was assessed by quantitative real-time polymerase chain reaction in both glioblastoma cells and human tumors. Lentiviruses of miR-100 mimics and inhibitors were transfected into U251 and T98G cells. The regulatory effects of either overexpressing or downregulating miR-100 on glioblastoma were evaluated by a viability assay, growth assay, migration assay, chemosensitivity assay, and an in vivo tumor transplantation assay. Expression of fibroblast growth factor receptor 3 (FGFR3, the bioinformatically predicted target of miR-100, was examined by Western blot in glioblastoma. FGFR3 was then ectopically overexpressed in U251 and T98G cells, and its effects on miR-100-mediated cancer regulation were evaluated by growth, migration, and chemosensitivity assays. Results: MiR-100 was markedly downregulated in both glioblastoma cell lines and human tumors. Overexpressing miR-100 through lentiviral transfection in U251 and T98G cells significantly inhibited cancer growth (both in vitro and in vivo and migration and increased chemosensitivity to cisplatin and 1, 3-bis (2-chloroethyl-l-nitrosourea, whereas downregulation of miR-100 had no effects on development of cancer. FGFR3 was directly regulated by miR-100 in glioblastoma. Ectopically overexpressing FGFR3 was able to ameliorate the anticancer effects of upregulation of miR-100 on glioblastoma growth, migration, and chemosensitivity. Conclusion: MiR-100 was generally downregulated in glioblastoma. Overexpressing mi

  15. Fractionated irradiation combined with carbogen breathing and nicotinamide of two human glioblastomas grafted in nude mice

    OpenAIRE

    SUN, Lin-Quan; BUCHEGGER, Franz; COUCKE, Philippe; MIRIMANOFF

    2001-01-01

    This study addressed the potential radiosensitizing effect of nicotinamide and/or carbogen on human glioblastoma xenografts in nude mice. U-87MG and LN-Z308 tumors were irradiated with either 20 fractions over 12 days or 5 fractions over 5 days in air-breathing mice, mice injected with nicotinamide, mice breathing carbogen, or mice receiving nicotinamide plus carbogen. The responses to treatment were assessed using local control and moist desquamation. In U-87MG tumors, the enhancement ratios...

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

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    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.

  17. 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

  18. Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells

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    Araceli Gutiérrez-Rodríguez

    2017-01-01

    Full Text Available Progesterone-induced blocking factor (PIBF is a progesterone (P4 regulated protein expressed in different types of high proliferative cells including astrocytomas, the most frequent and aggressive brain tumors. It has been shown that PIBF increases the number of human astrocytoma cells. In this work, we evaluated PIBF regulation by P4 and the effects of PIBF on proliferation, migration, and invasion of U87 and U251 cells, both derived from human glioblastomas. PIBF mRNA expression was upregulated by P4 (10 nM from 12 to 24 h. Glioblastoma cells expressed two PIBF isoforms, 90 and 57 kDa. The content of the shorter isoform was increased by P4 at 24 h, while progesterone receptor antagonist RU486 (10 μM blocked this effect. PIBF (100 ng/mL increased the number of U87 cells on days 4 and 5 of treatment and induced cell proliferation on day 4. Wound-healing assays showed that PIBF increased the migration of U87 (12–48 h and U251 (24 and 48 h cells. Transwell invasion assays showed that PIBF augmented the number of invasive cells in both cell lines at 24 h. These data suggest that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells.

  19. Clinical implications of microRNAs in human glioblastoma

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    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.

  20. MiR-18a regulates the proliferation, migration and invasion of human glioblastoma cell by targeting neogenin

    Energy Technology Data Exchange (ETDEWEB)

    Song, Yichen, E-mail: jeff200064017@163.com [Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004 (China); Wang, Ping, E-mail: pingwang8000@163.com [Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001 (China); Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001 (China); Zhao, Wei, E-mail: 15669746@qq.com [Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001 (China); Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001 (China); Yao, Yilong, E-mail: yaoyilong_322@163.com [Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004 (China); Liu, Xiaobai, E-mail: paganizonda1991@qq.com [The 96th Class, 7-year Program, China Medical University, Shenyang, Liaoning Province 110001 (China); Ma, Jun, E-mail: majun_724@163.com [Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001 (China); Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001 (China); Xue, Yixue, E-mail: xueyixue888@163.com [Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001 (China); Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001 (China); Liu, Yunhui, E-mail: liuyh@sj-hospital.org [Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004 (China)

    2014-05-15

    MiR-17-92 cluster has recently been reported as an oncogene in some tumors. However, the association of miR-18a, an important member of this cluster, with glioblastoma remains unknown. Therefore, this study aims to investigate the expression of miR-18a in glioblastoma and its role in biological behavior of U87 and U251 human glioblastoma cell lines. Quantitative RT-PCR results showed that miR-18a was highly expressed in glioblastoma tissues and U87 and U251 cell lines compared with that in human brain tissues and primary normal human astrocytes, and the expression levels were increased along with the rising pathological grades of glioblastoma. Neogenin was identified as the target gene of miR-18a by dual-luciferase reporter assays. RT-PCR and western blot results showed that its expression levels were decreased along with the rising pathological grades of glioblastoma. Inhibition of miR-18a expression was established by transfecting exogenous miR-18a inhibitor into U87 and U251 cells, and its effects on the biological behavior of glioblastoma cells were studied using CCK-8 assay, transwell assay and flow cytometry. Inhibition of miR-18a expression in U87 and U251 cells significantly up-regulated neogenin, and dramatically suppressed the abilities of cell proliferation, migration and invasion, induced cell cycle arrest and promoted cellular apoptosis. Collectively, these results suggest that miR-18a may regulate biological behavior of human glioblastoma cells by targeting neogenin, and miR-18a can serve as a potential target in the treatment of glioblastoma. - Highlights: • MiR-18a was highly expressed in glioblastoma tissues and U87 and U251 cell lines. • Neogenin was identified as the target gene of miR-18a. • Neogenin expressions were decreased along with the rising pathological grades of glioblastoma. • Inhibition of miR-18a suppressed biological behavior of glioma cells by up-regulating neogenin.

  1. The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes

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    Yuan Xie

    2015-10-01

    Full Text Available Glioblastoma (GBM is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called glioma stem cells (GSCs. To meet the present shortage of relevant GBM cell (GC lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional subtypes. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

  2. Transcriptomics Evidence for Common Pathways in Human Major Depressive Disorder and Glioblastoma

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    Yongfang Xie

    2018-01-01

    Full Text Available Depression as a common complication of brain tumors. Is there a possible common pathogenesis for depression and glioma? The most serious major depressive disorder (MDD and glioblastoma (GBM in both diseases are studied, to explore the common pathogenesis between the two diseases. In this article, we first rely on transcriptome data to obtain reliable and useful differentially expressed genes (DEGs by differential expression analysis. Then, we used the transcriptomics of DEGs to find out and analyze the common pathway of MDD and GBM from three directions. Finally, we determine the important biological pathways that are common to MDD and GBM by statistical knowledge. Our findings provide the first direct transcriptomic evidence that common pathway in two diseases for the common pathogenesis of the human MDD and GBM. Our results provide a new reference methods and values for the study of the pathogenesis of depression and glioblastoma.

  3. Primary ciliogenesis defects are associated with human astrocytoma/glioblastoma cells

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    Rattner Jerome B

    2009-12-01

    Full Text Available Abstract Background Primary cilia are non-motile sensory cytoplasmic organelles that have been implicated in signal transduction, cell to cell communication, left and right pattern embryonic development, sensation of fluid flow, regulation of calcium levels, mechanosensation, growth factor signaling and cell cycle progression. Defects in the formation and/or function of these structures underlie a variety of human diseases such as Alström, Bardet-Biedl, Joubert, Meckel-Gruber and oral-facial-digital type 1 syndromes. The expression and function of primary cilia in cancer cells has now become a focus of attention but has not been studied in astrocytomas/glioblastomas. To begin to address this issue, we compared the structure and expression of primary cilia in a normal human astrocyte cell line with five human astrocytoma/glioblastoma cell lines. Methods Cultured normal human astrocytes and five human astrocytoma/glioblastoma cell lines were examined for primary cilia expression and structure using indirect immunofluorescence and electron microscopy. Monospecific antibodies were used to detect primary cilia and map the relationship between the primary cilia region and sites of endocytosis. Results We show that expression of primary cilia in normal astrocytes is cell cycle related and the primary cilium extends through the cell within a unique structure which we show to be a site of endocytosis. Importantly, we document that in each of the five astrocytoma/glioblastoma cell lines fully formed primary cilia are either expressed at a very low level, are completely absent or have aberrant forms, due to incomplete ciliogenesis. Conclusions The recent discovery of the importance of primary cilia in a variety of cell functions raises the possibility that this structure may have a role in a variety of cancers. Our finding that the formation of the primary cilium is disrupted in cells derived from astrocytoma/glioblastoma tumors provides the first

  4. Cellular and molecular portrait of eleven human glioblastoma cell lines under photon and carbon ion irradiation.

    Science.gov (United States)

    Ferrandon, S; Magné, N; Battiston-Montagne, P; Hau-Desbat, N-H; Diaz, O; Beuve, M; Constanzo, J; Chargari, C; Poncet, D; Chautard, E; Ardail, D; Alphonse, G; Rodriguez-Lafrasse, C

    2015-04-28

    This study aimed to examine the cellular and molecular long-term responses of glioblastomas to radiotherapy and hadrontherapy in order to better understand the biological effects of carbon beams in cancer treatment. Eleven human glioblastoma cell lines, displaying gradual radiosensitivity, were irradiated with photons or carbon ions. Independently of p53 or O(6)-methylguanine-DNA methyltransferase(1) status, all cell lines responded to irradiation by a G2/M phase arrest followed by the appearance of mitotic catastrophe, which was concluded by a ceramide-dependent-apoptotic cell death. Statistical analysis demonstrated that: (i) the SF2(2) and the D10(3) values for photon are correlated with that obtained in response to carbon ions; (ii) regardless of the p53, MGMT status, and radiosensitivity, the release of ceramide is associated with the induction of late apoptosis; and (iii) the appearance of polyploid cells after photon irradiation could predict the Relative Biological Efficiency(4) to carbon ions. This large collection of data should increase our knowledge in glioblastoma radiobiology in order to better understand, and to later individualize, appropriate radiotherapy treatment for patients who are good candidates. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells

    Directory of Open Access Journals (Sweden)

    Diane D. Mao

    2015-06-01

    Full Text Available Glioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma.

  6. [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.

  7. 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.

  8. Regulation of YKL-40 expression during genotoxic or microenvironmental stress in human glioblastoma cells

    DEFF Research Database (Denmark)

    Junker, Nanna; Johansen, Julia S; Hansen, Lasse T

    2005-01-01

    material from glioblastomas patients. We investigated the expression of YKL-40 in three human malignant glioma cell lines exposed to different types of stress. Whereas a polymerase chain reaction transcript was detectable in all three cell lines, only U87 produced measurable amounts of YKL-40 protein. In U...... is attenuated by p53. In contrast, both basic fibroblast growth factor and tumor necrosing factor-alpha repressed YKL-40. These are the first data on regulation of YKL-40 in cancer cells. Diverse types of stress resulted in YKL-40 elevation, which strongly supports an involvement of YKL-40 in the malignant...

  9. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    NARCIS (Netherlands)

    Chin, L.; Meyerson, M.; Aldape, K.; Bigner, D.; Mikkelsen, T.; VandenBerg, S.; Kahn, A.; Penny, R.; Gerhard, D. S.; Getz, G.; Brennan, C.; Taylor, B. S.; Winckler, W.; Park, P.; Ladanyi, M.; Hoadley, K. A.; Verhaak, R. G. W.; Hayes, D. N.; Spellman, Paul T.; Absher, D.; Weir, B. A.; Ding, L.; Wheeler, D.; Lawrence, M. S.; Cibulskis, K.; Mardis, E.; Zhang, Jinghui; Wilson, R. K.; Donehower, L.; Wheeler, D. A.; Purdom, E.; Wallis, J.; Laird, P. W.; Herman, J. G.; Schuebel, K. E.; Weisenberger, D. J.; Baylin, S. B.; Schultz, N.; Yao, Jun; Wiedemeyer, R.; Weinstein, J.; Sander, C.; Gibbs, R. A.; Gray, J.; Kucherlapati, R.; Lander, E. S.; Myers, R. M.; Perou, C. M.; McLendon, Roger; Friedman, Allan; Van Meir, Erwin G; Brat, Daniel J; Mastrogianakis, Gena Marie; Olson, Jeffrey J; Lehman, Norman; Yung, W. K. Alfred; Bogler, Oliver; Berger, Mitchel; Prados, Michael; Muzny, Donna; Morgan, Margaret; Scherer, Steve; Sabo, Aniko; Nazareth, Lynn; Lewis, Lora; Hall, Otis; Zhu, Yiming; Ren, Yanru; Alvi, Omar; Yao, Jiqiang; Hawes, Alicia; Jhangiani, Shalini; Fowler, Gerald; San Lucas, Anthony; Kovar, Christie; Cree, Andrew; Dinh, Huyen; Santibanez, Jireh; Joshi, Vandita; Gonzalez-Garay, Manuel L.; Miller, Christopher A.; Milosavljevic, Aleksandar; Sougnez, Carrie; Fennell, Tim; Mahan, Scott; Wilkinson, Jane; Ziaugra, Liuda; Onofrio, Robert; Bloom, Toby; Nicol, Rob; Ardlie, Kristin; Baldwin, Jennifer; Gabriel, Stacey; Fulton, Robert S.; McLellan, Michael D.; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.; O'Kelly, Michael; Robinson, Jim; Alexe, Gabriele; Beroukhim, Rameen; Carter, Scott; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Garraway, Levi; Golub, Todd; Protopopov, Alexei; Perna, Ilana; Aronson, Sandy; Sathiamoorthy, Narayan; Ren, Georgia; Kim, Hyunsoo; Kong, Sek Won; Xiao, Yonghong; Kohane, Isaac S.; Seidman, Jon; Cope, Leslie; Pan, Fei; Van Den Berg, David; Van Neste, Leander; Yi, Joo Mi; Li, Jun Z.; Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin; Brooks, James D.; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Choi, Yoon Gi; Han, Ju; Ray, Amrita; Wang, Victoria; Durinck, Steffen; Robinson, Mark; Wang, Nicholas J.; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Fontenay, Gerald V.; Ngai, John; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.; Speed, Terence P.; Socci, Nicholas D.; Olshen, Adam; Lash, Alex; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wang, Wei Qing; Qin, Li-Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Topal, Michael D.; Qi, Yuan; Balu, Sai; Shi, Yan; Wu, George; Bittner, Michael; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin; Schaefer, Carl; Madhavan, Subha; Buetow, Ken; Barker, Anna; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth

    2008-01-01

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular

  10. 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

  11. 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.

  12. Platinum (IV) coiled coil nanotubes selectively kill human glioblastoma cells.

    Science.gov (United States)

    Thanasupawat, Thatchawan; Bergen, Hugo; Hombach-Klonisch, Sabine; Krcek, Jerry; Ghavami, Saeid; Del Bigio, Marc R; Krawitz, Sherry; Stelmack, Gerald; Halayko, Andrew; McDougall, Matthew; Meier, Markus; Stetefeld, Jörg; Klonisch, Thomas

    2015-05-01

    Malignant glioma are often fatal and pose a significant therapeutic challenge. Here we have employed α-helical right handed coiled coils (RHCC) which self-assemble into tetrameric nanotubes that stably associate with platinum (Pt) (IV) compound. This Pt(IV)-RHCC complex showed superior in vitro and in vivo toxicity in human malignant glioma cells at up to 5 fold lower platinum concentrations when compared to free Pt(IV). Pt(IV)-RHCC nanotubes activated multiple cell death pathways in GB cells without affecting astrocytes in vitro or causing damage to normal mouse brain. This Pt(IV)-RHCC nanotubes may serve as a promising new therapeutic tool for low dose Pt(IV) prodrug application for highly efficient and selective treatment of human brain tumors. The prognosis of malignant glioma remains poor despite medical advances. Platinum, one of the chemotherapeutic agents used, has significant systemic side effects. In this article, the authors employed α-helical right handed coiled coil (RHCC) protein nanotubes as a carrier for cisplatin. It was shown that the new compound achieved higher tumor kill rate but lower toxicity to normal cells and thus may hold promise to be a highly efficient treatment for the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Comparing sequencing assays and human-machine analyses in actionable genomics for glioblastoma.

    Science.gov (United States)

    Wrzeszczynski, Kazimierz O; Frank, Mayu O; Koyama, Takahiko; Rhrissorrakrai, Kahn; Robine, Nicolas; Utro, Filippo; Emde, Anne-Katrin; Chen, Bo-Juen; Arora, Kanika; Shah, Minita; Vacic, Vladimir; Norel, Raquel; Bilal, Erhan; Bergmann, Ewa A; Moore Vogel, Julia L; Bruce, Jeffrey N; Lassman, Andrew B; Canoll, Peter; Grommes, Christian; Harvey, Steve; Parida, Laxmi; Michelini, Vanessa V; Zody, Michael C; Jobanputra, Vaidehi; Royyuru, Ajay K; Darnell, Robert B

    2017-08-01

    To analyze a glioblastoma tumor specimen with 3 different platforms and compare potentially actionable calls from each. Tumor DNA was analyzed by a commercial targeted panel. In addition, tumor-normal DNA was analyzed by whole-genome sequencing (WGS) and tumor RNA was analyzed by RNA sequencing (RNA-seq). The WGS and RNA-seq data were analyzed by a team of bioinformaticians and cancer oncologists, and separately by IBM Watson Genomic Analytics (WGA), an automated system for prioritizing somatic variants and identifying drugs. More variants were identified by WGS/RNA analysis than by targeted panels. WGA completed a comparable analysis in a fraction of the time required by the human analysts. The development of an effective human-machine interface in the analysis of deep cancer genomic datasets may provide potentially clinically actionable calls for individual patients in a more timely and efficient manner than currently possible. NCT02725684.

  14. Overexpression of FADD and Caspase-8 inhibits proliferation and promotes apoptosis of human glioblastoma cells.

    Science.gov (United States)

    Wang, Hong-Bin; Li, Tao; Ma, Dong-Zhou; Ji, Yan-Xin; Zhi, Hua

    2017-09-01

    The study aimed at exploring the effects involved in Fas-Associated protein with Death Domain (FADD) expression and cysteine-aspartic acid specific protease-8 (Caspase-8) in relation to the proliferation and apoptosis of human glioblastoma (GBM) cells. 93 GBM tissues and 64 normal brain tissues were the central mediums used for the investigation of the study. Cultured human GBM SC189 cells were divided into separate groups including the blank negative control (NC), FADD and Caspase-8 groups. The mRNA and protein expressions of FADD and Caspase-8 in tissues and human glioblastoma (GBM) cells were detected using qRT-PCR and Western blotting techniques. Cell proliferation was tested by CCK-8. Flow cytometry was used for the measure of cell cycle and apoptosis rates. The mRNA and protein expressions of FADD and Caspase-8 in GBM tissues were less than the levels of expression displayed in normal brain tissues. Correlations between the expressions of FADD and Caspase-8 in GBM tissues were analyzed as being linked with the clinical grades of GBM patients. Patients in stage III+IV displayed lower expressions of FADD and Caspase-8 than patients in stage I+II. In comparison with the blank group, the FADD and Caspase-8 groups showed decreased proliferation rates of SHG44 cells and lower ratios of cells in the S phase and Bcl-2 expression. Greater ratios of cells in the G0/G1 stage as well as increased cell apoptosis and expressions of Caspase-8 and Bax were exhibited. The expression of FADD in the FADD group was higher than the blank group, however no significant differences in FADD expression was observed between the blank and Caspase-8 groups. The data obtained during the study demonstrated that overexpression of FADD and Caspase-8 suppresses proliferation whilst promoting the apoptosis of human GBM cells. Copyright © 2017. Published by Elsevier Masson SAS.

  15. 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.

  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. Modeled microgravity suppressed invasion and migration of human glioblastoma U87 cells through downregulating store-operated calcium entry

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Zi-xuan [Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Rao, Wei [Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Wang, Huan [Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Wang, Nan-ding [Department of Cardiology, Xi' an Traditional Chinese Medicine Hospital, Xi' an, 710032 (China); Si, Jing-Wen; Zhao, Jiao; Li, Jun-chang [Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Wang, Zong-ren, E-mail: zongren@fmmu.edu.cn [Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China)

    2015-02-13

    Glioblastoma is the most common brain tumor and is characterized with robust invasion and migration potential resulting in poor prognosis. Previous investigations have demonstrated that modeled microgravity (MMG) could decline the cell proliferation and attenuate the metastasis potential in several cell lines. In this study, we studied the effects of MMG on the invasion and migration potentials of glioblastoma in human glioblastoma U87 cells. We found that MMG stimulation significantly attenuated the invasion and migration potentials, decreased thapsigargin (TG) induced store-operated calcium entry (SOCE) and downregulated the expression of Orai1 in U87 cells. Inhibition of SOCE by 2-APB or stromal interaction molecule 1 (STIM1) downregulation both mimicked the effects of MMG on the invasion and migration potentials in U87 cells. Furthermore, upregulation of Orai1 significantly weakened the effects of MMG on the invasion and migration potentials in U87 cells. Therefore, these findings indicated that MMG stimulation inhibited the invasion and migration potentials of U87 cells by downregulating the expression of Orai1 and sequentially decreasing the SOCE, suggesting that MMG might be a new potential therapeutic strategy in glioblastoma treatment in the future. - Highlights: • Modeled microgravity (MMG) suppressed migration and invasion in U87 cells. • MMG downregulated the SOCE and the expression of Orai1. • SOCE inhibition mimicked the effects of MMG on migration and invasion potentials. • Restoration of SOCE diminished the effects of MMG on migration and invasion.

  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. 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.

  20. 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

  1. In vitro and in vivo effect of human lactoferrin on glioblastoma growth.

    Science.gov (United States)

    Arcella, Antonietta; Oliva, Maria Antonietta; Staffieri, Sabrina; Aalberti, Silvia; Grillea, Giovanni; Madonna, Michele; Bartolo, Marcello; Pavone, Luigi; Giangaspero, Felice; Cantore, Giampaolo; Frati, Alessandro

    2015-10-01

    Human lactoferrin (HLF) is a natural protein with antitumor activity. The aim of this study was to investigate the effects of HLF alone and in combination with temozolomide (TMZ), a conventional chemotherapeutic, on human glioblastoma (GBM) cells. The authors cultured fresh human primary cell lines NMD and FN and the continuous cell line U87MG to evaluate proliferation in the presence of HLF alone at different doses (1, 10, and 100 mg/ml, and 1 mg/ml) and in combination with TMZ. In in vivo experiments they assessed tumor size reduction in CD1 nude mice carrying an orthotopic GBM xenograft and orally treated with HLF. Lactoferrin causes growth inhibition in the NMD and FN primary cell lines and in the U87MG continuous cell line. This inhibition seemed to be modulated by the downregulation of cyclin D1 and D4. Western blot and fluorescence-activated cell sorting analysis showed inhibition of the cell cycle in G0/G1 and G2 phases. When administered in nude mice, HLF (60 mg/kg/day) decreased tumor size about 30%, as shown in both histological analyses and high-field brain MRI. Administration of HLF with TMZ enhanced the effect of chemotherapy both in vitro and in vivo. This study demonstrated that HLF can inhibit GBM cell growth, suggesting that this nontoxic substance may have a role in potentiating the effect of current TMZ treatment of GBM.

  2. Evaluation of the potential of mobile phone specific electromagnetic fields (UMTS) to produce micronuclei in human glioblastoma cell lines.

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    Al-Serori, Halh; Kundi, Michael; Ferk, Franziska; Mišík, Miroslav; Nersesyan, Armen; Murbach, Manuel; Lah, Tamara T; Knasmüller, Siegfried

    2017-04-01

    Some epidemiological studies indicate that mobile phones cause glioblastomas in humans. Since it is known that genomic instability plays a key role in the etiology of cancer, we investigated the effects of the universal mobile telecommunications system radiofrequency (UMTS-RF) signal, which is used in "smart" phones, on micronucleus (MN) formation and other anomalies such as nuclear buds (NBUDs) and nucleoplasmatic bridges (NPBs). MN are formed by structural and numerical aberrations, NBs reflect gene amplification and NPBs are formed from dicentric chromosomes. The experiments were conducted with human glioblastoma cell lines, which differ in regard to their p53 status, namely U87 (wild-type) and U251 (mutated). The cells were cultivated for 16h in presence and absence of fetal calf serum and exposed to different SAR doses (0.25, 0.50 and 1.00W/kg), which reflect the exposure of humans, in presence and absence of mitomycin C as former studies indicate that RF may cause synergistic effects in combination with this drug. We found no evidence for induction of MN and other anomalies. However, with the highest dose, induction of apoptosis was observed in U251 cells on the basis of the morphological features of the cells. Our findings indicate that the UMTS-RF signal does not cause chromosomal damage in glioblastoma cells; the mechanisms which lead to induction of programmed cell death will be investigated in further studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Developmental Pathway Inhibits Differentiation of Human Glioblastoma Tumor Initiating Cells

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    Lee, Jeongwu; Son, Myung Jin; Woolard, Kevin; Donin, Nicholas M.; Li, Aiguo; Cheng, Chui H.; Kotliarova, Svetlana; Kotliarov, Yuri; Walling, Jennifer; Ahn, Susie; Kim, Misuk; Totonchy, Mariam; Cusack, Thomas; Ene, Chibawanye; Ma, Hilary; Su, Qin; Zenklusen, Jean Claude; Zhang, Wei; Maric, Dragan; Fine, Howard A.

    2008-01-01

    SUMMARY Despite similarities between tumor initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues, and by converting otherwise cytostatic signals to pro-proliferative signals. SIGNIFICANCE Elucidation of the differentiation pathways operative and/or aberrant in both normal stem cells and TICs will be critical to fully understand the pathogenesis of primary human tumors and may help lead to better therapies. To this end, we utilized several TICs isolated from primary glioblastomas and compared them to normal human NSCs and mouse NSCs from various developmental stages. We demonstrate a major differentiation block in a subset of glioblastoma TICs is caused by the Polycomb repressor complex (PRC) mediated epigenetic silencing of the BMPR1B promoter, analogous to early embryonic NSCs. We provide here an example of a temporally deregulated and aberrantly fixed developmental block to differentiation contributing to the pathogenesis of a subset of human GBMs. PMID:18167341

  4. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma.

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    Son, Myung Jin; Woolard, Kevin; Nam, Do-Hyun; Lee, Jeongwu; Fine, Howard A

    2009-05-08

    CD133+ populations of human glioblastoma multiforme (GBM) cells are reportedly enriched for tumor stem cells (TSCs) or tumor-initiating cells (TICs). Approximately 40% of freshly isolated GBM specimens, however, do not contain CD133+ tumor cells, raising the possibility that CD133 may not be a universal enrichment marker for GBM TSCs/TICs. Here we demonstrate that stage-specific embryonic antigen 1(SSEA-1/LeX)+ GBM cells fulfill the functional criteria for TSC/TIC, since (1) SSEA-1+ cells are highly tumorigenic in vivo, unlike SSEA-1- cells; (2) SSEA-1+ cells can give rise to both SSEA-1+ and SSEA-1- cells, thereby establishing a cellular hierarchy; and (3) SSEA-1+ cells have self-renewal and multilineage differentiation potentials. A distinct subpopulation of SSEA-1+ cells was present in all but one of the primary GBMs examined (n = 24), and most CD133+ tumor cells were also SSEA-1+, suggesting that SSEA-1 may be a general TSC/TIC enrichment marker in human GBMs.

  5. Identification of novel tumor-associated cell surface sialoglycoproteins in human glioblastoma tumors using quantitative proteomics.

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    François Autelitano

    Full Text Available Glioblastoma multiform (GBM remains clinical indication with significant "unmet medical need". Innovative new therapy to eliminate residual tumor cells and prevent tumor recurrences is critically needed for this deadly disease. A major challenge of GBM research has been the identification of novel molecular therapeutic targets and accurate diagnostic/prognostic biomarkers. Many of the current clinical therapeutic targets of immunotoxins and ligand-directed toxins for high-grade glioma (HGG cells are surface sialylated glycoproteins. Therefore, methods that systematically and quantitatively analyze cell surface sialoglycoproteins in human clinical tumor samples would be useful for the identification of potential diagnostic markers and therapeutic targets for malignant gliomas. In this study, we used the bioorthogonal chemical reporter strategy (BOCR in combination with label-free quantitative mass spectrometry (LFQ-MS to characterize and accurately quantify the individual cell surface sialoproteome in human GBM tissues, in fetal, adult human astrocytes, and in human neural progenitor cells (NPCs. We identified and quantified a total of 843 proteins, including 801 glycoproteins. Among the 843 proteins, 606 (72% are known cell surface or secreted glycoproteins, including 156 CD-antigens, all major classes of cell surface receptor proteins, transporters, and adhesion proteins. Our findings identified several known as well as new cell surface antigens whose expression is predominantly restricted to human GBM tumors as confirmed by microarray transcription profiling, quantitative RT-PCR and immunohistochemical staining. This report presents the comprehensive identification of new biomarkers and therapeutic targets for the treatment of malignant gliomas using quantitative sialoglycoproteomics with clinically relevant, patient derived primary glioma cells.

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

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    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.

  7. Autotaxin inhibition with PF8380 enhances the radiosensitivity of human and murine glioblastoma cell lines

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    Sandeep R Bhave

    2013-09-01

    Full Text Available Purpose: Glioblastoma multiforme (GBM is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo and radiotherapy. Autotaxin (ATX is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM.Methods and Materials: Mouse GL-261 and Human U87MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin-fold model in Gl-261. Heterotopic mouse GL-261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer.Results: Pretreatment of GL-261 and U87-MG cells with 1µM PF-8380 followed by 4Gy irradiation resulted in decreased clonogenic survival, decreased migration (33% in GL-261;P = 0.002 and 17.9% in U87; P = 0.012 decreased invasion (35.6% in GL-261; P = 0.0037 and 31.8% in U87; P = 0.002, and attenuated radiation induced Akt phosphorylation. In the tumor window model inhibition of ATX abrogated radiation-induced tumor neovascularization (65%; P=0.011. In a heterotopic mouse GL-261 tumors untreated mice took 11.2 days to reach a tumor volume of 7000 mm3 , however combination of PF-8380 (10mg/kg with irradiation (5 fractions of 2Gy took more than 32 days to reach a tumor volume of 7000 mm3 .Conclusion: Inhibition of ATX by PF8380 led to decreased invasion and enhanced radiosensitization of glioma cells. Radiation induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate glioblastoma response to radiotherapy.

  8. HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.

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    Ingo Staudacher

    Full Text Available Glioblastoma (GB is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K(+ channels (hERG; Kv11.1, KCNH2 are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC50 = 35 µM and U87MG (EC50 = 29 µM GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3, and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.

  9. HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.

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    Staudacher, Ingo; Jehle, Julian; Staudacher, Kathrin; Pledl, Hans-Werner; Lemke, Dieter; Schweizer, Patrick A; Becker, Rüdiger; Katus, Hugo A; Thomas, Dierk

    2014-01-01

    Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K(+) channels (hERG; Kv11.1, KCNH2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC50 = 35 µM) and U87MG (EC50 = 29 µM) GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3), and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.

  10. 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.

  11. Genome-wide transcriptional profiling of human glioblastoma cells in response to ITE treatment

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    Bo Kang

    2015-09-01

    Full Text Available A ligand-activated transcription factor aryl hydrocarbon receptor (AhR is recently revealed to play a key role in embryogenesis and tumorigenesis (Feng et al. [1], Safe et al. [2] and 2-(1′H-indole-3′-carbonyl-thiazole-4-carboxylic acid methyl ester (ITE (Song et al. [3] is an endogenous AhR ligand that possesses anti-tumor activity. In order to gain insights into how ITE acts via the AhR in embryogenesis and tumorigenesis, we analyzed the genome-wide transcriptional profiles of the following three groups of cells: the human glioblastoma U87 parental cells, U87 tumor sphere cells treated with vehicle (DMSO and U87 tumor sphere cells treated with ITE. Here, we provide the details of the sample gathering strategy and show the quality controls and the analyses associated with our gene array data deposited into the Gene Expression Omnibus (GEO under the accession code of GSE67986.

  12. Response of sodium pump to ouabain challenge in human glioblastoma cells in culture.

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    Huang, Xian; Lei, Zhenmin; Li, Xiao-Ping; El-Mallakh, Rif S

    2009-01-01

    Bipolar disorder is a severe psychiatric condition that manifests with abnormalities in ion regulation. Previous studies have suggested that glia may be specifically involved in the pathophysiology of this condition. Since the potent sodium pump inhibitor, ouabain, has been used previously to model the ionic changes of bipolar illness, we investigated its effect of on sodium pump expression and activity in a human glioblastoma cell line. LN229 cells were grown with or without ouabain 10(-7) M for 3 days, and the effect of a therapeutic concentration of lithium was also examined. The mRNA transcription of sodium pump isoforms was determined by reverse transcriptase polymerase chain reaction (RT-PCR), and the protein expression of phosphorylated and non-phosphorylated pump isoforms was semi-quantified utilizing Western blot. Ouabain treatment caused an increase of some 6-fold in alpha1 protein expression and a doubling of alpha1 mRNA. alpha3 protein and alpha2 and alpha3 mRNA more than doubled. Lithium treatment alone had no effect, but lithium co-administered with ouabain normalized Na pump protein and mRNA expression for alpha1 and 2, but not alpha3. These results suggest that disturbance of ion regulation induces changes in glial cell sodium regulatory systems which are normalized by lithium treatment.

  13. 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.

  14. Adult, embryonic and fetal hemoglobin are expressed in human glioblastoma cells.

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    Emara, Marwan; Turner, A Robert; Allalunis-Turner, Joan

    2014-02-01

    Hemoglobin is a hemoprotein, produced mainly in erythrocytes circulating in the blood. However, non-erythroid hemoglobins have been previously reported in other cell types including human and rodent neurons of embryonic and adult brain, but not astrocytes and oligodendrocytes. Human glioblastoma multiforme (GBM) is the most aggressive tumor among gliomas. However, despite extensive basic and clinical research studies on GBM cells, little is known about glial defence mechanisms that allow these cells to survive and resist various types of treatment. We have shown previously that the newest members of vertebrate globin family, neuroglobin (Ngb) and cytoglobin (Cygb), are expressed in human GBM cells. In this study, we sought to determine whether hemoglobin is also expressed in GBM cells. Conventional RT-PCR, DNA sequencing, western blot analysis, mass spectrometry and fluorescence microscopy were used to investigate globin expression in GBM cell lines (M006x, M059J, M059K, M010b, U87R and U87T) that have unique characteristics in terms of tumor invasion and response to radiotherapy and hypoxia. The data showed that α, β, γ, δ, ζ and ε globins are expressed in all tested GBM cell lines. To our knowledge, we are the first to report expression of fetal, embryonic and adult hemoglobin in GBM cells under normal physiological conditions that may suggest an undefined function of those expressed hemoglobins. Together with our previous reports on globins (Ngb and Cygb) expression in GBM cells, the expression of different hemoglobins may constitute a part of series of active defence mechanisms supporting these cells to resist various types of treatments including chemotherapy and radiotherapy.

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

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    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.

  16. Involvement of miRNAs in the differentiation of human glioblastoma multiforme stem-like cells.

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    Beatriz Aldaz

    Full Text Available Glioblastoma multiforme (GBM-initiating cells (GICs represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process.

  17. A highly invasive human glioblastoma pre-clinical model for testing therapeutics

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    Cao Brian

    2008-12-01

    Full Text Available Abstract Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino-17-demethoxy geldanamycin (17AAG. Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2. These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents.

  18. Rational development and characterization of humanized anti–EGFR variant III chimeric antigen receptor T cells for glioblastoma

    Science.gov (United States)

    Johnson, Laura A.; Scholler, John; Ohkuri, Takayuki; Kosaka, Akemi; Patel, Prachi R.; McGettigan, Shannon E.; Nace, Arben K.; Dentchev, Tzvete; Thekkat, Pramod; Loew, Andreas; Boesteanu, Alina C.; Cogdill, Alexandria P.; Chen, Taylor; Fraietta, Joseph A.; Kloss, Christopher C.; Posey, Avery D.; Engels, Boris; Singh, Reshma; Ezell, Tucker; Idamakanti, Neeraja; Ramones, Melissa H.; Li, Na; Zhou, Li; Plesa, Gabriela; Seykora, John T.; Okada, Hideho; June, Carl H.; Brogdon, Jennifer L.; Maus, Marcela V.

    2015-01-01

    Chimeric antigen receptors (CARs) are synthetic molecules designed to redirect T cells to specific antigens. CAR-modified T cells can mediate long-term durable remissions in B cell malignancies, but expanding this platform to solid tumors requires the discovery of surface targets with limited expression in normal tissues. The variant III mutation of the epidermal growth factor receptor (EGFRvIII) results from an in-frame deletion of a portion of the extracellular domain, creating a neoepitope. We chose a vector backbone encoding a second-generation CAR based on efficacy of a murine scFv–based CAR in a xenograft model of glioblastoma. Next, we generated a panel of humanized scFvs and tested their specificity and function as soluble proteins and in the form of CAR-transduced T cells; a low-affinity scFv was selected on the basis of its specificity for EGFRvIII over wild-type EGFR. The lead candidate scFv was tested in vitro for its ability to direct CAR-transduced T cells to specifically lyse, proliferate, and secrete cytokines in response to antigen-bearing targets. We further evaluated the specificity of the lead CAR candidate in vitro against EGFR-expressing keratinocytes and in vivo in a model of mice grafted with normal human skin. EGFRvIII-directed CAR T cells were also able to control tumor growth in xenogeneic subcutaneous and orthotopic models of human EGFRvIII+ glioblastoma. On the basis of these results, we have designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII in patients with either residual or recurrent glioblastoma (NCT02209376). PMID:25696001

  19. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma.

    Science.gov (United States)

    Johnson, Laura A; Scholler, John; Ohkuri, Takayuki; Kosaka, Akemi; Patel, Prachi R; McGettigan, Shannon E; Nace, Arben K; Dentchev, Tzvete; Thekkat, Pramod; Loew, Andreas; Boesteanu, Alina C; Cogdill, Alexandria P; Chen, Taylor; Fraietta, Joseph A; Kloss, Christopher C; Posey, Avery D; Engels, Boris; Singh, Reshma; Ezell, Tucker; Idamakanti, Neeraja; Ramones, Melissa H; Li, Na; Zhou, Li; Plesa, Gabriela; Seykora, John T; Okada, Hideho; June, Carl H; Brogdon, Jennifer L; Maus, Marcela V

    2015-02-18

    Chimeric antigen receptors (CARs) are synthetic molecules designed to redirect T cells to specific antigens. CAR-modified T cells can mediate long-term durable remissions in B cell malignancies, but expanding this platform to solid tumors requires the discovery of surface targets with limited expression in normal tissues. The variant III mutation of the epidermal growth factor receptor (EGFRvIII) results from an in-frame deletion of a portion of the extracellular domain, creating a neoepitope. We chose a vector backbone encoding a second-generation CAR based on efficacy of a murine scFv-based CAR in a xenograft model of glioblastoma. Next, we generated a panel of humanized scFvs and tested their specificity and function as soluble proteins and in the form of CAR-transduced T cells; a low-affinity scFv was selected on the basis of its specificity for EGFRvIII over wild-type EGFR. The lead candidate scFv was tested in vitro for its ability to direct CAR-transduced T cells to specifically lyse, proliferate, and secrete cytokines in response to antigen-bearing targets. We further evaluated the specificity of the lead CAR candidate in vitro against EGFR-expressing keratinocytes and in vivo in a model of mice grafted with normal human skin. EGFRvIII-directed CAR T cells were also able to control tumor growth in xenogeneic subcutaneous and orthotopic models of human EGFRvIII(+) glioblastoma. On the basis of these results, we have designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII in patients with either residual or recurrent glioblastoma (NCT02209376). Copyright © 2015, American Association for the Advancement of Science.

  20. MitoCeption: Transferring Isolated Human MSC Mitochondria to Glioblastoma Stem Cells.

    Science.gov (United States)

    Nzigou Mombo, Brice; Gerbal-Chaloin, Sabine; Bokus, Aleksandra; Daujat-Chavanieu, Martine; Jorgensen, Christian; Hugnot, Jean-Philippe; Vignais, Marie-Luce

    2017-02-22

    Mitochondria play a central role for cell metabolism, energy production and control of apoptosis. Inadequate mitochondrial function has been found responsible for very diverse diseases, ranging from neurological pathologies to cancer. Interestingly, mitochondria have recently been shown to display the capacity to be transferred between cell types, notably from human mesenchymal stem cells (MSC) to cancer cells in coculture conditions, with metabolic and functional consequences for the mitochondria recipient cells, further enhancing the current interest for the biological properties of these organelles. Evaluating the effects of the transferred MSC mitochondria in the target cells is of primary importance to understand the biological outcome of such cell-cell interactions. The MitoCeption protocol described here allows the transfer of the mitochondria isolated beforehand from the donor cells to the target cells, using MSC mitochondria and glioblastoma stem cells (GSC) as a model system. This protocol has previously been used to transfer mitochondria, isolated from MSCs, to adherent MDA-MB-231 cancer cells. This mitochondria transfer protocol is adapted here for GSCs that present the specific particularity of growing as neurospheres in vitro. The transfer of the isolated mitochondria can be followed by fluorescence-activated cell sorting (FACS) and confocal imaging using mitochondria vital dyes. The use of mitochondria donor and target cells with distinct haplotypes (SNPs) also allows detection of the transferred mitochondria based on the concentration of their circular mitochondrial DNA (mtDNA) in the target cells. Once the protocol has been validated with these criteria, the cells harboring the transferred mitochondria can be further analyzed to determine the effects of the exogenous mitochondria on biological properties such as cell metabolism, plasticity, proliferation and response to therapy.

  1. Antitumour action on human glioblastoma A1235 cells through cooperation of bee venom and cisplatin.

    Science.gov (United States)

    Gajski, Goran; Čimbora-Zovko, Tamara; Rak, Sanjica; Osmak, Maja; Garaj-Vrhovac, Vera

    2016-08-01

    Cisplatin (cDDP) is one of the most widely used anticancer-drugs in both therapy and research. However, cDDP-resistance is the greatest obstacle for the successful treatment of cancer patients. In the present study, the possible joint anticancer effect of bee venom (BV), as a natural toxin, and cDDP towards human glioblastoma A1235 cells was evaluated. Treatment with BV alone in concentrations of 2.5-30 μg/ml displayed dose-dependent cytotoxicity towards A1235 cells, as evaluated with different cytotoxicity assays (MTT, Cristal violet and Trypan blue exclusion assay), with an IC50 value of 22.57 μg/ml based on the MTT results. Furthermore, BV treatment induced necrosis, which was confirmed by typical morphological features and fast staining with ethidium-bromide dye. Pre-treatment with BV induced cell sensitization to cDDP, indicating that BV could improve the killing effect of selected cells when combined with cDDP. The isobologram method used to determine the extent of synergism in combining two agents to examine their possible therapeutic effect showed that combined treatment induced an additive and/or synergistic effect towards selected cells depending on the concentration of both. Hence, a greater anticancer effect could be triggered if BV was used in the course of chemotherapy. The obtained results indicate that joint treatment with BV could be useful from the point of minimizing the cDDP concentration during chemotherapy, thus reducing and/or postponing the development of drug resistance. Our data, in accordance with previously reported results, suggests that BV could be used in the development of a new strategy for cancer treatment.

  2. The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro

    Directory of Open Access Journals (Sweden)

    Budach Wilfried

    2006-03-01

    Full Text Available Abstract Background Alkylphosphocholines constitute a novel class of antineoplastic synthetic phospholipid derivatives that induce apoptosis of human tumor cell lines by targeting cellular membranes. We could recently show that the first intravenously applicable alkylphosphocholine erucylphosphocholine (ErPC is a potent inducer of apoptosis in highly resistant human astrocytoma/glioblastoma cell lines in vitro. ErPC was shown to cross the blood brain barrier upon repeated intravenous injections in rats and thus constitutes a promising candidate for glioblastoma therapy. Aim of the present study was to analyze putative beneficial effects of ErPC and its clinically more advanced derivative erucylphosphohomocholine (erucyl-N, N, N-trimethylpropanolaminphosphate, ErPC3, Erufosine™ on radiation-induced apoptosis and eradication of clonogenic tumor cells in human astrocytoma/glioblastoma cell lines in vitro. Results While all cell lines showed high intrinsic resistance against radiation-induced apoptosis as determined by fluorescence microscopy, treatment with ErPC and ErPC3 strongly increased sensitivity of the cells to radiation-induced cell death (apoptosis and necrosis. T98G cells were most responsive to the combined treatment revealing highly synergistic effects while A172 showed mostly additive to synergistic effects, and U87MG cells sub-additive, additive or synergistic effects, depending on the respective radiation-dose, drug-concentration and treatment time. Combined treatment enhanced therapy-induced damage of the mitochondria and caspase-activation. Importantly, combined treatment also increased radiation-induced eradication of clonogenic T98G cells as determined by standard colony formation assays. Conclusion Our observations make the combined treatment with ionizing radiation and the membrane targeted apoptosis modulators ErPC and ErPC3 a promising approach for the treatment of patients suffering from malignant glioma. The use of this

  3. 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

  4. 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

  5. Impact of anemia prevention by recombinant human erythropoietin on the sensitivity of xenografted glioblastomas to fractionated irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Stueben, G.; Poettgen, C.; Knuehmann, K.; Sack, H.; Stuschke, M. [West German Tumor Center, Dept. of Radiotherapy, Univ. Hospital Essen (Germany); Thews, O.; Vaupel, P. [Inst. of Physiology and Pathophysiology, Univ. of Mainz (Germany)

    2003-09-01

    Background: Pronounced oxygen deficiency in tumors which might be caused by a diminished oxygen transport capacity of the blood (e.g., in anemia) reduces the efficacy of ionizing radiation. The aim of this study was to analyze whether anemia prevention by recombinant human erythropoietin (rHuEPO) affects the radiosensitivity of human glioblastoma xenografts during fractionated irradiation. Material and Methods: Anemia was induced by total body irradiation (TBI, 2 x 4 Gy) of mice prior to tumor implantation into the subcutis of the hind leg. In one experimental group, the development of anemia was prevented by rHuEPO (750 U/kg s.c.) given three times weekly starting 10 days prior to TBI. 13 days after tumor implantation (tumor volume approx. 40 mm{sup 3}), fractionated irradiation (4 x 7 Gy, one daily fraction) of the glioblastomas was performed resulting in a growth delay with subsequent regrowth of the tumors. Results: Compared to nonanemic control animals (hemoglobin concentration cHb = 14.7 g/dl), the growth delay in anemic mice (cHb = 9.9 g/dl) was significantly shorter (49 {+-} 5 days vs. 79 {+-} 4 days to reach four times the initial tumor volume) upon fractionated radiation. The prevention of anemia by rHuEPO treatment (cHb = 13.3 g/dl) resulted in a significantly prolonged growth delay (61 {+-} 5 days) compared to the anemia group, even though the growth inhibition found in control animals was not completely achieved. Conclusions: These data indicate that moderate anemia significantly reduces the efficacy of radiotherapy. Prevention of anemia with rHuEPO partially restores the radiosensitivity of xenografted glioblastomas to fractionated irradiation. (orig.)

  6. 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.)

  7. 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

  8. Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal?

    Science.gov (United States)

    Clavreul, Anne; Pourbaghi-Masouleh, Milad; Roger, Emilie; Lautram, Nolwenn; Montero-Menei, Claudia N; Menei, Philippe

    2017-09-29

    Glioblastoma (GB) is the most malignant brain tumor in adults. It is characterized by angiogenesis and a high proliferative and invasive capacity. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) is of limited efficacy. Innovative anticancer drugs targeting both tumor cells and angiogenesis are urgently required, together with effective systems for their delivery to the brain. We assessed the ability of human mesenchymal stromal cells (MSCs) to uptake the multikinase inhibitor, sorafenib (SFN), and to carry this drug to a brain tumor following intranasal administration. MSCs were primed with SFN and drug content and release were quantified by analytical chemistry techniques. The ability of SFN-primed MSCs to inhibit the survival of the human U87MG GB cell line and endothelial cells was assessed in in vitro assays. These cells were then administered intranasally to nude mice bearing intracerebral U87MG xenografts. Their effect on tumor growth and angiogenesis was evaluated by magnetic resonance imaging and immunofluorescence analyses, and was compared with the intranasal administration of unprimed MSCs or SFN alone. MSCs took up about 9 pg SFN per cell, with no effect on viability, and were able to release 60% of the primed drug. The cytostatic activity of the released SFN was entirely conserved, resulting in a significant inhibition of U87MG and endothelial cell survival in vitro. Two intranasal administrations of SFN-primed MSCs in U87MG-bearing mice resulted in lower levels of tumor angiogenesis than the injection of unprimed MSCs or SFN alone, but had no effect on tumor volume. We also observed an increase in the proportion of small intratumoral vessels in animals treated with unprimed MSCs; this effect being abolished if the MSCs were primed with SFN. We show the potential of MSCs to carry SFN to brain tumors following an intranasal administration. However, the therapeutic effect is modest probably due to the pro

  9. Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of U-87MG Human Glioblastoma in Nude Mice

    Directory of Open Access Journals (Sweden)

    Hippokratis Kiaris

    2000-05-01

    Full Text Available Antagonists of growth hormone-releasing hormone(GH-RH inhibit the growth of various cancers by mechanisms that involve the suppression of the insulin-like growth factor (IGF -I and/or IGF-II. In view of the importance of the IGF system in glioma tumorigenesis, the effects of GH-RH antagonists MZ-5-156 and JV-1-36 were investigated in nude mice bearing subcutaneous and orthotopic xenografts of U-87MG human glioblastomas. After 4 weeks of therapy with MZ-5-156 or JV-1-36 at the dose of 20 µmg/day per animal, the final volume of subcutaneous U-87MG tumors was significantly (P < .01 decreased by 84% and 76%, respectively, as compared with controls. Treatment with GHRH antagonists also reduced tumor weight and the levels of mRNA for IGF receptor type I (IGFR-I. A reduction in the mRNA levels for IGF-II was found in tumors of mice treated with MZ-5-156. Treatment with MZ-5-156 or JV-1-36 also extended the survival of nude mice implanted orthotopically with U-87MG glioblastomas by 81% (P < .005 and 18%, respectively, as compared with the controls. Exposure in vitro to GH-RH antagonists MZ-5-156 or JV-1-36 at 1 MM concentration for 24 hours decreased the tumorigenicity of U-87MG cells in nude mice by 10% to 30% and extended the latency period for the development of subcutaneous palpable tumors by 31% to 56%, as compared with the controls. Exposure of U-87MG cells to GH-RH antagonists in vitro also resulted in a time-dependent increase in the mRNA levels of IGFR-II or a decrease in the mRNA levels of IGFR-I. mRNA for GH-RH was detected in U87MG cells and xenografts implying that GH-RH may play a role in the pathogenesis of this tumor. Our results suggest that GH-RH antagonists MZ-5-156 and JV-136 inhibit the growth of U-87MG human glioblastoma by mechanisms that involve the suppression of IGF system. Antagonistic analogs of GH-RH merit further development for the treatment of malignant glioblastoma.

  10. Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215.

    Science.gov (United States)

    Szereday, Z; Schally, A V; Nagy, A; Plonowski, A; Bajo, A M; Halmos, G; Szepeshazi, K; Groot, K

    2002-04-22

    Some brain tumours, such as glioblastomas express high levels of receptors for bombesin/gastrin releasing peptide. We investigated whether bombesin/gastrin releasing peptide receptors found in glioblastoma cell lines can be utilised for targeting of a cytotoxic bombesin analogue, AN-215 consisting of a potent derivative of doxorubicin, 2-pyrrolino-doxorubicin (AN-201) linked to a bombesin-like peptide carrier. This study reports the effect of AN-215 on the growth of U-87MG human glioblastomas xenografted into nude mice. High affinity binding of AN-215 to U-87MG tumours was characterised by an IC(50) value of 4.0+/-0.1 nM, as determined by radioreceptor assays. mRNA analyses revealed the presence of mRNA for BN receptor subtypes 1 and 2. Treatment with AN-215 significantly (P<0.05) extended tumour doubling time from 4.54+/-0.2 days to 8.18+/-1.8 days and inhibited tumour growth as demonstrated by a 69.6% reduction in final tumour volume (P<0.001) and a 64.6% decrease in tumour weight as compared to controls. Cytotoxic radical AN-201 at the same dose was ineffective. The antitumour effect of AN-215 could be blocked by pretreatment with an excess of a bombesin antagonist, indicating that the action of this cytotoxic analogue is receptor-mediated. Our results suggest that patients with inoperable brain tumours such as malignant gliomas may benefit from targeted chemotherapy based on cytotoxic bombesin analogue AN-215. Copyright 2002 Cancer Research UK

  11. 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.

  12. Combination of Oncolytic Herpes Simplex Viruses Armed with Angiostatin and IL-12 Enhances Antitumor Efficacy in Human Glioblastoma Models

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    2013-06-01

    Full Text Available Oncolytic herpes simplex virus (oHSV can potentially spread throughout the tumor, reach isolated infiltrating cells, kill them, and deliver anticancer agents. However, the host responds to oHSV by inducing intratumoral infiltration of macrophages that can engulf the virus, limiting the potential of this therapeutic strategy. Hypervascularity is a pathognomonic feature of glioblastoma (GBM and is a promising therapeutic target. Antiangiogenic treatments have multiple benefits, including the capacity to increase oHSV efficacy by suppressing macrophage extravasation and infiltration into the tumor. Angiostatin is an antiangiogenic polypeptide, and interleukin-12 (IL-12 is an immunostimulatory cytokine with strong antiangiogenic effects. Clinical use of each has been limited by delivery issues and systemic toxicity.We tested a combination treatment strategy using oHSVs expressing angiostatin (G47Δ-mAngio and IL-12 (G47Δ-mIL12 in two orthotopic human GBMmodels. Intratumoral injection of G47Δ-mAngio and G47Δ-mIL12 in mice bearing intracranial U87 or tumors derived from glioblastoma stem cells significantly prolonged survival compared to each armed oHSV alone. This was associated with increased antiangiogenesis and virus spread and decreased macrophages. These data support the paradigm of using oHSV expressing different antiangiogenic agents and show for the first time that oHSVs expressing angiostatin and IL-12 can improve efficacy in human GBM models.

  13. 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.

  14. Delayed IFN response differentiates replication of West Nile virus and Japanese encephalitis virus in human neuroblastoma and glioblastoma cells.

    Science.gov (United States)

    Takamatsu, Yuki; Uchida, Leo; Morita, Kouichi

    2015-08-01

    West Nile virus (WNV) and Japanese encephalitis virus (JEV) are important causes of human encephalitis cases, which result in a high mortality ratio and neurological sequelae after recovery. Understanding the mechanism of neuropathogenicity in these viral infections is important for the development of specific antiviral therapy. Here, we focused on human-derived neuronal and glial cells to understand the cellular responses against WNV and JEV infection. It was demonstrated that early IFN-β induction regulated virus replication in glioblastoma tbl98G cells, whereas delayed IFN-β induction resulted in efficient virus replication in neuroblastoma SK-N-SH cells. Moreover, the concealing of viral dsRNA in the intracellular membrane resulted in the delayed IFN response in SK-N-SH cells. These results, which showed different IFN responses between human neuronal and glial cells after WNV or JEV infection, are expected to contribute to our understanding of the molecular mechanisms for neuropathology in these viral infections.

  15. Columbia University: Computational Human High-grade Glioblastoma Multiforme Interactome - miRNA (Post-transcriptional) Layer | Office of Cancer Genomics

    Science.gov (United States)

    The Human High-Grade Glioma Interactome (HGi) contains a genome-wide complement of molecular interactions that are Glioblastoma Multiforme (GBM)-specific. HGi v3 contains the post-transcriptional layer of the HGi, which includes the miRNA-target (RNA-RNA) layer of the interactome. Read the Abstract

  16. [Initial antiretroviral treatment in human immunodeficiency virus-infected patients in Spain: Decisions made in relation to particular immunovirological characteristics (PERFIL-es study)].

    Science.gov (United States)

    Viciana, Pompeyo; Ocampo, Antonio; Hevia, Henar; Palazuelos, Marta; Ledesma, Francisco

    2014-02-01

    The purpose of Perfil-es study was to identify the proportion of patients starting ARV treatment based on NNRTIs or PI/r, and to identify the variables involved in the therapeutic decision-making in standard clinical practice. An observational retrospective study performed in 65 Spanish hospitals. Was a total of 1,687 starts: 53% with NNRTI-based regimen and 42% with PI/r, and of the 642 patients analyzed, 72% had a CD4 count<350 cells/μl. The initiation of ARV treatment is still late in Spain. NNRTIs are the more frequent choice, although PI/r plays an important role. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  17. 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...

  18. Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells

    DEFF Research Database (Denmark)

    Fornara, O; Bartek, J; Rahbar, A

    2016-01-01

    Glioblastoma (GBM) is associated with poor prognosis despite aggressive surgical resection, chemotherapy, and radiation therapy. Unfortunately, this standard therapy does not target glioma cancer stem cells (GCSCs), a subpopulation of GBM cells that can give rise to recurrent tumors. GBMs express......-expression of these two proteins predicted poor patient survival. Infection of GBM cells with HCMV led to upregulation of CD133 and other GSCS markers (Notch1, Sox2, Oct4, Nestin). HCMV infection also promoted the growth of GBM cells as neurospheres, a behavior typically displayed by GCSCs, and this phenotype...... cells to promote GCSC features and may thereby increase the aggressiveness of this tumor....

  19. 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...

  20. 18F-FET and 18F-FCH uptake in human glioblastoma T98G cell lines

    Directory of Open Access Journals (Sweden)

    Persico Marco Giovanni

    2016-06-01

    Full Text Available Despite complex treatment of surgery, radiotherapy and chemotherapy, high grade gliomas often recur. Differentiation between post-treatment changes and recurrence is difficult. 18F-methyl-choline (18F-FCH is frequently used in staging and detection of recurrent prostate cancer disease as well as some brain tumours; however accumulation in inflammatory tissue limits its specificity. The 18F-ethyl-tyrosine (18F-FET shows a specific uptake in malignant cells, resulting from increased expression of amino acid transporters or diffusing through the disrupted blood-brain barrier. 18F-FET exhibits lower uptake in machrophages and other inflammatory cells. Aim of this study was to evaluate 18F-FCH and 18F-FET uptake by human glioblastoma T98G cells.

  1. Calcium-independent disruption of microtubule dynamics by nanosecond pulsed electric fields in U87 human glioblastoma cells

    Science.gov (United States)

    Carr, Lynn; Bardet, Sylvia M.; Burke, Ryan C.; Arnaud-Cormos, Delia; Leveque, Philippe; O’Connor, Rodney P.

    2017-01-01

    High powered, nanosecond duration, pulsed electric fields (nsPEF) cause cell death by a mechanism that is not fully understood and have been proposed as a targeted cancer therapy. Numerous chemotherapeutics work by disrupting microtubules. As microtubules are affected by electrical fields, this study looks at the possibility of disrupting them electrically with nsPEF. Human glioblastoma cells (U87-MG) treated with 100, 10 ns, 44 kV/cm pulses at a frequency of 10 Hz showed a breakdown of their interphase microtubule network that was accompanied by a reduction in the number of growing microtubules. This effect is temporally linked to loss of mitochondrial membrane potential and independent of cellular swelling and calcium influx, two factors that disrupt microtubule growth dynamics. Super-resolution microscopy revealed microtubule buckling and breaking as a result of nsPEF application, suggesting that nsPEF may act directly on microtubules. PMID:28117459

  2. Identification of a novel antagonist of the ErbB1 receptor capable of inhibiting migration of human glioblastoma cells

    DEFF Research Database (Denmark)

    Staberg, Mikkel; Riemer, Christian; Xu, Ruodan

    2013-01-01

    BACKGROUND: Receptors of the ErbB family are involved in the development of various cancers, and the inhibition of these receptors represents an attractive therapeutic concept. Upon ligand binding, ErbB receptors become activated as homo- or heterodimers, leading to the activation of downstream......B1 targeting peptide, termed Herfin-1, was designed based on a model of the tertiary structure of the EGF-EGFR ternary complex. The binding kinetics of this peptide were determined employing surface plasmon resonance analyses. ErbB1-4 expression and phosphorylation in human glioblastoma cell lines U....... Additionally, Herfin-1 was found to increase neurite outgrowth in cerebellar granule neurons, likely through the inhibition of a sustained weak ErbB1 activation. CONCLUSIONS: Targeting the ErbB1 receptor dimerization interface is a promising strategy to inhibit receptor activation in ErbB1-expressing glioma...

  3. Targeting CXCR4 by a selective peptide antagonist modulates tumor microenvironment and microglia reactivity in a human glioblastoma model.

    Science.gov (United States)

    Mercurio, Laura; Ajmone-Cat, Maria Antonietta; Cecchetti, Serena; Ricci, Alessandro; Bozzuto, Giuseppina; Molinari, Agnese; Manni, Isabella; Pollo, Bianca; Scala, Stefania; Carpinelli, Giulia; Minghetti, Luisa

    2016-03-25

    The CXCL12/CXCR4 pathway regulates tumor cell proliferation, metastasis, angiogenesis and the tumor-microenvironment cross-talk in several solid tumors, including glioblastoma (GBM), the most common and fatal brain cancer. In the present study, we evaluated the effects of peptide R, a new specific CXCR4 antagonist that we recently developed by a ligand-based approach, in an in vitro and in vivo model of GBM. The well-characterized CXCR4 antagonist Plerixafor was also included in the study. The effects of peptide R on CXCR4 expression, cell survival and migration were assessed on the human glioblastoma cell line U87MG exposed to CXCL12, by immunofluorescence and western blotting, MTT assay, flow cytometry and transwell chamber migration assay. Peptide R was then tested in vivo, by using U87MG intracranial xenografts in CD1 nude mice. Peptide R was administered for 23 days since cell implantation and tumor volume was assessed by magnetic resonance imaging (MRI) at 4.7 T. Glioma associated microglia/macrophage (GAMs) polarization (anti-tumor M1 versus pro-tumor M2 phenotypes) and expressions of vascular endothelial growth factor (VEGF) and CD31 were assessed by immunohistochemistry and immunofluorescence. We found that peptide R impairs the metabolic activity and cell proliferation of human U87MG cells and stably reduces CXCR4 expression and cell migration in response to CXCL12 in vitro. In the orthotopic U87MG model, peptide R reduced tumor cellularity, promoted M1 features of GAMs and astrogliosis, and hindered intra-tumor vasculature. Our findings suggest that targeting CXCR4 by peptide R might represent a novel therapeutic approach against GBM, and contribute to the rationale to further explore in more complex pre-clinical settings the therapeutic potential of peptide R, alone or in combination with standard therapies of GBM.

  4. The critical role of EGF-β-catenin signaling in the epithelial-mesenchymal transition in human glioblastoma

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    Wang X

    2017-05-01

    Full Text Available Xingqiang Wang, Shanshi Wang, Xiaolong Li, Shigang Jin, Feng Xiong, Xin Wang Department of Neurosurgery, People’s Hospital of Rizhao, Jining Medical University, Rizhao, China Abstract: To date, β-catenin has been reported to be implicated in mediating the epithelial-mesenchymal transition (EMT in a variety of human cancers, which can be triggered by EGF. However, the mechanisms underlying EGF-β-catenin pathway-induced EMT of glioblastoma multiforme (GBM have not been reported previously. In the present study, immunohistochemistry, reverse transcription polymerase chain reaction, and Western blot were applied to investigate the effect of EGF-β-catenin pathway on EMT of GBM. Here, we identified that β-catenin mRNA and protein levels were up-regulated in GBM tissues and four kinds of glioblastoma cell lines, including T98G, A172, U87, and U251 cells, compared with normal brain tissue and astrocytes. In U87 cell line, inhibition of β-catenin by siRNA suppressed EGF-induced proliferation, migration, invasiveness, and the expression of EMT activators (Snail and Slug. In addition, the expression of epithelial markers (E-cadherin was up-regulated and the expression of mesenchymal markers (N-cadherin and MMP9 was down-regulated. Finally, inhibitor of PI3K/Akt signaling pathways inactivated the EGF-β-catenin-induced EMT. In conclusion, β-catenin-EMT pathway induced by EGF is important for GBM progression by the PI3K/Akt pathways. Inhibition of β-catenin leads to suppression of EGF pathway-induced EMT, which provides a new way to treat GBM patients. Keywords: EGF, β-catenin, EMT, GBM

  5. The Effect of Z-Ligustilide on the Mobility of Human Glioblastoma T98G Cells.

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    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.

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

    Science.gov (United States)

    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.

  7. 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

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

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    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.

  9. 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.

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

    Science.gov (United States)

    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 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. CONCLUSIONS: These results indicate that Mirin can effectively enhance glioma cell radiosensitivity. It suggests that Mirin is a potent radiosensitizer for treating glioma cells. SECONDARY CATEGORY: n/a.

  11. Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells.

    Science.gov (United States)

    Chou, Yu-Cheng; Chang, Meng-Ya; Wang, Mei-Jen; Liu, Hsin-Chung; Chang, Shu-Jen; Harnod, Tomor; Hung, Chih-Huang; Lee, Hsu-Tung; Shen, Chiung-Chyi; Chung, Jing-Gung

    2017-01-01

    Glioblastoma is the most common and aggressive primary brain malignancy. Phenethyl isothiocyanate (PEITC), a member of the isothiocyanate family, can induce apoptosis in many human cancer cells. Our previous study disclosed that PEITC induces apoptosis through the extrinsic pathway, dysfunction of mitochondria, reactive oxygen species (ROS)-induced endoplasmic reticulum (ER) stress, and intrinsic (mitochondrial) pathway in human brain glioblastoma multiforme (GBM) 8401 cells. To the best of our knowledge, we first investigated the effects of PEITC on the genetic levels of GBM 8401 cells in vitro. PEITC may induce G0/G1 cell-cycle arrest through affecting the proteins such as cdk2, cyclin E, and p21 in GBM 8401 cells. Many genes associated with cell-cycle regulation of GBM 8401 cells were changed after PEITC treatment: 48 genes were upregulated and 118 were downregulated. The cell-division cycle protein 20 (CDC20), Budding uninhibited by benzimidazole 1 homolog beta (BUB1B), and cyclin B1 were downregulated, and clusterin was upregulated in GBM 8401 cells treated with PEITC. These changes of gene expression can provide the effects of PEITC on the genetic levels and potential biomarkers for glioblastoma. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 176-187, 2017. © 2015 Wiley Periodicals, Inc.

  12. Enhanced antitumor efficacy of an oncolytic herpes simplex virus expressing an endostatin-angiostatin fusion gene in human glioblastoma stem cell xenografts.

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    Guobin Zhang

    Full Text Available Viruses have demonstrated strong potential for the therapeutic targeting of glioblastoma stem cells (GSCs. In this study, the use of a herpes simplex virus carrying endostatin-angiostatin (VAE as a novel therapeutic targeting strategy for glioblastoma-derived cancer stem cells was investigated. We isolated six stable GSC-enriched cultures from 36 human glioblastoma specimens and selected one of the stable GSCs lines for establishing GSC-carrying orthotopic nude mouse models. The following results were obtained: (a VAE rapidly proliferated in GSCs and expressed endo-angio in vitro and in vivo 48 h and 10 d after infection, respectively; (b compared with the control gliomas treated with rHSV or Endostar, the subcutaneous gliomas derived from the GSCs showed a significant reduction in microvessel density after VAE treatment; (c compared with the control, a significant improvement was observed in the length of the survival of mice with intracranial and subcutaneous gliomas treated with VAE; (d MRI analysis showed that the tumor volumes of the intracranial gliomas generated by GSCs remarkably decreased after 10 d of VAE treatment compared with the controls. In conclusion, VAE demonstrated oncolytic therapeutic efficacy in animal models of human GSCs and expressed an endostatin-angiostatin fusion gene, which enhanced antitumor efficacy most likely by restricting tumor microvasculature development.

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

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    Yongsheng Li

    2014-01-01

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

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

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    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.

  15. The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV Infected Glioblastoma Cells

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    Melpomeni Tseliou

    2016-01-01

    Full Text Available Background/Aims: Rho GTPases are crucial regulators of the actin cytoskeleton, membrane trafficking and cell signaling and their importance in cell migration and invasion is well- established. The human cytomegalovirus (HCMV is a widespread pathogen responsible for generally asymptomatic and persistent infections in healthy people. Recent evidence indicates that HCMV gene products are expressed in over 90% of malignant type glioblastomas (GBM. In addition, the HCMV Immediate Early-1 protein (IE1 is expressed in >90% of tumors analyzed. Methods: RhoA, RhoB and RhoC were individually depleted in U373MG glioblastoma cells as well as U373MG cells stably expressing the HCMV IE1 protein (named U373MG-IE1 cells shRNA lentivirus vectors. Cell proliferation assays, migration as well as wound-healing assays were performed in uninfected and HCMV-infected cells. Results: The depletion of RhoA, RhoB and RhoC protein resulted in significant alterations in the morphology of the uninfected cells, which were further enhanced by the cytopathic effect caused by HCMV. Furthermore, in the absence or presence of HCMV, the knockdown of RhoB and RhoC proteins decreased the proliferation rate of the parental and the IE1-expressing glioblastoma cells, whereas the knockdown of RhoA protein in the HCMV infected cell lines restored their proliferation rate. In addition, wound healing assays in U373MG cells revealed that depletion of RhoA, RhoB and RhoC differentially reduced their migration rate, even in the presence or the absence of HCMV. Conclusion: Collectively, these data show for the first time a differential implication of Rho GTPases in morphology, proliferation rate and motility of human glioblastoma cells during HCMV infection, further supporting an oncomodulatory role of HCMV depending on the Rho isoforms' state.

  16. Metformin Inhibits Growth of Human Glioblastoma Cells and Enhances Therapeutic Response

    Science.gov (United States)

    Sesen, Julie; Dahan, Perrine; Scotland, Sarah J.; Saland, Estelle; Dang, Van-Thi; Lemarié, Anthony; Tyler, Betty M.; Brem, Henry; Toulas, Christine; Cohen-Jonathan Moyal, Elizabeth; Sarry, Jean-Emmanuel; Skuli, Nicolas

    2015-01-01

    High-grade gliomas, glioblastomas (GB), are refractory to conventional treatment combining surgery, chemotherapy, mainly temozolomide, and radiotherapy. This highlights an urgent need to develop novel therapies and increase the efficacy of radio/chemotherapy for these very aggressive and malignant brain tumors. Recently, tumor metabolism became an interesting potential therapeutic target in various cancers. Accordingly, combining drugs targeting cell metabolism with appropriate chemotherapeutic agents or radiotherapy has become attractive. In light of these perspectives, we were particularly interested in the anti-cancer properties of a biguanide molecule used for type 2 diabetes treatment, metformin. In our present work, we demonstrate that metformin decreases mitochondrial-dependent ATP production and oxygen consumption and increases lactate and glycolytic ATP production. We show that metformin induces decreased proliferation, cell cycle arrest, autophagy, apoptosis and cell death in vitro with a concomitant activation of AMPK, Redd1 and inhibition of the mTOR pathway. Cell sensitivity to metformin also depends on the genetic and mutational backgrounds of the different GB cells used in this study, particularly their PTEN status. Interestingly, knockdown of AMPK and Redd1 with siRNA partially, but incompletely, abrogates the induction of apoptosis by metformin suggesting both AMPK/Redd1-dependent and –independent effects. However, the primary determinant of the effect of metformin on cell growth is the genetic and mutational backgrounds of the glioma cells. We further demonstrate that metformin treatment in combination with temozolomide and/or irradiation induces a synergistic anti-tumoral response in glioma cell lines. Xenografts performed in nude mice demonstrate in vivo that metformin delays tumor growth. As current treatments for GB commonly fail to cure, the need for more effective therapeutic options is overwhelming. Based on these results, metformin could

  17. 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.

  18. Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response.

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    Julie Sesen

    Full Text Available High-grade gliomas, glioblastomas (GB, are refractory to conventional treatment combining surgery, chemotherapy, mainly temozolomide, and radiotherapy. This highlights an urgent need to develop novel therapies and increase the efficacy of radio/chemotherapy for these very aggressive and malignant brain tumors. Recently, tumor metabolism became an interesting potential therapeutic target in various cancers. Accordingly, combining drugs targeting cell metabolism with appropriate chemotherapeutic agents or radiotherapy has become attractive. In light of these perspectives, we were particularly interested in the anti-cancer properties of a biguanide molecule used for type 2 diabetes treatment, metformin. In our present work, we demonstrate that metformin decreases mitochondrial-dependent ATP production and oxygen consumption and increases lactate and glycolytic ATP production. We show that metformin induces decreased proliferation, cell cycle arrest, autophagy, apoptosis and cell death in vitro with a concomitant activation of AMPK, Redd1 and inhibition of the mTOR pathway. Cell sensitivity to metformin also depends on the genetic and mutational backgrounds of the different GB cells used in this study, particularly their PTEN status. Interestingly, knockdown of AMPK and Redd1 with siRNA partially, but incompletely, abrogates the induction of apoptosis by metformin suggesting both AMPK/Redd1-dependent and -independent effects. However, the primary determinant of the effect of metformin on cell growth is the genetic and mutational backgrounds of the glioma cells. We further demonstrate that metformin treatment in combination with temozolomide and/or irradiation induces a synergistic anti-tumoral response in glioma cell lines. Xenografts performed in nude mice demonstrate in vivo that metformin delays tumor growth. As current treatments for GB commonly fail to cure, the need for more effective therapeutic options is overwhelming. Based on these results

  19. Immune genes are associated with human glioblastoma pathology and patient survival

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    Vauléon Elodie

    2012-09-01

    Full Text Available Abstract Background Glioblastoma (GBM is the most common and lethal primary brain tumor in adults. Several recent transcriptomic studies in GBM have identified different signatures involving immune genes associated with GBM pathology, overall survival (OS or response to treatment. Methods In order to clarify the immune signatures found in GBM, we performed a co-expression network analysis that grouped 791 immune-associated genes (IA genes in large clusters using a combined dataset of 161 GBM specimens from published databases. We next studied IA genes associated with patient survival using 3 different statistical methods. We then developed a 6-IA gene risk predictor which stratified patients into two groups with statistically significantly different survivals. We validated this risk predictor on two other Affymetrix data series, on a local Agilent data series, and using RT-Q-PCR on a local series of GBM patients treated by standard chemo-radiation therapy. Results The co-expression network analysis of the immune genes disclosed 6 powerful modules identifying innate immune system and natural killer cells, myeloid cells and cytokine signatures. Two of these modules were significantly enriched in genes associated with OS. We also found 108 IA genes linked to the immune system significantly associated with OS in GBM patients. The 6-IA gene risk predictor successfully distinguished two groups of GBM patients with significantly different survival (OS low risk: 22.3 months versus high risk: 7.3 months; p  Conclusions This study demonstrates the immune signatures found in previous GBM genomic analyses and suggests the involvement of immune cells in GBM biology. The robust 6-IA gene risk predictor should be helpful in establishing prognosis in GBM patients, in particular in those with a proneural GBM subtype, and even in the well-known good prognosis group of patients with methylated MGMT promoter-bearing tumors.

  20. The silencing of adenine nucleotide translocase isoform 1 induces oxidative stress and programmed cell death in ADF human glioblastoma cells.

    Science.gov (United States)

    Lena, Annalisa; Rechichi, Mariarosa; Salvetti, Alessandra; Vecchio, Donatella; Evangelista, Monica; Rainaldi, Giuseppe; Gremigni, Vittorio; Rossi, Leonardo

    2010-07-01

    Adenine nucleotide translocases (ANTs) are multitask proteins involved in several aspects of cell metabolism, as well as in the regulation of cell death/survival processes. We investigated the role played by ANT isoforms 1 and 2 in the growth of a human glioblastoma cell line (ADF cells). The silencing of ANT2 isoform, by small interfering RNA, did not produce significant changes in ADF cell viability. By contrast, the silencing of ANT1 isoform strongly reduced ADF cell viability by inducing a non-apoptotic cell death process resembling paraptosis. We demonstrated that cell death induced by ANT1 depletion cannot be ascribed to the loss of the ATP/ADP exchange function of this protein. By contrast, our findings indicate that ANT1-silenced cells experience oxidative stress, thus allowing us to hypothesize that the effect of ANT1-silencing on ADF is mediated by the loss of the ANT1 uncoupling function. Several studies ascribe a pro-apoptotic role to ANT1 as a result of the observation that ANT1 overexpression sensitizes cells to mitochondrial depolarization or to apoptotic stimuli. In the present study, we demonstrate that, despite its pro-apoptotic function at a high expression level, the reduction of ANT1 density below a physiological baseline impairs fundamental functions of this protein in ADF cells, leading them to undertake a cell death process.

  1. Heterogeneous intratumoral distribution of gadolinium nanoparticles within U87 human glioblastoma xenografts unveiled by micro-PIXE imaging.

    Science.gov (United States)

    Carmona, Asuncion; Roudeau, Stéphane; L'Homel, Baptiste; Pouzoulet, Frédéric; Bonnet-Boissinot, Sarah; Prezado, Yolanda; Ortega, Richard

    2017-04-15

    Metallic nanoparticles have great potential in cancer radiotherapy as theranostic drugs since, they serve simultaneously as contrast agents for medical imaging and as radio-therapy sensitizers. As with other anticancer drugs, intratumoral diffusion is one of the main limiting factors for therapeutic efficiency. To date, a few reports have investigated the intratumoral distribution of metallic nanoparticles. The aim of this study was to determine the quantitative distribution of gadolinium (Gd) nanoparticles after direct intratumoral injection within U87 human glioblastoma tumors grafted in mice, using micro-PIXE (Particle Induced X-ray Emission) imaging. AGuIX (Activation and Guiding of Irradiation by X-ray) 3 nm particles composed of a polysiloxane network surrounded by gadolinium chelates were used. PIXE results indicate that the direct injection of Gd nanoparticles in tumors results in their heterogeneous diffusion, probably related to variations in tumor density. All tumor regions contain Gd, but with markedly different concentrations, with a more than 250-fold difference. Also Gd can diffuse to the healthy adjacent tissue. This study highlights the usefulness of mapping the distribution of metallic nanoparticles at the intratumoral level, and proposes PIXE as an imaging modality to probe the quantitative distribution of metallic nanoparticles in tumors from experimental animal models with micrometer resolution. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Int6/eIF3e Is Essential for Proliferation and Survival of Human Glioblastoma Cells

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    Julie Sesen

    2014-01-01

    Full Text Available Glioblastomas (GBM are very aggressive and malignant brain tumors, with frequent relapses despite an appropriate treatment combining surgery, chemotherapy and radiotherapy. In GBM, hypoxia is a characteristic feature and activation of Hypoxia Inducible Factors (HIF-1α and HIF-2α has been associated with resistance to anti-cancer therapeutics. Int6, also named eIF3e, is the “e” subunit of the translation initiation factor eIF3, and was identified as novel regulator of HIF-2α. Eukaryotic initiation factors (eIFs are key factors regulating total protein synthesis, which controls cell growth, size and proliferation. The functional significance of Int6 and the effect of Int6/EIF3E gene silencing on human brain GBM has not yet been described and its role on the HIFs is unknown in glioma cells. In the present study, we show that Int6/eIF3e suppression affects cell proliferation, cell cycle and apoptosis of various GBM cells. We highlight that Int6 inhibition induces a diminution of proliferation through cell cycle arrest and increased apoptosis. Surprisingly, these phenotypes are independent of global cell translation inhibition and are accompanied by decreased HIF expression when Int6 is silenced. In conclusion, we demonstrate here that Int6/eIF3e is essential for proliferation and survival of GBM cells, presumably through modulation of the HIFs.

  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. Isolation of cancer stem cells from three human glioblastoma cell lines: characterization of two selected clones.

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    Fortunata Iacopino

    Full Text Available Cancer stem cells (CSC were isolated via a non-adherent neurosphere assay from three glioma cell lines: LI, U87, and U373. Using a clonal assay, two clones (D2 and F11 were selected from spheres derived from LI cells and were characterized for the: expression of stem cell markers (CD133, Nestin, Musashi-1 and Sox2; proliferation; differentiation capability (determined by the expression of GalC, βIII-Tubulin and GFAP; Ca(2+ signaling and tumorigenicity in nude mice. Both D2 and F11 clones expressed higher levels of all stem cell markers with respect to the parental cell line. Clones grew more slowly than LI cells with a two-fold increase in duplication time. Markers of differentiation (βIII-Tubulin and GFAP were expressed at high levels in both LI cells and in neurospheres. The expression of Nestin, Sox2, and βIII-Tubulin was down-regulated in D2 and F11 when cultured in serum-containing medium, whereas Musashi-1 was increased. In this condition, duplication time of D2 and F11 increased without reaching that of LI cells. D2, F11 and parental cells did not express voltage-dependent Ca(2+-channels but they exhibited increased intracellular Ca(2+ levels in response to ATP. These Ca(2+ signals were larger in LI cells and in spheres cultured in serum-containing medium, while they were smaller in serum-free medium. The ATP treatment did not affect cell proliferation. Both D2 and F11 induced the appearance of tumors when ortotopically injected in athymic nude mice at a density 50-fold lower than that of LI cells. All these data indicate that both clones have characteristics of CSC and share the same stemness properties. The findings regarding the expression of differentiation markers and Ca(2+-channels show that both clones are unable to reach the terminal differentiation. Both D2 and F11 might represent a good model to improve the knowledge on CSC in glioblastoma and to identify new therapeutic approaches.

  5. Potent antiproliferative cembrenoids accumulate in tobacco upon infection with Rhodococcus fascians and trigger unusual microtubule dynamics in human glioblastoma cells.

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    Aminata P Nacoulma

    Full Text Available AIMS: Though plant metabolic changes are known to occur during interactions with bacteria, these were rarely challenged for pharmacologically active compounds suitable for further drug development. Here, the occurrence of specific chemicals with antiproliferative activity against human cancer cell lines was evidenced in hyperplasia (leafy galls induced when plants interact with particular phytopathogens, such as the Actinomycete Rhodococcus fascians. METHODS: We examined leafy galls fraction F3.1.1 on cell proliferation, cell division and cytoskeletal disorganization of human cancer cell lines using time-lapse videomicroscopy imaging, combined with flow cytometry and immunofluorescence analysis. We determined the F3.1.1-fraction composition by gas chromatography coupled to mass spectrometry. RESULTS: The leafy galls induced on tobacco by R. fascians yielded fraction F3.1.1 which inhibited proliferation of glioblastoma U373 cells with an IC50 of 4.5 µg/mL, F.3.1.1 was shown to increase cell division duration, cause nuclear morphological deformations and cell enlargement, and, at higher concentrations, karyokinesis defects leading to polyploidization and apoptosis. F3.1.1 consisted of a mixture of isomers belonging to the cembrenoids. The cellular defects induced by F3.1.1 were caused by a peculiar cytoskeletal disorganization, with the occurrence of fragmented tubulin and strongly organized microtubule aggregates within the same cell. Colchicine, paclitaxel, and cembrene also affected U373 cell proliferation and karyokinesis, but the induced microtubule rearrangement was very different from that provoked by F3.1.1. Altogether our data indicate that the cembrenoid isomers in F3.1.1 have a unique mode of action and are able to simultaneously modulate microtubule polymerization and stability.

  6. Genetic epidemiology of glioblastoma multiforme: confirmatory and new findings from analyses of human leukocyte antigen alleles and motifs.

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    Wei Song

    2009-09-01

    Full Text Available Human leukocyte antigen (HLA class I genes mediate cytotoxic T-lymphocyte responses and natural killer cell function. In a previous study, several HLA-B and HLA-C alleles and haplotypes were positively or negatively associated with the occurrence and prognosis of glioblastoma multiforme (GBM.As an extension of the Upper Midwest Health Study, we have performed HLA genotyping for 149 GBM patients and 149 healthy control subjects from a non-metropolitan population consisting almost exclusively of European Americans. Conditional logistic regression models did not reproduce the association of HLA-B*07 or the B*07-Cw*07 haplotype with GBM. Nonetheless, HLA-A*32, which has previously been shown to predispose GBM patients to a favorable prognosis, was negatively associated with occurrence of GBM (odds ratio=0.41, p=0.04 by univariate analysis. Other alleles (A*29, A*30, A*31 and A*33 within the A19 serology group to which A*32 belongs showed inconsistent trends. Sequencing-based HLA-A genotyping established that A*3201 was the single A*32 allele underlying the observed association. Additional evaluation of HLA-A promoter and exon 1 sequences did not detect any unexpected single nucleotide polymorphisms that could suggest differential allelic expression. Further analyses restricted to female GBM cases and controls revealed a second association with a specific HLA-B sequence motif corresponding to Bw4-80Ile (odds ratio=2.71, p=0.02.HLA-A allelic product encoded by A*3201 is likely to be functionally important to GBM. The novel, sex-specific association will require further confirmation in other representative study populations.

  7. Characterization of ABCG2 gene amplification manifesting as extrachromosomal DNA in mitoxantrone-selected SF295 human glioblastoma cells.

    Science.gov (United States)

    Rao, V Koneti; Wangsa, Darawalee; Robey, Robert W; Huff, Lyn; Honjo, Yasumasa; Hung, Jeffrey; Knutsen, Turid; Ried, Thomas; Bates, Susan E

    2005-07-15

    The human ABCG2 gene, located on chromosome 4, encodes an ATP-binding cassette half-transporter that has been shown to confer resistance to chemotherapeutic agents. Relatively little is known about the mechanisms controlling expression of ABCG2. In previous studies, we had shown that overexpression of ABCG2 can result from rearrangement or gene amplification involving chromosome 4. To better characterize the mechanisms of ABCG2 overexpression, SF295 glioblastoma cells were exposed to increasing amounts of mitoxantrone to generate the SF295 MX50, MX100, MX250, and MX500 sublines, maintained in mitoxantrone concentrations ranging from 50 to 500 nmol/L. Northern blot analysis confirmed overexpression of ABCG2 mRNA, and immunoblot analysis demonstrated increased protein expression in the selected cell lines. Efflux of BODIPY-prazosin confirmed a functional protein. ABCG2 gene amplification was observed in all resistant sublines, as determined by Southern blot analysis. Fluorescence in situ hybridization (FISH) revealed amplification of ABCG2 via double minute chromosomes (dmins) detected in metaphase chromosome spreads in the SF295 MX50 and MX100 sublines. At higher levels of drug selection, in the MX250 and MX500 sublines, fewer dmins were observed but homogeneously staining regions (hsr) were visible with FISH analysis, revealing reintegration of the ABCG2 gene into multiple chromosomes. Spectral karyotyping (SKY) demonstrated multiple clonal and nonclonal rearrangements of chromosome 4, including hsrs. These results suggest that amplification of ABCG2 occurred initially in the form of dmins, followed by chromosomal reintegration of the amplicon at multiple sites. This occurred with increasing drug-selection pressure, generating a more stable genotype.

  8. Photofrin based photodynamic therapy and miR-99a transfection inhibited FGFR3 and PI3K/Akt signaling mechanisms to control growth of human glioblastoma In vitro and in vivo.

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    Mrinmay Chakrabarti

    Full Text Available Glioblastoma is the most common malignant brain tumor in humans. We explored the molecular mechanisms how the efficacy of photofrin based photodynamic therapy (PDT was enhanced by miR-99a transfection in human glioblastoma cells. Our results showed almost similar uptake of photofrin after 24 h in different glioblastoma cells, but p53 wild-type cells were more sensitive to radiation and photofrin doses than p53 mutant cells. Photofrin based PDT induced apoptosis, inhibited cell invasion, prevented angiogenic network formation, and promoted DNA fragmentation and laddering in U87MG and U118MG cells harvoring p53 wild-type. Western blotting showed that photofrin based PDT was efficient to block the angiogenesis and cell survival pathways. Further, photofrin based PDT followed by miR-99a transfection dramatically increased miR-99a expression and also increased apoptosis in glioblastoma cell cultures and drastically reduced tumor growth in athymic nude mice, due to down regulation of fibroblast growth factor receptor 3 (FGFR3 and PI3K/Akt signaling mechanisms leading to inhibition of cell proliferation and induction of molecular mechanisms of apoptosis. Therefore, our results indicated that the anti-tumor effects of photofrin based PDT was strongly augmented by miR-99a overexpression and this novel combination therapeutic strategy could be used for controlling growth of human p53 wild-type glioblastomas both in vitro and in vivo.

  9. Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma

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    Spyros Darmanis

    2017-10-01

    Full Text Available Summary: Glioblastoma (GBM is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor’s genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration. : Darmanis et al. perform single-cell transcriptomic analyses of neoplastic and stromal cells within and proximal to primary glioblastomas. The authors describe a population of neoplastic-infiltrating glioblastoma cells as well as a putative role of tumor-infiltrating immune cells in supporting tumor growth. Keywords: single cell, RNA-seq, glioma, glioblastoma, GBM, brain, heterogeneity, infiltrating, diffuse, checkpoint

  10. 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 ...

  11. 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.

  12. Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients using an IVIVE-PBPK Modeling Approach.

    Science.gov (United States)

    Li, Jing; Wu, Jianmei; Bao, Xun; Honea, Norissa; Xie, Youming; Kim, Seongho; Sparreboom, Alex; Sanai, Nader

    2017-09-19

    AZD1775, a first-in-class, small molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radio-sensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across human blood-brain barrier (BBB). AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 glioblastoma patients. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a 4-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process. AZD1775 exhibited good tumor penetration in glioblastoma patients, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII-ABCB1 or MDCKII-ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue. In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors. Copyright ©2017, American Association for Cancer Research.

  13. Mesothelin as a novel biomarker and immunotherapeutic target in human glioblastoma

    DEFF Research Database (Denmark)

    Liu, Zhenjiang; Rao, Martin; Poiret, Thomas

    2017-01-01

    anti-GBM cellular immune responses. Mesothelin is a tumor-associated antigen (TAA) which is expressed in several solid tumors with different histology. Here, we report the immunological significance of mesothelin in human malignant glioma. Expression of mature, surface-bound mesothelin protein...

  14. Neuronal markers are expressed in human gliomas and NSE knockdown sensitizes glioblastoma cells to radiotherapy and temozolomide

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    Yan Tao

    2011-12-01

    Full Text Available Abstract Background Expression of neuronal elements has been identified in various glial tumors, and glioblastomas (GBMs with neuronal differentiation patterns have reportedly been associated with longer survival. However, the neuronal class III β-tubulin has been linked to increasing malignancy in astrocytomas. Thus, the significance of neuronal markers in gliomas is not established. Methods The expressions of class III β-tubulin, neurofilament protein (NFP, microtubule-associated protein 2 (MAP2 and neuron-specific enolase (NSE were investigated in five GBM cell lines and two GBM biopsies with immunocytochemistry and Western blot. Moreover, the expression levels were quantified by real-time qPCR under different culture conditions. Following NSE siRNA treatment we used Electric cell-substrate impedance sensing (ECIS to monitor cell growth and migration and MTS assays to study viability after irradiation and temozolomide treatment. Finally, we quantitated NSE expression in a series of human glioma biopsies with immunohistochemistry using a morphometry software, and collected survival data for the corresponding patients. The biopsies were then grouped according to expression in two halves which were compared by survival analysis. Results Immunocytochemistry and Western blotting showed that all markers except NFP were expressed both in GBM cell lines and biopsies. Notably, qPCR demonstrated that NSE was upregulated in cellular stress conditions, such as serum-starvation and hypoxia, while we found no uniform pattern for the other markers. NSE knockdown reduced the migration of glioma cells, sensitized them to hypoxia, radio- and chemotherapy. Furthermore, we found that GBM patients in the group with the highest NSE expression lived significantly shorter than patients in the low-expression group. Conclusions Neuronal markers are aberrantly expressed in human GBMs, and NSE is consistently upregulated in different cellular stress conditions

  15. TRIM28 and β-actin identified via nanobody-based reverse proteomics approach as possible human glioblastoma biomarkers.

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    Ivana Jovčevska

    Full Text Available Malignant gliomas are among the rarest brain tumours, and they have the worst prognosis. Grade IV astrocytoma, known as glioblastoma multiforme (GBM, is a highly lethal disease where the standard therapies of surgery, followed by radiation and chemotherapy, cannot significantly prolong the life expectancy of the patients. Tumour recurrence shows more aggressive form compared to the primary tumour, and results in patient survival from 12 to 15 months only. Although still controversial, the cancer stem cell hypothesis postulates that cancer stem cells are responsible for early relapse of the disease after surgical intervention due to their high resistance to therapy. Alternative strategies for GBM therapy are thus urgently needed. Nanobodies are single-domain antigen-binding fragments of heavy-chain antibodies, and together with classical antibodies, they are part of the camelid immune system. Nanobodies are small and stable, and they share a high degree of sequence identity to the human heavy chain variable domain, and these characteristics offer them advantages over classical antibodies or antibody fragments. We first immunised an alpaca with a human GBM stem-like cell line prepared from primary GBM cultures. Next, a nanobody library was constructed in a phage-display vector. Using nanobody phage-display technology, we selected specific GBM stem-like cell binders through a number of affinity selections, using whole cell protein extracts and membrane protein-enriched extracts from eight different GBM patients, and membrane protein-enriched extracts from two established GBM stem-like cell lines (NCH644 and NCH421K cells. After the enrichment, periplasmic extract ELISA was used to screen for specific clones. These nanobody clones were recloned into the pHEN6 vector, expressed in Escherichia coli WK6, and purified using immobilised metal affinity chromatography and size-exclusion chromatography. Specific nanobody:antigen pairs were obtained and mass

  16. The expression of human papillomavirus type 16 (HPV16 E7) induces cell cycle arrest and apoptosis in radiation and hypoxia resistant glioblastoma cells.

    Science.gov (United States)

    Moon, Sung-Ung; Choi, Soo Kyoung; Kim, Han Jo; Kumar Bokara, Kiran; Park, Kyung Ah; Lee, Won Taek; Lee, Jong-Eun

    2011-01-01

    p53 is a widely known tumor-suppressor gene product that plays a key role in apoptotic cell death induced by DNA-damaging chemotherapeutic agents. Human glioma cells with functional p53 are known to be more resistant to γ-radiation. The aim of this study was to investigate whether the mutant glioblastoma cells (U87MG) transfected with human papilloma virus-type 16 E7 (HPV16 E7) genes were capable of increasing sensitivity towards irradiation and hypoxia-induced cell death. The pLXSN retroviral vector expressed HPV-16E7 genes and was infected into the p53 mutated U87MG cell line. A specific amplification band of HPV16 E7 genes was detected in E7 genes and transfected in the U87MG cell line using a reverse transcriptase polymerase chain reaction. The experimental groups included the mutant glioblastoma cell line (U87MG), empty vector (pLXSN) transfected to mutant glioblastoma cell line (U87MG-LXSN), and retrovirus carrying HPV16 E7 genes transfected to the mutant glioblastoma cell line (U87MG-E7). Hypoxic conditions were optimized using LDH assay and the subjects were exposed to hypoxia (16 and 20 h) and irradiation (9 h). Hoechst-propidium iodide (PI) staining results showed that hypoxia and irradiation increased the number of dead cells in the U87MG-E7 cells compared to U87MG and U87MG-LXSN cells. Results of the FACS analysis showed a similar pattern and recorded 80.44 and 58.94% of apoptotic cells in U87MG-E7 and U87MG cells, respectively. Cell cycle analysis by FACS revealed that, following irradiation and hypoxia, cells showed G2-M arrest. Additionally, the Western blot analysis results showed altered expression of E2F-1, Rb and p53 in the irradiation- and hypoxia-induced U87MG-E7 cells compared to U87MG and U87MG LXSN cells. In conclusion, the over-expression of HPV16 E7 genes in U87MG cell lines increasd cell apoptosis and E2F1 expression compared to the HPV non-infected U87MG cells following irradiation and hypoxia. These results indicate that tumor

  17. Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival.

    Science.gov (United States)

    Fischer, Walter; Gustafsson, Lotta; Mossberg, Ann-Kristin; Gronli, Janne; Mork, Sverre; Bjerkvig, Rolf; Svanborg, Catharina

    2004-03-15

    Malignant brain tumors present a major therapeutic challenge because no selective or efficient treatment is available. Here, we demonstrate that intratumoral administration of human alpha-lactalbumin made lethal to tumor cells (HAMLET) prolongs survival in a human glioblastoma (GBM) xenograft model, by selective induction of tumor cell apoptosis. HAMLET is a protein-lipid complex that is formed from alpha-lactalbumin when the protein changes its tertiary conformation and binds oleic acid as a cofactor. HAMLET induces apoptosis in a wide range of tumor cells in vitro, but the therapeutic effect in vivo has not been examined. In this study, invasively growing human GBM tumors were established in nude rats (Han:rnu/rnu Rowett, n = 20) by transplantation of human GBM biopsy spheroids. After 7 days, HAMLET was administered by intracerebral convection-enhanced delivery for 24 h into the tumor area; and alpha-lactalbumin, the native, folded variant of the same protein, was used as a control. HAMLET reduced the intracranial tumor volume and delayed the onset of pressure symptoms in the tumor-bearing rats. After 8 weeks, all alpha-lactalbumin-treated rats had developed pressure symptoms, but the HAMLET-treated rats remained asymptomatic. Magnetic resonance imaging scans revealed large differences in tumor volume (456 versus 63 mm(3)). HAMLET caused apoptosis in vivo in the tumor but not in adjacent intact brain tissue or in nontransformed human astrocytes, and no toxic side effects were observed. The results identify HAMLET as a new candidate in cancer therapy and suggest that HAMLET should be additionally explored as a novel approach to controlling GBM progression.

  18. Cytotoxicity of catechol towards human glioblastoma cells via superoxide and reactive quinones generation Citotoxicidade do catecol para células de glioblastoma humano via geração de superóxido e quinonas reativas

    Directory of Open Access Journals (Sweden)

    Marco Roberto Guimarães Pereira

    2004-08-01

    Full Text Available It is known that the exposure to benzene in the petroleum industry causes lympho-haematopoietic cancer among workers. However, there is little data concerning the toxicity of benzene to the central nervous system. Benzene easily penetrates the brain where it is metabolized to catechol. Since catechol autoxidizes in physiological phosphate buffer, we hypothesized that it could be toxic towards glial cells due to the generation of reactive oxygen species and quinones. In this work we studied the cytotoxic properties of catechol towards human glioblastoma cells. We found that catechol was toxic towards these cells after 72 hours and this toxicity was related to the formation of quinones. Catechol at 230µM killed 50% of cells. The catechol-induced cytotoxicity was prevented by the addition of 100U superoxide dismutase, which also inhibited the formation of quinones. These data suggest that catechol induces cytotoxicity via the extracellular generation of superoxide and quinones.Sabe-se que a exposição de trabalhadores ao benzeno na indústria petrolífera é uma causa de câncer do sistema linfo-hematopoiético. Pouco se sabe, contudo, a respeito da toxicidade do benzeno no sistema nervoso central. O benzeno penetra facilmente no cérebro, onde é metabolizado a catecol. Como o catecol se auto-oxida em tampão fosfato no pH fisiológico, supôs-se que esse composto poderia ser tóxico para células gliais por gerar espécies reativas do oxigênio e quinonas. Nesse trabalho estudou-se a citotoxicidade do catecol para células de glioblastoma humano. O catecol foi tóxico após 72 horas e essa toxicidade relacionou-se com a formação de quinonas. O catecol a 230mM matou metade das células em cultura. A toxicidade do catecol e a produção de quinonas foram inibidas por 100U de superóxido dismutase. Esses dados sugerem que a toxicidade induzida pelo catecol deve-se à produção extracelular de superóxido e quinonas reativas.

  19. Analysis of the cytotoxicity of carbon-based nanoparticles, diamond and graphite, in human glioblastoma and hepatoma cell lines.

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    Karolina Ewa Zakrzewska

    Full Text Available Nanoparticles have attracted a great deal of attention as carriers for drug delivery to cancer cells. However, reports on their potential cytotoxicity raise questions of their safety and this matter needs attentive consideration. In this paper, for the first time, the cytotoxic effects of two carbon based nanoparticles, diamond and graphite, on glioblastoma and hepatoma cells were compared. First, we confirmed previous results that diamond nanoparticles are practically nontoxic. Second, graphite nanoparticles exhibited a negative impact on glioblastoma, but not on hepatoma cells. The studied carbon nanoparticles could be a potentially useful tool for therapeutics delivery to the brain tissue with minimal side effects on the hepatocytes. Furthermore, we showed the influence of the nanoparticles on the stable, fluorescently labeled tumor cell lines and concluded that the labeled cells are suitable for drug cytotoxicity tests.

  20. Analysis of the Cytotoxicity of Carbon-Based Nanoparticles, Diamond and Graphite, in Human Glioblastoma and Hepatoma Cell Lines

    Science.gov (United States)

    Wierzbicki, Mateusz; Jaworski, Sławomir; Kutwin, Marta; Sawosz, Ewa; Chwalibog, André; Pijanowska, Dorota Genowefa; Pluta, Krzysztof Dariusz

    2015-01-01

    Nanoparticles have attracted a great deal of attention as carriers for drug delivery to cancer cells. However, reports on their potential cytotoxicity raise questions of their safety and this matter needs attentive consideration. In this paper, for the first time, the cytotoxic effects of two carbon based nanoparticles, diamond and graphite, on glioblastoma and hepatoma cells were compared. First, we confirmed previous results that diamond nanoparticles are practically nontoxic. Second, graphite nanoparticles exhibited a negative impact on glioblastoma, but not on hepatoma cells. The studied carbon nanoparticles could be a potentially useful tool for therapeutics delivery to the brain tissue with minimal side effects on the hepatocytes. Furthermore, we showed the influence of the nanoparticles on the stable, fluorescently labeled tumor cell lines and concluded that the labeled cells are suitable for drug cytotoxicity tests. PMID:25816103

  1. Osthole Suppresses the Migratory Ability of Human Glioblastoma Multiforme Cells via Inhibition of Focal Adhesion Kinase-Mediated Matrix Metalloproteinase-13 Expression

    Directory of Open Access Journals (Sweden)

    Cheng-Fang Tsai

    2014-03-01

    Full Text Available Glioblastoma multiforme (GBM is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells.

  2. 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.

  3. Carbon-ion beams effectively induce growth inhibition and apoptosis in human neural stem cells compared with glioblastoma A172 cells.

    Science.gov (United States)

    Isono, Mayu; Yoshida, Yukari; Takahashi, Akihisa; Oike, Takahiro; Shibata, Atsushi; Kubota, Yoshiki; Kanai, Tatsuaki; Ohno, Tatsuya; Nakano, Takashi

    2015-09-01

    Carbon-ion radiotherapy (CIRT) holds promise in the treatment of glioblastoma, an aggressive X-ray-resistant brain tumor. However, since glioblastoma cells show a highly invasive nature, carbon-ion (C-ion) irradiation of normal tissues surrounding the tumor is inevitable. Recent studies have revealed the existence of neural stem cells in the adult brain. Therefore, the damaging effect of C-ion beams on the neural stem cells has to be carefully considered in the treatment planning of CIRT. Here, we investigated the growth and death mode of human neural stem cells (hNSCs) and glioblastoma A172 cells after X-ray or C-ion beam irradiation. The X-ray dose resulting in a 50% growth rate (D(50)) was 0.8 Gy in hNSCs and 3.0 Gy in A172 cells, while the D(50) for C-ion beams was 0.4 Gy in hNSCs and 1.6 Gy in A172 cells; the relative biological effectiveness value of C-ion beams was 2.0 in hNSCs and 1.9 in A172 cells. Importantly, both X-rays and C-ion beams preferentially induced apoptosis, not necrosis, in hNSCs; however, radiation-induced apoptosis was less evident in A172 cells. The apoptosis-susceptible nature of the irradiated hNSCs was associated with prolonged upregulation of phosphorylated p53, whereas the apoptosis-resistant nature of A172 cells was associated with a high basal level of nuclear factor kappa B expression. Taken together, these data indicate that apoptosis is the major cell death pathway in hNSCs after irradiation. The high sensitivity of hNSCs to C-ion beams underscores the importance of careful target volume delineation in the treatment planning of CIRT for glioblastoma. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  4. Uptake of 18F-FET and 18F-FCH in Human Glioblastoma T98G Cell Line after Irradiation with Photons or Carbon Ions

    Directory of Open Access Journals (Sweden)

    Francesca Pasi

    2017-01-01

    Full Text Available The differential diagnosis between recurrence of gliomas or brain metastases and this phenomenon is important in order to choose the best therapy and predict the prognosis but is still a big problem for physicians. The new emerging MRI, CT, and PET diagnostic modalities still lack sufficient accuracy. Radiolabeled choline and amino acids have been reported to show great tumor specificity. ​We studied the uptake kinetics of [18F]fluoromethyl-choline (FCH and O-(2-[18F]fluoroethyl-L-tyrosine (FET by the T98G human glioblastoma cells from 20 to 120 min after irradiation either with photons at 2-10-20 Gy or with carbon ions at 2 Gy (at the National Centre for Oncological Hadrontherapy (CNAO, Pavia, Italy. We also evaluated the cell death and morphology changes induced by radiation treatment. Both FET and FCH are able to trace tumor behavior in terms of higher uptake for increased doses of radiation treatment, due to the upregulation of cells attempts to repair nonlethal damage. Our data suggest that both FCH and FET could be useful to analyze the metabolic pathways of glioblastoma cells before and after radiotherapy. Physicians will have to consider the different kinetics pathways of uptake concerning the two radiopharmaceuticals.

  5. Time until initiation of tumor growth is an effective measure of the anti-angiogenic effect of TNP-470 on human glioblastoma in nude mice

    DEFF Research Database (Denmark)

    Kragh, M; Spang-Thomsen, M; Kristjansen, P E

    1999-01-01

    We examined the effect of the anti-angiogenic compound TNP-470 on early tumor growth characteristics following subcutaneous implantation of 1 mm3 tissue blocks of human glioblastoma U87, in nude mice. The mice received daily injections with TNP-470, 7 mg/kg, from one day before until either 3, 7......, 11, or 15 days after inoculation. The time from inoculation until initiation of exponential tumor growth was determined along with the post-therapeutic growth delay and the initial tumor doubling time (TD) for each individual tumor (n=103) on the basis of tumor volume growth curves. We found that: i....... These findings demonstrate that the in vivo effect of TNP-470 on tumor growth is tumor inhibitory rather than cytotoxic. The lack of effect of the anti-angiogenic compound, TNP-470, in the early 3-day schedule is consistent with the existence of an early avascular phase which precede the angiogenesis...

  6. In silico enhanced restriction enzyme based methylation analysis of the human glioblastoma genome using Agilent 244K CpG Island microarrays

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    Anh Tran

    2010-01-01

    Full Text Available Genome wide methylation profiling of gliomas is likely to provide important clues to improving treatment outcomes. Restriction enzyme based approaches have been widely utilized for methylation profiling of cancer genomes and will continue to have importance in combination with higher density microarrays. With the availability of the human genome sequence and microarray probe sequences, these approaches can be readily characterized and optimized via in silico modeling. We adapted the previously described HpaII/MspI based Methylation Sensitive Restriction Enzyme (MSRE assay for use with two-color Agilent 244K CpG island microarrays. In this assay, fragmented genomic DNA is digested in separate reactions with isoschizomeric HpaII (methylation-sensitive and MspI (methylation-insensitive restriction enzymes. Using in silico hybridization, we found that genomic fragmentation with BfaI was superior to MseI, providing a maximum effective coverage of 22,362 CpG islands in the human genome. In addition, we confirmed the presence of an internal control group of fragments lacking HpaII/MspI sites which enable separation of methylated and unmethylated fragments. We used this method on genomic DNA isolated from normal brain, U87MG cells, and a glioblastoma patient tumor sample and confirmed selected differentially methylated CpG islands using bisulfite sequencing. Along with additional validation points, we performed a receiver operating characteristics (ROC analysis to determine the optimal threshold (p ≤ 0.001. Based on this threshold, we identified ~2400 CpG islands common to all three samples and 145 CpG islands unique to glioblastoma. These data provide more general guidance to individuals seeking to maximize effective coverage using restriction enzyme based methylation profiling approaches.

  7. 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.

  8. 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.

  9. [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.

  10. 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.

  11. Neurofibromatosis type 2 tumor suppressor protein, NF2, induces proteasome-mediated degradation of JC virus T-antigen in human glioblastoma.

    Directory of Open Access Journals (Sweden)

    Sarah Beltrami

    Full Text Available Neurofibromatosis type 2 protein (NF2 has been shown to act as tumor suppressor primarily through its functions as a cytoskeletal scaffold. However, NF2 can also be found in the nucleus, where its role is less clear. Previously, our group has identified JC virus (JCV tumor antigen (T-antigen as a nuclear binding partner for NF2 in tumors derived from JCV T-antigen transgenic mice. The association of NF2 with T-antigen in neuronal origin tumors suggests a potential role for NF2 in regulating the expression of the JCV T-antigen. Here, we report that NF2 suppresses T-antigen protein expression in U-87 MG human glioblastoma cells, which subsequently reduces T-antigen-mediated regulation of the JCV promoter. When T-antigen mRNA was quantified, it was determined that increasing expression of NF2 correlated with an accumulation of T-antigen mRNA; however, a decrease in T-antigen at the protein level was observed. NF2 was found to promote degradation of ubiquitin bound T-antigen protein via a proteasome dependent pathway concomitant with the accumulation of the JCV early mRNA encoding T-antigen. The interaction between T-antigen and NF2 maps to the FERM domain of NF2, which has been shown previously to be responsible for its tumor suppressor activity. Co-immunoprecipitation assays revealed a ternary complex among NF2, T-antigen, and the tumor suppressor protein, p53 within a glioblastoma cell line. Further, these proteins were detected in various degrees in patient tumor tissue, suggesting that these associations may occur in vivo. Collectively, these results demonstrate that NF2 negatively regulates JCV T-antigen expression by proteasome-mediated degradation, and suggest a novel role for NF2 as a suppressor of JCV T-antigen-induced cell cycle regulation.

  12. Nutraceutical phycocyanin nanoformulation for efficient drug delivery of paclitaxel in human glioblastoma U87MG cell line

    Science.gov (United States)

    Agrawal, Madhunika; Yadav, Sanjeev Kumar; Agrawal, Satyam Kumar; Karmakar, Surajit

    2017-08-01

    To enhance the therapeutic efficacy of chemotherapy on glioblastoma U87MG cell line, paclitaxel-loaded phycocyanin nanoparticles (PTX-PcNPs) were prepared by modified desolvation process. PTX-PcNPs were characterised in terms of size, zeta potential, drug loading efficiency and drug release. Confocal laser scanning microscopy showed PTX-PcNPs could be internalised by U87MG cells. The anti-cancer activity was investigated in vitro by 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with and without photodynamic therapy. It was observed that formulation could significantly inhibit growth of U87MG cells as compared to PTX alone and also induced apoptosis, which was evidenced by presence of apoptotic bodies and nuclear fragmentation in treated cells. The present study suggests that PTX-PcNPs can act as a promising drug delivery system for cancer treatment. [Figure not available: see fulltext.

  13. 4-IBP, a σ1 Receptor Agonist, Decreases the Migration of Human Cancer Cells, Including Glioblastoma Cells, In Vitro and Sensitizes Them In Vitro and In Vivo to Cytotoxic Insults of Proapoptotic and Proautophagic Drugs

    Directory of Open Access Journals (Sweden)

    Veronique Mégalizzi

    2007-05-01

    Full Text Available Although the molecular function of cr receptors has not been fully defined and the natural ligand(s is still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-tibenzylpiperidin-4-yl-4iodobenzamide (4-IBP, a selective σ1, agonist, has been used to investigate whether this compound is able to modify: 1 in vitro the migration and proliferation of human cancer cells; 2 in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3 in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC models the survival of mice coadministered cytotoxic agents. 4-IBP has revealed weak anti proliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly antimigratory in all four cancer cell lines. This may result, at least in U373-MG cells, from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.

  14. 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.

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

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    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.

  16. Cytotoxicity of temozolomide on human glioblastoma cells is enhanced by the concomitant exposure to an extremely low-frequency electromagnetic field (100Hz, 100G).

    Science.gov (United States)

    Akbarnejad, Zeinab; Eskandary, Hossein; Dini, Luciana; Vergallo, Cristian; Nematollahi-Mahani, Seyed Noureddin; Farsinejad, Alireza; Abadi, Maryam Fekri Soofi; Ahmadi, Meysam

    2017-08-01

    Glioblastoma multiforme (GBM) is the most malignant brain cancer that causes high mortality in humans. It responds poorly to the most common cancer treatments, such as surgery, chemo- and radiation therapy. Temozolomide (TMZ) is an alkylating agent that has been widely used to treat GBM; resistance to this drug is often found. One unexplored possibility for overcoming this resistance is a treatment based on concomitant exposure to electromagnetic fields (EMF) and TMZ. Indeed, many evidences show that EMF affects cancer cells and drug performance. In this study, we evaluated the potential synergistic effect of 100μM TMZ and EMF (100Hz, 100G) on two human glioma cells line, i.e., U87 and T98G above single treatments, TMZ or EMF. Co-treatment synergistically enhanced apoptosis in U87 and T98G cells, by increasing the expression of P53, Bax, and Caspase-3 and decreasing that of Bcl-2 and Cyclin-D1. We also observed an increase in reactive oxygen species (ROS) production and the overexpression of the heme oxygenase-1 (HO-1) gene in comparison to controls. In conclusion, since EMF enhanced the apoptotic effect of TMZ, possibly through a redox regulation mechanism, the TMZ/EMF combination may be effective for glioma cancer treating. Further studies are needed to reveal the action mechanism of this possible novel therapeutic approach. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. Deciphering molecular mechanisms of arginine deiminase-based therapy - Comparative response analysis in paired human primary and recurrent glioblastomas.

    Science.gov (United States)

    Maletzki, Claudia; Rosche, Yvonne; Riess, Christin; Scholz, Aline; William, Doreen; Classen, Carl Friedrich; Kreikemeyer, Bernd; Linnebacher, Michael; Fiedler, Tomas

    2017-12-25

    Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Our results suggest an alternative treatment regimen for this fatal cancer type which circumvents many of the traditional barriers. Using the metabolic defect in GBM thus warrants further (pre-) clinical evaluation. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Massively parallel signature sequencing and bioinformatics analysis identifies up-regulation of TGFBI and SOX4 in human glioblastoma.

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    Biaoyang Lin

    Full Text Available BACKGROUND: A comprehensive network-based understanding of molecular pathways abnormally altered in glioblastoma multiforme (GBM is essential for developing effective therapeutic approaches for this deadly disease. METHODOLOGY/PRINCIPAL FINDINGS: Applying a next generation sequencing technology, massively parallel signature sequencing (MPSS, we identified a total of 4535 genes that are differentially expressed between normal brain and GBM tissue. The expression changes of three up-regulated genes, CHI3L1, CHI3L2, and FOXM1, and two down-regulated genes, neurogranin and L1CAM, were confirmed by quantitative PCR. Pathway analysis revealed that TGF- beta pathway related genes were significantly up-regulated in GBM tumor samples. An integrative pathway analysis of the TGF beta signaling network identified two alternative TGF-beta signaling pathways mediated by SOX4 (sex determining region Y-box 4 and TGFBI (Transforming growth factor beta induced. Quantitative RT-PCR and immunohistochemistry staining demonstrated that SOX4 and TGFBI expression is elevated in GBM tissues compared with normal brain tissues at both the RNA and protein levels. In vitro functional studies confirmed that TGFBI and SOX4 expression is increased by TGF-beta stimulation and decreased by a specific inhibitor of TGF-beta receptor 1 kinase. CONCLUSIONS/SIGNIFICANCE: Our MPSS database for GBM and normal brain tissues provides a useful resource for the scientific community. The identification of non-SMAD mediated TGF-beta signaling pathways acting through SOX4 and TGFBI (GENE ID:7045 in GBM indicates that these alternative pathways should be considered, in addition to the canonical SMAD mediated pathway, in the development of new therapeutic strategies targeting TGF-beta signaling in GBM. Finally, the construction of an extended TGF-beta signaling network with overlaid gene expression changes between GBM and normal brain extends our understanding of the biology of GBM.

  19. Hydrogen sulfide generation from l-cysteine in the human glioblastoma-astrocytoma U-87 MG and neuroblastoma SHSY5Y cell lines.

    Science.gov (United States)

    Bronowicka-Adamska, Patrycja; Bentke, Anna; Wróbel, Maria

    2017-01-01

    Hydrogen sulfide (H2S) is endogenously synthesized from l-cysteine in reactions catalyzed by cystathionine beta-synthase (CBS, EC 4.2.1.22) and gamma-cystathionase (CSE, EC 4.4.1.1). The role of 3-mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2) in H2S generation is also considered; it could be important for tissues with low CTH activity, e.g. cells of the nervous system. The expression and activity of CBS, CTH, and MPST were detected in the human glioblastoma-astrocytoma (U-87 MG) and neuroblastoma (SHSY5Y) cell lines. In both cell lines, the expression and activity of MPST were the highest among the investigated enzymes, suggesting its possible role in the generation of H2S. The RP-HPLC method was used to determine the concentration of cystathionine and alpha-ketobutyrate, products of the CBS- and CTH-catalyzed reactions. The difference in cystathionine levels between cell homogenates treated with totally CTH-inhibiting concentrations of dl-propargylglycine and without the inhibitor was used to evaluate the activity of CBS. The higher expression and activity of CBS, CTH and MPST in the neuroblastoma cells were associated with more intensive generation of H2S in the presence of 2 mM cysteine. A threefold higher level of sulfane sulfur, a potential source of hydrogen sulfide, was detected in the astrocytoma cells in comparison to the neuroblastoma cells.

  20. Suppression of virus replication via down-modulation of mitochondrial short chain enoyl-CoA hydratase in human glioblastoma cells.

    Science.gov (United States)

    Takahashi, Megumi; Watari, Eiji; Shinya, Eiji; Shimizu, Takako; Takahashi, Hidemi

    2007-08-01

    Several viruses have been demonstrated to be the etiologic agent in chronic progressive diseases, associated with persistence; however, major questions concerning the pathogenic mechanisms of viral persistence are still unanswered. With the aim of identifying host cellular proteins that may play a role in viral replication, we established long-term persistently infected human glioblastoma cell lines with mutant measles virus (MV) and analyzed the host proteins by two-dimensional gel electrophoresis (2-DE) with mass spectrometry. We observed significant down-modulation in the expression of mitochondrial short chain enoyl-CoA hydratase (ECHS), which catalyzes the beta-oxidation pathway of fatty acid. Knockdown of this gene by a short interference RNA (siRNA) apparently impaired wild-type MV replication and the cytopathic effects (CPEs) of MV were significantly reduced in siRNA-transfected cells. These findings will shed light upon a new important notion for the interaction between virus replication and lipid metabolism in host cells and might provide a new strategy for virus control.

  1. 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.

  2. Epidermal Growth Factor Receptor Expression Modulates Antitumor Efficacy of Vandetanib or Cediranib Combined With Radiotherapy in Human Glioblastoma Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Wachsberger, Phyllis R., E-mail: Phyllis.wachsberger@jeffersonhospital.org [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Lawrence, Yaacov R.; Liu Yi; Daroczi, Borbala [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Xu Xia [Merck Research Laboratories, North Wales, Pennsylvania (United States); Dicker, Adam P. [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2012-01-01

    Purpose: The purpose of this study was to determine the ability of radiation therapy (RT) combined with the tyrosine kinase inhibitors (TKI) vandetanib (antiepidermal growth factor receptor [EGFR] plus antivascular endothelial growth factor receptor [anti-VEGFR]) and cediranib (anti-VEGFR) to inhibit glioblastoma multiforme (GBM) growth. A secondary aim was to investigate how this regimen is modulated by tumor EGFR expression. Methods and Materials: Radiosensitivity was assessed by clonogenic cell survival assay. VEGF secretion was quantified by enzyme-linked immunosorbent assay. GBM (U87MG wild-type EGFR [wtEGFR] and U87MG EGFR-null) xenografts were treated with vandetanib, cediranib, and RT, alone or in combinations. Excised tumor sections were stained for proliferative and survival biomarkers. Results: In vitro, U87MG wtEGFR and U87 EGFR-null cells had similar growth kinetics. Neither TKI affected clonogenic cell survival following RT. However, in vivo, exogenous overexpression of wtEGFR decreased tumor doubling time (T2x) in U87MG xenografts (2.70 vs. 4.41 days for U87MG wtEGFR vs. U87MG vector, respectively). In U87MG EGFR-null cells, TKI combined with radiation was no better than radiation therapy alone. In U87MG wtEGFR, RT in combination with vandetanib (but not with cediranib) significantly increased tumor T2x compared with RT alone (T2x, 10.4 days vs. 4.8 days; p < 0.001). In vivo, growth delay correlated with suppression of pAkt, survivin, and Ki67 expression in tumor samples. The presence of EGFR augmented RT-stimulated VEGF release; this effect was inhibited by vandetanib. Conclusions: EGFR expression promoted tumor growth in vivo but not in vitro, suggesting a microenvironmental effect. GBM xenografts expressing EGFR exhibited greater sensitivity to both cediranib and vandetanib than EGFR-null tumors. Hence EGFR status plays a major role in determining a tumor's in vivo response to radiation combined with TKI, supporting a &apos

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

    Directory of Open Access Journals (Sweden)

    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.

  4. 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.

  5. Antigens in human glioblastomas and meningiomas: Search for tumour and onco-foetal antigens. Estimation of S-100 and GFA protein

    DEFF Research Database (Denmark)

    Dittmann, L; Axelsen, N H; Norgaard-Pedersen, B

    1977-01-01

    Extracts of glioblastomas and meningiomas were analysed by quantitative immunoelectrophoresis for the presence of foetal brain antigens and tumour-associated antigens, and levels of 2 normal brain-specific proteins were also determined. The following antibodies were used: monospecific anti-S-100......-alpha-foetoprotein; and monospecific anti-ferritin. Using the antibodies raised against the tumours, several antigens not present in foetal or adult normal brain were found in the glioblastomas and the meningiomas. These antigens cross-reacted with antigens present in normal liver and were therefore not tumour-associated. S-100...... was found in glioblastomas in approximately one tenth the amount in whole brain homogenate, whereas GFA was found 2-4 times enriched. The 2 proteins were absent in meningiomas. The possible use of the GFA protein as a marker for astroglial neoplasia is discussed. Five foetal antigens were found in foetal...

  6. 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.

  7. Successful inhibition of intracranial human glioblastoma multiforme xenograft growth via systemic adenoviral delivery of soluble endostatin and soluble vascular endothelial growth factor receptor-2: laboratory investigation.

    Science.gov (United States)

    Szentirmai, Oszkar; Baker, Cheryl H; Bullain, Szofia S; Lin, Ning; Takahashi, Masaya; Folkman, Judah; Mulligan, Richard C; Carter, Bob S

    2008-05-01

    Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice. Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control. Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad-ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups. These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM.

  8. Successful inhibition of intracranial human glioblastoma multiforme xenograft growth via systemic adenoviral delivery of soluble endostatin and soluble vascular endothelial growth factor receptor-2

    Science.gov (United States)

    Szentirmai, Oszkar; Baker, Cheryl H.; Bullain, Szofia S.; Lin, Ning; Takahashi, Masaya; Folkman, Judah; Mulligan, Richard C.; Carter, Bob S.

    2015-01-01

    Object Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice. Methods Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control. Results Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad-ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups. Conclusions These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM. PMID:18447716

  9. Modulation of temozolomide action towards rat and human glioblastoma cells in vitro by its combination with doxorubicin and immobilization with nanoscale polymeric carrier

    Directory of Open Access Journals (Sweden)

    N. S. Finiuk

    2016-04-01

    Full Text Available Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma occur more frequently than other types of primary central nervous system tumors, having a combined incidence of 5–8/100,000 population. Even with aggressive treatment using surgery, radiation, and chemotherapy, median reported survival is less than one year. Alkylating agents, such as temozolomide (TMZ, are among the most effective cytotoxic agents used for malignant gliomas, however, the responses still remain poor. Here, we present data about an enhancement of TMZ treatment effect towards rat and human glioma cells in vitro by immobilizing this drug with a new nanoscale polymeric-phospholipidic delivery system. It is a water-soluble comb-like poly(PM-co-GMA-graft-PEG polymer consisting of a backbone that is a copolymer of 5-tert-butyl-peroxy-5-methyl-l-hexene-3-yne (PM and glycidyl methacrylate (GMA and polyethylene glycol (PEG side chains. The molecular weight of the carrier was 94,000 g/mol. Conjugation of TMZ with a novel polymeric carrier functionalized with phosphatidylcholine resulted in approximately 2 times enhancement of anticancer activity of TMZ. Combining of TMZ with doxorubicin (50 nM resulted in further enhancement by 23% of the anti-proliferative effect of TMZ. TMZ caused apoptosis in glioma cells via activation of MAPK signaling pathway, inhibition of STAT3, and affected a transition through G2/M phase of cell cycle. These features make the novel nano-formulation of TMZ a perspective strategy for further development of this drug.

  10. The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

    Directory of Open Access Journals (Sweden)

    Giada Catalogna

    2017-08-01

    Full Text Available Background/Aims: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and β-radiations, is indicated for the labeling of a large number of molecules suitable for radionuclide imaging as well as radionuclide therapy. Glioblastoma multiforme (GBM is the CNS tumor with the worse prognosis, characterized by high number of recurrences and strong resistance to chemo-radio therapy, strongly affecting patients survival. We have recently discovered and studied the small molecule SI113, as inhibitor of SGK1, a serine/threonine protein kinase, that affects several neoplastic phenotypes and signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation, perturbs cell cycle progression and restores chemo-radio sensibility by modulating SGK1-related substrates. In the present paper we aim to characterize the combined effects of 64CuCl2 and SI113 on human GBM cell lines with variable p53 expression. Methods: Cell viability, cell death and stress/authopagic related pathways were then analyzed by FACS and WB-based assays, after exposure to SI113 and/or 64CuCl2. Results: We demonstrate here, that i 64CuCl2 is able to induce a time and dose dependent modulation of cell viability (with different IC50 values in highly malignant gliomas and that the co-treatment with SI113 leads to ii additive/synergistic effects in terms of cell death; iii enhancement of the effects of ionizing radiations, probably by a TRC1 modulation; iv modulation of the autophagic response. Conclusions: Evidence reported here underlines the therapeutic potential of the combined treatment with SI113 and 64CuCl2 in GBM cells.

  11. PEITC inhibits human brain glioblastoma GBM 8401 cell migration and invasion through the inhibition of uPA, Rho A, and Ras with inhibition of MMP-2, -7 and -9 gene expression.

    Science.gov (United States)

    Chou, Yu-Cheng; Chang, Meng-Ya; Wang, Mei-Jen; Yu, Fu-Shun; Liu, Hsin-Chung; Harnod, Tomor; Hung, Chih-Huang; Lee, Hsu-Tung; Chung, Jing-Gung

    2015-11-01

    Glioblastoma is the most aggressive primary brain malignancy, and the efficacy of multimodality treatments remains unsatisfactory. Phenethyl isothiocyanate (PEITC), one member of the isothiocyanate family, was found to inhibit the migration and invasion of many types of human cancer cells. In our previous study, PEITC induced the apoptosis of human brain glioblastoma GBM 8401 cells through the extrinsic and intrinsic signaling pathways. In the present study, we first investigated the effects of PEITC on the migration and invasion of GBM 8401 cells. PEITC decreased the migration of GBM 8401 cells in a dose-dependent manner as determined from scratch wound healing and Transwell migration assays. The percentage of inhibition ranged from 46.89 to 15.75%, and from 27.80 to 7.31% after a 48-h treatment of PEITC as determined from the Transwell migration assay and invasion assay, respectively. The western blot analysis indicated that PEITC decreased the levels of proteins associated with migration and invasion, Ras, uPA, RhoA, GRB2, p-p38, p-JNK, p-ERK, p65, SOS1, MMP-2, MMP-9 and MMP-13, in a dose-dependent manner. Real-time PCR analyses revealed that PEITC reduced the mRNA levels of MMP-2, MMP-7, MMP-9 and RhoA in a dose- and time-dependent manner. PEITC exhibited potent anticancer activities through the inhibition of migration and invasion in the GBM 8401 cells. Our findings elucidate the possible molecular mechanisms and signaling pathways of the anti-metastatic effects of PEITC on human brain glioblastoma cells, and PEITC may be considered as a therapeutic agent.

  12. PERFIL PROFESIONAL Y PERFIL LABORAL EN LOS DOCENTES DEL INSTITUTO SUPERIOR PEDAGÓGICO PÚBLICO AREQUIPA AREQUIPA, 2012

    OpenAIRE

    MONTESINOS CHÁVEZ, MARÍA ELENA

    2014-01-01

    GESTIÓN SOCIAL Y RECURSOS HUMANOS EL PERFIL PROFESIONAL CARACTERÍSTICAS DEL PERFIL PROFESIONAL DIMENSIONES DEL PERFIL PROFESIONAL DOCENTE NIVELES DE ESPECIFICACIÓN DEL PERFIL PROFESIONAL GESTIÓN EDUCATIVA Y PERFILES PROFESIONAL Y DOCENTE PERFIL PROFESIONAL DOCENTE ASPECTOS FUNDAMENTALES ANÁLISIS DEL PERFIL DOCENTE EVALUACIÓN DEL PERFIL DOCENTE LAS UNIVERSIDADES Y EL PERFIL PROFESIONAL DE DOCENTES EL PERFIL LABORAL DOCENTE DEFINICIÓN COMPONENTES DEL PERFIL LABORAL OBJETIVOS DE LA ELABORACIÓN D...

  13. Characterization of human glioblastoma cell lines in vitro and their xenografts in nude mice by DNA fingerprinting

    DEFF Research Database (Denmark)

    Türeci, O; Fischer, H; Lagoda, P

    1990-01-01

    Human gliomas were grown as permanent tissue cultures and xenografts in nude mice. DNA fingerprint patterns from two human gliomas were established using two different hypervariable multilocus probes [( GTG]5 and 33.15). In general the cell lines investigated showed an overall stability in the DN...

  14. Immunological Evasion in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Roxana Magaña-Maldonado

    2016-01-01

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

  15. 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

  16. 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

  17. Perfil. Nuria Riaza

    OpenAIRE

    Riaza, Nuria; EME, Revista

    2016-01-01

    Licenciada en Bellas Artes en la Universitat Politècnica de València www.nuriariaza.com   Inicios en ilustración, motivación y valores del trabajo personal. Proyectos destacados o significativos y planes de futuro Riaza, N.; Eme, R. (2016). Perfil. Nuria Riaza. EME Experimental Illustration, Art & Design. (4):50-51. doi:10.4995/eme.2016.5392. 50 51 4

  18. Caffeine-induced nuclear translocation of FoxO1 triggers Bim-mediated apoptosis in human glioblastoma cells.

    Science.gov (United States)

    Sun, Fei; Han, Dong-Feng; Cao, Bo-Qiang; Wang, Bo; Dong, Nan; Jiang, De-Hua

    2016-03-01

    Caffeine is one of the most commonly ingested neuroactive compounds and exhibits anticancer effects through induction of apoptosis and suppression of cell proliferation. However, the mechanisms underlying these effects are currently unknown. In this study, we investigated the mechanisms of caffeine-induced apoptosis in U251 cells (human glioma cell line). We analyzed the inhibitory effects of caffeine on cell proliferation by performing WST-8 and colony formation assays; in addition, cell survival was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and flow cytometric analysis. Western blotting was used to investigate the role played by FoxO1 in the proapoptotic effects of caffeine on glioma cells. Results showed that caffeine inhibited proliferation and survival of human glioma cells, induced apoptosis, and increased the expression of FoxO1 and its proapoptotic target Bim. In addition, we found that FoxO1 enhanced the transcription of its proapoptotic target Bim. In summary, our data indicates that FoxO1-Bim mediates caffeine-induced regression of glioma growth by activating cell apoptosis, thereby providing new mechanistic insight into the possible use of caffeine in treating human cancer.

  19. Perfil CIO Colombiano

    OpenAIRE

    Charry Viuchy, Yuly Andrea; Cabrera Pardo, Daniel Felipe; Ortega Torres, Raúl Fernando

    2014-01-01

    La identificación del perfil del Chief Information Officer (CIO) en el entorno empresarial nacional responde a la necesidad de comparar o constatar el rol aplicado en Colombia en relación a la expectativa de la academia y la pertinencia que lleva en un entorno empresarial global. La migración del concepto de CIO y sus definiciones es resultado de la implementación local de prácticas, teorías y estrategias de alto impacto en mercados internacionales. En el presente documento, se profundi...

  20. Perfil calórico do leite pasteurizado no banco de leite humano de um hospital escola Perfil calórico de la leche pasteurizada en el banco de leche humana de un hospital escuela en Londrina, Paraná, Brasil Caloric profile of pasteurized milk in the human milk bank at a university hospital

    Directory of Open Access Journals (Sweden)

    Priscila Santa de Moraes

    2013-03-01

    .846 muestras de leche humana de donantes de varias localidades, totalizando 5.869L de leche recogida y distribuida, siendo que el 55,3% de esta leche humana pasteurizada fue clasificada como hipocalórica (menos que 580kcal/L, el 36,4% como calórico y el 8,3% como hipercalórico (más que 711kcal/L. Conforme a las varias localidades de origen de las leches, el Banco de Leche Humana de Londrina fue el local en el que se observó una mayor cantidad de donación en las tres clasificaciones. Al examen de la titulación de acidez Dornic de la leche humana recogida, se encontró el 60,8%, con valores entre 4,1° y 8,0° Dornic. CONCLUSIONES: Gran parte de la leche recogida es hipocalórica y está propia para el consumo respecto al perfil higiénico sanitario. Es necesario intensificar la recolección de este alimento para atender a la demanda de leche hipocalórica para los recién nacidos prematuros.OBJECTIVE: To verify the caloric and sanitary profile of human milk stored at the Human Milk Bank at Londrina University Hospital. METHODS: Cross-sectional study. Data were obtained from the Human Milk Bank registry regarding the source, the amount collected in liters, the amount of calories by liter assessed by crematocrit, and the acidity of human milk determined by titration in degrees Dornic. RESULTS: Between 2006 and 2009, 30,846 samples of human milk were collected from donors coming from different locations and analyzed. A total of 5,869L of milk were collected and distributed. From the total human pasteurized milk, 53,5% was classified as hypocaloric (711kcal/L. Regarding the several locations where the milk was collected, the Human Milk Bank at Londrina University Hospital was the location in which a larger number of donations were observed in the three classifications. The result of the Dornic test for acidity of the collected milk revealed that 60.8% had 4.1º to 8.0º Dornic. CONCLUSIONS: A large volume of the collected human milk is hypocaloric and appropriate for human

  1. In vivo PET/CT in a human glioblastoma chicken chorioallantoic membrane model: a new tool for oncology and radiotracer development.

    Science.gov (United States)

    Warnock, Geoff; Turtoi, Andrei; Blomme, Arnaud; Bretin, Florian; Bahri, Mohamed Ali; Lemaire, Christian; Libert, Lionel Cyrille; Seret, Alain E J J; Luxen, André; Castronovo, Vincenzo; Plenevaux, Alain R E G

    2013-10-01

    For many years the laboratory mouse has been used as the standard model for in vivo oncology research, particularly in the development of novel PET tracers, but the growth of tumors on chicken chorioallantoic membrane (CAM) provides a more rapid, low cost, and ethically sustainable alternative. For the first time, to our knowledge, we demonstrate the feasibility of in vivo PET and CT imaging in a U87 glioblastoma tumor model on chicken CAM, with the aim of applying this model for screening of novel PET tracers. U87 glioblastoma cells were implanted on the CAM at day 11 after fertilization and imaged at day 18. A small-animal imaging cell was used to maintain incubation and allow anesthesia using isoflurane. Radiotracers were injected directly into the exposed CAM vasculature. Sodium (18)F-fluoride was used to validate the imaging protocol, demonstrating that image-degrading motion can be removed with anesthesia. Tumor glucose metabolism was imaged using (18)F-FDG, and tumor protein synthesis was imaged using 2-(18)F-fluoro-l-tyrosine. Anatomic images were obtained by contrast-enhanced CT, facilitating clear delineation of the tumor, delineation of tracer uptake in tumor versus embryo, and accurate volume measurements. PET imaging of tumor glucose metabolism and protein synthesis was successfully demonstrated in the CAM U87 glioblastoma model. Catheterization of CAM blood vessels facilitated dynamic imaging of glucose metabolism with (18)F-FDG and demonstrated the ability to study PET tracer uptake over time in individual tumors, and CT imaging improved the accuracy of tumor volume measurements. We describe the novel application of PET/CT in the CAM tumor model, with optimization of typical imaging protocols. PET imaging in this valuable tumor model could prove particularly useful for rapid, high-throughput screening of novel radiotracers.

  2. 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

  3. Over-expression of CHAF1A promotes cell proliferation and apoptosis resistance in glioblastoma cells via AKT/FOXO3a/Bim pathway

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Honghai; Du, Bin [Department of Neurosurgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013 (China); Jiang, Huili [Friendship Nephrology and Blood Purification Center, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013 (China); Gao, Jun, E-mail: gaoj1666@126.com [Department of Neurosurgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013 (China)

    2016-01-22

    Chromatinassembly factor 1 subunit A (CHAF1A) has been reported to be involved in several human diseases including cancer. However, the biological and clinical significance of CHAF1A in glioblastoma progression remains largely unknown. In this study, we found that up-regulation of CHAF1A happens frequently in glioblastoma tissues and is associated with glioblastoma prognosis. Knockout of CHAF1A by CRISPR/CAS9 technology induce G1 phase arrest and apoptosis in glioblastoma cell U251 and U87. In addition, inhibition of CHAF1A influenced the signal transduction of the AKT/FOXO3a/Bim axis, which is required for glioblastoma cell proliferation. Taken together, these results show that CHAF1A contributes to the proliferation of glioblastoma cells and may be developed as a de novo drug target and prognosis biomarker of glioblastoma.

  4. 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.

  5. Ex vivo tissue imaging of human glioblastoma using a small bore 7T MRI and correlation with digital pathology and proteomics profiling

    Science.gov (United States)

    Matsuda, Kant M.; Lopes-Calcas, Ana; Magyar, Thalia; O'Brien-Moran, Zoe; Buist, Richard; Martin, Melanie

    2017-03-01

    Recent advancement in MRI established multi-parametric imaging for in vivo characterization of pathologic changes in brain cancer, which is expected to play a role in imaging biomarker development. Diffusion Tensor Imaging (DTI) is a prime example, which has been deployed for assessment of therapeutic response via analysis of apparent diffusion coefficient (ADC) / mean diffusivity (MD) values. They have been speculated to reflect apoptosis/necrosis. As newer medical imaging emerges, it is essential to verify that apparent abnormal features in imaging correlate with histopathology. Furthermore, the feasibility of imaging correlation with molecular profile should be explored in order to enhance the potential of biomedical imaging as a reliable biomarker. We focus on glioblastoma, which is an aggressive brain cancer. Despite the increased number of studies involving DTI in glioblastoma; however, little has been explored to bridge the gap between the molecular biomarkers and DTI data. Due to spatial heterogeneity in, MRI signals, pathologic change and protein expression, precise correlation is required between DTI, pathology and proteomics data in a histoanatomically identical manner. The challenge is obtaining an identical plane from in vivo imaging data that exactly matches with histopathology section. Thus, we propose to incorporate ex vivo tissue imaging to bridge between in vivo imaging data and histopathology. With ex vivo scan of removed tissue, it is feasible to use high-field 7T MRI scanner, which can achieve microscopic resolution. Once histology section showing the identical plane, it is feasible to correlate protein expression by a unique technology, "multiplex tissue immunoblotting".

  6. Resistance to hypoxia-induced, BNIP3-mediated cell death contributes to an increase in a CD133-positive cell population in human glioblastomas in vitro.

    Science.gov (United States)

    Kahlert, Ulf Dietrich; Maciaczyk, Donata; Dai, Fangping; Claus, Rainer; Firat, Elke; Doostkam, Soroush; Bogiel, Tomasz; Carro, Maria Stella; Döbrössy, Mate; Herold-Mende, Christel; Niedermann, Gabriele; Prinz, Marco; Nikkhah, Guido; Maciaczyk, Jaroslaw

    2012-12-01

    In addition to intrinsic regulatory mechanisms, brain tumor stemlike cells (BTSCs), a small subpopulation of malignant glial tumor-derived cells, are influenced by environmental factors. Previous reports showed that lowering oxygen tension induced an increase of BTSCs expressing CD133 and other stem cell-related genes and more pronounced clonogenic capacity in vitro. We investigated the mechanisms responsible for hypoxia-dependent induction of CD133-positive BTSCs in glioblastomas. We confirmed that cultures exposed to lowered oxygen levels showed a severalfold increase of CD133-positive BTSCs. Both the increase of CD133-positive cells and deceleration of the growth kinetics were reversible after transfer to normoxic conditions. Exposure to hypoxia induced BNIP3 (BCL2/adenovirus E1B 19-kDa protein-interacting protein 3)-dependent apoptosis preferentially in CD133-negative cells. In contrast, CD133-positive cells proved to be more resistant to hypoxia-induced programmed cell death. Application of the demethylating agent 5'-azacitidine resulted in an increase of BNIP3 expression levels in CD133-positive cells. Thus, epigenetic modifications led to their better survival in lowered oxygen tension. Moreover, the, hypoxia-induced increase of CD133-positive cells was inhibited after 5'-azacitidine treatment. These results suggest the possible efficacy of a novel therapy for glioblastoma focused on eradication of BTSCs by modifications of epigenetic regulation of gene expression.

  7. Comparative Expression Study of the Endo–G Protein Coupled Receptor (GPCR) Repertoire in Human Glioblastoma Cancer Stem-like Cells, U87-MG Cells and Non Malignant Cells of Neural Origin Unveils New Potential Therapeutic Targets

    Science.gov (United States)

    Lennon, Sarah; Carapito, Christine; Dong, Jihu; Van Dorsselaer, Alain; Junier, Marie-Pierre; Chneiweiss, Hervé; Cianférani, Sarah; Haiech, Jacques; Kilhoffer, Marie-Claude

    2014-01-01

    Glioblastomas (GBMs) are highly aggressive, invasive brain tumors with bad prognosis and unmet medical need. These tumors are heterogeneous being constituted by a variety of cells in different states of differentiation. Among these, cells endowed with stem properties, tumor initiating/propagating properties and particularly resistant to chemo- and radiotherapies are designed as the real culprits for tumor maintenance and relapse after treatment. These cells, termed cancer stem-like cells, have been designed as prominent targets for new and more efficient cancer therapies. G-protein coupled receptors (GPCRs), a family of membrane receptors, play a prominent role in cell signaling, cell communication and crosstalk with the microenvironment. Their role in cancer has been highlighted but remains largely unexplored. Here, we report a descriptive study of the differential expression of the endo-GPCR repertoire in human glioblastoma cancer stem-like cells (GSCs), U-87 MG cells, human astrocytes and fetal neural stem cells (f-NSCs). The endo-GPCR transcriptome has been studied using Taqman Low Density Arrays. Of the 356 GPCRs investigated, 138 were retained for comparative studies between the different cell types. At the transcriptomic level, eight GPCRs were specifically expressed/overexpressed in GSCs. Seventeen GPCRs appeared specifically expressed in cells with stem properties (GSCs and f-NSCs). Results of GPCR expression at the protein level using mass spectrometry and proteomic analysis are also presented. The comparative GPCR expression study presented here gives clues for new pathways specifically used by GSCs and unveils novel potential therapeutic targets. PMID:24662753

  8. Shikonin Inhibits the Migration and Invasion of Human Glioblastoma Cells by Targeting Phosphorylated β-Catenin and Phosphorylated PI3K/Akt: A Potential Mechanism for the Anti-Glioma Efficacy of a Traditional Chinese Herbal Medicine.

    Science.gov (United States)

    Zhang, Feng-Ying; Hu, Yi; Que, Zhong-You; Wang, Ping; Liu, Yun-Hui; Wang, Zhen-Hua; Xue, Yi-Xue

    2015-10-09

    Shikonin is an anthraquinone derivative extracted from the root of lithospermum. Shikonin is traditionally used in the treatment of inflammatory and infectious diseases such as hepatitis. Shikonin also inhibits proliferation and induces apoptosis in various tumors. However, the effect of shikonin on gliomas has not been fully elucidated. In the present study, we aimed to investigate the effects of shikonin on the migration and invasion of human glioblastoma cells as well as the underlying mechanisms. U87 and U251 human glioblastoma cells were treated with shikonin at 2.5, 5, and 7.5 μmol/L and cell viability, migration and invasiveness were assessed with CCK8, scratch wound healing, in vitro Transwell migration, and invasion assays. The expression and activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) and the expression of phosphorylated β-catenin (p-β-catenin) and phosphorylated PI3K/Akt were also checked. Results showed that shikonin significantly inhibited the cell proliferation, migration, invasion, and expression of MMP-2 and MMP-9 in U87 and U251 cells. The expression of p-β-catenin showed contrary trends in two cell lines. It was significantly inhibited in U87 cells and promoted in U251 cells. Results in this work indicated that shikonin displayed an inhibitory effect on the migration and invasion of glioma cells by inhibiting the expression and activity of MMP-2 and -9. In addition, shikonin also inhibited the expression of p-PI3K and p-Akt to attenuate cell migration and invasion and MMP-2 and MMP-9 expression in both cell lines, which could be reversed by the PI3K/Akt pathway agonist, insulin-like growth factor-1 (IGF-1).

  9. 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.

  10. 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.

  11. Emerging Biomarkers in Glioblastoma

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    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.

  12. 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.

  13. 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.

  14. 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.)

  15. Nuclear SMAD2 Restrains Proliferation of Glioblastoma

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    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.

  16. 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...

  17. 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

  18. 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.

  19. 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.

  20. Inhibition of Acetyl-CoA Carboxylase 1 (ACC1) and 2 (ACC2) Reduces Proliferation and De Novo Lipogenesis of EGFRvIII Human Glioblastoma Cells.

    Science.gov (United States)

    Jones, Jessica E C; Esler, William P; Patel, Rushi; Lanba, Adhiraj; Vera, Nicholas B; Pfefferkorn, Jeffrey A; Vernochet, Cecile

    2017-01-01

    Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis and de novo lipogenesis. Since acetyl-CoA carboxylase (ACC) is at the junction of lipids synthesis and oxidative metabolic pathways, we investigated whether use of a dual ACC inhibitor would provide a potential therapy against certain lipogenic cancers. The impact of dual ACC1/ACC2 inhibition was investigated using a dual ACC1/ACC2 inhibitor as well as dual siRNA knock down on the cellular viability and metabolism of two glioblastoma multiform cancer cell lines, U87 and a more aggressive form, U87 EGFRvIII. We first demonstrated that while ACCi inhibited DNL in both cell lines, ACCi preferentially blunted the U87 EGFRvIII cellular proliferation capacity. Metabolically, chronic treatment with ACCi significantly upregulated U87 EGFRvIII cellular respiration and extracellular acidification rate, a marker of glycolytic activity, but impaired mitochondrial health by reducing maximal respiration and decreasing mitochondrial ATP production efficiency. Moreover, ACCi treatment altered the cellular lipids content and increased apoptotic caspase activity in U87 EGFRvIII cells. Collectively these data indicate that ACC inhibition, by reducing DNL and increasing cellular metabolic rate, may have therapeutic utility for the suppression of lipogenic tumor growth and warrants further investigation.

  1. Inhibition of Acetyl-CoA Carboxylase 1 (ACC1 and 2 (ACC2 Reduces Proliferation and De Novo Lipogenesis of EGFRvIII Human Glioblastoma Cells.

    Directory of Open Access Journals (Sweden)

    Jessica E C Jones

    Full Text Available Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis and de novo lipogenesis. Since acetyl-CoA carboxylase (ACC is at the junction of lipids synthesis and oxidative metabolic pathways, we investigated whether use of a dual ACC inhibitor would provide a potential therapy against certain lipogenic cancers. The impact of dual ACC1/ACC2 inhibition was investigated using a dual ACC1/ACC2 inhibitor as well as dual siRNA knock down on the cellular viability and metabolism of two glioblastoma multiform cancer cell lines, U87 and a more aggressive form, U87 EGFRvIII. We first demonstrated that while ACCi inhibited DNL in both cell lines, ACCi preferentially blunted the U87 EGFRvIII cellular proliferation capacity. Metabolically, chronic treatment with ACCi significantly upregulated U87 EGFRvIII cellular respiration and extracellular acidification rate, a marker of glycolytic activity, but impaired mitochondrial health by reducing maximal respiration and decreasing mitochondrial ATP production efficiency. Moreover, ACCi treatment altered the cellular lipids content and increased apoptotic caspase activity in U87 EGFRvIII cells. Collectively these data indicate that ACC inhibition, by reducing DNL and increasing cellular metabolic rate, may have therapeutic utility for the suppression of lipogenic tumor growth and warrants further investigation.

  2. 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.

  3. Cross-platform Q-TOF validation of global exo-metabolomic analysis: application to human glioblastoma cells treated with the standard PI 3-Kinase inhibitor LY294002.

    Science.gov (United States)

    Pandher, R; Ducruix, C; Eccles, S A; Raynaud, F I

    2009-05-01

    The reproducibility of a metabolomics method has been assessed to identify changes in tumour cell metabolites. Tissue culture media extracts were analyzed by reverse phase chromatography on a Waters Acquity T3 column with a 13 min 0.1% formic acid: acetonitrile gradient on Agilent and Waters LC-Q-TOF instruments. Features (m/z, RT) were extracted by MarkerLynx (Waters) and Molecular Feature Extractor (Agilent) in positive and negative ionization modes. The number of features were similar on both instruments and the reproducibility of ten replicates was <35% signal variability for approximately 50% and 40% of all ions detected in positive and negative ionization modes, respectively. External standards spiked to the matrix showed CVs <25% in peak areas within and between days. U87MG glioblastoma cells exposed to the PI 3-Kinase inhibitor LY294002 showed significant alterations of several confirmed features. These included glycerophosphocholine, already shown by NMR to be modulated by LY294002, highlighting the power of this technology for biomarker discovery.

  4. Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells.

    Science.gov (United States)

    Daniele, Simona; Sestito, Simona; Pietrobono, Deborah; Giacomelli, Chiara; Chiellini, Grazia; Di Maio, Danilo; Marinelli, Luciana; Novellino, Ettore; Martini, Claudia; Rapposelli, Simona

    2017-01-18

    The poor prognosis of glioblastoma multiforme (GBM) is mainly attributed to drug resistance mechanisms and to the existence of a subpopulation of glioma stem cells (GSCs). Multitarget compounds able to both affect different deregulated pathways and the GSC subpopulation could escape tumor resistance and, most importantly, eradicate the stem cell reservoir. In this respect, the simultaneous inhibition of phosphoinositide-dependent kinase-1 (PDK1) and aurora kinase A (AurA), each one playing a pivotal role in cellular survival/migration/differentiation, could represent an innovative strategy to overcome GBM resistance and recurrence. Herein, the cross-talk between these pathways was investigated, using the single-target reference compounds MP7 (PDK1 inhibitor) and Alisertib (AurA inhibitor). Furthermore, a new ligand, SA16, was identified for its ability to inhibit the PDK1 and the AurA pathways at once, thus proving to be a useful tool for the simultaneous inhibition of the two kinases. SA16 blocked GBM cell proliferation, reduced tumor invasiveness, and triggered cellular apoptosis. Most importantly, the AurA/PDK1 blocker showed an increased efficacy against GSCs, inducing their differentiation and apoptosis. To the best of our knowledge, this is the first report on combined targeting of PDK1 and AurA. This drug represents an attractive multitarget lead scaffold for the development of new potential treatments for GBM and GSCs.

  5. Quantitative evaluation of boron neutron capture therapy (BNCT) drugs for boron delivery and retention at subcellular scale resolution in human glioblastoma cells with imaging secondary ion mass spectrometry (SIMS)

    Science.gov (United States)

    Chandra, S.; Ahmad, T.; Barth, R. F.; Kabalka, G. W.

    2014-01-01

    Boron neutron capture therapy (BNCT) of cancer depends on the selective delivery of a sufficient number of boron-10 (10B) atoms to individual tumor cells. Cell killing results from the 10B (n, α)7Li neutron capture and fission reactions that occur if a sufficient number of 10B atoms are localized in the tumor cells. Intranuclear 10B localization enhances the efficiency of cell killing via damage to the DNA. The net cellular content of 10B atoms reflects both bound and free pools of boron in individual tumor cells. The assessment of these pools, delivered by a boron delivery agent, currently cannot be made at subcellular scale resolution by clinically applicable techniques such as PET and MRI. In this study, secondary ion mass spectrometry (SIMS) based imaging instrument, a CAMECA IMS 3f ion microscope, capable of 500 nm spatial resolution was employed. Cryogenically prepared cultured human T98G glioblastoma cells were evaluated for boron uptake and retention of two delivery agents. The first, L-p-boronophenylalanine (BPA), has been used clinically for BNCT of high grade gliomas, recurrent tumors of the head and neck region and melanomas. The second, a boron analogue of an unnatural amino acid, 1-amino-3-borono-cyclopentanecarboxylic acid (cis-ABCPC), has been studied in rodent glioma and melanoma models by quantification of boron in the nucleus and cytoplasm of individual tumor cells. The bound and free pools of boron were assessed by exposure of cells to boron-free nutrient medium. Both BPA and cis-ABCPC delivered almost 70% of the pool of boron in the free or loosely bound form to the nucleus and cytoplasm of human glioblastoma cells. This free pool of boron could be easily mobilized out of the cell and was in some sort of equilibrium with extracellular boron. In the case of BPA, the intracellular free pool of boron also was affected by the presence of phenylalanine in the nutrient medium. This suggests that it might be advantageous if patients were placed on a

  6. Quantitative evaluation of boron neutron capture therapy (BNCT) drugs for boron delivery and retention at subcellular-scale resolution in human glioblastoma cells with imaging secondary ion mass spectrometry (SIMS).

    Science.gov (United States)

    Chandra, S; Ahmad, T; Barth, R F; Kabalka, G W

    2014-06-01

    Boron neutron capture therapy (BNCT) of cancer depends on the selective delivery of a sufficient number of boron-10 ((10)B) atoms to individual tumour cells. Cell killing results from the (10)B (n, α)(7) Li neutron capture and fission reactions that occur if a sufficient number of (10)B atoms are localized in the tumour cells. Intranuclear (10)B localization enhances the efficiency of cell killing via damage to the DNA. The net cellular content of (10)B atoms reflects both bound and free pools of boron in individual tumour cells. The assessment of these pools, delivered by a boron delivery agent, currently cannot be made at subcellular-scale resolution by clinically applicable techniques such as positron emission tomography and magnetic resonance imaging. In this study, a secondary ion mass spectrometry based imaging instrument, a CAMECA IMS 3f ion microscope, capable of 500 nm spatial resolution was employed. Cryogenically prepared cultured human T98G glioblastoma cells were evaluated for boron uptake and retention of two delivery agents. The first, L-p-boronophenylalanine (BPA), has been used clinically for BNCT of high-grade gliomas, recurrent tumours of the head and neck region and melanomas. The second, a boron analogue of an unnatural amino acid, 1-amino-3-borono-cyclopentanecarboxylic acid (cis-ABCPC), has been studied in rodent glioma and melanoma models by quantification of boron in the nucleus and cytoplasm of individual tumour cells. The bound and free pools of boron were assessed by exposure of cells to boron-free nutrient medium. Both BPA and cis-ABCPC delivered almost 70% of the pool of boron in the free or loosely bound form to the nucleus and cytoplasm of human glioblastoma cells. This free pool of boron could be easily mobilized out of the cell and was in some sort of equilibrium with extracellular boron. In the case of BPA, the intracellular free pool of boron also was affected by the presence of phenylalanine in the nutrient medium. This

  7. 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...

  8. Perfil das doadoras de leite do banco de leite humano de um hospital universitário = Profile of breast milk donors at the human milk bank of a university hospital

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    Danielle Talita dos Santos

    2009-01-01

    Full Text Available Esta pesquisa tem como objetivo conhecer o perfil socioeconômico dasdoadoras de leite do Banco de Leite Humano do Hospital Universitário de Londrina, Estado do Paraná (BLH/HUL. Trata-se de um estudo transversal, em que foram coletados dados a partir de formulário aplicado às doadoras externas do BLH/HUL no período de junho a agosto de 2005. Constatou-se que 11% são adolescentes. Com relação àescolaridade, 41,8% possuem segundo grau completo ou superior incompleto. De acordo com a literatura, quanto maior a escolaridade das mães, mais informações elas absorvem por meio das orientações e das campanhas que são realizadas sobre aleitamento materno. Dototal das doadoras, 37,4% receberam informações sobre doação de leite e sobre os serviços do BLH/HU de Londrina por intermédio dos profissionais dos serviços de saúde. O conhecimento do perfil das doadoras permitirá direcionar as informações sobre doação deleite em nível local e regional, otimizando o trabalho realizado pelo Banco de Leite Humano do HU/L.This objective of this research is to understand the socioeconomic profile of the milk donors at the Human Milk Bank of the University Hospital of Londrina, Paraná State (BLH/HUL. It is a cross-sectional study in which data was collected by means of a questionnaire applied to the external donors of the BLH/ HUL, between June and Augustof 2005. It was observed that 11.0% are adolescents. According to the study, 41.8% have at least some high school education. According to the literature, the higher the educational level of the donors, the more information they are able to absorb through orientations andcampaigns on breastfeeding. Of the total, 37.4% had received information on breast milk donation and the services offered by the BLH/HUL from the health professionals. The knowledge of the donors’ profile will allow the HU/Londrina Human Milk Bank to directinformation on milk donation at the local and regional levels, thus

  9. The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma

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    Giovanni Luca Gravina

    2017-01-01

    Full Text Available Abstract Background Glioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF antibody bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. It has been demonstrated that anti-VEGF/VEGFR therapies control the invasive phenotype and that relapse occurs through the increased activity of CXCR4. We therefore hypothesized that combining bevacizumab or sunitinib with the novel CXCR4 antagonist, PRX177561, would have superior antitumor activity. Methods The effects of bevacizumab, sunitinib, and PRX177561 were tested alone or in combination in subcutaneous xenografts of U87MG, U251, and T98G cells as well as on intracranial xenografts of luciferase tagged U87MG cells injected in CD1-nu/nu mice. Animals were randomized to receive vehicle, bevacizumab (4 mg/kg iv every 4 days, sunitinib (40 mg/kg po qd, or PRX177561 (50 mg/kg po qd. Results The in vivo experiments demonstrated that bevacizumab and sunitinib increase the in vivo expression of CXCR4, SDF-1α, and TGFβ1. In addition, we demonstrate that the co-administration of the novel brain-penetrating CXCR4 antagonist, PRX177561, with bevacizumab or sunitinib inhibited tumor growth and reduced the inflammation. The combination of PRX177561 with bevacizumab resulted in a synergistic reduction of tumor growth with an increase of disease-free survival (DSF and overall survival (OS, whereas the combination of PRX177561 with sunitinib showed a mild additive effect. Conclusions The CXC4 antagonist PRX177561 may be a valid therapeutic complement to anti-angiogenic therapy, particularly when used in combination with VEGF/VEGFR inhibitors. Therefore, this compound deserves to be considered for future clinical evaluation.

  10. Polish natural bee honeys are anti-proliferative and anti-metastatic agents in human glioblastoma multiforme U87MG cell line.

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    Justyna Moskwa

    Full Text Available Honey has been used as food and a traditional medicament since ancient times. However, recently many scientists have been concentrating on the anti-oxidant, anti-proliferative, anti-inflammatory and other properties of honey. In this study, we investigated for the first time an anticancer effect of different honeys from Poland on tumor cell line - glioblastoma multiforme U87MG. Anti-proliferative activity of honeys and its interferences with temozolomide were determined by a cytotoxicity test and DNA binding by [H3]-thymidine incorporation. A gelatin zymography was used to conduct an evaluation of metalloproteinases (MMP-2 and MMP-9 expression in U87MG treatment with honey samples. The honeys were previously tested qualitatively (diastase activity, total phenolic content, lead and cadmium content. The data demonstrated that the examined honeys have a potent anti-proliferative effect on U87MG cell line in a time- and dose-dependent manner, being effective at concentrations as low as 0.5% (multifloral light honey - viability 53% after 72 h of incubation. We observed that after 48 h, combining honey with temozolomide showed a significantly higher inhibitory effect than the samples of honey alone. We observed a strong inhibition of MMP-2 and MMP-9 for the tested honeys (from 20 to 56% and from 5 to 58% compared to control, respectively. Our results suggest that Polish honeys have an anti-proliferative and anti-metastatic effect on U87MG cell line. Therefore, natural bee honey can be considered as a promising adjuvant treatment for brain tumors.

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

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    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

  12. A novel berbamine derivative inhibits cell viability and induces apoptosis in cancer stem-like cells of human glioblastoma, via up-regulation of miRNA-4284 and JNK/AP-1 signaling.

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    Fan Yang

    Full Text Available Glioblastoma (GBM is the most common primary brain tumor, accounting for approximately 40% of all central nervous system malignancies. Despite standard treatment consisting of surgical resection, radiotherapy and/or chemotherapy, the prognosis for GBM is poor; with a median survival of 14.6 months. The cancer stem cell or cancer-initiating cell model has provided a new paradigm for understanding development and recurrence of GBM following treatment. Berbamine (BBM is a natural compound derived from the Berberis amurensis plant, and along with its derivatives, has been shown to exhibit antitumor activity in several cancers. Here, we reported that a novel synthetic Berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of cancer stem-like cells (CSCs in a time- and dose-dependent manner when the CSCs from four GBM patients (PBT003, PBT008, PBT022, and PBT030 were cultured. These CSCs grew in neurospheres and expressed CD133 and nestin as markers. Treatment with BBMD3 destroyed the neurosphere morphology, and led to the induction of apoptosis in the CSCs. Induction of apoptosis in these CSCs is dependent upon activation of caspase-3 and cleavage of poly (ADP-ribose polymerase (PARP. MicroRNA-4284 (miR-4284 was shown to be over-expressed about 4-fold in the CSCs following BBMD3 treatment. Furthermore, transfection of synthetic anti-sense oligonucleotide against human miR-4284 partially blocked the anticancer effects of BBMD3 on the GBM derived CSCs. BBMD3 also increased phosphorylation of the c-Jun N-terminal kinase (JNK/stress-activated protein kinase (SAPK, resulting in an increase expression of phosphorylated c-Jun and total c-Fos; the major components of transcriptional factor AP-1. The JNK-c-Jun/AP-1 signaling pathway plays an important role in the induction of apoptosis in response to UV irradiation and some drug treatments. Targeting glioblastoma stem-like cells with BBMD3 is therefore novel, and may have promise as an

  13. Widespread dispersion of adeno-associated virus serotype 1 and adeno-associated virus serotype 6 vectors in the rat central nervous system and in human glioblastoma multiforme xenografts.

    Science.gov (United States)

    Huszthy, Peter C; Svendsen, Agnete; Wilson, James M; Kotin, Robert M; Lønning, Per Eystein; Bjerkvig, Rolf; Hoover, Frank

    2005-03-01

    The transduction patterns of recombinant adeno-associated virus serotype 1 (AAV1) and serotype 6 (AAV6) vectors were assessed in human glioblastoma multiforme (GBM) cell lines, in human GBM biopsy spheroids, and in tumor xenografts growing in nude rat brains. All the cell lines tested (A172, D37, GaMg, HF66, and U373Mg) were found to be permissive to both AAV1 and AAV6 vectors, and thus displayed a transduction pattern similar to AAV2 vectors. For every cell line tested, the transduction efficiency displayed by AAV2 vectors was better than by isogenic and isopromoter AAV1 vectors. Transduction efficiency was dependent on the viral particle number used, suggesting that the receptors for these vectors are widely distributed in GBM tissues. Interestingly, AAV1, AAV2, and AAV6 vectors were able to infect and transduce the same cells when added simultaneously to monolayer cultures. Infection of human GBM biopsy spheroids with AAV1 and AAV6 vectors resulted in transgene expression both at the surface layers and in the core of the spheroids. Following injection of AAV1 and AAV6 vectors into human GBM biopsy xenografts growing in nude rat brains, reporter gene expression was seen both in the periphery as well as in the central regions of the tumors. When injected into the normal rat brain, both AAV1 and AAV6 vectors were found to transduce several central nervous system (CNS) regions. The presented results suggest a potential therapeutic role for AAV1 and AAV6 vectors in gene therapy for GBM and also for other CNS malignancies.

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

    Science.gov (United States)

    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.

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

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    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.

  16. All-trans retinoic acid influences viability, migration and adhesion of U251 glioblastoma cells

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    Marjanović-Vićentić Jelena

    2017-01-01

    Full Text Available Glioblastoma (GBM is one of the most aggressive and deadly forms of cancer. Literature data reveals that all-trans retinoic acid (ATRA has anticancer effects on different types of tumor cells. However, data about the effects of ATRA on glioblastoma cells are contradictory. In this study, we examined whether ATRA treatment affects features of human glioblastoma U251 cells. To that end, the cells were treated with different concentrations of ATRA. Results obtained by MTT and the crystal violet assays imply that ATRA affected the viability of U251 glioblastoma cells in a dose- and time-dependent manner. Fluorescence staining of microtubule cytoskeleton protein α-tubulin revealed that ATRA induced changes in cell morphology. Using semi-quantitative RT-PCR we found that the expression of SOX3 and GFAP genes, as markers of neural differentiation, was not changed upon ATRA treatment. Thus, the observed changes in cell morphology after ATRA treatment are not associated with neural differentiation of U251 glioblastoma cells. The scratch-wound healing assay revealed that ATRA changed the mode of U251 cell migration from collective to single cell motility. The cell-matrix adhesion assay demonstrated that the pharmacologically relevant concentration of ATRA lowered the cell-matrix adhesion capability of U251 cells. In conclusion, our results imply that further studies are needed before ATRA could be considered for the treatment of glioblastoma. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173051

  17. 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.

  18. 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.

  19. Long-term In Vitro Treatment of Human Glioblastoma Cells with Temozolomide Increases Resistance In Vivo through Up-regulation of GLUT Transporter and Aldo-Keto Reductase Enzyme AKR1C Expression

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    Benjamin Le Calvé

    2010-09-01

    Full Text Available Glioblastoma (GBM is the most frequent malignant glioma. Treatment of GBM patients is multimodal with maximum surgical resection, followed by concurrent radiation and chemotherapy with the alkylating drug temozolomide (TMZ. The present study aims to identify genes implicated in the acquired resistance of two human GBM cells of astrocytic origin, T98G and U373, to TMZ. Resistance to TMZ was induced by culturing these cells in vitro for months with incremental TMZ concentrations up to 1 mM. Only partial resistance to TMZ has been achieved and was demonstrated in vivo in immunocompromised mice bearing orthotopic U373 and T98G xenografts. Our data show that long-term treatment of human astroglioma cells with TMZ induces increased expression of facilitative glucose transporter/solute carrier GLUT/SLC2A family members, mainly GLUT-3, and of the AKR1C family of proteins. The latter proteins are phase 1 drug-metabolizing enzymes involved in the maintenance of steroid homeostasis, prostaglandin metabolism, and metabolic activation of polycyclic aromatic hydrocarbons. GLUT-3 has been previously suggested to exert roles in GBM neovascularization processes, and TMZ was found to exert antiangiogenic effects in experimental gliomas. AKR1C1 was previously shown to be associated with oncogenic potential, with proproliferative effects similar to AKR1C3 in the latter case. Both AKR1C1 and AKR1C2 proteins are involved in cancer pro-proliferative cell chemoresistance. Selective targeting of GLUT-3 in GBM and/or AKR1C proteins (by means of jasmonates, for example could thus delay the acquisition of resistance to TMZ of astroglioma cells in the context of prolonged treatment with this drug.

  20. PERFILES MOTIVACIONALES EN SALVAMENTO DEPORTIVO

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    J.A. Moreno

    2010-09-01

    Full Text Available

     

    RESUMEN

    El objetivo de este trabajo fue establecer diferentes perfiles motivacionales en una muestra compuesta por 283 deportistas federados de salvamento deportivo (141 hombres y 142 mujeres, de edades comprendidas entre los 14 y los 38 años. Las variables analizadas fueron la percepción del clima motivacional, la motivación intrínseca, la motivación extrínseca, la desmotivación y el flow disposicional. El análisis cluster reveló tres perfiles motivacionales. El “perfil no autodeterminado” obtuvo puntuaciones altas en la percepción de un clima ego y en desmotivación, moderadas en motivación intrínseca, extrínseca y flow disposicional, y bajas en la percepción de un clima tarea. El “perfil autodeterminado” mostró puntuaciones altas en la percepción de un clima tarea y en motivación intrínseca, revelando los valores más altos de flow disposicional. También obtuvo puntuaciones moderadas en motivación extrínseca y bajas en desmotivación y en la percepción de un clima ego. El “perfil pobremente motivado” reflejó una puntuación moderada en la percepción de un clima ego y baja en el resto de variables de estudio. La puntuación más alta que obtuvo fue en desmotivación. Además, los resultados mostraron que en niveles de competición más elevados los perfiles motivacionales parecían ser más negativos.
    Palabras Clave: motivación, autodeterminación, clima motivacional, flow, salvamento deportivo.

     

    ABSTRACT

    The main purpose of this article has been to analyze the motivational profiles in a group of 283 lifesavers (141 male and 142 female, of ages 14 to 38 years. There were several variables that were analyzed: perception

  1. Perfil. María Rodilla

    OpenAIRE

    Rodilla, María

    2017-01-01

    [ES] Perfil sobre María Rodilla, ilustradora valenciana que centra su trabajo en el feminismo Rodilla, M. (2017). Perfil. María Rodilla. EME Experimental Illustration, Art & Design. (5):52-53. doi:10.4995/eme.2017.7616. 52 53 5

  2. 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.

  3. Cadherin-11 regulates motility in normal cortical neural precursors and glioblastoma.

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    Jessica D Schulte

    Full Text Available Metastasizing tumor cells undergo a transformation that resembles a process in normal development when non-migratory epithelial cells modulate the expression of cytoskeletal and adhesion proteins to promote cell motility. Here we find a mesenchymal cadherin, Cadherin-11 (CDH11, is increased in cells exiting the ventricular zone (VZ neuroepithelium during normal cerebral cortical development. When overexpressed in cortical progenitors in vivo, CDH11 causes premature exit from the neuroepithelium and increased cell migration. CDH11 expression is elevated in human brain tumors, correlating with higher tumor grade and decreased patient survival. In glioblastoma, CDH11-expressing tumor cells can be found localized near tumor vasculature. Endothelial cells stimulate TGFβ signaling and CDH11 expression in glioblastoma cells. TGFβ promotes glioblastoma cell motility, and knockdown of CDH11 expression in primary human glioblastoma cells inhibits TGFβ-stimulated migration. Together, these findings show that Cadherin-11 can promote cell migration in neural precursors and glioblastoma cells and suggest that endothelial cells increase tumor aggressiveness by co-opting mechanisms that regulate normal neural development.

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

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    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.

  5. Radiation-induced glioblastoma signaling cascade regulates viability, apoptosis and differentiation of neural stem cells (NSC).

    Science.gov (United States)

    Ivanov, Vladimir N; Hei, Tom K

    2014-12-01

    Ionizing radiation alone or in combination with chemotherapy is the main treatment modality for brain tumors including glioblastoma. Adult neurons and astrocytes demonstrate substantial radioresistance; in contrast, human neural stem cells (NSC) are highly sensitive to radiation via induction of apoptosis. Irradiation of tumor cells has the potential risk of affecting the viability and function of NSC. In this study, we have evaluated the effects of irradiated glioblastoma cells on viability, proliferation and differentiation potential of non-irradiated (bystander) NSC through radiation-induced signaling cascades. Using media transfer experiments, we demonstrated significant effects of the U87MG glioblastoma secretome after gamma-irradiation on apoptosis in non-irradiated NSC. Addition of anti-TRAIL antibody to the transferred media partially suppressed apoptosis in NSC. Furthermore, we observed a dramatic increase in the production and secretion of IL8, TGFβ1 and IL6 by irradiated glioblastoma cells, which could promote glioblastoma cell survival and modify the effects of death factors in bystander NSC. While differentiation of NSC into neurons and astrocytes occurred efficiently with the corresponding differentiation media, pretreatment of NSC for 8 h with medium from irradiated glioblastoma cells selectively suppressed the differentiation of NSC into neurons, but not into astrocytes. Exogenous IL8 and TGFβ1 increased NSC/NPC survival, but also suppressed neuronal differentiation. On the other hand, IL6 was known to positively affect survival and differentiation of astrocyte progenitors. We established a U87MG neurosphere culture that was substantially enriched by SOX2(+) and CD133(+) glioma stem-like cells (GSC). Gamma-irradiation up-regulated apoptotic death in GSC via the FasL/Fas pathway. Media transfer experiments from irradiated GSC to non-targeted NSC again demonstrated induction of apoptosis and suppression of neuronal differentiation of NSC. In

  6. 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.

  7. 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.

  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. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. A REST derived gene signature stratifies glioblastomas into chemotherapy resistant and responsive disease

    Directory of Open Access Journals (Sweden)

    Wagoner Matthew P

    2012-12-01

    Full Text Available Abstract Background Glioblastomas are the most common central nervous system neoplasia in adults, with 9,000 cases in the US annually. Glioblastoma multiformae, the most aggressive glioma subtype, has an 18% one-year survival rate, and 3% two year survival rate. Recent work has highlighted the role of the transcription factor RE1 Silencing Transcription Factor, REST in glioblastoma but how REST function correlates with disease outcome has not been described. Method Using a bioinformatic approach and mining of publicly available microarray datasets, we describe an aggressive subtype of gliomas defined by a gene signature derived from REST. Using this REST gene signature we predict that REST function is enhanced in advanced glioblastoma. We compare disease outcomes between tumors based on REST status and treatment regimen, and describe downstream targets of REST that may contribute to the decreased benefits observed with high dose chemotherapy in REM tumors. Results We present human data showing that patients with “REST Enhanced Malignancies” (REM tumors present with a shorter disease free survival compared to non-REM gliomas. Importantly, REM tumors are refractory to multiple rounds of chemotherapy and patients fail to respond to this line of treatment. Conclusions This report is the first to describe a REST gene signature that predicts response to multiple rounds of chemotherapy, the mainline therapy for this disease. The REST gene signature may have important clinical implications for the treatment of glioblastoma.

  15. A novel small molecule that selectively inhibits glioblastoma cells expressing EGFRvIII

    Directory of Open Access Journals (Sweden)

    Oberlies Nicholas H

    2007-04-01

    Full Text Available Abstract Background Mutations of the epidermal growth factor receptor (EGFR are a possible molecular target for cancer therapy. EGFR is frequently amplified in glioblastomas and 30 to 40% of glioblastomas also express the deletion mutation EGFRvIII. This frequent oncogenic mutation provides an opportunity for identifying new anti-glioblastoma therapies. In this study, we sought small molecule inhibitors specific for cancer cells expressing EGFRvIII, using isogenic parental cells without EGFRvIII as a control. Results A screen of the NCI small molecule diversity set identified one compound, NSC-154829, which consistently inhibited growth of different human glioblastoma cells expressing EGFRvIII, but permitted normal growth of matched control cells. NSC-154829 had no previously established medicinal use, but has a purine-like structural component. Further experiments showed this compound increased apoptosis in cells with EGFRvIII, and moderately affected the expression of p21, independent of any changes in p53 levels or in Akt phosphorylation. Conclusion These initial results suggest that NSC-154829 or a closely related structure might be further investigated for its potential as an anti-glioblastoma drug, although its precise molecular mechanism is still undefined.

  16. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    Science.gov (United States)

    Pollak, Julia; Rai, Karan G; Funk, Cory C; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D; Paddison, Patrick J; Ramirez, Jan-Marino; Rostomily, Robert C

    2017-01-01

    Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  17. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    Directory of Open Access Journals (Sweden)

    Julia Pollak

    Full Text Available Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  18. 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

  19. 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...

  20. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma.

    Science.gov (United States)

    Patel, Anoop P; Tirosh, Itay; Trombetta, John J; Shalek, Alex K; Gillespie, Shawn M; Wakimoto, Hiroaki; Cahill, Daniel P; Nahed, Brian V; Curry, William T; Martuza, Robert L; Louis, David N; Rozenblatt-Rosen, Orit; Suvà, Mario L; Regev, Aviv; Bernstein, Bradley E

    2014-06-20

    Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy. Copyright © 2014, American Association for the Advancement of Science.

  1. 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.

  2. Perfiles de neohablantes de gallego

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    Fernando Ramallo

    2014-05-01

    Full Text Available Aunque el fenómeno es muy anterior, al menos desde los inicios del proceso de recuperación lingüística de mediados del siglo xx, un rasgo definitorio de la realidad sociolingüística gallega actual es la presencia de neohablantes de gallego. Con la introducción de este idioma en nuevos ámbitos de uso, particularmente en el sistema educativo, una parte de la población que había tenido su primera socialización en español desplaza esta lengua a un lugar secundario y se hace hablante consciente y comprometido de gallego. En este trabajo, presentamos una aproximación a los perfiles generales de neohablantes de gallego, a partir del criterio intensidad de uso del idioma aprendido. Así, diferenciamos entre neohablantes esenciales, neohablantes funcionales, neohablantes ocasionales y neohablantes potenciales. Aunque para la sociolingüística académica y para el imaginario social de la población gallega la persona neohablante se limita al tipo que denominamos «esencial», desde una visión menos restrictiva tanto los neohablantes funcionales y, en menor medida, los neohablantes ocasionales cumplen con el perfil de personas con L1 español que incorporan el gallego a sus prácticas. Los neohablantes potenciales constituyen un grupo de índole diferente al darse en ellos algunas de las condiciones necesarias para el cambio, aunque tal cambio no ha tenido lugar.

  3. Enhancement of effects of irradiation by gemcitabine in a glioblastoma cell line and cell line spheroids

    NARCIS (Netherlands)

    Genç, Mine; Castro Kreder, Natasja; Barten-van Rijbroek, Angelique; Stalpers, Lukas J. A.; Haveman, Jaap

    2004-01-01

    Background and purpose. To determine the cytotoxicity of, and radioenhancement by, gemcitabine on a glioma cell line grown as a monolayer and as spheroid cultures. Material and methods. We used a human glioma cell line, Gli-6, which originated from a biopsy specimen of a patient with a glioblastoma

  4. The ER stress inducer DMC enhances TRAIL-induced apoptosis in glioblastoma

    NARCIS (Netherlands)

    van Roosmalen, Ingrid A. M.; Dos Reis, Carlos R; Setroikromo, Rita; Yuvaraj, Saravanan; Joseph, Justin V.; Tepper, Pieter G.; Kruyt, Frank A. E.; Quax, Wim J.

    2014-01-01

    Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour in humans and is highly resistant to current treatment modalities. We have explored the combined treatment of the endoplasmic reticulum (ER) stress-inducing agent 2,5-dimethyl-celecoxib (DMC) and TNF-related

  5. 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

  6. Vesicle amine transport protein-1 (VAT-1) is upregulated in glioblastomas and promotes migration.

    Science.gov (United States)

    Mertsch, S; Becker, M; Lichota, A; Paulus, W; Senner, V

    2009-08-01

    Diffuse invasion of single-glioma cells is the main obstacle to successful therapy of these tumours. After identifying vesicle amine transport protein-1 (VAT-1) as being upregulated in invasive human gliomas, we study its possible function in glioblastoma cell migration. Based on data obtained from previous oligonucleotide arrays, we investigated expression of VAT-1 in glioblastoma tissue and cell lines on mRNA levels using reverse transcriptase PCR. Furthermore, we examined the amount and localization of VAT-1 protein using immunoblotting and immunohistochemistry. Using small interfering RNA technology we repressed VAT-1 expression in human glioma cell lines and analysed their migration using wound healing and transwell migration assays. Increased VAT-1 mRNA and protein levels were found in glioblastoma tissues and cell lines compared with normal human brain. Small interfering RNA-mediated VAT-1 knockdown led to significantly reduced migration of human glioma cells. VAT-1 is overexpressed in glioblastomas and functionally involved in glioma cell migration, representing a new component involved in glioma invasion

  7. Generation of Microtumors Using 3D Human Biogel Culture System and Patient-derived Glioblastoma Cells for Kinomic Profiling and Drug Response Testing.

    Science.gov (United States)

    Gilbert, Ashley N; Shevin, Rachael S; Anderson, Joshua C; Langford, Catherine P; Eustace, Nicholas; Gillespie, G Yancey; Singh, Raj; Willey, Christopher D

    2016-06-09

    The use of patient-derived xenografts for modeling cancers has provided important insight into cancer biology and drug responsiveness. However, they are time consuming, expensive, and labor intensive. To overcome these obstacles, many research groups have turned to spheroid cultures of cancer cells. While useful, tumor spheroids or aggregates do not replicate cell-matrix interactions as found in vivo. As such, three-dimensional (3D) culture approaches utilizing an extracellular matrix scaffold provide a more realistic model system for investigation. Starting from subcutaneous or intracranial xenografts, tumor tissue is dissociated into a single cell suspension akin to cancer stem cell neurospheres. These cells are then embedded into a human-derived extracellular matrix, 3D human biogel, to generate a large number of microtumors. Interestingly, microtumors can be cultured for about a month with high viability and can be used for drug response testing using standard cytotoxicity assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and live cell imaging using Calcein-AM. Moreover, they can be analyzed via immunohistochemistry or harvested for molecular profiling, such as array-based high-throughput kinomic profiling, which is detailed here as well. 3D microtumors, thus, represent a versatile high-throughput model system that can more closely replicate in vivo tumor biology than traditional approaches.

  8. 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

  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. 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.

  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. Ketamine suppresses the substance P-induced production of IL-6 and IL-8 by human U373MG glioblastoma/astrocytoma cells.

    Science.gov (United States)

    Yamaguchi, Keisuke; Kumakura, Seiichiro; Murakami, Taisuke; Someya, Akimasa; Inada, Eiichi; Nagaoka, Isao

    2017-03-01

    The neuropeptide substance P (SP) is an important mediator of neurogenic inflammation within the central and peripheral nervous systems. SP has been shown to induce the expression of pro-inflammatory cytokines implicated in the pathogenesis of several disorders of the human brain via the neurokinin-1 receptor (NK-1R). Ketamine, an intravenous anesthetic agent, functions as a competitive antagonist of the excitatory neurotransmission N-methyl-D‑aspartate (NMDA) receptor, and also antagonizes the NK-1R by interfering with the binding of SP. In the present study, we investigated the anti-inflammatory effects of ketamine on the SP-induced activation of a human astrocytoma cell line, U373MG, which expresses high levels of NK-1R. The results from our experiments indicated that ketamine suppressed the production of interleukin (IL)-6 and IL-8 by the U373MG cells. Furthermore, ketamine inhibited the SP-induced activation of extracellular signal‑regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). Taken together, these observations suggest that ketamine may suppress the SP-induced activation (IL-6 and IL-8 production) of U373MG cells by inhibiting the phosphorylation of signaling molecules (namely ERK1/2, p38 MAPK and NF-κB), thereby exerting anti‑inflammatory effects. Thus, ketamine may modulate SP-induced inflammatory responses by NK-1R‑expressing cells through the suppression of signaling molecules (such as ERK1/2, p38 MAPK and NF-κB).

  14. Human resources in artificial insemination of beef cattle: profile of managers and inseminators Recursos humanos na inseminação artificial em bovinos de corte: perfil dos administradores e inseminadores

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    Lívia dos Santos Russi

    2010-07-01

    Full Text Available The objective of the present study was to outline the profile of managers and inseminators involved in beef cattle artificial insemination programs to characterize the management processes involved in this activity. Additionally, by interviewing managers and inseminators, it was searched to detect particularities concerned to personal life and work that can be used to evaluate the quality of life of inseminators on farms. The open questions were analyzed by frequency of answer, after being grouped by similarity. Accordingly to the results, managers associate the concept of human resource management to work supervision, mainly, prioritizing technical factors such as professional experience and indexes in the selection processes, although problems in interpersonal relationships have been shown as the main reason for dismissal. In general, education level of the inseminators is not good because most of these workers studied only to the first series of primary school. Inseminators prefer conventional artificial insemination although they recognize that fixed-time artificial insemination can make animal handling on the farm easier. The performance of these workers seems to be determined more by interpersonal relationships than by the salaries.Objetivou-se delinear o perfil de administradores e inseminadores envolvidos em programas de inseminação artificial em bovinos de corte no intuito de caracterizar os processos gerenciais envolvidos nesta atividade. Adicionalmente, por meio de entrevistas com administradores e inseminadores, buscou-se detectar fatores ligados à vida pessoal e ao trabalho que possam ser utilizados como medida da qualidade de vida dos inseminadores nas propriedades rurais. As questões abertas foram analisadas por frequência de respostas, depois de agrupadas por similaridade. De acordo com os resultados, os administradores associam o conceito de gestão de recursos humanos principalmente à supervisão do trabalho priorizando

  15. 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.

    Science.gov (United States)

    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.

  16. 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.

  17. Expression of R132H mutational IDH1 in human U87 glioblastoma cells affects the SREBP1a pathway and induces cellular proliferation.

    Science.gov (United States)

    Zhu, Jian; Cui, Gang; Chen, Ming; Xu, Qinian; Wang, Xiuyun; Zhou, Dai; Lv, Shengxiang; Fu, Linshan; Wang, Zhong; Zuo, Jianling

    2013-05-01

    Sterol regulatory element-binding protein-1a (SREBP1a) is a member of the SREBP family of transcription factors, which mainly controls homeostasis of lipids. SREBP1a can also activate the transcription of isocitrate dehydrogenase 1 (IDH1) by binding to its promoter region. IDH1 mutations, especially R132H mutation of IDH1, are a common feature of a major subset of human gliomas. There are few data available on the relationship between mutational IDH1 expression and SREBP1a pathway. In this study, we investigated cellular effects and SREBP1a pathway alterations caused by R132H mutational IDH1 expression in U87 cells. Two glioma cell lines, stably expressing mutational (U87/R132H) or wild type (U87/wt) IDH1, were established. A cell line, stably transfected with pcDNA3.1(+) (U87/vector), was generated as a control. Click-iT EdU assay, sulforhodamine B assay, and wound healing assay respectively showed that the expression of R132H induced cellular proliferation, cell growth, and cell migration. Western blot revealed that SREBP1 was increased in U87/R132H compared with that in U87/wt. Elevated SREBP1a and several its target genes, but not SREBP1c, were detected by real-time polymerase chain reaction in U87/R132H. All these findings indicated that R132H mutational IDH1 is involved in the regulation of proliferation, growth, and migration of glioma cells. These effects may partially be mediated by SREBP1a pathway.

  18. Perfil do pesquisador fisioterapeuta brasileiro

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    HJCG Coury

    Full Text Available OBJETIVO: Traçar um perfil do pesquisador fisioterapeuta quanto a sua formação, produção científica e fomento e bolsas obtidos pela área do Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq. MÉTODOS: Foram consultados os curricula vitae de cada pesquisador fisioterapeuta com doutorado disponíveis na Plataforma Lattes do CNPq, que é uma agência do MCT dedicada à promoção da pesquisa científica e à formação de recursos humanos para a pesquisa. A escolha dessa fonte pública de informação ocorreu porque cada pesquisador interessado em auxílios de pesquisa ou envolvidos com a pós-graduação deve preencher eletronicamente um curriculum vitae com informações sobre formação e produção científica. O sistema requer uma senha pessoal e uma declaração do pesquisador atestando a veracidade das informações fornecidas, o que assegura precisão no preenchimento. Estatísticas sobre fomento e bolsas disponíveis foram também consultadas. Uma análise de regressão binária foi rodada para explicar a ocorrência de publicações ISI/JCR. RESULTADOS: Houve um crescimento extraordinário (900% no número de doutores com graduação em Fisioterapia, na última década, em áreas tradicionais ou novos campos de atuação e crescimento expressivo em número de artigos publicados, dissertações e teses orientadas. Os fatores analisados pela regressão conseguiram explicar 49,8% da ocorrência de artigos indexados. Dados de fomento e bolsas mostram um investimento pequeno do CNPq na Fisioterapia comparativamente às demais áreas da Saúde. CONCLUSÕES: O perfil do pesquisador traçado aqui poderá prover à comunidade acadêmica uma perpectiva de sua identidade e auxiliar no estabelecimento de prioridades futuras para o aprimoramento do conhecimento e prática profissional.

  19. Perfil nutricional na artrite reumatoide

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    Rachel Simone Maccarini Zarpellon

    2014-01-01

    Full Text Available Objetivo: Estudar o perfil nutricional de pacientes com artrite reumatoide (AR. Métodos: Estudo transversal observacional de 102 pacientes com AR. Os pacientes foram estudados para dados clínicos, demográficos, sorológicos, atividade de doença e perfil nutricional. Neste último incluiu-se a medida do índice de massa corporal (IMC, relação quadril/cintura, pregas cutâneas bicipitais (PCB e sua adequação; prega cutânea tricipital (PCT e sua adequação e circunferência muscular do braço (CMB e sua adequação. Estudos de associação foram feitos usando os testes de Fisher e qui-quadrado para dados nominais e teste t não pareado e Mann Whitney para dados numéricos. Para cálculo de correlação usou-se o teste de Spearman. Resultado: Na amostra existiam 14/102 homens e 88/102 mulheres com idade média de 52,1 ± 11,5 anos e duração média de doença de 10,6 ± 7,4 anos. A relação cintura/quadril média era de 0,92 ± 0,07. De acordo com IMC, 30,3% tinham peso normal e 65,5% tinham peso acima do normal. De acordo com PCB, 74,5% eram normais e 25,5% tinham depleção; de acordo com a PCT, 83,3% eram normais e 16,7% tinham depleção. Associação de variáveis nutricionais com gênero, fator reumatoide, nódulos e atividade da doença não mostraram diferenças (p = NS exceto, por uma relação cintura/quadril menor em indivíduos com nódulos (p = 0,02 e uma correlação modesta da PCT com a duração de doença (p = 0,02; R = 0,22; 95% IC = 0,01-0,40. Conclusão: Existe uma alta prevalência de sobrepeso e obesidade em artrite reumatoide e uma pequena frequência de depleção muscular.

  20. New perspectives in glioblastoma antiangiogenic therapy

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    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.

  1. Advance Care Planning in Glioblastoma Patients

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    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.

  2. Protocols for BNCT of glioblastoma multiforme at Brookhaven: Practical considerations

    Energy Technology Data Exchange (ETDEWEB)

    Chanana, A.D.; Coderre, J.A.; Joel, D.D.; Slatkin, D.N.

    1996-12-31

    In this report we discuss some issues considered in selecting initial protocols for boron neutron capture therapy (BNCT) of human glioblastoma multiforme. First the tolerance of normal tissues, especially the brain, to the radiation field. Radiation doses limits were based on results with human and animal exposures. Estimates of tumor control doses were based on the results of single-fraction photon therapy and single fraction BNCT both in humans and experimental animals. Of the two boron compounds (BSH and BPA), BPA was chosen since a FDA-sanctioned protocol for distribution in humans was in effect at the time the first BNCT protocols were written and therapy studies in experimental animals had shown it to be more effective than BSH.

  3. The in vitro effects of caffeine on viability, cycle cycle profiles, proliferation, and apoptosis of glioblastomas.

    Science.gov (United States)

    Jiang, J; Lan, Y-Q; Zhang, T; Yu, M; Liu, X-Y; Li, L-H; Chen, X-P

    2015-09-01

    We studied the effects of caffeine on cell viability, cell cycle profiles, proliferation, and apoptosis in rat C6 and human U87MG glioblastoma cell lines. Cell viability was quantified by the methyl thiazolyl tetrazolium (MTT) assay. Flow cytometry was used to quantify the relative number of cells in different phases of the cell cycle, while cell proliferation was quantified using the Cell Counting Kit-8. The proportion of apoptotic cells was determined by flow cytometry, and expression of apoptosis-related proteins Caspase-3, Cyt-C, Bax and Bcl-2 by Western blot. Caffeine at doses of up to 0.5 mM did not affect cell viability in both rat C6 and human U87MG glioblastoma cells. Further studies were done using the dose of 0.5 mM. Percentage of cells in the G0/G1 phase was markedly increased, while percentage of cells in the S phase decreased, after cell treatment with caffeine. Cell proliferation was significantly inhibited by caffeine. Furthermore, caffeine induced cell apoptosis, decreased expression of Bcl-2, and increased expression of Cyt-C and Caspase-3. Caffeine inhibits proliferation and induces apoptosis in glioblastoma cells. Our results provide the experimental basis for further studies of potential role of caffeine in the treatment of glioblastomas.

  4. Live attenuated measles virus vaccine therapy for locally established malignant glioblastoma tumor cells

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    Al-Shammari AM

    2014-05-01

    Full Text Available Ahmed M Al-Shammari,1 Farah E Ismaeel,2 Shahlaa M Salih,2 Nahi Y Yaseen11Experimental Therapy Department, Iraqi Center for Cancer and Medical Genetic Researches, Mustansiriya University, 2Departments of Biotechnology, College of Science, Al-Nahrain University, Baghdad, IraqAbstract: Glioblastoma multiforme is the most aggressive malignant primary brain tumor in humans, with poor prognosis. A new glioblastoma cell line (ANGM5 was established from a cerebral glioblastoma multiforme in a 72-year-old Iraqi man who underwent surgery for an intracranial tumor. This study was carried out to evaluate the antitumor effect of live attenuated measles virus (MV Schwarz vaccine strain on glioblastoma multiforme tumor cell lines in vitro. Live attenuated MV Schwarz strain was propagated on Vero, human rhabdomyosarcoma, and human glioblastoma-multiform (ANGM5 cell lines. The infected confluent monolayer appeared to be covered with syncytia with granulation and vacuolation, as well as cell rounding, shrinkage, and large empty space with cell debris as a result of cell lysis and death. Cell lines infected with virus have the ability for hemadsorption to human red blood cells after 72 hours of infection, whereas no hemadsorption of uninfected cells is seen. Detection of MV hemagglutinin protein by monoclonal antibodies in infected cells of all cell lines by immunocytochemistry assay gave positive results (brown color in the cytoplasm of infected cells. Cell viability was measured after 72 hours of infection by 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay. Results showed a significant cytotoxic effect for MV (P≤0.05 on growth of ANGM5 and rhabdomyosarcoma cell lines after 72 hours of infection. Induction of apoptosis by MV was assessed by measuring mitochondrial membrane potentials in tumor cells after 48, 72, and 120 hours of infection. Apoptotic cells were counted, and the mean percentage of dead cells was significantly higher after 48, 72

  5. 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.

  6. Mesenchymal Migration as a Therapeutic Target in Glioblastoma

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    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.

  7. 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.

  8. 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.

  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. Coordination of glioblastoma cell motility by PKCι

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    Baldwin R Mitchell

    2010-09-01

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

  11. 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) ...

  12. Perfil das doadoras de leite do banco de leite humano de um hospital universitário = Profile of breast milk donors at the human milk bank of a university hospital

    OpenAIRE

    Danielle Talita dos Santos; Marli Terezinha Oliveira Vannuchi; Márcia Maria Benevenuto Oliveira; José Carlos Dalmas

    2009-01-01

    Esta pesquisa tem como objetivo conhecer o perfil socioeconômico dasdoadoras de leite do Banco de Leite Humano do Hospital Universitário de Londrina, Estado do Paraná (BLH/HUL). Trata-se de um estudo transversal, em que foram coletados dados a partir de formulário aplicado às doadoras externas do BLH/HUL no período de junho a agosto de 2005. Constatou-se que 11% são adolescentes. Com relação àescolaridade, 41,8% possuem segundo grau completo ou superior incompleto. De acordo com a literatura,...

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

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    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.

  14. Identification of novel SNPs in glioblastoma using targeted resequencing.

    Science.gov (United States)

    Keller, Andreas; Harz, Christian; Matzas, Mark; Meder, Benjamin; Katus, Hugo A; Ludwig, Nicole; Fischer, Ulrike; Meese, Eckart

    2011-01-01

    High-throughput sequencing opens avenues to find genetic variations that may be indicative of an increased risk for certain diseases. Linking these genomic data to other "omics" approaches bears the potential to deepen our understanding of pathogenic processes at the molecular level. To detect novel single nucleotide polymorphisms (SNPs) for glioblastoma multiforme (GBM), we used a combination of specific target selection and next generation sequencing (NGS). We generated a microarray covering the exonic regions of 132 GBM associated genes to enrich target sequences in two GBM tissues and corresponding leukocytes of the patients. Enriched target genes were sequenced with Illumina and the resulting reads were mapped to the human genome. With this approach we identified over 6000 SNPs, including over 1300 SNPs located in the targeted genes. Integrating the genome-wide association study (GWAS) catalog and known disease associated SNPs, we found that several of the detected SNPs were previously associated with smoking behavior, body mass index, breast cancer and high-grade glioma. Particularly, the breast cancer associated allele of rs660118 SNP in the gene SART1 showed a near doubled frequency in glioblastoma patients, as verified in an independent control cohort by Sanger sequencing. In addition, we identified SNPs in 20 of 21 GBM associated antigens providing further evidence that genetic variations are significantly associated with the immunogenicity of antigens.

  15. Identification of novel SNPs in glioblastoma using targeted resequencing.

    Directory of Open Access Journals (Sweden)

    Andreas Keller

    Full Text Available High-throughput sequencing opens avenues to find genetic variations that may be indicative of an increased risk for certain diseases. Linking these genomic data to other "omics" approaches bears the potential to deepen our understanding of pathogenic processes at the molecular level. To detect novel single nucleotide polymorphisms (SNPs for glioblastoma multiforme (GBM, we used a combination of specific target selection and next generation sequencing (NGS. We generated a microarray covering the exonic regions of 132 GBM associated genes to enrich target sequences in two GBM tissues and corresponding leukocytes of the patients. Enriched target genes were sequenced with Illumina and the resulting reads were mapped to the human genome. With this approach we identified over 6000 SNPs, including over 1300 SNPs located in the targeted genes. Integrating the genome-wide association study (GWAS catalog and known disease associated SNPs, we found that several of the detected SNPs were previously associated with smoking behavior, body mass index, breast cancer and high-grade glioma. Particularly, the breast cancer associated allele of rs660118 SNP in the gene SART1 showed a near doubled frequency in glioblastoma patients, as verified in an independent control cohort by Sanger sequencing. In addition, we identified SNPs in 20 of 21 GBM associated antigens providing further evidence that genetic variations are significantly associated with the immunogenicity of antigens.

  16. Gaussian graphical modeling reveals specific lipid correlations in glioblastoma cells

    Science.gov (United States)

    Mueller, Nikola S.; Krumsiek, Jan; Theis, Fabian J.; Böhm, Christian; Meyer-Bäse, Anke

    2011-06-01

    Advances in high-throughput measurements of biological specimens necessitate the development of biologically driven computational techniques. To understand the molecular level of many human diseases, such as cancer, lipid quantifications have been shown to offer an excellent opportunity to reveal disease-specific regulations. The data analysis of the cell lipidome, however, remains a challenging task and cannot be accomplished solely based on intuitive reasoning. We have developed a method to identify a lipid correlation network which is entirely disease-specific. A powerful method to correlate experimentally measured lipid levels across the various samples is a Gaussian Graphical Model (GGM), which is based on partial correlation coefficients. In contrast to regular Pearson correlations, partial correlations aim to identify only direct correlations while eliminating indirect associations. Conventional GGM calculations on the entire dataset can, however, not provide information on whether a correlation is truly disease-specific with respect to the disease samples and not a correlation of control samples. Thus, we implemented a novel differential GGM approach unraveling only the disease-specific correlations, and applied it to the lipidome of immortal Glioblastoma tumor cells. A large set of lipid species were measured by mass spectrometry in order to evaluate lipid remodeling as a result to a combination of perturbation of cells inducing programmed cell death, while the other perturbations served solely as biological controls. With the differential GGM, we were able to reveal Glioblastoma-specific lipid correlations to advance biomedical research on novel gene therapies.

  17. Protective Effect of Gwakhyangjeonggisan Herbal Acupuncture Solution in Glioblastoma Cells: Microarray Analysis of Gene Expression

    Directory of Open Access Journals (Sweden)

    Hong-Seok Lee

    2005-12-01

    Full Text Available Objectives : Neurological disorders have been one of main therapeutic targets of acupuncture. The present study investigated the protective effects of Gwakhyangjeonggisan herbal acupuncture solution (GHAS. Methods : We performed 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay in glioblastoma cells, and did microarray analysis with cells exposed to reactive oxigen species (ROS of hydrogen peroxide by 8.0 k Human cDNA, with cut-off level of 2-fold changes in gene expression. Results : MTT assay showed protective effect of GHAS on the glioblastoma cells exposed to hydrogen peroxide. When glioblastoma cells were exposed to hydrogen peroxide, 24 genes were downregulated. When the cells were pretreated with GHAS before exposure to hydrogen peroxide, 46 genes were downregulated. Many of the genes downregulated by hydrogen peroxide stimulation were decreased in the amount of downregulation or reversed to upregulation. Conclusions : The gene expression changes observed in the present study are supposed to be related to the protective molecular mechanism of GHAS in the glioblastoma cells exposed to ROS stress.

  18. Classification of microvascular patterns via cluster analysis reveals their prognostic significance in glioblastoma.

    Science.gov (United States)

    Chen, Long; Lin, Zhi-Xiong; Lin, Guo-Shi; Zhou, Chang-Fu; Chen, Yu-Peng; Wang, Xing-Fu; Zheng, Zong-Qing

    2015-01-01

    There are limited researches focusing on microvascular patterns (MVPs) in human glioblastoma and their prognostic impact. We evaluated MVPs of 78 glioblastomas by CD34/periodic acid-Schiff dual staining and by cluster analysis of the percentage of microvascular area for distinct microvascular formations. The distribution of 5 types of basic microvascular formations, that is, microvascular sprouting (MS), vascular cluster (VC), vascular garland (VG), glomeruloid vascular proliferation (GVP), and vasculogenic mimicry (VM), was variable. Accordingly, cluster analysis classified MVPs into 2 types: type I MVP displayed prominent MSs and VCs, whereas type II MVP had numerous VGs, GVPs, and VMs. By analyzing the proportion of microvascular area for each type of formation, we determined that glioblastomas with few MSs and VCs had many GVPs and VMs, and vice versa. VG seemed to be a transitional type of formation. In case of type I MVP, expression of Ki-67 and p53 but not MGMT was significantly higher as compared with those of type II MVP (P < .05). Survival analysis showed that the type of MVPs presented as an independent prognostic factor of progression-free survival (PFS) and overall survival (OS) (both P < .001). Type II MVP had a more negative influence on PFS and OS than did type I MVP. We conclude that the heterogeneous MVPs in glioblastoma can be categorized properly by certain histopathologic and statistical analyses and may influence clinical outcome. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. 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.

  1. 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)

  2. 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...

  3. 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,.

  4. 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.

  5. 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...

  6. [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.

  7. 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.

  8. 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...

  9. 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.

  10. Remission of invasive, cancer stem-like glioblastoma xenografts using lentiviral vector-mediated suicide gene therapy.

    Directory of Open Access Journals (Sweden)

    Peter C Huszthy

    Full Text Available BACKGROUND: Glioblastoma is the most frequent and most malignant primary brain tumor with a poor prognosis. The translation of therapeutic strategies for glioblastoma from the experimental phase into the clinic has been limited by insufficient animal models, which lack important features of human tumors. Lentiviral gene therapy is an attractive therapeutic option for human glioblastoma, which we validated in a clinically relevant animal model. METHODOLOGY/PRINCIPAL FINDINGS: We used a rodent xenograft model that recapitulates the invasive and angiogenic features of human glioblastoma to analyze the transduction pattern and therapeutic efficacy of lentiviral pseudotyped vectors. Both, lymphocytic choriomeningitis virus glycoprotein (LCMV-GP and vesicular stomatitis virus glycoprotein (VSV-G pseudotyped lentiviral vectors very efficiently transduced human glioblastoma cells in vitro and in vivo. In contrast, pseudotyped gammaretroviral vectors, similar to those evaluated for clinical therapy of glioblastoma, showed inefficient gene transfer in vitro and in vivo. Both pseudotyped lentiviral vectors transduced cancer stem-like cells characterized by their CD133-, nestin- and SOX2-expression, the ability to form spheroids in neural stem cell medium and to express astrocytic and neuronal differentiation markers under serum conditions. In a therapeutic approach using the suicide gene herpes simplex virus thymidine kinase (HSV-1-tk fused to eGFP, both lentiviral vectors mediated a complete remission of solid tumors as seen on MRI resulting in a highly significant survival benefit (p<0.001 compared to control groups. In all recurrent tumors, surviving eGFP-positive tumor cells were found, advocating prodrug application for several cycles to even enhance and prolong the therapeutic effect. CONCLUSIONS/SIGNIFICANCE: In conclusion, lentiviral pseudotyped vectors are promising candidates for gene therapy of glioma in patients. The inefficient gene delivery

  11. Giant-cell glioblastoma of childhood associated with HIV-1 and JC virus coinfection.

    Science.gov (United States)

    Brassesco, María Sol; Darrigo, Luiz Guilherme; Valera, Elvis Terci; Oliveira, Ricardo Santos; Yamamoto, Yulie Aparecida; de Castro Barros, Marcus Vinícius; Tone, Luiz Gonzaga

    2013-08-01

    John Cunningham (JC) viral DNA sequence has seldom been reported in patients with brain tumors such as high grade gliomas and medulloblastomas, pointing to a role in the etiopathogenesis of such tumors. We present a unique clinical case of an HIV-positive pediatric patient with multifocal leukoencephalopathy and confirmed JC virus (JCV) infection that developed a giant-cell glioblastoma. Experimental data with infected primates has previously hypothesized an association of human giant-cell glioblastoma with JCV or progressive multifocal leukoencephalopathy, though such association has not been documented in the literature for humans. Future studies with larger cohorts and molecular pathological analyses are still needed to corroborate the role of the widely spread human neurotropic virus in early transformation and in the development of brain tumors with different histology in the setting of HIV-related severe immunosuppression.

  12. Perfiles de autor en repositorios institucionales

    Directory of Open Access Journals (Sweden)

    Patricia Genovés

    2017-10-01

    Full Text Available Este trabajo describe las funciones y utilidades de la implementación de perfiles de autor en repositorios institucionales, como un servicio de valor agregado dirigido a acrecentar su uso entre los miembros de una institución y mejorar la visibilidad de la producción científica alojada en el repositorio. Incluye un relevamiento de servicios de perfiles de autor implementados en repositorios institucionales argentinos y extranjeros. Advierte que, ante el establecimiento de mandatos nacionales de depósito, la necesidad de contar con repositorios institucionales fuertes y sostenibles en el tiempo es aún mayor que antes. Integrar a los repositorios las funcionalidades de los sistemas curriculares y de gestión de información científica y tecnológica es un camino para lograr esa fortaleza, y los perfiles de autor son el resultado visible de dicha integración. Señala que el beneficio que representa para un autor contar con un perfil público en el repositorio de su institución es equivalente al beneficio que para una institución representa contar con un repositorio digital, en términos de ventaja competitiva, valor añadido, incremento de la visibilidad y facilidades de recuperación y acceso a la producción generada.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  15. 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

  16. Extracellular Vesicles in Glioblastoma: Role in Biological Processes and in Therapeutic Applications.

    Science.gov (United States)

    Giusti, Ilaria; Di Francesco, Marianna; Dolo, Vincenza

    2017-01-01

    Glioblastoma is the most common and malignant form of primary brain cancer; it is characterized by one of the highest mortality among human cancers. Maximal and aggressive surgical resection is the first approach treatment even if not usually definitive, being the tumor characterized by a high proliferative rate and extensive invasion. Early diagnosis, associated to careful monitoring, is pivotal in glioblastoma treatment; Magnetic Resonance Imaging is used for monitoring purpose, but it's not sensitive enough to detect very small tumors; a valid alternative could be a repeated biopsy, but it is associated to a significant morbidity: less invasive options for diagnosis and therapeutic monitoring are unfailingly researched. A careful search was performed on PubMed, mainly considering papers in the last 10 years. In recent years it has begun to take hold the knowledge that glioblastoma cells secrete extracellular vesicles (microvesicles and exosomes), which mirror the molecular features of parental cells and are able to escape from tumor microenvironment, reaching cerebrospinal fluid and systemic blood circulation. Such information led to consider the possibility to use extracellular vesicles in biological fluids as markers of glioblastoma pathology and to use them as a more feasible "liquid-biopsy" to gain diagnostic information, follow the disease progression and the response to clinical treatment, just through a blood test or cerebrospinal fluid collection. The most interesting extracellular vesiclesassociated molecules studied as glioblastoma markers are taken into account, as well as approaches aiming to use extracellular vesicles as cell-free vaccines or vehicle of therapeutic molecules. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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...

  3. 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...

  4. Combination of temozolomide with immunocytokine F16-IL2 for the treatment of glioblastoma.

    Science.gov (United States)

    Pedretti, M; Verpelli, C; Mårlind, J; Bertani, G; Sala, C; Neri, D; Bello, L

    2010-09-07

    Glioblastoma patients are still not cured by the treatments available at the moment. We investigated the therapeutic properties of temozolomide in combination with F16-IL2, a clinical-stage immunocytokine consisting of human interleukin (IL)-2 fused to the human antibody F16, specific to the A1 domain of tenascin-C. We conducted three preclinical therapy studies, using subcutaneous and intracranial U87MG glioblastoma tumours xenografted in BALB/c nude mice. The same therapeutic schedule was used, consisting of five total administrations every third day, of 0.525 mg temozolomide, 20 microg F16-IL2, the combination, or the control solution. Immunohistochemical analysis of U87MG xenografts and of human glioblastoma specimens showed selective tumour staining of F16. A quantitative biodistribution confirmed the preferential tumour accumulation of radiolabelled F16-IL2. In the study with subcutaneous xenografts, the combination of F16-IL2 with temozolomide induced complete remission of the animals, which remained tumour free for over 160 days. The same treatment led to a consistent size reduction of intracranial xenografts and to a longer survival of animals. The immunocytokine promoted the recruitment of leukocytes into tumours of both models. The combined use of temozolomide with F16-IL2 deserves clinical investigations, which will be facilitated by the excellent safety profile in cynomolgus monkeys, and by the fact that F16-IL2 is in clinical trials in patients with cancer.

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

    Science.gov (United States)

    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.

  6. 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.

  7. 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

  8. Perfiles Latinoamericanos: Regional sociology, connected sociologies

    Directory of Open Access Journals (Sweden)

    Nelson Arteaga Botello

    2017-07-01

    Full Text Available The landscape of sociology published in the 48 numbers of the Perfiles Latinoamericanos magazineis analyzed. The diversity of topics, perspectives, and methodologies of the articles define aseries of fields of reflection around civil society, collective action, subjectivities and social identities,cities, media, violence, and theory. The essay suggests how the sociology that is producedin Latin America is not isolated but connected with international debates. It converges forms ofdoing theory and research with resonances on a global scale.

  9. El perfil psicosocial del emprendedor universitario

    OpenAIRE

    JUAN ANTONIO MORIANO LEÓN; FRANCISCO JOSÉ PALACÍ DESCALS; JOSÉ FRANCISCO MORALES DOMÍNGUEZ

    2006-01-01

    Desde la perspectiva de estudio de la intención emprendedora, el presente trabajo analiza las variables psicosociales que permiten elaborar el perfil del emprendedor universitario en España. Para ello, se utiliza un modelo de desarrollo de la carrera profesional que permite clasificar las variables psicosociales en tres espacios: familiar, sociolaboral y personal. La muestra utilizada estaba formada por 601 estudiantes universitarios procedentes de la Comunidad Autónoma de Castilla y León. Lo...

  10. El Perfil Profesional y el Plan de Estudio

    OpenAIRE

    Barrientos Jiménez, Elsa

    2014-01-01

    El perfil profesional es una descripción de características que se requiere del profesional para abarcar y solucionar las necesidades sociales. El docente debe ser formado con un buen perfil profesional que le permita desempeñar ecicientemente. La exisgencia de un buen perfil en el docente es de suma importancia dado que tiene en sus manos a seres pensadores y actuantes, a los cuales tiene que ir formando con sus conocimientos.

  11. Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene.

    Directory of Open Access Journals (Sweden)

    Rebecca L Skalsky

    Full Text Available Glioblastoma is a highly aggressive malignant tumor involving glial cells in the human brain. We used high-throughput sequencing to comprehensively profile the small RNAs expressed in glioblastoma and non-tumor brain tissues. MicroRNAs (miRNAs made up the large majority of small RNAs, and we identified over 400 different cellular pre-miRNAs. No known viral miRNAs were detected in any of the samples analyzed. Cluster analysis revealed several miRNAs that were significantly down-regulated in glioblastomas, including miR-128, miR-124, miR-7, miR-139, miR-95, and miR-873. Post-transcriptional editing was observed for several miRNAs, including the miR-376 family, miR-411, miR-381, and miR-379. Using the deep sequencing information, we designed a lentiviral vector expressing a cell suicide gene, the herpes simplex virus thymidine kinase (HSV-TK gene, under the regulation of a miRNA, miR-128, that was found to be enriched in non-tumor brain tissue yet down-regulated in glioblastomas, Glioblastoma cells transduced with this vector were selectively killed when cultured in the presence of ganciclovir. Using an in vitro model to recapitulate expression of brain-enriched miRNAs, we demonstrated that neuronally differentiated SH-SY5Y cells transduced with the miRNA-regulated HSV-TK vector are protected from killing by expression of endogenous miR-128. Together, these results provide an in-depth analysis of miRNA dysregulation in glioblastoma and demonstrate the potential utility of these data in the design of miRNA-regulated therapies for the treatment of brain cancers.

  12. 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.).

  13. 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

  14. 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.

  15. 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...

  16. NHERF-1: Modulator of Glioblastoma Cell Migration and Invasion

    Directory of Open Access Journals (Sweden)

    Kerri L. Kislin

    2009-04-01

    Full Text Available The invasive nature of malignant gliomas is a clinical problem rendering tumors incurable by conventional treatment modalities such as surgery, ionizing radiation, and temozolomide. Na+/H+ exchanger regulatory factor 1 (NHERF-1 is a multifunctional adaptor protein, recruiting cytoplasmic signaling proteins and membrane receptors/transporters into functional complexes. This study revealed that NHERF-1 expression is increased in highly invasive cells that reside in the rim of glioblastoma multiforme (GBM tumors and that NHERF-1 sustains glioma migration and invasion. Gene expression profiles were evaluated from laser capture-microdissected human GBM cells isolated from patient tumor cores and corresponding invaded white matter regions. The role of NHERF-1 in the migration and dispersion of GBM cell lines was examined by reducing its expression with small-interfering RNA followed by radial migration, three-dimensional collagen dispersion, immunofluorescence, and survival assays. The in situ expression of NHERF-1 protein was restricted to glioma cells and the vascular endothelium, with minimal to no detection in adjacent normal brain tissue. Depletion of NHERF-1 arrested migration and dispersion of glioma cell lines and caused an increase in cell-cell cohesiveness. Glioblastoma multiforme cells with depleted NHERF-1 evidenced a marked decrease in stress fibers, a larger cell size, and a more rounded shape with fewer cellular processes. When NHERF-1 expression was reduced, glioma cells became sensitized to temozolomide treatment resulting in increased apoptosis. Taken together, these results provide the first evidence for NHERF-1 as a participant in the highly invasive phenotype of malignant gliomas and implicate NHERF-1 as a possible therapeutic target for treatment of GBM.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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 (

  2. Network modeling of the transcriptional effects of copy number aberrations in glioblastoma

    Science.gov (United States)

    Jörnsten, Rebecka; Abenius, Tobias; Kling, Teresia; Schmidt, Linnéa; Johansson, Erik; Nordling, Torbjörn E M; Nordlander, Bodil; Sander, Chris; Gennemark, Peter; Funa, Keiko; Nilsson, Björn; Lindahl, Linda; Nelander, Sven

    2011-01-01

    DNA copy number aberrations (CNAs) are a hallmark of cancer genomes. However, little is known about how such changes affect global gene expression. We develop a modeling framework, EPoC (Endogenous Perturbation analysis of Cancer), to (1) detect disease-driving CNAs and their effect on target mRNA expression, and to (2) stratify cancer patients into long- and short-term survivors. Our method constructs causal network models of gene expression by combining genome-wide DNA- and RNA-level data. Prognostic scores are obtained from a singular value decomposition of the networks. By applying EPoC to glioblastoma data from The Cancer Genome Atlas consortium, we demonstrate that the resulting network models contain known disease-relevant hub genes, reveal interesting candidate hubs, and uncover predictors of patient survival. Targeted validations in four glioblastoma cell lines support selected predictions, and implicate the p53-interacting protein Necdin in suppressing glioblastoma cell growth. We conclude that large-scale network modeling of the effects of CNAs on gene expression may provide insights into the biology of human cancer. Free software in MATLAB and R is provided. PMID:21525872

  3. 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.

  4. 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.

  5. Efficient chemotherapy of rat glioblastoma using doxorubicin-loaded PLGA nanoparticles with different stabilizers.

    Directory of Open Access Journals (Sweden)

    Stefanie Wohlfart

    Full Text Available BACKGROUND: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid (PLGA nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. METHODOLOGY: The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA or human serum albumin (PLGA/HSA as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3 × 2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. CONCLUSION: The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.

  6. PERFIL PROFESIONAL – INSERCIÓN LABORAL

    OpenAIRE

    Coscarelli, Nélida; Albarracín, Silvia; Rueda, Leticia; Mosconi, Etel; Papel, Gustavo; Irigoyen, Silvia; Medina, Maria Mercedes

    2005-01-01

    Los cambios que se están procesando en los mercados laborales hace que las posibilidades de inserción sean cada vez más complejas, esto lleva al cuestionamiento por parte de las instituciones formadoras, de los perfiles de capacitación buscando brindar las competencias indispensables para su ingreso en el mercado del trabajo en las mejores condiciones posibles. El objetivo de éste estudio fue conocer el destino laboral de los egresados de la F.O.L.P., que servirá de base para un próximo estud...

  7. PERFIL PROFESIONAL – INSERCIÓN LABORAL

    OpenAIRE

    Coscarelli, N; Albarracin, S.; Medina, M.; Irigoyen, S; Mosconi, E; Rueda, L.; Papel, G.; Seara, S.; Tomas, L.; Lezcano, D.

    2007-01-01

    Los cambios que se están procesando en los mercados laborales hace que las posibilidades de inserción sean cada vez más complejas, esto lleva al cuestionamiento por parte de las instituciones formadoras, de los perfiles de capacitación buscando brindar las competencias indispensables para su ingreso en el mercado del trabajo en las mejores condiciones posibles. El objetivo de éste estudio fue conocer el destino laboral de los egresados de la F.O.L.P., que servirá de base para un próximo estud...

  8. Perfil logístico de Colombia

    OpenAIRE

    Cardozo Maglioni, María Victoria; Lozano Suarez, María Goretty

    2012-01-01

    El presente documento ofrece un estudio del perfil logístico de Colombia con la finalidad de dar a conocer el estado de arte de las ciudades, puertos e infraestructura principal para facilitar la toma de decisiones de los empresarios. Para el desarrollo de este trabajo se determinaron a partir de un análisis competitivo del país; las principales ciudades y puertos; logrando establecer un inventario de maquinaria y equipo e infraestructura logística; enmarcados en retos ya establecidos en las ...

  9. Perfil logístico de Portugal

    OpenAIRE

    Rodríguez Páez, Johanna Marcela

    2014-01-01

    El presente documento ofrece un estudio del perfil logístico de Portugal, abarcando diferentes aspectos que afectan la competitividad y el desempeño de la cadena logística de un país, con la finalidad de conocer a uno de los socios comerciales con los cuáles Colombia se encuentra negociando, en este caso Portugal, uno de los 28 países que hace parte del reciente tratado de libre comercio aprobado con la Unión Europea, es preciso estudiar las ventajas competitivas que poseen dichos socios, a l...

  10. Perfil psicosocial de la persona emprendedora

    OpenAIRE

    Trejo López, Enrique A.

    2015-01-01

    El objeto de la tesis es estudiar el perfil psicosocial de la persona emprendedora y de la emprendedora que continúa a pesar de la crisis, constatando las diferencias respecto al resto de los grupos laborales. Se realiza un estudio multidimensional, psicosocial, de nivel descriptivo y analítico, con un carácter longitudinal, aplicando instrumentos y metodologías cualitativas y cuantitativas y aportando datos disgregado por sexo En el marco teórico recogemos los estudios e investigacion...

  11. In vivo preclinical low field MRI monitoring of tumor growth following a suicide gene therapy in an ortho-topic mice model of human glioblastoma;Controle par IRM bas champ in vivo de l'efficacite d'une therapie genique par gene suicide dans un modele murin de glioblastome orthotopique

    Energy Technology Data Exchange (ETDEWEB)

    Breton, E.; Goetz, Ch.; Aubertin, G.; Constantinesco, A.; Choquet, Ph. [Service de biophysique et medecine nucleaire, hopital de Hautepierre, CHRU de Strasbourg, 67 - Strasbourg (France); Institut de mecanique des fluides et des solides, CNRS, universite de Strasbourg, 67 - Strasbourg (France); Kintz, J.; Accart, N.; Grellier, B.; Erbs, Ph.; Rooke, R. [Transgene SA, parc d' innovation, 67 - Illkirch Graffenstaden (France)

    2010-03-15

    Purpose The aim of this study was to monitor in vivo with low field MRI growth of a murine ortho-topic glioma model following a suicide gene therapy. Methods The gene therapy consisted in the stereotactic injection in the mice brain of a modified vaccinia virus Ankara (M.V.A.) vector encoding for a suicide gene (FCU1) that transforms a non toxic pro-drug 5-fluoro-cytosine (5-F.C.) to its highly cytotoxic derivatives 5-fluorouracil (5-F.U.) and 5-fluoro-uridine-5 monophosphate (5-F.U.M.P.). Using a warmed-up imaging cell, sequential 3D T1 and T2 0.1T MRI brain examinations were performed on 16 Swiss female nu/nu mice bearing ortho-topic human glioblastoma (U 87-MG cells). The 6-week in vivo MRI follow-up consisted in a weekly measurement of the intracerebral tumor volume leading to a total of 65 examinations. Mice were divided in four groups: sham group (n = 4), sham group treated with 5-F.C. only (n = 4), sham group with injection of M.V.A.-FCU1 vector only (n = 4), therapy group administered with M.V.A.-FCU1 vector and 5-F.C. (n = 4). Measurements of tumor volumes were obtained after manual segmentation of T1- and T2-weighted images. Results Intra-observer and inter-observer tumor volume measurements show no significant differences. No differences were found between T1 and T2 volume tumor doubling times between the three sham groups. A significant statistical difference (p < 0.05) in T1 and T2 volume tumor doubling times between the three sham groups and the animals treated with the intratumoral injection of M.V.A.-FCU1 vector in combination with 2 weeks per os 5-F.C. administration was demonstrated. Conclusion Preclinical low field MRI was able to monitor efficacy of suicide gene therapy in delaying the tumor growth in an in vivo mouse model of ortho-topic glioblastoma. (authors)

  12. Perfil das doadoras de leite do banco de leite humano de um hospital universitário - DOI: 10.4025/actascihealthsci.v31i1.891 Profile of breast milk donors at the human milk bank of a university hospital - DOI: 10.4025/actascihealthsci.v31i1.891

    Directory of Open Access Journals (Sweden)

    Márcia Maria Benevenuto Oliveira

    2009-05-01

    Full Text Available Esta pesquisa tem como objetivo conhecer o perfil socioeconômico das doadoras de leite do Banco de Leite Humano do Hospital Universitário de Londrina, Estado do Paraná (BLH/HUL. Trata-se de um estudo transversal, em que foram coletados dados a partir de formulário aplicado às doadoras externas do BLH/HUL no período de junho a agosto de 2005. Constatou-se que 11% são adolescentes. Com relação à escolaridade, 41,8% possuem segundo grau completo ou superior incompleto. De acordo com a literatura, quanto maior a escolaridade das mães, mais informações elas absorvem por meio das orientações e das campanhas que são realizadas sobre aleitamento materno. Do total das doadoras, 37,4% receberam informações sobre doação de leite e sobre os serviços do BLH/HU de Londrina por intermédio dos profissionais dos serviços de saúde. O conhecimento do perfil das doadoras permitirá direcionar as informações sobre doação de leite em nível local e regional, otimizando o trabalho realizado pelo Banco de Leite Humano do HU/L.This objective of this research is to understand the socioeconomic profile of the milk donors at the Human Milk Bank of the University Hospital of Londrina, Paraná State (BLH/HUL. It is a cross-sectional study in which data was collected by means of a questionnaire applied to the external donors of the BLH/ HUL, between June and August of 2005. It was observed that 11.0% are adolescents. According to the study, 41.8% have at least some high school education. According to the literature, the higher the educational level of the donors, the more information they are able to absorb through orientations and campaigns on breastfeeding. Of the total, 37.4% had received information on breast milk donation and the services offered by the BLH/HUL from the health professionals. The knowledge of the donors’ profile will allow the HU/Londrina Human Milk Bank to direct information on milk donation at the local and regional levels

  13. Pulsed Electromagnetic Field with Temozolomide Can Elicit an Epigenetic Pro-apoptotic Effect on Glioblastoma T98G Cells.

    Science.gov (United States)

    Pasi, Francesca; Fassina, Lorenzo; Mognaschi, Maria Evelina; Lupo, Giuseppe; Corbella, Franco; Nano, Rosanna; Capelli, Enrica

    2016-11-01

    Treatment with pulsed electromagnetic fields (PEMFs) is emerging as an interesting therapeutic option for patients with cancer. The literature has demonstrated that low-frequency/low-energy electromagnetic fields do not cause predictable effects on DNA; however, they can epigenetically act on gene expression. The aim of the present work was to study a possible epigenetic effect of a PEMF, mediated by miRNAs, on a human glioblastoma cell line (T98G). We tested a PEMF (maximum magnetic induction, 2 mT; frequency, 75 Hz) that has been demonstrated to induce autophagy in glioblastoma cells. In particular, we studied the effect of PEMF on the expression of genes involved in cancer progression and a promising synergistic effect with temozolomide, a frequently used drug to treat glioblastoma multiforme. We found that electromagnetic stimulation in combination with temozolomide can elicit an epigenetic pro-apoptotic effect in the chemo- and radioresistant T98G glioblastoma cell line. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  14. PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status.

    Science.gov (United States)

    Roodakker, Kenney R; Elsir, Tamador; Edqvist, Per-Henrik D; Hägerstrand, Daniel; Carlson, Joseph; Lysiak, Malgorzata; Henriksson, Roger; Pontén, Fredrik; Rosell, Johan; Söderkvist, Peter; Stupp, Roger; Tchougounova, Elena; Nistér, Monica; Malmström, Annika; Smits, Anja

    2016-11-08

    PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytomas. For this purpose, we analyzed protein expression in tissue microarrays of tumor samples stratified by patient age and IDH mutation status. We initially screened 86 unselected high-grade astrocytomas, followed by 174 IDH1-R132H1 immunonegative glioblastomas derived from patients aged 60 years and older enrolled in the Nordic phase III trial of elderly patients with newly diagnosed glioblastoma. Representing the younger population of glioblastomas, we studied 80 IDH-wildtype glioblastomas from patients aged 18-60 years. There was no correlation between PROX1 protein and survival for patients with primary glioblastomas included in these cohorts. In contrast, high expression of PROX1 protein predicted shorter survival in the group of patients with IDH-mutant anaplastic astrocytomas and secondary glioblastomas. The prognostic impact of PROX1 in IDH-mutant 1p19q non-codeleted high-grade astrocytomas, as well as the negative findings in primary glioblastomas, was corroborated by gene expression data extracted from the Cancer Genome Atlas. We conclude that PROX1 is a new prognostic biomarker for 1p19q non-codeleted high-grade astrocytomas that have progressed from pre-existing low-grade tumors and harbor IDH mutations.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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...

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

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

    Science.gov (United States)

    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.

  7. Combination of temozolomide with immunocytokine F16–IL2 for the treatment of glioblastoma

    Science.gov (United States)

    Pedretti, M; Verpelli, C; Mårlind, J; Bertani, G; Sala, C; Neri, D; Bello, L

    2010-01-01

    Background: Glioblastoma patients are still not cured by the treatments available at the moment. We investigated the therapeutic properties of temozolomide in combination with F16–IL2, a clinical-stage immunocytokine consisting of human interleukin (IL)-2 fused to the human antibody F16, specific to the A1 domain of tenascin-C. Methods: We conducted three preclinical therapy studies, using subcutaneous and intracranial U87MG glioblastoma tumours xenografted in BALB/c nude mice. The same therapeutic schedule was used, consisting of five total administrations every third day, of 0.525 mg temozolomide, 20 μg F16–IL2, the combination, or the control solution. Results: Immunohistochemical analysis of U87MG xenografts and of human glioblastoma specimens showed selective tumour staining of F16. A quantitative biodistribution confirmed the preferential tumour accumulation of radiolabelled F16–IL2. In the study with subcutaneous xenografts, the combination of F16–IL2 with temozolomide induced complete remission of the animals, which remained tumour free for over 160 days. The same treatment led to a consistent size reduction of intracranial xenografts and to a longer survival of animals. The immunocytokine promoted the recruitment of leukocytes into tumours of both models. Conclusion: The combined use of temozolomide with F16–IL2 deserves clinical investigations, which will be facilitated by the excellent safety profile in cynomolgus monkeys, and by the fact that F16–IL2 is in clinical trials in patients with cancer. PMID:20736949

  8. 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.

  9. Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo

    Science.gov (United States)

    Kahn, Suzana A.; Azad, Tej D.; Gholamin, Sharareh; Xu, Chelsea Y.; Liu, Jie; Achrol, Achal S.; Richard, Chase; Sommerkamp, Pia; Schoen, Matthew Kenneth; McCracken, Melissa N.; Majeti, Ravi; Weissman, Irving; Mitra, Siddhartha S.; Cheshier, Samuel H.

    2016-01-01

    Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo. PMID:27092773

  10. Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo.

    Science.gov (United States)

    Zhang, Michael; Hutter, Gregor; Kahn, Suzana A; Azad, Tej D; Gholamin, Sharareh; Xu, Chelsea Y; Liu, Jie; Achrol, Achal S; Richard, Chase; Sommerkamp, Pia; Schoen, Matthew Kenneth; McCracken, Melissa N; Majeti, Ravi; Weissman, Irving; Mitra, Siddhartha S; Cheshier, Samuel H

    2016-01-01

    Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

  11. Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo.

    Directory of Open Access Journals (Sweden)

    Michael Zhang

    Full Text Available Tumor-associated macrophages (TAMs represent an important cellular subset within the glioblastoma (WHO grade IV microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

  12. 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

  13. 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,

  14. Medios online y publicidad. Perfiles profesionales en educacion superior

    National Research Council Canada - National Science Library

    Papi-Galvez, Natalia; Lopez-Berna, Sonia

    2012-01-01

    .... Esta situacion es especialmente significativa en aquellas carreras con perfiles profesionales definidos y que utilizan los medios para llegar a sus publicos, como es el caso de la Publicidad y las Relaciones Publicas...

  15. EL PERFIL DEL EDITOR DE JUEGOS DE ROL

    Directory of Open Access Journals (Sweden)

    Héctor Sevillano Pareja

    2010-11-01

    Full Text Available El presente trabajo estudia y analiza, a través de diversas encuestas personalizadas, el perfil tipo que presentan los profesionales que se dedican al arte de editar libros de rol en España.

  16. Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence.

    Directory of Open Access Journals (Sweden)

    Gabrielle C Nickel

    Full Text Available Human cancers are driven by the acquisition of somatic mutations. Separating the driving mutations from those that are random consequences of general genomic instability remains a challenge. New sequencing technology makes it possible to detect mutations that are present in only a minority of cells in a heterogeneous tumor population. We sought to leverage the power of ultra-deep sequencing to study various levels of tumor heterogeneity in the serial recurrences of a single glioblastoma multiforme patient. Our goal was to gain insight into the temporal succession of DNA base-level lesions by querying intra- and inter-tumoral cell populations in the same patient over time. We performed targeted "next-generation" sequencing on seven samples from the same patient: two foci within the primary tumor, two foci within an initial recurrence, two foci within a second recurrence, and normal blood. Our study reveals multiple levels of mutational heterogeneity. We found variable frequencies of specific EGFR, PIK3CA, PTEN, and TP53 base substitutions within individual tumor regions and across distinct regions within the same tumor. In addition, specific mutations emerge and disappear along the temporal spectrum from tumor at the time of diagnosis to second recurrence, demonstrating evolution during tumor progression. Our results shed light on the spatial and temporal complexity of brain tumors. As sequencing costs continue to decline and deep sequencing technology eventually moves into the clinic, this approach may provide guidance for treatment choices as we embark on the path to personalized cancer medicine.

  17. Tumor-initiating cell frequency is relevant for glioblastoma aggressiveness.

    Science.gov (United States)

    Richichi, Cristina; Osti, Daniela; Del Bene, Massimiliano; Fornasari, Lorenzo; Patanè, Monica; Pollo, Bianca; DiMeco, Francesco; Pelicci, Giuliana

    2016-11-01

    Glioblastoma (GBM) is maintained by a small subpopulation of tumor-initiating cells (TICs). The arduous assessment of TIC frequencies challenges the prognostic role of TICs in predicting the clinical outcome in GBM patients. We estimated the TIC frequency in human GBM injecting intracerebrally in mice dissociated cells without any passage in culture.All GBMs contained rare TICsand were tumorigenic in vivo but only 54% of them grew in vitro as neurospheres. We demonstrated that neurosphere formation in vitro did not foretell tumorigenic ability in vivo and frequencies calculated in vitro overestimated the TIC content.Our findings assert the pathological significance of GBM TICs. TIC number correlated positively with tumor incidence and inversely with survival of tumor-bearing mice. Stratification of GBM patients according to TIC content revealed that patients with low TIC frequency experienced a trend towards a longer progression free survival. The expression of either putative stem-cell markers or markers associated with different GBM molecular subtypes did not associate with either TIC content or neurosphere formation underlying the limitations of TIC identification based on the expression of some putative stem cell-markers.

  18. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment.

    Science.gov (United States)

    van Tellingen, O; Yetkin-Arik, B; de Gooijer, M C; Wesseling, P; Wurdinger, T; de Vries, H E

    2015-03-01

    Gliomas are the most common primary brain tumors. Particularly in adult patients, the vast majority of gliomas belongs to the heterogeneous group of diffuse gliomas, i.e. glial tumors characterized by diffuse infiltrative growth in the preexistent brain tissue. Unfortunately, glioblastoma, the most aggressive (WHO grade IV) diffuse glioma is also by far the most frequent one. After standard treatment, the 2-year overall survival of glioblastoma patients is approximately only 25%. Advanced knowledge in the molecular pathology underlying malignant transformation has offered new handles and better treatments for several cancer types. Unfortunately, glioblastoma multiforme (GBM) patients have not yet profited as although numerous experimental drugs have been tested in clinical trials, all failed miserably. This grim prognosis for GBM is at least partly due to the lack of successful drug delivery across the blood-brain tumor barrier (BBTB). The human brain comprises over 100 billion capillaries with a total length of 400 miles, a total surface area of 20 m(2) and a median inter-capillary distance of about 50 μm, making it the best perfused organ in the body. The BBTB encompasses existing and newly formed blood vessels that contribute to the delivery of nutrients and oxygen to the tumor and facilitate glioma cell migration to other parts of the brain. The high metabolic demands of high-grade glioma create hypoxic areas that trigger increased expression of VEGF and angiogenesis, leading to the formation of abnormal vessels and a dysfunctional BBTB. Even though the BBTB is considered 'leaky' in the core part of glioblastomas, in large parts of glioblastomas and, even more so, in lower grade diffuse gliomas the BBTB more closely resembles the intact blood-brain barrier (BBB) and prevents efficient passage of cancer therapeutics, including small molecules and antibodies. Thus, many drugs can still be blocked from reaching the many infiltrative glioblastoma cells that

  19. Perfil de las bibliotecas universitarias de Puerto Rico

    OpenAIRE

    Montalvo-Montalvo, Marilyn

    2007-01-01

    Perfil de las Bibliotecas Universitarias Puertorriqueñas is the product of a research conducted during the year 2006-2007in which ninety three academic libraries participated. The work allows a diagnostic of the Puerto Rican academic libraries, through the thorough collection of cualitative and cuantitative facts, as well as its characterization according to the types of libraries and the nature of the institutions they support. The Perfil also provides useful information for the development ...

  20. Perfiles motivacionales de deportistas adolescentes españoles

    Directory of Open Access Journals (Sweden)

    Bartolom\\u00E9 J. Almagro

    2012-01-01

    Full Text Available El objetivo del estudio fue detectar posibles perfiles motivacionales en una muestra de deportistas adolescentes. Además, el estudio analizó las diferencias en los subfactores del clima motivacional percibido y en la satisfacción de las necesidades psicológicas básicas de los diferentes perfiles encontrados. Se utilizó una muestra de 608 deportistas, con una edad media de 14.43 años. Se midió el clima motivacional percibido (PMCSQ-2, los mediadores psicológicos (BPNES y la motivación en el deporte (SMS. El análisis de cluster reveló dos perfiles: un perfil altamente motivado, con puntuaciones altas tanto en formas de motivación autodeterminada (motivación intrínseca y regulación identificada como en motivación no autodeter- minada (regulación introyectada y externa, salvando la desmotivación; y un perfil moderadamente motivado, con puntuaciones moderadas (en torno a 3 y 4 en formas de motivación autodeterminada y no autodeterminada. En el análisis multivariante de los subfactores del clima motivacional percibido y de las necesidades piscológicas básicas según el perfil, se encontraron diferencias significativas a favor del perfil altamente motivado tanto en los sub- factores del clima motivacional tarea como ego, así como en los tres mediadores psicológicos. Se discuten los resultados en función de la importancia de fomentar un clima que implique a la tarea y que trate de satisfacer las necesidades de autonomía, competencia y relación con los demás durante los entrenamientos para obtener perfiles motivacionales más autodeterminados.

  1. 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

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

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  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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

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

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    Xiao-Hong Shu

    2013-05-01

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

  20. Sociodemographic and clinical factors associated with the preference between NNRTIs and PIs for the initial treatment of HIV infection: Perfil-es study.

    Science.gov (United States)

    Viciana, Pompeyo; Ocampo, Antonio; Hevia, Henar; Palazuelos, Marta; Ledesma, Francisco

    2016-10-01

    The Perfil-es study demonstrated that, while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based initial antiretroviral therapy (ART) is more frequently used in human immunodeficiency virus (HIV)-infected naïve patients, ritonavir-boosted protease inhibitors (PI/r)-based regimens are the preferred option in patients with advanced infectious stages or high baseline viral load. The present analysis focused on the second phase of the Perfil-es study, where sociodemographic and clinical data were retrospectively collected from patients starting NNRTI- or PI/r-based regimens in order to identify factors that could influence the choice of initial ART. Patients' characteristics were compared by both bivariate and multivariate analyses. A total of 642 patients were evaluated. The main transmission group was men who have sex with men (MSM) (48%), and 24% of patients were coinfected with hepatitis B or C. Patients with cardiovascular risk accounted for 56%, and 15% had a neuropsychiatric history. Anxiolytics (29%), antidepressants (18%) and methadone (18%) were the most frequent concomitant medications. The use of PI/r-based regimens was more frequent in older patients, childbearing potential women patients coinfected with hepatitis B or C, and those with cardiovascular risk and a neuropsychiatric history. The presence of a neuropsychiatric disorder (OR: 1.912; CI 95%: 1.146-3.191; p < .05) and the use of concomitant medication (OR: 1.736; CI 95%: 1.204-2.502; p < .01) were identified as independent factors associated with the selection of PI/r-based regimens. MSM sexual conduct was the only independent factor related to the selection of NNRTI-based ART (OR: 0.699; CI 95%: 0.504-0.970; p < .05). Neither the physicians' characteristics nor the geographical area where HIV patients were attended influenced the choice of ART. In conclusion, patients' comorbidity, pregnancy potential and lifestyle seem to influence the choice of ART. Neuropsychiatric

  1. El perfil psicosocial del emprendedor universitario

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    JUAN ANTONIO MORIANO LEÓN

    2006-01-01

    Full Text Available Desde la perspectiva de estudio de la intención emprendedora, el presente trabajo analiza las variables psicosociales que permiten elaborar el perfil del emprendedor universitario en España. Para ello, se utiliza un modelo de desarrollo de la carrera profesional que permite clasificar las variables psicosociales en tres espacios: familiar, sociolaboral y personal. La muestra utilizada estaba formada por 601 estudiantes universitarios procedentes de la Comunidad Autónoma de Castilla y León. Los resultados indican que los estudiantes, en general, tienen una alta intención de trabajar por cuenta ajena, en una empresa privada o en la Administración Pública, y una baja intención de desarrollar su carrera profesional a través del autoempleo. Específicamente, se ha encontrado que el género, la familia, la experiencia laboral, la educación hacia el autoempleo, el apoyo social, la percepción de barreras y los valores individualistas y colectivistas permiten predecir la intención de crear una empresa o trabajar por cuenta propia.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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...

  12. 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.

  13. 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.

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

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    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.

  15. 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 ...

  16. 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.

  17. PERFILES DE CONSUMO TELEVISIVO: UN ESTUDIO TRANSCULTURAL

    Directory of Open Access Journals (Sweden)

    Concepción Medrano

    2015-01-01

    Full Text Available En esta investigación se parte de la idea básica de que el medio televisivo es un agente de socialización en la adolescencia. Su objetivo general fue conocer algunos indicadores del perfil de consumo televisivo en una muestra transcultural de adolescentes. La muestra total estuvo compuesta por 1.238 participantes, pertenecientes a ocho regiones de diversos países. El instrumento de medida utilizado fue el cuestionario de hábitos televisivos (CH-TV.02. La recogida de datos se realizó a través de una plataforma on-line y presencial. Respecto a los hallazgos encontrados, existen diferencias transculturales y significativas en los indicadores estudiados: actividades alternativas, razones de elección del personaje, identificación con el personaje favorito y realismo percibido. En el análisis de resultados, destaca como actividad alternativa a ver la televisión estar con la familia, siendo la lectura una de las actividades a las que menos horas dedican. Así mismo eligen a su personaje favorito, sobre todo, por su simpatía y humor y se identifican con él porque intentan ver las cosas desde su punto de vista. Perciben que la televisión es muy realista en cómo presenta las consecuencias de las drogas y el alcohol y muy poco realista en cómo presenta las situaciones escolares. Las narraciones mediáticas, desde el punto de vista educativo, deberían trabajarse en las aulas con el fin de evitar una recepción pasiva y favorecer la decodificación de los mensajes.

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

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    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.

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

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    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. 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

  1. Genome-wide methylation analyses in glioblastoma multiforme.

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    Rose K Lai

    Full Text Available Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM. Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1, 5 methyl-deoxycytidine (5m-dC and 5 hydroxylmethyl-deoxycytidine (5hm-dC in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal.

  2. Genome-wide methylation analyses in glioblastoma multiforme.

    Science.gov (United States)

    Lai, Rose K; Chen, Yanwen; Guan, Xiaowei; Nousome, Darryl; Sharma, Charu; Canoll, Peter; Bruce, Jeffrey; Sloan, Andrew E; Cortes, Etty; Vonsattel, Jean-Paul; Su, Tao; Delgado-Cruzata, Lissette; Gurvich, Irina; Santella, Regina M; Ostrom, Quinn; Lee, Annette; Gregersen, Peter; Barnholtz-Sloan, Jill

    2014-01-01

    Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1), 5 methyl-deoxycytidine (5m-dC) and 5 hydroxylmethyl-deoxycytidine (5hm-dC) in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes) that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal.

  3. Identification of epidermal growth factor receptor-positive glioblastoma using lipid-encapsulated targeted superparamagnetic iron oxide nanoparticles in vitro

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    Huai-Lu Chen

    2017-11-01

    Full Text Available Abstract Background Targeted superparamagnetic iron oxide (SPIO nanoparticles have emerged as a promising biomarker detection tool for molecular magnetic resonance (MR image diagnosis. To identify patients who could benefit from Epidermal growth factor receptor (EGFR-targeted therapies, we introduce lipid-encapsulated SPIO nanoparticles and hypothesized that anti-EGFR antibody cetuximab conjugated of such nanoparticles can be used to identify EGFR-positive glioblastomas in non-invasive T2 MR image assays. The newly introduced lipid-coated SPIOs, which imitate biological cell surface and thus inherited innate nonfouling property, were utilized to reduce nonspecific binding to off-targeted cells and prevent agglomeration that commonly occurs in nanoparticles. Results The synthesized targeted EGFR-antibody-conjugated SPIO (EGFR-SPIO nanoparticles were characterized using dynamic light scattering, zeta potential assays, gel electrophoresis mobility shift assays, transmission electron microscopy (TEM images, and cell line affinity assays, and the results showed that the conjugation was successful. The targeting efficiency of the synthesized EGFR-SPIO nanoparticles was confirmed through Prussian blue staining and TEM images by using glioblastoma cell lines with high or low EGFR expression levels. The EGFR-SPIO nanoparticles preferentially targeted U-251 cells, which have high EGFR expression, and were internalized by cells in a prolonged incubation condition. Moreover, the T2 MR relaxation time of EGFR-SPIO nanoparticles could be used for successfully identifying glioblastoma cells with elevated EGFR expression in vitro and distinguishing U-251 cells from U-87MG cells, which have low EFGR expression. Conclusion These findings reveal that the lipid-encapsulated EGFR-SPIO nanoparticles can specifically target cells with elevated EGFR expression in the three tested human glioblastoma cell lines. The results of this study can be used for noninvasive

  4. Polymer Nanocomposites Based Thermo-Sensitive Gel for Paclitaxel and Temozolomide Co-Delivery to Glioblastoma Cells.

    Science.gov (United States)

    Xu, Yuanyuan; Shen, Ming; Sun, Ying; Gao, Pei; Duan, Yourong

    2015-12-01

    In this work, we have reported the preparation and optimization of paclitaxel (PTX) and temozolomide (TMZ) loaded monomethoxy (polyethylene glycol)-poly(D, L-lactide-co-glycolide) (mPEG-PLGA) nanocomposite which is a thermo-sensitive gel delivery system to glioblastoma. We utilized the orthogonal design and homogeneous design for the optimal drug-loaded nanoparticles (NPs) and composite gel prescription, respectively. The physicochemical characteristics of NPs and rheological properties of the gel were analyzed. Then the in vitro release of the gel was determined with a membrane-less diffusion system. Finally, the cytotoxic and apoptosis-inducing effects of the gel on the human malignant glioblastoma cell line U87 and C6 rat glioblastoma cell line were evaluated by MTT and flow cytometry apoptosis assay, respectively. The transmission electron microscopy (TEM) analysis revealed the optimized NPs with a relatively uniform diameter and distribution. The homogeneous design and rheological determination showed that the optimized gel prescription was 250 mg/mL Pluronic F127 (F127), 0.5% hydroxy propyl methylcellulose (HPMC-100M), 0.5% Pluronic F68 (F68), 0.5% sodium alginate (SA) and suitable NPs, which possessed the appropriate gelation behaviors: gelation temperature 28.01 degrees C, gelation time 127.1 s and corrosion speed 0.1892 g/cm2 x hr; and rheological properties: suitable elasticity modulus, viscosity modulus and low phase angle. The in vitro results suggested that the PTX and TMZ were sustainedly released from nanoparticles or the composite gel, and the release and elimination time greatly prolonged; and the composite gel possessed much higher growth-inhibiting effect and apoptosis-inducing rate in U87 and C6 cells than other formulations. These findings demonstrated that the optimal gel was a promising delivery system for the interstitial chemotherapy to glioblastoma.

  5. Cancer Stem Cells in Glioblastoma Multiforme

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    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.

  6. 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.

  7. Mathematical modeling identifies optimum lapatinib dosing schedules for the treatment of glioblastoma patients.

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    Shayna Stein

    2018-01-01

    Full Text Available Human primary glioblastomas (GBM often harbor mutations within the epidermal growth factor receptor (EGFR. Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. However, EGFR inhibitors have shown little efficacy in the clinic, partly because of inappropriate dosing. Here, we developed a computational approach to model the in vitro cellular dynamics of the EGFR-mutant cell line SF268 in response to different lapatinib concentrations and dosing schedules. We then used this approach to identify an effective treatment strategy within the clinical toxicity limits of lapatinib, and developed a partial differential equation modeling approach to study the in vivo GBM treatment response by taking into account the heterogeneous and diffusive nature of the disease. Despite the inability of lapatinib to induce tumor regressions with a continuous daily schedule, our modeling approach consistently predicts that continuous dosing remains the best clinically feasible strategy for slowing down tumor growth and lowering overall tumor burden, compared to pulsatile schedules currently known to be tolerated, even when considering drug resistance, reduced lapatinib tumor concentrations due to the blood brain barrier, and the phenotypic switch from proliferative to migratory cell phenotypes that occurs in hypoxic microenvironments. Our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment schedules in search for optimal dosing strategies for glioblastoma and other cancer types.

  8. m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells

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    Qi Cui

    2017-03-01

    Full Text Available RNA modifications play critical roles in important biological processes. However, the functions of N6-methyladenosine (m6A mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m6A mRNA modification is critical for glioblastoma stem cell (GSC self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m6A enrichment and altered mRNA expression of genes (e.g., ADAM19 with critical biological functions in GSCs. In summary, this study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma.

  9. m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells.

    Science.gov (United States)

    Cui, Qi; Shi, Hailing; Ye, Peng; Li, Li; Qu, Qiuhao; Sun, Guoqiang; Sun, Guihua; Lu, Zhike; Huang, Yue; Yang, Cai-Guang; Riggs, Arthur D; He, Chuan; Shi, Yanhong

    2017-03-14

    RNA modifications play critical roles in important biological processes. However, the functions of N6-methyladenosine (m6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m6A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m6A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  10. In vitro evaluation of photon and carbon ion radiotherapy in combination with chemotherapy in glioblastoma cells

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    Combs Stephanie E

    2012-01-01

    Full Text Available Abstract Background To evaluate the cytotoxic effect of carbon ion radiotherapy and chemotherapy in glioblastoma cells in vitro. Methods and Materials The human glioblastoma (GBM cell line U87 was irradiated with photon radiotherapy (RT doses of 2 Gy, 4 Gy and 6 Gy. Likewise, irradiation with carbon ions was performed with single carbon doses of 0.125, 0.5, 2 and 3 Gy. Four chemotherapeutic substances, camptothecin, gemcitabine, paclitaxel and cisplatinum, were used for single and combination experiments. The assessment of the effect of single and double treatment on cell viability was performed using the clonogenic growth assay representing the radiobiological gold standard. Results The RBE of carbon ions ranges between 3.3 and 3.9 depending on survival level and dose. All chemotherapeutic substances showed a clear does-response relationhips. in their characteristic concentrations. For subsequent combination experiments, two dose levels leading to low and medium reduction of cell survival were chosen. Combination experiments showed additive effects independently of the drugs' mechanisms of action. Paclitaxel and campthothecin demonstrated the most prominent cytotoxic effect in combination with carbon ion radiotherapy. Conclusion In conclusion, combination of carbon ion radiotherapy with chemotherapies of different mechanisms of action demonstrates additive effects. The most dominant effect was produced by paclitaxel, followed by camptothecin, as espected from previously published work. The present data serve as an important radiobiological basis for further combination experiments, as well as clinical studies on combination treatments.

  11. Hacia un perfil profesional del traductor en Colombia

    OpenAIRE

    Liliana Patricia Franco Uribe; Gabriel Quiroz Herrera

    2013-01-01

    En este artículo, se presentan los resultados de una investigación en la que se buscaba determinar el perfil del traductor en Colombia. Para ello, se empleó una encuesta a la cual respondieron 45 traductores consultados. El perfil del traductor en Colombia se resume como un profesional de entre 36 y 45 años de edad, que vive y trabaja principalmente en Medellín o Bogotá, con estudios universitarios de pregrado y posgrado en traducción, que se desempeña como traductor independiente entre tiemp...

  12. Estudo do perfil do trauma raquimedular em Porto Alegre

    OpenAIRE

    Frison, Verônica Baptista; Teixeira, Glaciéle de Oliveira; Oliveira, Thais Fonseca de; Resende, Thais de Lima; Netto, Carlos Alexandre

    2013-01-01

    Este estudo de coorte retrospectivo foi desenvolvido com o objetivo de traçar o perfil da população que sofreu trauma raquimedular (TRM) e foi internada em hospitais de pronto atendimento de Porto Alegre/RS. O perfil da população que sofreu TRM de janeiro de 2005 a janeiro de 2010 foi investigado retrospectivamente a partir da coleta de dados em registros médicos. Foram analisados 1320 prontuários, dos quais 63,3% eram do sexo masculino, com média de idade de 47,02±19,60 anos. Os mecanismos d...

  13. Perfil profesional del cirujano general: Professional profile General surgeon

    OpenAIRE

    José Antonio Hernández Varea; Ada Hilda de la Concepción de la Peña; Iris Soberón Varela

    2009-01-01

    El perfil del egresado es un elemento clave para confección del currículo, y constituye el modelo de las características, conocimientos y habilidades que se aspira formar en el futuro cirujano. Dicho perfil debe responder a las necesidades sociales, permitir la planificación del proceso docente-educativo y concretar la relación universidad-sociedad. En el presente artículo se analizan, a partir de la situación actual, los antecedentes históricos del modelo de formación del especialista en cir...

  14. Perfil de importaciones de Colombia desde Canadá

    OpenAIRE

    Hurtado Escobar, Paula Andrea; Morales Cely, Maria Camila; Diaz Morales, Diana Carolina

    2014-01-01

    El Proyecto Perfiles de Mercado de importaciones para Colombia desde Canadá, consiste en una guía de apoyo para los importadores colombianos, que facilita la toma de decisiones a partir de un panorama amplio de cada una de los departamentos que conforman el país. En este documento se exponen el perfil demográfico, político, geográfico, económico y logístico de cada departamento, donde se expone información acerca de rutas de acceso, aeropuertos, puertos, zonas francas e infraestructura de ...

  15. Targeting the alpha 1 subunit of the sodium pump to combat glioblastoma cells.

    Science.gov (United States)

    Lefranc, Florence; Mijatovic, Tatjana; Kondo, Yasuko; Sauvage, Sébastien; Roland, Isabelle; Debeir, Olivier; Krstic, Danijela; Vasic, Vesna; Gailly, Philippe; Kondo, Seiji; Blanco, Gustavo; Kiss, Robert

    2008-01-01

    Ion transporters play pivotal roles in cancer cell migration in general and in glioblastomas (GBMs) in particular. However, the specific role of Na/K-ATPase (the sodium pump) and, in particular, its alpha1 subunit, has remained unexplored in GBMs. The expression of Na+/K+ -ATPase alpha1 in GBM clinical samples, normal brain tissue, and a human GBM cell line has been investigated. Using the novel cardenolide UNBS1450 (Unibioscreen, Brussels, Belgium), which is a ligand of the sodium pump, we have characterized the effects of inhibiting Na+/K+ -ATPase alpha1 in human GBM cells with respect to cell proliferation; morphology; impact on intracellular Na+, Ca2+, and adenosine triphosphate; and changes in the actin cytoskeleton. We have investigated the mechanism by which UNBS1450 overcomes the apoptosis resistance of GBMs and determined its anti-tumor effects in comparative studies in vitro in GBM cell viability assays and in vivo using an orthotopic human GBM xenograft model. Overall, the alpha1 subunit of Na+/K+ -ATPase is highly expressed in a majority of glioblastomas compared with normal brain tissues, and by binding to this subunit in human U373-MG GBM cells, UNBS1450 impairs cell proliferation and migration via an intracellular adenosine triphosphate decrease-mediated disorganization of the actin cytoskeleton and cytotoxic proautophagic effects. UNBS1450 also significantly increases the in vivo survival of mice orthotopically grafted with U373-MG GBM cells. Inhibition of the Na+/K+ -ATPase alpha1 subunit in human GBM cells impairs both cell migration and cell proliferation.

  16. 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.

  17. 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

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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 ...

  3. 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...

  4. 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 ...

  5. 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...

  6. 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...

  7. 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...

  8. 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.

  9. 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...

  10. 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.

  11. Profile of immune cells in lymph nodes draining human malignant tumors Perfil de las células inmunes en los ganglios linfáticos que drenan tumores malignos humanos

    Directory of Open Access Journals (Sweden)

    Wanda Di Girolamo

    2008-12-01

    Full Text Available The purpose of this study was to characterize and quantify cells involved in immune response in metastasis-free regional lymph nodes (RLNs draining different human epithelial tumors and compare them (by immunohistochemistry with control lymph nodes from patients with non malignant diseases. We showed that T cells number was decreased in RLNs as compared to the controls with reduction in both CD4+ T cells and CD8+ T cells subsets and an inverted ratio (CD4+: CD8+. B lymphocytes and follicular dendritic cells were decreased with respect to the controls. S100+ dendritic cells (DCs and mature DCs were detected in T dependent areas. Their mean number was significantly lower as compared to control. Immature DCs were significantly diminished compared to RLN and control nodes. CD57+ cells, follicular T helper cells and/or NK cells, were localized in the clear zone of germinal centres and their mean number was significantly increased. There were no CD57+ cells in hypoplastic follicles. In this study we show that RLNs draining human cancer present reduction in almost all immune cells, except CD57+ cells. These findings may be related to the deficient anti-tumor immune response in patients with cancer and subsequent tumor progression.El objetivo del trabajo fue caracterizar y cuantificar utilizando inmuno-histoquímica, las células involucradas en la respuesta inmune en ganglios linfáticos regionales (GLRs que drenan distintos tumores epiteliales malignos humanos y compararlas con ganglios controles (GLCs provenientes de pacientes sin enfermedad neoplásica maligna. Determinamos que los GLRs presentaban una marcada depleción de linfocitos B y T, células dendríticas (CD foliculares y CD interdigitantes maduras respecto a los controles. En los linfocitos T, además de estar disminuidos, se observó una inversión de la relación T CD4+: T CD8+, a favor de los T CD8+. La depleción de CD inmaduras fue mayor respecto a las maduras. Las células CD57+, c

  12. Human Leukocyte Antigen-G Is Frequently Expressed in a Multicentric Study on Glioblastoma and May Be Induced in Vitro by Combined 5-aza-2'-deoxycytidine and Interferon-γ Treatments

    DEFF Research Database (Denmark)

    Wastowski, Isabela J; Simões, Renata T; Yaghi, Layale

    2012-01-01

    Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex (MHC) class I molecule involved in immune tolerance processes, playing an important role in the maintenance of the semi-allogeneic fetus. Although HLA-G expression is restricted in normal tissues, it is broadly......-G protein expression was associated with a better long-term survival rate. The mechanisms underlying HLA-G gene expression were investigated in glioma cell lines U251MG, D247MG, and U138MG. Induction of HLA-G transcriptional activity was dependent of 5-aza-2'-deoxycytidine treatment and enhanced...... by interferon-γ. HLA-G protein expression was observed in U251MG cells only. These cells exhibited a permissive chromatin state at the HLA-G gene promoter and the highest levels of induced HLA-G transcriptional activity following 5-aza-2'-deoxycytidine treatment. Several antigen-presenting machinery components...

  13. Serum zinc and hormonal profile in male dialysis patients receiving human recombinant erythropoietin Zinco sérico e perfil hormonal de pacientes do sexo masculino submetidos à hemodiálise em uso de eritropoetina humana recombinante

    Directory of Open Access Journals (Sweden)

    Maria Mouranilda Schleicher

    2005-08-01

    Full Text Available INTRODUCTION: Treatment with recombinant human erythropoietin (rHuEpo is associated with an improvement in well-being and quality of life in patients submitted to maintenance hemodialysis (HD. OBJECTIVES: The goal of this work was to evaluate the levels of sex hormones, hematocrit, albumin and zinc in HD patients with rHuEpo therapy and compare them with those observed in patients without rHuEpo treatment. MATERIAL AND METHODS: Two groups of twelve male HD patients each were selected for a transversal study; one did not receive rHuEpo (group 1 whereas the other one did (group 2. Levels of hematocrit, albumin, zinc, luteinizing hormone (LH, follicle-stimulating hormone (FSH, prolactin, and testosterone were determined. RESULTS: Group 2 patients showed significantly higher medians (p INTRODUÇÃO: Em pacientes submetidos à hemodiálise crônica (HD, o tratamento com eritropoetina humana recombinante (rHuEpo está associado a melhora no bem-estar geral e na qualidade de vida. OBJETIVOS: O objetivo do presente trabalho foi avaliar os níveis dos hormônios sexuais e do zinco em pacientes sob HD e em uso de rHuEpo em comparação com pacientes sem tratamento com essa droga. MATERIAL E MÉTODOS: Dois grupos de doze pacientes do sexo masculino cada um, submetidos à HD, sendo um deles sem uso de rHuEpo (grupo 1 e o outro utilizando a droga (grupo 2, foram selecionados para um estudo transversal, comparando-se os níveis séricos do zinco, da albumina, dos hormônios FSH, LH, prolactina, testosterona e do hematócrito. RESULTADOS: No grupo 2, os valores de testosterona (4,65 vs. 3,5ng/ml, hematócrito (30,5 vs. 22%, albumina (3,9 vs. 3,7g/dl e zinco (62,5 vs. 50,5microg/dl foram significativamente maiores do que no grupo 1 (p < 0,05. DISCUSSÃO: Sugere-se que, em pacientes recipientes da rHuEpo, os níveis mais altos de hematócrito, zinco, albumina e testosterona possam ser fatores que contribuam para melhorar a disfunção sexual e a qualidade de

  14. Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma.

    Science.gov (United States)

    Sonabend, Adam M; Carminucci, Arthur S; Amendolara, Benjamin; Bansal, Mukesh; Leung, Richard; Lei, Liang; Realubit, Ronald; Li, Hai; Karan, Charles; Yun, Jonathan; Showers, Christopher; Rothcock, Robert; O, Jane; Califano, Andrea; Canoll, Peter; Bruce, Jeffrey N

    2014-09-01

    Glioblastoma subtypes have been defined based on transcriptional profiling, yet personalized care based on molecular classification remains unexploited. Topoisomerase II (TOP2) contributes to the transcriptional signature of the proneural glioma subtype. Thus, we targeted TOP2 pharmacologically with etoposide in proneural glioma models. TOP2 gene expression was evaluated in mouse platelet derived growth factor (PDGF)(+)phosphatase and tensin homolog (PTEN)(-/-)p53(-/-) and PDGF(+)PTEN(-/-) proneural gliomas and cell lines, as well as human glioblastoma from The Cancer Genome Atlas. Correlation between TOP2 transcript levels and etoposide susceptibility was investigated in 139 human cancer cell lines from the Cancer Cell Line Encyclopedia public dataset and in mouse proneural glioma cell lines. Convection-enhanced delivery (CED) of etoposide was tested on cell-based PDGF(+)PTEN(-/-)p53(-/-) and retroviral-based PDGF(+)PTEN(-/-) mouse proneural glioma models. TOP2 expression was significantly higher in human proneural glioblastoma and in mouse proneural tumors at early as well as late stages of development compared with normal brain. TOP2B transcript correlated with susceptibility to etoposide in mouse proneural cell lines and in 139 human cancer cell lines from the Cancer Cell Line Encyclopedia. Intracranial etoposide CED treatment (680 μM) was well tolerated by mice and led to a significant survival benefit in the PDGF(+)PTEN(-/-)p53(-/-) glioma model. Moreover, etoposide CED treatment at 80 μM but not 4 μM led to a significant survival advantage in the PDGF(+)PTEN(-/-) glioma model. TOP2 is highly expressed in proneural gliomas, rendering its pharmacological targeting by intratumoral administration of etoposide by CED effective on murine proneural gliomas. We provide evidence supporting clinical testing of CED of etoposide with a molecular-based patient selection approach. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2014

  15. Perfil do idoso acusado de cometer crime

    Directory of Open Access Journals (Sweden)

    Sérgio Vieira Brandão

    2017-06-01

    Full Text Available É verdade que o idoso, muitas vezes, é vítima de diversas formas de agressões, mas também é agente da prática de delitos. Por meio de pesquisa documental realizada em 2013 com todos os boletins de ocorrência registrados na delegacia de polícia de Imbé, Rio Grande do Sul, Brasil, realizamos análise estatística e evidenciamos o perfil do idoso acusado de cometer crime e os tipos de crimes cometidos. No período pesquisado, 3,28% do total de idosos de Imbé foi acusado de cometer algum tipo de crime. Este artigo recomenda uma ação contínua e integrada da rede de saúde e de segurança pública com as demais áreas sociais para antecipar situações de risco para idosos (e comunidade em geral, de modo a promover a cidadania, gerenciar conflitos e reduzir a violência urbana. It is genuine that the elderly frequently are victims of several kinds of hostility, but the fact remains that he or she, too, is also an agent of the committal of criminal offenses. Through documentary research realized in 2013 with the total occurrences bulletins registered in police stations in Imbé, Rio Grande do Sul, Brazil, we realize statistical analysis and show the profile of the elderly accused of committing crime and the types of crimes committed. In the period surveyed, 3.28% of the total number of elderly of Imbé was accused of committing some type of crime. Profile of the Elderly Accused of Committing Crime recommends a continuous and integrated action of the health and public safety network with the other social areas to anticipate risk situations for the elderly (and the community in general, in order to promote citizenship, manage conflicts and reduce urban violence. Keywords: violence, seniors, aging, public health, crime

  16. Perfil das doadoras do banco de leite humano do Hospital Universitário de Maringá, Estado do Paraná, Brasil = Human milk bank donors’ profile at Hospital Universitário de Maringá, State of Paraná, Brazil

    Directory of Open Access Journals (Sweden)

    Renata de Campos Dias

    2006-04-01

    Full Text Available Amamentação exclusiva até os seis meses de idade é fato importante para a saúde e para a relação mãe e filho. Quando essa amamentação é prejudicada, o desmame precoce pode ocorrer. O objetivo da pesquisa foi investigar o perfil das doadoras do Banco de Leite Humano do Hospital Universitário de Maringá, Estado do Paraná. Foramentrevistadas 48 nutrizes doadoras de leite humano durante os meses de outubro e novembro de 2004. O estudo foi observacional transversal e os dados foram coletados utilizando-se um questionário estruturado. Observou-se que 41,7% das nutrizes tinham entre 20 e 29 anos, 33,3% ensino médio completo e 66,6% receberam informações sobre amamentação. A falta de informação, contudo, sobre mama ingurgitada (20,8%, estimulação para produção de leite (29,1% e outras funções do leite materno, além da alimentação (31,3%, foram relevantes. Apenas metade das nutrizes não tinha oferecido qualquer outro alimento para o bebê antes dos seis meses de vida. Dados apontam paraimportância de orientação das nutrizes de forma direcionada, ainda durante a gestação.Exclusive maternal breast feeding until six months of age is an important practice for health and mother and son’s relationship. However, when that exclusive maternal breast feeding is harmed, precocious weans may occur. This work aims at investigating the Human Milk Bank donors’ profile at Hospital Universitário de Maringá,State of Paraná. Forty-eight nursing mothers were interviewed during two months: October and November, 2004. A transversal and observational study was carried out and the data were collected by means of individual interviews conducted by structured questionnaire. 41.7% of the women were aged between 20 and 29, 33.3% had concluded secondary school and 66.6% had received information on breast-feeding. The lack of information on engorged breast (20.8%, on stimulation for milk production (29.1% and other maternal milk functions

  17. Glioblastoma extracellular vesicles: reservoirs of potential biomarkers

    Directory of Open Access Journals (Sweden)

    Redzic JS

    2014-02-01

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

  18. Determinación del perfil instrumental del EBASIM

    Science.gov (United States)

    Nieva, M. F.; Rodriguez, M. V.; Pintado, O. I.

    Se calcula el perfil instrumental para el telescopio de 2,15m del CASLEO con EBASIM. Para ello se usaron flats de cielo y el espectro solar FTS de Kurucz. El método, que se puede utilizar para otras configuraciones instrumentales, es convolucionar ambos espectros para obtener los coeficientes de corrección.

  19. Las funciones inalterables del periodista ante los perfiles multimedia emergentes

    Directory of Open Access Journals (Sweden)

    P Sánchez-García

    2015-03-01

    Full Text Available Introducción. Esta investigación aborda el estudio de las funciones y de los perfiles del periodista en el nuevo entorno multimedia. Metodología. Se recurre a una metodología cualitativa de revisión documental, que contribuye a una actualización del campo de conocimiento, junto a una entrevista con cuestionario a colectivos de periodistas españoles sobre el objeto de estudio. Resultados. Refleja las coincidencias entre el ámbito académico y profesional en torno a las funciones inalterables del periodista frente a los nuevos perfiles multimedia emergentes y desarrolla el modelo de los perfiles formativos que establece la Aneca. Discusión. El nuevo entorno mediático evidencia la necesidad de revisión de conceptos desfasados y mantiene abierto el debate científico acerca de las tareas que se potencian en la labor periodística, así como la redefinición de perfiles profesionales y formativos que aún están en proceso de configuración en un panorama mediático en transición.

  20. 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.

  1. Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis.

    Science.gov (United States)

    Cui, Xin; Morales, Renee-Tyler Tan; Qian, Weiyi; Wang, Haoyu; Gagner, Jean-Pierre; Dolgalev, Igor; Placantonakis, Dimitris; Zagzag, David; Cimmino, Luisa; Snuderl, Matija; Lam, Raymond H W; Chen, Weiqiang

    2018-02-02

    Glioblastoma (GBM) is the most lethal primary adult brain tumor and its pathology is hallmarked by distorted neovascularization, diffuse tumor-associated macrophage infiltration, and potent immunosuppression. Reconstituting organotypic tumor angiogenesis models with biomimetic cell heterogeneity and interactions, pro-/anti-inflammatory milieu and extracellular matrix (ECM) mechanics is critical for preclinical anti-angiogenic therapeutic screening. However, current in vitro systems do not accurately mirror in vivo human brain tumor microenvironment. Here, we engineered a three-dimensional (3D), microfluidic angiogenesis model with controllable and biomimetic immunosuppressive conditions, immune-vascular and cell-matrix interactions. We demonstrate in vitro, GL261 and CT-2A GBM-like tumors steer macrophage polarization towards a M2-like phenotype for fostering an immunosuppressive and proangiogenic niche, which is consistent with human brain tumors. We distinguished that GBM and M2-like immunosuppressive macrophages promote angiogenesis, while M1-like pro-inflammatory macrophages suppress angiogenesis, which we coin "inflammation-driven angiogenesis." We observed soluble immunosuppressive cytokines, predominantly TGF-β1, and surface integrin (α v β 3 ) endothelial-macrophage interactions are required in inflammation-driven angiogenesis. We demonstrated tuning cell-adhesion receptors using an integrin (α v β 3 )-specific collagen hydrogel regulated inflammation-driven angiogenesis through Src-PI3K-YAP signaling, highlighting the importance of altered cell-ECM interactions in inflammation. To validate the preclinical applications of our 3D organoid model and mechanistic findings of inflammation-driven angiogenesis, we screened a novel dual integrin (α v β 3 ) and cytokine receptor (TGFβ-R1) blockade that suppresses GBM tumor neovascularization by simultaneously targeting macrophage-associated immunosuppression, endothelial-macrophage interactions, and

  2. 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 ...

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. PET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Pappata, S.; Cornu, P.; Samson, Y.; Prenant, C.; Benavides, J.; Scatton, B.; Crouzel, C.; Hauw, J.J.; Syrota, A. (INSERM U. 334 Service Hospitalier Frederic Joliot, Paris (France))

    1991-08-01

    The utility of the peripheral type benzodiazepine site ligand 11C-PK 11195, for imaging human glioma in conjunction with Positron Emission Tomography, relies on a high specific binding of the tracer to tumoral peripheral type benzodiazepines sites. In a patient with glioblastoma, the authors found that 11C-PK 11195 binding was two-fold higher in the tumor than in normal gray matter and that 30% of tumoral binding could be displaced by a large excess of unlabeled drug. These findings suggest that tumoral retention of the ligand is due, in part, to specific binding.

  8. Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth.

    Directory of Open Access Journals (Sweden)

    Tae Hyong Kim

    Full Text Available Glioblastoma multiforme (GBM, the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4 is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future.

  9. 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.

  10. 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.

  11. 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.

  12. 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...

  13. 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.

  14. 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...

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

    Indian Academy of Sciences (India)

    Celltype-specific toxicity of GMT-3:DOX complex was showed by XTT assay and terminated cytotoxic effects were screenedfor both target cell and a control breast cancer cell line. The result of this contribution demonstrated the potential utility ofGMT-3 aptamer-mediated therapeutic drug transportation in the treatment of ...

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma

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    Lu Lizhi

    2006-12-01

    Full Text Available Abstract Background Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. Results In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol and etoposide (VP16 compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors. Conclusion Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in

  1. El nuevo perfil profesional de los profesores de secundaria

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    Gemma Tribó Travería

    2008-01-01

    Full Text Available El objetivo del artículo es definir el nuevo perfil profesional de los profesores de secundaria. Una de las debilidades del sistema educativo español es que ha cambiado el marco legal y no se ha aplicado un nuevo modelo de formación inicial a los docentes de secundaria. El debate sobre las competencias profesionales está en la base de la propuesta de las competencias específicas del profesor del futuro. Se insiste en la importancia de las prácticas profesionales en el proceso de adquisición y de desarrollo de las competencias profesionales. Se valora positivamente que el master de formación inicial del profesorado de secundaria tenga presente en su diseño este nuevo perfil competencial profesional.

  2. Hacia un perfil profesional del traductor en Colombia

    Directory of Open Access Journals (Sweden)

    Liliana Patricia Franco Uribe

    2013-08-01

    Full Text Available En este artículo, se presentan los resultados de una investigación en la que se buscaba determinar el perfil del traductor en Colombia. Para ello, se empleó una encuesta a la cual respondieron 45 traductores consultados. El perfil del traductor en Colombia se resume como un profesional de entre 36 y 45 años de edad, que vive y trabaja principalmente en Medellín o Bogotá, con estudios universitarios de pregrado y posgrado en traducción, que se desempeña como traductor independiente entre tiempo completo y medio tiempo del inglés al español y que emplea herramientas informáticas.

  3. Perfil multidimensional de personas que han realizado intento de suicidio

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    Nicolás Arturo Núñez Gómez

    2008-01-01

    Full Text Available Establecer el perfil multidimensional de personas con intento de suicidio. Se estudiaron 116 personas reportadas con intento de suicidio en servicios de urgencias e instituciones educativas del departamento del Huila. Diseño descriptivo; con entrevista semi-estructurada, prueba de personalidad, inventario de depresión, evaluación de alcoholismo, evaluación de ideación e intento de suicidio. El perfil multidimensional se caracterizó: adolescentes rurales, adultos citadinos; son de consideración: ama de casa, con relación de pareja estable, y personas solas, divorciadas, desempleadas. La relación neuroticismo bajo y piscoticismo alto podría ayudar a explicar que el intento de suicidio haya sido realizado de "repente" sin existir ningún síntoma previo. La estructura y dinámica familiar disfuncional están altamente asociadas a la persona con intento de suicidio.

  4. Perfil docente para alumnos/as con altas capacidades

    Directory of Open Access Journals (Sweden)

    María Leonor Conejeros-Solar

    2013-01-01

    Full Text Available El presente artículo tiene por objeto determinar un perfil de competencias docentes construido desde la percepción de estudiantes con altas capacidades pertenecientes a un programa universitario para talentos académicos. Se utiliza una metodología cualitativa con una estrategia documental de carácter retrospectivo. Los resultados indican que los estudiantes realizan una evaluación profunda sobre la docencia, incluyendo elementos pedagógicos como flexibilidad, ritmo e integración teoría-práctica. Las percepciones de los estudiantes, poco incorporadas en discusiones relativas a la enseñanza, permiten repensar y delinear un perfil de las competencias docentes relevadas para un trabajo pedagógico efectivo con talentosos en el aula.

  5. PERFIL EMPRESARIAL, ESTRATÉGIA E PERFORMANCE EM MERCADOS INTERNACIONAIS

    Directory of Open Access Journals (Sweden)

    Flávia Luciane Scherer

    2008-12-01

    Full Text Available Uma das questões centrais do campo da estratégia transita em torno das suas relações com a performance empresarial. Considerando a importância desta temática, o artigo objetiva descrever e analisar, em empresas gaúchas do setor de couros e calçados, como se dão as relações entre perfil empresarial, estratégia adotada e performance em mercados internacionais. A análise do perfil empresarial identificou empresas de médio e grande porte, maduras no setor, que realizam planejamento para orientar suas ações e que se preocupam em monitorar alterações no ambiente com o qual se relacionam. O uso de um modelo multivariado de análise estatística evidenciou que as principais variáveis que discriminam o grupo pesquisado são o perfil estratégico, a realização de planejamento e o monitoramento ambiental. As empresas com Receita Operacional Bruta superior apresentam menor porte, realizam atividades de planejamento apenas eventualmente, não efetuam monitoramento ambiental e adotam uma postura estratégica defensiva.

  6. Geometría de los perfiles alveolares

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    Monfort Lleonart, José

    1988-10-01

    Full Text Available The most common castellated profiles series are established from a reduced set of templates to cut the original profiles. This means that no consideration is given to some parameters that could improve the beam strength behavior obtained from the same profile. In this paper the influence of some of these parameters are studied and some easy to use charts are given for simple beams with uniform load.

    Las series de perfiles alveolares, usualmente utilizadas, se establecen a partir de un conjunto reducido de plantillas/patrón para realizar el corte del perfil original, cuya utilización sistemática equivale a no considerar la influencia de algunos parámetros que podrían mejorar el comportamiento resistente de la viga alveolada obtenida a partir del mismo perfil original. En este trabajo se analiza la influencia de algunos de estos parámetros, y se obtienen gráficas de fácil aplicación para el caso de vigas bi apoyad as con carga uniformemente repartida.

  7. Perfil profesional del cirujano general: Professional profile General surgeon

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    José Antonio Hernández Varea

    2009-09-01

    Full Text Available El perfil del egresado es un elemento clave para confección del currículo, y constituye el modelo de las características, conocimientos y habilidades que se aspira formar en el futuro cirujano. Dicho perfil debe responder a las necesidades sociales, permitir la planificación del proceso docente-educativo y concretar la relación universidad-sociedad. En el presente artículo se analizan, a partir de la situación actual, los antecedentes históricos del modelo de formación del especialista en cirugía general, la definición de cirugía general, los principales cambios internacionales en el modelo de formación de cirujanos y las funciones generales que se deben considerar en el perfil profesional del cirujano y su cumplimiento en el programa de cirugía.Graduate profile is a key element to make the curriculum, and it is a representation of the possible features, knowledges, and abilities in the future surgeon. Such profile must to account for social needs, to allow the planning of teaching-educational process, and to stay exactly the university-society relation. In present paper, from a current situation, are analyzed the historical backgrounds of training model of general surgery specialist, general surgery definition, the main international changes in the training model of surgeon, and its fulfillment in surgery program.

  8. Perfil das doadoras de leite do banco de leite humano de um hospital universitário - DOI: 10.4025/actascihealthsci.v31i1.891 Profile of breast milk donors at the human milk bank of a university hospital - DOI: 10.4025/actascihealthsci.v31i1.891

    OpenAIRE

    Márcia Maria Benevenuto Oliveira; Marli Terezinha Oliveira Vannuchi; Danielle Talita dos Santos; José Carlos Dalmas

    2009-01-01

    Esta pesquisa tem como objetivo conhecer o perfil socioeconômico das doadoras de leite do Banco de Leite Humano do Hospital Universitário de Londrina, Estado do Paraná (BLH/HUL). Trata-se de um estudo transversal, em que foram coletados dados a partir de formulário aplicado às doadoras externas do BLH/HUL no período de junho a agosto de 2005. Constatou-se que 11% são adolescentes. Com relação à escolaridade, 41,8% possuem segundo grau completo ou superior incompleto. De acordo com a literatur...

  9. Adaptação transcultural e análise das propriedades psicométricas da versão brasileira do Perfil de Atividade Humana Cross-cultural adaptation and analysis of the psychometric properties in the Brazilian version of the Human Activity Profile

    Directory of Open Access Journals (Sweden)

    Aline Cristina Souza

    2006-12-01

    Full Text Available O objetivo deste estudo foi avaliar as propriedades psicométricas da versão brasileira do Perfil de Atividade Humana (PAH, um instrumento de avaliação funcional e do nível de atividade física. O PAH foi traduzido para o português segundo metodologia recomendada e aplicado em 230 idosos (66,32 ± 8,5 anos da comunidade da cidade de Belo Horizonte, Minas Gerais, Brasil. Os dados foram submetidos à análise Rasch, que detectou itens muito fáceis e muito difíceis, possibilitando sua utilização em pessoas mais debilitadas ou mais capazes. O índice de separação de 3,1 indica que os itens dividiram os indivíduos em três níveis de habilidade funcional. Dos 94 itens, seis (6,38% foram considerados erráticos. Esse resultado compromete a validade de constructo do teste, pois significa que nem todos os itens se "encaixaram" em um contínuo, sendo recomendada cautela ao interpretar o escore do PAH em idosos com características semelhantes às da amostra. Caso em novos estudos o número de itens erráticos continue acima de 5%, sugere-se modificação, substituição ou exclusão desses itens, para garantir que o PAH meça um constructo unidimensional.The aim of the present study was to evaluate the psychometric properties in the Brazilian version of the Human Activity Profile (HAP, an instrument for the assessment of daily functions and level of physical activity. The HAP was translated into Portuguese following the recommended methodology and applied to 230 community-dwelling elderly (66.32 ± 8.5 years from the city of Belo Horizonte, Minas Gerais State, Brazil. The data were submitted to Rasch analysis, which detected very easy and difficult items, making it possible to employ the instrument with both frail and highly functional individuals. The separation index of 3.1 indicated that the items divided the individuals into three levels of functional ability. Of the 94 HAP items, six (6.38% did not fit the statistical model, which

  10. Supplementation with the omega-3 docosahexaenoic acid: influence on the lipid composition and fatty acid profile of human milk Suplementação com ácido graxo ômega-3 docosahexaenoico: influência sobre a composição lipídica e perfil de ácidos graxos no leite humano

    Directory of Open Access Journals (Sweden)

    Eliana Aparecida Fagundes Queiroz Bortolozo

    2013-02-01

    Full Text Available OBJECTIVE: This study assessed the impact of supplementing the diet of women during pregnancy and lactation with fish oil containing the omega-3 fatty acid docosahexaenoic acid, and its influence on the composition of human milk. METHODS: The sample comprised 60 women aged 18 to 38 years with appropriate dietary pattern, all of them healthy and nonsmokers. The intervention consisted of a daily supplementation with fish oil capsules that corresponded to a daily intake of 315mg of docosahexaenoic acid and 80mg of eicosapentaenoic acid during the third trimester of pregnancy and the first three months postpartum. The total fat content and fatty acid profile of their milk were determined by creamatocrit and gas chromatography. Descriptive statistics were used for data analysis and the significance level was set at pOBJETIVO: Este estudo teve como objetivo avaliar o impacto da suplementação na dieta de gestantes e de lactantes com ácidos graxos ômega-3 docosahexaenoico, sob a forma de óleo de peixe, e sua influência na composição do leite humano. MÉTODOS: A amostra foi constituída de 60 gestantes, com idade entre 18 e 38 anos, saudáveis, com padrão alimentar adequado e não fumantes. A intervenção consistiu na suplementação da dieta com cápsulas de óleo de peixe, totalizando um consumo diário de 315mg de ácido docosahexaenoico e 80mg de ácido eicosapentaenoico, no período entre o terceiro trimestre de gravidez e o terceiro mês após o parto. O teor de lipídeos totais e do perfil de ácidos graxos foi determinado pelos métodos de crematócrito e de cromatografia gasosa. Para a análise dos dados foi utilizada estatística descritiva e nível de significância de p<0,05. RESULTADOS: Entre o grupo sujeito à dieta suplementada (cápsulas de óleo de peixe e o grupo controle (cápsulas contendo amido de milho como excipiente, não se constatou diferença estatística quanto aos valores totais de lipídeos. Entretanto, no leite

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    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...

  12. 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)

  13. 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.

  14. 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.

  15. 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,

  16. 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.

  17. 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

  18. 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

  19. Perfil lipídico em escolares de Recife - PE

    Directory of Open Access Journals (Sweden)

    Patrícia Brazil Pereira

    2010-10-01

    Full Text Available FUNDAMENTO: A ocorrência de dislipidemias é crescente na população infanto-juvenil. Níveis alterados do perfil lipídico estão relacionados com maior incidência de hipertensão e doença aterosclerótica. OBJETIVO: Avaliar a magnitude das dislipidemias e investigar a relação do perfil lipídico com o excesso de peso e a obesidade abdominal em adolescentes escolares da cidade do Recife - PE. MÉTODOS: Foram coletados dados pessoais, situação socioeconômica, medidas antropométricas e perfil lipídico de 470 adolescentes de 10 a 14 anos, de ambos os sexos, da rede pública de ensino de Recife - PE. A análise estatística foi realizada com os programas Epi-info 6.04 e SPSS 13.0. Adotou-se o nível de significância de 5%. RESULTADOS: A maior parte da população era dislipidêmica (63,8%, IC95% 59,3 - 68,2, sendo a hipoalfalipoproteinemia a dislipidemia mais prevalente (56%, IC95% 51,3 - 60,5. Adolescentes com excesso de peso ou com obesidade abdominal apresentaram valores mais elevados de triglicerídeos e mais baixos de HDL-colesterol (p < 0,05. As concentrações do colesterol total e frações não diferiram em relação ao sexo. CONCLUSÃO: Ficou demonstrada a elevada ocorrência do perfil lipídico desfavorável, o que faz alertar para a necessidade da dosagem do perfil lipídico já nessa faixa etária. Medidas de estilo de vida saudável devem ser incentivadas nessa população.

  20. Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis.

    Science.gov (United States)

    Richardson, Timothy E; Snuderl, Matija; Serrano, Jonathan; Karajannis, Matthias A; Heguy, Adriana; Oliver, Dwight; Raisanen, Jack M; Maher, Elizabeth A; Pan, Edward; Barnett, Samuel; Cai, Chunyu; Habib, Amyn A; Bachoo, Robert M; Hatanpaa, Kimmo J

    2017-05-01

    According to the recently updated World Health Organization (WHO) classification (2016), grade II-III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II-III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II-III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II-III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

  1. Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation.

    Science.gov (United States)

    Blake, Sophia M; Stricker, Stefan H; Halavach, Hanna; Poetsch, Anna R; Cresswell, George; Kelly, Gavin; Kanu, Nnennaya; Marino, Silvia; Luscombe, Nicholas M; Pollard, Steven M; Behrens, Axel

    2016-03-17

    Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors.

  2. 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

  3. Meningeoma e glioblastoma concomitantes: registro de um caso

    Directory of Open Access Journals (Sweden)

    Apio Claudio Martins Antunes

    1978-09-01

    Full Text Available É relatado um caso com associação de glioblastoma heteromorfo e de meningioma meningotelial, cuja manifestação inicial foi crise convulsiva focal. Por ser infrequente a associação de neoplasias intracranianas, discute-se a forma de expressão clínica, as teorias referentes à presença concomitante de tais associações tumorais e, ainda, o valor do diagnóstico pré-operatório no estabelecimento da conduta cirúrgica e do prognóstico em tais ocasiões.

  4. Glioblastoma Stem-Like Cells—Biology and Therapeutic Implications

    Energy Technology Data Exchange (ETDEWEB)

    Gürsel, Demirkan B., E-mail: jab2029@nyp.org; Shin, Benjamin J.; Burkhardt, Jan-Karl; Kesavabhotla, Kartik; Schlaff, Cody D.; Boockvar, John A., E-mail: jab2029@nyp.org [Laboratory for Translational Brain Tumor and Stem Cell Research, Department of Neurological Surgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College, New York, NY 10021 (United States)

    2011-06-10

    The cancer stem-cell hypothesis proposes that malignant tumors are likely to encompass a cellular hierarchy that parallels normal tissue and may be responsible for the maintenance and recurrence of glioblastoma multiforme (GBM) in patients. The purpose of this manuscript is to review methods for optimizing the derivation and culturing of stem-like cells also known as tumor stem cells (TSCs) from patient-derived GBM tissue samples. The hallmarks of TSCs are that they must be able to self-renew and retain tumorigenicity. The isolation, optimization and derivation of TSCs as outlined in this review, will be important in understanding biology and therapeutic applications related to these cells.

  5. Transferrin Receptor 2 Is Frequently and Highly Expressed in Glioblastomas

    OpenAIRE

    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

    2010-01-01

    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 exp...

  6. SOX9-mediated upregulation of LGR5 is important for glioblastoma tumorigenicity

    Energy Technology Data Exchange (ETDEWEB)

    Hiraoka, Koji; Hayashi, Tomoatsu; Kaneko, Ryusuke; Nasu-Nishimura, Yukiko; Koyama-Nasu, Ryo; Kawasaki, Yoshihiro; Akiyama, Tetsu, E-mail: akiyama@iam.u-tokyo.ac.jp

    2015-05-01

    LGR5 plays an important role in the self-renewal of stem cells and is used as a marker identifying self-renewing stem cells in small intestine and hair follicles. Moreover, LGR5 has been reported to be overexpressed in several cancers. SOX9 is a transcription factor that plays a key role in development, differentiation and lineage commitment in various tissues. It has also been reported that SOX9 is overexpressed in a variety of cancers and contributes to their malignant phenotype. Here we show that LGR5 is required for the tumorigenicity of glioblastoma cells. We further show that SOX9 is upregulated in glioblastoma cells and directly enhances the expression of LGR5. We also demonstrate that knockdown of SOX9 suppresses the proliferation and tumorigenicity of glioblastoma cells. These results suggest that SOX9-mediated transcriptional regulation of LGR5 is critical for the tumorigenicity of glioblastoma cells. We speculate that the SOX9-LGR5 pathway could be a potentially promising target for the therapy of glioblastoma. - Highlights: • LGR5 is required for the tumorigenicity of glioblastoma cells. • SOX9 directly enhances the expression of LGR5. • SOX9 is required for the tumorigenicity of glioblastoma cells.

  7. 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

  8. 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.

  9. Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma.

    Science.gov (United States)

    Oakes, Eimile; Anderson, Ashley; Cohen-Gadol, Aaron; Hundley, Heather A

    2017-03-10

    RNA editing is a cellular process that precisely alters nucleotide sequences, thus regulating gene expression and generating protein diversity. Over 60% of human transcripts undergo adenosine to inosine RNA editing, and editing is required for normal development and proper neuronal function of animals. Editing of one adenosine in the transcript encoding the glutamate receptor subunit B, glutamate receptor ionotropic AMPA 2 (GRIA2), modifies a codon, replacing the genomically encoded glutamine (Q) with arginine (R); thus this editing site is referred to as the Q/R site. Editing at the Q/R site of GRIA2 is essential, and reduced editing of GRIA2 transcripts has been observed in patients suffering from glioblastoma. In glioblastoma, incorporation of unedited GRIA2 subunits leads to a calcium-permeable glutamate receptor, which can promote cell migration and tumor invasion. In this study, we identify adenosine deaminase that acts on RNA 3 (ADAR3) as an important regulator of Q/R site editing, investigate its mode of action, and detect elevated ADAR3 expression in glioblastoma tumors compared with adjacent brain tissue. Overexpression of ADAR3 in astrocyte and astrocytoma cell lines inhibits RNA editing at the Q/R site of GRIA2 Furthermore, the double-stranded RNA binding domains of ADAR3 are required for repression of RNA editing. As the Q/R site of GRIA2 is specifically edited by ADAR2, we suggest that ADAR3 directly competes with ADAR2 for binding to GRIA2 transcript, inhibiting RNA editing, as evidenced by the direct binding of ADAR3 to the GRIA2 pre-mRNA. Finally, we provide evidence that both ADAR2 and ADAR3 expression contributes to the relative level of GRIA2 editing in tumors from patients suffering from glioblastoma. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. 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.

  11. Cyclic-RGDyC functionalized liposomes for dual-targeting of tumor vasculature and cancer cells in glioblastoma: An in vitro boron neutron capture therapy study.

    Science.gov (United States)

    Kang, Weirong; Svirskis, Darren; Sarojini, Vijayalekshmi; McGregor, Ailsa L; Bevitt, Joseph; Wu, Zimei

    2017-05-30

    The efficacy of boron neutron capture therapy depends on the selective delivery of 10B to the target. Integrins αvβ3 are transmembrane receptors over-expressed in both glioblastoma cells and its neovasculature. In this study, a novel approach to dual-target glioblastoma vasculature and tumor cells was investigated. Liposomes (124 nm) were conjugated with a αvβ3 ligand, cyclic arginine-glycine-aspartic acid-tyrosine-cysteine peptide (c(RGDyC)-LP) (1% molar ratio) through thiol-maleimide coupling. Expression of αvβ3 in glioblastoma cells (U87) and human umbilical vein endothelial cells (HUVEC), representing tumor angiogenesis, was determined using Western Blotting with other cells as references. The results showed that both U87 and HUVEC had stronger expression of αvβ3 than other cell types, and the degree of cellular uptake of c(RGDyC)-LP correlated with the αvβ3-expression levels of the cells. In contrast, control liposomes without c(RGDyC) showed little cellular uptake, regardless of cell type. In an in vitro boron neutron capture therapy study, the c(RGDyC)-LP containing sodium borocaptate generated more rapid and significant lethal effects to both U87 and HUVEC than the control liposomes and drug solution. Interestingly, neutron irradiated U87 and HUVEC showed different types of subsequent cell death. In conclusion, this study has demonstrated the potential of a new dual-targeting strategy using c(RGDyC)-LP to improve boron neutron capture therapy for glioblastoma.

  12. Glioblastoma multiforme of the pineal region: case report Glioblastoma multiforme de região pineal: relato de caso

    Directory of Open Access Journals (Sweden)

    Emerson Leandro Gasparetto

    2003-06-01

    Full Text Available PURPOSE: pineal region tumors are uncommon, and comprise more frequently three categories: germ cell, parenchymal cell and glial tumors. Most pineal gliomas are low-grade astrocytomas. Glioblastoma multiforme, the most aggressive and common brain tumor, is extremely rare at this location with only few cases reported. CASE DESCRIPTION: a 29-year-old woman with a two month history of headache, nuchal pain, fever, nausea and seizures and physical examination showing nuchal rigidity, generalized hypotony, hypotrophy and hyper-reflexia, Babinski sign and left VI cranial par palsy. CT scan examination revealed a ill-defined hypodense lesion at the pineal region with heterogeneous contrast enhancement. MRI showed a lesion at the pineal region infiltrating the right thalamic region. The patient underwent a right craniotomy with partial resection of the mass. The histological examination of paraffin-embedded material defined the diagnosis of glioblastoma multiforme. Post-operative radiotherapy was indicated but the patient refused the treatment and died two months afterwards. CONCLUSION: in spite of its rarity at this location, glioblastoma multiforme should be considered in the differential diagnosis of aggressive lesions at the pineal region.OBJETIVO: Os tumores da região pineal são incomuns e podem ser divididos em três categorias de acordo com a sua origem: células germinativas, células do parênquima e células gliais. Em sua maioria, os gliomas de pineal são astrocitomas de baixo grau, sendo que o seu correspondente maligno, glioblastoma multiforme, é o mais comum e agressivo tumor encefálico e é extremamente raro nesta localização, com apenas alguns casos relatados na literatura. CASO: Mulher com 29 anos apresentando há 2 meses cefaléia, nucalgia, febre, náuseas e crises convulsivas. O exame físico mostrou rigidez de nuca, hipotonia, hipotrofia e hiperreflexia generalizadas, sinal de Babinski e paralisia do VI nervo craniano. A

  13. Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma

    Directory of Open Access Journals (Sweden)

    Anthony R. Guastella BS

    2016-04-01

    Full Text Available Increasing evidence demonstrates the immunosuppressive kynurenine pathway’s (KP role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[11C]-methyl-l-tryptophan (AMT. The AMT-positron emission tomography (PET has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM. We generated patient-derived xenograft (PDX models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM.

  14. Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma.

    Science.gov (United States)

    Guastella, Anthony R; Michelhaugh, Sharon K; Klinger, Neil V; Kupsky, William J; Polin, Lisa A; Muzik, Otto; Juhász, Csaba; Mittal, Sandeep

    2016-01-01

    Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[(11)C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM. © The Author(s) 2016.

  15. Perfil dos estudantes de medicina da PUC-SP

    OpenAIRE

    Maria Beatriz C. Gozzano; José Rafael C. Gozzano; Maria Beatriz B. Beraldo; Mariana S. Garcia; José Otávio A. Gozzano

    2008-01-01

    Objetivos: conhecer o perfil e qualidades dos estudantes de Medicina da PUC-SP. Material e Métodos: amostra - 143 alunos da 1ª e 2ª séries do curso de Medicina no ano de 2005. Métodos: Escala Auto-aplicada de Adaptação Social (SASS) e questões sobre conhecimento de idiomas, viagem ao exterior, idade e sexo. Delineamento do trabalho: pesquisa vertical prospectiva. Resultados: idade - 20,17 ± 1,49 anos. Oitenta (80) mulheres e sessenta e três (63) homens. SASS entre 27 e 55. Dois (2) alunos com...

  16. PERFIL PARA REPRESENTAR UNA ARQUITECTURA DE COMPONENTES EN UML

    OpenAIRE

    Fernando Oreja