WorldWideScience

Sample records for f98 rat glioma

  1. Preparation, biodistribution and neurotoxicity of liposomal cisplatin following convection enhanced delivery in normal and F98 glioma bearing rats

    OpenAIRE

    Tianyao Huo; Barth, Rolf F.; Weilian Yang; Nakkula, Robin J.; Rumiana Koynova; Boris Tenchov; Abhik Ray Chaudhury; Lawrence Agius; Teni Boulikas; Helene Elleaume; Lee, Robert J.

    2012-01-01

    International audience; 12 Hide Figures Abstract Introduction Materials and Methods Results Discussion Acknowledgments Author Contributions References Reader Comments (0) Figures Abstract The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (...

  2. Preparation, biodistribution and neurotoxicity of liposomal cisplatin following convection enhanced delivery in normal and F98 glioma bearing rats.

    Directory of Open Access Journals (Sweden)

    Tianyao Huo

    Full Text Available The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (NSCLC. The second, produced in our laboratory, was based on the ability of cisplatin to form coordination complexes with lipid cholesteryl hemisuccinate (CHEMS. The in vitro tumoricidal activity of the former previously has been described in detail by other investigators. The CHEMS liposomal formulation had a Pt loading efficiency of 25% and showed more potent in vitro cytotoxicity against F98 glioma cells than free cisplatin at 24 h. In vivo CHEMS liposomes showed high retention at 24 h after intracerebral (i.c. convection enhanced delivery (CED to F98 glioma bearing rats. Neurotoxicologic studies were carried out in non-tumor bearing Fischer rats following i.c. CED of Lipoplatin™ or CHEMS liposomes or their "hollow" counterparts. Unexpectedly, Lipoplatin™ was highly neurotoxic when given i.c. by CED and resulted in death immediately following or within a few days after administration. Similarly "hollow" Lipoplatin™ liposomes showed similar neurotoxicity indicating that this was due to the liposomes themselves rather than the cisplatin. This was particularly surprising since Lipoplatin™ has been well tolerated when administered intravenously. In contrast, CHEMS liposomes and their "hollow" counterparts were clinically well tolerated. However, a variety of dose dependent neuropathologic changes from none to severe were seen at either 10 or 14 d following their administration. These findings suggest that further refinements in the design and formulation of cisplatin containing liposomes will be required before they can be administered i.c. by CED for the treatment of brain tumors and that a formulation that may be safe when given

  3. Preparation, biodistribution and neurotoxicity of liposomal cisplatin following convection enhanced delivery in normal and F98 glioma bearing rats.

    Science.gov (United States)

    Huo, Tianyao; Barth, Rolf F; Yang, Weilian; Nakkula, Robin J; Koynova, Rumiana; Tenchov, Boris; Chaudhury, Abhik Ray; Agius, Lawrence; Boulikas, Teni; Elleaume, Helene; Lee, Robert J

    2012-01-01

    The purpose of this study was to evaluate two novel liposomal formulations of cisplatin as potential therapeutic agents for treatment of the F98 rat glioma. The first was a commercially produced agent, Lipoplatin™, which currently is in a Phase III clinical trial for treatment of non-small cell lung cancer (NSCLC). The second, produced in our laboratory, was based on the ability of cisplatin to form coordination complexes with lipid cholesteryl hemisuccinate (CHEMS). The in vitro tumoricidal activity of the former previously has been described in detail by other investigators. The CHEMS liposomal formulation had a Pt loading efficiency of 25% and showed more potent in vitro cytotoxicity against F98 glioma cells than free cisplatin at 24 h. In vivo CHEMS liposomes showed high retention at 24 h after intracerebral (i.c.) convection enhanced delivery (CED) to F98 glioma bearing rats. Neurotoxicologic studies were carried out in non-tumor bearing Fischer rats following i.c. CED of Lipoplatin™ or CHEMS liposomes or their "hollow" counterparts. Unexpectedly, Lipoplatin™ was highly neurotoxic when given i.c. by CED and resulted in death immediately following or within a few days after administration. Similarly "hollow" Lipoplatin™ liposomes showed similar neurotoxicity indicating that this was due to the liposomes themselves rather than the cisplatin. This was particularly surprising since Lipoplatin™ has been well tolerated when administered intravenously. In contrast, CHEMS liposomes and their "hollow" counterparts were clinically well tolerated. However, a variety of dose dependent neuropathologic changes from none to severe were seen at either 10 or 14 d following their administration. These findings suggest that further refinements in the design and formulation of cisplatin containing liposomes will be required before they can be administered i.c. by CED for the treatment of brain tumors and that a formulation that may be safe when given systemically may be

  4. Convection-enhancement delivery of platinum-based drugs and Lipoplatin™ to optimize the concomitant effect with radiotherapy in F98 glioma rat model

    OpenAIRE

    SHI, MINGHAN; Fortin, David; Sanche, Léon; Paquette, Benoit

    2015-01-01

    The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection-enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and Lipoplatin™-liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with γ radiation (15 Gy). CED increased by facto...

  5. Estradiol Receptors Regulate Differential Connexin 43 Expression in F98 and C6 Glioma Cell Lines.

    Directory of Open Access Journals (Sweden)

    Zahra Moinfar

    Full Text Available Glioma is the most common malignant primary brain tumour with male preponderance and poor prognosis. Glioma cells express variable amounts of connexin 43 (Cx43 and estrogen receptors (ERs. Both, Cx43 and ERs, play important roles in cell proliferation and migration. Therefore, we investigated the effects of 17-ß estradiol (E2 on Cx43 expression in two glioma cell lines with variable native expression of Cx43.F98 and C6 rat glioma cells were cultured for 24 h in the presence of 10 nM or 100 nM E2, and the E2-antagonist, Fulvestrant. An MTT assay was performed to evaluate cell viability. ERα, ERβ and Cx43 protein expressions were analysed by western blotting and Cx43 mRNA expression was analysed by real-time polymerase chain reaction. To quantify cell migration, an exclusive zone migration assay was used. Functional coupling of cells via gap junctions was examined using whole-cell patch-clamp technique.E2 reduced Cx43 expression in C6 cells, but increased Cx43 expression in F98 cultures. These effects were mediated via ERs. Moreover, E2 promoted C6 cell migration, but it did not affect F98 cell migration. The expression level of ERα was found to be high in C6, but low in F98 cells. ERβ was exclusively expressed in C6 cells. In addition, E2 treatment induced a significant decrease of ERβ in C6 cultures, while it decreased ERα expression in F98 glioma cells.These findings show that E2 differentially modulates Cx43 expression in F98 and C6 glioma cells, likely due to the differential expression of ERs in each of these cell lines. Our findings point to the molecular mechanisms that might contribute to the gender-specific differences in the malignancy of glioma and could have implications for therapeutic strategies against glioma.

  6. Convection-enhancement delivery of platinum-based drugs and Lipoplatin™ to optimize the concomitant effect with radiotherapy in F98 glioma rat model

    Science.gov (United States)

    Shi, Minghan; Fortin, David; Sanche, Léon; Paquette, Benoit

    2015-01-01

    The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection-enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and Lipoplatin™-liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with γ radiation (15 Gy). CED increased by factors varying between 17 and 111, the concentration of these platinum-based drugs in the brain tumor compared to intra-venous (i.v.) administration, and by 9- to 34-fold, when compared to intra-arterial (i.a.) administration. Furthermore, CED resulted in a better systemic tolerance to platinum drugs compared to their i.a. injection. Among the drugs tested, carboplatin showed the highest maximum tolerated dose (MTD). Treatment with carboplatin resulted in the best median survival time (MeST) (38.5 days), which was further increased by the addition of radiotherapy (54.0 days). Although the DNA-bound platinum adduct were higher at 4 h after CED than 24 h for carboplatin group, combination with radiotherapy led to similar improvement of median survival time. However, less toxicity was observed in animals irradiated 24 h after CED-based chemotherapy. In conclusion, CED increased the accumulation of platinum drugs in tumor, reduced the toxicity, and resulted in a higher median survival time. The best treatment was obtained in animals treated with carboplatin and irradiated 24 h later. PMID:25784204

  7. Convection-enhancement delivery of platinum-based drugs and Lipoplatin(TM) to optimize the concomitant effect with radiotherapy in F98 glioma rat model.

    Science.gov (United States)

    Shi, Minghan; Fortin, David; Sanche, Léon; Paquette, Benoit

    2015-06-01

    The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum-based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection-enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and Lipoplatin(TM) - liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with γ radiation (15 Gy). CED increased by factors varying between 17 and 111, the concentration of these platinum-based drugs in the brain tumor compared to intra-venous (i.v.) administration, and by 9- to 34-fold, when compared to intra-arterial (i.a.) administration. Furthermore, CED resulted in a better systemic tolerance to platinum drugs compared to their i.a. injection. Among the drugs tested, carboplatin showed the highest maximum tolerated dose (MTD). Treatment with carboplatin resulted in the best median survival time (MeST) (38.5 days), which was further increased by the addition of radiotherapy (54.0 days). Although the DNA-bound platinum adduct were higher at 4 h after CED than 24 h for carboplatin group, combination with radiotherapy led to similar improvement of median survival time. However, less toxicity was observed in animals irradiated 24 h after CED-based chemotherapy. In conclusion, CED increased the accumulation of platinum drugs in tumor, reduced the toxicity, and resulted in a higher median survival time. The best treatment was obtained in animals treated with carboplatin and irradiated 24 h later.

  8. Synergistic effect of cisplatin and synchrotron irradiation on F98 gliomas growing in nude mice

    Energy Technology Data Exchange (ETDEWEB)

    Ricard, Clement; Fernandez, Manuel [Grenoble Institut des Neurosciences, Grenoble (France); Université Joseph Fourier, Grenoble (France); Requardt, Herwig [European Synchrotron Radiation Facility, Grenoble (France); Wion, Didier [Grenoble Institut des Neurosciences, Grenoble (France); Université Joseph Fourier, Grenoble (France); Vial, Jean-Claude [Université Joseph Fourier, Grenoble (France); Laboratoire Interdisciplinaire de Physique, St Martin d’Hères (France); Segebarth, Christoph; Sanden, Boudewijn van der, E-mail: boudewijn.vandersanden@ujf-grenoble.fr [Grenoble Institut des Neurosciences, Grenoble (France); Université Joseph Fourier, Grenoble (France)

    2013-09-01

    Synchrotron photoactivation therapy of cisplatin relies on a synergistic effect of synchrotron X-rays and platinum and leads to tumor-cell-killing effects and reduction of the tumor blood perfusion. Among brain tumors, glioblastoma multiforme appears as one of the most aggressive forms of cancer with poor prognosis and no curative treatment available. Recently, a new kind of radio-chemotherapy has been developed using synchrotron irradiation for the photoactivation of molecules with high-Z elements such as cisplatin (PAT-Plat). This protocol showed a cure of 33% of rats bearing the F98 glioma but the efficiency of the treatment was only measured in terms of overall survival. Here, characterization of the effects of the PAT-Plat on tumor volume and tumor blood perfusion are proposed. Changes in these parameters may predict the overall survival. Firstly, changes in tumor growth of the F98 glioma implanted in the hindlimb of nude mice after the PAT-Plat treatment and its different modalities have been characterized. Secondly, the effects of the treatment on tumor blood perfusion have been observed by intravital two-photon microscopy. Cisplatin alone had no detectable effect on the tumor volume. A reduction of tumor growth was measured after a 15 Gy synchrotron irradiation, but the whole therapy (15 Gy irradiation + cisplatin) showed the largest decrease in tumor growth, indicating a synergistic effect of both synchrotron irradiation and cisplatin treatment. A high number of unperfused vessels (52%) were observed in the peritumoral area in comparison with untreated controls. In the PAT-Plat protocol the transient tumor growth reduction may be due to synergistic interactions of tumor-cell-killing effects and reduction of the tumor blood perfusion.

  9. Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation

    OpenAIRE

    Charest, Gabriel; Paquette, Benoit; Fortin, David; Mathieu, David; Sanche, Léon

    2009-01-01

    Despite significant advances, the radiotherapy and chemotherapy protocols marginally improve the overall survival of patients with glioblastoma. Lipoplatin™, and Lipoxal™, the liposomal formulations of cisplatin and oxaliplatin respectively, were tested on the F98 glioma cells for their ability to improve the cell uptake and increase the synergic effect when combined with ionizing radiation. The cytotoxicity and synergic effect of platinum compounds were assessed by colony formation assay, wh...

  10. Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation.

    Science.gov (United States)

    Charest, Gabriel; Paquette, Benoit; Fortin, David; Mathieu, David; Sanche, Léon

    2010-04-01

    Despite significant advances, the radiotherapy and chemotherapy protocols marginally improve the overall survival of patients with glioblastoma. Lipoplatin(TM), and Lipoxal(TM), the liposomal formulations of cisplatin and oxaliplatin respectively, were tested on the F98 glioma cells for their ability to improve the cell uptake and increase the synergic effect when combined with ionizing radiation. The cytotoxicity and synergic effect of platinum compounds were assessed by colony formation assay, while the cellular uptake was measured by Inductively Coupled Plasma Mass Spectrometer (ICP-MS). After 4 h exposure with platinum compounds, cells were irradiated (1.5-6.6 Gy) with a (60)Co source. The liposomal formulations were compared to their liposome-free analogs and to carboplatin. The concomitant treatment of F98 cells with carboplatin and radiation produced the highest radiosensitizing effect (30-fold increase). Among the platinum compounds tested, Lipoplatin(TM) produced the most promising results. This liposomal formulation of cisplatin improved the cell uptake by 3-fold, and its radiosensitizing potential was enhanced by 14-fold. Although Lipoxal(TM) can potentially reduce the adverse effect of oxaliplatin, a synergic effect with radiation was measured only when incubated at a concentration higher than its IC50. Conversely, concomitant treatment with cisplatin did not result in a synergic effect, as in fact a radioprotective effect was measured on the F98 cells. In conclusion, among the five platinum compounds tested, carboplatin and Lipoplatin(TM) showed the best radiosensitizing effect. Lipoplatin(TM) seems the most promising since it led to the best cellular incorporation and has already been reported to be less neurotoxic than other platinum compounds.

  11. Tumoricidal activity of low-energy 160-KV versus 6-MV X-rays against platinum-sensitized F98 glioma cells.

    Science.gov (United States)

    Lim, Sara N; Pradhan, Anil K; Barth, Rolf F; Nahar, Sultana N; Nakkula, Robin J; Yang, Weilian; Palmer, Alycia M; Turro, Claudia; Weldon, Michael; Bell, Erica Hlavin; Mo, Xiaokui

    2015-01-01

    The purposes of this study were (i) to investigate the differences in effects between 160-kV low-energy and 6-MV high-energy X-rays, both by computational analysis and in vitro studies; (ii) to determine the effects of each on platinum-sensitized F98 rat glioma and murine B16 melanoma cells; and (iii) to describe the in vitro cytotoxicity and in vivo toxicity of a Pt(II) terpyridine platinum (Typ-Pt) complex. Simulations were performed using the Monte Carlo code Geant4 to determine enhancement in absorption of low- versus high-energy X-rays by Pt and to determine dose enhancement factors (DEFs) for a Pt-sensitized tumor phantom. In vitro studies were carried out using Typ-Pt and again with carboplatin due to the unexpected in vivo toxicity of Typ-Pt. Cell survival was determined using clonogenic assays. In agreement with computations and simulations, in vitro data showed up to one log unit reduction in surviving fractions (SFs) of cells treated with 1-4 µg/ml of Typ-Pt and irradiated with 160-kV versus 6-MV X-rays. DEFs showed radiosensitization in the 50-200 keV range, which fell to approximate unity at higher energies, suggesting marginal interactions at MeV energies. Cells sensitized with 1-5 or 7 µg/ml of carboplatin and then irradiated also showed a significant decrease (P < 0.05) in SFs. However, it was unlikely this was due to increased interactions. Theoretical and in vitro studies presented here demonstrated that the tumoricidal activity of low-energy X-rays was greater than that of high-energy X-rays against Pt-sensitized tumor cells. Determining whether radiosensitization is a function of increased interactions will require additional studies.

  12. A micro-PET/CT approach using O-(2-[{sup 18}F]fluoroethyl)-L-tyrosine in an experimental animal model of F98 glioma for BNCT

    Energy Technology Data Exchange (ETDEWEB)

    Menichetti, L., E-mail: luca.menichetti@ifc.cnr.it [CNR Institute of Clinical Physiology, Pisa (Italy); Petroni, D.; Panetta, D. [CNR Institute of Clinical Physiology, Pisa (Italy); Burchielli, S. [Fondazione CNR/Regione Toscana G. Monasterio, Pisa (Italy); Bortolussi, Silva [Dept. Theoretical and Nuclear Physics, University of Pavia, Pavia (Italy); Matteucci, M. [Scuola Superiore Sant' Anna, Pisa (Italy); Pascali, G.; Del Turco, S. [CNR Institute of Clinical Physiology, Pisa (Italy); Del Guerra, A. [Department of Physics, University of Pisa, Pisa (Italy); Altieri, S. [Dept. Theoretical and Nuclear Physics, University of Pavia, Pavia (Italy); Salvadori, P.A. [CNR Institute of Clinical Physiology, Pisa (Italy)

    2011-12-15

    The present study focuses on a micro-PET/CT application to be used for experimental Boron Neutron Capture Therapy (BNCT), which integrates, in the same frame, micro-CT derived anatomy and PET radiotracer distribution. Preliminary results have demonstrated that {sup 18}F-fluoroethyl-tyrosine (FET)/PET allows the identification of the extent of cerebral lesions in F98 tumor bearing rat. Neutron autoradiography and {alpha}-spectrometry on axial tissues slices confirmed the tumor localization and extraction, after the administration of fructose-boronophenylalanine (BPA). Therefore, FET-PET approach can be used to assess the transport, the net influx, and the accumulation of FET, as an aromatic amino acid analog of BPA, in experimental animal model. Coregistered micro-CT images allowed the accurate morphological localization of the radiotracer distribution and its potential use for experimental BNCT.

  13. Magnetic paclitaxel nanoparticles inhibit glioma growth and improve the survival of rats bearing glioma xenografts.

    Science.gov (United States)

    Zhao, Ming; Liang, Chao; Li, Anmin; Chang, Jin; Wang, Hanjie; Yan, Runmin; Zhang, Jiajing; Tai, Junli

    2010-06-01

    Paclitaxel has fared poorly in clinical trials against brain glioma. We hypothesized that superparamagnetic nanocarriers may enhance its bioactivities by delivering it into the brain. The magnetic paclitaxel nanoparticles (MPNPs) were fabricated and their cytotoxicity against glioma was tested both in vitro and in glioma-bearing rats. MPNPs exhibited superparamagnetism and produced an extended release of paclitaxel over 15 days in vitro. They were easily internalized into glioma cells and exerted remarkable toxicity, as free paclitaxel did. Furthermore, after intravenous injection of MPNPs to glioma-bearing rats and magnetic targeting with a 0.5 T magnet, drug content increased for 6- to 14-fold in implanted glioma and 4.6- to 12.1-fold in the normal brain compared to free paclitaxel. The survival of glioma-bearing rats was significantly prolonged after magnetic targeting therapy with MPNPs. MPNPs efficiently delivered paclitaxel into brain glioma by magnetic targeting and enhance its antitumor activity. They are promising for local chemotherapy for malignant glioma.

  14. Influence of blood-brain barrier permeability on O-(2-{sup 18}F-fluoroethyl)-L-tyrosine uptake in rat gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Stegmayr, Carina; Bandelow, Ulrike; Oliveira, Dennis; Lohmann, Philipp; Willuweit, Antje; Galldiks, Norbert; Luebke, Joachim H.R. [Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich (Germany); Filss, Christian; Ermert, Johannes; Langen, Karl-Josef [Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich (Germany); RWTH/University Hospital Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Shah, N. Jon [Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich (Germany); RWTH/University Hospital Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Juelich-Aachen Research Alliance (JARA) - Section JARA-Brain, Aachen (Germany)

    2017-03-15

    O-(2-{sup 18}F-fluoroethyl)-L-tyrosine ({sup 18}F-FET) is an established tracer for the diagnosis of brain tumors with PET. This study investigates the influence of blood-brain barrier (BBB) permeability on {sup 18}F-FET uptake in two rat glioma models and one human xenograft model. F98 glioma, 9L gliosarcoma or human U87 glioblastoma cells were implanted into the striatum of 56 Fischer or RNU rats. Thereafter, animals were divided into a control group and a group receiving injections of the glucocorticoid dexamethasone (Dex). After 12-13 days of tumor growth animals received injection of Evans blue dye (EBD) to visualize BBB disturbance and underwent {sup 18}F-FET PET followed by autoradiography. Time activity curves, standardized uptake values (SUV) and Tumor-to-brain ratios (TBR) of {sup 18}F-FET uptake [18-61 min post injection (p.i.)] were evaluated using a volume-of-Interest (VOI) analysis. BBB disturbance was quantitatively evaluated by EBD fluorescence. The membrane gaps of blood vessel endothelial tight junctions were measured using electron microscopy to visualize ultrastructural BBB alterations in one untreated and one Dex treated F98 glioma. Data were analyzed by two-way ANOVAs. In Dex treated animals EBD extravasation was significantly reduced in 9L (P < 0.001) and U87 (P = 0.008) models and showed a trend in F98 models (P = 0.053). In contrast, no significant differences of {sup 18}F-FET uptake were observed between Dex treated animals and control group except a decrease of the TBR in the 9L tumor model in PET (P < 0.01). Ultrastructural evaluation of tumor blood vessel endothelia revealed significant reduction of the cleft diameter between endothelial cells after Dex treatment in F98 model (P = 0.010). Despite a considerable reduction of BBB permeability in rat gliomas after Dex treatment, no relevant changes of {sup 18}F-FET uptake were noted in this experimental study. Thus, {sup 18}F-FET uptake in gliomas appears to be widely independent of the

  15. In vivo micro-CT imaging of rat brain glioma: a comparison with 3T MRI and histology.

    Science.gov (United States)

    Engelhorn, Tobias; Eyupoglu, Ilker Y; Schwarz, Marc A; Karolczak, Marek; Bruenner, Holger; Struffert, Tobias; Kalender, Willi; Doerfler, Arnd

    2009-07-10

    The aim of this study was to evaluate the potential of a novel micro-CT system to image in vivo the extent of tumor in a rat model of malignant glioma compared to 3T magnetic resonance imaging (MRI) and histology. Fourteen animals underwent double dose contrast-enhanced imaging with micro-CT and 3T MRI using a clinical machine at day 10 after stereotactic F98 glioma cell implantation. Calculation of the volume of the contrast-uptaking part of the tumor was done by manually outlining the tumor contours by two experienced neuroradiologists. The micro-CT- and MRI-derived tumor volumes were compared to histology as gold standard (hematoxylin and eosin staining and fluorescence staining). There was high interobserver reability regarding the tumor volumes (Crombach's alpha>0.81). Also, there was good correlation of micro-CT- and high-field MRI-derived tumor volumes compared to histology: 72+/-21 mm3 and 69+/-23 mm3 compared to 81+/-14 mm3, respectively (r>0.76). Both the micro-CT- and MRI-derived tumor volumes were not significantly smaller compared to histology (P>0.14). In conclusion, micro-CT allows in vivo imaging of the contrast-enhancing part of experimental gliomas with an accuracy comparable to high-field MRI.

  16. Establishment of intramedullary spinal cord glioma model in rats

    Institute of Scientific and Technical Information of China (English)

    REN Tian-jian; WANG Zhong-cheng; ZHANG Ya-zhuo; LI Dan; WANG Hong-yun; LI Zhen-zong

    2010-01-01

    Background Treating intramedullary spinal cord gliomas is a big challenge because of limited options, high recurrence rate and poor prognosis. An intramedullary glioma model is prerequisite for testing new treatments. This paper describes the establishment of a rodent intramedullary glioma model and presents functional progression, neuroimaging and histopathological characterization of the tumour model.Methods Fischer344 rats (n=24) were randomized into two groups. Group 1 (n=16) received a 5 μl intramedullary implantation of 9L gliosarcomal (105) cells. Group 2 (n=8) received a 5 μl intramedullary injection of Dulbecco's modified Eagle medium. The rats were anesthetized, the spinous process of the T10 vertebra and the ligamentum flavum were removed to expose the T10-11 intervertebral space and an intramedullary injection was conducted into the spinal cord. The rats were evaluated preoperatively and daily postoperatively for neurological deficits using the Basso, Beattie and Bresnahan scale. High resolution magnetic resonance images were acquired preoperatively and weekly postoperatively.When score equal to 0, rats were sacrificed for histopathological examination.Results Rats implanted with 9L gliosarcoma cells had a statistically significant median onset of hind limb paraplegia at (16.0±0.4) days, compared with rats in the control group in which neurological deficits were absent. Imaging and pathological cross sections confirmed intramedullary 9L gliosarcoma invading the spinal cord. Rats in the control group showed no significant functional, radiological or histopathological findings of tumour.Conclusions Rats implanted with 9L cells regularly develop paraplegia in a reliable and reproducible manner. The progression of neurological deficits, neuroimaging and histopathological characteristics of intramedullary spinal cord gliomas in rats is comparable with the behaviour of infiltrative intramedullary spinal cord gliomas in patients.

  17. Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model

    Directory of Open Access Journals (Sweden)

    Huang FYJ

    2015-01-01

    Full Text Available Feng-Yun J Huang,1 Te-Wei Lee,2 Chih-Hsien Chang,2 Liang-Cheng Chen,2 Wei-Hsin Hsu,2 Chien-Wen Chang,1 Jem-Mau Lo1 1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; 2Institute of Nuclear Energy Research, Longtan, Taiwan Purpose: In this study, the 188Re-labeled PEGylated nanoliposome (188Re-liposome was prepared and evaluated as a therapeutic agent for glioma.Materials and methods: The reporter cell line, F98luc was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of 188Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered 188Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the 188Re-liposome-treated rats.Results: By using bioluminescent imaging, the well-established reporter cell line (F98luc showed a high relationship between cell number and its bioluminescent intensity (R2=0.99 in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of 188Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the 188Re-liposome-treated group than the control group (P<0.05. As a result, the

  18. Focused ultrasound enhanced molecular imaging and gene therapy for multifusion reporter gene in glioma-bearing rat model.

    Science.gov (United States)

    Yang, Feng-Yi; Chang, Wen-Yuan; Lin, Wei-Ting; Hwang, Jeng-Jong; Chien, Yi-Chun; Wang, Hsin-Ell; Tsai, Min-Lan

    2015-11-03

    The ability to monitor the responses of and inhibit the growth of brain tumors during gene therapy has been severely limited due to the blood-brain barrier (BBB). A previous study has demonstrated the feasibility of noninvasive in vivo imaging with 123I-2'-fluoro-2'-deoxy-5-iodo-1-β-D-arabinofuranosyluracil (123I-FIAU) for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) cancer gene expression in an experimental animal model. Here, we tested the enhancement of SPECT with 123I-FIAU and ganciclovir (GCV) treatment in brain tumors after BBB disruption induced by focused ultrasound (FUS) in the presence of microbubbles. We established an orthotopic F98 glioma-bearing rat model with trifusion reporter genes. The results of this study showed that the rat model of HSV1-tk-expressing glioma cells could be successfully detected by SPECT imaging after FUS-induced BBB disruption on day 10 after implantation. Compared to the control group, animals receiving the GCV with or without sonication exhibited a significant antitumor activity (P therapy in brain diseases.

  19. Monochromatic Minibeams Radiotherapy: From Healthy Tissue-Sparing Effect Studies Toward First Experimental Glioma Bearing Rats Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Deman, Pierre [INSERM, Grenoble (France); Universite Joseph Fourier, Institut des Neurosciences, Grenoble (France); European Synchrotron Radiation Facility, Grenoble (France); Vautrin, Mathias [INSERM, Grenoble (France); Universite Joseph Fourier, Institut des Neurosciences, Grenoble (France); European Synchrotron Radiation Facility, Grenoble (France); DOSIsoft, Cachan (France); Edouard, Magali [INSERM, Grenoble (France); Universite Joseph Fourier, Institut des Neurosciences, Grenoble (France); European Synchrotron Radiation Facility, Grenoble (France); Stupar, Vasile [INSERM, Grenoble (France); Universite Joseph Fourier, Institut des Neurosciences, Grenoble (France); Bobyk, Laure; Farion, Regine [INSERM, Grenoble (France); Universite Joseph Fourier, Institut des Neurosciences, Grenoble (France); European Synchrotron Radiation Facility, Grenoble (France); Elleaume, Helene [INSERM, Grenoble (France); Universite Joseph Fourier, Institut des Neurosciences, Grenoble (France); European Synchrotron Radiation Facility, Grenoble (France); Grenoble University Hospital, Grenoble (France); Remy, Chantal; Barbier, Emmanuel L. [INSERM, Grenoble (France); Universite Joseph Fourier, Institut des Neurosciences, Grenoble (France); Esteve, Francois [INSERM, Grenoble (France); Universite Joseph Fourier, Institut des Neurosciences, Grenoble (France); European Synchrotron Radiation Facility, Grenoble (France); Grenoble University Hospital, Grenoble (France); Adam, Jean-Francois, E-mail: adam@esrf.fr [INSERM, Grenoble (France); Universite Joseph Fourier, Institut des Neurosciences, Grenoble (France); European Synchrotron Radiation Facility, Grenoble (France); Grenoble University Hospital, Grenoble (France)

    2012-03-15

    Purpose: The purpose of this study was to evaluate high-dose single fraction delivered with monochromatic X-rays minibeams for the radiotherapy of primary brain tumors in rats. Methods and Materials: Two groups of healthy rats were irradiated with one anteroposterior minibeam incidence (four minibeams, 123 Gy prescribed dose at 1 cm depth in the brain) or two interleaved incidences (54 Gy prescribed dose in a 5 Multiplication-Sign 5 Multiplication-Sign 4.8 mm{sup 3} volume centered in the right hemisphere), respectively. Magnetic resonance imaging (MRI) follow-up was performed over 1 year. T2-weighted (T2w) images, apparent diffusion coefficient (ADC), and blood vessel permeability maps were acquired. F98 tumor bearing rats were also irradiated with interleaved minibeams to achieve a homogeneous dose of 54 Gy delivered to an 8 Multiplication-Sign 8 Multiplication-Sign 7.8 mm{sup 3} volume centered on the tumor. Anatomic and functional MRI follow-up was performed every 10 days after irradiation. T2w images, ADC, and perfusion maps were acquired. Results: All healthy rats were euthanized 1 year after irradiation without any clinical alteration visible by simple examination. T2w and ADC measurements remain stable for the single incidence irradiation group. Localized Gd-DOTA permeability, however, was observed 9 months after irradiation for the interleaved incidences group. The survival time of irradiated glioma bearing rats was significantly longer than that of untreated animals (49 {+-} 12.5 days versus 23.3 {+-} 2 days, p < 0.001). The tumoral cerebral blood flow and blood volume tend to decrease after irradiation. Conclusions: This study demonstrates the sparing effect of minibeams on healthy tissue. The increased life span achieved for irradiated glioma bearing rats was similar to the one obtained with other radiotherapy techniques. This experimental tumor therapy study shows the feasibility of using X-ray minibeams with high doses in brain tumor radiotherapy.

  20. Gliomas

    OpenAIRE

    Berger, M.; Weller, M.

    2016-01-01

    Key Features •Synthesizes widely dispersed information on the management of gliomas into one comprehensive resource •Chapters written by international authors who are preeminent researchers in the field •Fully explores the therapeutic options for patient care, from chemotherapy to radiotherapy to personalized approaches Description Researchers’ knowledge of gliomas continues to advance rapidly at both the basic and translational levels, and Gliomas provides a thorough overview ...

  1. Extracellular diffusion quantified by magnetic resonance imaging during rat C6 glioma cell progression

    Directory of Open Access Journals (Sweden)

    G. Song

    Full Text Available Solution reflux and edema hamper the convection-enhanced delivery of the standard treatment for glioma. Therefore, a real-time magnetic resonance imaging (MRI method was developed to monitor the dosing process, but a quantitative analysis of local diffusion and clearance parameters has not been assessed. The objective of this study was to compare diffusion into the extracellular space (ECS at different stages of rat C6 gliomas, and analyze the effects of the extracellular matrix (ECM on the diffusion process. At 10 and 20 days, after successful glioma modeling, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA was introduced into the ECS of rat C6 gliomas. Diffusion parameters and half-life of the reagent were then detected using MRI, and quantified according to the mathematical model of diffusion. The main ECM components [chondroitin sulfate proteoglycans (CSPGs, collagen IV, and tenascin C] were detected by immunohistochemical and immunoblot analyses. In 20-day gliomas, Gd-DTPA diffused more slowly and derived higher tortuosity, with lower clearance rate and longer half-life compared to 10-day gliomas. The increased glioma ECM was associated with different diffusion and clearance parameters in 20-day rat gliomas compared to 10-day gliomas. ECS parameters were altered with C6 glioma progression from increased ECM content. Our study might help better understand the glioma microenvironment and provide benefits for interstitial drug delivery to treat brain gliomas.

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

    Directory of Open Access Journals (Sweden)

    Meurer Luise

    2006-09-01

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

  3. Therapeutic vaccination against malignant gliomas based on allorecognition and syngeneic tumour antigens: proof of principle in two strains of rat

    NARCIS (Netherlands)

    Stathopoulos, A.; Samuelson, C.; Milbouw, G.; Hermanne, J.P.; Schijns, V.E.J.C.; Chen, T.C.

    2008-01-01

    In the present study we investigated whether allogeneic glioma cells can be utilized to evoke prophylactic or therapeutic immune-mediated elimination of syngeneic glioma in two rat strains. Fisher 344 and Sprague–Dawley (SD) rats were injected with two syngeneic glioma cell lines, 9L and C6, respect

  4. Boron neutron capture therapy of EGFR or EGFRvIII positive gliomas using either boronated monoclonal antibodies or epidermal growth factor as molecular targeting agents

    Energy Technology Data Exchange (ETDEWEB)

    Yang, W. [Department of Pathology, Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210 (United States); Barth, R.F. [Department of Pathology, Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210 (United States)], E-mail: rolf.barth@osumc.edu; Wu, G. [Department of Pathology, Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210 (United States); Tjarks, W. [College of Pharmacy, Ohio State University, Columbus, OH 43210 (United States); Binns, P.; Riley, K. [Nuclear Reactor Laboratory and Department of Nuclear Engineering, Massachusetts Institute of Technology, Cambridge, MA 02215 (United States)

    2009-07-15

    In the present report we have summarized studies carried out over the past five years on molecular targeting of the epidermal growth factor receptor (EGFR) and its mutant isoform, EFGRvIII, for BNCT of genetically engineered F98 rat gliomas, expressing either wildtype (F98{sub EGFR}) or mutant receptors (F98{sub npEGFRvIII}). EGF or the monoclonal antibodies (mAbs), cetuximab (IMC-C225) and L8A4, which recognize wildtype EGFR and EGFRvIII, respectively, were heavily boronated using polyamidoamine (PAMAM) dendrimers (BD) linked to the targeting vehicles by means of heterobifunctional reagents. Boronated EGF or mAbs, alone or in combination with i.v. boronophenylalanine (BPA), were administered intracerebrally (i.c.) by either intratumoral (i.t.) injection or convection enhanced delivery (CED) to rats bearing F98 gliomas following which BNCT was initiated. The best survival data were obtained in rats bearing F98{sub npEGFRvIII} gliomas that had received CED of BD-L8A4 either alone or in combination with i.v. boronophenylalanine (BPA). Studies carried out in rats bearing composite tumors (F98{sub EGFR}/F98{sub npEGFRvIII}) demonstrated that it was essential to target both tumor cell populations in order to obtain an optimal therapeutic effect. Based on these observations, we have concluded that EGFR targeting vehicles are useful, but not stand-alone boron delivery agents due to the heterogeneity of receptor expression in brain tumors. They could, however, be quite useful in combination with the two drugs that currently are being used clinically, BPA and sodium borocaptate (BSH) for BNCT of either brain tumors or head and neck cancers.

  5. The 9LLUC/Wistar rat glioma model is not suitable for immunotherapy

    Institute of Scientific and Technical Information of China (English)

    Liping Yang; Jingxiang Zhao; Guihong Zhou; Yunfang Wang; Lusi Li; Hongfeng Yuan; Xue Nan; Lidong Guan; Xuetao Pei

    2012-01-01

    The availability of a well-characterized animal brain tumor model will play an important role in identifying treatments for human brain tumors. Wistar rats bearing 9L glioma cells can develop solid, well-circumcised tumors, and may be a useful animal model for the evaluation of various therapeutic approaches for gliosarcomas. In this study, the 9L/Wistar rat glioma model was produced by intracerebral implantation of 9LLUC glioma cells syngenic to Fischer 344 (F344) rats. Bioluminescence imaging showed that tumors progressively grew from day 7 to day 21 in 9LLUC/F344 rats, and tumor regression was found in some 9LLUC/Wistar rats. Hematoxylin-eosin staining verified that intracranial tumors were gliomas. Immunohistochemistry results demonstrated that no CD4- and CD8-positive cells were found in the syngeneic 9LLUC/F344 model. However, many infiltrating CD4- and CD8-positive cells were observed within the tumors of the 9LLUC/Wistar model. Our data suggests that compared with 9L/F344 rats, 9L glioma Wistar rats may not be suitable for evaluating brain glioma immunotherapies, even though the model induced an immune response and exhibited tumor regression.

  6. Photochemical internalization for the treatment of malignant gliomas

    Science.gov (United States)

    Madsen, Steen J.; Kharkhuu, Khishigzaya; Berg, Kristian; Hirschberg, Henry

    2007-02-01

    Photochemical internalization (PCI) is a technique to improve the utilization of macromolecules (e.g. chemotherapeutic agents) in cancer therapy in a site-specific manner. The concept is based on the use of specially designed photosensitizers which localize preferentially in the membranes of endocytic vesicles. Upon exposure to light the photosensitizers induce the formation of reactive oxygen species such as singlet molecular oxygen. The photooxidation of the endocytic membranes leads to the release of the contents of the vesicles into the cytosol. In this way, macromolecules encapsulated by the vesicles will reach the cytosol and exert their biological activity instead of being degraded by lysosomal hydrolases. The utility of PCI for the treatment of malignant gliomas was investigated in vitro using an F98 rat glioma cell line. The cytotoxicity of 5-aminolevulinic acid (ALA) based PCI of bleomycin was compared to: (1) ALA-PDT, and (2) bleomycin. In all cases, monolayers were incubated in ALA, bleomycin, or ALA + bleomycin for 4 hours and were subsequently exposed to 635 nm light. Toxicity was evaluated using colony formation assays. F98 rat glioma cells in monolayer were found to be susceptible to the effects of both ALA-PDT and bleomycin. ALA-PDT was found to be particularly effective when light was delivered at a low irradiance of 5 mW cm -2. In this case, a radiant exposure of 20 J cm -2 resulted in only 4% survival. Bleomycin was found to be toxic at relatively low concentrations, incubation of F98 cells in 10 μg ml -1 for 4 hours resulted in 1% survival. The PCI effect was found to be negligible for the parameters investigated in the F98 cell line suggesting that: (1) the incubation time was sub-optimal and/or (2) ALA was inappropriate for this application.

  7. Reproducibility of O-(2-{sup 18}F-fluoroethyl)-L-tyrosine uptake kinetics in brain tumors and influence of corticoid therapy: an experimental study in rat gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Stegmayr, Carina; Schoeneck, Michael; Oliveira, Dennis; Willuweit, Antje [Institute of Neuroscience and Medicine, Research Center Juelich, Juelich (Germany); Filss, Christian; Coenen, Heinz H.; Langen, Karl-Josef [Institute of Neuroscience and Medicine, Research Center Juelich, Juelich (Germany); University of Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Galldiks, Norbert [Institute of Neuroscience and Medicine, Research Center Juelich, Juelich (Germany); University of Cologne, Department of Neurology, Cologne (Germany); Shah, N. Jon [Institute of Neuroscience and Medicine, Research Center Juelich, Juelich (Germany); University of Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Juelich-Aachen Research Alliance (JARA) - Section JARA-Brain, Juelich (Germany)

    2016-06-15

    Positron emission tomography (PET) using O-(2-{sup 18}F-fluoroethyl)-L-tyrosine ({sup 18}F-FET) is a well-established method for the diagnostics of brain tumors. This study investigates reproducibility of {sup 18}F-FET uptake kinetics in rat gliomas and the influence of the frequently used dexamethasone (Dex) therapy. F98 glioma or 9L gliosarcoma cells were implanted into the striatum of 31 Fischer rats. After 10-11 days of tumor growth, the animals underwent dynamic PET after injection of {sup 18}F-FET (baseline). Thereafter, animals were divided into a control group and a group receiving Dex injections, and all animals were reinvestigated 2 days later. Tumor-to-brain ratios (TBR) of {sup 18}F-FET uptake (18-61 min p.i.) and the slope of the time-activity-curves (TAC) (18-61 min p.i.) were evaluated using a Volume-of-Interest (VOI) analysis. Data were analyzed by two-way repeated measures ANOVA and reproducibility by the intraclass correlation coefficient (ICC). The slope of the tumor TACs showed high reproducibility with an ICC of 0.93. A systematic increase of the TBR in the repeated scans was noted (3.7 ± 2.8 %; p < 0.01), and appeared to be related to tumor growth as indicated by a significant correlation of TBR and tumor volume (r = 0.77; p < 0.0001). After correction for tumor growth TBR showed high longitudinal stability with an ICC of 0.84. Dex treatment induced a significant decrease of the TBR (-8.2 ± 6.1 %; p < 0.03), but did not influence the slope of the tumor TAC. TBR of {sup 18}F-FET uptake and tracer kinetics in brain tumors showed high longitudinal stability. Dex therapy may induce a minor decrease of the TBR; this needs further investigation. (orig.)

  8. β-diketone-cobalt complexes inhibit DNA synthesis and induce S-phase arrest in rat C6 glioma cells

    OpenAIRE

    ZHANG, KAIZHI; Zhao, Xingli; Liu, Junzhi; FANG, XIANGYANG; Wang, Xuepeng; Wang, Xiaohong; Li, Rui

    2013-01-01

    β-diketone-cobalt complexes, a family of newly synthesized non-platinum metal compounds, exhibit potential antitumor activity; however, the antitumor mechanism is unclear. The current study investigated the mechanism by which β-diketone-cobalt complexes inhibit rat C6 glioma cell proliferation. It was found that β-diketone-cobalt complexes suppress rat C6 glioma cell viability in a dose-dependent manner (3.125–100 μg/ml). In rat C6 glioma cells, the IC50 value of β-diketone-cobalt complexes w...

  9. Experimental Study on Treatment of Glioma by Embyonic Neural Stem Cell Transplnation in Rats

    Institute of Scientific and Technical Information of China (English)

    LUO Jie; ZHANG Li; TU Hanjun; HU Juntao; LI Xinjian; LI Dongsheng; LEI Ting

    2007-01-01

    The neural stem cells in Wistar rats were cultured in vitro, purified, and transplanted into C6 glioma model in order to observe their biological characters and provide a basic foundation for treatment of neurological diseases by neural stem cell transplantation. The cells at hippocampal area from gestation 15-day rats were cultured in vitro, and frozen and preserved in liquid nitrogen. C6 tu-mor-bearing models (n=25) and neural stem cells transplantation models (n=35) were established.When the tumor grew to 3 to 4 weeks,5 rats in each group were randomly selected for MRI examina-tion. At different intervals, the rats were perfused and sampled for HE staining, GFAP and BrdU im-munohistochemical staining. The results showed that after resuscitation of neural stem cells at 1-4 passages, the cell viability was 40%-63% with the difference being not significant. The cells could proliferate, passage, and most cells transplanted into glioma model survived. The mean survival time in neural stem cell transplantation group and control was 4.28 and 3.88 weeks respectively, and the average tumor size in the former was smaller than in the latter. It was concluded that embryonic neu- ral stem cells in rats could proliferate and differentiate, and after resuscitation the biological charac- teristic and viability of the cells were not influenced. Neural stem cells had inhibitory effects on the growth of glioma cells and could prolong the survival of rat model.

  10. Resistance to DNA Damaging Agents Produced Invasive Phenotype of Rat Glioma Cells-Characterization of a New in Vivo Model

    National Research Council Canada - National Science Library

    Stojković, Sonja; Podolski-Renić, Ana; Dinić, Jelena; Pavković, Željko; Ayuso, Jose M; Fernández, Luis J; Ochoa, Ignacio; Pérez-García, Victor M; Pešić, Vesna; Pešić, Milica

    2016-01-01

    .... Previously, we established RC6 rat glioma cell line resistant to DNA damaging agents including antiglioma approved therapies such as 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ...

  11. Apoptosis in glioma-bearing rats after neural stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    Hua Li; Zhenjun Chen; Shaopeng Zhou

    2013-01-01

    Abnormal activation of the Ras/Raf/Mek/Erk signaling cascade plays an important role in glioma. Inhibition of this aberrant activity could effectively hinder glioma cel proliferation and promote cell apoptosis. To investigate the mechanism of glioblastoma treatment by neural stem cel trans-plantation with respect to the Ras/Raf/Mek/Erk pathway, C6 glioma cel s were prepared in sus-pension and then infused into the rat brain to establish a glioblastoma model. Neural stem cells isolated from fetal rats were then injected into the brain of this glioblastoma model. Results showed that Raf-1, Erk and Bcl-2 protein expression significantly increased, while Caspase-3 protein expression decreased. After transplantation of neural stem cells, Raf-1, Erk and Bcl-2 protein expression significantly decreased, while Caspase-3 protein expression significantly in-creased. Our findings indicate that transplantation of neural stem cel s may promote apoptosis of glioma cells by inhibiting Ras/Raf/Mek/Erk signaling, and thus may represent a novel treatment approach for glioblastoma.

  12. ALA-PDT of glioma cell micro-clusters in BD-IX rat brain

    Science.gov (United States)

    Madsen, Steen J.; Angell-Petersen, Even; Spetalen, Signe; Carper, Stephen W.; Ziegler, Sarah A.; Hirschberg, Henry

    2006-02-01

    A significant contributory factor to the poor prognosis of patients with glioblastoma multiforme is the inability of conventional treatments to eradicate infiltrating glioma cells. A syngeneic rat brain tumor model is used to investigate the effects of aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) on small clusters of tumor cells sequestered in normal brain. The intrinsic sensitivity of rat glioma cells to PDT was investigated by exposing ALA-incubated cells to a range of radiant exposures and irradiances using 635 nm light. Biodistribution studies were undertaken on tumor-bearing animals in order to determine the tumor selectivity of the photosensitizer following systemic administration (i.p.) of ALA. Effects of ALA-PDT on normal brain and gross tumor were evaluated using histopathology. Effects of PDT on isolated glioma cells in normal brain were investigated by treating animals 48 h after tumor cell implantation: a time when the micro-clusters of cells are protected by an intact blood-brain-barrier (BBB). Rat glioma cells in monolayer are susceptible to ALA-PDT - lower irradiances are more effective than higher ones. Fluorescence microscopy of frozen tissue sections showed that photosensitizer is produced with better than 200:1 tumor-to-normal tissue selectivity following i.p. ALA administration. ALA-PDT resulted in significant damage to both gross tumor and normal brain, however, the treatment failed to prolong survival of animals with newly implanted glioma cells compared to non-treated controls if the drug was delivered either i.p. or directly into the brain. In contrast, animals inoculated with tumor cells pre-incubated in vitro with ALA showed a significant survival advantage in response to PDT.

  13. Resection of C6 gliomas in rats with the aid of the waterjet technique.

    Science.gov (United States)

    Keiner, Doerthe; Heimann, Axel; Kronfeld, Andrea; Sommer, Clemens; Mueller-Forell, Wibke; Kempski, Oliver; Oertel, Joachim

    2016-07-01

    While clinically the safety and efficacy of waterjet resection of brain tumors have been shown, evidence that waterjet dissection improves tumor resection radicality in comparison with conventional techniques is still missing. In the present study, resection radicality and tumor-free long-term survival of both techniques were evaluated in a C6-glioma model. Fifty-thousand C6-glioma cells were stereotactically transplanted in the left frontal lobe of 100 male Sprague-Dawley rats. After MRI-scanning for evaluation of tumor extension, microsurgical tumor resection was performed with conventional techniques (n=50) or with the waterjet dissector at pressures of 6bar (n=50). Twenty-five animals of each group were sacrificed after surgery for histological analysis. For analysis of survival after tumor resection, twenty-five animals of each group were followed-up to analyze tumor-free survival using the Kaplan Meier method. In the waterjet group, the resection cavity was free of C6-tumor cells in 10/25 (40%) rats showing a trend (p=0.3) towards better resection radicality compared to the rats that were treated conventionally (7/10; 28%). R1-resection with up to 250C6 cells/object slice was found in 14/25 (56%) rats after waterjet dissection compared to 6/25 (24%) rats treated conventionally showing significance (prats. In this experimental model, waterjet tumor resection did reveal significantly better resection radicality compared to the conventional technique. Although a direct transfer of these results to human glioma surgery is prohibited, the waterjet technique might contribute to the best possible resection radicality in human gliomas. Nevertheless, tumor cell spreading remains a major problem. Further studies have to address that the surgical results - in deed - improve the postoperative outcome. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Gamma knife treatment of rat glioma Influences of irradiation dose on apoptosis and necrosis

    Institute of Scientific and Technical Information of China (English)

    Peng Wang; Mianshun Pan; Xinggen Fang

    2008-01-01

    BACKGROUND: Apoptosis and necrosis are cellular death mechanisms that are induced in glioma cells following gamma knife irradiation. Increased apoptosis is essential for maintaining and enhancing treatment efficacy.OBJECTIVE: To observe apoptotic and necrotic mechanisms of rat glioma models induced by gamma knife treatment and to analyze the influences of irradiation doses on apoptosis and necrosis. DESIGN: Controlled animal experiment. SETTING: Cancer Hospital of Tianjin Medical University and Gamma Knife Center of Hefei Brain Hospital.MATERIALS: Eighteen female specific pathogen free Sprague Dawley rats, weighing 180-210 g and 5-6 weeks old, were purchased from the Experimental Animal Center, Medical College of Suzhou University. Rat C6 glioma cells were purchased from the cell bank of Chinese Academy of Sciences. Annexin V-FITC Reagent Kit (Bender Med System. Company, USA) and a flow cytometer (Becton Dickinson FACSCalibur) were provided.METHODS: The experiment was conducted at the Cancer Hospital of Tianjin Medical University and Gamma Knife Center of Hefei Brain Hospital from December 2006 to May 2007. All rats were inoculated with C6 glioma cells, i.e., 4 μL of a C6 glioma cell suspension was injected 5 mm deep in the cortex. All rats were divided randomly into a model group, 9-Gy treatment group, and 12-Gy treatment group. There were six rats in each group.MAIN OUTCOME MEASURES: Apoptosis and necrosis of normal brain tissue and glioma were observed by Flow Cytometry one week after irradiation, and pathological changes to tumor tissue were identified by HE staining.RESULTS: Eighteen rats were initially selected for the study: two rats from the model and 12-Gy treatment groups died from accidental anesthesia. The remaining 16 rats were included in the final result analysis. Cellular apoptosis and necrosis: apoptosis and necrosis were significantly increased in the treatment groups after gamma knife irradiation, compared to the model group (P < 0

  15. Establishment of 9L/F344 rat intracerebral glioma model of brain tumor stem cells

    Directory of Open Access Journals (Sweden)

    Zong-yu XIAO

    2015-04-01

    Full Text Available Objective To establish the 9L/F344 rat intracerebral glioma model of brain tumor stem cells.  Methods Rat 9L gliosarcoma stem-like cells were cultured in serum-free suspension. The expression of CD133 and nestin were tested by immunohistochemistry. A total of 48 inbredline male F344 rats were randomly divided into 2 groups, and 9L tumor sphere cells and 9L monolayer cells were respectively implanted into the right caudate nucleus of F344 rats in 2 groups. Survival time was observed and determined using the method of Kaplan-Meier survival analysis. Fourteen days after implantation or when the rats were dying, their brains were perfused and sectioned for HE staining, and CD133 and nestin were detected by immunohistochemistry.  Results Rat 9L tumor spheres were formed with suspension culture in serum-free medium. The gliomas formed in both groups were invasive without obvious capsule. More new vessels, bleeding and necrosis could be detected in 9L tumor spheres group. The tumor cells in both groups were positive for CD133 and nestin. There was no significant difference in the expression of CD133 and nestin between 2 groups (P > 0.05, for all. According to the expression of nestin, the tumors formed by 9L tumor sphere cells were more invasive. The median survival time of the rats bearing 9L tumor sphere cells was 15 d (95%CI: 15.219-15.781, and the median survival time of the rats bearing 9L monolayer cells was 21 d (95%CI: 20.395-21.605. There was significant difference between 2 groups (χ2 = 12.800, P = 0.000.  Conclusions 9L/F344 rat intracerebral glioma model of brain tumor stem cells is successfully established, which provides a glioma model for the future research. DOI: 10.3969/j.issn.1672-6731.2015.04.012

  16. Optic glioma

    Science.gov (United States)

    Glioma - optic; Optic nerve glioma; Juvenile pilocytic astrocytoma; Brain cancer - optic glioma ... Optic gliomas are rare. The cause of optic gliomas is unknown. Most optic gliomas are slow-growing ...

  17. Concurrent Chemotherapy of Malignant Glioma in Rats by Using Multidrug-Loaded Biodegradable Nanofibrous Membranes

    Science.gov (United States)

    Tseng, Yuan-Yun; Huang, Yin-Chen; Yang, Tao-Chieh; Yang, Shun-Tai; Liu, Shou-Cheng; Chang, Tzu-Min; Kau, Yi-Chuan; Liu, Shih-Jung

    2016-07-01

    Glioblastoma multiforme has a poor prognosis and is highly chemoresistant. In this study, we implanted biodegradable 1,3-bis[2-chloroethyl]-1-nitroso-urea-, irinotecan-, and cisplatin-eluting poly[(d,l)-lactide-co-glycolide] (BIC/PLGA) and virgin nanofibrous membranes on the brain surface of C6 glioma-bearing rats in concurrent and virgin groups, respectively. The concentrations of all applied drugs were significantly higher in the brain than in the blood for more than 8 weeks in all studied rats. Tumor growth was more rapid in the vehicle-treated group, and tumor volumes were significantly higher in the vehicle-treated group. Moreover, the average survival time was significantly shorter in the vehicle-treated group (P = 0.026), and the BIC/PLGA nanofibrous membranes significantly reduced the risk of mortality (P < 0.001). Furthermore, the results suggested that the BIC/PLGA nanofibers reduced the malignancy of C6 glioma. The experimental findings indicate that the multianticancer drug (i.e., BIC)-eluting PLGA nanofibers are favorable candidates for treating malignant glioma.

  18. 5-Aminolevulinic acid-mediated sonosensitization of rat RG2 glioma cells in vitro

    Directory of Open Access Journals (Sweden)

    Krzysztof Bilmin

    2016-10-01

    Full Text Available Sonodynamic therapy (SDT is a promising technique based on the ability of certain substances, called sonosensitizers, to sensitize cancer cells to non-thermal effects of low-energy ultrasound waves, allowing their destruction. Sonosensitization is thought to induce cell death by direct physical effects such as cavitation and acoustical streaming as well as by complementary chemical reactions generating oxygen free radicals. One of the promising sonosensitizers is 5-aminolevulinic acid (ALA which upon selective uptake by cancer cells is metabolized and accumulated as protoporphyrin IX. The objective of the study was to describe ALA-mediated sonodynamic effects in vitro on a rat RG2 glioma cell line. Glioma cells, seeded at the bottom of 96-well plates and incubated with ALA (10 µg/ml for 6 h, were exposed to the sinusoidal US pulses with a resonance frequency of 1 MHz, 1000 µs duration, 0.4 duty-cycle, and average acoustic power varying from 2 W to 6 W. Ultrasound waves were generated by a flat circular piezoelectric transducer with a diameter of 25 mm. Cell viability was determined by MTT assay. Structural cellular changes were visualized with a fluorescence microscope. Signs of cytotoxicity such as a decrease in cell viability, chromatin condensation and apoptosis were found. ALA-mediated SDT evokes cytotoxic effects of low intensity US on rat RG2 glioma cells in vitro . This cell line is indicated for further preclinical assessment of SDT in in vivo conditions.

  19. 5-Aminolevulinic acid-mediated sonosensitization of rat RG2 glioma cells in vitro.

    Science.gov (United States)

    Bilmin, K; Kujawska, T; Secomski, W; Nowicki, A; Grieb, P

    2016-01-01

    Sonodynamic therapy (SDT) is a promising technique based on the ability of certain substances, called sonosensitizers, to sensitize cancer cells to non-thermal effects of low-energy ultrasound waves, allowing their destruction. Sonosensitization is thought to induce cell death by direct physical effects such as cavitation and acoustical streaming as well as by complementary chemical reactions generating oxygen free radicals. One of the promising sonosensitizers is 5-aminolevulinic acid (ALA) which upon selective uptake by cancer cells is metabolized and accumulated as protoporphyrin IX. The objective of the study was to describe ALA-mediated sonodynamic effects in vitro on a rat RG2 glioma cell line. Glioma cells, seeded at the bottom of 96-well plates and incubated with ALA (10 µg/ml) for 6 h, were exposed to the sinusoidal US pulses with a resonance frequency of 1 MHz, 1000 µs duration, 0.4 duty-cycle, and average acoustic power varying from 2 W to 6 W. Ultrasound waves were generated by a flat circular piezoelectric transducer with a diameter of 25 mm. Cell viability was determined by MTT assay. Structural cellular changes were visualized with a fluorescence microscope. Signs of cytotoxicity such as a decrease in cell viability, chromatin condensation and apoptosis were found. ALA-mediated SDT evokes cytotoxic effects of low intensity US on rat RG2 glioma cells in vitro. This cell line is indicated for further preclinical assessment of SDT in in vivo conditions.

  20. Migratory, invasive and metastatic capacity of NCAM transfected rat glioma cells

    DEFF Research Database (Denmark)

    Edvardsen, K; Brünner, N; Spang-Thomsen, M

    1993-01-01

    A cDNA encoding a transmembrane 140 kDa isoform of the neural cell adhesion molecule, NCAM, was transfected into the rat glioma cell line BT4Cn. Transfectants with a homogeneously high expression of NCAM-B showed a decreased capacity for penetration of an artificial basement membrane when compared...... to cells transfected with expression-vector alone or untransfected cells. However, when injected subcutaneously into nude mice, both NCAM expressing cells and control cells produced invasive tumors. Nude mice injected with NCAM positive cells developed tumors with slower growth rates as compared to those...... induced by NCAM negative cells. This implies that NCAM may not only be involved in adhesive and motile behaviour of glioma cells, but also in their growth regulation....

  1. Endothelial progenitor cells (EPCs as gene carrier system for rat model of human glioma.

    Directory of Open Access Journals (Sweden)

    Nadimpalli Ravi S Varma

    Full Text Available BACKGROUND: Due to their unique property to migrate to pathological lesions, stem cells are used as a delivery vehicle for therapeutic genes to tumors, especially for glioma. It is critically important to track the movement, localization, engraftment efficiency and functional capability or expression of transgenes of selected cell populations following transplantation. The purposes of this study were to investigate whether 1 intravenously administered, genetically transformed cord blood derived EPCs can carry human sodium iodide symporter (hNIS to the sites of tumors in rat orthotopic model of human glioma and express transgene products, and 2 whether accumulation of these administered EPCs can be tracked by different in vivo imaging modalities. METHODS AND RESULTS: Collected EPCs were cultured and transduced to carry hNIS. Cellular viability, differential capacity and Tc-99m uptake were determined. Five to ten million EPCs were intravenously administered and Tc-99-SPECT images were acquired on day 8, to determine the accumulation of EPCs and expression of transgenes (increase activity of Tc-99m in the tumors. Immunohistochemistry was performed to determine endothelial cell markers and hNIS positive cells in the tumors. Transduced EPCs were also magnetically labeled and accumulation of cells was confirmed by MRI and histochemistry. SPECT analysis showed increased activity of Tc-99m in the tumors that received transduced EPCs, indicative of the expression of transgene (hNIS. Activity of Tc-99m in the tumors was also dependent on the number of administered transduced EPCs. MRI showed the accumulation of magnetically labeled EPCs. Immunohistochemical analysis showed iron and hNIS positive and, human CD31 and vWF positive cells in the tumors. CONCLUSION: EPC was able to carry and express hNIS in glioma following IV administration. SPECT detected migration of EPCs and expression of the hNIS gene. EPCs can be used as gene carrier/delivery system for

  2. p38MAPK gene transfection induced the apoptosis of rat glioma cells C6

    Institute of Scientific and Technical Information of China (English)

    ZHANG Bi-cheng; LI Qing; YE Jing; WANG Ying-mei; LIN Sheng-cai

    2001-01-01

    To study the effect ofp38MAPK transfecfion on the biological characteristics of rat glioma cells C6. Methods: p38MAPK was transfected into C6 cells by lipofectin. Expression ofp38MAPK in C6 cells before and after transfection was detected by immunocytochemistry and Western-blot analysis. HE staining,transmission electron microscopy and flow cytometry were used to observe the cell morphology, adhesion and study the cell cycle. Results: p38MAPK expressed in C6 cells after transfection. Cell biological characteristics changed,and apoptotic cells emerged. Conclusion: Exogenous p38MAPK could induce the apoptosis of C6 cells.

  3. Resistance to DNA Damaging Agents Produced Invasive Phenotype of Rat Glioma Cells—Characterization of a New in Vivo Model

    Directory of Open Access Journals (Sweden)

    Sonja Stojković

    2016-06-01

    Full Text Available Chemoresistance and invasion properties are severe limitations to efficient glioma therapy. Therefore, development of glioma in vivo models that more accurately resemble the situation observed in patients emerges. Previously, we established RC6 rat glioma cell line resistant to DNA damaging agents including antiglioma approved therapies such as 3-bis(2-chloroethyl-1-nitrosourea (BCNU and temozolomide (TMZ. Herein, we evaluated the invasiveness of RC6 cells in vitro and in a new orthotopic animal model. For comparison, we used C6 cells from which RC6 cells originated. Differences in cell growth properties were assessed by real-time cell analyzer. Cells’ invasive potential in vitro was studied in fluorescently labeled gelatin and by formation of multicellular spheroids in hydrogel. For animal studies, fluorescently labeled cells were inoculated into adult male Wistar rat brains. Consecutive coronal and sagittal brain sections were analyzed 10 and 25 days post-inoculation, while rats’ behavior was recorded during three days in the open field test starting from 25th day post-inoculation. We demonstrated that development of chemoresistance induced invasive phenotype of RC6 cells with significant behavioral impediments implying usefulness of orthotopic RC6 glioma allograft in preclinical studies for the examination of new approaches to counteract both chemoresistance and invasion of glioma cells.

  4. β-diketone-cobalt complexes inhibit DNA synthesis and induce S-phase arrest in rat C6 glioma cells.

    Science.gov (United States)

    Zhang, Kaizhi; Zhao, Xingli; Liu, Junzhi; Fang, Xiangyang; Wang, Xuepeng; Wang, Xiaohong; Li, Rui

    2014-03-01

    β-diketone-cobalt complexes, a family of newly synthesized non-platinum metal compounds, exhibit potential antitumor activity; however, the antitumor mechanism is unclear. The current study investigated the mechanism by which β-diketone-cobalt complexes inhibit rat C6 glioma cell proliferation. It was found that β-diketone-cobalt complexes suppress rat C6 glioma cell viability in a dose-dependent manner (3.125-100 μg/ml). In rat C6 glioma cells, the IC50 value of β-diketone-cobalt complexes was 24.7±3.395 μg/ml and the IC10 value was 4.37±1.53 μg/ml, indicating a strong inhibitory effect. Further investigation suggested that β-diketone-cobalt complexes inhibit rat C6 glioma cell proliferation, which is associated with S-phase arrest and DNA synthesis inhibition. During this process, β-diketone-cobalt complexes decreased cyclin A expression and increased cyclin E and p21 expression. In addition, β-diketone-cobalt complexes exhibit a stronger antitumor capability than the antineoplastic agent, 5-fluorouracil.

  5. The Effect of Gabapentin and Tramadol in Cancer Pain Induced by Glioma Cell in Rat Femur.

    Science.gov (United States)

    Corona-Ramos, Janette Nallely; Déciga-Campos, Myrna; Romero-Piña, Mario; Medina, Luis A; Martínez-Racine, Issac; Jaramillo-Morales, Osmar A; García-López, Patricia; López-Muñoz, Francisco Javier

    2017-08-01

    Preclinical Research The presence of pain as part of the cancer process is variable. Glioblastoma multiform (GBM) can produce bone metastasis, a condition that involves other pathological phenotypes including neuropathic and inflammatory pain. Tramadol and gabapentin are drugs used in the treatment of neuropathic pain. However, there are no studies evaluating their analgesic effects in bone metastasis. We produced a pain model induced by the inoculation of glioma cells (10(5) ) into the rat femur, by perforating the intercodiloid fossa. Painful behavior was evaluated by measuring mechanical allodynia using the Von Frey test while thermal hyperalgesia was assessed in the plantar test. Histopathological features were evaluated and antinociceptive responses were compared using tramadol and gabapentin. The inoculation of cells inside the right femur produced nociceptive behaviors. Tramadol and gabapentin produced an anti-allodynic effect in this condition, but tramadol did not produce an anti-hyperalgesic response. The development of this model will allow us to perform tests to elucidate the pathology of bone metastasis, cancer pain, and in particular the pain produced by glioma. Drug Dev Res 78 : 173-183, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. Combination Adenovirus-Mediated HSV-tk/GCV and Antisense IGF-1 Gene Therapy for Rat Glioma

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective To investigate the effects of combination adenovirus-mediated HSV-tk/GCV system and antisense IGF-1 gene therapy for rat glioma and analyze the mechanism.Methods Using the recombinant adenovirus vector,GCV killing effeciency after combined gene transfer of HSV-tk and antisense IGF-1 was observed in vitro.Rat glioma was treated with HSV-tk/GCV and antisense IGF-1 and the survival rate of rats was observed.Results C6 cells transfected with tk and antisense IGF-1 gene were more sensitive to GCV than that transfected with tk gene alone.The survival of the combination gene therapy group was prolonged significantly and large amounts of CD+4,CD+8 lymphocytes were detected in the tumor tissues.Conclusion Antisense IGF-1 gene may enhance the tumor-killing effects of HSV-tk/GCV.

  7. Radiation immunomodulatory gene tumor therapy of rats with intracerebral glioma tumors

    DEFF Research Database (Denmark)

    Persson, Bertil R R; Koch, Catrin Bauréus; Grafström, Gustav

    2010-01-01

    Single-fraction radiation therapy with 5 or 15 Gy (60)Co gamma radiation was combined with intraperitoneal injections of syngeneic interferon gamma (IFN-gamma)-transfected cells in rats with intracerebral N29 or N32 glioma tumors at days 7, 21 and 35 after inoculation. For intracerebral N29 tumors......, single-fraction radiation therapy with 5 or 15 Gy had no significant effect on the survival time. Immunization with IFN-gamma-transfected N29 cells significantly increased the survival time by 61%. Single-fraction radiation therapy with 5 Gy combined with immunization increased the survival time...... significantly by 87% and complete remissions by 75% while with 15 Gy the survival time increased 45% with 38% complete remissions. For intracerebral N32 tumors, single-fraction radiation therapy with 15 Gy increased the survival time significantly by 20%. Immunization by itself had no significant effect...

  8. Pc 4 photodynamic therapy of U87 (human glioma) orthotopic tumor in nude rat brain

    Science.gov (United States)

    Dean, David; George, John E., III; Ahmad, Yusra; Wolfe, Michael S.; Lilge, Lothar; Morris, Rachel L.; Peterson, Allyn; Lust, W. D.; Totonchi, Ali; Varghai, Davood; Li, Xiaolin; Hoppel, Charles L.; Sun, Jiayang; Oleinick, Nancy L.

    2005-04-01

    Introduction: Photodynamic therapy (PDT) for Barrett"s esophagus, advanced esophageal cancer, and both early and late inoperable lung carcinoma is now FDA-approved using the first generation photosensitizer PhotofrinTM (Axcan Pharma, Birmingham, AL). Photofrin-mediated PDT of glioma is now in Phase III clinical trials. A variety of second generation photosensitizers have been developed to provide improved: (1) specificity for the target tissue, (2) tumoricidal capability, and (3) rapid clearance the vascular compartment, skin, and eyes. The phthalocyanine Pc 4 is a second generation photosensitizer that is in early phase I clinical trials for skin cancer. We have undertaken a preclinical study that seeks to determine if Pc 4-mediated PDT can be of benefit for the intra-operative localization and treatment of glioma. Methods: Using a stereotactic frame, 250,000 U87 cells were injected via Hamilton syringe through a craniotomy, and the dura, 1-2 mm below the cortical surface of nude (athymic) rat brains (N=91). The craniotomy was filled with a piece of surgical PVC and the scalp closed. After two weeks of tumor growth, the animals received 0.5 mg/kg Pc 4 via tail vein injection. One day later the scalp was re-incised, and the PVC removed. The tumor was then illuminated with either 5 or 30 Joule/cm2 of 672-nm light from a diode laser at 50 mW/cm2. The animals were sacrificed one day later and the brain was cold-perfused with formaldehyde. Two thirds of the explanted brains are now being histologically surveyed for necrosis after staining with hematoxylin and eosin and for apoptosis via immunohistochemistry (i.e., TUNEL assay). The other third were analyzed by HPLC-mass spectrometry for the presence of drug in tumor, normal brain, and plasma at sacrifice. Initial histological results show PDT-induced apoptosis and necrosis confined to the growing (live) portion of the tumor. Preliminary analysis shows an average selectivity of Pc 4 uptake in the bulk tumor to be 3

  9. Impact of Focused Ultrasound-enhanced Drug Delivery on Survival in Rats with Glioma

    Science.gov (United States)

    Treat, Lisa Hsu; Zhang, Yongzhi; McDannold, Nathan; Hynynen, Kullervo

    2009-04-01

    Malignancies of the brain remain difficult to treat with chemotherapy because the selective permeability of the blood-brain barrier (BBB) blocks many potent agents from reaching their target. Previous studies have illustrated the feasibility of drug and antibody delivery across the BBB using MRI-guided focused ultrasound. In this study, we investigated the impact of focused ultrasound-enhanced delivery of doxorubicin on survival in rats with aggressive glioma. Sprague-Dawley rats were implanted with 9 L gliosarcoma cells in the brain. Eight days after implantation, each rat received one of the following: (1) no treatment (control), (2) a single treatment with microbubble-enhanced MRI-guided focused ultrasound (FUS only), (3) a single treatment with i.v. liposomal doxorubicin (DOX only), or (4) a single treatment with microbubble-enhanced MRI-guided focused ultrasound and concurrent i.v. injections of liposomal doxorubicin (FUS+DOX). The survival time from implantation to death or euthanasia was recorded. We observed a modest but significant increase in median survival time in rats treated with combined MRI-guided focused ultrasound chemotherapy, compared to chemotherapy alone (p0.10). Our study demonstrates for the first time a therapeutic benefit achieved with ultrasound-enhanced drug delivery across the blood-brain barrier. This confirmation of efficacy in an in vivo tumor model indicates that targeted drug delivery using MRI-guided focused ultrasound has the potential to have a major impact on the treatment of patients with brain tumors and other neurological disorders.

  10. Strong inhibition of replicative DNA synthesis in the developing rat cerebral cortex and glioma cells by roscovitine.

    Science.gov (United States)

    Yakisich, Juan Sebastian; Vita, Marina Fernanda; Siden, Ake; Tasat, Deborah Ruth; Cruz, Mabel

    2010-06-01

    The effects of the cyclin-dependent kinase inhibitors roscovitine and olomoucine on DNA synthesis rate during normal rat brain development were studied by using short time (90 min) incubation. Both purine analogues at 100 microM concentration decreased the DNA synthesis of rat cerebral cortex in an age-dependent manner. The maximum inhibitory effect (approximately 90% for roscovitine, approximately 60% for olomoucine) occurred in rats of 2-13 days postnatal age. In adult rats (> 60 days postnatal age), the effect of both purine analogues was low. Roscovitine even at 200 microM concentration did not inhibit the fraction of DNA synthesis insensitive to hydroxyurea (unscheduled DNA synthesis (UDS)). In addition, in the RG2 rat glioma model, roscovitine produced a strong inhibition of DNA synthesis in glioma cells when compared to adult normal tissue. Since in adult rat brain more than 60% of DNA synthesis is related to DNA repair, usually measured as UDS, our results indicate that roscovitine strongly blocks ongoing DNA synthesis connected with replicative processes.

  11. Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Tian; Wang, Chenlong; Chen, Xuewei; Duan, Chenfan; Zhang, Xiaoyan [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Zhang, Jing [Animal Experimental Center of Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Chen, Honglei [Department of Pathology and Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yue, Jiang [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Li, Ying, E-mail: lyying0@163.com [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China)

    2015-07-15

    Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50 mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1α expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. - Highlights: • Dopamine induces tumor growth inhibition and vascular normalization in rat C6 glioma. • Dopamine switches macrophage phenotype from M2 to M1. • Dopamine-induced vascular normalization is mediated by macrophage polarization. • Dopamine is a promising agent targeting the microvasculature in tumor

  12. Anticancer and antiangiogenic effects of methanol extracts of Lonicera caprifolium L. on C6 rat glioma cells

    Directory of Open Access Journals (Sweden)

    Nergiz Hacer Turgut

    2016-03-01

    Full Text Available Objective: Gliomas are brain tumors with high morbidity and mortality. For the treatment of gliomas, it is important to develop new and powerful treatments that could complement existing clinical treatment. Lonicera caprifolium L. (L. caprifolium has various uses in herbal traditional medicine. This study was conducted to determine the phenolic acid levels and DNA damage protection potential of L. caprifolium extract, and to explore the antitumor effect of the extract by investigating its toxicity on C6 rat glioma cell lines and normal L929 mouse fibroblast cell lines. We also aimed to investigate the antiangiogenic potential of the extract. Method: Phenolic acid content was determined by HPLC analysis. DNA damage protection potential was evaluated on pBR322 plasmid DNA. The effect of extracts on the proliferation of cancer cells was evaluated by XTT assay. Antiangiogenic effect was determined with Chorioallantoic membrane model. Results: The extract was found rich in vanillic acid (273.003 µg/g; while the amount of chlorogenic acid was almost at negligible level (0.028 µg/g. 0.005-0.05 mg / ml extract protected against the hazardous effects of UV and H2O2 in all DNA bands. The presence of the extract significantly reduced C6 cell proliferation compared to control (p<0.05. The extract had antiproliferative effect with a half maximum inhibition of concentration (IC50 value of 0.45 mg/ml. L. caprifolium extract in 10-6, 10-5 and 10-4 M concentrations caused antiangiogenic effect. Antiangiogenic scores of L. caprifolium were 0.6, 0.73 and 1.6, respectively. Conclusions: These results show that L. caprifolium has potential cytotoxic and antiangiogenic effect on C6 rat glioma cells and that the phenolic acid content of the plant may partially influence these activities.

  13. Cisplatin treatment of C6 rat glioma in vivo did not influence copy number alterations and growth pattern of tumor-derived resistant cells

    Directory of Open Access Journals (Sweden)

    Stepanenko A. A.

    2015-06-01

    Full Text Available Aim. To investigate whether the cisplatin treatment of C6 rat glioma in vivo impacts the copy number alterations (CNAs, proliferation and colony formation efficiency (CFE of tumor-derived cisplatin-resistant cells. Methods. The glioma modeling was performed by means of intracerebral stereotactic implantation of rat glioma C6 cells into the striatum region of rats. The rats received 20 % dimethyl sulfoxide DMSO (C6R1 or cisplatin (C6R4CIS and C6R5CIS injected intraperitoneally (5 mg/kg three times per week. After 10 injections, gliomas were resected and the cells were cultured for in vitro analysis. CNAs were analyzed by array comparative genome hybridization, proliferation by direct cell counting in hemocytometer, CFE by soft agar assay. Results. No significant changes in the CNAs and CFE of cisplatin-treated rat glioma C6R4CIS and C6R5CIS cell lines were observed compared to the vehicle-treated control C6R1 cells. However, C6R5CIS but not C6R4CIS had a reduced proliferation. Interestingly, both cisplatin- and vehicle-treated brain-grown cells had a reduced proliferation and CFE in comparison to the parental C6 cells. Conclusions. Despite numerous reports on the destabilizing effects of cisplatin on genome and phenotype, the cisplatin treatment of C6 cells in vivo did not affect genome stability, CFE, and had an inconsistent effect on the proliferation in vitro. The rat brain microenvironment may potentially impact the growth characteristics of rat glioma cells.

  14. Comparative effects on rat primary astrocytes and C6 rat glioma cells cultures after 24-h exposure to silver nanoparticles (AgNPs)

    Energy Technology Data Exchange (ETDEWEB)

    Salazar-García, Samuel; Silva-Ramírez, Ana Sonia; Ramirez-Lee, Manuel A.; Rosas-Hernandez, Hector [Universidad Autonoma de San Luis Potosi, Facultad de Ciencias Quimicas (Mexico); Rangel-López, Edgar [Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suárez, Laboratorio de Aminoacidos Excitadores (Mexico); Castillo, Claudia G. [Facultad de Medicina, Universidad Autonoma de San Luis Potosi (Mexico); Santamaría, Abel [Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suárez, Laboratorio de Aminoacidos Excitadores (Mexico); Martinez-Castañon, Gabriel A. [Universidad Autonoma de San Luis Potosi, Facultad de Estomatologia (Mexico); Gonzalez, Carmen, E-mail: cgonzalez.uaslp@gmail.com, E-mail: gonzalez.castillocarmen@fcq.uaslp.mx [Universidad Autonoma de San Luis Potosi, Facultad de Ciencias Quimicas (Mexico)

    2015-11-15

    The aim of this work was to compare the effects of 24-h exposure of rat primary astrocytes and C6 rat glioma cells to 7.8 nm AgNPs. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and current treatments lead to diverse side-effects; for this reason, it is imperative to investigate new approaches, including those alternatives provided by nanotechnology, like nanomaterials (NMs) such as silver nanoparticles. Herein, we found that C6 rat glioma cells, but no primary astrocytes, decreased cell viability after AgNPs treatment; however, both cell types diminished their proliferation. The decrease of glioma C6 cells proliferation was related with necrosis, while in primary astrocytes, the decreased proliferation was associated with the induction of apoptosis. The ionic control (AgNO{sub 3}) exerted a different profile than AgNPs; the bulk form did not modify the basal effect in each determination, whereas cisplatin, a well-known antitumoral drug used as a comparative control, promoted cytotoxicity in both cell types at specific concentrations. Our findings prompt the need to determine the fine molecular and cellular mechanisms involved in the differential biological responses to AgNPs in order to develop new tools or alternatives based on nanotechnology that may contribute to the understanding, impact and use of NMs in specific targets, like glioblastoma cells.

  15. Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Yukinari, E-mail: yukinari-k@bea.hi-ho.ne.j [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Oncology Research Center, Advanced Molecular Epidemiology Research Institute, Yamagata University Faculty of Medicine, Yamagata 990-9585 (Japan); Vaidyanathan, Ganesan [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States); Kaneko, Mika Kato [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Oncology Research Center, Advanced Molecular Epidemiology Research Institute, Yamagata University Faculty of Medicine, Yamagata 990-9585 (Japan); Mishima, Kazuhiko [Saitama Medical University International Medical Center 1397-1 Yamane Hidaka-shi, Saitama 350-1298 (Japan); Srivastava, Nidhi; Chandramohan, Vidyalakshmi; Pegram, Charles [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Keir, Stephen T. [Department of Surgery, Duke University Medical Center, Durham, NC 27710 (United States); Kuan, C.-T.; Bigner, Darell D. [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Zalutsky, Michael R. [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States)

    2010-10-15

    Introduction: Podoplanin/aggrus is a mucin-like sialoglycoprotein that is highly expressed in malignant gliomas. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. The purpose of this study was to determine whether an anti-podoplanin antibody is suitable to target radionuclides to malignant gliomas. Methods: The binding affinity of an anti-podoplanin antibody, NZ-1 (rat IgG{sub 2a}), was determined by surface plasmon resonance and Scatchard analysis. NZ-1 was radioiodinated with {sup 125}I using Iodogen [{sup 125}I-NZ-1(Iodogen)] or N-succinimidyl 4-guanidinomethyl 3-[{sup 131}I]iodobenzoate ([{sup 131}I]SGMIB-NZ-1), and paired-label internalization assays of NZ-1 were performed. The tissue distribution of {sup 125}I-NZ-1(Iodogen) and that of [{sup 131}I]SGMIB-NZ-1 were then compared in athymic mice bearing glioblastoma xenografts. Results: The dissociation constant (K{sub D}) of NZ-1 was determined to be 1.2x10{sup -10} M by surface plasmon resonance and 9.8x10{sup -10} M for D397MG glioblastoma cells by Scatchard analysis. Paired-label internalization assays in LN319 glioblastoma cells indicated that [{sup 131}I]SGMIB-NZ-1 resulted in higher intracellular retention of radioactivity (26.3{+-}0.8% of initially bound radioactivity at 8 h) compared to that from the {sup 125}I-NZ-1(Iodogen) (10.0{+-}0.1% of initially bound radioactivity at 8 h). Likewise, tumor uptake of [{sup 131}I]SGMIB-NZ-1 (39.9{+-}8.8 %ID/g at 24 h) in athymic mice bearing D2159MG xenografts in vivo was significantly higher than that of {sup 125}I-NZ-1(Iodogen) (29.7{+-}6.1 %ID/g at 24 h). Conclusions: The overall results suggest that an anti-podoplanin antibody NZ-1 warrants further evaluation for antibody-based therapy against glioblastoma.

  16. Underlying mechanism of ASIC1a involved in acidosis-induced cytotoxicity in rat C6 glioma cells

    Institute of Scientific and Technical Information of China (English)

    Xie-chuan WENG; Jian-quan ZHENG; Jin LI; Wen-bin XIAO

    2007-01-01

    Aim:To investigate the underlying mechanism of acid-sensing ion channel (ASIC) la involved in the acidosis-induced cytotoxicity of rat C6 glioma cells. Methods:The stable ASICla-silenced C6 cells built with the RNA interference technology were confirmed by RT-PCR and Western blot analysis. Intracellular calcium ([Ca2+]i) in both the wild-type rat C6 glioma cells and the ASIC I a-silenced C6 cells were analyzed before and after acid application/exposure with the calcium imaging experiment. Results:The rapid extracellular pH drop induced the increase of [Ca2+]i in the wild-type C6 cells,but not in the ASICla-silenced C6 cells. During the prolonged acid exposure,[Ca2+]i was lower in the ASICla-silenced C6 cells than that in the control cells. Conclusion:The resultant toxicity of [Ca2+]i might contribute to the acidosis-induced cytotoxicity.

  17. Combination hyperbaric oxygen and temozolomide therapy in c6 rat glioma model Terapia combinada de oxigênio hiperbárico e temozomida no modelo C6 de glioma em ratos

    Directory of Open Access Journals (Sweden)

    Yaşar Dagıstan

    2012-06-01

    Full Text Available PURPOSE: Temozolomide (TMZ has anti-tumor activity in patients with malignant glioma. Hyperbaric oxygen (HBO may enhance the efficacy of certain therapies that are limited because of the hypoxic tumor microenvironment. We examined the combined effects of TMZ-HBO in a rat glioma model. METHODS: After stereotactic injection of C6/LacZ rat glioma cells into the Wistar rats brain, the rats were randomly assigned to three treatment groups [group 1, control treatment; group 2, TMZ alone; group 3, a combination of TMZ and HBO]. Rats were sacrificed 18 days after treatment, and number of intra-/peri-tumoral vessels, microendothelial proliferations, immunohistochemistry and necrotic area were evaluated. RESULTS: Tumoral tissue was stained only sparsely with GFAP. Temozolomide treatment was significantly decreased in tumor tissue intratumoral vessel number / total tumor area level. The level of Ki67 was significantly decreased in the tumor tissue of the group 3. Additionally, the total necrotic area / total tumor volume (% was decreased significantly in tumor tissue of the group 3 rats compared to group1 and 2. CONCLUSION: The combination of hyperbaric oxygen with temozolomide produced an important reduction in glioma growth and effective approach to the treatment of glioblastoma.OBJETIVO: A temozolomida (TMZ tem atividade anti-tumoral em pacientes com glioma maligno. Oxigênio hiperbárico (HBO pode aumentar a eficácia de terapias que são limitadas devido a um microambiente do tumor hipóxico. Foram examinados os efeitos combinados de TMZ-HBO em um modelo de glioma em rato. MÉTODOS: Após a injeção estereotáxica de células de glioma de rato C6/LacZ no cérebro de ratos Wistar, os ratos foram distribuídos aleatoriamente em três grupos de tratamento: Grupo 1: tratamento de controle. Grupo 2: TMZ sozinho. Grupo 3: uma combinação de TMZ e HBO. Os ratos foram sacrificados 18 dias após o tratamento. Foram avaliados o número de vasos intra

  18. Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1-13C]pyruvate and 13C magnetic resonance spectroscopic imaging

    OpenAIRE

    Day, Sam E.; Kettunen, Mikko I.; Cherkuri, Murali Krishna; James B Mitchell; Lizak, Martin J.; Morris, H. Douglas; Koretsky, Alan P.; Brindle, Kevin M.

    2010-01-01

    13C chemical shift images acquired following intravenous injection of hyperpolarized [1-13C]pyruvate into rats with implanted C6 gliomas showed significant labeling of lactate within the tumors but not in surrounding brain tissue. Signal from pyruvate was observed in blood vessels above the brain and from other major vessels elsewhere in the rat head. Pyruvate was largely undetectable within the tumor or surrounding normal brain tissue. The ratio of hyperpolarized 13C label in the injected py...

  19. Multiple Gliomas

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Multiple gliomas are well-recognized but uncommon tumors. The incidence of multiple gliomas according to some reports ranges from 0.5% to 20% of all gliomas diagnosed. Multiple gliomas can be divided into two categories. One is by location of the lesions (multifocal and multicentric). The second type is by the time of the lesions occur (synchronous and metachronous). The lesions generally show hypo, or isodensity on CT; a hypo- or isointense signal on T1-weighted images, and a hyperintense signal on T2-weighted images. Glioblastoma is the most frequent histotype. The prognosis of multiple gliomas remains unfavorable. The treatment of multiple gliomas includes surgery, radiotherapy and chemotherapy. Distinction between multicentric and multifocal gliomas is difficult. This report reviews in detail the aspects of multiple gliomas mentioned above.

  20. Paramagnetic Gd2O3 Nanoparticle-Based Targeting Theranostic Agent for C6 Rat Glioma Cell

    Directory of Open Access Journals (Sweden)

    Seong-Pyo Hong

    2016-01-01

    Full Text Available This study aimed to synthesize theranostic agent targeting C6 rat glioma cell, which was based on the dextran coated paramagnetic gadolinium oxide nanoparticles (D-PGONs conjugated with folic acid (FA or paclitaxel (PTX. The D-PGONs were synthesized by the in situ coprecipitation method, and the average value of the size distribution was 2.9 nm. FTIR spectroscopy was fulfilled to confirm the conjugations of FA or PTX with D-PGONs. The bioprotective effects of dextran coating and chemotherapeutic effect of PTX in the C6 glioma cell were evaluated by the MTT assay. The differences in uptakes between the synthesized theranostic agents into C6 cells were observed by confocal laser scanning microscopy. In addition, the magnetic contrast enhancement with different concentration of the synthesized agent was compared by the T1-weighted MRI imaging. It was experimentally shown that the synthesized theranostic agent targets C6 cells due to the ligand-receptor-mediated endocytosis and provides enhancement in MR contrast depending on the concentration due to the paramagnetic property of gadolinium nanoparticle. In addition, it was shown by the results of MTT assay that the synthesized nanocomposites were more effective in reducing cell viability than bare gadolinium nanoparticles. In conclusion, it was shown that FA and PTX conjugated D-PGONs could be used as the theranostic agent with paramagnetism and chemotherapeutic property.

  1. CT perfusion imaging as an early biomarker of differential response to stereotactic radiosurgery in C6 rat gliomas.

    Directory of Open Access Journals (Sweden)

    Timothy Pok Chi Yeung

    Full Text Available BACKGROUND: The therapeutic efficacy of stereotactic radiosurgery for glioblastoma is not well understood, and there needs to be an effective biomarker to identify patients who might benefit from this treatment. This study investigated the efficacy of computed tomography (CT perfusion imaging as an early imaging biomarker of response to stereotactic radiosurgery in a malignant rat glioma model. METHODS: Rats with orthotopic C6 glioma tumors received either mock irradiation (controls, N = 8 or stereotactic radiosurgery (N = 25, 12 Gy in one fraction delivered by Helical Tomotherapy. Twelve irradiated animals were sacrificed four days after stereotactic radiosurgery to assess acute CT perfusion and histological changes, and 13 irradiated animals were used to study survival. Irradiated animals with survival >15 days were designated as responders while those with survival ≤15 days were non-responders. Longitudinal CT perfusion imaging was performed at baseline and regularly for eight weeks post-baseline. RESULTS: Early signs of radiation-induced injury were observed on histology. There was an overall survival benefit following stereotactic radiosurgery when compared to the controls (log-rank P<0.04. Responders to stereotactic radiosurgery showed lower relative blood volume (rBV, and permeability-surface area (PS product on day 7 post-stereotactic radiosurgery when compared to controls and non-responders (P<0.05. rBV and PS on day 7 showed correlations with overall survival (P<0.05, and were predictive of survival with 92% accuracy. CONCLUSIONS: Response to stereotactic radiosurgery was heterogeneous, and early selection of responders and non-responders was possible using CT perfusion imaging. Validation of CT perfusion indices for response assessment is necessary before clinical implementation.

  2. Enhanced cell growth and tumorigenicity of rat glioma cells by stable expression of human CD133 through multiple molecular actions.

    Science.gov (United States)

    Fang, Kuan-Min; Lin, Tzu-Chien; Chan, Ti-Chun; Ma, Shi-Zhang; Tzou, Bo-Cheng; Chang, Wen-Ruei; Liu, Jun-Jen; Chiou, Shih-Hwa; Yang, Chung-Shi; Tzeng, Shun-Fen

    2013-09-01

    CD133 (Prominin-1/AC133) is generally treated as a cell surface marker found on multipotent stem cells and tumor stem-like cells, and its biological function remains debated. Genetically modified rat glioma cell lines were generated by lentiviral gene delivery of human CD133 into rat C6 glioma cells (hCD133(+) -C6) or by infection of C6 cells with control lentivirus (mock-C6). Stable hCD133 expression promoted the self-renewal ability of C6-formed spheres with an increase in the expression of the stemness markers, Bmi-1 and SOX2. Akt phosphorylation, Notch-1 activation, and Notch-1 target gene expression (Hes-1, Hey1 and Hey2) were increased in hCD133(+) -C6 when compared to mock-C6. The inhibition of Akt phosphorylation, Notch-1 activation, and Hes-1 in hCD133(+) -C6 cells effectively suppressed their clonogenic ability, indicating that these factors are involved in expanding the growth of hCD133(+) -C6. An elevated expression of GTPase-activating protein 27 (Arhgap27) was detected in hCD133(+) -C6. A decline in the invasion of hCD133(+) -C6 by knockdown of Arhgap27 expression indicated the critical role of Arhgap27 in promoting cell migration of hCD133(+) -C6. In vivo study further showed that hCD133(+) -C6 formed aggressive tumors in vivo compared to mock-C6. Exposure of hCD133(+) -C6 to arsenic trioxide not only reduced Akt phosphorylation, Notch-1 activation and Hes-1 expression in vitro, but also inhibited their tumorigenicity in vivo. The results show that C6 glioma cells with stable hCD133 expression enhanced their stemness properties with increased Notch-1/Hes-1 signaling, Akt activation, and Arhgap27 action, which contribute to increased cell proliferation and migration of hCD133(+) -C6 in vitro, as well as progressive tumor formation in vivo.

  3. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer.

    Science.gov (United States)

    Connolly, Nina P; Stokum, Jesse A; Schneider, Craig S; Ozawa, Tatsuya; Xu, Su; Galisteo, Rebeca; Castellani, Rudolph J; Kim, Anthony J; Simard, J Marc; Winkles, Jeffrey A; Holland, Eric C; Woodworth, Graeme F

    2017-01-01

    Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor

  4. Quantitative correlational study of microbubble-enhanced ultrasound imaging and magnetic resonance imaging of glioma and early response to radiotherapy in a rat model

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Chen [Department of Ultrasound, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022 (China); Lee, Dong-Hoon; Zhang, Kai; Li, Wenxiao; Zhou, Jinyuan [Division of MR Research, Department of Radiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287 (United States); Mangraviti, Antonella; Tyler, Betty [Department of Neurosurgery, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287 (United States); Su, Lin; Zhang, Yin; Zhang, Bin; Wong, John; Wang, Ken Kang-Hsin; Velarde, Esteban; Ding, Kai, E-mail: kding1@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21231 (United States)

    2015-08-15

    Purpose: Radiotherapy remains a major treatment method for malignant tumors. Magnetic resonance imaging (MRI) is the standard modality for assessing glioma treatment response in the clinic. Compared to MRI, ultrasound imaging is low-cost and portable and can be used during intraoperative procedures. The purpose of this study was to quantitatively compare contrast-enhanced ultrasound (CEUS) imaging and MRI of irradiated gliomas in rats and to determine which quantitative ultrasound imaging parameters can be used for the assessment of early response to radiation in glioma. Methods: Thirteen nude rats with U87 glioma were used. A small thinned skull window preparation was performed to facilitate ultrasound imaging and mimic intraoperative procedures. Both CEUS and MRI with structural, functional, and molecular imaging parameters were performed at preradiation and at 1 day and 4 days postradiation. Statistical analysis was performed to determine the correlations between MRI and CEUS parameters and the changes between pre- and postradiation imaging. Results: Area under the curve (AUC) in CEUS showed significant difference between preradiation and 4 days postradiation, along with four MRI parameters, T{sub 2}, apparent diffusion coefficient, cerebral blood flow, and amide proton transfer-weighted (APTw) (all p < 0.05). The APTw signal was correlated with three CEUS parameters, rise time (r = − 0.527, p < 0.05), time to peak (r = − 0.501, p < 0.05), and perfusion index (r = 458, p < 0.05). Cerebral blood flow was correlated with rise time (r = − 0.589, p < 0.01) and time to peak (r = − 0.543, p < 0.05). Conclusions: MRI can be used for the assessment of radiotherapy treatment response and CEUS with AUC as a new technique and can also be one of the assessment methods for early response to radiation in glioma.

  5. Quantitative correlational study of microbubble-enhanced ultrasound imaging and magnetic resonance imaging of glioma and early response to radiotherapy in a rat model.

    Science.gov (United States)

    Yang, Chen; Lee, Dong-Hoon; Mangraviti, Antonella; Su, Lin; Zhang, Kai; Zhang, Yin; Zhang, Bin; Li, Wenxiao; Tyler, Betty; Wong, John; Wang, Ken Kang-Hsin; Velarde, Esteban; Zhou, Jinyuan; Ding, Kai

    2015-08-01

    Radiotherapy remains a major treatment method for malignant tumors. Magnetic resonance imaging (MRI) is the standard modality for assessing glioma treatment response in the clinic. Compared to MRI, ultrasound imaging is low-cost and portable and can be used during intraoperative procedures. The purpose of this study was to quantitatively compare contrast-enhanced ultrasound (CEUS) imaging and MRI of irradiated gliomas in rats and to determine which quantitative ultrasound imaging parameters can be used for the assessment of early response to radiation in glioma. Thirteen nude rats with U87 glioma were used. A small thinned skull window preparation was performed to facilitate ultrasound imaging and mimic intraoperative procedures. Both CEUS and MRI with structural, functional, and molecular imaging parameters were performed at preradiation and at 1 day and 4 days postradiation. Statistical analysis was performed to determine the correlations between MRI and CEUS parameters and the changes between pre- and postradiation imaging. Area under the curve (AUC) in CEUS showed significant difference between preradiation and 4 days postradiation, along with four MRI parameters, T2, apparent diffusion coefficient, cerebral blood flow, and amide proton transfer-weighted (APTw) (all p correlated with three CEUS parameters, rise time (r = - 0.527, p correlated with rise time (r = - 0.589, p < 0.01) and time to peak (r = - 0.543, p < 0.05). MRI can be used for the assessment of radiotherapy treatment response and CEUS with AUC as a new technique and can also be one of the assessment methods for early response to radiation in glioma.

  6. Antitumor effect of intra-arterial tumor necrosis factor-{alpha} in rats with transplanted intracerebral glioma and its evaluation by MRI

    Energy Technology Data Exchange (ETDEWEB)

    Harada, Kunyu; Yoshida, Jun; Wakabayashi, Toshihiko; Sugita, Kenichiro [Nagoya Univ. (Japan). School of Medicine; Kurisu, Kaoru; Uozumi, Tohru; Zieroth, B.F.; Takahashi, Masaya; Yamanaka, Tsuyoshi

    1995-12-01

    Recombinant human TNF-{alpha} was administrated intra-arterially to rats with transplanted intracerebral glioma. 1 x 10{sup 6} of T9 rat glioma cells were transplanted into Fisher 344 rat brain stereotaxically and 1000 units of TNF-{alpha} was administrated at a rate of 100{mu}l/min via an internal carotid artery 1 or 3 weeks after the transplantation. The effects of TNF-{alpha} were evaluated by MRI and histopathological examinations. Neurological symptoms, i.e. hemiparesis, appeared after 9.0{+-}0.63 days and all rats died of tumor overloading 14.5{+-}0.84 days after the transplantation. Single injection of TNF-{alpha} on 7th day after the transplantation induced regression of the tumor size in one of six rats. The tumors were detected 3 days after transplantation by MRI and they were revealed as low/iso intensity mass in T1WI, iso/high intensity in T2WI, and were enhanced by Gd-DTPA heterogenously. On 7/14 days after the transplantation, the tumor grew approximately 7/10 mm in diameter. The single 1000 units of TNF-{alpha} were administrated via an internal carotid artery. Three days after the administration or TNF-{alpha}, regression of the tumor size was seen in one of six rats and decrease of peritumoral edema was seen in three. These effects of TNF-{alpha} were, however, transient and they were not demonstrated on day 7. Single injection of TNF-{alpha} was not effective for large tumors more than 10 mm in diameter seen 14 days after the transplantation. These data suggest that intra-arterial TNF-{alpha} should be administrated at an early stage of the tumor growth and several injections are needed to cause regression in the size of the gliomas. (author).

  7. Angiopep-2-conjugated poly(ethylene glycol)-co- poly(ε-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats

    Science.gov (United States)

    Lu, Fei; Pang, Zhiyong; Zhao, Jingjing; Jin, Kai; Li, Haichun; Pang, Qiang; Zhang, Long; Pang, Zhiqing

    2017-01-01

    The blood–brain barrier is a formidable obstacle for glioma chemotherapy due to its compact structure and drug efflux ability. In this study, a dual-targeting drug delivery system involving Angiopep-2-conjugated biodegradable polymersomes loaded with doxorubicin (Ang-PS-DOX) was developed to exploit transport by the low-density lipoprotein receptor-related protein 1 (LRP1), which is overexpressed in both blood–brain barrier and glioma cells. The polymersomes (PS) were prepared using a thin-film hydration method. The PS were loaded with doxorubicin using the pH gradient method (Ang-PS-DOX). The resulting PS were uniformly spherical, with diameters of ~135 nm and with ~159.9 Angiopep-2 molecules on the surface of each PS. The drug-loading capacity and the encapsulation efficiency for doxorubicin were 7.94%±0.17% and 95.0%±1.6%, respectively. Permeability tests demonstrated that the proton diffusion coefficient across the PS membrane was far slower than that across the liposome membrane, and the common logarithm value was linearly dependent on the dioxane content in the external phase. Compared with PS-DOX, Ang-PS-DOX demonstrated significantly higher cellular uptake and stronger cytotoxicity in C6 cells. In vivo pharmacokinetics and brain distribution experiments revealed that Ang-PS-DOX achieved a more extensive distribution and more abundant accumulation in glioma cells than PS-DOX. Moreover, the survival time of glioma-bearing rats treated with Ang-PS-DOX was significantly prolonged compared with those treated with PS-DOX or a solution of free doxorubicin. These results suggested that Ang-PS-DOX can target glioma cells and enhance chemotherapeutic efficacy. PMID:28356732

  8. Heat shock induction of a 65 kDa ATP—binding proteinase in rat C6 glioma cells

    Institute of Scientific and Technical Information of China (English)

    XUCUNSHUAN; MARCOMEYER; 等

    1999-01-01

    The 45,55,65 and 100kDa ATP-binding proteinases(ATP-BPases) of the heat-shocked (44℃ for 30 min,recovery for 12h) rat C6 glioma cells were purified by DEAE-ionexchange and ATP-affinity chromatography.Their molecular masses,isoelectric points (pI),pH-optima and other properties were analyzed by native proteinase gels.It was shown that the 65 kDa ATP-BPase is specifically induced by heat shock and not detectable in control cells.Its N-terminal 1-9amino acid sequence was determined by Edman degradation,but no homologies to other proteins in the protein data bases were found.30 and 31kDa proteinases can be cleaved from the 45,55 and 65 kDa proteinases to which they are linked.A possible relationship of the heat-induced 65 kDa ATP-BPase with the ATP-dependent proteinases (ATP-DPases) in prokaryotes and eukaryotes is discussed.

  9. Effect of combined treatment with x-irradiation and 5-fluorouracil in multicellular spheroids of rat glioma

    Energy Technology Data Exchange (ETDEWEB)

    Kuwahara, Kenji; Katakura, Ryuichi; Suzuki, Jiro; Sasaki, Takehito; Mori, Teruaki

    1987-12-01

    The effect of combined treatment with X-irradiation and 5-fluorouracil (5-Fu) on the spheroids of rat glioma clone-6 cells was compared with that on exponentially grown monolayer cells. Isobolographic analysis showed the effect of the combined treatment to be supra-additive in both multicellular spheroids and monolayer cells when irradiation followed 24 hours of treatment with 5-Fu. X-irradiation prior to 5-Fu treatment showed an additive effect. The effect of X-irradiation on spheroids was enhanced after 3 hours of 5-Fu treatment, whereas its effect on monolayer cells was augmented only when prior 5-Fu treatment exceeded 12 hours. Potentiation of the effect of X-irradiation on spheroids by prior treatment with 5-Fu is thought to be due to reoxygenation of previously hypoxic cells and partial synchronization of proliferating cells. These results suggest that when X-irradiation is applied shortly after 5-Fu treatment the effect on solid tumors is selectively enhanced, while the effect on actively proliferating normal tissues is reduced.

  10. Effects of quercetin and quercetin-3-O-glycosides on oxidative damage in rat C6 glioma cells.

    Science.gov (United States)

    Zielińska, Małgorzata; Gülden, Michael; Seibert, Hasso

    2003-01-01

    Flavonoids are reported to be powerful antioxidants in cell free systems. They naturally occur as glycosides rather than as aglycon. In this study the ability of the flavonoid quercetin and its glycosides, quercetin-3-O-rutinoside (rutin), quercetin-3-O-glucoside and quercetin-3-O-(6″-O-acetyl)-glucoside, to protect in vitro rat C6 glioma cells from oxidative damage induced by cumene hydroperoxide was investigated. Cumene hydroperoxide induced cell death and lipid peroxidation. The cytotoxicity of cumene hydroperoxide could be prevented by the radical scavenger dimethyl thiourea and the ferric iron chelator deferoxamine, indicating that its cytotoxic activity is related to the generation of reactive oxygen radicals in the ferrous iron dependent Fenton reaction. Quercetin, in a concentration range of 10-100 μM, but neither rutin nor the other two glycosides, were able to protect C6 cells from cytotoxicity and lipid peroxidation. Furthermore, cytoprotective concentrations of quercetin proved to be cytotoxic itself. These results call in question potential beneficial effects of dietary intake or therapeutic use of naturally occurring flavonoids.

  11. Feasibility of synchrotron radiation computed tomography on rats bearing glioma after iodine or gadolinium injection. Jeune Equipe RSRM-UJF.

    Science.gov (United States)

    Le Duc, G; Corde, S; Elleaume, H; Estève, F; Charvet, A M; Brochard, T; Fiedler, S; Collomb, A; Le Bas, J F

    2000-01-01

    The purpose of this work was to demonstrate the feasibility of a new imaging technique called synchrotron radiation computed tomography (SRCT). This technique leads to a direct assessment of the in vivo concentration of an iodine- or gadolinium-labeled compound. Rats bearing C6 glioma were imaged by MRI prior to the SRCT experiment. The SRCT experiments were performed after a 1.3 g I/kg (n = 5) or a 0.4 g Gd/kg (n = 5) injection. Finally, brains were sampled for histology. The SRCT images exhibited contrast enhancement at the tumor location. Ten minutes after injection, iodine and gadolinium tissular concentrations were equal to 0.80 ( +/- 0.40) mg/cm3 and 0.50 ( +/- 0.10) mg/cm3, respectively in the peripheral area of the tumor (respective background value: 0.20 +/- 0.02 to 0.10 +/- 0.01). Correlation to MRI and histology revealed that the contrast uptake occurred in the most vascularized area of the tumor. The present study summarizes the feasibility of in vivo SRCT to obtain quantitative information about iodine and gadolinium-labeled compounds. Beyond brain tumor pathology, the SRCT appears as a complementary approach to MRI and CT, for studying iodine- and gadolinium-labeled compounds by the direct achievement of the tissular concentration value in the tissue.

  12. Angiopep-2-conjugated poly(ethylene glycol-co-poly(ε-caprolactone polymersomes for dual-targeting drug delivery to glioma in rats

    Directory of Open Access Journals (Sweden)

    Lu F

    2017-03-01

    Full Text Available Fei Lu,1,2 Zhiyong Pang,2,3 Jingjing Zhao,2 Kai Jin,4 Haichun Li,2 Qiang Pang,2 Long Zhang,2 Zhiqing Pang2 1Department of Pharmacy, Xianju People’s Hospital, Xianju, Zhejiang, 2Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai, 3Chongyang Center for Disease Control and Prevention, Xianning, Hubei, 4School of Life Science, Fudan University, Shanghai, People’s Republic of China Abstract: The blood–brain barrier is a formidable obstacle for glioma chemotherapy due to its compact structure and drug efflux ability. In this study, a dual-targeting drug delivery system involving Angiopep-2-conjugated biodegradable polymersomes loaded with doxorubicin (Ang-PS-DOX was developed to exploit transport by the low-density lipoprotein receptor-related protein 1 (LRP1, which is overexpressed in both blood–brain barrier and glioma cells. The polymersomes (PS were prepared using a thin-film hydration method. The PS were loaded with doxorubicin using the pH gradient method (Ang-PS-DOX. The resulting PS were uniformly spherical, with diameters of ~135 nm and with ~159.9 Angiopep-2 molecules on the surface of each PS. The drug-loading capacity and the encapsulation efficiency for doxorubicin were 7.94%±0.17% and 95.0%±1.6%, respectively. Permeability tests demonstrated that the proton diffusion coefficient across the PS membrane was far slower than that across the liposome membrane, and the common logarithm value was linearly dependent on the dioxane content in the external phase. Compared with PS-DOX, Ang-PS-DOX demonstrated significantly higher cellular uptake and stronger cytotoxicity in C6 cells. In vivo pharmacokinetics and brain distribution experiments revealed that Ang-PS-DOX achieved a more extensive distribution and more abundant accumulation in glioma cells than PS-DOX. Moreover, the survival time of glioma-bearing rats treated with Ang-PS-DOX was

  13. Synthesis of dihydropyrimidin-2-one/thione library and cytotoxic activity against the human U138-MG and Rat C6 glioma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Canto, Romulo F.S.; Eifler-Lima, Vera Lucia [Universidade Federal do Rio Grande do Sul (LaSOM/PPGCF/UFRGS), Porto Alegre, RS (Brazil). Programa de Pos Graduacao em Ciencias Farmaceuticas. Lab. de Sintese Organica; Bernardi, Andressa; Battastini, Ana Maria O. [Universidade Federal do Rio Grande do Sul (ICBS/UFRGS), Porto Alegre, RS (Brazil). Inst. de Ciencias Basicas da Saude; Russowsky, Dennis [Universidade Federal do Rio Grande do Sul (IQ/UFRGS), Porto Alegre, RS (Brazil). Inst. de Quimica

    2011-07-01

    Two series of 4-aryl-3,4-dihydropyrimidin-2(1H)-(thio)ones including monastrol (1a), have been synthesized by an environment-friendly methodology based on the combined use of citric acid or oxalic acid and TEOF (triethylorthoformate). The library was evaluated as inhibitor of cell proliferation on two glioma cell lines (human-U138-MG and Rat-C6). The compounds derived from thiourea 1f and 1d were more cytotoxic than monastrol. The compound derived from urea 2d showed the highest cytotoxic activity among the analyzed compounds. (author)

  14. Dynamic contrast enhancement of experimental glioma an intra-individual comparative study to assess the optimal time delay.

    Science.gov (United States)

    Engelhorn, Tobias; Schwarz, Marc A; Eyupoglu, Ilker Y; Kloska, Stephan P; Struffert, Tobias; Doerfler, Arnd

    2010-02-01

    The aim of this study was to compare tumor signal and contrast media uptake characteristics on contrast-enhanced T1-weighted sequences at 3 Tesla over 30 minutes after double-dose administration of different contrast agents in an animal model of brain glioma. Nine rats underwent magnetic resonance imaging (MRI) after stereotactic F98 glioma cell implantation before and repetitively for 30 minutes after injection of gadobutrol, gadopentetate, and gadobenate, respectively. Signal-to-noise ratio (SNR) and tumor contrast-to-noise ratio (CNR) were evaluated and MRI-derived tumor volumes were compared to histology. Postcontrast tumor SNR and CNR peaked at 4 minutes after contrast application. While contrast-enhancement within the tumor was fading, tumor volume increased by continuous contrast-uptake of peripheral parts between 4 minutes (137 + or - 29 mm(3), 126 + or - 16 mm(3), 141 + or - 24 mm(3)) and 20 minutes (182 + or - 35 mm(3), 164 + or - 32 mm(3), 191 + or - 25 mm(3)), respectively. At 8 and 12 minutes, 84% and 91% of the tumor volume were definable, respectively. Optimal correlation between MRI-derived tumor volume and histology is achieved by imaging up to 20 minutes after contrast application. At 4 minutes (this delay is mostly used in clinical routine), only 75% of the enhancing tumor volume is assessable. A delay of 8 minutes already reveals 84% of the tumor and seems to be a practical clinical compromise. Copyright 2010 AUR. Published by Elsevier Inc. All rights reserved.

  15. Dynamic contrast enhanced MRI parameters and tumor cellularity in a rat model of cerebral glioma at 7T

    Science.gov (United States)

    Aryal, Madhava Prasad

    This dissertation mainly focuses on establishing and evaluating a stable and reproducible procedure for assessing tumor microvasculature by measuring the tissue parameters: plasma volume (vp), forward transfer constant (Ktrans), interstitial volume (ve) and distribution volume (VD), utilizing T1-weighted dynamic contrast enhanced MRI (DCE-MRI) and examining their relationship with a histo measure, cell counting. In the first part of the work, two T1-weighted DCE-MRI studies at 24 hrs time interval, using a dual-echo gradient-echo pulse sequence, were performed in 18 athymic rats implanted with U251 cerebral glioma. Using the "standard," or "consensus" model, and a separate Logan graphical analysis, T1-weighted images before, during and after the injection of a gadolinium contrast agent were used to estimate the tissue parameters mentioned above. After MRI study rats were sacrificed, and sectioned brain tissues were stained with Hematoxylin and Eosin for cell counting. Measurements in a region where a model selection process demonstrates that it can be reliably shown that contrast agent leaks from the capillary into the interstitial space quickly enough, and a concentration sufficient to measure its back flux to the vasculature, especially for Ktrans and ve, showed a remarkable stability. The combined mean parameter values in this region were: vp = (0.79+/-0.36)%, Ktrans = (2.23+/-0.71) x10-2 min -1, ve = (6.99+/-2.14)%, and VD = (7.57+/-2.32)%. In the second part of this work, the Logan graphical approach, after establishing its stability in an untreated control group, was applied to investigate a cohort of animals in which a therapeutic dose of 20 Gy radiation had been administered. In this cohort, tissue normalization appeared to be the most effective at 8 h after irradiation; this implies that the 8 hrs post-treatment time might be an ideal combination time for optimized therapeutic outcome in combined modalities. The relationship between non-invasive DCE

  16. Influence of physicochemical properties of laser-modified polystyrene on bovine serum albumin adsorption and rat C6 glioma cell behavior.

    Science.gov (United States)

    Wang, Xuefeng; Ohlin, C André; Lu, Qinghua; Hu, Jun

    2006-09-15

    Biomaterial surface modification is an efficient way of improving cell-material interactions. In this study, sub-micrometer laser-induced periodic surface structures (LIPSS) were produced on polystyrene by laser irradiation. FT-IR analysis confirmed that this treatment also led to surface oxidation and anisotropic orientation of the produced carbonyl groups. As a consequence, the surface energy of the laser-treated polystyrene was 1.45 times that of the untreated polystyrene, as measured by contact-angle goniometry. Protein adsorption and rat C6 glioma cell behavior on the two substrates were investigated, showing that the changed physicochemical properties of laser-modified polystyrene surface led to an increase in the quantity of adsorbed bovine serum albumin and significantly affected the behavior of rat C6 glioma cells. In the early stages of cell spreading, cells explored their microenvironment using filopodium as the main sensor. Moreover, cells actively aligned themselves along the direction of LIPSS gradually and cell attachment and proliferation were significantly enhanced.

  17. C6大鼠脑胶质瘤动物模型建立及病理观察%Animal Model Establishment and Pathological Observation of C6 Cerebral Glioma in Rats

    Institute of Scientific and Technical Information of China (English)

    张荣; 段美美

    2013-01-01

    Objective To establish the simple, feasible, reliable and stable C6 cerebral glioma model in rats so as to provide the platform for the stud)' of the pathogenesis and the method of prevention and treatment of cerebral glioma. Methods The stereotaxic technique was adopted. C6 glioma cells in rats cultured in vitro were condensed and placed in suspension. C6 glioma cells( containing 2. 5 × 106 C6 cells/25 μL )were implanted into the right caudate nucleus in SD rats. The survival conditions of the rats were consecutively observed. Separately, in the 7th, 14th and 21sl days of the implantation, the rats were sacrificed and the brains were collected to prepare the pathological sections. With HE staining, they were observed under light -microscope. Results In about 7 days,after C6 glioma cells implanted,the survival state of rats was good. In about 14 days, the intracranial hypertension was apparent. In about 21 days, most of the rats were in critical condition. In the gross specimen examination, except the accidental death of 3 rats, the tumor formation rate was 100% in the rest of 18 rats. Along with the aging of the rats, the tumor size was enlarged, the midline structure was migrated obviously and the occupied effect was getting marked. HE staining discovered the significant formation of cerebral glioma in the rats. Conclusion The animal model of C6 rat cerebral glioma is reliable and stable. The tumor growth property and pathological characteristics are similar to human cerebral glioma. Hence,the model is applicable satisfactorily for the clinical basic research of glioma.%目的 建立简单易行、可靠稳定的大鼠C6脑胶质瘤模型,为研究脑胶质瘤的发病机制和防治方法提供操作平台.方法 采用立体定向技术,将体外培养的大鼠C6胶质瘤细胞浓缩悬置,2.5×106 个·25 μL-1接种于SD大鼠的右侧尾壳核区,种植后连续观察大鼠的生存状态,并分别于7、14、21 d处死大鼠,立刻取脑,制作病理切

  18. A Truncated form of CD200 (CD200S Expressed on Glioma Cells Prolonged Survival in a Rat Glioma Model by Induction of a Dendritic Cell-Like Phenotype in Tumor-Associated Macrophages

    Directory of Open Access Journals (Sweden)

    Kana Kobayashi

    2016-04-01

    Full Text Available CD200 induces immunosuppression in myeloid cells expressing its receptor CD200R, which may have consequences for tumor immunity. We found that human carcinoma tissues express not only full-length CD200 (CD200L but also its truncated form, CD200S. Although CD200S is reported to antagonize the immunosuppressive actions of CD200L, the role of CD200S in tumor immunity has never been investigated. We established rat C6 glioma cell lines that expressed either CD200L or CD200S; the original C6 cell line did not express CD200 molecules. The cell lines showed no significant differences in growth. Upon transplantation into the neonatal Wistar rat forebrain parenchyma, rats transplanted with C6-CD200S cells survived for a significantly longer period than those transplanted with the original C6 and C6-CD200L cells. The C6-CD200S tumors were smaller than the C6-CD200L or C6-original tumors, and many apoptotic cells were found in the tumor cell aggregates. Tumor-associated macrophages (TAMs in C6-CD200S tumors displayed dendritic cell (DC-like morphology with multiple processes and CD86 expression. Furthermore, CD3+, CD4+ or CD8+ cells were more frequently found in C6-CD200S tumors, and the expression of DC markers, granzyme, and perforin was increased in C6-CD200S tumors. Isolated TAMs from original C6 tumors were co-cultured with C6-CD200S cells and showed increased expression of DC markers. These results suggest that CD200S activates TAMs to become DC-like antigen presenting cells, leading to the activation of CD8+ cytotoxic T lymphocytes, which induce apoptotic elimination of tumor cells. The findings on CD200S action may provide a novel therapeutic modality for the treatment of carcinomas.

  19. Enhancement of Raman Light Scattering in Dye-Labeled Rat Glioma Cells by Langmuir-Blodgett CNT-Bundles Arranged on Metal-Containing Conducting Polymer Film

    CERN Document Server

    Egorov, A S; Grushevskaya, H V; Krot, V I; Krylova, N G; Lipnevich, I V; Orekhovskaya, T I; Shulitsky, B G

    2015-01-01

    We have fabricated layered nanocomposite consisting of a nanoporous anodic alumina sublayer (AOA), an ultrathin metal-containing polymer Langmuir-Blodgett (LB) film coating AOA, and multi-walled carbon nanotube (MCNT) - bundles which are arranged on the LB-film. MCNTs were preliminarily chemically modified by carboxyl groups and functionalized by stearic acid. We have experimentally observed an enhancement of Raman light scattering on surface plasmons in the LB-monolayers. This enhancement is due to charge and energy transfer. We demonstrate that propidium iodide (PI) fluorescence is quenched by the MCNT-bundles. A method of two-dimensional system imaging based on the MCNT-enhanced Raman spectroscopy has been proposed. This method has been applied to visualize focal adhesion sites on membranes of living PI-labeled rat glioma cells.

  20. Prolongation of life in rats with malignant glioma by intranasal siRNA/drug codelivery to the brain with cell-penetrating peptide-modified micelles.

    Science.gov (United States)

    Kanazawa, Takanori; Morisaki, Kazuki; Suzuki, Shohei; Takashima, Yuuki

    2014-05-01

    New therapeutic strategies are required to develop candidate drugs and ensure efficient delivery of these drugs to the brain and the central nervous system (CNS). Small interfering RNA (siRNA)-based therapies have been investigated as potential novel approaches for the treatment of brain disorders. Previously, we showed that Tat, a cell-penetrating peptide derived from HIV-Tat, and the modified block copolymers (MPEG-PCL-Tat) can form stable complexes with siRNA or can be loaded with an anticancer drug and efficiently deliver the drugs to the brain tissue via intranasal delivery. In this study, to develop a novel, efficient, and safe therapeutic strategy for managing brain disorders, we used MPEG-PCL-Tat micelles with a nose-to-brain delivery system to investigate its therapeutic effects on a rat model of malignant glioma using siRNA with a Raf-1 (siRaf-1)/camptothecin (CPT) codelivery system. MPEG-PCL-Tat and CPT-loaded MPEG-PCL-Tat can form a stable complex with siRNA with a particle size from 60 to 200 nm and a positive charge at N/P ratios up to 5. Additionally, MPEG-PCL-Tat/siRaf-1 and CPT-loaded MPEG-PCL-Tat/siRaf-1 have fostered cell death in rat glioma cells after the high cellular uptake of siRaf-1/drug by the MPEG-PCL-Tat carrier. Furthermore, compared to the unloaded MPEG-PCL-Tat/siRaf-1 complex, a CPT-loaded MPEG-PCL-Tat/siRaf-1 complex achieved the high therapeutic effect because of the additive effects of CPT and siRaf-1. These results indicate that drug/siRNA codelivery using MPEG-PCL-Tat nanomicelles with nose-to-brain delivery is an excellent therapeutic approach for brain and CNS diseases.

  1. [Genetic characterization of the entire genome of an H9N2 avian influenza virus A/Chicken/Shanghai/F/98].

    Science.gov (United States)

    Lu, Jianhong; Liu, Xiufan; Shao, Weixing; Zhang, Pinghu; Wei, Dongping

    2003-08-01

    Eight full-length genes of an H9N2 subtype avian influenza virus A/Chicken/Shanghai/F/ 98(H9N2), were amplified by RT-PCR and rapid amplification of cDNA ends (RACE) and sequenced. The results of phylogenetic analysis showed that A/Chicken/Shanghai/F/98 was entirely different from Quail/Hong Kong/G1/97 which was directly related to human infection with avian influenza virus in Hong Kong, whereas its HA, NA, M and NS genes belonged to A/Chicken/Beijing/ 1/94-like sublineage with the nucleotide homology of 96.7%, 96.4%, 97.5% and 98.0% respectively. The homology of NA gene between A/Chicken/Shanghai/F/98 and A/Duck/Hong Kong/Y280/ 97 was 97.4% and they both lost 9 nucleotides between nt 205 to 206. However, the PB2, PB1, PA, NP genes did not show any close relationship with those of the three known sublineages and the later three didn't share immediate ancestors with available isolates whose sequences had been reported. Therefore, A/Chicken/Shanghai/F/98 is a product of natural reassortment between H9N2 avian influenza viruses from different sublineages.

  2. Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats.

    Science.gov (United States)

    Tyler, Betty; Wadsworth, Scott; Recinos, Violette; Mehta, Vivek; Vellimana, Ananth; Li, Khan; Rosenblatt, Joel; Do, Hiep; Gallia, Gary L; Siu, I-Mei; Wicks, Robert T; Rudek, Michelle A; Zhao, Ming; Brem, Henry

    2011-07-01

    Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated.

  3. Wild Type p53 gene sensitizes rat C6 glioma cells to HSV-TK/ACV treatment in vitro and in vivo.

    Science.gov (United States)

    Huang, Qiang; Xia, Zhibo; You, Yongping; Pu, Peiyu

    2010-12-01

    Suicide gene therapy using herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV), has been extensively tested for the treatment of glioma. Our previous study showed that exogenous wild type p53 (wt-p53) enhanced the anti-tumor effect of HSV-TK/GCV therapy. However, the use of GCV is hindered by its low penetration to the brain and its toxicity when used at higher dose. In the present study, we used another pro-drug, acyclovir (ACV), and examined the therapeutic efficacy of HSV-TK/ACV combining with wt-p53 in C6 glioma cells. We observed that wt-p53 combined with HSV-TK/ACV resulted in the super-additive anti-tumor effect in vitro. Exogenous wt-p53 significantly enhanced the sensitivity of TK positive C6 cells to ACV in vitro. Our in vivo experiment demonstrated that the effect of wt-p53 and HSV-TK/ACV combination therapy was better than that of HSV-TK/ACV alone. The survival time of tumor-bearing rats treated with wt-p53 in combination with HSV-TK/ACV was also significantly prolonged than those treated with HSV-TK/ACV alone. These results suggest that wt-p53 can enhance the therapeutic efficacy of HSV-TK/ACV both in vitro and in vivo. These findings are considerably valuable with the respect of using less toxic ACV as prodrug. This novel strategy could provide benefit to HSV-TK/prodrug gene therapy.

  4. Conjugation Magnetic PAEEP-PLLA Nanoparticles with Lactoferrin as a Specific Targeting MRI Contrast Agent for Detection of Brain Glioma in Rats

    Science.gov (United States)

    Luo, Binhua; Wang, Siqi; Rao, Rong; Liu, Xuhan; Xu, Haibo; Wu, Yun; Yang, Xiangliang; Liu, Wei

    2016-04-01

    The diagnosis of malignant brain gliomas is largely based on magnetic resonance imaging (MRI) with contrast agents. In recent years, nano-sized contrast agents have been developed for improved MRI diagnosis. In this study, oleylamine-coated Fe3O4 magnetic nanoparticles (OAM-MNPs) were synthesized with thermal decomposition method and encapsulated in novel amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) copolymer nanoparticles. The OAM-MNP-loaded PAEEP-PLLA nanoparticles (M-PAEEP-PLLA-NPs) were further conjugated with lactoferrin (Lf) for glioma tumor targeting. The Lf-conjugated M-PAEEP-PLLA-NPs (Lf-M-PAEEP-PLLA-NPs) were characterized by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), thermo-gravimetric analysis (TGA), X-ray diffraction (XRD), and vibrating sample magnetometer (VSM). The average size of OAM-MNPs, M-PAEEP-PLLA-NPs, and Lf-M-PAEEP-PLLA-NPs were 8.6 ± 0.3, 165.7 ± 0.6, and 218.2 ± 0.4 nm, with polydispersity index (PDI) of 0.185 ± 0.023, 0.192 ± 0.021, and 0.224 ± 0.036, respectively. TEM imaging showed that OAM-MNPs were monodisperse and encapsulated in Lf-M-PAEEP-PLLA-NPs. TGA analysis showed that the content of iron oxide nanoparticles was 92.8 % in OAM-MNPs and 45.2 % in Lf-M-PAEEP-PLLA-NPs. VSM results indicated that both OAM-MNPs and Lf-M-PAEEP-PLLA-NPs were superparamagnetic, and the saturated magnetic intensity were 77.1 and 74.8 emu/g Fe. Lf-M-PAEEP-PLLA-NPs exhibited good biocompatibility in cytotoxicity assay. The high cellular uptake of Lf-M-PAEEP-PLLA-NPs in C6 cells indicated that Lf provided effective targeting for the brain tumor cells. The T 2 relaxation rate ( r 2) of M-PAEEP-PLLA-NPs and Lf-M-PAEEP-PLLA-NPs were calculated to be 167.2 and 151.3 mM-1 s-1. In MRI on Wistar rat-bearing glioma tumor, significant contrast enhancement could clearly appear at 4 h after injection and last 48 h. Prussian blue staining of the section clearly

  5. Conjugation Magnetic PAEEP-PLLA Nanoparticles with Lactoferrin as a Specific Targeting MRI Contrast Agent for Detection of Brain Glioma in Rats.

    Science.gov (United States)

    Luo, Binhua; Wang, Siqi; Rao, Rong; Liu, Xuhan; Xu, Haibo; Wu, Yun; Yang, Xiangliang; Liu, Wei

    2016-12-01

    The diagnosis of malignant brain gliomas is largely based on magnetic resonance imaging (MRI) with contrast agents. In recent years, nano-sized contrast agents have been developed for improved MRI diagnosis. In this study, oleylamine-coated Fe3O4 magnetic nanoparticles (OAM-MNPs) were synthesized with thermal decomposition method and encapsulated in novel amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) copolymer nanoparticles. The OAM-MNP-loaded PAEEP-PLLA nanoparticles (M-PAEEP-PLLA-NPs) were further conjugated with lactoferrin (Lf) for glioma tumor targeting. The Lf-conjugated M-PAEEP-PLLA-NPs (Lf-M-PAEEP-PLLA-NPs) were characterized by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), thermo-gravimetric analysis (TGA), X-ray diffraction (XRD), and vibrating sample magnetometer (VSM). The average size of OAM-MNPs, M-PAEEP-PLLA-NPs, and Lf-M-PAEEP-PLLA-NPs were 8.6 ± 0.3, 165.7 ± 0.6, and 218.2 ± 0.4 nm, with polydispersity index (PDI) of 0.185 ± 0.023, 0.192 ± 0.021, and 0.224 ± 0.036, respectively. TEM imaging showed that OAM-MNPs were monodisperse and encapsulated in Lf-M-PAEEP-PLLA-NPs. TGA analysis showed that the content of iron oxide nanoparticles was 92.8 % in OAM-MNPs and 45.2 % in Lf-M-PAEEP-PLLA-NPs. VSM results indicated that both OAM-MNPs and Lf-M-PAEEP-PLLA-NPs were superparamagnetic, and the saturated magnetic intensity were 77.1 and 74.8 emu/g Fe. Lf-M-PAEEP-PLLA-NPs exhibited good biocompatibility in cytotoxicity assay. The high cellular uptake of Lf-M-PAEEP-PLLA-NPs in C6 cells indicated that Lf provided effective targeting for the brain tumor cells. The T 2 relaxation rate (r 2) of M-PAEEP-PLLA-NPs and Lf-M-PAEEP-PLLA-NPs were calculated to be 167.2 and 151.3 mM(-1) s(-1). In MRI on Wistar rat-bearing glioma tumor, significant contrast enhancement could clearly appear at 4 h after injection and last 48 h. Prussian

  6. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

    Science.gov (United States)

    Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

    2015-03-01

    Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P tumors by a factor of two or more (2222  ±  784, 3687  ±  796 and 5658  ±  821 ng g-1) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement

  7. EXPERIMENTAL STUDY ON THE GENE THERAPY OF MALIGNANT GLIOMA WITH ANTISENSE VEGF RNA

    Institute of Scientific and Technical Information of China (English)

    浦佩玉; 王建桢; 黄强; 张敬; 张云亭

    2003-01-01

    Objective: To study the effect of antisense VEGF RNA on rat C6 gliomas in vivo and find out the feasibility of antiangiogenesis therapy with antisense VEGF RNA for malignant gliomas. Methods: Parental rat C6 glioma cells and C6 cells transfected with antisense VEGF cDNA were implanted intracerebrally and subcutaneously into SD rats as control and transfected group. Rats bearing cerebral and subcutaneous C6 gliomas were treated with antisense VEGF cDNA as treated group and sense VEGF cDNA and empty vector as control of treated group. The general manifestation, survival time, MRI and histopathological changes of all rats were observed. The volume of subcutaneously implanted tumors was determined regularly. In situ hybridization and immunohistochemical staining were used for detection of VEGF gene expression of gliomas while PCNA immunostaining and TUNEL method for examination of proliferation activity and apoptosis of gliomas, respectively. Results: The survival of the rats in transfected and treated group was prolonged. There were two rats surviving over 90 d in the treated group and their tumors disappeared. The VEGF gene expression, the number of microvessels and the proliferation activity were decreased and a large amount of apoptotic cells could be found in cerebral and subcutaneous gliomas in treated and transfected groups. Conclusion: VEGF is one of the candidate genes for gene therapy of malignant gliomas. Antisense VEGF RNA combined with other therapies should be studied further for enhancing the therapeutic effect of malignant gliomas.

  8. Cellular and molecular toxicology of lead. I. Effect of lead on cultured cell proliferation. [Comparison of toxicity to rat liver, glioma, and neuroblastoma cell lives

    Energy Technology Data Exchange (ETDEWEB)

    Kusell, M.; O' Cheskey, S.; Gerschenson, L.E.

    1978-07-01

    Growth studies were done on a cultured rat liver cell line (RLC-GAI) grown in a chemically defined medium in the presence of lead nitrate. Lead reversibly inhibited the growth of these cells even after 6 d of exposure to the heavy metal. To compare lead sensitivity in various cell lines, G150 and LD50 values were determined in the RLC-GAI cells as well as two glioma cell lines (B82 and C/sub 6/) and a neuroblastoma cell line (N18). The LD50 values paralleled but were consistently lower than the G150 values. Since lead is known to affect heme synthesis, hemin was added to test the possibility of preventing the growth-inhibitory effect of the lead. The growth capacity of lead-treated cells did not change with the addition of hemin. It is thought that differential cultured cell lines such as these could be useful in examining the molecular mechanism of lead toxicity.

  9. High-resolution magic angle spinning 1H NMR spectroscopy and reverse transcription-PCR analysis of apoptosis in a rat glioma.

    Science.gov (United States)

    Griffin, Julian L; Blenkiron, Cherie; Valonen, Piia K; Caldas, Carlos; Kauppinen, Risto A

    2006-03-01

    The functional genomic approaches of transcriptomics, proteomics and metabolomics aim to measure the mRNA, protein or metabolite complement of a cell, tissue or organism. In this study we have investigated the compatibility of transcriptional analysis, using Reverse Transcription (RT)-PCR, and metabolite analysis, by high-resolution magic angle spinning (HRMAS) 1H NMR spectroscopy, in BT4C rat glioma following the induction of programmed cell death. The metabolite and transcriptional changes that accompanied apoptosis were examined at 0, 4 and 8 days of ganciclovir/thymidine kinase gene therapy. Despite the high spinning speeds employed during HRMAS 1H NMR spectroscopy of one-half of the tumor samples, RT-PCR analysis of the pro-apoptotic transcripts Bcl-2, BAK-1, caspase-9 and FAS was possible, producing similar results to those detected in the unspun half of the tumors. Furthermore, the expression of FAS was inversely correlated with some of the key metabolic changes across the time period examined including the increases CH=CH and CH=CHCH2 lipid resonances which accompany apoptosis. This study demonstrates how combined transcriptomic and metabolomic studies of tumors can be used to understand the molecular events that accompany well documented metabolic perturbations during cell death processes.

  10. Improved survival in rats with glioma using MRI-guided focused ultrasound and microbubbles to disrupt the blood-brain barrier and deliver Doxil

    Science.gov (United States)

    Aryal, Muna; Zhi Zhang, Yong; Vykhodtseva, Natalia; Park, Juyoung; Power, Chanikarn; McDannold, Nathan

    2012-02-01

    Blood-brain-barrier (BBB) limits the transportation of most neuropeptides, proteins (enzymes, antibodies), chemotherapeutic agents, and genes that have therapeutic potential for the treatment of brain diseases. Different methods have been used to overcome this limitation, but they are invasive, non-targeted, or require the development of new drugs. We have developed a method that uses MRI-guided focused ultrasound (FUS) combined with circulating microbubbles to temporarily open BBB in and around brain tumors to deliver chemotherapy agents. Here, we tested whether this noninvasive technique could enhance the effectiveness of a chemotherapy agent (Doxil). Using 690 kHz FUS transducer and microbubble (Definity), we induced BBB disruption in intracranially-implanted 9L glioma tumors in rat's brain in three weekly sessions. Animals who received BBB disruption and Doxil had a median survival time of 34.5 days, which was significantly longer than that found in control animals which is 16, 18.5, 21 days who received no treatment, BBB disruption only and Doxil only respectively This work demonstrates that FUS technique has promise in overcoming barriers to drug delivery, which are particularly stark in the brain due to the BBB.

  11. Effect of extremely low frequency electromagnetic fields on rat C6 glioma cells in vivo%极低频电磁场暴露对大鼠脑内C6胶质细胞瘤的影响

    Institute of Scientific and Technical Information of China (English)

    周厚俊; 余化霖; 孙涛; 田冰峰; 周勇; 马以骝

    2012-01-01

      Objective To order to establish C6 rat intracerebral glioma model, investigate rat brain glioma impact by the way of extremely low frequency electromagnetic field exposure. Methods C6 cells were inplanted into all the SD rats, the number is 1×106 each rat. SD rat with intracranial C6 gliomas were established using stereotactic methods,then rats were randomly divided into treatment group(n=15) and control group(n=15). From 3 days after tumor inoculation, the rats in treatments group were exposesd three hours in the magnetic field every day ,it lasted a week, the control group were not exposed to magnetic field, during the time, we observe the spirit of rats, neural function(hemiplegia), the survival any time and death in rats with pathological biopsy autopsy. Results The rats of control group died in 16-27 days from the inoculation of C6 glioma cell, with an average survival of 22 days, while the rats of experimental group died in 21-33 days from the inoculation of C6 glioma cell, with an average survival of 26 days. Significant difference had happened between the experimental group and the control group(P<0.05). The C6 glioma were founded both in experimental group and control group. The morphological difference of the C6 glioma between the experimental group and the control group was not founded. Conclusion Extremely low frequency electromagnetic field exposure may be extended survival time of tumor-bearing rats, but it can not cure glioblastoma. Short-term exposure of low-intensity extremely low frequency electromagnetic field on patients with glioma has non-toxic or treatment, but long-term exposure of low-intensity extremely low frequency electromagnetic field may have a therapeutic effect on patients with glioma.%  目的通过建立荷瘤大鼠胶质瘤模型,探讨极低频电磁场暴露对大鼠脑内胶质细胞瘤的影响,为胶质瘤的实验性治疗提供理论依据.方法将1×106/ml的C6细胞悬液10μl注入

  12. Interstitial Chemotherpy with doxorubicin-loaded PLA polymer for S.C. C6 glioma model in rats and examining PLA-doxorubicin controlled-release capacity with HPLC

    Institute of Scientific and Technical Information of China (English)

    WANG Qin; LI Bao-lu; ZHANG Ming-chen; LI Xin-gang; HAO Xiao-guang

    2001-01-01

    @@ Glioma has the highest incidence in the brain tumors. Though treated with surgical resection, external beam radiation therapy, and systemic chemotherapy, patients with glioma have poor prognosis because of glioma recurrence.

  13. Epidemiology of gliomas.

    Science.gov (United States)

    Ostrom, Quinn T; Gittleman, Haley; Stetson, Lindsay; Virk, Selene M; Barnholtz-Sloan, Jill S

    2015-01-01

    Gliomas are the most common type of primary intracranial tumors. Some glioma subtypes cause significant mortality and morbidity that are disproportionate to their relatively rare incidence. A very small proportion of glioma cases can be attributed to inherited genetic disorders. Many potential risk factors for glioma have been studied to date, but few provide explanation for the number of brain tumors identified. The most significant of these factors includes increased risk due to exposure to ionizing radiation, and decreased risk with history of allergy or atopic disease. The potential effect of exposure to cellular phones has been studied extensively, but the results remain inconclusive. Recent genomic analyses, using the genome-wide association study (GWAS) design, have identified several inherited risk variants that are associated with increased glioma risk. The following chapter provides an overview of the current state of research in the epidemiology of intracranial glioma.

  14. Conditioned medium from neural stem cells inhibits glioma cell growth.

    Science.gov (United States)

    Li, Z; Zhong, Q; Liu, H; Liu, P; Wu, J; Ma, D; Chen, X; Yang, X

    2016-10-31

    Malignant glioma is one of the most common brain tumors in the central nervous system. Although the significant progress has been made in recent years, the mortality is still high and 5-year survival rate is still very low. One of the leading causes to the high mortality for glioma patients is metastasis and invasion. An efficient method to control the tumor metastasis is a promising way to treat the glioma. Previous reports indicated that neural stem cells (NSCs) were served as a delivery vector to the anti-glioma therapy. Here, we used the conditioned medium from rat NSCs (NSC-CM) to culture the human glioblastoma cell lines. We found that NSC-CM could inhibit the glioma cell growth, invasion and migration in vitro and attenuate the tumor growth in vivo. Furthermore, this anti-glioma effect was mediated by the inactivation of mitogen activated protein kinase (MAPK) pathway. Above all, this study provided the direct evidence to put forward a simple and efficient method in the inhibition of glioma cells/tumor growth, potentially advancing the anti-glioma therapy.

  15. Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain

    Science.gov (United States)

    Charest, Gabriel; Sanche, Léon; Fortin, David; Mathieu, David; Paquette, Benoit

    2013-01-01

    Treatment of glioblastoma with platinum compounds modestly improves progression-free survival and may cause toxic effects which prevent use at higher dose that would otherwise improve the antineoplastic effect. To reduce toxicity, we propose to encapsulate the platinum drug in a liposome. We have also tested three methods of drug administration (intra-venous, intra-arterial and intra-arterial combined with blood brain barrier disruption) to determine which one optimizes the tumor cell uptake, limits the toxicity and delivers the best concomitance effect with radiotherapy. Cisplatin, oxaliplatin, their respective liposomal formulations, Lipoplatin™ and Lipoxal™, and carboplatin were assessed in F98 glioma, orthotopically implanted in Fischer rats. We found that the modest accumulation of drugs in tumor cells after intra-venous injection was significantly improved when the intra-arterial route was used and further increased after the transient opening of the blood brain barrier with mannitol. The liposomal formulations have largely reduced the toxicity and have allowed a better exploitation of the anti-cancer activity of platinum agent. Although the liposomes Lipoplatin™ and Lipoxal™ have shown a similar ability to that of carboplatin, to accumulate in brain tumors, the highest additive effect with radiotherapy was obtained with carboplatin. We conclude that the intra-arterial infusion of carboplatin or Lipoxal™ in concomitance with radiation therapy leads to the best tumor control as measured by an increase of mean survival time in Fischer rats implanted with the F98 glioma with a benefit in survival time of 13.4 and 6.5 days respectively compared to intra-venous. PMID:24026531

  16. 苦参碱对胶质瘤大鼠模型中Fas表达的调节作用的实验研究%Effect of mtrine on Fas expression in C6 glioma in rats

    Institute of Scientific and Technical Information of China (English)

    戚基萍; 刘微; 张淑君; 昝丽坤; 孙玉兰; 宋月佳

    2009-01-01

    目的 探讨苦参碱应用前后C6脑胶质瘤大鼠模型中Fas因子的表达变化及意义.方法采用脑立体定向技术,将体外培养的C6胶质瘤细胞注入大鼠尾状核区制备胶质瘤大鼠模型,并根据是否用药及用药量的多少分为空白对照组、冰片组、苦参碱低剂量组、苦参碱高剂量组、苦参碱低剂量+冰片组、苦参碱高剂量+冰片组.通过大鼠生存状态、标本的大体所见、MRI、HE染色观察苦参碱对胶质瘤大鼠模型生存质量及胶质瘤体积的影响,用免疫组织化学方法检测苦参碱对胶质瘤大鼠模型肿瘤细胞中Fas表达的影响.结果 大鼠生存状态、标本的大体所见、MRI及HE染色显示苦参碱可显著提高胶质瘤大鼠模型的生存质量,抑制胶质瘤细胞增殖.免疫组化结果显示,苦参碱低剂量+冰片组(98.16±11.82)、苦参碱高剂量+冰片组(1 12.80±12.12)Fas表达高于空白对照组(39.09±7.79)、冰片组(46.87±7.43)、苦参碱低剂量组(42.41±7.83)、苦参碱高剂量组(44.20±7.47),苦参碱高剂量+冰片组Fas表达高于苦参碱低剂量+冰片组,差异均有统计学意义(P<0.05).结论 苦参碱能增加胶质瘤细胞中Fas的表达,抑制胶质瘤细胞增殖.%Objective To investigate the effect of matrine on Fas expression in C6 glima in a tumor-bearing rat model. Methods Cultured cerebral glioma C6 cells wgre injected stereotactically into the lef tcaudate nucleus of the rats.The ratswere randomized into untreated group,bomeol-treated group,low-dose matrine group,high-dose maaine group,low-dose matrine+bomeol group,and high-dose matrine+borneol group.The effect of matrine on the quality of life of the rats and the glioma volume was evaluated according to the survival state of the rats and by gross observation,magnetic resonance imaging(MRJ)and HE smining of the brain tissue.Immunohistochemistry was performed to detect Fas expression in the glioma cells. Results The survival state

  17. Efficacy of argon-helium cryosurgery for gliomas in 9L/Fischer344 rats%氩氦冷冻治疗9L/Fischer344大鼠脑胶质瘤疗效观察

    Institute of Scientific and Technical Information of China (English)

    刘剑; 马国亮; 夏爱祥; 张世忠; 黄传平; 林武鹏; 王德才

    2013-01-01

    Objective To research the efficacy of argon-helium cryotherapy for glioma and the prognosis in 9L/Fischer344 rats.Methods Fischer344 rat glioma models were successfully established and divided into blank control group,surgery group and cryotherapy group,10 rats each.The size of the tumor was measured and calculated by vemier caliper.The behavior and survival of rats was observed before and atter cryotherapy.Results The survival time in blank control group,surgery group and cryotherapy group was 78.5±1.1,171.0±10.8 and 252.8±5.0 days respectively,and the difference was statistically significant (P =0.002).The tumor volume showed a trend to decrease in cryotherapy group.Conclusions Cryosurgery is an effective treatment for glioma,presumably due to the tumor cell rupture-caused antigen exposure stimulating the body to produce anti-tumor antibodies.%目的 研究氩氦冷冻治疗9L/Fischer344大鼠脑胶质瘤的疗效及预后.方法 Fischer344大鼠胶质瘤模型建立成功后,随机分为空白对照组、手术组、氩氦冷冻组,每组10只.游标卡尺测量并计算肿瘤体积,观察各组大鼠行为及生存期.结果 空白对照组、手术组和氩氦冷冻组大鼠生存时间分别为(78.5±1.1)d、(171.0±10.8)d和(252.8±5.0)d,差异具有统计学意义(P=0.002).氩氦冷冻组肿瘤体积呈逐渐缩小趋势.结论 氩氦冷冻是治疗胶质瘤有效方法,推测可能与瘤细胞破裂,抗原暴露,而刺激机体产生抗肿瘤的抗体有关.

  18. Depot delivery of dexamethasone and cediranib for the treatment of brain tumor associated edema in an intracranial rat glioma model.

    Science.gov (United States)

    Ong, Qunya; Hochberg, Fred H; Cima, Michael J

    2015-11-10

    Treatments of brain tumor associated edema with systemically delivered dexamethasone, the standard of care, and cediranib, a novel anti-edema agent, are associated with systemic toxicities in brain tumor patients. A tunable, reservoir-based drug delivery device was developed to investigate the effects of delivering dexamethasone and cediranib locally in the brain in an intracranial 9L gliosarcoma rat model. Reproducible, sustained releases of both dexamethasone and solid dispersion of cediranib in polyvinylpyrrolidone (AZD/PVP) from these devices were achieved. The water-soluble AZD/PVP, which exhibited similar bioactivity as cediranib, was developed to enhance the release of cediranib from the device. Local and systemic administration of both dexamethasone and cediranib was equally efficacious in alleviating edema but had no effect on tumor growth. Edema reduction led to modest but significant improvement in survival. Local delivery of dexamethasone prevented dexamethasone-induced weight loss, an adverse effect seen in animals treated with systemic dexamethasone. Local deliveries of dexamethasone and cediranib via these devices used only 2.36% and 0.21% of the systemic doses respectively, but achieved similar efficacy as systemic drug deliveries without the side effects associated with systemic administration. Other therapeutic agents targeting brain tumor can be delivered locally in the brain to provide similar improved treatment outcomes. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Effects of Photodynamic Therapy on the Ultrastructure of Glioma Cells

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective To study the change in ultrastructure of C6 glioma cells after photodynamic therapy (PDT), to compare morphological differences in necrosis and apoptosis before and after PDT treatment, and to evaluate the effect of photodynamic therapy on the blood brain tumor barrier (BTB) of C6 glioma. Methods The model was produced by transplanting C6 glioma cells cultured in vitro using Peterson method into the caudate nuclei of Wister rats. The experiment group received PDT for two weeks after the operation. The sub-cellular structure, blood-brain-barrier (BBB) and BTB in both groups were observed under electron microscope. Results Apoptosis in different phases and necrosis could be observed in some C6 glioma cells.Swelling occurred on the ultrastructure of cellular organs such as mitochondria and endoplasmic reticulum in most of the cells.Damage to the BTB, reduction of the number of cellular organs in endothelial cells of the capillary blood vessels, stretch of the tight junction, and enlargement of the gaps between endothelial cells were also seen in the experiment group. Meanwhile,limited impact on the normal sub-cellular structures and BBB was observed. Conclusion PDT could induce apoptosis and necrosis of C6 glioma cells due to the damage to the ultrastructure of mitochondria and endoplasmic reticulum. The weakened function of C6 glioma BTB initiated by PDT makes it possible to perform a combined therapy of PDT and chemotherapy for glioma.

  20. Establishment of C6 brain glioma models through stereotactic technique for laser interstitial thermotherapy research

    Directory of Open Access Journals (Sweden)

    Jian Shi

    2015-01-01

    Conclusion: The rat C6 brain glioma model established in the study was a perfect model to study LITT of glioma. Infrared thermograph technique measured temperature conveniently and effectively. The technique is noninvasive, and the obtained data could be further processed using software used in LITT research. To measure deep-tissue temperature, combining thermocouple with infrared thermograph technique would present better results.

  1. Temozolomide in malignant glioma

    OpenAIRE

    Gregor Dresemann

    2010-01-01

    Gregor DresemannCenter for Neurooncology at Aerztehaus Velen, Velen, GermanyAbstract: Glioblastoma multiforme WHO grade IV (GBM) is the most aggressive ­malignant glioma and the most frequent primary tumor of the central nervous system. The median ­survival of newly diagnosed GBM patients was between 9 to 12 months prior to treatment with ­temozolomide being introduced. Primary resection that is as complete as possible is recommended for malignant glioma. Conventional ...

  2. Genetic Alterations in Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Bralten, Linda B. C.; French, Pim J., E-mail: p.french@erasmusmc.nl [Department of Neurology, Erasmus University Medical Center, Erasmus University Rotterdam, Dr Molewaterplein 50, 3000 CA, Rotterdam (Netherlands)

    2011-03-07

    Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes.

  3. Intracellular labeling and quantification process by magnetic resonance imaging using iron oxide magnetic nanoparticles in rat C6 glioma cell line; Marcacao intracelular e processo de quantificacao por imagem por ressonancia magnetica utilizando nanoparticulas magneticas de oxido de ferro em celulas da linhagem C6 de glioma de rato

    Energy Technology Data Exchange (ETDEWEB)

    Mamani, Javier Bustamante; Pavon, Lorena Favaro; Sibov, Tatiana Tais; Rossan, Fabiana; Silveira, Paulo Henrique; Cardenas, Walter Humberto; Gamarra, Lionel Fernel, E-mail: javierbm@einstein.br [Instituto do Cerebro - InCe, Hospital Israelita Albert Einstein - HIAE, Sao Paulo, SP (Brazil); Miyaki, Liza Aya Mabuchi [Faculdade de Enfermagem, Hospital Israelita Albert Einstein - HIAE, Sao Paulo, SP (Brazil); Amaro Junior, Edson [Departamento de Diagnostico por Imagem e Instituto do Cerebro - InCe, Hospital Israelita Albert Einstein - HIAE, Sao Paulo, SP (Brazil)

    2012-04-15

    Objective: To assess intracellular labeling and quantification by magnetic resonance imaging using iron oxide magnetic nanoparticles coated with biocompatible materials in rat C6 glioma cells in vitro. These methods will provide direction for future trials of tumor induction in vivo as well as possible magnetic hyperthermia applications. Methods: Aminosilane, dextran, polyvinyl alcohol, and starch-coated magnetic nanoparticles were used in the qualitative assessment of C6 cell labeling via light microscopy. The influence of the transfection agent poly-L-lysine on cellular uptake was examined. The quantification process was performed by relaxometry analysis in T{sub 1} and T{sub 2} weighted phantom images. Results: Light microscopy revealed that the aminosilane-coated magnetic nanoparticles alone or complexed with poly-L-lysine showed higher cellular uptake than did the uncoated magnetic particles. The relaxactivities of the aminosilane-coated magnetic nanoparticles with a hydrodynamic diameter of 50nm to a 3-T field were r{sub 1}=(6.1 +- 0.3) x10{sup -5} ms{sup -1}mL/{mu}g, r{sub 2}=(5.3 +- 0.1) x 10{sup -4} ms{sup -1}mL/{mu}g, with a ratio of r{sub 2} / r{sub 1}{approx_equal} 9. The iron uptake in the cells was calculated by analyzing the relaxation rates (R{sub 1}and R{sub 2}) using a mathematical relationship. Conclusions: C6 glioma cells have a high uptake efficiency for aminosilane-coated magnetic nanoparticles complexed with the transfection agent poly-L-lysine. The large ratio r{sub 2} / r{sub 1}{approx_equal} 9 indicates that these magnetic nanoparticles are ideal for quantification by magnetic resonance imaging with T{sub 2}-weighted imaging techniques. (author)

  4. Transferrin modified PEG-PLA-resveratrol conjugates: in vitro and in vivo studies for glioma.

    Science.gov (United States)

    Guo, Wanhua; Li, Aimei; Jia, Zhijun; Yuan, Yi; Dai, Haifeng; Li, Hongxiu

    2013-10-15

    Glioblastoma is one of the most malignant brain tumors with a poor prognosis. In this study, we examined the effects of transferrin (Tf)-modified poly ethyleneglycol-poly lactic acid (PEG-PLA) nanoparticles conjugated with resveratrol (Tf-PEG-PLA-RSV) to glioma therapy in vitro and in vivo. The cell viability of Tf-PEG-PLA-RSV on C6 and U87 glioma cells was determined by the MTT assay. In vivo biodistribution and antitumor activity were investigated in Brain glioma bearing rat model of C6 glioma by i.p. administration of RSV-polymer conjugates. We found that the average diameter of each Tf-PEG-PLA-RSV is around 150 nm with 32 molecules of Tf on surface. In vitro cytotoxicity of PEG-PLA-RSV against C6 and U87 cells was higher than that of free RSV, and further the modification of Tf enhanced the cytotoxicity of the RSV-polymer conjugates as a result of the increased cellular uptake of the RSV-modified conjugates by glioma cells. In comparison with free RSV, RSV conjugates could significantly decrease tumor volume and accumulate in brain tumor, which resulted in prolonging the survival of C6 glioma-bearing rats. These results suggest that Tf-NP-RSV had a potential of therapeutic effect to glioma both in vitro and in vivo and might be a potential candidate for targeted therapy of glioma and worthy of further investigation.

  5. Molecular Profiling of Gliomas

    NARCIS (Netherlands)

    A.M. Gravendeel (Lonneke)

    2012-01-01

    textabstractGliomas are the most common type of primary brain tumors in adults with an incidence rate of 5.27 per 100.000 patients every year 1-2. In 1926, Bailey and Cushing suggested a classification model based on distinct histological morphologies 3, which forms the basis of the currently used W

  6. Establishment of a Wistar rat model bearing brain glioma C6 cells and its experimental application%Wistar大鼠C6胶质瘤脑移植模型的应用

    Institute of Scientific and Technical Information of China (English)

    易林华; 傅相平; 李安民; 闫润民

    2011-01-01

    Objective To establish a rat model bearing brain glioma and investigate the optimal conditions for its experimental application. Methods C6 cells were implanted into the unilateral brain hemisphere of 20 Wistar rats. The growth behaviors of the brain tumor and behavioral changes of the rats were observed at different time points after the implantation. Results On day 3 after the implantation, only a slight increase of signal intensity was observed on T2-weighted images. By day 5, the tumor became visible in 15/18 of the rats in at least two sections. By day 11,16/ 18 of the rats showed space-occupying effect in the brain, and by day 14, the tumor occupied over 1/2 of the hemisphere in 14/18 of the rats. By day 20, 14/18 of the rats showed a tumor mass occupying over 2/3 of the hemisphere, and some tumor cells had migrated into the contralateral hemisphere. Conclusion In this model of brain glioma, the optimal time widow for experiment is between 14 and 18 days after the cell implantation. The cell density and viability for implantation and the site of implantation may also affect the experimental time widow.%目的 通过观察C6胶质瘤大鼠脑移植模型,了解该模型的牛物学特点,以帮助实验中有效应用.方法 Wistar大鼠20只,将活性较好的C6胶质瘤细胞微量移植人大鼠大脑半球,观察肿瘤生长特点及行为学改变.结果 肿瘤移植后第3天,TW2即可出现轻微高信号改变.15/18的大鼠在第5天至少能看到2个层面的信号改变.16/18的大鼠在第11天能看见实质性肿瘤.13/18的大鼠第14天生长至半侧大脑的1/2.14/18的大鼠第20大大部分肿瘤达到半侧大脑的2/3,部分生长至对侧半球.结论 实验可能的最佳时间窗在14~18 d.同时,肿瘤移植的初始细胞浓度、细胞活性和移植部位可能也对实验时间窗会有较大影响.

  7. Invasion of primary glioma- and cell line-derived spheroids implanted into corticostriatal slice cultures

    DEFF Research Database (Denmark)

    Aaberg-Jessen, Charlotte; Nørregaard, Annette; Christensen, Karina

    2013-01-01

    preserving the invasive features and stem cell features of glioma cells. Fluorescently labelled primary glioma spheroids and U87MG cell line-derived spheroids were implanted into organotypic rat corticostriatal slice cultures and the invasion was followed over time by confocal microscopy. The invasion......Gliomas are highly invasive tumors and the pronounced invasive features of gliomas prevent radical surgical resection. In the search for new therapeutics targeting invasive glioma cells, in vivo-like in vitro models are of great interest. We developed and evaluated an in vivo-like in vitro model...... was validated immunohistochemically with paraffin sections using a human-specific vimentin antibody. Moreover, the preservation of immature stem cell features was evaluated immunohistochemically using the stem cell markers CD133, Sox2, Bmi-1 and nestin. The confocal and immunohistochemical results showed...

  8. WE-E-BRE-08: Impact of IUdR in Rat 9L Glioma Cell Survival for 25–35 KeV Photo-Activated Auger Electron Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Alvarez, D; Hogstrom, K [Louisiana State University, Baton Rouge, LA (United States); Mary Bird Perkins Cancer Center, Baton Rouge, LA (United States); Brown, T; Dugas, J; Varnes, M [Mary Bird Perkins Cancer Center, Baton Rouge, LA (United States); Matthews, K [Louisiana State University, Baton Rouge, LA (United States)

    2014-06-15

    Purpose: To determine the biological effect from Auger electrons with 9% and 18% iododeoxyuridine (IUdR) incorporated into the DNA of rat 9L glioma cells at photon energies above and below the K-edge of iodine (33.2 keV). Methods: Rat 9L glioma cell survival versus dose curves with 0%, 9%, and 18% thymidine replacement with IUdR were measured using four irradiation energies (4 MV x-rays; monochromatic 35, 30, and 25 keV synchrotron photons). For each of 11 conditions (Energy, %IUdR) survival curves were fit to the data (826 cell cultures) using the linear-quadratic model. The ratio of doses resulting in 10% survival gave sensitization enhancement ratios (SER10) from which contributions due to linear-energy transfer (LET), radiosensitization (RS), and Auger effect (AE) were extracted. Results: At 35, 30, and 25 keV, SER10,LET values were 1.08±0.03, 1.22±0.02, and 1.37±0.02, respectively. At 4 MV SER10,RS values for 9% and 18% IUdR were 1.28±0.02 and 1.40±0.02, respectively. Assuming LET effects are independent of %IUdR and radiosensitization effects are independent of energy, SER10,AE values for 18% IUdR at 35, 30, and 25 keV were 1.35±0.05, 1.06±0.03, and 0.98±0.03, respectively; values for 9% IUdR at 35 and 25 keV were 1.01±0.04 and 0.82±0.02, respectively. Conclusion: For 18% IUdR the radiosensitization effect of 1.40 and the Auger effect of 1.35 at 35 keV are equally important to the combined effect of 1.90. No measureable Auger effect was observed for energies below the K-edge at 20 and 25 keV, as expected. The insignificant Auger effect at 9% IUdR was not expected. Additional data (40–70 keV) and radiobiological modeling are being acquired to better understand the energy dependence of Auger electron therapy with IUdR. Funding support in part by the National Science Foundation Graduate Research Fellowship Program and in part by Contract No. W81XWH-10-1-0005 awarded by the U.S. Army Research Acquisition Activity. This paper does not necessarily

  9. Silver nanoparticles: a novel radiation sensitizer for glioma?

    Science.gov (United States)

    Liu, Peidang; Huang, Zhihai; Chen, Zhongwen; Xu, Ruizhi; Wu, Hao; Zang, Fengchao; Wang, Cailian; Gu, Ning

    2013-11-01

    Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after AgNP injection, rats bearing glioma received 10 Gy radiation. The mean survival times were 100.5 and 98 days, the corresponding percent increase in life spans was 513.2% and 497.7%, and the cure rates were 41.7 and 38.5% at 200 days for the 10 and 20 μg AgNPs and radiation combination groups, respectively. In contrast, the mean survival times for irradiated controls, 10 and 20 μg AgNPs alone, and untreated controls were 24.5, 16.1, 19.4, and 16.4 days, respectively. Furthermore, a cooperative antiproliferative and proapoptotic effect was obtained when gliomas were treated with AgNPs followed by radiotherapy. Our results showed the therapeutic efficacy of AgNPs in combination with radiotherapy without apparent systemic toxicity, suggesting the clinical potential of AgNPs in improving the outcome of malignant glioma radiotherapy.Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after Ag

  10. Angiogenic Signalling Pathways Altered in Gliomas: Selection Mechanisms for More Aggressive Neoplastic Subpopulations with Invasive Phenotype

    Directory of Open Access Journals (Sweden)

    Susana Bulnes

    2012-01-01

    Full Text Available The angiogenesis process is a key event for glioma survival, malignancy and growth. The start of angiogenesis is mediated by a cascade of intratumoural events: alteration of the microvasculature network; a hypoxic microenvironment; adaptation of neoplastic cells and synthesis of pro-angiogenic factors. Due to a chaotic blood flow, a consequence of an aberrant microvasculature, tissue hypoxia phenomena are induced. Hypoxia inducible factor 1 is a major regulator in glioma invasiveness and angiogenesis. Clones of neoplastic cells with stem cell characteristics are selected by HIF-1. These cells, called “glioma stem cells” induce the synthesis of vascular endothelial growth factor. This factor is a pivotal mediator of angiogenesis. To elucidate the role of these angiogenic mediators during glioma growth, we have used a rat endogenous glioma model. Gliomas induced by prenatal ENU administration allowed us to study angiogenic events from early to advanced tumour stages. Events such as microvascular aberrations, hypoxia, GSC selection and VEGF synthesis may be studied in depth. Our data showed that for the treatment of gliomas, developing anti-angiogenic therapies could be aimed at GSCs, HIF-1 or VEGF. The ENU-glioma model can be considered to be a useful option to check novel designs of these treatment strategies.

  11. Angiogenic Signalling Pathways Altered in Gliomas: Selection Mechanisms for More Aggressive Neoplastic Subpopulations with Invasive Phenotype

    Science.gov (United States)

    Bulnes, Susana; Bengoetxea, Harkaitz; Ortuzar, Naiara; Argandoña, Enrike G.; Garcia-Blanco, Álvaro; Rico-Barrio, Irantzu; Lafuente, José V.

    2012-01-01

    The angiogenesis process is a key event for glioma survival, malignancy and growth. The start of angiogenesis is mediated by a cascade of intratumoural events: alteration of the microvasculature network; a hypoxic microenvironment; adaptation of neoplastic cells and synthesis of pro-angiogenic factors. Due to a chaotic blood flow, a consequence of an aberrant microvasculature, tissue hypoxia phenomena are induced. Hypoxia inducible factor 1 is a major regulator in glioma invasiveness and angiogenesis. Clones of neoplastic cells with stem cell characteristics are selected by HIF-1. These cells, called “glioma stem cells” induce the synthesis of vascular endothelial growth factor. This factor is a pivotal mediator of angiogenesis. To elucidate the role of these angiogenic mediators during glioma growth, we have used a rat endogenous glioma model. Gliomas induced by prenatal ENU administration allowed us to study angiogenic events from early to advanced tumour stages. Events such as microvascular aberrations, hypoxia, GSC selection and VEGF synthesis may be studied in depth. Our data showed that for the treatment of gliomas, developing anti-angiogenic therapies could be aimed at GSCs, HIF-1 or VEGF. The ENU-glioma model can be considered to be a useful option to check novel designs of these treatment strategies. PMID:22852079

  12. Human gliomas contain morphine

    DEFF Research Database (Denmark)

    Olsen, Peter; Rasmussen, Mads; Zhu, Wei

    2005-01-01

    morphine via high pressure liquid chromatography (HPLC). The HPLC peak corresponding to an authentic morphine standard had its morphine level determined via radioimmune assay. The identity of this material was established by Q-TOF-MS analysis. RESULTS: Each glioma exhibited an endogenous morphine presence....... Tumor extractions demonstrated a molecular mass of 286.14 da, identical to authentic morphine. Subsequent fragmentation analysis of this molecule revealed fragment masses of 129.01 da, 183.09 da and 201.07 da, corresponding to authentic morphine fragments. This material was not found in any......BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogenous...

  13. Gene Therapy for Gliomas

    OpenAIRE

    Nanda, Dharminderkoemar

    2008-01-01

    textabstractThe overall median survival in glioblastoma multiforme (GBM) patients is less than one year and fewer than 5% of patients survive more than 5 years. The current standard of care for GBM patients involves neurosurgical resection of the tumor followed by radiotherapy with concomitant and adjuvant temozolomide chemotherapy. After initial treatment, all malignant gliomas eventually recur, mostly within a 2-3 cm margin of the original tumor on CT/MRI. The poor prognosis warrants resear...

  14. External irradiation models for intracranial 9L glioma studies

    Directory of Open Access Journals (Sweden)

    Feuvret Loïc

    2010-11-01

    Full Text Available Abstract Purpose Radiotherapy has been shown to be an effective for the treatment human glioma and consists of 30 fractions of 2 Gy each for 6-7 weeks in the tumor volume with margins. However. in preclinical studies, many different radiation schedules are used. The main purpose of this work was to review the relevant literature and to propose an external whole-brain irradiation (WBI protocol for a rat 9L glioma model. Materials and methods 9L cells were implanted in the striatum of twenty 344-Fisher rats to induce a brain tumor. On day 8, animals were randomized in two groups: an untreated group and an irradiated group with three fractions of 6 Gy at day 8, 11 and 14. Survival and toxicity were assessed. Results Irradiated rats had significantly a longer survival (p = 0.01. No deaths occurred due to the treatment. Toxicities of reduced weight and alopecia were increased during the radiation period but no serious morbidity or mortality was observed. Moreover, abnormalities disappeared the week following the end of the therapeutic schedule. Conclusions Delivering 18 Gy in 3 fractions of 6 Gy every 3 days, with mild anaesthesia, is safe, easy to reproduce and allows for standardisation in preclinical studies of different treatment regimens glioma rat model.

  15. 牛蒡子苷元对大鼠脑胶质瘤的作用及初步作用机制探讨%Effects and primary mechanism of arctigenin in C6 rat glioma

    Institute of Scientific and Technical Information of China (English)

    苏勤勇; 李晓梅; 姚景春; 王平平; 张贵民

    2015-01-01

    Aim To observe the effect and primary mechanism of arctigenin ( ARG) in C6 rat glioma. At the same time, to investigate the effect of ARG com-bined with temozolomide. Methods C6 glioma rat model was established, and 90 rats were divided into six groups, which were subcutaneously administered with model, low and high ARG (0. 05 and 0. 1 mg· kg-1 , sc) , temozolomide (20 mg·kg-1 , p. o. ) , low ARG combined with temozolomide(TMZ / ARG 0. 05) and high ARG combined with temozolomide ( TMZ /ARG 0. 1 ) . The tumor specimens of brain were col-lected after tumor graft. Proliferating cell nuclear anti-gen ( PCNA ) , glial fibrillary acidic protein ( GFAP ) and CD40 in tumor specimens were determined by im-munohistochemistry. Results ① Compared with the model group, the tumor sizes of rats in the arctigenin treatment groups were decreased ( P significantly decreased PCNA and CD40 expression ( P<0. 05 ) and increased GFAP expression ( P<0. 05 ) .③ Compared with model group, arctigenin combined with temozolomide decreased the tumor sizes ( P <0. 01 ) , and the tumor inhibition rate was higher than that of the arctigenin and temozolomide. At the same time, arctigenin combined with temozolomide de-creased PCNA and CD40 expression ( P <0. 01 ) and increased GFAP expression ( P <0. 05 ) , which was better than arctigenin and temozolomide. Conclusion Arctigenin inhibits rat glioma growth, and synergizes with temozolomide, which may be associated with in-hibiting PCNA and CD40 expression and strengthening GFAP expression.%目的:观察牛蒡子苷元对大鼠C6胶质瘤的作用及作用机制的研究。同时探讨牛蒡子苷元与替莫唑胺合用对脑胶质瘤是否有协同作用。方法采用脑内注射C6胶质瘤细胞建立大鼠C6胶质瘤模型;牛蒡子苷元连续皮下给药15 d,替莫唑胺从d5开始给药,连续灌胃给药5 d;测量肿瘤的长短径,计算肿瘤体积;采用免疫组化方法检测脑瘤组织中GFAP、PCNA和CD40的表达。结

  16. The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma

    Directory of Open Access Journals (Sweden)

    Chen JQ

    2015-09-01

    Full Text Available Jian-qiang Chen,1 Yue-fu Zhan,2 Wei Wang,1 Sheng-nan Jiang,2,3 Xiang-ying Li21Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Department of Radiology, Affiliated to Haikou Hospital Xiangya School of Medicine, Central South University, Haikou, People’s Republic of China; 3Department of Nuclear Medicine, Central South University Xiangya School of Medicine Affiliated HaiKou Hospital, Haikou, Hainan, People’s Republic of ChinaObjective: To explore the antitumor role of the attenuated Salmonella typhimurium ΔppGpp with inducible cytolysin A (ClyA in advanced stage of glioma.Materials and methods: The C6 rat glioma cells were orthotopically implanted by surgery into the caudate nucleus of rat brains. The rats were then randomly divided into the treatment group (SL + ClyA (n=12, negative control group (SL (n=12, and control group (phosphate-buffered saline [PBS] (n=12. In the treatment group, the attenuated S. typhimurium were transformed with the plasmid-encoded antitumor gene ClyA. The expression of ClyA was controlled by the TetR-regulated promoter in response to extracellular doxycycline. The plasmid also contained an imaging gene lux to allow illumination of the tumor infected by the bacteria. The rat glioma C6 cells were implanted into the caudate nucleus of all rats. The engineered S. typhimurium and respective controls were injected intravenously into the rats 21 days after initial tumor implantation. The pathological analysis of the glioma tumor was performed at 21 days and 28 days (7 days after doxycycline treatment postimplantation. All rats underwent MRI (magnetic resonance imaging and bioluminescence study at 21 days and 28 days postimplantation to detect tumor volume. The differences between the three groups in tumor volume and survival time were analyzed.Results: Advanced stage glioma  was detected at 21 days postimplantation. Bioluminescence showed that the

  17. Temozolomide in malignant glioma

    Directory of Open Access Journals (Sweden)

    Gregor Dresemann

    2010-07-01

    Full Text Available Gregor DresemannCenter for Neurooncology at Aerztehaus Velen, Velen, GermanyAbstract: Glioblastoma multiforme WHO grade IV (GBM is the most aggressive ­malignant glioma and the most frequent primary tumor of the central nervous system. The median ­survival of newly diagnosed GBM patients was between 9 to 12 months prior to treatment with ­temozolomide being introduced. Primary resection that is as complete as possible is recommended for malignant glioma. Conventional fractionated irradiation 55 to 60 gy with concomitant temozolomide followed by standard temozolomide 6 cycles (5/28 (EORTC/NCIC-regime published by R Stupp in 2005 is the standard of care for newly diagnosed GBM after surgery, independent of the methylation status of the MGM-T gene promoter. Age is no ­contraindication for treatment with temozolomide, although comorbidity and performance status have to be ­considered. For temozolomide naive GBM and astrocytoma grade III patients with disease progression, temozolomide is still the treatment of choice outside of clinical studies. A ­general consensus regarding the schedule of choice has not yet been achieved; so far the 5 out of 28 days regimen (5/28 is the standard of care in most countries. Patients with disease progression after standard temozolomide (5/28 are candidates for clinical studies. Outside of clinical ­studies, dose-dense (7/7, prolonged (21/28, or metronomic (28/28 temozolomide, or alternatively a nitrosourea-based regimen can be an option. The excellent toxicity profile of ­temozolomide allows for various combinations with antitumor agents. None of these ­combinations, however, have been demonstrated to be statistically significantly superior compared to temozolomide alone. The role of lower dosed, dose-dense, or continuous regimen with or without drug combination and the role of temozolomide for newly diagnosed astrocytoma grade III and low grade glioma still has to be determined.Keywords: glioblastoma

  18. Glioma-derived mutations in isocitrate dehydrogenase 2 beneficial to traditional chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Yuejun, E-mail: yjfu@sxu.edu.cn [Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006 (China); Huang, Rui; Zheng, Yali; Zhang, Zhiyun; Liang, Aihua [Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006 (China)

    2011-07-01

    Highlights: {yields} IDH1 and IDH2 mutations are not detected in the rat C6 glioma cell line model. {yields} IDH2 mutations are not required for the tumorigenesis of glioma. {yields} IDH2{sup R172G} can sensitize glioma sensitivity to chemotherapy through NADPH levels. {yields} IDH2{sup R172G} can give a benefit to traditional chemotherapy of glioma. {yields} This finding serves as an important complement to existing research on this topic. -- Abstract: Heterozygous mutations in either the R132 residue of isocitrate dehydrogenase I (IDH1) or the R172 residue of IDH2 in human gliomas were recently highlighted. In the present study, we report that mutations of IDH1 and IDH2 are not detected in the rat C6 glioma cell line model, which suggests that these mutations are not required for the development of glioblastoma induced by N,N'-nitroso-methylurea. The effects of IDH2 and IDH2{sup R172G} on C6 cells proliferation and sensitivity to chemotherapy and the possible mechanism are analyzed at the cellular level. IDH1 and IDH2 mutations lead to simultaneous loss and gain of activities in the production of {alpha}-ketoglutarate ({alpha}-KG) and 2-hydroxyglutarate (2HG), respectively, and result in lowering NADPH levels even further. The low NADPH levels can sensitize tumors to chemotherapy, and account for the prolonged survival of patients harboring the mutations. Our data extrapolate potential importance of the in vitro rat C6 glioma cell model, show that the IDH2{sup R172G} mutation in gliomas may give a benefit to traditional chemotherapy of this cancer and serve as an important complement to existing research on this topic.

  19. 替莫唑胺联合小剂量缓激肽对延长胶质瘤大鼠生存期的观察%Observe effects of Temozolomide combined with low dose Bradykinin in prolonging survival time of rat with glioma

    Institute of Scientific and Technical Information of China (English)

    于倩; 宋飞; 刘贺; 白莉娜

    2012-01-01

    Objective To investigate the effect of Temozolomide combined with low dose Bradykinin for glioma therapy. Methods To use the stereotactic method to establish the C6 glioma model rats,and lest the glioma growth by MRI. Observerd the survival condition of the models treated with Temozolomide and Temozolomide with low dose Bradykinin,studied the survival times in different groups by statistical analysis. Resnlts Temozolomide could prolong the survival times of the models,and prolonged more signally after treated with low dose Bradykinin. Conclusion Temozolomide has curative effect for glioma,low dose Bradykinin can open blood brain barrier,temozolomide combined with low dose Bradykinin can treat glioma effectively,prolong the survival times of the rat models.%目的 探讨替莫唑胺联合小剂量缓激肽对胶质瘤的治疗作用.方法 立体定向法建立大鼠C6胶质瘤模型,MRI检测胶质瘤生长情况.观察常规使用替莫唑胺及替莫唑胺联合小剂量缓激肽后C6胶质瘤大鼠的生存情况,不同组别大鼠的生存期进行统计学分析.结果 替莫唑胺可以有效延长C6胶质瘤大鼠的生存期,联合小剂量缓激肽后C6胶质瘤大鼠的生存期延长更显著.结论 替莫唑胺对胶质瘤有治疗作用,小剂量缓激肽可以选择性开放血脑屏障,替莫唑胺联合小剂量缓激肽可以有效治疗胶质瘤,延长大鼠生存期.

  20. Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy

    Directory of Open Access Journals (Sweden)

    Mueller-Klieser Wolfgang

    2011-07-01

    Full Text Available Abstract Background Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. Methods To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. Results The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2, 3-oxoacid-CoA transferase 1 (OXCT1 and acetyl-CoA acetyltransferase 1 (ACAT1 were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. Conclusion In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic

  1. Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy

    Science.gov (United States)

    2011-01-01

    Background Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. Methods To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. Results The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. Conclusion In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently

  2. Tricyclic Neovibsanin Scaffold Inhibits Glioma by Targeting Glioma ...

    African Journals Online (AJOL)

    formation capacity and induction of apoptosis in glioma cells. Methods: ... present in plants and possess polyfunctional structures ... the ethics and review committee for the animal studies at .... adhered and started to differentiate forming U138.

  3. A human brainstem glioma xenograft model enabled for bioluminescence imaging

    OpenAIRE

    Hashizume, Rintaro; Ozawa, Tomoko; Dinca, Eduard B.; Banerjee, Anuradha; Prados, Michael D.; James, Charles D.; Gupta, Nalin

    2009-01-01

    Despite the use of radiation and chemotherapy, the prognosis for children with diffuse brainstem gliomas is extremely poor. There is a need for relevant brainstem tumor models that can be used to test new therapeutic agents and delivery systems in pre-clinical studies. We report the development of a brainstem-tumor model in rats and the application of bioluminescence imaging (BLI) for monitoring tumor growth and response to therapy as part of this model. Luciferase-modified human glioblastoma...

  4. Extract from Buthus martensii Karsch is associated with potassium channels on glioma cells

    Institute of Scientific and Technical Information of China (English)

    Mingxian Li; Hongmei Meng; Shao Wang; Min Huang; Li Cui; Weihong Lin

    2011-01-01

    Catilan extracted from Leiurus quinquestriatus is a specific ion channel blocker.It can specifically bind chloride channels of glioma cells and kill these tumor cells.The questions remain as to whether antigliomatin,the extract from scorpion venom of Buthus martensii Karsch in China,can inhibit glioma growth,and whether this inhibition is correlated with ion channels of tumor cells.The present study treated rat C6 glioma cells with 0.8,1.2,and 1.6 μg/mL antigliomatin for 20 hours.Whole-cell patch clamp technique showed that antigliomatin delayed rectifier potassium channels of C6 glioma cells.Antigliomatin inhibited tumor growth,which could potentially involve potassium channels of tumor cells.

  5. [Controversy on treatments for gliomas].

    Science.gov (United States)

    Nomura, K

    1998-09-01

    Gliomas are representative primary malignant brain tumors, and with such tumors it is difficult to define the advanced stage. If the advanced stage indicates no curability by surgery alone, most gliomas would belong to this criterion because of their poor prognosis without any completely effective treatment. In this sense, no one could show a standard therapy to treat these unfortunate patients, for example, patients with glioblastoma, they could permit only 1 year survived even they had any applicable treatments to the lesions, these days. Treatment for low-grade gliomas has been most controversial for a long time, and no standard treatments have been determined so far. In this paper, as the treatment of low-grade gliomas it was intended to report what must be done for this patient and the present results of opinion survey for the treatment of gliomas which was done to professors of 80 institutes, from schools of medicine at all universities and medical colleges in Japan. For high-grade gliomas, some effectiveness of radiation therapy was disclosed as well as chemotherapy from recent papers. Gene therapy was also discussed briefly, its present status and future.

  6. Notch Promotes Radioresistance of Glioma Stem Cells

    OpenAIRE

    Wang, Jialiang; Wakeman, Timothy P.; Latha, Justin D.; Hjelmeland, Anita B.; Wang, Xiao-Fan; White, Rebekah R.; Rich, Jeremy N.; Sullenger, Bruce A.

    2010-01-01

    Radiotherapy represents the most effective nonsurgical treatments for gliomas. Yet, gliomas are highly radioresistant and recurrence is nearly universal. Results from our laboratory and other groups suggest that cancer stem cells contribute to radioresistance in gliomas and breast cancers. The Notch pathway is critically implicated in stem cell fate determination and cancer. In this study, we showed that inhibition of Notch pathway with gamma-secretase inhibitors (GSIs) rendered the glioma st...

  7. Use of statins and risk of glioma

    DEFF Research Database (Denmark)

    Gaist, David; Andersen, L; Hallas, Jesper;

    2013-01-01

    Laboratory studies and a single case-control study have suggested a protective effect of statins on the risk of glioma. We wished to investigate the influence of statin use on the risk of glioma in a population-based setting.......Laboratory studies and a single case-control study have suggested a protective effect of statins on the risk of glioma. We wished to investigate the influence of statin use on the risk of glioma in a population-based setting....

  8. Imaging of adult brainstem gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Purohit, Bela, E-mail: purohitbela@yahoo.co.in; Kamli, Ali A.; Kollias, Spyros S.

    2015-04-15

    Highlights: •BSG are classified on MRI into diffuse low-grade, malignant, focal tectal and exophytic subtypes. •Their prognosis and treatment is variable and is almost similar to adult supratentorial gliomas. •This article illustrates the imaging of adult BSGs on MRI and FET-PET. •We also describe prognostic factors and the treatment options of these tumours. -- Abstract: Brainstem gliomas (BSGs) are uncommon in adults accounting for about 2% of all intracranial neoplasms. They are often phenotypically low-grade as compared to their more common paediatric counterparts. Since brainstem biopsies are rarely performed, these tumours are commonly classified according to their MR imaging characteristics into 4 subgroups: (a) diffuse intrinsic low-grade gliomas, (b) enhancing malignant gliomas, (c) focal tectal gliomas and (d) exophytic gliomas/other subtypes. The prognosis and treatment is variable for the different types and is almost similar to adult supratentorial gliomas. Radiotherapy (RT) with adjuvant chemotherapy is the standard treatment of diffuse low-grade and malignant BSGs, whereas, surgical resection is limited to the exophytic subtypes. Review of previous literature shows that the detailed imaging of adult BSGs has not received significant attention. This review illustrates in detail the imaging features of adult BSGs using conventional and advanced MR techniques like diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), MR perfusion weighted imaging (PWI), MR spectroscopy (MRS), as well as {sup 18}F-fluoro-ethyl-tyrosine positron emission tomography ({sup 18}F-FET/PET). We have discussed the pertinent differences between childhood and adult BSGs, imaging mimics, prognostic factors and briefly reviewed the treatment options of these tumours.

  9. Bystander effect in glioma suicide gene therapy using bone marrow stromal cells.

    Science.gov (United States)

    Li, Shaoyi; Gu, Chunyu; Gao, Yun; Amano, Shinji; Koizumi, Shinichiro; Tokuyama, Tsutomu; Namba, Hiroki

    2012-11-01

    An established rat intracranial glioma was successfully treated through the tumoricidal bystander effect generated by intratumoral injection of rat bone marrow stromal cells (BMSCs) transduced with the herpes simplex virus-thymidine kinase gene (BMSCtk cells) followed by systemic ganciclovir administration. In the present study, we tested the bystander effect of this treatment strategy when using human BMSCs as the vector cells. Human BMSCtk cells were mixed with various kinds of brain tumor cell lines (human and rat glioma cells) and examined in vitro and in vivo tumoricidal bystander effects, by co-culture study and co-implantation study in the nude mouse, respectively. A significant in vitro bystander effect was observed between human BMSCtk cells and any of the tumor cells examined in the ganciclovir-containing medium. A potent in vivo bystander effect against human and rat glioma cells was also demonstrated when ganciclovir was administered. Migratory activity of the human BMSCs toward the tumor cells was enhanced by the conditioned media obtained from both human and rat glioma cells compared to the fresh media. The results of this study have demonstrated that the bystander effect generated by BMSCtk cells and ganciclovir is not cell type-specific, suggesting that the strategy would be quite feasible for clinical use. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. 胶质瘤氩氦冻融产物负载树突状细胞对颅内胶质瘤大鼠的免疫治疗研究%Immunotherapy effect of dendritic cells pulsed by lysate of tumor cell Ar-He cryoablation on rat models of intracraniai gliomas

    Institute of Scientific and Technical Information of China (English)

    苏道庆; 卢国辉; 胡丽娟; 王保安; 李明; 何骁征; 姜晓丹; 柯以铨; 张世忠

    2012-01-01

    Objective To investigate the role of C6 glioma cells mediated by rapid freezing and thawing ofAr-He cryoablation in the maturation of marrow-derived dendritic cells (BM-DCs) in Wistar rats,and the anti-tumor effect of these DCs on rat models of intracranial gliomas. Methods C6 glioma cells were routinely cultured in vitro; rapid freezing and thawing of Ar-He cryoablation was employed in C6 glioma cells of the experimental group, and C6 glioma cells of the negative control group were only performed insertion of the probe; blank control group (using rapid freezing and thawing of Ar-He cryoablation on the same amount of PBS) was also employed.Bone marrow-derived mononuclear cells (MNCs) were first prepared from tibia and femur bones of Wistar rats. These cells were cultured with such cytokines as recombinant granulocyte-macrophage colony-stimulating factor (rmGM-CSF),recombinant interleukin-4 (rmIL-4) and tumor necrosis factor-alpha (TNFα) to induce their maturation; BM-DCs were pulsed with or without tumor cell lysate obtained by rapid freezing and thawing of Ar-Hecryoablation at a ratio of (DC:tumor cells =1:3) 7 d after that.Morphological observation of BM-DCs was performed by light microscopy and the expression of DCs costimulatory molecules CD80 and CD86 were measured by flow cytometry 48 h after the addiction; the IL-12 level in the supematant of DCs was detected by ELISA. In order to determine whether or not vaccination with C6 TP DCs can induce the therapeutic potential in the established glioma-bearing models, the C6 cells cultured in vitro were stereotaxically implanted into the left caudate nucleus of Wistar rat brain; glioma-bearing rats were injected with vaccination with DCs,cells from the blank control group and negative control group on the 3rd and 10th d. Survival time was observed and determined using the method of Kaplan-Meier and Log-Rank analysis. Results DCs from rats' bone marrow cells cultured with cytokines and pulsed with tumor lysates

  11. Isocitrate dehydrogenase mutations in gliomas.

    Science.gov (United States)

    Waitkus, Matthew S; Diplas, Bill H; Yan, Hai

    2016-01-01

    Over the last decade, extraordinary progress has been made in elucidating the underlying genetic causes of gliomas. In 2008, our understanding of glioma genetics was revolutionized when mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) were identified in the vast majority of progressive gliomas and secondary glioblastomas (GBMs). IDH enzymes normally catalyze the decarboxylation of isocitrate to generate α-ketoglutarate (αKG), but recurrent mutations at Arg(132) of IDH1 and Arg(172) of IDH2 confer a neomorphic enzyme activity that catalyzes reduction of αKG into the putative oncometabolite D-2-hydroxyglutate (D2HG). D2HG inhibits αKG-dependent dioxygenases and is thought to create a cellular state permissive to malignant transformation by altering cellular epigenetics and blocking normal differentiation processes. Herein, we discuss the relevant literature on mechanistic studies of IDH1/2 mutations in gliomas, and we review the potential impact of IDH1/2 mutations on molecular classification and glioma therapy.

  12. Rehabilitation of patients with glioma.

    Science.gov (United States)

    Vargo, Mary; Henriksson, Roger; Salander, Pär

    2016-01-01

    Disabling sequelae occur in a majority of patients diagnosed with brain tumor, including glioma, such as cognitive deficits, weakness, and visual perceptual changes. Often, multiple impairments are present concurrently. Healthcare staff must be aware of the "biographic disruption" the patient with glioma has experienced. While prognostic considerations factor into rehabilitation goals and expectations, regardless of prognosis the treatment team must offer cohesive support, facilitating hope, function, and quality of life. Awareness of family and caregiver concerns plays an important role in the overall care. Inpatient rehabilitation, especially after surgical resection, has been shown to result in functional improvement and homegoing rates on a par with individuals with other neurologic conditions, such as stroke or traumatic brain injury. Community integration comprises a significant element of life satisfaction, as has been shown in childhood glioma survivors. Employment is often affected by the glioma diagnosis, but may be ameliorated, when appropriate, by addressing modifiable factors such as depression, fatigue, or sleep disturbance, or by workplace accommodations. Further research is needed into many facets of rehabilitation in the setting of glioma, including establishing better care models for consistently identifying and addressing functional limitations in this population, measuring outcomes of various levels of rehabilitation care, identifying optimal physical activity strategies, delineating the long-term effects of rehabilitation interventions, and exploring impact of rehabilitation interventions on caregiver burden. The effective elements of cognitive rehabilitation, including transition of cognitive strategies to everyday living, need to be better defined.

  13. Migration capacity of human umbilical cord mesenchymal stem cells towards glioma in vivo*

    Institute of Scientific and Technical Information of China (English)

    Cungang Fan; Dongliang Wang; Qingjun Zhang; Jingru Zhou

    2013-01-01

    High-grade glioma is the most common malignant primary brain tumor in adults. The poor prognosis of glioma, combined with a resistance to currently available treatments, necessitates the ment of more effective tumor-selective therapies. Stem cel-based therapies are emerging as novel cel-based delivery vehicle for therapeutic agents. In the present study, we successful y isolated human umbilical cord mesenchymal stem cel s by explant culture. The human umbilical cord senchymal stem cel s were adherent to plastic surfaces, expressed specific surface phenotypes of mesenchymal stem cel s as demonstrated by flow cytometry, and possessed multi-differentiation potentials in permissive induction media in vitro. Furthermore, human umbilical cord mesenchymal stem cel s demonstrated excel ent glioma-specific targeting capacity in established rat glioma models after intratumoral injection or contralateral ventricular administration in vivo. The excellent glioma-specific targeting ability and extensive intratumoral distribution of human umbilical cord mesenchymal stem cel s indicate that they may serve as a novel cel ular vehicle for delivering the-rapeutic molecules in glioma therapy.

  14. Aptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery.

    Science.gov (United States)

    Guo, Jianwei; Gao, Xiaoling; Su, Lina; Xia, Huimin; Gu, Guangzhi; Pang, Zhiqing; Jiang, Xinguo; Yao, Lei; Chen, Jun; Chen, Hongzhuan

    2011-11-01

    Targeted delivery of therapeutic nanoparticles in a disease-specific manner represents a potentially powerful technology especially when treating infiltrative brain tumors such as gliomas. We developed a nanoparticulate drug delivery system decorated with AS1411 (Ap), a DNA aptamer specifically binding to nucleolin which was highly expressed in the plasma membrane of both cancer cells and endothelial cells in angiogenic blood vessels, as the targeting ligand to facilitate anti-glioma delivery of paclitaxel (PTX). Ap was conjugated to the surface of PEG-PLGA nanoparticles (NP) via an EDC/NHS technique. With the conjugation confirmed by Urea PAGE and XPS, the resulting Ap-PTX-NP was uniformly round with particle size at 156.0 ± 54.8 nm and zeta potential at -32.93 ± 3.1 mV. Ap-nucleolin interaction significantly enhanced cellular association of nanoparticles in C6 glioma cells, and increased the cytotoxicity of its payload. Prolonged circulation and enhanced PTX accumulation at the tumor site was achieved for Ap-PTX-NP, which eventually obtained significantly higher tumor inhibition on mice bearing C6 glioma xenografts and prolonged animal survival on rats bearing intracranial C6 gliomas when compared with PTX-NP and Taxol(®). The results of this contribution demonstrated the potential utility of AS1411-functionalized nanoparticles for a therapeutic application in the treatment of gliomas.

  15. NUMB does not impair growth and differentiation status of experimental gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Euskirchen, Philipp, E-mail: philipp.euskirchen@charite.de [Department of Biomedicine, University of Bergen (Norway); Laboratory for Gene Therapy and Molecular Imaging, Max-Planck-Institute for Neurological Research, Cologne (Germany); Skaftnesmo, Kai-Ove; Huszthy, Peter C.; Brekka, Narve [Department of Biomedicine, University of Bergen (Norway); Bjerkvig, Rolf [Department of Biomedicine, University of Bergen (Norway); NorLux Neuro-Oncology Laboratory, Centre de Public de la Sante, Luxembourg (Luxembourg); Jacobs, Andreas H. [Laboratory for Gene Therapy and Molecular Imaging, Max-Planck-Institute for Neurological Research, Cologne (Germany); European Institute for Molecular Imaging, Muenster (Germany); Miletic, Hrvoje [Department of Biomedicine, University of Bergen (Norway); Department of Pathology, Haukeland University Hospital, Bergen (Norway)

    2011-12-10

    The cell fate determinant NUMB orchestrates asymmetric cell division in flies and mammals and has lately been suggested to have a tumor suppressor function in breast and lung cancer. Here, we studied NUMB in the context of malignant gliomas. We used ectopic expression of NUMB in order to inhibit proliferation and induce differentiation in glioma cells by alteration of Notch, Hedgehog and p53 signaling. We found that NUMB is consistently expressed in glioma biopsies with predominance of NUMB2/4 isoforms as determined by isoform-specific real-time PCR and Western blotting. Upon lentiviral overexpression, in vitro proliferation rate and the grade of differentiation as assessed by morphology and expression of neural and glial markers remained unchanged. Orthotopic xenografts of NUMB-transduced human U87 glioma cells could be established in nude rats without impairing engraftment or causing significant changes in morphology based on magnetic resonance imaging (MRI). The previously reported alteration of Hedgehog and p53 signaling by NUMB could not be recapitulated in glioma cells. We thus show that in experimental gliomas, NUMB overexpression most likely does not exert a tumor suppressor function such as seen in epithelial cancers.

  16. Paediatric and adult malignant glioma

    DEFF Research Database (Denmark)

    Jones, Chris; Perryman, Lara; Hargrave, Darren

    2012-01-01

    Gliomas in children differ from their adult counterparts by their distribution of histological grade, site of presentation and rate of malignant transformation. Although rare in the paediatric population, patients with high-grade gliomas have, for the most part, a comparably dismal clinical outcome...... to older patients with morphologically similar lesions. Molecular profiling data have begun to reveal the major genetic alterations underpinning these malignant tumours in children. Indeed, the accumulation of large datasets on adult high-grade glioma has revealed key biological differences between...... the adult and paediatric disease. Furthermore, subclassifications within the childhood age group can be made depending on age at diagnosis and tumour site. However, challenges remain on how to reconcile clinical data from adult patients to tailor novel treatment strategies specifically for paediatric...

  17. Immunotherapy for malignant glioma

    Directory of Open Access Journals (Sweden)

    Carter M Suryadevara

    2015-01-01

    Full Text Available Malignant gliomas (MG are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM, the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

  18. Frequent Nek1 overexpression in human gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Jun [School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai (China); Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Cai, Yu, E-mail: aihaozuqiu22@163.com [School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai (China); Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Liu, Pin [Med-X Research Institute, Shanghai Jiao Tong University, Shanghai (China); Zhao, Weiguo [Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China)

    2016-08-05

    Never in mitosis A (NIMA)-related kinase 1 (Nek1) regulates cell cycle progression to mitosis. Its expression and potential functions in human gliomas have not been studied. Here, our immunohistochemistry (IHC) assay and Western blot assay results showed that Nek1 expression was significantly upregulated in fresh and paraffin-embedded human glioma tissues. Its level in normal brain tissues was low. Nek1 overexpression in human gliomas was correlated with the proliferation marker (Ki-67), tumor grade, Karnofsky performance scale (KPS) and more importantly, patients’ poor survival. Further studies showed that Nek1 expression level was also increased in multiple human glioma cell lines (U251-MG, U87-MG, U118, H4 and U373). Significantly, siRNA-mediated knockdown of Nek1 inhibited glioma cell (U87-MG/U251-MG) growth. Nek1 siRNA also sensitized U87-MG/U251-MG cells to temozolomide (TMZ), causing a profound apoptosis induction and growth inhibition. The current study indicates Nek1 might be a novel and valuable oncotarget of glioma, it is important for glioma cell growth and TMZ-resistance. - Highlights: • Nek1 is upregulated in multiple human glioma tissues and cell lines. • Nek1 overexpression correlates with glioma grades and patients’ KPS score. • Nek1 overexpression correlates with patients’ poor overall survival. • siRNA knockdown of Nek1 inhibits glioma cell growth. • siRNA knockdown of Nek1 sensitizes human glioma cells to temozolomide.

  19. Neuronavigator-guided glioma surgery

    Institute of Scientific and Technical Information of China (English)

    杜固宏; 周良辅; 毛颖

    2003-01-01

    Objective To evaluate the effectiveness of neuronavigator-guided surgery for the resection of gliomas. Methods A total of 80 patients with gliomas underwent surgical treatment under the StealthStation neuronavigator to estimate the extent of the tumors. In 27 cases, the measurements of brain shifts at the dura, cortical surface and lesion margin were recorded during the operations. A technique termed "micro-catheter fence post" was used in superficial gliomas to compensate for brain shift.Results Mean fiducial error and predicted accuracy in the 80 cases were 2.03 mm±0.89 mm and 2.43 mm±0.99 mm, respectively. The shifts at the dura, cortical surface and lesion margin were 3.44 mm±2.39 mm, 7.58 mm±3.75 mm, and 6.55 mm±3.19 mm, respectively. Although neuronavigation revealed residual tumors, operations were discontinued in 5 cases of deep-seated gliomas. In the other 75 cases, total tumor removals were achieved in 62 (82.7%), and subtotal removals were achieved in 13 (17.3%). Post-operation, neurological symptoms were improved or unchanged in 68 cases (85.0%), and worsened in 12 (15.0%). No deaths occurred during the operations and post-operations. Conclusions Intraoperative brain shifts mainly contribute to the fail of spatial accuracy during neuronavigator-guided glioma surgery. The "micro-catheter fence post" technique used for glioma surgery is shown to be useful for compensating for intraoperative brain shifts. This technique, thus, contributes to an increase in total tumor removal and a decrease in surgical complications.

  20. Pediatric gliomas as neurodevelopmental disorders.

    Science.gov (United States)

    Baker, Suzanne J; Ellison, David W; Gutmann, David H

    2016-06-01

    Brain tumors represent the most common solid tumor of childhood, with gliomas comprising the largest fraction of these cancers. Several features distinguish them from their adult counterparts, including their natural history, causative genetic mutations, and brain locations. These unique properties suggest that the cellular and molecular etiologies that underlie their development and maintenance might be different from those that govern adult gliomagenesis and growth. In this review, we discuss the genetic basis for pediatric low-grade and high-grade glioma in the context of developmental neurobiology, and highlight the differences between histologically-similar tumors arising in children and adults.

  1. Epidermal growth factor (EGF) as a potential targeting agent for delivery of boron to malignant gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Capala, J.; Barth, R.F.; Adams, D.M.; Bailey, M.Q.; Soloway, A.H. [Ohio State Univ., Columbus, OH (United States); Carlsson, J. [Uppsala Univ. (Sweden). Dept. of Radiation Sciences

    1994-12-31

    The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and this often is associated with an increase in cell surface receptor expression. The rapid internalization and degradation of EGF-EGFR complexes, as well as their high affinity make EGF a potential targeting agent for delivery of {sup 10}B to tumor cells with an amplified number of EGFR. Human glioma cells can expresses as many as 10{sup 5} {minus}10{sup 6} EGF receptors per cell, and if these could be saturated with boronated EGF, then > 10{sup 8} boron atoms would be delivered per cell. Since EGF has a comparatively low molecular weight ({approximately} 6 kD), this has allowed us to construct relatively small bioconjugates containing {approximately} 900 boron atoms per EGF molecule{sup 3}, which also had high affinity for EGFR on tumor cells. In the present study, the feasibility of using EGF receptors as a potential target for therapy of gliomas was investigated by in vivo scintigraphic studies using {sup 131}I{minus} or {sup 99m}{Tc}-labeled EGF in a rat brain tumor model. Our results indicate that intratumorally delivered boron- EGF conjugates might be useful for targeting EGFR on glioma cells if the boron containing moiety of the conjugates persisted intracellularly. Further studies are required, however, to determine if this approach can be used for BNCT of the rat glioma.

  2. The translocator protein ligand [{sup 18}F]DPA-714 images glioma and activated microglia in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Winkeler, Alexandra; Boisgard, Raphael; Awde, Ali R.; Dubois, Albertine; Theze, Benoit; Zheng, Jinzi [Universite Paris Sud, Inserm, U1023, Laboratoire d' Imagerie Moleculaire Experimentale, Orsay (France); CEA, I2BM, SHFJ, Orsay (France); Ciobanu, Luisa [CEA, DSV, I2BM, NeuroSpin, LRMN, Gif sur Yvette (France); Dolle, Frederic [CEA, I2BM, SHFJ, Orsay (France); Viel, Thomas; Jacobs, Andreas H. [Westfaelische Wilhelm-Universitaet Muenster (WWU), European Institute for Molecular Imaging (EIMI), Muenster (Germany); Tavitian, Bertrand [Universite Paris Sud, Inserm, U1023, Laboratoire d' Imagerie Moleculaire Experimentale, Orsay (France)

    2012-05-15

    In recent years there has been an increase in the development of radioligands targeting the 18-kDa translocator protein (TSPO). TSPO expression is well documented in activated microglia and serves as a biomarker for imaging neuroinflammation. In addition, TSPO has also been reported to be overexpressed in a number of cancer cell lines and human tumours including glioma. Here we investigated the use of [{sup 18}F]DPA-714, a new TSPO positron emission tomography (PET) radioligand to image glioma in vivo. We studied the uptake of [{sup 18}F]DPA-714 in three different rat strains implanted with 9L rat glioma cells: Fischer (F), Wistar (W) and Sprague Dawley (SD) rats. Dynamic [{sup 18}F]DPA-714 PET imaging, kinetic modelling of PET data and in vivo displacement studies using unlabelled DPA-714 and PK11195 were performed. Validation of TSPO expression in 9L glioma cell lines and intracranial 9L gliomas were investigated using Western blotting and immunohistochemistry of brain tissue sections. All rats showed significant [{sup 18}F]DPA-714 PET accumulation at the site of 9L tumour implantation compared to the contralateral brain hemisphere with a difference in uptake among the three strains (F > W > SD). The radiotracer showed high specificity for TSPO as demonstrated by the significant reduction of [{sup 18}F]DPA-714 binding in the tumour after administration of unlabelled DPA-714 or PK11195. TSPO expression was confirmed by Western blotting in 9L cells in vitro and by immunohistochemistry ex vivo. The TSPO radioligand [{sup 18}F]DPA-714 can be used for PET imaging of intracranial 9L glioma in different rat strains. This preclinical study demonstrates the feasibility of employing [{sup 18}F]DPA-714 as an alternative radiotracer to image human glioma. (orig.)

  3. D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate.

    Science.gov (United States)

    El Sayed, S M; Abou El-Magd, R M; Shishido, Y; Chung, S P; Sakai, T; Watanabe, H; Kagami, S; Fukui, K

    2012-01-01

    Glioma tumors are refractory to conventional treatment. Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans. In this study, we introduce oxidative stress-energy depletion (OSED) therapy as a new suggested treatment for glioblastoma. OSED utilizes D-amino acid oxidase (DAO), which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide (H2O2). OSED combines DAO with 3-bromopyruvate (3BP), a hexokinase II (HK II) inhibitor that interferes with Warburg effect, a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis. Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action. C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation, clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes. DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague-Dawley (SD) rats, especially after combination with 3BP. OSED treatment was safe and tolerable in SD rats. OSED therapy may be a promising therapeutic modality for glioma.

  4. Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc-, leading to glutathione depletion.

    Science.gov (United States)

    Sleire, L; Skeie, B S; Netland, I A; Førde, H E; Dodoo, E; Selheim, F; Leiss, L; Heggdal, J I; Pedersen, P-H; Wang, J; Enger, P Ø

    2015-12-03

    Glioblastomas (GBMs) are aggressive brain tumors that always recur after radiotherapy. Cystine, mainly provided by the system X(c)(-) antiporter, is a requirement for glioma cell synthesis of glutathione (GSH) which has a critical role in scavenging free radicals, for example, after radiotherapy. Thus, we hypothesized that the X(c)(-)-inhibitor sulfasalazine (SAS) could potentiate the efficacy of radiotherapy against gliomas. Here, we show that the catalytic subunit of system X(c)(-), xCT, was uniformly expressed in a panel of 30 human GBM biopsies. SAS treatment significantly reduced cystine uptake and GSH levels, whereas it significantly increased the levels of reactive oxygen species (ROS) in glioma cells in vitro. Furthermore, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death, whereas adding the antioxidant N-acetyl-L-cysteine (NAC) reversed cell death. Moreover, SAS and gamma knife radiosurgery (GKRS) synergistically prolonged survival in nude rats harboring human GBM xenografts, compared with controls or either treatment alone. In conclusion, SAS effectively blocks cystine uptake in glioma cells in vitro, leading to GSH depletion and increased ROS levels, DNA damage and cell death. Moreover, it potentiates the anti-tumor efficacy of GKRS in rats with human GBM xenografts, providing a survival benefit. Thus, SAS may have a role as a radiosensitizer to enhance the efficacy of current radiotherapies for glioma patients.

  5. 替莫唑胺诱导大鼠脑胶质瘤C6细胞caspase非依赖的程序性死亡%Caspase-independent programmed cell death induced by temozolomide in rat glioma C6 cell line

    Institute of Scientific and Technical Information of China (English)

    刘丽华; 张明

    2015-01-01

    Objective To investigate programmed cell death induced by temozolomide in rat glioma C6 cell line. Methods Rat glioma C6 cell line was treated by temozolomide at different concentrations and for different time lengths. MTT assay was used to evaluate the cell inhibition rate to determine the optimal exposure time and concentration. After the exposure to 400μg/ml temozolomide for 24 h, the cells were observed for programmed cell death using HE staining, Hochest and Tunnel assay, Western blotting, and immunohistochemistry. Results MTT, HE staining, and Hochest and Tunnel assay all showed temozolomide-induced apoptosis in rat glioma C6 cell line. Western blotting and immunohistochemistry revealed up-regulation of Bax and down-regulation of Bcl-2 expression in the exposed cells, where the expressions of caspases 3, 8, 9, and 12 remained unchanged. Conclusion Temozolomide induces apoptosis in rat glioma C6 cell line through a caspase-independent pathway.%目的:观察替莫唑胺对大鼠脑胶质瘤C6细胞程序性死亡的诱导效应,并探讨可能的分子机制。方法观察不同浓度替莫唑胺在不同时间点处理大鼠脑胶质瘤大鼠脑胶质瘤C6细胞系,MTT法观察抑制率并筛选出最优的作用时间和作用浓度。应用400μg/ml替莫唑胺处理细胞24 h,通过HE染色、Hochest、Western blot、Tunnel、免疫组化观察替莫唑胺对大鼠脑胶质瘤C6细胞系的程序性死亡的诱导效应。结果 MTT法、HE染色、Hochest和Tunnel结果显示替莫唑胺对大鼠脑胶质瘤C6细胞具有凋亡诱导效应;免疫组化和Western blot结果显示促凋亡蛋白Bax表达水平上调,凋亡抑制蛋白Bcl-2表达的下调。未发现主要的caspase蛋白的表达变化。结论替莫唑胺对脑胶质瘤C6细胞具有凋亡诱导效应,而这种效应可能是通过caspase非依赖途径完成的。

  6. RETROVIRAL-MEDIATED SUICIDE GENE THERAPY OF EXPERIMENTAL GLIOMA

    Institute of Scientific and Technical Information of China (English)

    Xu Lingfei; Ge Kai; Zheng Zhongcheng; Sun Lanying; Liu Xinyuan

    1998-01-01

    Objective: To establish a retroviral-mediated suicide gene therapy system for experimental glioma and test its efficacy. Methods: C6 rat glioma cells were infected with recombinant retrovirus containing HSV-tk gene. The C6/tk cell line which stably expressed tk was selected and cloned. The sensitivities of C6/tk cells to several nucleoside analogues, such as GCV, BVdU, ACV were compared by the growth inhibition studies. Antitumor effects were also observed after GCV treatment in nude mice bearing tumors derived from C6/tk cells. Results:The growth inhibition studies showed that GCV was the most efficient prodrug in this system. C6/tk cells were highly sensitive to GCV, with an IC50<0.2 μmol/L, being 500-fold less than that in tk-negative C6 cells. In vivo studies showed significant tumor inhibition in the treatment group. Conclusion: Glioma cells can be eradicated by using retroviral-mediated suicide gene system in vitro as well as in vivo.

  7. MicroRNA in Human Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Li, Mengfeng, E-mail: limf@mail.sysu.edu.cn [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080 (China); Li, Jun [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080 (China); Liu, Lei; Li, Wei [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080 (China); Yang, Yi [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080 (China); Yuan, Jie [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Key Laboratory of Functional Molecules from Oceanic Microorganisms (Sun Yat-sen University), Department of Education of Guangdong Province, Guangzhou 510080 (China)

    2013-10-23

    Glioma represents a serious health problem worldwide. Despite advances in surgery, radiotherapy, chemotherapy, and targeting therapy, the disease remains one of the most lethal malignancies in humans, and new approaches to improvement of the efficacy of anti-glioma treatments are urgently needed. Thus, new therapeutic targets and tools should be developed based on a better understanding of the molecular pathogenesis of glioma. In this context, microRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in the development of the malignant phenotype of glioma cells, including cell survival, proliferation, differentiation, tumor angiogenesis, and stem cell generation. This review will discuss the biological functions of miRNAs in human glioma and their implications in improving clinical diagnosis, prediction of prognosis, and anti-glioma therapy.

  8. The Glioma International Case-Control Study

    DEFF Research Database (Denmark)

    Amirian, E. Susan; Armstrong, Georgina N; Zhou, Renke

    2016-01-01

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly...... describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen...

  9. Identification of proteins involved in neural progenitor cell targeting of gliomas

    Directory of Open Access Journals (Sweden)

    Honeth Gabriella

    2009-06-01

    Full Text Available Abstract Background Glioblastoma are highly aggressive tumors with an average survival time of 12 months with currently available treatment. We have previously shown that specific embryonic neural progenitor cells (NPC have the potential to target glioma growth in the CNS of rats. The neural progenitor cell treatment can cure approximately 40% of the animals with malignant gliomas with no trace of a tumor burden 6 months after finishing the experiment. Furthermore, the NPCs have been shown to respond to signals from the tumor environment resulting in specific migration towards the tumor. Based on these results we wanted to investigate what factors could influence the growth and progression of gliomas in our rodent model. Methods Using microarrays we screened for candidate genes involved in the functional mechanism of tumor inhibition by comparing glioma cell lines to neural progenitor cells with or without anti-tumor activity. The expression of candidate genes was confirmed at RNA level by quantitative RT-PCR and at the protein level by Western blots and immunocytochemistry. Moreover, we have developed in vitro assays to mimic the antitumor effect seen in vivo. Results We identified several targets involved in glioma growth and migration, specifically CXCL1, CD81, TPT1, Gas6 and AXL proteins. We further showed that follistatin secretion from the NPC has the potential to decrease tumor proliferation. In vitro co-cultures of NPC and tumor cells resulted in the inhibition of tumor growth. The addition of antibodies against proteins selected by gene and protein expression analysis either increased or decreased the proliferation rate of the glioma cell lines in vitro. Conclusion These results suggest that these identified factors might be useful starting points for performing future experiments directed towards a potential therapy against malignant gliomas.

  10. The pathobiology of glioma tumors.

    Science.gov (United States)

    Gladson, Candece L; Prayson, Richard A; Liu, Wei Michael

    2010-01-01

    The ongoing characterization of the genetic and epigenetic alterations in the gliomas has already improved the classification of these heterogeneous tumors and enabled the development of rodent models for analysis of the molecular pathways underlying their proliferative and invasive behavior. Effective application of the targeted therapies that are now in development will depend on pathologists' ability to provide accurate information regarding the genetic alterations and the expression of key receptors and ligands in the tumors. Here we review the mechanisms that have been implicated in the pathogenesis of the gliomas and provide examples of the cooperative nature of the pathways involved, which may influence the initial therapeutic response and the potential for development of resistance.

  11. Tumor Metabolism of Malignant Gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Ru, Peng; Williams, Terence M.; Chakravarti, Arnab; Guo, Deliang, E-mail: deliang.guo@osumc.edu [Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center & Arthur G James Cancer Hospital, Columbus, OH 43012 (United States)

    2013-11-08

    Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation.

  12. Tumor Metabolism of Malignant Gliomas

    Directory of Open Access Journals (Sweden)

    Deliang Guo

    2013-11-01

    Full Text Available Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation.

  13. Boronophenylalanine uptake in C6 glioma model is dramatically increased by L-DOPA preloading

    Energy Technology Data Exchange (ETDEWEB)

    Capuani, S. [CNR-INFM SOFT, Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 2, Rome (Italy); Enrico Fermi Center, Compendio Viminale, Rome (Italy)], E-mail: silvia.capuani@roma1.infn.it; Gili, T. [CNR-INFM SOFT, Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 2, Rome (Italy); Enrico Fermi Center, Compendio Viminale, Rome (Italy); Bozzali, M. [Neuroimaging Laboratory, Santa Lucia Foundation, Via Ardeatina 306, Rome (Italy); Russo, S. [Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London (United Kingdom); Porcari, P. [CNR-INFM SOFT, Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 2, Rome (Italy); Cametti, C. [CNR-INFM SOFT, Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 2, Rome (Italy); Department of Physics, Sapienza University of Rome, Piazzale Aldo Moro 2, Rome (Italy); Muolo, M. [Department of Biological Science, University ' Rome III' , Viale G. Marconi 446, Rome (Italy); D' Amore, E. [Serv. Qual./Sicurezza Sperim. Anim., Istituto Superiore di Sanita, Rome (Italy); Maraviglia, B. [Enrico Fermi Center, Compendio Viminale, Rome (Italy); Neuroimaging Laboratory, Santa Lucia Foundation, Via Ardeatina 306, Rome (Italy); Lazzarino, G. [Laboratory of Biochemistry, Department of Chemical Sciences, University of Catania, Viale A. Doria 6, Catania (Italy); Pastore, F.S. [Department of Neuroscience, Institute of Neurosurgery, University ' Tor Vergata' , Via Montpellier 1, Rome (Italy)

    2009-07-15

    One of the main limitations for BNCT effectiveness is the insufficient intake of {sup 10}B nuclei within tumour cells. This work was aimed at investigating the use of L-DOPA as enhancer for boronophenylalanine (BPA) uptake in the C6 glioma model. The investigation was first performed in vitro, and then extended in vivo to the animal model. BPA accumulation in C6 glioma cells was assessed, using radiowave dielectric spectroscopy (RDS), with and without L-DOPA preloading. C6 glioma cells were also implanted in the brain of 25 rats, randomly assigned to two experimental branches: (1) intra-carotid BPA infusion; (2) intra-carotid BPA infusion after pre-treatment with L-DOPA, administrated 24 h before BPA infusion. All animals were sacrificed, and assessment of BPA concentrations in tumour tissue, normal brain, and blood samples was performed using high performance liquid chromatography (HPLC). L-DOPA preloading induced a massive increase of BPA concentration either in vitro on C6 glioma cells or in vivo in the animal model tumour. Moreover, no significant difference was found in the normal brain and blood samples between the two animal groups. This study suggests the potential use of L-DOPA as enhancer for BPA accumulation in malignant gliomas eligible for BNCT.

  14. Characterization of highly proliferative secondary tumor clusters along host blood vessels in malignant glioma.

    Science.gov (United States)

    Wang, Ting-Chung; Cheng, Chun-Yu; Yang, Wei-Hsun; Chen, Wen-Cheng; Chang, Pey-Jium

    2015-11-01

    The aim of the present study was to investigate the extensive invasion of tumor cells into normal brain tissue, a life‑threatening feature of malignant gliomas. How invasive tumor cells migrate into normal brain tissue and form a secondary tumor structure remains to be elucidated. In the present study, the morphological and phenotypic changes of glioma cells during invasion in a C6 glioma model were investigated. C6 glioma cells were stereotactically injected into the right putamen region of adult Sprague‑Dawley rats. The brain tissue sections were then subjected to hematoxylin and eosin, immunohistochemical or immunofluorescent staining. High magnification views of the tissue sections revealed that C6 cells formed tumor spheroids following implantation and marked invasion was observed shortly after spheroid formation. In the later stages of invasion, certain tumor cells invaded the perivascular space and formed small tumor clusters. These small tumor clusters exhibited certain common features, including tumor cell multilayers surrounding an arteriole, which occurred up to several millimeters away from the primary tumor mass; a high proliferation rate; and similar gene expression profiles to the primary tumor. In conclusion, the present study revealed that invading tumor cells are capable of forming highly proliferative cell clusters along arterioles near the tumor margin, which may be a possible cause of the recurrence of malignant glioma.

  15. The Pathobiology of Glioma Tumors

    OpenAIRE

    Gladson, Candece L.; Prayson, Richard A.; LIU Wei

    2010-01-01

    The ongoing characterization of the genetic and epigenetic alterations in the gliomas has already improved the classification of these heterogeneous tumors and enabled the development of rodent models for analysis of the molecular pathways underlying their proliferative and invasive behavior. Effective application of the targeted therapies that are now in development will depend on pathologists’ ability to provide accurate information regarding the genetic alterations and the expression of ke...

  16. The anti-tumor effects of calorie restriction are correlated with reduced oxidative stress in ENU-induced gliomas

    Directory of Open Access Journals (Sweden)

    Megan A. Mahlke

    2011-06-01

    Full Text Available The anti-tumor effects of calorie restriction (CR and the possible underlying mechanisms were investigated using ethylnitrosourea (ENU-induced glioma in rats. ENU was given transplacentally at gestational day 15, and male offspring were used in this experiment. The brain from 4-, 6-, and 8-month-old rats fed either ad libitum (AL or calorie-restricted diets (40% restriction of total calories compared to AL rats was studied. Tumor burden was assessed by comparing the number and size of gliomas present in sections of the brain. Immunohistochemical analysis was used to document lipid peroxidation [4-hydroxy-2-nonenal (HNE and malondialdehyde (MDA], protein oxidation (nitrotyrosine, glycation and AGE formation [methylglyoxal (MG and carboxymethyllysine (CML], cell proliferation activity [proliferating cell nuclear antigen (PCNA], cell death [single-stranded DNA (ssDNA], presence of thioredoxin 1 (Trx1, and presence of heme oxygenase-1 (HO-1 associated with the development of gliomas. The results showed that the number of gliomas did not change with age in the AL groups; however, the average size of the gliomas was significantly larger in the 8-month-old group compared to that of the younger groups. Immunopositivity was observed mainly in tumor cells and reactive astrocytes in all histological types of ENU-induced glioma. Immunopositive areas for HNE, MDA, nitrotyrosine, MG, CML, HO-1, and Trx1 increased with the growth of gliomas. The CR group showed both reduced number and size of gliomas, and tumors exhibited less accumulation of oxidative damage, decreased formation of glycated end products, and a decreased presence of HO-1 and Trx1 compared to the AL group. Furthermore, gliomas of the CR group showed less PCNA positive and more ssDNA positive cells, which are correlated to the retarded growth of tumors. Interestingly, we also discovered that the anti-tumor effects of CR were associated with decreased hypoxia-inducible factor-1α (HIF-1α levels

  17. Current treatment of low grade gliomas

    NARCIS (Netherlands)

    M.J. van den Bent (Martin); T.A.B. Snijders (Tom); J.E.C. Bromberg (Jacolien)

    2012-01-01

    textabstractLow grade gliomas affect predominantly young adults, and have a relatively favorable prognosis compared to grade III and grade IV gliomas. The challenge for an optimal management of these patients is to find the balance between an optimal survival and the preservation of neurological fun

  18. Transcriptional network analysis reveals that AT1 and AT2 angiotensin II receptors are both involved in the regulation of genes essential for glioma progression.

    Science.gov (United States)

    Azevedo, Hátylas; Fujita, André; Bando, Silvia Yumi; Iamashita, Priscila; Moreira-Filho, Carlos Alberto

    2014-01-01

    Gliomas are aggressive primary brain tumors with high infiltrative potential. The expression of Angiotensin II (Ang II) receptors has been associated with poor prognosis in human astrocytomas, the most common type of glioma. In this study, we investigated the role of Angiotensin II in glioma malignancy through transcriptional profiling and network analysis of cultured C6 rat glioma cells exposed to Ang II and to inhibitors of its membrane receptor subtypes. C6 cells were treated with Ang II and specific antagonists of AT1 and AT2 receptors. Total RNA was isolated after three and six hours of Ang II treatment and analyzed by oligonucleotide microarray technology. Gene expression data was evaluated through transcriptional network modeling to identify how differentially expressed (DE) genes are connected to each other. Moreover, other genes co-expressing with the DE genes were considered in these analyses in order to support the identification of enriched functions and pathways. A hub-based network analysis showed that the most connected nodes in Ang II-related networks exert functions associated with cell proliferation, migration and invasion, key aspects for glioma progression. The subsequent functional enrichment analysis of these central genes highlighted their participation in signaling pathways that are frequently deregulated in gliomas such as ErbB, MAPK and p53. Noteworthy, either AT1 or AT2 inhibitions were able to down-regulate different sets of hub genes involved in protumoral functions, suggesting that both Ang II receptors could be therapeutic targets for intervention in glioma. Taken together, our results point out multiple actions of Ang II in glioma pathogenesis and reveal the participation of both Ang II receptors in the regulation of genes relevant for glioma progression. This study is the first one to provide systems-level molecular data for better understanding the protumoral effects of Ang II in the proliferative and infiltrative behavior of

  19. Transcriptional network analysis reveals that AT1 and AT2 angiotensin II receptors are both involved in the regulation of genes essential for glioma progression.

    Directory of Open Access Journals (Sweden)

    Hátylas Azevedo

    Full Text Available Gliomas are aggressive primary brain tumors with high infiltrative potential. The expression of Angiotensin II (Ang II receptors has been associated with poor prognosis in human astrocytomas, the most common type of glioma. In this study, we investigated the role of Angiotensin II in glioma malignancy through transcriptional profiling and network analysis of cultured C6 rat glioma cells exposed to Ang II and to inhibitors of its membrane receptor subtypes. C6 cells were treated with Ang II and specific antagonists of AT1 and AT2 receptors. Total RNA was isolated after three and six hours of Ang II treatment and analyzed by oligonucleotide microarray technology. Gene expression data was evaluated through transcriptional network modeling to identify how differentially expressed (DE genes are connected to each other. Moreover, other genes co-expressing with the DE genes were considered in these analyses in order to support the identification of enriched functions and pathways. A hub-based network analysis showed that the most connected nodes in Ang II-related networks exert functions associated with cell proliferation, migration and invasion, key aspects for glioma progression. The subsequent functional enrichment analysis of these central genes highlighted their participation in signaling pathways that are frequently deregulated in gliomas such as ErbB, MAPK and p53. Noteworthy, either AT1 or AT2 inhibitions were able to down-regulate different sets of hub genes involved in protumoral functions, suggesting that both Ang II receptors could be therapeutic targets for intervention in glioma. Taken together, our results point out multiple actions of Ang II in glioma pathogenesis and reveal the participation of both Ang II receptors in the regulation of genes relevant for glioma progression. This study is the first one to provide systems-level molecular data for better understanding the protumoral effects of Ang II in the proliferative and infiltrative

  20. Specific targeting of gliomas with multifunctional superparamagnetic iron oxide nanoparticle optical and magnetic resonance imaging contrast agents

    Institute of Scientific and Technical Information of China (English)

    Xiang-xi MENG; Jia-qi WAN; Meng JING; Shi-guang ZHAO; Wei CAI; En-zhong LIU

    2007-01-01

    Aim: To determine whether glioma cells can be specifically and efficiently tar- geted by superparamagnetic iron oxide nanoparticle (SPIO)-fluorescein isothiocyanate (FITC)-chlorotoxin (SPIOFC) that is detectable by magnetic reso- nance imaging (MRI) and optical imaging. Methods: SPIOFC was synthesized by conjugating SPIO with FITC and chlorotoxin. Glioma cells (human U251-MG and rat C6) were cultured with SPIOFC and SPIOF (SPIO-FITC), respectively. Neural cells were treated with SPIOFC as the control for SPIOFC-targeted glioma cells. The internalization of SPIOFC by glioma cells was assessed by MRI and was quantified using inductively-coupled plasma emission spectroscopy. The optical imaging ability of SPIOFC was evaluated by confocal laser scanning microscopy. Results: Iron per cell of U251 (72.5±1.8 pg) and C6 (74.9±2.2 pg) cells cultured with SPIOFC were significantly more than those of U251 (6.6±1.0 pg) and C6 (7.1±0.8 pg) cells incubated with SPIOF. The T2 signal intensity of U251 and C6 cells cultured with SPIOFC (233.6±25.9 and 211.4±17.2, respectively) were substantially lower than those of U251 and C6 cells incubated with SPIOF (2275.3±268.6 and 2342.7±222.4, respectively). Moreover, there were significant differences in iron per cell and T2 signal intensity between SPIOFC-treated neural cells (1.3±0.3; 2533.6±199.2) and SPIOFC-treated glioma cells. SPIOFC internalized by glioma cells exhibited green fluorescence by confocal laser scanning microscopy. Conclusion: SPIOFC is suitable for the specific and efficient targeting of glioma cells. MRI and optical imaging in conjunction with SPIOFC can differentiate glioma cells from normal brain tissue cells.

  1. 仙台病毒 Tianjin 株缺陷干扰颗粒体内外诱导大鼠脑胶质瘤细胞凋亡的研究%Study on the apoptosis of rat glioma cells induced by defective interfering particles of Sendai virus strain Tianjin

    Institute of Scientific and Technical Information of China (English)

    韩哲; 周洪经; 赵杰; 贾浩波; 陈曦腾; 石立莹

    2013-01-01

    Objective To investigate the apoptosis of rat glioma C 6 cells induced by defective in-terfering( DI) particles of Sendai virus strain Tianjin .Methods Rat glioma C6 cells were treated with dif-ferent titers of DI particles of Sendai virus strain Tianjin in vitro with culture media as negative control and intact virus as positive control .At different time point , cells were collected and their apoptosis was detected by DNA gel electrophorsis , TUNEL assay and AnnexinⅤ/PI double-labeled flow cytometry .The C6 glioma-bearing rat model was established and then treated with three intratumoral injections of DI particles , intact virus or saline three times at interval of two days .The antitumor effects of ID particles were evaluated through daily measuring of the tumor size .Hematoxylin-eosin( HE) staining was used to observe the patho-logical changes in tumor tissues .TUNEL assay was performed to detect the apoptosis of tumor tissues .Re-sults Rat glioma C6 cells treated with DI particles or intact virus in vitro showed typical DNA ladder pattern in agarose gel electrophoresis in a time-and dose-dependent manner .With the intervention of DI particles , the apoptosis rate of C6 cells showed a time-and dose-dependent manner and was significantly higher than that of the control group (P0.05).Conclusion The DI particles of Sendai virus strain Tianjin could induce apoptosis of rat glioma C 6 cells in a time-and dose-dependent manner both in vitro and in vivo, suggesting that the DI particles might be applicable for the treatment of neurogliocytoma in the future.%目的探讨仙台病毒Tianjin株缺损干扰颗粒( defective interfering particles ,DI颗粒)体内外诱导大鼠脑胶质瘤细胞C6凋亡的作用。方法将不同滴度仙台病毒Tianjin株DI颗粒分别与大鼠脑胶质瘤细胞C6作用不同时间,以培养基作为阴性对照、完整病毒作为阳性对照,通过DNA片段琼脂糖凝胶电泳、TUNEL染色、AnnexinⅤ-FITC/PI标记流

  2. Dynamic contrast-enhanced susceptibility-weighted perfusion MRI (DSC-MRI) in a glioma model of the rat brain using a conventional receive-only surface coil with a inner diameter of 47 mm at a clinical 1.5 T scanner.

    Science.gov (United States)

    Ulmer, Stephan; Reeh, Matthias; Krause, Joerg; Herdegen, Thomas; Heldt-Feindt, Janka; Jansen, Olav; Rohr, Axel

    2008-07-30

    Magnetic resonance (MR) imaging in animal models is usually performed in expensive dedicated small bore animal scanners of limited availability. In the present study a standard clinical 1.5 T MR scanner was used for morphometric and dynamic contrast-enhanced susceptibility-weighted MR imaging (DSC-MRI) of a glioma model of the rat brain. Ten male Wistar rats were examined with coronal T2-weighted, and T1-weighted images (matrix 128 x 128, FOV 64 mm) after implantation of an intracerebral tumor xenografts (C6) using a conventional surface coil. For DSC-MRI a T2*-weighted sequence (TR/TE=30/14 ms, matrix 64 x 64, FOV 90 mm; slice thickness of 1.5mm) was performed. Regions of interest were defined within the tumor and the non-affected contralateral hemisphere and the mean transit time (MTT) was determined. Tumor dimensions in MR predicted well its real size as proven by histology. The MTT of contrast agent passing through the brain was significantly decelerated in the tumor compared to the unaffected hemisphere (pscanners or dedicated custom-made coils.

  3. 突变型胸苷激酶对鼠C6胶质瘤细胞的杀伤效应%Killing effect of mutant herpes simplex virus type 1 thymidine kinase on rat C6 glioma cells

    Institute of Scientific and Technical Information of China (English)

    徐晓燕; 刘伟国; 杨小锋; 郑学胜; 沈罡

    2009-01-01

    Objective To explore the killing effect of mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk) and its wild type (HSV1-tk) on rat C6 glioma cells after Ganciclovir (GCV) treatment. Methods Eukaryotic expressing vector pcDNA3.1 containing HSV1-tk or HSV1-sr39tk was transfected into C6 cells and identified with RT-PCR. GCV killing efficiencies after gene transfer of HSV1-tk or HSV1-sr39tk were observed and compared in vitro and in vivo. Results 308bp DNA fragment was amplified through RT-PCR in both cells transfected with HSV1-tk (C6/tk) and those with HSV1-sr39tk (C6/sr39tk). As the prodrug GCV concentrations increasing from 0 μmol/L to 400 μmol/L, the cell survival rates in C6/sr39tk group declined from (99.96 ± 3.54) % to (4. 75 ± 1.79) %, while in C6/tk group from (100.03±2. 95)% to (59. 16±3.48)% and in C6 group from(100. 29±1.20)% to (83.62 ±7.56)%. There was a significant difference in killing effect among C6、C6/tk and C6/sr39tk group after GCV treatment(P < 0. 05). In vivo experiment, the rate of tumor formation was 100%. After 10 day treatment of GCV following tumor formation, tumors in animals implantated with C6/sr39tk、C6/tk or C6 got an average volume equaling (574. 08±107.72) mm3、(928.47±165.61) mm3 and (1287.24±364. 84) mm3 respectively. The most powerful tumor growth inhibition was observed in C6/sr39tk + GCV group, with an inhibition rate of tumor growth about 55.40%. Conclusion C6 cells transfected with HSV1-sr39tk were more sensitive to GCV than those with HSV1-tk both in vitro and in vivo, and thus HSV1-sr39tk can be considered as a mean to improve the overall efficacy of the HSV1-tk/GCV suicide gene system.%目的 观察比较突变型单纯疱疹胸苷激酶(HSV1-sr39tk)/更昔洛韦(GCV)和野生型HSV1-tk/GCV对鼠C6胶质瘤细胞的杀伤效应.方法 利用真核表达载体转染目的 基因到C6细胞,RT-PCR鉴定.通过MTT实验和活体植瘤,比较各组对GCV敏感性.结果

  4. Cyclic hexapeptide-conjugated nanoparticles enhance curcumin delivery to glioma tumor cells and tissue.

    Science.gov (United States)

    Zhang, Xuemei; Li, Xuejuan; Hua, Hongchen; Wang, Aiping; Liu, Wanhui; Li, Youxin; Fu, Fenghua; Shi, Yanan; Sun, Kaoxiang

    2017-01-01

    Glioma has one of the highest mortality rates among primary brain tumors. The clinical treatment for glioma is very difficult due to its infiltration and specific growth locations. To achieve improved drug delivery to a brain tumor, we report the preparation and in vitro and in vivo evaluation of curcumin nanoparticles (Cur-NPs). The cyclic hexapeptide c(RGDf(N-me) VK)-C (cHP) has increased affinity for cells that overexpress integrins and was designed to target Cur-NPs to tumors. Functional polyethyleneglycol-modified poly(d,l-lactide-co-glycolide) (PEG-PLGA) conjugated to cHP was synthesized, and targeted Cur-NPs were prepared using a self-assembly nanoprecipitation process. The physicochemical properties and the in vitro cytotoxicity, accuracy, and penetration capabilities of Cur-NPs targeting cells with high levels of integrin expression were investigated. The in vivo targeting and penetration capabilities of the NPs were also evaluated against glioma in rats using in vivo imaging equipment. The results showed that the in vitro cytotoxicity of the targeted cHP-modified curcumin nanoparticles (cHP/Cur-NPs) was higher than that of either free curcumin or non-targeted Cur-NPs due to the superior ability of the cHP/Cur-NPs to target tumor cells. The targeted cHP/Cur-NPs, c(RGDf(N-me)VK)-C-modified Cur-NPs, exhibited improved binding, uptake, and penetration abilities than non-targeting NPs for glioma cells, cell spheres, and glioma tissue. In conclusion, c(RGDf(N-me)VK)-C can serve as an effective targeting ligand, and cHP/Cur-NPs can be exploited as a potential drug delivery system for targeting gliomas.

  5. The mechanisms of in vitro cytotoxicity of mountain tea, Sideritis scardica, against the C6 glioma cell line.

    Science.gov (United States)

    Jeremic, Ivica; Tadic, Vanja; Isakovic, Andjelka; Trajkovic, Vladimir; Markovic, Ivanka; Redzic, Zoran; Isakovic, Aleksandra

    2013-11-01

    Sideritis scardica (mountain tea) is an endemic plant on the Balkan Peninsula traditionally used for treating different conditions, mainly of inflammatory nature. This study was aimed to examine the cytotoxic activity of different S. scardica extracts against the rat glioma C6 line and rat astrocytes in primary culture. The obtained data revealed that diethyl ether (extract 2) and ethyl acetate (extract 3) extracts of S. scardica exerted a cytotoxic effect on C6 rat glioma cells. Diethyl ether extract induced an increase in reactive oxygen species production, leading to apoptotic and autophagic cell death. Ethyl acetate extract induced G2 M cell cycle arrest and autophagy. None of the tested extracts was cytotoxic to rat astrocytes in primary culture. Cytotoxic effects of S. scardica extracts were, at least in part, mediated by their flavonoid constituents apigenin and luteolin that, when applied alone, induced cell cycle arrest, apoptosis, and autophagy.

  6. Adult high-grade malignant gliomas

    Directory of Open Access Journals (Sweden)

    Fable Zustovich

    2011-12-01

    Full Text Available Central nervous system (CNS malignant gliomas are relatively rare diseases. Prognosis is poor but has improved over recent years due to the improvement in the multi-disciplinary treatment: surgery, radiotherapy and chemotherapy...

  7. Targeting immune checkpoints in malignant glioma

    Science.gov (United States)

    Li, Tete; Liu, Yong-Jun; Chen, Wei; Chen, Jingtao

    2017-01-01

    Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the bodys anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered immune privileged and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma. In this review, we focus on immune checkpoint inhibitors, specifically, antagonizing monoclonal antibodies for programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). We discuss advances in the working mechanisms of these immune checkpoint molecules, their status in malignant glioma, and current preclinical and clinical trials targeting these molecules in malignant glioma. PMID:27756892

  8. The Art of Intraoperative Glioma Identification

    Directory of Open Access Journals (Sweden)

    Zoe Z Zhang

    2015-07-01

    Full Text Available A major dilemma in brain tumor surgery is the identification of tumor boundaries to maximize tumor excision and minimize postoperative neurological damage. Gliomas, especially low-grade tumors, and normal brain have a similar color and texture which poses a challenge to the neurosurgeon. Advances in glioma resection techniques combine the experience of the neurosurgeon and various advanced technologies. Intraoperative methods to delineate gliomas from normal tissue consist of 1 image-based navigation, 2 intraoperative sampling, 3 electrophysiological monitoring, and 4 enhanced visual tumor demarcation. The advantages and disadvantages of each technique are discussed. A combination of these methods is becoming widely accepted in routine glioma surgery. Gross total resection in conjunction with radiation, chemotherapy, or immune/gene therapy may increase the rates of cure in this devastating disease.

  9. Post Traumatic Glioma – An association questioned

    Directory of Open Access Journals (Sweden)

    Chaurasia I.D.

    2015-03-01

    Full Text Available Post traumatic glioma has been a matter of debate. Few reports favor its occurrence in previous head injury scar, subsequently developing into glioma. Here we report a case of young patient presented with headache, seizures and gradual loss of vision. On investigation found to have brain tumor. Patient had head injury occurred 3 yrs back. It fulfills all the criteria required to establish traumatic origin, further supporting the association.

  10. Targeted Radiolabeled Compounds in Glioma Therapy.

    Science.gov (United States)

    Cordier, Dominik; Krolicki, Leszek; Morgenstern, Alfred; Merlo, Adrian

    2016-05-01

    Malignant gliomas of World Health Organization (WHO) grades II-IV represent the largest entity within the group of intrinsic brain tumors and are graded according to their pathophysiological features with survival times between more than 10 years (WHO II) and only several months (WHO IV). Gliomas arise from astrocytic or oligodendrocytic precursor cells and exhibit an infiltrative growth pattern lacking a clearly identifiable tumor border. The development of effective treatment strategies of the invasive tumor cell front represents the main challenge in glioma therapy. The therapeutic standard consists of surgical resection and, depending on the extent of resection and WHO grade, adjuvant external beam radiotherapy or systemic chemotherapy. Within the last decades, there has been no major improvement of the prognosis of patients with glioma. The consistent overexpression of neurokinin type 1 receptors in gliomas WHO grades II-IV has been used to develop a therapeutic substance P-based targeting system. A substance P-analogue conjugated to the DOTA or DOTAGA chelator has been labeled with different alpha-particle or beta-particle emitting radionuclides for targeted glioma therapy. The radiopharmaceutical has been locally injected into the tumors or the resection cavity. In several clinical studies, the methodology has been examined in adjuvant and neoadjuvant clinical settings. Although no large controlled series have so far been generated, the results of radiolabeled substance P-based targeted glioma therapy compare favorably with standard therapy. Recently, labeling with the alpha particle emitting Bi-213 has been found to be promising due to the high linear energy transfer and the very short tissue range of 0.08 mm. Further development needs to focus on the improvement of the stability of the compound and the application by dedicated catheter systems to improve the intratumoral distribution of the radiopharmaceutical within the prognostically critical

  11. Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells.

    Science.gov (United States)

    Zhang, Rong; Saito, Ryuta; Shibahara, Ichiyo; Sugiyama, Shinichiro; Kanamori, Masayuki; Sonoda, Yukihiko; Tominaga, Teiji

    2016-01-01

    Temozolomide is a standard chemotherapy agent for malignant gliomas, but the efficacy is still not satisfactory. Therefore, combination chemotherapy using temozolomide with other anti-tumor compounds is now under investigation. Here we studied the mechanism of the synergistic anti-tumor effect achieved by temozolomide and doxorubicin, and elucidated the inhibitory effect of temozolomide on P-glycoprotein (P-gp). Temozolomide significantly enhanced sensitivity to P-gp substrate in glioma cells, particularly in P-gp-overexpressed cells. Synergetic effects, as determined by isobologram analysis, were observed by combining temozolomide and doxorubicin. Subsequently, flow cytometry was utilized to assess the intracellular retention of doxorubicin in cells treated with doxorubicin with or without temozolomide. Temozolomide significantly increased the accumulation of doxorubicin in these cells. The P-gp adenosine triphosphatase (ATPase) assay showed that temozolomide inhibited the ATPase activity of P-gp. In addition, temozolomide combined with doxorubicin significantly prolonged the survival of 9L intracranial allografted glioma-bearing rats compared to single agent treatment. Collectively, our findings suggest that temozolomide can reverse doxorubicin resistance by directly affecting P-gp transport activity. Combination chemotherapy using temozolomide with other agents may be effective against gliomas in clinical applications.

  12. Nestin+cells forming spheroids aggregates resembling tumorspheres in experimental ENU-induced gliomas.

    Science.gov (United States)

    García-Blanco, Alvaro; Bulnes, Susana; Pomposo, Iñigo; Carrasco, Alex; Lafuente, José Vicente

    2016-12-01

    Nestin+cells from spheroid aggregates display typical histopathological features compatible with cell stemness. Nestin and CD133+cells found in glioblastomas, distributed frequently around aberrant vessels, are considered as potential cancer stem cells. They are possible targets for antitumoral therapy because they lead the tumorigenesis, invasiveness and angiogenesis. However, little is known about their role and presence in low-grade gliomas. The aim of this work is to localize and characterize the distribution of these cells inside tumors during the development of experimental endogenous glioma. For this study, a single dose of Ethyl-nitrosourea was injected into pregnant rats. Double immunofluorescences were performed in order to identify stem-like and differentiated cells. Low-grade gliomas display Nestin+cells distributed throughout the tumor. More malignant gliomas show, in addition to that, a perivascular location with some Nestin+cells co-expressing CD133 or VEGF, and the intratumoral spheroid aggregates of Nestin/CD133+cells. These structures are encapsulated by well-differentiated VEGF/GFAP+cells. Spheroid aggregates increase in size in the most malignant stages. Spheroid aggregates have morphological and phenotypic similarities to in vitro neurospheres and could be an in vivo analogue of them. These arrangements could be a reservoir of undifferentiated cells formed to escape adverse microenvironments.

  13. Effect of inhibition of the ROCK isoform on RT2 malignant glioma cells.

    Science.gov (United States)

    Inaba, Nobuharu; Ishizawa, Sho; Kimura, Masaki; Fujioka, Kouki; Watanabe, Michiko; Shibasaki, Toshiaki; Manome, Yoshinobu

    2010-09-01

    Malignant glioma is one of the most intractable diseases in the human body. Rho-kinase (ROCK) is overexpressed and has been proposed as the main cause for the refractoriness of the disease. Since efficacious treatment is required, this study investigated the effect of inhibition of ROCK isoforms. The short hairpin RNA transcription vector was transfected into the RT2 rat glioma cell line and the characteristics of the cells were investigated. The effect of nimustine hydrochloride (ACNU) anti-neoplastic agent on cells was also measured. Inhibition of ROCK isoforms did not alter cell growth. Cell cycle analysis revealed that ROCK1 down-regulation reduced the G(0) phase population and ROCK2 down-regulation reduced the G(2)/M phase population. When ROCK1-down-regulated cells were exposed to ACNU, they demonstrated susceptibility to the agent. The roles of ROCK1 and ROCK2 may be different in glioma cells. Furthermore, the combination of ROCK1 down-regulation and an anti-neoplastic agent may be useful for the therapy of malignant glioma.

  14. Suppression of glioma progression by Egln3.

    Directory of Open Access Journals (Sweden)

    Vicki A Sciorra

    Full Text Available Grade IV astrocytoma or glioblastoma has a poor clinical outcome that can be linked to hypoxia, invasiveness and active vascular remodeling. It has recently been suggested that hypoxia-inducible factors, Hifs, increase glioma growth and aggressiveness [1], [2], [3]. Here, we tested the hypothesis that Egl 9 homolog 3 (Egln3, a prolyl-hydroxylase that promotes Hif degradation, suppresses tumor progression of human and rodent glioma models. Through intracranial tumorigenesis and in vitro assays, we demonstrate for the first time that Egln3 was sufficient to decrease the kinetics of tumor progression and increase survival. We also find that Klf5, a transcription factor important to vascular remodeling, was regulated by hypoxia in glioma. An analysis of the tumor vasculature revealed that elevated Egln3 normalized glioma capillary architecture, consistent with a role for Egln3 in eliciting decreases in the production of Hif-regulated, angiogenic factors. We also find that the hydroxylase-deficient mutant, Egln3(H196A partially maintained tumor suppressive activity. These results highlight a bifurcation of Egln3 signaling and suggest that Egln3 has a non-hydroxylase-dependent function in glioma. We conclude that Egln3 is a critical determinant of glioma formation and tumor vascular functionality.

  15. GliomaPredict: a clinically useful tool for assigning glioma patients to specific molecular subtypes

    Directory of Open Access Journals (Sweden)

    Fine Howard A

    2010-07-01

    Full Text Available Abstract Background Advances in generating genome-wide gene expression data have accelerated the development of molecular-based tumor classification systems. Tools that allow the translation of such molecular classification schemas from research into clinical applications are still missing in the emerging era of personalized medicine. Results We developed GliomaPredict as a computational tool that allows the fast and reliable classification of glioma patients into one of six previously published stratified subtypes based on sets of extensively validated classifiers derived from hundreds of glioma transcriptomic profiles. Our tool utilizes a principle component analysis (PCA-based approach to generate a visual representation of the analyses, quantifies the confidence of the underlying subtype assessment and presents results as a printable PDF file. GliomaPredict tool is implemented as a plugin application for the widely-used GenePattern framework. Conclusions GliomaPredict provides a user-friendly, clinically applicable novel platform for instantly assigning gene expression-based subtype in patients with gliomas thereby aiding in clinical trial design and therapeutic decision-making. Implemented as a user-friendly diagnostic tool, we expect that in time GliomaPredict, and tools like it, will become routinely used in translational/clinical research and in the clinical care of patients with gliomas.

  16. Microglia-glioma cross-talk: a two way approach to new strategies against glioma.

    Science.gov (United States)

    Arcuri, Cataldo; Fioretti, Bernard; Bianchi, Roberta; Mecca, Carmen; Tubaro, Claudia; Beccari, Tommaso; Franciolini, Fabio; Giambanco, Ileana; Donato, Rosario

    2017-01-01

    Glioblastoma (GBM) is the most malignant and aggressive among primary brain tumors, characterized by very low life expectancy. In vivo, glioma and glioblastoma in particular contain large numbers of immune cells (myeloid cells) such as microglia and tumour-infiltrating macrophages (or glioma associated macrophages). These glioma-infiltrating myeloid cells comprise up to 30% of total tumor mass and have been suggested to play several roles in glioma progression including proliferation, survival, motility and immunosuppression. Although tumor microglia and macrophages can acquire proinflammatory (M1) phenotype being capable of releasing proinflammatory cytokines, phagocytosing and presenting antigens, their effector immune function in gliomas appears to be suppressed by the acquisition of an anti-inflammatory (M2) phenotype. In the present work we review the microglia-glioma interactions to highlight the close relationship between the two cell types and the factors that can influence their properties (chemokines, cytokines, S100B protein). A future therapeutic possibility might be to simultaneously targeting, for example with nanomedicine, glioma cells and microglia to push the microglia towards an antitumor phenotype (M1) and/or prevent glioma cells from "conditioning" by microglia.

  17. Known glioma risk loci are associated with glioma with a family history of brain tumours

    DEFF Research Database (Denmark)

    Melin, Beatrice; Dahlin, Anna M; Andersson, Ulrika

    2013-01-01

    Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive...

  18. Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells.

    Science.gov (United States)

    Ma, Jian; Yang, Yan-Ru; Chen, Wei; Chen, Mei-Hua; Wang, Hao; Wang, Xiao-Dan; Sun, Li-Li; Wang, Feng-Ze; Wang, De-Cai

    2016-08-01

    Although temozolomide (TMZ) is the most effective chemotherapy agent for glioma, chemotherapy resistance has limited its clinical use. Fluoxetine (FLT), which is widely used in cancer-related depression, has exhibited potent anticancer properties in different cancer cell types. The aim of this study was i) to evaluate the antitumor mechanism of FLT, and ii) to further evaluate the effects of a combination of FLT and TMZ on glioma cells. Glioma cell lines were exposed to FLT and/or TMZ. Cell viability and apoptosis were examined by CCK-8 assay, flow cytometry and caspase-3 activity assay, respectively. The expression of endoplasmic reticulum-stress (ERS) apoptosis-related proteins was measured using real-time PCR and western blotting. Synergism between the two drugs was evaluated by the combination index (CI) through CompuSyn software. FLT significantly and dose-dependently inhibited the proliferation of various glioma cell lines, and rat glioma C6 cells had a highly sensitive response to the addition of FLT. FLT treatment increased the early apoptosis rate, induced typical apoptotic morphology in the C6 cells and activated caspase-3 with no change in the mitochondrial membrane potential. Further study showed that FLT activated the ERS marker, CHOP. This induction was associated with activation of the PERK-eIF2α-ATF4 and ATF6 cascade. Concomitantly, GADD34, a downstream molecule of CHOP, was also increased. Combined FLT and TMZ treatment showed a synergistic cytotoxic effect in the C6 glioma cells. Knockdown of CHOP expression abolished the synergistic effect of FLT and TMZ in the C6 cells, which suggests that FLT may sensitize glioma cells to TMZ through activation of the CHOP-dependent apoptosis pathway. These results revealed that FLT induced glioma cell apoptosis and sensitized glioma cells to TMZ through activation of the CHOP‑dependent apoptosis pathway. The present study provides a primary basis for using the combination of these drugs in patients with

  19. Natural killer cells require monocytic Gr-1(+)/CD11b(+) myeloid cells to eradicate orthotopically engrafted glioma cells.

    Science.gov (United States)

    Baker, Gregory J; Chockley, Peter; Zamler, Daniel; Castro, Maria G; Lowenstein, Pedro R

    2016-06-01

    Malignant gliomas are resistant to natural killer (NK) cell immune surveillance. However, the mechanisms used by these cancers to suppress antitumor NK cell activity remain poorly understood. We have recently reported on a novel mechanism of innate immune evasion characterized by the overexpression of the carbohydrate-binding protein galectin-1 by both mouse and rat malignant glioma. Here, we investigate the cytokine profile of galectin-1-deficient GL26 cells and describe the process by which these tumors are targeted by the early innate immune system in RAG1(-/-) and C57BL/6J mice. Our data reveal that galectin-1 knockdown in GL26 cells heightens their inflammatory status leading to the rapid recruitment of Gr-1(+)/CD11b(+) myeloid cells and NK1.1(+) NK cells into the brain tumor microenvironment, culminating in tumor clearance. We show that immunodepletion of Gr-1(+) myeloid cells in RAG1(-/-) mice permits the growth of galectin-1-deficient glioma despite the presence of NK cells, thus demonstrating an essential role for myeloid cells in the clearance of galectin-1-deficient glioma. Further characterization of tumor-infiltrating Gr-1(+)/CD11b(+) cells reveals that these cells also express CCR2 and Ly-6C, markers consistent with inflammatory monocytes. Our results demonstrate that Gr-1(+)/CD11b(+) myeloid cells, often referred to as myeloid-derived suppressor cells (MDSCs), are required for antitumor NK cell activity against galectin-1-deficient GL26 glioma. We conclude that glioma-derived galectin-1 represents an important factor in dictating the phenotypic behavior of monocytic Gr-1(+)/CD11b(+) myeloid cells. Galectin-1 suppression may be a valuable treatment approach for clinical glioma by promoting their innate immune-mediated recognition and clearance through the concerted effort of innate myeloid and lymphoid cell lineages.

  20. Construction of rat glioma cell line C6-Luc for reproducing an animal model with stable expression of luciferase%大鼠脑胶质瘤荧光素酶动物模型建模细胞株C6-Luc的构建

    Institute of Scientific and Technical Information of China (English)

    黄伟; 吕明; 李保卫; 王玉丽; 邵荣光; 高钟镐

    2011-01-01

    Objective To construct the rat glioma cell line C6-Luc to stably express the firefly luciferase.Methods The optimal concentration of hygromycin for screening C6 rat glioma cells was determined by concentration gradient method.The eukaryotic plasmid pGL4.50 expressing luciferase was transfected into C6 cells by using FuGENE* HD transfection reagent, followed by screening the polyclonal cell lines with hygromycin, subsequently screening the monoclonal cell line by limited dilution.The positive monoclonal cell lines were identified with reporter gene assay, thereafter the expression stability of luciferase was investigated in the positive cell lines.The bioluminescence detection in vitro in the positive monoclonal cell line was performed to determine the minimum detection amount of cells,and the correlation between bioluminescence intensity and ce11 amount was analyzed by linear regression analysis.The positive monoclonal cells were implanted into the brain of Wistar rats, and the tumor growth in rats brain was detected in vivo using the bioluminescence imaging detection system.Results The optimal concentration of hygromycin used in screening C6 cells was 250 μg/mL The eukaryotic plasmids pGL4.50 was successfully transfected into C6 cells, and 12 monoclonal cell lines were obtained by anti-hygromycin screening.A positive clone with the highest activity of luciferase, designated as C6-Luc, was successfully identified by using luciferase reporter gene assay, which showed a stable activity of expressing luciferase after 3 continuous passages of cultivation.The bioluminescence detection in vitro showed that the minimum detection amount of C6-Luc cells was 78.A good linear correlation existed between bioluminescence intensity and the amount of C6-Luc cells, with an equation of y=81.348x-2143.1 and correlation coefficient(r) of 0.997.The in vivo bioluminescence imaging detection showed tumorigenesis could be detected after implantation of C6-Luc cells into the brain of

  1. BmNPV or f98对家蚕核型多角体杆状病毒复制、转录及包装的影响%Influence of BmNPV orf98 on DNA replication,transcription and virus package of Bombyx mori nucleopolyhedrovirus

    Institute of Scientific and Technical Information of China (English)

    史利利; 蒋彩英; 于威; 陈琛; 蒋磊; 巩成见; 童富淡

    2015-01-01

    为了研究家蚕核型多角体病毒( Bombyx mori nucleopolyhedrovirus ,BmNPV)基因 orf98的功能,通过λRed重组系统定点敲除BmNPV or f98基因,构建缺失型重组病毒 Bm98‐ko‐Bacmid;以Bac‐to‐Bac系统补回BmNPV or f98基因,构建补回型重组病毒 Bm98‐re‐Bacmid;将野生型病毒( w tBacmid)、缺失型病毒( Bm98‐ko‐Bacmid)和补回型病毒( Bm98‐re‐Bacmid)分别转染家蚕细胞BmN .病毒滴度检测结果显示,Bm98‐ko‐Bacmid可形成侵染性的病毒粒子,但数量显著降低( P<0.05).透射电子显微镜观察发现,Bm98‐ko‐Bacmid只产生游离的杆状病毒粒子,数量明显减少,而w tBacmid和 Bm98‐re‐Bacmid产生大量具有囊膜结构的成熟病毒粒子.荧光定量聚合酶链反应分析结果表明,BmNPV or f98基因缺失对BmNPV病毒复制没有影响,而早期基因 le f3、晚期基因 v p39和极晚期基因p10的转录水平显著降低( P<0.05).综上所述,BmNPV or f98基因对病毒复制是非必需的,但显著影响病毒的繁殖速度和包装( P<0.05);对病毒各个时期的基因转录也具有重要影响.%Summary Baculoviruses have been considered as the powerful vectors to express the exogenous gene . And the representative vectors in baculovirus expression vector system is Autographa californica multinucleocapsid nucleopolyhedrovirus (AcMNPV) and Bombyx mori nucleopolyhedrovirus (BmNPV) . The AcMNPV expression system has been widely applied in American and European countries . However , the BmNPV expression reaches a higher level over other systems , because BmNPV can infect silkworm larva or pupa . Moreover , silkworm is pretty normal in China , with lower cost and mature breeding technology , thus it is really popular to use the silkworm as a biofactory" to produce recombinant protein . The BmNPV genome sequenced in 1999 was 128 413 nucleotides long with a G + C content of 40% and contained about 136 open reading frames ( ORFs) encoding predicted

  2. Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel.

    Science.gov (United States)

    Zacher, Angela; Kaulich, Kerstin; Stepanow, Stefanie; Wolter, Marietta; Köhrer, Karl; Felsberg, Jörg; Malzkorn, Bastian; Reifenberger, Guido

    2017-03-01

    Current classification of gliomas is based on histological criteria according to the World Health Organization (WHO) classification of tumors of the central nervous system. Over the past years, characteristic genetic profiles have been identified in various glioma types. These can refine tumor diagnostics and provide important prognostic and predictive information. We report on the establishment and validation of gene panel next generation sequencing (NGS) for the molecular diagnostics of gliomas. We designed a glioma-tailored gene panel covering 660 amplicons derived from 20 genes frequently aberrant in different glioma types. Sensitivity and specificity of glioma gene panel NGS for detection of DNA sequence variants and copy number changes were validated by single gene analyses. NGS-based mutation detection was optimized for application on formalin-fixed paraffin-embedded tissue specimens including small stereotactic biopsy samples. NGS data obtained in a retrospective analysis of 121 gliomas allowed for their molecular classification into distinct biological groups, including (i) isocitrate dehydrogenase gene (IDH) 1 or 2 mutant astrocytic gliomas with frequent α-thalassemia/mental retardation syndrome X-linked (ATRX) and tumor protein p53 (TP53) gene mutations, (ii) IDH mutant oligodendroglial tumors with 1p/19q codeletion, telomerase reverse transcriptase (TERT) promoter mutation and frequent Drosophila homolog of capicua (CIC) gene mutation, as well as (iii) IDH wildtype glioblastomas with frequent TERT promoter mutation, phosphatase and tensin homolog (PTEN) mutation and/or epidermal growth factor receptor (EGFR) amplification. Oligoastrocytic gliomas were genetically assigned to either of these groups. Our findings implicate gene panel NGS as a promising diagnostic technique that may facilitate integrated histological and molecular glioma classification.

  3. The Effects of Thermal Preconditioning on Oncogenic and Intraspinal Cord Growth Features of Human Glioma Cells.

    Science.gov (United States)

    Zeng, Xiang; Han, Inbo; Abd-El-Barr, Muhammad; Aljuboori, Zaid; Anderson, Jamie E; Chi, John H; Zafonte, Ross D; Teng, Yang D

    2016-12-13

    The adult rodent spinal cord presents an inhibitory environment for donor cell survival, impeding efficiency for xenograft-based modeling of gliomas. We postulated that mild thermal preconditioning may influence the fate of the implanted tumor cells. To test this hypothesis, high-grade human astrocytoma G55 and U87 cells were cultured under 37C and 38.5C to mimic regular experimental or core body temperatures of rodents, respectively. In vitro, the 38.5C-conditioned cells, relative to 37C, grew slightly faster. Compared to U87 cells, G55 cells demonstrated a greater response to the temperature difference. Hyperthermal culture markedly increased production of Hsp27 in most G55 cells, but only promoted transient expression of cancer stem cell marker CD133 in a small cell subpopulation. We subsequently transplanted G55 cells following 37C or 38.5C culture into the C2 or T10 spinal cord of adult female immunodeficient rats (3 rats/each locus/per temperature; total: 12 rats). Systematic analyses revealed that 38.5C-preconditioned G55 cells grew more malignantly at either C2 or T10 as determined by tumor size, outgrowth profile, resistance to bolus intratumor administration of 5-fluorouracil (0.1 mol), and posttumor survival (p0.05; n=6/group). Therefore, thermal preconditioning of glioma cells may be an effective way to influence the in vitro and in vivo oncological contour of glioma cells. Future studies are needed for assessing the potential oncogenic modifying effect of hyperthermia regimens on glioma cells.

  4. New similarity search based glioma grading

    Energy Technology Data Exchange (ETDEWEB)

    Haegler, Katrin; Brueckmann, Hartmut; Linn, Jennifer [Ludwig-Maximilians-University of Munich, Department of Neuroradiology, Munich (Germany); Wiesmann, Martin; Freiherr, Jessica [RWTH Aachen University, Department of Neuroradiology, Aachen (Germany); Boehm, Christian [Ludwig-Maximilians-University of Munich, Department of Computer Science, Munich (Germany); Schnell, Oliver; Tonn, Joerg-Christian [Ludwig-Maximilians-University of Munich, Department of Neurosurgery, Munich (Germany)

    2012-08-15

    MR-based differentiation between low- and high-grade gliomas is predominately based on contrast-enhanced T1-weighted images (CE-T1w). However, functional MR sequences as perfusion- and diffusion-weighted sequences can provide additional information on tumor grade. Here, we tested the potential of a recently developed similarity search based method that integrates information of CE-T1w and perfusion maps for non-invasive MR-based glioma grading. We prospectively included 37 untreated glioma patients (23 grade I/II, 14 grade III gliomas), in whom 3T MRI with FLAIR, pre- and post-contrast T1-weighted, and perfusion sequences was performed. Cerebral blood volume, cerebral blood flow, and mean transit time maps as well as CE-T1w images were used as input for the similarity search. Data sets were preprocessed and converted to four-dimensional Gaussian Mixture Models that considered correlations between the different MR sequences. For each patient, a so-called tumor feature vector (= probability-based classifier) was defined and used for grading. Biopsy was used as gold standard, and similarity based grading was compared to grading solely based on CE-T1w. Accuracy, sensitivity, and specificity of pure CE-T1w based glioma grading were 64.9%, 78.6%, and 56.5%, respectively. Similarity search based tumor grading allowed differentiation between low-grade (I or II) and high-grade (III) gliomas with an accuracy, sensitivity, and specificity of 83.8%, 78.6%, and 87.0%. Our findings indicate that integration of perfusion parameters and CE-T1w information in a semi-automatic similarity search based analysis improves the potential of MR-based glioma grading compared to CE-T1w data alone. (orig.)

  5. Immunoglobulin genes implicated in glioma risk.

    Science.gov (United States)

    Pandey, Janardan P; Kaur, Navtej; Costa, Sandra; Amorim, Julia; Nabico, Rui; Linhares, Paulo; Vaz, Rui; Viana-Pereira, Marta; Reis, Rui M

    2014-01-01

    Both genetic and environmental factors are thought to be causal in gliomagenesis. Several genes have been implicated in glioma development, but the putative role of a major immunity-related gene complex member, immunoglobulin heavy chain γ (IGHG) has not been evaluated. Prior observations that IGHG-encoded γ marker (GM) allotypes exhibit differential sensitivity to an immunoevasion strategy of cytomegalovirus, a pathogen implicated as a promoter of gliomagenesis, has lead us to hypothesize that these determinants are risk factors for glioma. To test this hypothesis, we genotyped the IGHG locus comprising the GM alleles, specifically GM alleles 3 and 17, of 120 glioma patients and 133 controls via TaqMan® genotyping assay. To assess the associations between GM genotypes and the risk of glioma, we applied an unconditional multivariate logistic regression analysis adjusted for potential confounding variables. In comparison to subjects who were homozygous for the GM 17 allele, the GM 3 homozygotes were over twice as likely, and the GM 3/17 heterozygotes were over three times as likely, to develop glioma. Similar results were achieved when analyzed by combining the data corresponding to alleles GM 3 and GM 3/17 in a dominant model. The GM 3/17 genotype and the combination of GM 3 and GM 3/17 were found to be further associated with over 3 times increased risk for high-grade astrocytoma (grades III-IV). Allele frequency analyses also showed an increased risk for gliomas and high-grade astrocytoma in association with GM 3. Our findings support the premise that the GM 3 allele may present risk for the development of glioma, possibly by modulating immunity to cytomegalovirus.

  6. Incubation and application of transgenic green fluorescent nude mice in visualization studies on glioma tissue remodeling

    Institute of Scientific and Technical Information of China (English)

    DONG Jun; LAN Qing; HUANG Qiang; DAI Xing-liang; LU Zhao-hui; FEI Xi-feng; CHEN Hua; ZHANG Quan-bin; ZHAO Yao-dong; WANG Zhi-min; WANG Ai-dong

    2012-01-01

    Background The primary reasons for local recurrence and therapeutic failure in the treatment of malignant gliomas are the invasion and interactions of tumor cells with surrounding normal brain cells.However,these tumor cells are hard to be visualized directly in histopathological preparations,or in experimental glioma models.Therefore,we developed an experimental human dual-color in vivo glioma model,which made tracking solitary invasive glioma cells possible,for the purpose of visualizing the interactions between red fluorescence labeled human glioma cells and host brain cells.This may offer references for further studying the roles of tumor microenvironment during glioma tissue remodeling.Methods Transgenic female C57BL/6 mice expressing enhanced green fluorescent protein (EGFP) were crossed with male Balb/c nude mice.Then sib mating was allowed to occur continuously in order to establish an inbred nude mice strain with 50% of their offspring that are EGFP positive.Human glioma cell lines U87-MG and SU3 were transfected with red fluorescent protein (RFP) gene,and a rat C6 glioma cell line was stained directly with CM-Dil,to establish three glioma cell lines emitting red fluorescence (SU3-RFP,U87-RFP,and C6-CM-Dil).Red fluorescence tumor cells were inoculated via intra-cerebral injection into caudate nucleus of the EGFP nude mice.Tumor-bearing mice were sacrificed when their clinical symptoms appeared,and the whole brain was harvested and snap frozen for further analysis.Confocal laser scanning microscopy was performed to monitor the mutual interactions between tumor cells and host brain cells.Results Almost all the essential tissues of the established EGFP athymic Balb/c nude mice,except hair and erythrocytes,fluoresced green under excitation using a blue light-emitting flashlight with a central peak of 470 nm,approximately 50% of the offsprings were nu/nu EGFP+.SU3-RFP,U87-RFP,and C6-CM-Dil almost 100% expressed red fluorescence under the fluorescence

  7. Imaging of a glioma using peripheral benzodiazepine receptor ligands

    Energy Technology Data Exchange (ETDEWEB)

    Starosta-Rubinstein, S.; Ciliax, B.J.; Penney, J.B.; McKeever, P.; Young, A.B.

    1987-02-01

    Two types of benzodiazepine receptors have been demonstrated in mammalian tissues, one which is localized on neuronal elements in brain and the other, on glial cells and in peripheral tissues such as kidney. In vivo administration of /sup 3/H-labeled PK 11195 (1-(2-chlorophenyl-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide) or (/sup 3/H)flunitrazepam with 5 mg of clonazepam per kg to rats with intracranial C6 gliomas resulted in high levels of tritiated-drug binding to the tumor as shown by quantitative autoradiography. Pharmacological studies indicated that the bound drugs labeled the peripheral benzodiazepine binding site. Binding to the peripheral benzodiazepine site was confirmed primarily to malignant cells with little binding to adjacent normal brain tissue or to necrotic tissue. Tumor cell binding was completely inhibited by preadministration of the peripheral benzodiazepine blocking agent PK 11195 at 5 mg/kg. The centrally selective benzodiazepine ligand clonazepam had no effect on PK 11195 binding to the tumor cells. When binding to other tumor cell lines grown in nude mice and nude athymic rats was evaluated, little or no peripheral benzodiazepine binding was detected on human pheochromocytoma (RN1) and neuroblastoma (SK-N-MC, SK-N-SH) tumor cells, respectively. However, high densities of peripheral benzodiazepine binding sites were observed on tumors derived from a human glioma cell line (ATCC HTB 14, U-87 MG). The presence of high concentrations of specific peripheral benzodiazepine receptors on glial tumors suggests that human primary central nervous system tumors could be imaged and diagnosed using peripheral benzodiazepine ligands labeled with positron- or gamma-emitting isotopes.

  8. Experimental study of magnetic resonance imaging and pathologies in rats with C6 gliomas after cryotherapy%氩氦冷冻治疗后的荷C6胶质瘤大鼠的磁共振成像和病理研究

    Institute of Scientific and Technical Information of China (English)

    李明; 黄凡衡; 胡丽娟; 周媛; 姜晓丹; 常海刚; 卢凤飞; 陈强; 张世忠

    2010-01-01

    目的 探讨荷C6胶质瘤大鼠经氩氦刀治疗后的影像学和病理学的变化. 方法 将51只Wistar大鼠背部皮下植入体外扩增的C6胶质瘤细胞,制作荷C6胶质瘤的动物模型,模型制作成功后按照随机数字表法分为假手术组(暴露肿瘤后只插入冷冻刀头不启动氩氦冷冻系统,n=18),外科手术切除组(将肿瘤完整切除,不进行冷冻操作,n=15)和氩氦冷冻组(暴露肿瘤后启动氩氦冷冻系统,n=18).观察各组大鼠治疗前后MRI影像变化,应用Tunel检测细胞凋亡情况.结果 外科手术成功切除胶质瘤.氩氦冷冻组MRI显示T1、W1信号较术前增强,T2WI信号较术前减低假手术组治疗后MRI无明显变化.氩氦冷冻组肿瘤组织Tunel染色可见大量凋亡细胞,外科手术切除组及假手术组可见少量散在的凋亡细胞.结论 经氩氦刀治疗胶质瘤MRI提示肿瘤细胞变性坏死,病理学提示可以介导细胞凋亡,有望成为脑胶质瘤的一种有效的辅助治疗手段.%Objective To explore the changes of imaging and pathologies in rots with bearing C6 gliomas after cryotherapy. Methods Animal models with subcutaneously transplanting C6 gliomas in the Wistar rates were established. Fifty-one rat models were randomized into sham-operated group (n=18), resection group (n=lS) and cryotherapy group (n=18). The tumors in the sham-operated group were exposed only and the tumors in the resection group were resected without the help of freezing system; the tumors in the cryotherapy group were performed argon-helium cryoablation. The changes of morphology and imaging were observed. TUNEL staining was employed to observe the cell apoptosis in the tumors. Results The tumors in the resection group were removed successfully by microsurgical resection. Cryotherapy group showed significantly enhanced T1WI signal and weak T2W1 signal after the treatment as compared with that before the treatment; no obvious difference of the MRI data was found

  9. Molecular Therapeutic Targets for Glioma Angiogenesis

    Directory of Open Access Journals (Sweden)

    Shingo Takano

    2010-01-01

    Full Text Available Due to the prominent angiogenesis that occurs in malignant glioma, antiangiogenic therapy has been attempted. There have been several molecular targets that are specific to malignant gliomas, as well as more broadly in systemic cancers. In this review, I will focus on some topics related to molecular therapeutic targets for glioma angiogenesis. First, important angiogenic factors that could be considered molecular targets are VEGF, VEGF-induced proteins on endothelial cells, tissue factor, osteopontin, v3 integrin, and thymidine phosphorylase as well as endogenous inhibitors, soluble Flt1, and thrombospondin 1. Second, hypoxic areas are also decreased by metronomic CPT11 treatment as well as temozolomide. Third, glioma-derived endothelial cells that are genetically and functionally distinct from normal endothelial cells should be targeted, for example, with SDF-1 and CXCR7 chemokine. Fourth, endothelial progenitor cells (EPCs likely contribute towards glioma angiogenesis in the brain and could be useful as a drug delivery tool. Finally, blockade of delta-like 4 (Dll4 results in a nonfunctioning vasculature and could be another important target distinct from VEGF.

  10. Genetic characterization of adult infratentorial gliomas.

    Science.gov (United States)

    Miwa, Tomoru; Hirose, Yuichi; Sasaki, Hikaru; Ikeda, Eiji; Yoshida, Kazunari; Kawase, Takeshi

    2009-02-01

    Adult infratentorial gliomas are rare and have not been well studied. We therefore conducted genetic analysis of those tumors to see if there was any characteristic that could be relevant in clinical management and understanding of tumorigenesis. Nineteen adult infratentorial gliomas were analyzed for chromosomal aberration by comparative genomic hybridization, and for expression of p53 and epidermal growth factor receptor (EGFR) by immunohistochemistry. The most frequent chromosomal aberration was the gain of 7p, and five of the seven cerebellar or fourth ventricle malignant gliomas had that aberration. However, the gain of 7q, the characteristic abnormality of supratentorial astrocytomas commonly associated with the gaining of 7p, was observed only in 1 of 11 adult infratentorial astrocytic tumors. Combined losses of 1p and 19q, the genetic hallmark of oligodendroglioma, were not observed. Results of immunohistochemistry of p53 and EGFR were comparable to those reported in supratentorial gliomas. Our findings might suggest the presence of distinct tumorigenic pathway in adult infratentorial gliomas.

  11. Sensitivity of Interstitial combined Chemotherapy against Glioma

    Institute of Scientific and Technical Information of China (English)

    WANG Ming-sheng; LIN Jian-ying; ZHOU Guo-sheng; ZHANG Xin-zhong

    2006-01-01

    Objective To investigate the inhibitory effects of combination chemotherapy of Carboplatin(CBP) ,Teniposide (Vm-26) ,Methasquin(MTX),and Nimodipine(NIM) on glioma,and to explore the sensitivity of glioma cells to different treatment regimens so as to provide some clues for clinical usage of interstitial combination chemotherapy. Methods MTT assay and 3H-TdR incorporation assay were performed to evaluate the inhibitory effects upon the proliferation of glioma cells,and to compare the sensitivity of glioma cells to administration of CBP,Vm-26, MTX, and NIM with that of the administration of CBP + NIM, Vm-26 + NIM, MTX + NIM, CBP + Vm-26 + MTX, or CBP + Vm-26 + MTX + NIM respectively. Results The inhibition rate of CBP + Vm-26 + MTX + NIM combination administration against glioma cells was 96.64%,which was higher than that of CBP + NIM (69.03%), Vm-26 + NIM (71.53%), MTX + NIM (52. 75% ), CBP + Vm-26 + MTX(78.59%)(P<0.01),and the dosage of CBP,Vm-26,and MTX was declined to 1/10 ~ 1/100 that of respective use of CBP,Vm-26,and MTX. Conclusions The curative effects of combination administration of CBP,Vm-26, MTX, and NIM was much better than that of respective administration,suggesting a higher inhibition rate and a lower dosage use.

  12. [Chemotherapy of chiasmal gliomas in children].

    Science.gov (United States)

    Helcl, F

    1995-04-01

    Chiasmal gliomas are rare tumors occurring predominantly in childhood. Their optimal treatment is still controversial. In the past only neurosurgeons (performing partial or subtotal removal of the tumor, biopsy or shunting procedure in hydrocephalus) and radiotherapeutists participated in their treatment. In the middle of the eighties there was only a single article dealing with chemotherapy of these tumors (Rosenstock, 1985). Since that time there was an increased number of articles about harmful effects of radiotherapy on the developing child's brain. Neurosurgeons are aware that they will not solve this problem alone. During the past 7 years we have observed gradual retreat from radiotherapy and an inclination to combined chemotherapy of the chiasmal gliomas in children. The author has been engaged in the research of this clinical entity for more than 10 years and he offers to readers a summary of the contemporary knowledge about chemotherapy of chiasmal gliomas in children. Despite the fact that there is lacking experience with long-term survivors after chemotherapy, which is extremely important especially in this disease, the preliminary short-term results of combined chemotherapy of chiasmal gliomas in children are promising. Rapid development of chemistry and pharmacology in the last few years is promising for the discovery of further, more effective anti-tumor drugs. Their new combinations could improve present non-satisfactory results of treatment of chiasmal gliomas in children. (Ref. 25.)

  13. Glioma cells on the run – the migratory transcriptome of 10 human glioma cell lines

    Directory of Open Access Journals (Sweden)

    Holz David

    2008-01-01

    Full Text Available Abstract Background Glioblastoma multiforme (GBM is the most common primary intracranial tumor and despite recent advances in treatment regimens, prognosis for affected patients remains poor. Active cell migration and invasion of GBM cells ultimately lead to ubiquitous tumor recurrence and patient death. To further understand the genetic mechanisms underlying the ability of glioma cells to migrate, we compared the matched transcriptional profiles of migratory and stationary populations of human glioma cells. Using a monolayer radial migration assay, motile and stationary cell populations from seven human long term glioma cell lines and three primary GBM cultures were isolated and prepared for expression analysis. Results Gene expression signatures of stationary and migratory populations across all cell lines were identified using a pattern recognition approach that integrates a priori knowledge with expression data. Principal component analysis (PCA revealed two discriminating patterns between migrating and stationary glioma cells: i global down-regulation and ii global up-regulation profiles that were used in a proband-based rule function implemented in GABRIEL to find subsets of genes having similar expression patterns. Genes with up-regulation pattern in migrating glioma cells were found to be overexpressed in 75% of human GBM biopsy specimens compared to normal brain. A 22 gene signature capable of classifying glioma cultures based on their migration rate was developed. Fidelity of this discovery algorithm was assessed by validation of the invasion candidate gene, connective tissue growth factor (CTGF. siRNA mediated knockdown yielded reduced in vitro migration and ex vivo invasion; immunohistochemistry on glioma invasion tissue microarray confirmed up-regulation of CTGF in invasive glioma cells. Conclusion Gene expression profiling of migratory glioma cells induced to disperse in vitro affords discovery of genomic signatures; selected

  14. Treatment of malignant glioma using hyperthermia*

    Institute of Scientific and Technical Information of China (English)

    Jiahang Sun; Mian Guo; Hengyuan Pang; Jingtao Qi; Jinwei Zhang; Yunlong Ge

    2013-01-01

    Thirty pathological y diagnosed patients with grade III-IV primary or recurrent malignant glioma (tumor diameter 3-7 cm) were randomly divided into two groups. The control group underwent conventional radiotherapy and chemotherapy. In the hyperthermia group, primary cases received hyperthermia treatment, and patients with recurrent tumors were treated with hyperthermia in com-bination with radiotherapy and chemotherapy. Hyperthermia treatment was administered using a 13.56-MHz radio frequency hyperthermia device. Electrodes were inserted into the tumor with the aid of a CT-guided stereotactic apparatus and heat was applied for 1 hour. During 3 months after hyperthermia, patients were evaluated with head CT or MRI every month. Gliomas in the hyper-thermia group exhibited growth retardation or growth termination. Necrosis was evident in 80%of the heated tumor tissue and there was a decrease in tumor diameter. Our findings indicate that ra-dio frequency hyperthermia has a beneficial effect in the treatment of malignant glioma.

  15. The experimental investigation of glioma-trophic capacity of human umbilical cord-derived mesenchymal stem cells after intraventricular administration

    Directory of Open Access Journals (Sweden)

    FAN Cun-gang

    2013-07-01

    Full Text Available Objective To explore the glioma-trophic migration capacity of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs by intraventricular administration. Methods The umbilical cord tissue were obtained during full-term pregnancy cesarean section under sterile conditions. This study was approved by Ethics Committee and got the informed consent of patient. The hUC-MSCs were isolated by trypsin and collagenase digestion, followed by adherent culture methods. The characteristics of isolated hUC-MSCs were demonstrated by cell morphylogy, phenotype analysis and multi-differentiation potentials into adipocytes, osteoblasts and neural cells. Then the hUC-MSCs were labeled with CM-DiI and injected into contralateral ventricle of glioma of the C6 glioma-bearing Sprague-Dawley (SD rats. Two weeks later, the rats were sacrificed and the brains were taken out to examine the migration and distribution of hUC-MSCs in the tumor bed, at the interface of tumor and cerebral parenchyma as well as the tumor satelites infiltrating into the normal brain. Results The hUC-MSCs demonstrated plastic-adherent characterization and homogeneous fibroblastic-like morphylogy in culture, expression of specific surface phenotypes of MSCs (CD13, CD29, CD44, CD90 but not endothelial or hematopoietic markers (CD14, CD31, CD34, CD38, CD45, CD133, and muti-differentiatiation potentials into Oil red O stained adipocytes, Alizarin red S stained osteoblasts, neuron-specific enolase (NSE-positive neurons and glial fibrillary acidic protein (GFAP-positive astrocytes in permissive inducive conditions. Importantly, after labeled hUC-MSCs injection into contralateral ventricle of glioma, the hUC-MSCs migrated from initial injection site to the glioma mass and along the interface of tumor and brain, and some of them "chasing" the glioma satellites infiltrated into the normal parenchyma. Conclusion The hUC-MSCs possess prominent tumor-specific targeting capacity and extensive intratumoral

  16. Characteristics of gliomas in patients with somatic IDH mosaicism.

    Science.gov (United States)

    Bonnet, Charlotte; Thomas, Laure; Psimaras, Dimitri; Bielle, Franck; Vauléon, Elodie; Loiseau, Hugues; Cartalat-Carel, Stéphanie; Meyronet, David; Dehais, Caroline; Honnorat, Jérôme; Sanson, Marc; Ducray, François

    2016-03-31

    IDH mutations are found in the majority of adult, diffuse, low-grade and anaplastic gliomas and are also frequently found in cartilaginous tumors. Ollier disease and Maffucci syndrome are two enchondromatosis syndromes characterized by the development of multiple benign cartilaginous tumors due to post-zygotic acquisition of IDH mutations. In addition to skeletal tumors, enchondromatosis patients sometimes develop gliomas. The aim of the present study was to determine whether gliomas in enchondromatosis patients might also result from somatic IDH mosaicism and whether their characteristics are similar to those of sporadic IDH-mutated gliomas. For this purpose, we analyzed the characteristics of 6 newly diagnosed and 32 previously reported cases of enchondromatosis patients who developed gliomas and compared them to those of a consecutive series of 159 patients with sporadic IDH-mutated gliomas. As was the case with sporadic IDH mutated gliomas, enchondromatosis gliomas were frequently located in the frontal lobe (54 %) and consisted of diffuse low-grade (73 %) or anaplastic gliomas (21 %). However, they were diagnosed at an earlier age (25.6 years versus 44 years, p mosaicism and that the timing of IDH mutation acquisition might affect the location and molecular characteristics of gliomas. Early acquisition of IDH mutations could shift gliomagenesis towards the brainstem thereby mimicking the regional preference of histone mutated gliomas.

  17. [Surgical treatment of chiasmal gliomas in children].

    Science.gov (United States)

    Helcl, F

    1997-03-01

    Chiasmal gliomas are rare brain tumors occurring especially in children. Their proper treatment is still controversial and consists of surgery, radiotherapy and chemotherapy. Surgical removal of these tumors can usually be only partial or subtotal and radiotherapy frequently follows. There are supporters of surgical approach, as well as its enemies. The author has been engaged in problems of optimal treatment of this entity for more than 10 years. He is offering a review of knowledge from the literature concerning surgical treatment of this disease in children. The great majority of articles in the literature are dealing with retrospective analysis of relatively small series of patients usually treated in single neurosurgical department and the surgical treatment is enclosed like a part of combined therapy. Articles dealing only with surgical treatment of chiasmal gliomas are few and reviews determining the contemporary role of surgery of this entity are also lacking. This was the main impulse for writing this compilation. The short history of surgical therapy is reviewed. Some new trends of this therapy are also mentioned (microsurgery, Cavitron Ultrasonic Surgical Aspirator and peroperative use of visual evoked potentials). Up to date criteria for surgical treatment of chiasmal gliomas in children are given-exploration of chiasmal region and performing a biopsy in all cases, radical surgery only in extrinsic gliomas of the chiasmal region and conservative surgical approach to intrinsic chiasmal gliomas. It is emphasized that the significance of obstructive hydrocephalus in this entity has not been fully estimated till now, as well as the role of shunting procedures. Surgical treatment remains, nevertheless, an important armamentarium in the management of chiasmal gliomas in children. (Ref. 20.)

  18. Molecular Alterations of KIT Oncogene in Gliomas

    Directory of Open Access Journals (Sweden)

    Ana L. Gomes

    2007-01-01

    Full Text Available Gliomas are the most common and devastating primary brain tumours. Despite therapeutic advances, the majority of gliomas do not respond either to chemo or radiotherapy. KIT, a class III receptor tyrosine kinase (RTK, is frequently involved in tumourigenic processes. Currently, KIT constitutes an attractive therapeutic target. In the present study we assessed the frequency of KIT overexpression in gliomas and investigated the genetic mechanisms underlying KIT overexpression. KIT (CD117 immunohistochemistry was performed in a series of 179 gliomas of various grades. KIT activating gene mutations (exons 9, 11, 13 and 17 and gene amplification analysis, as defined by chromogenic in situ hybridization (CISH and quantitative real-time PCR (qRT-PCR were performed in CD117 positive cases. Tumour cell immunopositivity was detected in 15.6% (28/179 of cases, namely in 25% (1/4 of pilocytic astrocytomas, 25% (5/20 of diffuse astrocytomas, 20% (1/5 of anaplastic astrocytomas, 19.5% (15/77 of glioblastomas and one third (3/9 of anaplastic oligoastrocytomas. Only 5.7% (2/35 of anaplastic oligodendrogliomas showed CD117 immunoreactivity. No association was found between tumour CD117 overexpression and patient survival. In addition, we also observed CD117 overexpression in endothelial cells, which varied from 0–22.2% of cases, being more frequent in high-grade lesions. No KIT activating mutations were identified. Interestingly, CISH and/or qRT-PCR analysis revealed the presence of KIT gene amplification in 6 glioblastomas and 2 anaplastic oligoastrocytomas, corresponding to 33% (8/24 of CD117 positive cases. In conclusion, our results demonstrate that KIT gene amplification rather than gene mutation is a common genetic mechanism underlying KIT expression in subset of malignant gliomas. Further studies are warranted to determine whether glioma patients exhibiting KIT overexpression and KIT gene amplification may benefit from therapy with anti-KIT RTK

  19. Isocitrate dehydrogenase status and molecular subclasses of glioma and glioblastoma.

    Science.gov (United States)

    Agnihotri, Sameer; Aldape, Kenneth D; Zadeh, Gelareh

    2014-12-01

    Diffuse gliomas and secondary glioblastomas (GBMs) that develop from low-grade gliomas are a common and incurable class of brain tumor. Mutations in the metabolic enzyme glioblastomas (IDH1) represent a distinguishing feature of low-grade gliomas and secondary GBMs. IDH1 mutations are one of the most common and earliest detectable genetic alterations in low-grade diffuse gliomas, and evidence supports this mutation as a driver of gliomagenesis. Here, the authors highlight the biological consequences of IDH1 mutations in gliomas, the clinical and therapeutic/diagnostic implications, and the molecular subtypes of these tumors. They also explore, in brief, the non-IDH1-mutated gliomas, including primary GBMs, and the molecular subtypes and drivers of these tumors. A fundamental understanding of the diversity of GBMs and lower-grade gliomas will ultimately allow for more effective treatments and predictors of survival.

  20. Enhanced invasion in vitro and the distribution patterns in vivo of CD133+ glioma stem cells

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

    Background Recent studies have suggested that cancer stem cells cause tumor recurrence based on their resistance to radiotherapy and chemotherapy.Although the highly invasive nature of glioblastoma cells is also implicated in the failure of current therapies,it is not clear whether cancer stem cells are involved in invasiveness.This study aimed to assess invasive ability of glioma stem cells (GSCs) derived from C6 glioma cell line and the distribution patterns of GSCs in Sprague-Dawley (SD) rat brain tumor.Methods Serum-free medium culture and magnetic isolation were used to gain purely CD133+ GSCs.The invasive stem cell markers and luxol fast blue staining for white matter tracts were performed to show the distribution patterns of GSCs in brain tumor of rats and the relationship among GSCs,vessels,and white matter tracts.The results of matrigel invasion assay were estimated using the Student's t test and the analysis of Western blotting was performed using the one-way analysis of variance (ANOVA) test.Results CD133+GSCs(number:85.3±4.1)were significantly more invasive in vitro than matched CD133- cells(number:25.9±3.1) (t=14.5,P <0.005).GSCs invaded into the brain diffusely and located in perivascular niche of tumor-brain interface or resided within perivascular niche next to white fiber tracts.The polarity of glioma cells containing GSCs was parallel to the white matter tracts.Conclusions Our data suggest that CD133+ GSCs exhibit more aggressive invasion in vitro and GSCs in vivo probably disseminate along the long axis of blood vessels and transit through the white matter tracts.The therapies targeting GSCs invasion combined with traditional glioblastoma multiforme therapeutic paradigms might be a new approach for avoiding malignant glioma recurrence.

  1. 携带CD基因骨髓间充质干细胞对C6大鼠胶质瘤体内抑制作用研究%Investigation on The Inhibition Effects of Bone Marrow Mesenchymal Stem Cells With CD Gene on Glioma in C6 Rat

    Institute of Scientific and Technical Information of China (English)

    宋飞; 邢琪; 宋克东; 刘健; 姬广春; 马郁芳; 刘天庆; 马学虎; 田晓峰

    2012-01-01

    The in vivo treatment effect of CD (cytosine deaminase) suicidal genetic system on the glioma in rat was explored. The lentivirus carrier which was composed of CD genes was fabricated and the mouse BMMSCs were transfected by such CD genes to obtain constantly expressed cells, then BMMSCs were transplanted into the animal model which was built through an intracranial stereotactic inoculating method using a group of 40 SD rats. The rats were divided into 5 groups uniformly according to the cell type inoculated, i.e. ① C6 glioma, ②C6 + MSCs(mesenchymal stems cells) cells (1 : 1), ③C6+MSC cells (1 : 2), ④C6+MSC -codA/eGFP cells (1 : 1) and ⑤C6+MSC-codA/eGFP ce))s (1 : 2). After 7 days of tumor formation, the abdominal cavity of rats were injected with 5-FC at 500 mg/(kg· d) for 14 days. Intensive scanning was carried out weekly to observe tumor volume using MR1. Simultaneously, survival times, routine pathological test, RT-PCR assay and HE staining were also operated. The results of MRI showed that the focus of infection in group ① presented round shape. The necrosis area of tumor found in the center, achieved an average volume of 246 mm3, and the survival time of the center area was 15.3 days. About the group ② and ③, the survival times were 16.0 and 16.6 days respectively. But in group ④ and ⑤, the survival times were both larger than 30 days, the necrosis area of tumor was 55 and 40 mm3 respectively at day 14, and the inhibition efficiency was 77.24% and 83.28% respectively after 28 days of treatment. It was concluded that the MRI scanning could clearly show the volume, shape, and internal structure of the tumor, which was highly related to the results of pathology. The treatment effect of bone marrow MSCs with CD genes and 5-FC therapy system on C6 intracranial glioma could be verified through dynamic MRI observation. Moreover, the RT-PCR test confirmed the exptession of cytosine deaminase inside tumor organization.%为了研究自杀基因—

  2. Molecular targeting for malignant gliomas (Review).

    Science.gov (United States)

    Kondo, Yasuko; Hollingsworth, Emporia F; Kondo, Seiji

    2004-05-01

    With tendency to invade rapidly in the brain, malignant gliomas are very resistant to conventional therapies including radiation and chemotherapy. Recent advances in genetic and molecular techniques have made it possible to define characteristic molecular profiles of malignant gliomas. Based on the list of the molecules closely related to glioblastoma tissues, we reviewed strategies targeting them. Target molecules extensively studied include EGFR, PTEN, telomerase and signal pathway modulators for Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. Therapies targeting specific molecules may result in killing tumor cells effectively while keeping normal cells intact.

  3. Using bioluminescence imaging in glioma research.

    Science.gov (United States)

    Luwor, Rodney B; Stylli, Stanley S; Kaye, Andrew H

    2015-05-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumour and has the worst prognosis. Over the last decade, the use of bioluminescence imaging technology has rapidly become widespread to further understand the mechanisms that drive GBM development and progression. Pre-clinical evaluation and optimisation of therapeutic efficacy in GBM research has also utilised this simple non-invasive technology. Here we summarise recent advances made in glioma biology and therapeutic intervention using bioluminescence imaging. This review also describes the current knowledge regarding the use of luciferase-based reporters in examining the role of specific cancer signalling cascades that promote glioma progression.

  4. Lymphoid Cell-Glioma Cell Interaction Enhances Cell Coat Production by Human Gliomas: Novel Suppressor Mechanism

    Science.gov (United States)

    Dick, Steven J.; Macchi, Beatrice; Papazoglou, Savvas; Oldfield, Edward H.; Kornblith, Paul L.; Smith, Barry H.; Gately, Maurice K.

    1983-05-01

    Certain human glioma lines produce mucopolysaccharide coats that impair the generation of cytolytic lymphocytes in response to these lines in vitro. Coat production is substantially enhanced by the interaction of glioma cells with a macromolecular factor released by human peripheral blood mononuclear cells in culture. This interaction thus constitutes an unusual mechanism by which inflammatory cells may nonspecifically suppress the cellular immune response to at least one class of solid tumors in humans.

  5. The Association between Some Nutrients and Adult Gliomas: A Case-Control Study of Adult Gliomas

    Directory of Open Access Journals (Sweden)

    M Shayanfar

    2014-02-01

    Full Text Available Abestract Background & aim: It has been estimated that about 30–40 percent of all cancers could be prevented by diet and lifestyle. In the present study, associations between food groups and some nutrients were studied in adult glioma. Methods: In the present hospital-based case-control study which took place in Tehran, Iran, from 2010 to 2012, socio-economic information, demographics, lifestyle factors, health and dietary intakes of 128 patients with glioma as cases, and 256 healthy controls, were collected through interviews and questionnaires. Logistic regression was used to estimate odds ratios. SPSS version 19 was used for all statistical analyses. Results: After adjusting for potential confounders, inverse associations between calcium intake and adult glioma and vitamin C were observed. (Highest tertile versus lowest: OR = 0.20, 95% CI = 0.87-0.46, P for trend = 0.001 and vitamin C (OR = 0.34, 95% CI = 0.15-0.76, P for trend = 0.002. In addition, we observed elevated ORs for highest vs. lowest tertile of cholesterol intake (OR = 2.78, 95% CI = 1.29-5.99, P for trend = 0.061. We observed no significant associations with adult glioma for intakes of total fat, carbohydrate, protein, vitamin A, vitamin E and beta carotene. Conclusion: the results showed that intake of calcium and vitamin C may possibly prevent glioma in adults. Key words: Gliomas, Adult, Ca, Vitamin C

  6. Kynurenic acid synthesis by human glioma

    DEFF Research Database (Denmark)

    Vezzani, A; Gramsbergen, J B; Versari, P;

    1990-01-01

    Biopsy material from human gliomas obtained during neurosurgery was used to investigate whether pathological human brain tissue is capable of producing kynurenic acid (KYNA), a natural brain metabolite which can act as an antagonist at excitatory amino acid receptors. Upon in vitro exposure to 40...

  7. Genetics and pharmacogenomics of diffuse gliomas

    NARCIS (Netherlands)

    Thuijl, H.F. van; Ylstra, B.; Wurdinger, T.; Nieuwenhuizen, D. van; Heimans, J.J.; Wesseling, P.; Reijneveld, J.C.

    2013-01-01

    Rapidly evolving techniques for analysis of the genome provide new opportunities for cancer therapy. For diffuse gliomas this has resulted in molecular markers with potential for personalized therapy. Some drugs that utilize pharmacogenomics are currently being tested in clinical trials. In melanoma

  8. Mean Diffusional Kurtosis in Patients with Glioma

    DEFF Research Database (Denmark)

    Tietze, A.; Hansen, Mikkel Bo; Østergaard, Leif

    2015-01-01

    , and the contralateral normal appearing white and grey matter of 34 patients (22 high-grade, 12 low-grade gliomas). MK’ and MD in different grades were compared using a Wilcoxon rank-sum test. Receiver Operating Characteristic curves and the area under the curve were calculated to determine the diagnostic accuracy of MK...

  9. Changing incidence and improved survival of gliomas

    NARCIS (Netherlands)

    Ho, Vincent K. Y.; Reijneveld, Jaap C.; Enting, Roeline; Bienfait, Henri P.; Robe, Pierre; Baumert, Brigitta G.; Visser, Otto

    2014-01-01

    BACKGROUND: Tumours of the central nervous system (CNS) represent a relatively rare but serious health burden. This study provides insight into the incidence and survival patterns of gliomas in the Netherlands diagnosed in adult patients during the time period 1989-2010, with a focus on glioblastoma

  10. Neuromyelitis Optica Lesion Mimicking Brainstem Glioma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2007-12-01

    Full Text Available A 12-year-old girl who presented with weakness of the left extremities and right sided sixth cranial nerve palsy had neuromyelitis optica (NMO mistaken for brainstem glioma on MRI, in a report from Brain Research Institute, Yonsei University College of Medicine,Seoul, Republic of KoreaNeuromyelitis Optica, Optic-Spinal Syndrome, Spectroscopy.

  11. Hormone replacement therapy and risk of glioma

    DEFF Research Database (Denmark)

    Andersen, Lene; Friis, Søren; Hallas, Jesper;

    2013-01-01

    Aim: Several studies indicate that use of hormone replacement therapy (HRT) is associated with an increased risk of intracranial meningioma, while associations between HRT use and risk of other brain tumors have been less explored. We investigated the influence of HRT use on the risk of glioma...

  12. Surgical strategies for glioma involving language areas

    Institute of Scientific and Technical Information of China (English)

    ZHANG Zhong; JIANG Tao; XIE Jian; LIU Fu-sheng; LI Shou-wei; QIAO Hui; WANG Zhong-cheng

    2008-01-01

    Background Successful treatment of gliomas in or adjacent to language areas constitutes a major challenge to neurosurgery. The present study was performed to evaluate the procedure of language mapping via intraoperative direct cortical electrical stimulation under awake anaesthesia when performed prior to resective glioma surgery.Methods Thirty patients with gliomas and left-hemisphere dominance and, who underwent language mapping via intraoperative direct cortical electrical stimulation under awake anaesthesia before resective glioma surgery, were analyzed retrospectively. All patients had tumors in or adjacent to cortical language areas. The brain lesions were removed according to anatomic-functional boundaries with preservation of areas of language function. Both preoperative and postoperative functional findings were evaluated.Results Intraoperative language areas were detected in 20 patients but not in four patients. Language mapping failure for reasons attributable to the anaesthesia or to an intraoperative increase in intracranial pressure occurred in six cases.Seven patients presented with moderate or severe language deficits after six months of follow-up. Total resection was achieved in 14 cases, near-total resection in 12 cases and subtotal resection in four cases.Conclusions Intraoperative cortical electrical stimulation is an accurate and safe approach to identification of the language cortex. Awake craniotomy intraoperative cortical electrical stimulation, in combination with presurgical neurological functional imaging to identify the anatomic-functional boundaries of tumor resection, permits extensive tumor excision while preserving normal language function and minimizing the risk of postoperative language deficits.

  13. A dual functional fluorescent probe for glioma imaging mediated by blood-brain barrier penetration and glioma cell targeting.

    Science.gov (United States)

    Ma, Hongwei; Gao, Zhiyong; Yu, Panfeng; Shen, Shun; Liu, Yongmei; Xu, Bainan

    2014-06-20

    Glioma is a huge threat for human being because it was hard to be completely removed owing to both the infiltrating growth of glioma cells and integrity of blood brain barrier. Thus effectively imaging the glioma cells may pave a way for surgical removing of glioma. In this study, a fluorescent probe, Cy3, was anchored onto the terminal of AS1411, a glioma cell targeting aptamer, and then TGN, a BBB targeting peptide, was conjugated with Cy3-AS1411 through a PEG linker. The production, named AsT, was characterized by gel electrophoresis, (1)H NMR and FTIR. In vitro cellular uptake and glioma spheroid uptake demonstrated the AsT could not only be uptaken by both glioma and endothelial cells, but also penetrate through endothelial cell monolayer and uptake by glioma spheroids. In vivo, AsT could effectively target to glioma with high intensity. In conclusion, AsT could be used as an effective glioma imaging probe.

  14. Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21

    Energy Technology Data Exchange (ETDEWEB)

    Dai, Bin [Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 (China); Hu, Zhiqiang, E-mail: zhiqhutg@126.com [Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 (China); Huang, Hui; Zhu, Guangtong; Xiao, Zhiyong [Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 (China); Wan, Weiqing; Zhang, Peng; Jia, Wang; Zhang, Liwei [Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050 (China)

    2014-11-07

    Highlights: • KDM5B is overexpressed in glioma samples. • KDM5B stimulated proliferation of glioma cells. • Inhibition of p21contributes to KDM5B-induced proliferation. - Abstract: Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. Upregulation of lysine (K)-specific demethylase 5B (KDM5B) has been reported in a variety of malignant tumors. However, the impact of KDM5B in glioma remains unclear. The objective of this study was to investigate the expression and prognostic value of KDM5B in glioma. In clinical glioma samples, we found that KDM5B expression was significantly upregulated in cancer lesions compared with normal brain tissues. Kaplan–Meier analysis showed that patients with glioma and higher KDM5B expression tend to have shorter overall survival time. By silencing or overexpressing KDM5B in glioma cells, we found that KDM5B could promote cell growth both in vitro and in vivo. Moreover, we demonstrated that KDM5B promoted glioma proliferation partly via regulation of the expression of p21. Our study provided evidence that KDM5B functions as a novel tumor oncogene in glioma and may be a potential therapeutic target for glioma management.

  15. IL-13Ra2- and glioma stem cell-pulsed dendritic cells induce glioma cell death in vitro

    Institute of Scientific and Technical Information of China (English)

    Ying Wang; Ruifan Xie; Hongquan Niu; Ting Lei

    2016-01-01

    Objective Gliomas are the most common malignant tumors in the central nervous system. Despite mul-tiple therapies including surgery, chemotherapy, and radiotherapy, the prognosis of patients remains poor. Immunotherapy is an alternative method of treating glioma, and the use of dendritic cel vaccines is one of the promising treatment options. However, there is no specific tumor cel antigen that can trigger dendritic cel s (DCs). IL-13Ra2 is a specific antigen expressed in glioma cel s; in the current study, we have at-tempted to explore whether IL-13Ra2 could be the antigen that triggers DCs and to envisage its application as potential therapy for glioma. Methods The expression of IL-13Ra2 was detected in U251 glioma cel lines and primary glioma tissues using dif erent methods. DCs from human blood were isolated and pulsed with recombinant IL-13Ra2, fol-lowing which the cytotoxicity of these DCs on glioma cel s was detected and analyzed. Results About 55.9% human glioma tissue cel s expressed IL-13Ra2, while normal brain tissue cel s did not show any expression. DC vaccines loaded with IL-13Ra2, glioma cel antigen, and brain tumor stem cel (BTSC) antigen could significantly stimulate the proliferation of T lymphocytes and induce cel death in the glioma tissue. Compared to other groups, DC vaccines loaded with BTSC antigen showed the strongest ability to activate cytotoxic T lymphocytes (CTLs), while the glioma cel antigen group showed no significant dif erence. Conclusion IL-13Ra2, which is expressed in gliomas and by glioma stem cel s, as wel as IL-13Ra2 could prove to be potential antigens for DC vaccine-based immunotherapy.

  16. Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas

    Science.gov (United States)

    2016-10-05

    Childhood Mixed Glioma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Fibrillary Astrocytoma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliosarcoma

  17. Receptor-Mediated Drug Delivery Systems Targeting to Glioma

    Directory of Open Access Journals (Sweden)

    Shanshan Wang

    2015-12-01

    Full Text Available Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS. The complexity of glioma, especially the existence of the blood-brain barrier (BBB, makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications.

  18. BMPs as Therapeutic Targets and Biomarkers in Astrocytic Glioma

    Directory of Open Access Journals (Sweden)

    Pilar González-Gómez

    2014-01-01

    Full Text Available Astrocytic glioma is the most common brain tumor. The glioma initiating cell (GIC fraction of the tumor is considered as highly chemoresistant, suggesting that GICs are responsible for glioma relapse. A potential treatment for glioma is to induce differentiation of GICs to a more benign and/or druggable cell type. Given BMPs are among the most potent inducers of GIC differentiation, they have been considered as noncytotoxic therapeutic compounds that may be of use to prevent growth and recurrence of glioma. We herein summarize advances made in the understanding of the role of BMP signaling in astrocytic glioma, with a particular emphasis on the effects exerted on GICs. We discuss the prognostic value of BMP signaling components and the implications of BMPs in the differentiation of GICs and in their sensitization to alkylating drugs and oncolytic therapy/chemotherapy. This mechanistic insight may provide new opportunities for therapeutic intervention of brain cancer.

  19. Slit2/Robo1 signaling in glioma migration and invasion.

    Science.gov (United States)

    Xu, Yun; Li, Wen-Liang; Fu, Li; Gu, Feng; Ma, Yong-Jie

    2010-12-01

    Slit2/Robo1 is a conserved ligand-receptor system, which greatly affects the distribution, migration, axon guidance and branching of neuron cells. Slit2 and its transmembrane receptor Robo1 have different distribution patterns in gliomas. The expression of Slit2 is at very low levels in pilocytic astrocytoma, fibrillary astrocytoma and glioblastoma, while Robo1 is highly expressed in different grades of gliomas at both mRNA and protein levels. Acquisition of insidious invasiveness by malignant glioma cells involves multiple genetic alterations in signaling pathways. Although the specific mechanisms of tumor-suppressive effect of Slit2/Robo1 have not been elucidated, it has been proved that Slit2/Robo1 signaling inhibits glioma cell migration and invasion by inactivation of Cdc42-GTP. With the research development on the molecular mechanisms of Slit2/Robo1 signaling in glioma invasion and migration, Slit2/Robo1 signaling may become a potential target for glioma prevention and treatment.

  20. LuIII parvovirus selectively and efficiently targets, replicates in, and kills human glioma cells.

    Science.gov (United States)

    Paglino, Justin C; Ozduman, Koray; van den Pol, Anthony N

    2012-07-01

    Because productive infection by parvoviruses requires cell division and is enhanced by oncogenic transformation, some parvoviruses may have potential utility in killing cancer cells. To identify the parvovirus(es) with the optimal oncolytic effect against human glioblastomas, we screened 12 parvoviruses at a high multiplicity of infection (MOI). MVMi, MVMc, MVM-G17, tumor virus X (TVX), canine parvovirus (CPV), porcine parvovirus (PPV), rat parvovirus 1A (RPV1A), and H-3 were relatively ineffective. The four viruses with the greatest oncolytic activity, LuIII, H-1, MVMp, and MVM-G52, were tested for the ability, at a low MOI, to progressively infect the culture over time, causing cell death at a rate higher than that of cell proliferation. LuIII alone was effective in all five human glioblastomas tested. H-1 progressively infected only two of five; MVMp and MVM-G52 were ineffective in all five. To investigate the underlying mechanism of LuIII's phenotype, we used recombinant parvoviruses with the LuIII capsid replacing the MVMp capsid or with molecular alteration of the P4 promoter. The LuIII capsid enhanced efficient replication and oncolysis in MO59J gliomas cells; other gliomas tested required the entire LuIII genome to exhibit enhanced infection. LuIII selectively infected glioma cells over normal glial cells in vitro. In mouse models, human glioblastoma xenografts were selectively infected by LuIII when administered intratumorally; LuIII reduced tumor growth by 75%. LuIII also had the capacity to selectively infect subcutaneous or intracranial gliomas after intravenous inoculation. Intravenous or intracranial LuIII caused no adverse effects. Intracranial LuIII caused no infection of mature mouse neurons or glia in vivo but showed a modest infection of developing neurons.

  1. Induction of apoptosis and inhibition of proliferation of C6 glioma cells in vitro by tamoxifen

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective To investigate the anti-tumor effect and mechanism of tamoxifen on rat C6 glioma cells. Methods C6 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with 3% fetal calf serum (FCS), and treated with tamoxifen of different concentrations, i.e. group A (1.25μmol/L), group B (2.50 μmol/L), group C (5.00 μmol/L), group D (10.00 μmol/L), group E (20.00 μmol/L) and control group (0.00 μmol/L). Morphological changes, MTT assay and 5-bromo-2'-deoxyuriding labeling ratio were assessed. Apoptosis was observed by flow cytometry. Results C6 cells treated with different doses of tamoxifen for 24, 48, and 72 hours became irregular in shape, while cells treated with vehicle grew normally. MTT assay showed that tamoxifen did not suppress C6 cell growth until 72 hours after treatment. Seventy-two hours after treatment, there were significant differences in cell viable rate between group A versus groups C, D and E; so did group B versus group D as well as group E (P<0.05). BrdU incorporation assay indicated significant difference of BrdU labbled index (BrdU LI) among groups A, C, E and control group 48 hours after treatment (P<0.05). And the BrdU LI decreased with the increased concentration of tamoxifen. Flow cytometry (FCM) showed significant difference between treated group and control group at 24, 48, and 72 hours after treatment (P<0.05). Conclusion Tamoxifen significantly suppresses the growth of C6 glioma cells in a time- and dose-dependent manner. The mechanism of tamoxifen suppressing C6 glioma cells may be inhibiting proliferation and inducing apoptosis. Therefore, tamoxifen can be a candidate as a chemotherapy agent for glioma.

  2. Significance of the expression of green fluorescent protein on detection of glioma invasion in vivo

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To investigate the invasion and metastasis of gliomain vivo by xenotransplanted tumor established by implanting C6 glioma cells transfected with green fluorescent protein (GFP) gene in vitro into the brain of SD rats. Methods: C6 cells were transfected with a plasmid vector (pEGEP-N3) containing the GFP gene. Stable GFP-expressing clones were isolated and performed examination by flow cytometry and electron microscope. GFP-expressing cells were stereotactically injected into the brain parenchyma of SD rats to establish xenotransplanted tumor. Four weeks later rats were killed and continuous brain sections respectively were examined by HE staining, immunohistochemistry method and fluorescence microscopy for detection of tumor cell invasion. Xenotransplanted tumor was primarily cultured to determine the storage of exotic GFP gene in vivo. Results: There were not obvious changes in cell cycle and ultrastructure for the cells transfected with GFP gene. C6 cells transfected with GFP gene maintained stable high-level GFP expression in the central nervous system during their growth in vivo. GFP fluorescence clearly demarcated the primary tumor margin and readily allowed for the detection of distant invasion on the single-cell level, which was evidently superior to HE and immunohistochemistry staining. There was not GFP gene loss of transfected cells in vivo. Conclusions: It is suggested that C6 cells transfected with GFP gene can be visualized by fluorescent microscopy after intracranial implantation. This model is an excellent experimental animal model in research on invasion of glioma.

  3. Activity of lysosomal exoglycosidases in human gliomas.

    Science.gov (United States)

    Wielgat, P; Walczuk, U; Szajda, S; Bień, M; Zimnoch, L; Mariak, Z; Zwierz, K

    2006-12-01

    There is a lot of data suggesting that modifications of cell glycoconjugates may be important in progression of cancer. In the present work we studied activities of lysosomal exoglycosidases: beta-hexosaminidase and its isoenzymes A and B, beta-galactosidase and alpha-mannosidase, in human gliomas. Enzyme activity was determined spectrophotometrically based on the release of p-nitrophenol from p-nitrophenyl-derivative of appropriate sugars. The activities of the exoglycosidases tested were significantly higher in malignant glial tumors than in control tissue (normal brain tissue) and non-glial tumors. The highest activities of exoglycosidases were observed in high-grade gliomas, and a positive correlation of enzyme activities and degree of malignancy was noted. Our results suggest that lysosomal exoglycosidases may participate in the progression and dynamical development of glial tumors.

  4. A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth.

    Science.gov (United States)

    De Feyter, Henk M; Behar, Kevin L; Rao, Jyotsna U; Madden-Hennessey, Kirby; Ip, Kevan L; Hyder, Fahmeed; Drewes, Lester R; Geschwind, Jean-François; de Graaf, Robin A; Rothman, Douglas L

    2016-08-01

    The dependence of tumor cells, particularly those originating in the brain, on glucose is the target of the ketogenic diet, which creates a plasma nutrient profile similar to fasting: increased levels of ketone bodies and reduced plasma glucose concentrations. The use of ketogenic diets has been of particular interest for therapy in brain tumors, which reportedly lack the ability to oxidize ketone bodies and therefore would be starved during ketosis. Because studies assessing the tumors' ability to oxidize ketone bodies are lacking, we investigated in vivo the extent of ketone body oxidation in 2 rodent glioma models. Ketone body oxidation was studied using (13)C MR spectroscopy in combination with infusion of a (13)C-labeled ketone body (beta-hydroxybutyrate) in RG2 and 9L glioma models. The level of ketone body oxidation was compared with nontumorous cortical brain tissue. The level of (13)C-beta-hydroxybutyrate oxidation in 2 rat glioma models was similar to that of contralateral brain. In addition, when glioma-bearing animals were fed a ketogenic diet, the ketone body monocarboxylate transporter was upregulated, facilitating uptake and oxidation of ketone bodies in the gliomas. These results demonstrate that rat gliomas can oxidize ketone bodies and indicate upregulation of ketone body transport when fed a ketogenic diet. Our findings contradict the hypothesis that brain tumors are metabolically inflexible and show the need for additional research on the use of ketogenic diets as therapy targeting brain tumor metabolism. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. Musical hallucinations following insular glioma resection.

    Science.gov (United States)

    Isolan, Gustavo Rassier; Bianchin, Marino Muxfeldt; Bragatti, José Augusto; Torres, Carolina; Schwartsmann, Gilberto

    2010-02-01

    Hallucinations can be auditory, visual, tactile, gustatory, or olfactory, and can be caused by psychiatric (such as schizophrenia and depression), neurological (such as cerebrovascular accidents, neoplasia, and infection), or endocrine and metabolic disorders. Musical hallucinations related to neurological disorders are rare. The authors present a case of a patient with a right insular glioma who developed transient musical hallucinations after microsurgical resection of the tumor.

  6. Synthesis and evaluation of boron compounds for neutron capture therapy of malignant brain tumors

    Energy Technology Data Exchange (ETDEWEB)

    Soloway, A.H.

    1991-01-01

    Current progress on this research includes the synthesis of chemical structures for malignant brain tumors. These structures include boron-containing derivatives of lipophilic anticonvulsants and CNS depressants; carboranyl precursors of nucleic acids and related structures; and carboranyl amino acids. Cellular uptake and persistence studies have also been carried out with F98 rat glioma cells. 1 fig., 1 tab.

  7. CURRENT APPROACHES TO CHEMORADIOTHERAPY FOR MALIGNANT GLIOMAS

    Directory of Open Access Journals (Sweden)

    Ye. L. Choinzonov

    2014-01-01

    Full Text Available High-grade malignant gliomas (WHO grade G III–IV account for more than 50% of all primary brain tumors. Despite aggressive treatment, survival rates are still very low with a median reported survival of no more than 1.5 years.Radiation therapy is an integral part of the combined treatment, but often does not influence lethally on resistant tumor cells. Thereby, in recent decades there has been an active search for novel approaches to the treatment of malignant gliomas (chemotherapeutic drugs, biological modifiers, local hyperthermia. Experimental data showed that the effect of high temperatures has both a direct damaging effect on tumor cells and a sensitizing effect. Significant advantages are achieved when the complex treatment of different malignant tumorsincludes local hyperthermia. However data on the treatment of patients with primary and recurrent gliomas G III–IV using local hyperthermia are scarce.The literature review is given in the article provides an overview of the existing treatment methods for brain tumors.

  8. Growth Inhibiting and Apoptosis-inducing Effects of the Aqueous Extract of Albizia julibrissin Durazz Flower on Rat Glioma Cells C6%合欢花水提物对大鼠脑胶质瘤C6细胞株的增殖抑制与凋亡诱导作用

    Institute of Scientific and Technical Information of China (English)

    昝亚伟; 张立伟; 陈廷贵

    2012-01-01

    采用MTT法检测合欢花水提物对C6细胞增殖活力的影响,流式细胞术检测该水提物对C6细胞的诱导凋亡作用.结果表明:合欢花水提物能抑制C6细胞的增殖,且具有剂量和时间依赖性,其在24 h、48 h、72 h时对C6细胞的半数抑制率(LD50)分别为:305 μg/mL、50 μg/mL、15 μg/mL.流式细胞术结果显示:200 tμg/mL、300μg/mL合欢花水提物均可诱导C6细胞发生早期凋亡,与对照组细胞相比,早期凋亡率分别由对照组的0.7%增加到了4.3%、14.3%.提示合欢花水提物抑制C6细胞增殖机理与诱导细胞凋亡途径有关.%The growth inhibiting and apotosis-inducing effects of aqueous extract of Albizia julibrissin Durazz flower(AJDF) on the rat glioma cells C6 in vitro were studied by MTT assays and flow cytometry methods. The results showed that the water extract of AJDF had obvious suppression on the proliferation of C6 cell lines,which had significant dose-and time-dependent relationships.the LD50 was respectively 305 μg/mL.50 μg/mL,15 μg/mL for 24 h,48 h.72 h. The flow cytometric analysis displayed that 200 μg/mL,300 μg/mL water extract of AJDF can both induce C6 cell lines early phase apotosis.apotosis rate was respectively 4. 3% .14. 3% ,but the blank control group was only 0. 7%. The mechanisim of inhibiting proliferation might be related to cell apoptosis.

  9. Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study.

    Science.gov (United States)

    Colen, Chaim B; Shen, Yimin; Ghoddoussi, Farhad; Yu, Pingyang; Francis, Todd B; Koch, Brandon J; Monterey, Michael D; Galloway, Matthew P; Sloan, Andrew E; Mathupala, Saroj P

    2011-07-01

    Glioblastoma multiforme (GBM) are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rate. To survive, GBMs efflux lactic acid to the tumor microenvironment through transmembrane transporters denoted monocarboxylate transporters (MCTs). We hypothesized that inhibition of MCT function would impair the glycolytic metabolism and affect both glioma invasiveness and survival. We examined the effect on invasiveness with α-cyano-4-hydroxy-cinnamic acid (ACCA, 4CIN, CHCA), a small-molecule inhibitor of lactate transport, through Matrigel-based and organotypic (brain) slice culture invasive assays using U87-MG and U251-MG glioma cells. We then conducted studies in immunodeficient rats by stereotaxic intracranial implantation of the glioma cells followed by programmed orthotopic application of ACCA through osmotic pumps. Effect on the implanted tumor was monitored by small-animal magnetic resonance imaging. Our assays indicated that glioma invasion was markedly impaired when lactate efflux was inhibited. Convection-enhanced delivery of inhibitor to the tumor bed caused tumor necrosis, with 50% of the animals surviving beyond the experimental end points (3 months after inhibitor exhaustion). Most importantly, control animals did not display any adverse neurologic effects during orthotopic administration of ACCA to brain through programmed delivery. These results indicate the clinical potential of targeting lactate efflux in glioma through delivery of small-molecule inhibitors of MCTs either to the tumor bed or to the postsurgical resection cavity.

  10. Metabolic Targeting of Lactate Efflux by Malignant Glioma Inhibits Invasiveness and Induces Necrosis: An In Vivo Study

    Directory of Open Access Journals (Sweden)

    Chaim B Colen

    2011-07-01

    Full Text Available Glioblastoma multiforme (GBM are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rate. To survive, GBMs efflux lactic acid to the tumor microenvironment through transmembrane transporters denoted monocarboxylate transporters (MCTs. We hypothesized that inhibition of MCT function would impair the glycolytic metabolism and affect both glioma invasiveness and survival. We examined the effect on invasiveness with α-cyano-4-hydroxy-cinnamic acid (ACCA, 4CIN, CHCA, a small-molecule inhibitor of lactate transport, through Matrigel-based and organotypic (brain slice culture invasive assays using U87-MG and U251-MG glioma cells. We then conducted studies in immunodeficient rats by stereotaxic intracranial implantation of the glioma cells followed by programmed orthotopic application of ACCA through osmotic pumps. Effect on the implanted tumor was monitored by small-animal magnetic resonance imaging. Our assays indicated that glioma invasion was markedly impaired when lactate efflux was inhibited. Convection-enhanced delivery of inhibitor to the tumor bed caused tumor necrosis, with 50% of the animals surviving beyond the experimental end points (3 months after inhibitor exhaustion. Most importantly, control animals did not display any adverse neurologic effects during orthotopic administration of ACCA to brain through programmed delivery. These results indicate the clinical potential of targeting lactate efflux in glioma through delivery of small-molecule inhibitors of MCTs either to the tumor bed or to the postsurgical resection cavity.

  11. Metabolic Targeting of Lactate Efflux by Malignant Glioma Inhibits Invasiveness and Induces Necrosis: An In Vivo Study1

    Science.gov (United States)

    Colen, Chaim B; Shen, Yimin; Ghoddoussi, Farhad; Yu, Pingyang; Francis, Todd B; Koch, Brandon J; Monterey, Michael D; Galloway, Matthew P; Sloan, Andrew E; Mathupala, Saroj P

    2011-01-01

    Glioblastoma multiforme (GBM) are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rate. To survive, GBMs efflux lactic acid to the tumor microenvironment through transmembrane transporters denoted monocarboxylate transporters (MCTs). We hypothesized that inhibition of MCT function would impair the glycolytic metabolism and affect both glioma invasiveness and survival. We examined the effect on invasiveness with α-cyano-4-hydroxy-cinnamic acid (ACCA, 4CIN, CHCA), a small-molecule inhibitor of lactate transport, through Matrigel-based and organotypic (brain) slice culture invasive assays using U87-MG and U251-MG glioma cells. We then conducted studies in immunodeficient rats by stereotaxic intracranial implantation of the glioma cells followed by programmed orthotopic application of ACCA through osmotic pumps. Effect on the implanted tumor was monitored by small-animal magnetic resonance imaging. Our assays indicated that glioma invasion was markedly impaired when lactate efflux was inhibited. Convection-enhanced delivery of inhibitor to the tumor bed caused tumor necrosis, with 50% of the animals surviving beyond the experimental end points (3 months after inhibitor exhaustion). Most importantly, control animals did not display any adverse neurologic effects during orthotopic administration of ACCA to brain through programmed delivery. These results indicate the clinical potential of targeting lactate efflux in glioma through delivery of small-molecule inhibitors of MCTs either to the tumor bed or to the postsurgical resection cavity. PMID:21750656

  12. Temozolomide in combination with metformin act synergistically to inhibit proliferation and expansion of glioma stem-like cells

    Science.gov (United States)

    YU, ZHIYUN; ZHAO, GANG; LI, PENGLIANG; LI, YUNQIAN; ZHOU, GUANGTONG; CHEN, YONG; XIE, GUIFANG

    2016-01-01

    Glioblastoma is the most common and most aggressive brain tumor in adults. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas, but it is not curative. The difficulties in treating glioblastoma may be as a result of the presence of glioma stem cells (GSCs), which are a source of relapse and chemoresistance. Another reason may be that endogenous Akt kinase activity may be activated in response to clinically relevant concentrations of TMZ. Akt activation is correlated with the increased tumorigenicity, invasiveness and stemness of cancer cells and overexpression of an active form of Akt increases glioma cell resistance to TMZ. Mounting evidence has demonstrated that cancer stem cells are preferentially sensitive to an inhibitor of Akt and down-regulation of the PI3K/Akt pathway may enhance the cytotoxicity of TMZ. Metformin (MET), the first-line drug for treating diabetes, it has been proved that it reduces AKT activation and selectively kills cancer stem cells, but whether it can potentiate the cytotoxicity of TMZ for GSCs remains unknown. In the present study, the GSCs isolated from human glioma cell line U87 and Rat glioma cell line C6, in vitro treatment with TMZ either alone or with MET. The present study demonstrates that MET acts synergistically with TMZ in inhibiting GSCs proliferation and generating the highest apoptotic rates when compared to either drug alone. These findings implicate that GSCs cytotoxicity mediated by TMZ may be stimulated by MET, have a synergistic effect, but the definite mechanisms remain elusive. PMID:27073554

  13. EGFR-directed Affibody for fluorescence-guided glioma surgery: time-dose analysis (Conference Presentation)

    Science.gov (United States)

    Ribeiro de Souza, Ana Luiza; Marra, Kayla; Gunn, Jason R.; Elliott, Jonathan T.; Samkoe, Kimberley S.; Paulsen, Keith D.; Draney, Daniel R.; Feldwisch, Joachim

    2016-03-01

    The key to fluorescence guided surgical oncology is the ability to create specific contrast between normal and glioma tissue. The blood brain barrier that limits the delivery of substances to the normal brain is broken in tumors, allowing accumulation of agents in the tumor interior. However, for a clinical success, imaging agents should be in the infiltrative edges to minimize the resection of normal brain while enable the removal of tumor. The aberrant overexpression and/or activation of EGFR is associated with many types of cancers, including glioblastoma and the injection of a fluorescent molecule targeted to these receptors would improve tumor contrast during fluorescence guided surgery. Affibody molecules have intentional medium affinity and high potential specificity, which are the desirable features of a good surgical imaging agent. The aim of this study was evaluate the brain/glioma uptake of ABY029 labeled with near-infrared dye IRDye800CW after intravenous injection. Rats were either inoculated with orthotopic implantations of U251 human glioma cell line or PBS (shams control) in the brain. The tumors were allowed to grow for 2-3 weeks before carrying out fluorescent tracer experiments. Fluorescent imaging of ex vivo brain slices from rats was acquired at different time points after infection of fluorescently labeled EGFR-specific affibody to verify which time provided maximal contrast tumor to normal brain. Although the tumor was most clearly visualized after 1h of IRDye800CW-labeled ABY029 injection, the tumor location could be identified from the background after 48h. These results suggest that the NIR-labeled affibody examined shows excellent potential to increase surgical visualization for confirmed EGFR positive tumors.

  14. Expression and prognostic value of JAM-A in gliomas

    DEFF Research Database (Denmark)

    Rosager, Ann Mari; Sørensen, Mia D; Dahlrot, Rikke H

    2017-01-01

    in WHO grade II and III gliomas. JAM-A protein expression was evaluated by immunohistochemistry and advanced quantitative image analysis with continuous estimates of staining intensity. The JAM-A antibody stained tumor cell membranes and cytoplasm to various extent in different glioma subtypes...

  15. Repeating hemorrhage after radiotherapy for glioma. Radiological and histological observations

    Energy Technology Data Exchange (ETDEWEB)

    Kawano, Hirokazu [Miyakonojo Medical Association Hospital, Miyazaki (Japan); Wakisaka, Shinichiro; Kubota, Toshihiko; Hosotani, Kazuo

    1998-02-01

    A case of radiation necrosis which was observed six years after radiotherapy for a glioma in the right parietal lobe is reported. This patient developed hemiparesis, and radiological examinations showed similar findings consisted with recurrent glioma. Histological examination disclosed that the lesion is correspond to the radiation necrosis. (author)

  16. A role for ion channels in perivascular glioma invasion.

    Science.gov (United States)

    Thompson, Emily G; Sontheimer, Harald

    2016-10-01

    Malignant gliomas are devastating tumors, frequently killing those diagnosed in little over a year. The profuse infiltration of glioma cells into healthy tissue surrounding the main tumor mass is one of the major obstacles limiting the improvement of patient survival. Migration along the abluminal side of blood vessels is one of the salient features of glioma cell invasion. Invading glioma cells are attracted to the vascular network, in part by the neuropeptide bradykinin, where glioma cells actively modify the gliovascular interface and undergo volumetric alterations to navigate the confined space. Critical to these volume modifications is a proposed hydrodynamic model that involves the flux of ions in and out of the cell, followed by osmotically obligated water. Ion and water channels expressed by the glioma cell are essential in this model of invasion and make opportune therapeutic targets. Lastly, there is growing evidence that vascular-associated glioma cells are able to control the vascular tone, presumably to free up space for invasion and growth. The unique mechanisms that enable perivascular glioma invasion may offer critical targets for therapeutic intervention in this devastating disease. Indeed, a chloride channel-blocking peptide has already been successfully tested in human clinical trials.

  17. Vasculogenic mimicry:a novel target for glioma therapy

    Institute of Scientific and Technical Information of China (English)

    Yin-Sheng Chen; Zhong-Ping Chen

    2014-01-01

    Anti-angiogenic therapy has shown promising but insufficient efficacy on gliomas. Recent studies suggest that vasculogenic mimicry (VM), or the formation of non-endothelial, tumor-cel-lined microvascular channels, occurs in aggressive tumors, including gliomas. There is also evidence of a physiological connection between the endothelial-lined vasculature and VM channels. Tumor cels, by virtue of their high plasticity, can form vessel-like structures themselves, which may function as blood supply networks. Our previous study on gliomas showed that microvessel density was comparably less in VM-positive tumors than in VM-negative tumors. Thus, VM may act as a complement to ensure tumor blood supply, especialy in regions with less microvessel density. Patients with VM-positive gliomas survived a shorter period of time than did patients with VM-negative gliomas. Although the detailed molecular mechanisms for VM are not fuly understood, glioma stem cels might play a key role, since they are involved in tumor tissue remodeling and contribute to neovascularization via transdifferentiation. In the future, successful treatment of gliomas should involve targeting both VM and angiogenesis. In this review, we summarize the progress and chalenges of VM in gliomas.

  18. Interaction between 5 genetic variants and allergy in glioma risk

    DEFF Research Database (Denmark)

    Schoemaker, Minouk J; Robertson, Lindsay; Wigertz, Annette

    2010-01-01

    The etiology of glioma is barely known. Epidemiologic studies have provided evidence for an inverse relation between glioma risk and allergic disease. Genome-wide association data have identified common genetic variants at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756...

  19. Glioma Association and Balancing Selection of ZFPM2.

    Directory of Open Access Journals (Sweden)

    Shui-Ying Tsang

    Full Text Available ZFPM2, encoding a zinc finger protein and abundantly expressed in the brain, uterus and smooth muscles, plays important roles in cardiac and gonadal development. Abnormal expression of ZFPM2 in ovarian tumors and neuroblastoma has been reported but hitherto its genetic association with cancer and effects on gliomas have not been studied. In the present study, the hexamer insertion-deletion polymorphism rs71305152, located within a large haplotype block spanning intron 1 to intron 3 of ZFPM2, was genotyped in Chinese cohorts of glioma (n = 350, non-glioma cancer (n = 354 and healthy control (n = 463 by direct sequencing and length polymorphism in gel electrophoresis, and ZFPM2 expression in glioma tissues (n = 69 of different grades was quantified by real-time RT-PCR. Moreover, potential natural selection pressure acting on the gene was investigated. Disease-association analysis showed that the overall genotype of rs71305152 was significantly associated with gliomas (P = 0.016, and the heterozygous genotype compared to the combined homozygous genotypes was less frequent in gliomas than in controls (P = 0.005 or non-glioma cancers (P = 0.020. ZFPM2 mRNA expression was negatively correlated with the grades of gliomas (P = 0.002, with higher expression levels in the low-grade gliomas. In the astrocytoma subtype, higher ZFPM2 expression was also correlated with the rs71305152 heterozygous genotype (P = 0.028. In addition, summary statistics tests gave highly positive values, demonstrating that the gene is under the influence of balancing selection. These findings suggest that ZFPM2 is a glioma susceptibility gene, its genotype and expression showing associations with incidence and severity, respectively. Moreover, the balancing selection acting on ZFPM2 may be related to the important roles it has to play in multiple organ development or associated disease etiology.

  20. Clinical significance of vasculogenic mimicry in human gliomas.

    Science.gov (United States)

    Liu, Xiao-mei; Zhang, Qing-ping; Mu, Yong-gao; Zhang, Xiang-hen; Sai, Ke; Pang, Jesse Chung-Sean; Ng, Ho-Keung; Chen, Zhong-ping

    2011-11-01

    Vasculogenic mimicry (VM) is known as non-endothelial tumor cell-lined microvascular channels in aggressive tumors. We have previously found the presence of VM in high-grade gliomas. In this study, we aimed to identify VM patterns in gliomas and to explore their clinical significance. Tumor samples as well as their detailed clinical/prognostic data were collected from 101 patients. Vasculogenic mimicry in the glioma samples was determined by dual staining for endothelial marker CD34 and periodic acid-Schiff (PAS). Tumor samples were also immunohistochemically stained for Ki-67, VEGF, COX-2 and MMP-9. The association between VM and the clinical characteristics of the patients were analyzed. A Kaplan-Meier survival analysis and log-rank tests were performed to compare survival times of the patients. Vasculogenic mimicry was present in 13 out of 101 samples. The higher grade gliomas had a higher incidence of VM than that of lower grade gliomas (P = 0.006). Vasculogenic mimicry channels were associated with the expression of COX-2 and MMP-9 (P age and preoperative epilepsy of the patients, or expression of Ki-67 and VEGF. However, patients with VM-positive gliomas survived a shorter period of time than those with VM negative gliomas (P = 0.027). Interestingly, in high-grade gliomas, the level of microvascular density was lower in VM positive tumors than those VM negative tumors (P = 0.039). Our results suggest that VM channels in gliomas correlate with increasing malignancy and higher aggressiveness, and may provide a complementation to the tumor's blood supply, especially in less vascularized regions, which may aid in the identification of glioma patients with a poorer prognosis.

  1. Morbidity profile following aggressive resection of parietal lobe gliomas.

    Science.gov (United States)

    Sanai, Nader; Martino, Juan; Berger, Mitchel S

    2012-06-01

    The impact of parietal lobe gliomas is typically studied in the context of parietal lobe syndromes. However, critical language pathways traverse the parietal lobe and are susceptible during tumor resection. The authors of this study reviewed their experience with parietal gliomas to characterize the impact of resection and the morbidity associated with language. The study population included adults who had undergone resection of parietal gliomas of all grades. Tumor location was identified according to a proposed classification system for parietal region gliomas. Low- and high-grade tumors were volumetrically analyzed using FLAIR and T1-weighted contrast-enhanced MR imaging. One hundred nineteen patients with parietal gliomas were identified--34 with low-grade gliomas and 85 with high-grade gliomas. The median patient age was 45 years, and most patients (53) presented with seizures, whereas only 4 patients had an appreciable parietal lobe syndrome. The median preoperative tumor volume was 31.3 cm(3), the median extent of resection was 96%, and the median postoperative tumor volume was 0.9 cm(3). Surprisingly, the most common early postoperative neurological deficit was dysphasia (16 patients), not weakness (12 patients), sensory deficits (14 patients), or parietal lobe syndrome (10 patients). A proposed parietal glioma classification system, based on surgical anatomy, was predictive of language deficits. This is the largest reported experience with parietal lobe gliomas. The findings suggested that parietal language pathways are compromised at a surprisingly high rate. The proposed parietal glioma classification system is predictive of postoperative morbidity associated with language and can assist with preoperative planning. Taken together, these data emphasize the value of identifying language pathways when operating within the parietal lobe.

  2. Cognitive impairments in patients with low grade gliomas and high grade gliomas

    Directory of Open Access Journals (Sweden)

    Eliane C. Miotto

    2011-08-01

    Full Text Available OBJECTIVE: The relationship between brain tumors and cognitive deficits is well established in the literature. However, studies investigating the cognitive status in low and high-grade gliomas patients are scarce, particularly in patients with average or lower educational level. This study aimed at investigating the cognitive functioning in a sample of patients with low and high-grade gliomas before surgical intervention. METHOD: The low-grade (G1, n=19 and high-grade glioma (G2, n=8 patients underwent a detailed neuropsychological assessment of memory, executive functions, visuo-perceptive and visuo-spatial abilities, intellectual level and language. RESULTS: There was a significant impairment on verbal and visual episodic memory, executive functions including mental flexibility, nominal and categorical verbal fluency and speed of information processing in G2. G1 showed only specific deficits on verbal and visual memory recall, mental flexibility and processing speed. CONCLUSION: These findings demonstrated different levels of impairments in the executive and memory domains in patients with low and high grade gliomas.

  3. Neurofibromatosis type 1 associated low grade gliomas : A comparison with sporadic low grade gliomas

    NARCIS (Netherlands)

    Helfferich, Jelte; Nijmeijer, Ronald; Brouwer, Oebele F.; Boon, Maartje; Fock, Annemarie; Hoving, Eelco W.; Meijer, Lisethe; den Dunnen, Wilfred F. A.; de Bont, Eveline S. J. M.

    2016-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including cafe-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which

  4. Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) of photodynamic therapy (PDT) outcome and associated changes in the blood-brain barrier following Pc 4-PDT of glioma in an athymic nude rat model

    Science.gov (United States)

    Belle, Vaijayantee; Anka, Ali; Cross, Nathan; Thompson, Paul; Mott, Eric; Sharma, Rahul; Gray, Kayla; Zhang, Ruozhen; Xu, Yueshuo; Sun, Jiayang; Flask, Chris A.; Oleinick, Nancy L.; Dean, David

    2012-02-01

    Introduction: Dynamic Contrast-Enhanced-Magnetic Resonance Imaging (DCE-MRI) appears to provide an unambiguous means of tracking the outcome of photodynamic therapy (PDT) of brain tumors with the photosensitizer Pc 4. The increase in Gd enhancement observed after Pc 4-PDT may be due to a temporary opening of the blood-brain-barrier which, as noted by others, may offer a therapeutic window. Methods: We injected 2.5 x 105 U87 cells into the brains of 9 athymic nude rats. After 8-9 days peri-tumor DCE-MRI images were acquired on a 7.0 T microMRI scanner before and after the administration of 150 μL Gd. DCE-MRI scans were repeated three times following Pc 4-PDT. Results: The average, normalized peak enhancement in the tumor region, approximately 30-90 seconds after Gd administration, was 1.31 times greater than baseline (0.03 Standard Error [SE]) prior to PDT and was 1.44 (0.02 SE) times baseline in the first Post-PDT scans (Day 11), a statistically significant (p ~ 0.014, N=8) increase over the Pre- PDT scans, and was 1.38 (0.02 SE) times baseline in the second scans (Day 12), also a statistically significant (p ~ 0.008, N=7) increase. Observations were mixed in the third Post-PDT scans (Day 13), averaging 1.29 (0.03 SE) times baseline (p ~ 0.66, N=7). Overall a downward trend in enhancement was observed from the first to the third Post-PDT scans. Discussion: DCE-MRI may provide an unambiguous indication of brain tumor PDT outcome. The initial increase in DCE-MRI signal may correlate with a temporary, PDT-induced opening of the blood-brain-barrier, creating a potential therapeutic window.

  5. PCR-Based Simple Subgrouping Is Validated for Classification of Gliomas and Defines Negative Prognostic Copy Number Aberrations in IDH Mutant Gliomas.

    Directory of Open Access Journals (Sweden)

    Shunsuke Nakae

    Full Text Available Genetic subgrouping of gliomas has been emphasized recently, particularly after the finding of isocitrate dehydrogenase 1 (IDH1 mutations. In a previous study, we investigated whole-chromosome copy number aberrations (CNAs of gliomas and have described genetic subgrouping based on CNAs and IDH1 mutations. Subsequently, we classified gliomas using simple polymerase chain reaction (PCR-based methods to improve the availability of genetic subgrouping. We selected IDH1/2 and TP53 as markers and analyzed 237 adult supratentorial gliomas using Sanger sequencing. Using these markers, we classified gliomas into three subgroups that were strongly associated with patient prognoses. These included IDH mutant gliomas without TP53 mutations, IDH mutant gliomas with TP53 mutations, and IDH wild-type gliomas. IDH mutant gliomas without TP53 mutations, which mostly corresponded to gliomas carrying 1p19q co-deletions, showed lower recurrence rates than the other 2 groups. In the other high-recurrence groups, the median progression-free survival (PFS and overall survival (OS of patients with IDH mutant gliomas with TP53 mutations were significantly longer than those of patients with IDH wild-type gliomas. Notably, most IDH mutant gliomas with TP53 mutations had at least one of the CNAs +7q, +8q, -9p, and -11p. Moreover, IDH mutant gliomas with at least one of these CNAs had a significantly worse prognosis than did other IDH mutant gliomas. PCR-based mutation analyses of IDH and TP53 were sufficient for simple genetic diagnosis of glioma that were strongly associated with prognosis of patients and enabled us to detect negative CNAs in IDH mutant gliomas.

  6. Transfection of glioma cells with the neural-cell adhesion molecule NCAM

    DEFF Research Database (Denmark)

    Edvardsen, K; Pedersen, P H; Bjerkvig, R

    1994-01-01

    The tumor growth and the invasive capacity of a rat glioma cell line (BT4Cn) were studied after transfection with the human transmembrane 140-kDa isoform of the neural-cell adhesion molecule, NCAM. After s.c. injection, the NCAM-transfected cells showed a slower growth rate than the parent cell...... of the injection site, with a sharply demarcated border between the tumor and brain tissue. In contrast, the parental cell line showed single-cell infiltration and more pronounced destruction of normal brain tissue. Using a 51Cr-release assay, spleen cells from rats transplanted with BT4Cn tumor cells generally...... line (BT4Cn). Upon intracerebral implantation with BT4Cn cells and different clones of NCAM-transfected cells, all animals developed neurological symptoms within 13-16 days. However, the tumors showed different growth characteristics. The NCAM-transfected BT4Cn cells were localized in the region...

  7. Plasmid pORF-hTRAIL targeting to glioma using transferrin-modified polyamidoamine dendrimer

    Directory of Open Access Journals (Sweden)

    Gao S

    2015-12-01

    Full Text Available Song Gao,1,* Jianfeng Li,2 Chen Jiang,2 Bo Hong,3 Bing Hao4,* 1Department of Clinical Laboratory, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 2Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 3Department of Pathology, The Second Affiliated Hospital, 4Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: A gene drug delivery system for glioma therapy based on transferrin (Tf-modified polyamidoamine dendrimer (PAMAM was prepared. Gene drug, tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL-encoding plasmid open reading frame (pORF-hTRAIL, Trail, was condensed by Tf-modified PAMAM to form nanoparticles (NPs. PAMAM-PEG-Tf/DNA NPs showed higher cellular uptake, in vitro gene expression, and cytotoxicity than PAMAM-PEG/DNA NPs in C6 cells. The in vivo targeting efficacy of NPs was visualized by ex vivo fluorescence imaging. Tf-modified NPs showed obvious glioma-targeting trend. Plasmid encoding green fluorescence protein (GFP was also condensed by modified or unmodified PAMAM to evaluate the in vivo gene expression level. The PAMAM-PEG-Tf/plasmid encoding enhanced green fluorescence protein (pEGFP NPs exhibited higher GFP expression level than PAMAM-PEG/pEGFP NPs. TUNEL assay revealed that Tf-modified NPs could induce much more tumor apoptosis. The median survival time of PAMAM-PEG-Tf/Trail-treated rats (28.5 days was longer than that of rats treated with PAMAM-PEG/Trail (25.5 days, temozolomide (24.5 days, PAMAM-PEG-Tf/pEGFP (19 days, or saline (17 days. The therapeutic effect was further confirmed by magnetic resonance imaging. This study demonstrated that targeting gene delivery system had potential application for the

  8. Tipifarnib in Treating Young Patients With Recurrent or Progressive High-Grade Glioma, Medulloblastoma, Primitive Neuroectodermal Tumor, or Brain Stem Glioma

    Science.gov (United States)

    2013-10-07

    Childhood High-grade Cerebral Astrocytoma; Childhood Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  9. Identification of molecular pathways facilitating glioma cell invasion in situ.

    Directory of Open Access Journals (Sweden)

    Ido Nevo

    Full Text Available Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion. In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC xenograft model to explore gene expression changes in situ in Invading Glioma Cells (IGCs compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy.

  10. PRG3 induces Ras-dependent oncogenic cooperation in gliomas

    Science.gov (United States)

    Yakubov, Eduard; Chen, Daishi; Broggini, Thomas; Sehm, Tina; Majernik, Gökce Hatipoglu; Hock, Stefan W.; Schwarz, Marc; Engelhorn, Tobias; Doerfler, Arnd; Buchfelder, Michael; Eyupoglu, Ilker Y.; Savaskan, Nicolai E.

    2016-01-01

    Malignant gliomas are one of the most devastating cancers in humans. One characteristic hallmark of malignant gliomas is their cellular heterogeneity with frequent genetic lesions and disturbed gene expression levels conferring selective growth advantage. Here, we report on the neuronal-associated growth promoting gene PRG3 executing oncogenic cooperation in gliomas. We have identified perturbed PRG3 levels in human malignant brain tumors displaying either elevated or down-regulated PRG3 levels compared to non-transformed specimens. Further, imbalanced PRG3 levels in gliomas foster Ras-driven oncogenic amplification with increased proliferation and cell migration although angiogenesis was unaffected. Hence, PRG3 interacts with RasGEF1 (RasGRF1/CDC25), undergoes Ras-induced challenges, whereas deletion of the C-terminal domain of PRG3 (PRG3ΔCT) inhibits Ras. Moreover PRG3 silencing makes gliomas resistant to Ras inhibition. In vivo disequilibrated PRG3 gliomas show aggravated proliferation, invasion, and deteriorate clinical outcome. Thus, our data show that the interference with PRG3 homeostasis amplifies oncogenic properties and foster the malignancy potential in gliomas. PMID:27058420

  11. Glioma epidemiology in the central Tunisian population: 1993-2012.

    Science.gov (United States)

    Trabelsi, Saoussen; Brahim, Dorra H'mida-Ben; Ladib, Mohamed; Mama, Nadia; Harrabi, Imed; Tlili, Kalthoum; Yacoubi, Mohamed Tahar; Krifa, Hedi; Hmissa, Sihem; Saad, Ali; Mokni, Moncef

    2014-01-01

    Glioma is a heterogeneous central nervous system (CNS) tumor group that encompasses different histological subtypes with high variability in prognosis. The lesions account for almost 80% of primary malignant brain tumors. The aim of this study is to extend our understanding of the glioma epidemiology in the central Tunisian region. We analyzed 393 gliomas recorded in cancer registry of central Tunisia from 1993 to 2012. Crude incidence rates (CR) and world age-standardized rates (ASR) were estimated using annual population data size and age structure. Statistic correlations were established using Chi-square and Kaplan-Meier test. Tunisian glioma patients were identified with a mean age at diagnosis of 48 years and 1.5 sex ratio (male/female). During the 19 years period of study the highest incidence value was observed in male group between 1998 and 2002 (CR: 0.28, ASR: 0.3). Incidence results underline increasing high grade glioma occurring in the adulthood in the last period (2007-2012). Median survival was 27 months, with 1-, 2- and 5-year survival rates of 42%, 30% and 26%, respectively. Survival was greater in patients with younger age, lower tumor grade, infratentrial tumor location and undergoing a palliative treatment. This central Tunisia gliomas registry study provides important information that could improve glioma management and healthcare practice.

  12. Long noncoding RNA profiles reveal three molecular subtypes in glioma.

    Science.gov (United States)

    Li, Rui; Qian, Jin; Wang, Ying-Yi; Zhang, Jun-Xia; You, Yong-Ping

    2014-04-01

    Gliomas are the most lethal type of primary brain tumor in adult. Long noncoding RNAs (lncRNAs), which are involved in the progression of various cancers, may offer a potential gene therapy target in glioma. We first classified gliomas into three molecular subtypes (namely LncR1, LncR2 and LncR3) in Rembrandt dataset using consensus clustering. Survival analysis indicated that LncR3 had the best prognosis, while the LncR1 subtype showed the poorest overall survival rate. The results were further validated in an independent glioma dataset GSE16011. Additionally, we collected and merged data of the two databases (Rembrandt and GSE16011 dataset) and analyzed prognosis of each subtype in WHO II, III and IV gliomas. The similar results were obtained. Gene Set Variation Analysis (GSVA) demonstrated that LncR1 subtype enriched cultured astroglia's gene signature, while LncR2 subtype was characterized by neuronal gene signature. Oligodendrocytic was rich in LncR3. In addition, IDH1 mutation and 1p/19q LOH were found rich with LncR3, and EGFR amplification showed high percentage in LncR1 in GSE16011 dataset. We report a novel molecular classification of glioma based on lncRNA expression profiles and believe that it would provide a potential platform for future studies on gene treatment for glioma and lead to more individualized therapies to improve survival rates. © 2014 John Wiley & Sons Ltd.

  13. Telomere maintenance and the etiology of adult glioma.

    Science.gov (United States)

    Walsh, Kyle M; Wiencke, John K; Lachance, Daniel H; Wiemels, Joseph L; Molinaro, Annette M; Eckel-Passow, Jeanette E; Jenkins, Robert B; Wrensch, Margaret R

    2015-11-01

    A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length.

  14. Selective Targeting to Glioma with Nucleic Acid Aptamers.

    Directory of Open Access Journals (Sweden)

    Shraddha Aptekar

    Full Text Available Malignant glioma is characterised by a rapid growth rate and high capacity for invasive infiltration to surrounding brain tissue; hence, diagnosis and treatment is difficult and patient survival is poor. Aptamers contribute a promising and unique technology for the in vitro imaging of live cells and tissues, with a potentially bright future in clinical diagnostics and therapeutics for malignant glioma. The binding selectivity, uptake capacity and binding target of two DNA aptamers, SA43 and SA44, were investigated in glioma cells and patient tissues. The binding assay showed that SA43 and SA44 bound with strong affinity (Kd, 21.56 ± 4.60 nM and Kd, 21.11 ± 3.30 nM respectively to the target U87MG cells. Quantitative analysis by flow cytometry showed that the aptamers were able to actively internalise in U87MG and 1321N1 glioma cells compared to the non-cancerous and non-glioma cell types. Confocal microscopy confirmed staining in the cytoplasm, and co-localisation studies with endoplasmic reticulum, Golgi apparatus and lysosomal markers suggested internalisation and compartmentalisation within the endomembrane system. Both aptamers selectively bound to Ku 70 and Ku 80 DNA repair proteins as determined by aptoprecipitation (AP followed by mass spectrometry analysis and confirmation by Western blot. In addition, aptohistochemical (AHC staining on paraffin embedded, formalin fixed patient tissues revealed that the binding selectivity was significantly higher for SA43 aptamer in glioma tissues (grade I, II, III and IV compared to the non-cancerous tissues, whereas SA44 did not show selectivity towards glioma tissues. The results indicate that SA43 aptamer can differentiate between glioma and non-cancerous cells and tissues and therefore, shows promise for histological diagnosis of glioma.

  15. Current status of cerebral glioma surgery in China

    Institute of Scientific and Technical Information of China (English)

    WU Jin-song; ZHANG Jie; ZHUANG Dong-xiao; YAO Cheng-jun; QIU Tian-ming; LU Jun-feng; ZHU Feng-ping; MAO Ying; ZHOU Liang-fu

    2011-01-01

    The treatment of gliomas is highly individualized.Surgery for gliomas is essentially for histological diagnosis,to alleviate mass effect,and most importantly,to favor longer survival expectancy.During the past two decades,many surgical techniques and adjuvants have been applied to glioma surgery in China,which lead to a rapid development in the field of cerebral glioma surgery.This article broadly and critically reviewed the existing studies on cerebral glioma surgery and to portrait the current status of glioma surgery in China.A literature search was conducted covering major innovative surgical techniques and adjuvants for glioma surgery in China.The following databases were searched:the Pubmed (January 1995 to date);China Knowledge Resource Integrated Database (January 1995 to date) and VIP Database for Chinese Technical Periodicals (January 1995 to date).A selection criterion was established to exclude duplicates and irrelevant studies.The outcome measures were extracted from included studies.A total of 3307 articles were initially searched.After excluded by abstracts and full texts,69 studies conducted in the mainland of China were included and went through further analysis.The philosophy of surgical strategies for cerebral gliomas in China is undergoing tremendous change.Nowadays Chinese neurosurgeons pay more attention to the postoperative neurofunctional status of the patients.The aim of the glioma surgery is not only the more extensive tumor resection but also the maximal safety of intervention.The well balance of longer overall survival and higher quality of life should be judged with respect to each individual patient.

  16. Season of Birth and Risk for Adult Onset Glioma

    Directory of Open Access Journals (Sweden)

    Jimmy T. Efird

    2010-04-01

    Full Text Available Adult onset glioma is a rare cancer which occurs more frequently in Caucasians than African Americans, and in men than women. The etiology of this disease is largely unknown. Exposure to ionizing radiation is the only well established environmental risk factor, and this factor explains only a small percentage of cases. Several recent studies have reported an association between season of birth and glioma risk. This paper reviews the plausibility of evidence focusing on the seasonal interrelation of farming, allergies, viruses, vitamin D, diet, birth weight, and handedness. To date, a convincing explanation for the occurrence of adult gliomas decades after a seasonal exposure at birth remains elusive.

  17. Noscapine inhibits tumor growth in TMZ-resistant gliomas.

    Science.gov (United States)

    Jhaveri, Niyati; Cho, Heeyeon; Torres, Shering; Wang, Weijun; Schönthal, Axel H; Petasis, Nicos A; Louie, Stan G; Hofman, Florence M; Chen, Thomas C

    2011-12-22

    Noscapine, a common oral antitussive agent, has been shown to have potent antitumor activity in a variety of cancers. Treatment of glioblastoma multiforme (GBM) with temozolomide (TMZ), its current standard of care, is problematic because the tumor generally recurs and is then resistant to this drug. We therefore investigated the effects of noscapine on human TMZ-resistant GBM tumors. We found that noscapine significantly decreased TMZ-resistant glioma cell growth and invasion. Using the intracranial xenograft model, we showed that noscapine increased survival of animals with TMZ-resistant gliomas. Thus noscapine can provide an alternative therapeutic approach for the treatment of TMZ-resistant gliomas.

  18. Notch Signaling Enhances Nestin Expression in Gliomas

    Directory of Open Access Journals (Sweden)

    Alan H. Shih

    2006-12-01

    Full Text Available Recent findings suggest that Notch signaling is active in brain tumors and stem cells, and that stem cells or cells with progenitor characteristics contribute to brain tumor formation. These stem cells are marked by expression of several markers, including nestin, an intermediate filament protein. We have studied how the Notch signaling pathway affects nestin expression in brain tumors. We find that Notch receptors and ligands are expressed in vitro and in human samples of glioblastomas, the highest grade of malignant gliomas. In culture, Notch activity activates the nestin promoter. Activation of the Notch pathway also occurs in a glioblastoma multiforme mouse model induced by Kras, with translational regulation playing a role in Notch expression. Combined activation of Notch and Kras in wild-type nestin-expressing cells leads to their expansion within the subventricular zone and retention of proliferation and nestin expression. However, activation of Notch alone is unable to induce this cellular expansion. These data suggest that Notch may have a contributing role in the stem-like character of glioma cells.

  19. Investigating effect of fusion gene therapy by MR diffusion-weighted imaging in a rat C6 glioma model%融合基因治疗大鼠C6胶质瘤的MR扩散加权成像研究

    Institute of Scientific and Technical Information of China (English)

    沈慧聪; 赵炜疆; 高培毅; 戴建平; 魏新华; 王建交; 李少武; 马军; 艾林; 刘福生; 柴奇

    2008-01-01

    Objective To evaluate the use of diffusion-weighted imaging(DWI)for early detection of tumor response to Angiostatin-Endostatin(Statin-AE)fusion gene therapy in a rat C6 glioma model.Methods Fifty male wistar rats with C6 tumor cells implanted into the striatum were examined by a 3.0T MR scanner,then the rats beating tmors were divided into two groups,treatment group and control group.Rats in the treatment group received 107 plaque forming unit(pfu)recombinant herps simplex viral (R-HSV)mediated Statin-AE fusion gene therapy on day 7,and then the tumors were conformed on MRI.Conventional MR and DWI examination were acquired on 1,2,3 weeks after implantation with a 5-inch surface coil.Two(1 w),eight(2 w)and all the residual rats(3 w)of each group were sacrificed to perform the histopathological examination after each MBI examination.Pretreatment and post treatment tumor volulnes and apparent diffusion coefficient(ADC)values were calculated.Rank sum test and t test were employed for statistical analysis.Results On MRI,43 rats demonstrated tumors on day 7 with a successful rate of 86%,On week 2,the tumor volumes of the controh and treatment group were 90.6 and 91.64 mm3,with no significant difference(Z=-0.14,P>0.05).On week 3,the tumor volumes of the controls and treatment group were 156.64 and 29.64 mm3,and a significant difference was observed(Z=-3.45,P<0.01).On week 2.the ADC values of the tumor centers of the treatment group and the control group were (1.20±0.25)×10-3 and(0.99±0.08)×10-3 mm2/s,and the values of the tumor peripheral parts of the two groups were(1.00±0.25)×10-3 and(0.83±0.12)×10-3mm2/s,the ADC values of both tumor centers and peripheral parts of the treatment group were significantly higher than those of the control group (t=-0.82 and-0.46,P<0.05).On week 3,the ADC values of the tumor centers of the treatment group and the control group were(0.92±0.21)× 10-3 and(0.99±0.09)×10-3mm2/s,and the values of the tumor peripheral parts of

  20. Alpinetin targets glioma stem cells by suppressing Notch pathway.

    Science.gov (United States)

    Wang, Jianpeng; Yan, Zhiyong; Liu, Xia; Che, Shusheng; Wang, Chao; Yao, Weicheng

    2016-07-01

    Glioma is among the most common human malignancies with poor prognosis. Glioma stem cells (GSCs) are the culprit of glioma, suggesting that GSCs are potential therapeutic targets. Notch signaling pathway plays a pivotal role for the function of GSCs, implying that suppression of Notch pathway may be an effective strategy for GSC-targeting therapy. In this study, we found that alpinetin, a natural compound, can suppress the proliferation and invasiveness of GSCs and induce apoptosis in GSCs. Immunoblot analysis and luciferase assay revealed that Notch signaling was suppressed by alpinetin. Furthermore, restoration of Notch signaling activity rescued the effect of alpinetin on GSC's function. The anti-tumor activity of alpinetin was further confirmed in an animal model. Collectively, targeting of GSC by alpinetin is an effective strategy for glioma therapy.

  1. The functional role of Notch signaling in human gliomas

    DEFF Research Database (Denmark)

    Stockhausen, Marie-Thérése; Kristoffersen, Karina; Poulsen, Hans Skovgaard

    2010-01-01

    have been referred to as brain cancer stem cells (bCSC), as they share similarities to normal neural stem cells in the brain. The Notch signaling pathway is involved in cell fate decisions throughout normal development and in stem cell proliferation and maintenance. The role of Notch in cancer is now......Gliomas are among the most devastating adult tumors for which there is currently no cure. The tumors are derived from brain glial tissue and comprise several diverse tumor forms and grades. Recent reports highlight the importance of cancer-initiating cells in the malignancy of gliomas. These cells...... firmly established, and recent data implicate a role for Notch signaling also in gliomas and bCSC. In this review, we explore the role of the Notch signaling pathway in gliomas with emphasis on its role in normal brain development and its interplay with pathways and processes that are characteristic...

  2. Epileptic seizures in patients with glioma: A single centrebased ...

    African Journals Online (AJOL)

    Epileptic seizures in patients with glioma: A single centrebased study in China. ... AFRICAN JOURNALS ONLINE (AJOL) · Journals · Advanced Search · USING AJOL ... Fisher's exact and Chi square tests were used for analysis of seizure ...

  3. Salinomycin inhibits the tumor growth of glioma stem cells by selectively suppressing glioma-initiating cells.

    Science.gov (United States)

    Chen, Tunan; Yi, Liang; Li, Fei; Hu, Rong; Hu, Shengli; Yin, Yi; Lan, Chuan; Li, Zhao; Fu, Chuhua; Cao, Liu; Chen, Zhi; Xian, Jishu; Feng, Hua

    2015-04-01

    Glioma‑initiating cells are a small population of cells that have the ability to undergo self‑renewal and initiate tumorigenesis. In the present study, the potential role of salinomycin, a polyether antibiotic, on the suppression of glioma cell growth was investigated. GL261 glioma cells were maintained in a stem‑cell‑like status [GL261 neurospheres (GL261‑NS)] or induced for differentiation [GL261 adherent cells (GL261‑AC)]. It was demonstrated that salinomycin significantly reduced the cell viability of GL261‑NS and GL261‑AC cells in a dose‑dependent manner, with a more substantial inhibition of GL261‑NS proliferation (Psalinomycin on cell growth was more effective than that of 1‑(4‑amino‑2‑methyl‑5‑pyrimid l)‑methyl‑3‑(2‑chloroethyl)‑3‑nitrosourea hydrochloride and vincristine (PSalinomycin depleted GL261‑NS from tumorspheres and induced cell apoptosis. In addition, salinomycin prolonged the median survival time of glioma‑bearing mice (Psalinomycin may preferentially inhibit glioma‑initiated cell growth by inducing apoptosis, suggesting that salinomycin may provide a valuable therapeutic strategy for the treatment of malignant glioma.

  4. Glioma-Associated Antigen HEATR1 Induces Functional Cytotoxic T Lymphocytes in Patients with Glioma

    Directory of Open Access Journals (Sweden)

    Zhe Bao Wu

    2014-01-01

    Full Text Available A2B5+ glioblastoma (GBM cells have glioma stem-like cell (GSC properties that are crucial to chemotherapy resistance and GBM relapse. T-cell-based antigens derived from A2B5+ GBM cells provide important information for immunotherapy. Here, we show that HEAT repeat containing 1 (HEATR1 expression in GBM tissues was significantly higher than that in control brain tissues. Furthermore, HEATR1 expression in A2B5+ U87 cells was higher than that in A2B5−U87 cells (P=0.016. Six peptides of HEATR1 presented by HLA-A*02 were selected for testing of their ability to induce T-cell responses in patients with GBM. When peripheral blood mononuclear cells from healthy donors (n=6 and patients with glioma (n=33 were stimulated with the peptide mixture, eight patients with malignant gliomas had positive reactivity with a significantly increased number of responding T-cells. The peptides HEATR1682–690, HEATR11126–1134, and HEATR1757–765 had high affinity for binding to HLA-A*02:01 and a strong capacity to induce CTL response. CTLs against HEATR1 peptides were capable of recognizing and lysing GBM cells and GSCs. These data are the first to demonstrate that HEATR1 could induce specific CTL responses targeting both GBM cells and GSCs, implicating that HEATR1 peptide-based immunotherapy could be a novel promising strategy for treating patients with GBM.

  5. Rats

    Directory of Open Access Journals (Sweden)

    Alexey Kondrashov

    2012-01-01

    Full Text Available We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol-free Alibernet red wine extract (AWE and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY and spontaneously hypertensive rats (SHRs. Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR.

  6. UNUSUAL PRESENTATION OF BRAINSTEM GLIOMA AS PROGRESSIVE BULBAR PALSY

    Directory of Open Access Journals (Sweden)

    Suma

    2015-04-01

    Full Text Available Brain stem gliomas/astrocytomas are slowly growing tumors affecting children and young adults. They usually present with unilateral cranial nerve palsies followed by long tract signs. Here we present a case report of a 42 year old male patient, who initially presented with thyrotoxicosis and slowly progressing dysphagia, dysarthria and dysphonia with no other long tract signs, and was later found to have brain stem glioma.

  7. Cas Ilgly Induces Apoptosis in Glioma C6 Cells In Vitro and In Vivo through Caspase-Dependent and Caspase-Independent Mechanisms

    Directory of Open Access Journals (Sweden)

    Cristina Trejo-Solís

    2005-06-01

    Full Text Available In this work, we investigated the effects of Casiopeina Il-gly (Cas ILgly—a new copper compound exhibiting antineoplastic activity—on glioma C6 cells under both in vitro and in vivo conditions, as an approach to identify potential therapeutic agents against malignant glioma. The exposure of C6 cells to Cas Ilgly significantly inhibited cell proliferation, increased reactive oxygen species (ROS formation, and induced apoptosis in a dose-dependent manner. In cultured C6 cells, Cas Ilgly caused mitochondrio-nuclear translocation of apoptosis induction factor (AIF and endonuclease G at all concentrations tested; in contrast, fragmentation of nucleosomal DNA, cytochrome c release, and caspase-3 activation were observed at high concentrations. Administration of N-acetyl-l-cystein, an antioxidant, resulted in significant inhibition of AIF translocation, nucleosomal DNA fragmentation, and caspase-3 activation induced by Cas Ilgly. These results suggest that caspase-dependent and caspase-independent pathways both participate in apoptotic events elicited by Cas Ilgly. ROS formation induced by Cas Ilgly might also be involved in the mitochondrio-nuclear translocation of AIF and apoptosis. In addition, treatment of glioma C6-positive rats with Cas Ilgly reduced tumor volume and mitotic and cell proliferation indexes, and increased apoptotic index. Our findings support the use of Cas Ilgly for the treatment of malignant gliomas.

  8. Gene expression of manganese superoxide dismutase in human glioma cells

    Directory of Open Access Journals (Sweden)

    Novi S. Hardiany

    2010-02-01

    Full Text Available Aim This study analyze the MnSOD gene expression as endogenous antioxidant in human glioma cells compared with leucocyte cells as control.Methods MnSOD gene expression of 20 glioma patients was analyzed by measuring the relative expression of mRNA and enzyme activity of MnSOD in brain and leucocyte cells. The relative expression of mRNA MnSOD was determined by using quantitative Real Time RT-PCR and the enzyme activity of MnSOD using biochemical kit assay (xantine oxidase inhibition. Statistic analysis for mRNA and enzyme activity of MnSOD was performed using Kruskal Wallis test.Results mRNA of MnSOD in glioma cells of 70% sample was 0.015–0.627 lower, 10% was 1.002-1.059 and 20% was 1.409-6.915 higher than in leucocyte cells. Also the specific activity of MnSOD enzyme in glioma cells of 80% sample showed 0,064-0,506 lower and 20% sample was 1.249-2.718 higher than in leucocyte cells.Conclusion MnSOD gene expression in human glioma cells are significantly lower than its expression in leucocytes cells. (Med J Indones 2010; 19:21-5Keywords : MnSOD, glioma, gene expression

  9. Fluorescence-Guided Resection of Malignant Glioma with 5-ALA

    Directory of Open Access Journals (Sweden)

    Sadahiro Kaneko

    2016-01-01

    Full Text Available Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD. Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD.

  10. Role of MicroRNAs in Malignant Glioma

    Institute of Scientific and Technical Information of China (English)

    Bao-Cheng Wang; Jie Ma

    2015-01-01

    Objective:This overview seeked to bring together the microRNA (miRNA) researches on biogenesis and bio-function in these areas of clinical diagnosis and therapy for malignant glioma.Data Sources:Using the keyword terms "glioma" and "miRNA," we performed the literature search in PubMed,Ovid,and web.metstr.com databases from their inception to October 2014.Study Selection:In screening out the quality of the articles,factors such as clinical setting of the study,the size of clinical samples were taken into consideration.Animal studied for verification and reviews article were also included in our data collection.Results:Despite many advance in miRNA for malignant glioma,further studies were still required to focus on the following aspects:(i) Improving the understanding about biogenesis of miRNA and up-down regulation;(ii) utilizing high-throughput miRNA expression analysis to screen out the core miRNA for glioma;(iii) Focusing related miRNAs on the signal transduction pathways that regulate the proliferation and growth of glioma.Conclusions:We discussed the most promising miRNA,correlative signaling pathway and their relation with gliomas in the way of prompting miRNA target into being a clinical therapeutic strategy.

  11. Ion channel gene expression predicts survival in glioma patients.

    Science.gov (United States)

    Wang, Rong; Gurguis, Christopher I; Gu, Wanjun; Ko, Eun A; Lim, Inja; Bang, Hyoweon; Zhou, Tong; Ko, Jae-Hong

    2015-08-03

    Ion channels are important regulators in cell proliferation, migration, and apoptosis. The malfunction and/or aberrant expression of ion channels may disrupt these important biological processes and influence cancer progression. In this study, we investigate the expression pattern of ion channel genes in glioma. We designate 18 ion channel genes that are differentially expressed in high-grade glioma as a prognostic molecular signature. This ion channel gene expression based signature predicts glioma outcome in three independent validation cohorts. Interestingly, 16 of these 18 genes were down-regulated in high-grade glioma. This signature is independent of traditional clinical, molecular, and histological factors. Resampling tests indicate that the prognostic power of the signature outperforms random gene sets selected from human genome in all the validation cohorts. More importantly, this signature performs better than the random gene signatures selected from glioma-associated genes in two out of three validation datasets. This study implicates ion channels in brain cancer, thus expanding on knowledge of their roles in other cancers. Individualized profiling of ion channel gene expression serves as a superior and independent prognostic tool for glioma patients.

  12. Theranostic 3-Dimensional nano brain-implant for prolonged and localized treatment of recurrent glioma

    Science.gov (United States)

    Ramachandran, Ranjith; Junnuthula, Vijayabhaskar Reddy; Gowd, G. Siddaramana; Ashokan, Anusha; Thomas, John; Peethambaran, Reshmi; Thomas, Anoop; Unni, Ayalur Kodakara Kochugovindan; Panikar, Dilip; Nair, Shantikumar V.; Koyakutty, Manzoor

    2017-03-01

    Localized and controlled delivery of chemotherapeutics directly in brain-tumor for prolonged periods may radically improve the prognosis of recurrent glioblastoma. Here, we report a unique method of nanofiber by fiber controlled delivery of anti-cancer drug, Temozolomide, in orthotopic brain-tumor for one month using flexible polymeric nano-implant. A library of drug loaded (20 wt%) electrospun nanofiber of PLGA-PLA-PCL blends with distinct in vivo brain-release kinetics (hours to months) were numerically selected and a single nano-implant was formed by co-electrospinning of nano-fiber such that different set of fibres releases the drug for a specific periods from days to months by fiber-by-fiber switching. Orthotopic rat glioma implanted wafers showed constant drug release (116.6 μg/day) with negligible leakage into the peripheral blood (4 month) survival of 85.7% animals whereas 07 day releasing implant showed tumor recurrence in 54.6% animals, rendering a median survival of only 74 days. In effect, we show that highly controlled drug delivery is possible for prolonged periods in orthotopic brain-tumor using combinatorial nanofibre libraries of bulk-eroding polymers, thereby controlling glioma recurrence.

  13. Copper compound induces autophagy and apoptosis of glioma cells by reactive oxygen species and jnk activation

    Directory of Open Access Journals (Sweden)

    Trejo-Solís Cristina

    2012-04-01

    Full Text Available Abstract Background Glioblastoma multiforme (GBM is the most aggressive of the primary brain tumors, with a grim prognosis despite intensive treatment. In the past decades, progress in research has not significantly increased overall survival rate. Methods The in vitro antineoplastic effect and mechanism of action of Casiopeina III-ia (Cas III-ia, a copper compound, on rat malignant glioma C6 cells was investigated. Results Cas III-ia significantly inhibited cell proliferation, inducing autophagy and apoptosis, which correlated with the formation of autophagic vacuoles, overexpression of LC3, Beclin 1, Atg 7, Bax and Bid proteins. A decrease was detected in the mitochondrial membrane potential and in the activity of caspase 3 and 8, together with the generation of intracellular reactive oxygen species (ROS and increased activity of c-jun NH2-terminal kinase (JNK. The presence of 3-methyladenine (as selective autophagy inhibitor increased the antineoplastic effect of Cas III-ia, while Z-VAD-FMK only showed partial protection from the antineoplastic effect induced by Cas III-ia, and ROS antioxidants (N-acetylcysteine decreased apoptosis, autophagy and JNK activity. Moreover, the JNK –specific inhibitor SP600125 prevented Cas III-ia-induced cell death. Conclusions Our data suggest that Cas III-ia induces cell death by autophagy and apoptosis, in part due to the activation of ROS –dependent JNK signaling. These findings support further studies of Cas III-ia as candidate for treatment of human malignant glioma.

  14. EXPRESSION AND SWITCHING OF TH 1/TH2 TYPE CYTOKINES GENE IN HUMAN GLIOMAS

    Institute of Scientific and Technical Information of China (English)

    Yong-sheng Hu; Xin-gang Li; Qing-lin Zhang; Dong-hai Wang; Song-feng Gong

    2005-01-01

    Objective To study the expression and switching of Th1/Th2 cytokines gene in hman gliomas and its effects on occurring and developing of human gliomas.Methods Interleukin(IL)-2 and intefferon-γ represent Th1 type cytokines. IL-4, IL-6, IL-10, and IL-13 represent Th2 type cytokines. The gene expressions of Th1/Th2 cytokines in human glioma cells, glioma infiltrating lymphocytes,and glioma cell lines were detected by reverse transcription polymerase chain reaction (RT-PCR). The biological activity of cytokines in the supematant of glioma cell lines was assayed by enzyme-linked immunosorbent assay (ELISA)method.Results The total positive rates of Th1 and Th2 type cytokines gene in human glioma cells were 14.77% and 75%. The total positive rates of Thl and Th2 type cytokines gene in glioma infiltrating lymphocytes were 22.73% and 68.17%. There was obviously predominant expression of Th2 type cytokines in human glioma tissues, glioma infiltrating lymphocytes, and glioma cell lines. There was no unbalanced expression of Th1/Th2 cytokines in normal brain tissues.Conclusion There is a predominant expression of Th2 type cytokines in human glioma cells. The switching of Th1/Th2 cytokines gene may play an important role in the occurring and developing of human gliomas.

  15. The flavonoid apigenin from Croton betulaster Mull inhibits proliferation, induces differentiation and regulates the inflammatory profile of glioma cells.

    Science.gov (United States)

    Coelho, Paulo L C; Oliveira, Mona N; da Silva, Alessandra B; Pitanga, Bruno P S; Silva, Victor D A; Faria, Giselle P; Sampaio, Geraldo P; Costa, Maria de Fatima D; Braga-de-Souza, Suzana; Costa, Silvia L

    2016-11-01

    This study aimed to investigate the antitumor and immunomodulatory properties of the flavonoid apigenin (5,7,4'-trihydroxyflavone), which was extracted from Croton betulaster Mull, in glioma cell culture using the high-proliferative rat C6 glioma cell line as a model. Apigenin was found to have the ability to reduce the viability and proliferation of C6 cells in a time-dependent and dose-dependent manner, with an IC50 of 22.8 µmol/l, 40 times lower than that of temozolomide (1000 µmol/l), after 72 h of apigenin treatment. Even after C6 cells were treated with apigenin for 48 h, high proportions of C6 cells entered apoptosis (39.56%) and autophagy (22%) as shown by flow cytometry using annexin V/propidium iodide and acridine orange staining, respectively. In addition, the flavonoid apigenin induced cell accumulation in the G0/G1 phase of the cell cycle and inhibited glioma cell migration efficiently. Moreover, apigenin induced astroglial differentiation and morphological changes in C6 cells, characterized by increased expression of glial fibrillary acidic protein and decreased expression of nestin protein, a typical marker of neuronal precursors. The immunomodulating effects of apigenin were also characterized by a change in the inflammatory profile as evidenced by a significant decrease in interleukin-10 and tumor necrosis factor production and increased nitric oxide levels. Because apigenin can induce differentiation, apoptosis, and autophagy, can alter the profile of cytokines involved in regulating the immune response, and can reduce the survival, growth, proliferation, and migration of C6 cells, this flavonoid may be considered a potential antitumor drug for the adjuvant treatment of malignant gliomas.

  16. Predicting in vivo glioma growth with the reaction diffusion equation constrained by quantitative magnetic resonance imaging data

    Science.gov (United States)

    Hormuth, David A., II; Weis, Jared A.; Barnes, Stephanie L.; Miga, Michael I.; Rericha, Erin C.; Quaranta, Vito; Yankeelov, Thomas E.

    2015-07-01

    Reaction-diffusion models have been widely used to model glioma growth. However, it has not been shown how accurately this model can predict future tumor status using model parameters (i.e., tumor cell diffusion and proliferation) estimated from quantitative in vivo imaging data. To this end, we used in silico studies to develop the methods needed to accurately estimate tumor specific reaction-diffusion model parameters, and then tested the accuracy with which these parameters can predict future growth. The analogous study was then performed in a murine model of glioma growth. The parameter estimation approach was tested using an in silico tumor ‘grown’ for ten days as dictated by the reaction-diffusion equation. Parameters were estimated from early time points and used to predict subsequent growth. Prediction accuracy was assessed at global (total volume and Dice value) and local (concordance correlation coefficient, CCC) levels. Guided by the in silico study, rats (n = 9) with C6 gliomas, imaged with diffusion weighted magnetic resonance imaging, were used to evaluate the model’s accuracy for predicting in vivo tumor growth. The in silico study resulted in low global (tumor volume error 0.92) and local (CCC values >0.80) level errors for predictions up to six days into the future. The in vivo study showed higher global (tumor volume error >11.7%, Dice silico study shows that model parameters can be accurately estimated and used to accurately predict future tumor growth at both the global and local scale. However, the poor predictive accuracy in the experimental study suggests the reaction-diffusion equation is an incomplete description of in vivo C6 glioma biology and may require further modeling of intra-tumor interactions including segmentation of (for example) proliferative and necrotic regions.

  17. β-Asarone promotes Temozolomide's entry into glioma cells and decreases the expression of P-glycoprotein and MDR1.

    Science.gov (United States)

    Wang, Nanbu; Zhang, Qinxin; Ning, Baile; Luo, Laiyu; Fang, Yongqi

    2017-06-01

    Glioma is the most common primary brain tumor and has an undesirable prognosis due to the blood-brain barrier (BBB) and drug resistance. A thorough investigation of the changes in intracellular drug concentrations is important to observe therapeutic effects and cell resistance. P-glycoprotein (P-gp) is an essential protein of Multi-drug resistance 1 (MDR1). The over-expression of P-gp and MDR1 is associated with poor prognosis and drug-resistance in glioma. However, β-asarone can pass through the BBB easily and increase the drug concentration in the rat brain. Our aim is to study the effect of β-asarone on promoting the entry of temozolomide (TMZ) into human glioma U251 cells. The cells were divided into three groups: model group, TMZ group (300μM) and co-administration group (360μM β-asarone; 300μM TMZ). We further detected P-gp and MDR1 expression in U251 and rat glioma C6 cells in four groups: model group (U251/C6), TMZ group (U251 300μM, C6 420μM), β-asarone group (U251 360μM, C6 450μM) and co-administration group (β-asarone 360μM, TMZ 300μM for U251; β-asarone 450μM, TMZ 420μM for C6). Then, high performance liquid chromatography was used to determine the intracellular and extracellular levels of TMZ. Morphological changes in both cells were observed by the microscope. The Counting Kit-8 assay was used to measure the cell proliferation and toxicity. Cell immunohistochemistry/immunofluorescence, flowcytometry and western blot were synchronously used to examine the expression of P-gp. We also determined the levels of MDR1 mRNA by RT-PCR. The results showed that β-asarone could promote the entry of TMZ into U251 cells through the membrane. The co-administration of β-asarone and TMZ also decreased cell proliferation and the expression of P-gp and MDR1 better than single medication in U251 and C6 cells. All of the data suggest that β-asarone might contribute to treatment by promoting TMZ's entry into glioma cells, thereby contributing to anti

  18. Cytotoxic, Antiproliferative and Apoptotic Effects of New Benzimidazole Derivatives on A549 Lung Carcinoma and C6 Glioma Cell Lines.

    Science.gov (United States)

    Yurttas, Leyla; Demirayak, Seref; Ciftci, Gulsen Akalın

    2015-01-01

    Benzimidazole ring is a versatile structure which has been extensively utilized in medicinal chemistry. Since we are working on 1,2-disubstutited benzimidazoles, we have reported new antitumor active derivatives. As a continuation to our previous work, we have synthesized a new series of 1-(2-aryl-2-oxoethyl)-2-[(N,Ndimethylamino/pyrrolidinyl/piperidinyl)thiocarbamoyl] benzimidazole derivatives. Anticancer activity of the compounds was evaluated using MTT assay, BrdU assay and flow cytometric analysis on A549 human lung carcinoma and C6 rat glioma cell lines. Compounds bearing dimethylamino moiety exhibited higher antitumor activity.

  19. [Surgical resection of gliomas in 2008].

    Science.gov (United States)

    Carpentier, A C

    2008-11-01

    Surgical resection of gliomas is a well-established treatment. It allows a histo-genetic diagnosis, a mass effect reduction, an intracranial hypertension treatment, a recovery of an eventual neurological deficit induced by the mass effect, but mostly brings a significant survival. New imaging sequences are optimizing the surgical management of brain tumors by bringing precisions on the tumor morphology, on cortical/subcortical eloquent areas (functional and diffusion MRI), on histology (spectroscopic MR). If the tumor is located in eloquent area, surgery is performed under electrostimulation control to take into account cerebral plasticity and to avoid postoperative functional deficits. Neuronavigation, per-operative echography, and per-operative MRI are recognized tools for optimizing the tumor resection. Ongoing researches concern the adjunction of local treatments within the surgical field (photodynamic therapy, chemotherapy, convection immunotherapy...), but also the development of minimal invasive procedures (radiosurgery, high intensity focalized ultrasounds, laser interstitial thermal therapy).

  20. Intraoperative radiation therapy for malignant glioma

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, Noboru; Yamada, Hiromu; Andoh, Takashi; Takada, Mitsuaki; Hirata, Toshifumi; Funakoshi, Takashi; Doi, Hidetaka; Yanagawa, Shigeo (Gifu Univ. (Japan). Faculty of Medicine)

    1989-04-01

    Intraoperative radiation therapy (IOR) is an ideal means of exterminating residual tumor after surgical resection. In this study, the clinical results of IOR using a Scanditronix Microtron MM-22 were evaluated in 14 patients with malignant glioma, five of whom had recurrent tumors. Between July, 1985 and October, 1986, 11 patients with glioblastoma multiforme (GB) were irradiated 18 times (mean, 1.6 times/case), and three with astrocytoma (Kernohan grade III) underwent IOR once each. The target-absorbed dose at 1 to 2 cm deeper than the tumor resection surface was 15 to 50 Gy. During irradiation, a cotton bolus was placed in the dead space after over 91% of the tumor had been resected. As a rule, external irradiation therapy was also given postoperatively at a dose of 30 to 52 Gy. One patient died of pneumonia and disseminated intravascular coagulation syndrome 1 month postoperatively. The 1- and 2-year survival rates of the ramaining 13 patients were 84.6% and 61.5%, respectively; among the 10 with GB, they were 80% and 50%. Generally, the smaller the tumor size, the better the results. There were no adverse effects, despite the dose 15 to 50 Gy applied temporally to the tumor bed. IOR was especially effective against small, localized tumors, but was not always beneficial in cases of large tumors, particularly those with a contralateral focus. The improved survival rate in this series demonstrates that IOR is significantly effective in the 'induction of remission' following surgical excision of malignant gliomas. (author).

  1. Effects of endostatin on C6 glioma-induced edema

    Institute of Scientific and Technical Information of China (English)

    YANG Li-juan; LIN Zhi-xiong; KANG De-zhi; WENG Shen-mei; LIN Jian-hua; HUANG Qiang; ZHANG Peng-fei

    2011-01-01

    Background Glioma-induced edema is considered as one of the most pathological characteristics of glioma and a significant source of morbidity and mortality.New strategies are needed for the treatment of peritumoral edema in glioma.Endostatin has been proven to be beneficial as an anti-angiogenic agent in experimental gliomas,but the effects are unclear.This study aimed to investigate the effects of endostatin on C6 glioma-induced edema.Methods Tumorigenic mice were established by subcutaneous injection of three glioma cell lines,C6-null cells and stable transfected-C6 cells overexpressing mock vector (C6-mock cells) and endostatin (C6-endo cells).Endostatin expression in xenograft C6 glioma was determined by immunostaining and Western blotting.Glioma-induced edema and tumor vessel permeability were assayed.The effect of endostatin on vascular enodothelial growth factor (VEGF) expression in vivo was analyzed by quantitative polymerase chain reaction (Q-PCR) and enzyme-linked immunosorbent assay (ELISA).The number of vesiculo-vascuolar organelles (VVOs) formed in tumor endothelia was calculated using electron microscopy.Data were analyzed by using one-way analysis of variance (ANOVA) followed by Dunnett's post hoc test for multiple comparisons to the control groups.Results Overexpression of endostatin (C6-endo cells) significantly suppressed tumor growth and reduced tumor edema and vessel permeability.ELISA analysis showed that the level of VEGF protein was markedly decreased in tumor from C6-endo cells compared with tumor from C6-null cells and C6-mock cells.Similar results were obtained by Q-PCR.Furthermore,the number of VVOs observed in tumor from C6-endo mice was significantly reduced compared with tumor from C6-null cells or C6-mock cells.Conclusions Our data provide primary evidence that endostatin reduces glioma-induced edema and vascular permeability.Using endostatin may be an effective strategy for treating glioma edema.

  2. DELETION AND 5'CPG ISLAND METHYLATION OF p15 GENE IN BRAIN GLIOMA

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To investigate the abnormality of p15 gene in brain glioma and the correlation of it with occurrence or malignant progression of brain glioma. Methods: Deletion and 5'CPG island methylation of p15 gene were detected by the methods of PCR and PCR-based methylation in 56 cases of brain glioma. Results: Out of 43 cases of high grade glioma, 14 cases were found to have homozygous deletion of p15E1, while none of the 13 cases of low grade glioma was found to have deletion of p15E1 (P<0.05). Methylation of 5'CPG Island of p15 gene was found only in four cases of glioma. Conclusion: Abnormality of p15 gene may involved in the occurrence and malignant progression of brain glioma. Homozygous deletion of gene is the major mechanism of inactivation for p15 gene in brain glioma.

  3. Changing paradigms - An update on the multidisciplinary management of malignant glioma

    NARCIS (Netherlands)

    R. Stupp (Roger); M.E. Hegi (Monika); M.J. van den Bent (Martin); W.P. Mason (Warren); M. Weller (Michael); R.O. Mirimanoff; J.G. Cairncross (Gregory)

    2006-01-01

    textabstractTreatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting

  4. Treating malignant glioma in Chinese patients: update on temozolomide

    Directory of Open Access Journals (Sweden)

    Chang L

    2014-02-01

    Full Text Available Liang Chang,1 Jun Su,1 Xiuzhi Jia,2,3 Huan Ren2,3 1Department of Neurosurgery, The Tumor Hospital of Harbin Medical University, 2Department of Immunology, Harbin Medical University, 3Key Lab Infection and Immunity, Heilongjiang Province, Harbin, People's Republic of China Abstract: Malignant glioma, ie, anaplastic astrocytoma and glioblastoma, is the most common type of primary malignant brain tumor in the People's Republic of China, and is particularly aggressive. The median survival of patients with newly diagnosed glioblastoma is only 12–14 months despite advanced therapeutic strategies. Treatment of malignant glioma consists mainly of surgical resection followed by adjuvant radiation and chemotherapy. Temozolomide (TMZ, a second-generation oral alkylating agent, is playing an increasingly important role in the treatment of malignant glioma in Chinese patients. Since the publication of a study by Stupp et al in 2005, which used a protocol of conventional fractionated irradiation with concomitant TMZ followed by standard TMZ for six cycles, many clinical studies in the People's Republic of China have demonstrated that such a treatment strategy has significantly improved efficacy with limited side effects for newly diagnosed glioblastoma after surgery as compared with strategies that do not contain TMZ. However, as a relatively new agent, the history and development of TMZ for malignant glioma is not well documented in Chinese patients. Multicenter, randomized controlled trials including appropriately sized patient populations investigating multiple aspects of TMZ therapy and related combination therapies are warranted in patients with malignant glioma. This review provides an update on the efficacy, mechanism of action, adverse reactions, and clinical role of TMZ in the treatment of malignant glioma in Chinese patients. Keywords: malignant glioma, chemotherapy, temozolomide, efficacy, side effect, People's Republic of China

  5. IDH1 mutation detection by droplet digital PCR in glioma.

    Science.gov (United States)

    Wang, Jing; Zhao, Yi-ying; Li, Jian-feng; Guo, Cheng-cheng; Chen, Fu-rong; Su, Hong-kai; Zhao, Hua-fu; Long, Ya-kang; Shao, Jian-yong; To, Shing shun Tony; Chen, Zhong-ping

    2015-11-24

    Glioma is the most frequent central nervous system tumor in adults. The overall survival of glioma patients is disappointing, mostly due to the poor prognosis of glioblastoma (Grade IV glioma). Isocitrate dehydrogenase (IDH) is a key factor in metabolism and catalyzes the oxidative decarboxylation of isocitrate. Mutations in IDH genes are observed in over 70% of low-grade gliomas and some cases of glioblastoma. As the most frequent mutation, IDH1(R132H) has been served as a predictive marker of glioma patients. The recently developed droplet digital PCR (ddPCR) technique generates a large amount of nanoliter-sized droplets, each of which carries out a PCR reaction on one template. Therefore, ddPCR provides high precision and absolute quantification of the nucleic acid target, with wide applications for both research and clinical diagnosis. In the current study, we collected 62 glioma tissue samples (Grade II to IV) and detected IDH1 mutations by Sanger direct sequencing, ddPCR, and quantitative real-time PCR (qRT-PCR). With the results from Sanger direct sequencing as the standard, the characteristics of ddPCR were compared with qRT-PCR. The data indicated that ddPCR was much more sensitive and much easier to interpret than qRT-PCR. Thus, we demonstrated that ddPCR is a reliable and sensitive method for screening the IDH mutation. Therefore, ddPCR is able to applied clinically in predicting patient prognosis and selecting effective therapeutic strategies. Our data also supported that the prognosis of Grade II and III glioma was better in patients with an IDH mutation than in those without mutation.

  6. Surgical Outcomes of High-Grade Spinal Cord Gliomas

    Science.gov (United States)

    Hida, Kazutoshi; Yano, Syunsuke; Aoyama, Takeshi; Koyanagi, Izumi; Houkin, Kiyohiro

    2015-01-01

    Study Design A retrospective study. Purpose The purpose of this study was to obtain useful information for establishing the guidelines for treating high-grade spinal cord gliomas. Overview of Literature The optimal management of high-grade spinal cord gliomas remains controversial. We report the outcomes of the surgical management of 14 high-grade spinal glioma. Methods We analyzed the outcomes of 14 patients with high-grade spinal cord gliomas who were surgically treated between 1989 and 2012. Survival was charted with the Kaplan-Meier plots and comparisons were made with the log-rank test. Results None of the patients with high-grade spinal cord gliomas underwent total resection. Subtotal resection was performed in two patients, partial resection was performed in nine patients, and open biopsy was performed in three patients. All patients underwent postoperative radiotherapy and six patients further underwent radiation cordotomy. The median survival time for patients with high-grade spinal cord gliomas was 15 months, with a 5-year survival rate of 22.2%. The median survival time for patients with World Health Organization grade III tumors was 25.5 months, whereas the median survival time for patients with glioblastoma multiforme was 12.5 months. Both univariate and multivariate Cox proportional hazards models demonstrated a significant effect only in the group that did not include cervical cord lesion as a factor associated with survival (p=0.04 and 0.03). Conclusions The surgical outcome of patients diagnosed with high-grade spinal cord gliomas remains poor. Notably, only the model which excluded cervical cord lesions as a factor significantly predicted survival. PMID:26713128

  7. Description of selected characteristics of familial glioma patients – Results from the Gliogene Consortium

    DEFF Research Database (Denmark)

    Sadetzki, Siegal; Bruchim, Revital; Oberman, Bernice

    2013-01-01

    While certain inherited syndromes (e.g. Neurofibromatosis or Li-Fraumeni) are associated with an increased risk of glioma, most familial gliomas are non-syndromic. This study describes the demographic and clinical characteristics of the largest series of non-syndromic glioma families ascertained...

  8. [18F]-fluoro-l-thymidine PET and advanced MRI for preoperative grading of gliomas

    Directory of Open Access Journals (Sweden)

    S. Collet

    2015-01-01

    Conclusion: Whereas advanced MRI parameters give indications for the grading of gliomas, the addition of [18F]-FLT-PET could be of interest for the accurate preoperative classification of diffuse gliomas, particularly for identification of doubtful grade III and IV gliomas.

  9. Spontaneous immune responses against glioma-associated antigens in a long term survivor with malignant glioma

    Directory of Open Access Journals (Sweden)

    Fujita Mitsugu

    2007-12-01

    Full Text Available Abstract Background In patients with high grade glioma, little is known regarding existence of naturally occurring adaptive T cell reactivity against glioma-associated antigens (GAAs. In this report, we characterized GAA-specific CD8+ T cells and innate immune cells in a patient who has survived with anaplastic astrocytoma (AA for over 12 years without recurrence. Methods Peripheral blood mononuclear cells (PBMCs derived from the long term survivor with AA were evaluated for the frequency, cytotoxic T lymphocyte (CTL activity and differentiation status of CD8+ cells recognizing GAA-derived epitopes as well as relative numbers of other immune cell subsets. This patient's AA tissue was evaluated for expression of two GAAs EphA2 and interleukin-13 receptor α2 subunit (IL-13Rα2 by immunohistochemistry. Results The patient's tumor expressed both EphA2 and IL-13Rα2, and in vitro stimulated PBMC demonstrated superior EphA2883–891 and IL-13Rα2345–353-specific CTL reactivity compared to PBMC samples from two other patients with progressing malignant glioma. Unstimulated EphA2883–891-reactive CD8+ T cells contained high numbers of CD45RA-/CCR7- late effector and CD45RA-/CCR7+ central memory cells. Among other leukocyte subsets, elevated numbers of NK-T cells were found. Conclusion To our knowledge, the current study is one of the first demonstrating the presence of antigen-experienced, GAA-reactive CD8+ T cells in a patient who has survived with AA for over 12 years without recurrence. Further studies are warranted to determine whether the status of GAA-reactive CD8+ T cells dictates survival of patients and/or response to therapeutic vaccines.

  10. Conditioned Medium from Adipose-Derived Stem Cells (ADSCs) Promotes Epithelial-to-Mesenchymal-Like Transition (EMT-Like) in Glioma Cells In vitro.

    Science.gov (United States)

    Iser, Isabele C; Ceschini, Stefanie M; Onzi, Giovana R; Bertoni, Ana Paula S; Lenz, Guido; Wink, Márcia R

    2016-12-01

    Mesenchymal stem cells (MSCs) have recently been described to home to brain tumors and to integrate into the tumor-associated stroma. Understanding the communication between cancer cells and MSCs has become fundamental to determine whether MSC-tumor interactions should be exploited as a vehicle for therapeutic agents or considered a target for intervention. Therefore, we investigated whether conditioned medium from adipose-derived stem cells (ADSCs-CM) modulate glioma tumor cells by analyzing several cell biology processes in vitro. C6 rat glioma cells were treated with ADSCs-CM, and cell proliferation, cell cycle, cell viability, cell morphology, adhesion, migration, and expression of epithelial-mesenchymal transition (EMT)-related surface markers were analyzed. ADSCs-CM did not alter cell viability, cell cycle, and growth rate of C6 glioma cells but increased their migratory capacity. Moreover, C6 cells treated with ADSC-CM showed reduced adhesion and underwent changes in cell morphology. Up-regulation of EMT-associated markers (vimentin, MMP2, and NRAS) was also observed following treatment with ADSC-CM. Our findings demonstrate that the paracrine factors released by ADSCs are able to modulate glioma cell biology. Therefore, ADSC-tumor cell interactions in a tumor microenvironment must be considered in the design of clinical application of stem cell therapy. Graphical Abstract Factors released by adipose-derived stem cells (ADSCs) may modulate the biology of C6 glioma cells. When C6 cells are exposed to a conditioned medium from adipose-derived stem cells (ADSCs-CM), some of these cells can undergo an EMT-like process and trans-differentiate into cells with a more mesenchymal phenotype, characterized by enhanced expression of EMT-related surface markers, reduced cell adhesion capacity, increased migratory capacity, as well as changes in cell and nuclei morphology.

  11. Facing Contrast-Enhancing Gliomas: Perfusion MRI in Grade III and Grade IV Gliomas according to Tumor Area

    Directory of Open Access Journals (Sweden)

    Anna Luisa Di Stefano

    2014-01-01

    Full Text Available Tumoral neoangiogenesis characterizes high grade gliomas. Relative Cerebral Blood Volume (rCBV, calculated with Dynamic Susceptibility Contrast (DSC Perfusion-Weighted Imaging (PWI, allows for the estimation of vascular density over the tumor bed. The aim of the study was to characterize putative tumoral neoangiogenesis via the study of maximal rCBV with a Region of Interest (ROI approach in three tumor areas—the contrast-enhancing area, the nonenhancing tumor, and the high perfusion area on CBV map—in patients affected by contrast-enhancing glioma (grades III and IV. Twenty-one patients were included: 15 were affected by grade IV and 6 by grade III glioma. Maximal rCBV values for each patient were averaged according to glioma grade. Although rCBV from contrast-enhancement and from nonenhancing tumor areas was higher in grade IV glioma than in grade III (5.58 and 2.68; 3.01 and 2.2, resp., the differences were not significant. Instead, rCBV recorded in the high perfusion area on CBV map, independently of tumor compartment, was significantly higher in grade IV glioma than in grade III (7.51 versus 3.78, P=0.036. In conclusion, neoangiogenesis encompasses different tumor compartments and CBV maps appear capable of best characterizing the degree of neovascularization. Facing contrast-enhancing brain tumors, areas of high perfusion on CBV maps should be considered as the reference areas to be targeted for glioma grading.

  12. Topoisomerase I inhibitors, shikonin and topotecan, inhibit growth and induce apoptosis of glioma cells and glioma stem cells.

    Directory of Open Access Journals (Sweden)

    Feng-Lei Zhang

    Full Text Available Gliomas, the most malignant form of brain tumors, contain a small subpopulation of glioma stem cells (GSCs that are implicated in therapeutic resistance and tumor recurrence. Topoisomerase I inhibitors, shikonin and topotecan, play a crucial role in anti-cancer therapies. After isolated and identified the GSCs from glioma cells successfully, U251, U87, GSCs-U251 and GSCs-U87 cells were administrated with various concentrations of shikonin or topotecan at different time points to seek for the optimal administration concentration and time point. The cell viability, cell cycle and apoptosis were detected using cell counting kit-8 and flow cytometer to observe the inhibitory effects on glioma cells and GSCs. We demonstrated that shikonin and topotecan obviously inhibited proliferation of not only human glioma cells but also GSCs in a dose- and time-dependent manner. According to the IC50 values at 24 h, 2 μmol/L of shikonin and 3 μmol/L of topotecan were selected as the optimal administration concentration. In addition, shikonin and topotecan induced cell cycle arrest in G0/G1 and S phases and promoted apoptosis. The down-regulation of Bcl-2 expression with the activation of caspase 9/3-dependent pathway was involved in the apoptosis process. Therefore, the above results showed that topoisomerase I inhibitors, shikonin and topotecan, inhibited growth and induced apoptosis of GSCs as well as glioma cells, which suggested that they might be the potential anticancer agents targeting gliomas to provide a novel therapeutic strategy.

  13. Efficacy of ribavirin against malignant glioma cell lines

    Science.gov (United States)

    OGINO, AKIYOSHI; SANO, EMIKO; OCHIAI, YUSHI; YAMAMURO, SHUN; TASHIRO, SHINYA; YACHI, KAZUNARI; OHTA, TAKASHI; FUKUSHIMA, TAKAO; OKAMOTO, YUTAKA; TSUMOTO, KOUHEI; UEDA, TAKUYA; YOSHINO, ATSUO; KATAYAMA, YOICHI

    2014-01-01

    Ribavirin (1-β-D-ribofuranosy-1,2,4-triazole-3-carboxamide) has been widely administered as an antiviral agent against RNA and DNA viruses. Ribavirin, in combination with interferon, has predominantly been applied in the treatment of the hepatitis C virus infection and its potential antitumor efficacy has recently become a point of interest. The aim of the present study was to evaluate the effect of ribavirin on the growth of malignant glioma cells, to identify novel predictive genes in malignant glioma cells (by analyzing gene expression profiles) and to assess the influence of ribavirin on the cell cycle of malignant glioma cells. The present study evaluated the antitumor efficacy of ribavirin against various malignant glioma cell lines (A-172, AM-38, T98G, U-87MG, U-138MG, U-251MG and YH-13). After culturing the cells in ribavirin-containing culture medium (final concentration, 0–1,000 μM) for 72 h, the viable proliferated cells were harvested and counted. The half maximal inhibitory concentration of ribavirin, with regard to the growth of the malignant glioma cell lines, was determined from the concentration of ribavirin required for 50% growth inhibition in comparison to the untreated control cells. Furthermore, the current study identified the genes in which the gene expression levels correlated with the ribavirin sensitivity of the malignant glioma cells lines, using a high-density oligonucleotide array. Finally, cell cycle analysis was performed on the U-87MG cell line. It was identified that ribavirin inhibited the growth of all of the malignant glioma cell lines in a dose-dependent manner, although the ribavirin sensitivity varied between each cell line. Of the extracted genes, PDGFRA demonstrated the strongest positive correlation between gene expression level and ribavirin sensitivity. Cell cycle analysis of the U-87MG cell line demonstrated that ribavirin treatment induces G0/G1 arrest and thus may be an effective agent for inhibiting malignant

  14. Isocitrate dehydrogenase 1 and 2 mutations in gliomas.

    Science.gov (United States)

    Megova, Magdalena; Drabek, Jiri; Koudelakova, Vladimira; Trojanec, Radek; Kalita, Ondrej; Hajduch, Marian

    2014-12-01

    Over the past few years, new biomarkers have allowed a deeper insight into gliomagenesis and facilitated the identification of possible targets for glioma therapy. Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations have been shown to be promising biomarkers for monitoring disease prognosis and predicting the response to treatment. This review summarizes recent findings in this field. Web of Science, Science Direct, and PubMed online databases were used to search for publications investigating the role of IDH in glioma. References were identified by searching for the keywords "IDH1 or IDH2 and glioma and diagnostic or predictive or prognostic" in papers published from January, 2008, to April, 2014. Only papers in English were reviewed. Publications available only as an abstract were not included. IDH1/2 mutations are tightly associated with grade II and III gliomas and secondary glioblastomas, with better prognosis and production of a recently described oncometabolite, 2-hydroxyglutarate (2HG). Although the contradictory positive effect of IDH mutation on prognosis and negative role of 2HG in tumor transformation remain unresolved, the future direction of personalized treatment strategies targeted to glioma development is likely to focus on IDH1/2 mutations.

  15. Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.

    Directory of Open Access Journals (Sweden)

    Moonsup Jeong

    Full Text Available Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, average survival for the patients with malignant gliomas is only about 1 year. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancers, but concerns over delivery and toxicity have limited progress. We have developed a secretable trimeric TRAIL (stTRAIL and here evaluated the therapeutic potential of this stTRAIL-based gene therapy in brain tumors. An adenovirus (Ad-stTRAIL delivering stTRAIL was injected into intra-cranial human glioma tumors established in nude mice and tumor growth monitored using the magnetic resonance imaging (MRI. Ad-stTRAIL gene therapy showed potent tumor suppressor activity with no toxic side effects at therapeutically effective doses. When compared with 1, 3-bis(2-chloroethyl-1-nitrosourea (BCNU, a conventional therapy for malignant gliomas, Ad-stTRAIL suppressed tumor growth more potently. The combination of Ad-stTRAIL and BCNU significantly increased survival compared to the control mice or mice receiving Ad-stTRAIL alone. Our data indicate that Ad-stTRAIL, either alone or combined with BCNU, has promise as a novel therapy for malignant gliomas.

  16. Cannabinoids as potential new therapy for the treatment of gliomas.

    Science.gov (United States)

    Parolaro, Daniela; Massi, Paola

    2008-01-01

    Gliomas constitute the most frequent and malignant primary brain tumors. Current standard therapeutic strategies (surgery, radiotherapy and chemotherapeutics, e.g., temozolomide, carmustin or carboplatin) for their treatment are only palliative and survival diagnosis is normally 6-12 months. The development of new therapeutic strategies for the management of gliomas is therefore essential. Interestingly, cannabinoids have been shown to exert antiproliferative effects on a wide spectrum of cells in culture. Of interest, cannabinoids have displayed a great potency in reducing glioma tumor growth either in vitro or in animal experimental models, curbing the growth of xenografts generated by subcutaneous or intratecal injection of glioma cells in immune-deficient mice. Moreover, cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of nontransformed counterparts. A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects, and may set the basis for further studies aimed at better evaluating the potential anticancer activity of cannabinoids.

  17. Impact of Temozolomide on Immune Response during Malignant Glioma Chemotherapy

    Directory of Open Access Journals (Sweden)

    Sadhak Sengupta

    2012-01-01

    Full Text Available Malignant glioma, or glioblastoma, is the most common and lethal form of brain tumor with a median survival time of 15 months. The established therapeutic regimen includes a tripartite therapy of surgical resection followed by radiation and temozolomide (TMZ chemotherapy, concurrently with radiation and then as an adjuvant. TMZ, a DNA alkylating agent, is the most successful antiglioma drug and has added several months to the life expectancy of malignant glioma patients. However, TMZ is also responsible for inducing lymphopenia and myelosuppression in malignant glioma patients undergoing chemotherapy. Although TMZ-induced lymphopenia has been attributed to facilitate antitumor vaccination studies by inducing passive immune response, in general lymphopenic conditions have been associated with poor immune surveillance leading to opportunistic infections in glioma patients, as well as disrupting active antiglioma immune response by depleting both T and NK cells. Deletion of O6-methylguanine-DNA-methyltransferase (MGMT activity, a DNA repair enzyme, by temozolomide has been determined to be the cause of lymphopenia. Drug-resistant mutation of the MGMT protein has been shown to render chemoprotection against TMZ. The immune modulating role of TMZ during glioma chemotherapy and possible mechanisms to establish a strong TMZ-resistant immune response have been discussed.

  18. Clinicopathologic implications of NF1 gene alterations in diffuse gliomas.

    Science.gov (United States)

    Vizcaíno, M Adelita; Shah, Smit; Eberhart, Charles G; Rodriguez, Fausto J

    2015-09-01

    Recent studies have identified somatic alterations in the gene encoding for neurofibromin (NF1) in a subset of glioblastoma (GBM), usually associated with the mesenchymal molecular subtype. To understand the significance of NF1 genetic alterations in diffuse gliomas in general, we evaluated public databases and tested for NF1 copy number alterations in a cohort using fluorescence in situ hybridization. NF1 genetic loss (homozygous NF1 deletions or mutations with predicted functional consequences) was present in 30 (of 281) (11%) GBM and 21 (of 286) (7%) lower-grade gliomas in The Cancer Genome Atlas data. Furthermore, NF1 loss was associated with worse overall and disease-specific survival in the lower-grade glioma, but not GBM, Group in The Cancer Genome Atlas cohort. IDH1 or 2 mutations co-existed in lower-grade gliomas with NF1 loss (36%) but not in GBM. In our cohort studied by fluorescence in situ hybridization, NF1/17q (n = 2) or whole Ch17 (n = 3) losses were only identified in the GBM group (5/86 [6%]). Tumors with NF1/Ch17 loss were predominantly adult GBM (4/5); lacked EGFR amplification (0/4), strong p53 immunolabeling (1/5), or IDH1 (R132H) protein expression (0/5); but expressed the mesenchymal marker podoplanin in 4/5. NF1 genetic loss occurs in a subset of diffuse gliomas, and its significance deserves further exploration.

  19. A graphic method for identification of novel glioma related genes.

    Science.gov (United States)

    Gao, Yu-Fei; Shu, Yang; Yang, Lei; He, Yi-Chun; Li, Li-Peng; Huang, GuaHua; Li, Hai-Peng; Jiang, Yang

    2014-01-01

    Glioma, as the most common and lethal intracranial tumor, is a serious disease that causes many deaths every year. Good comprehension of the mechanism underlying this disease is very helpful to design effective treatments. However, up to now, the knowledge of this disease is still limited. It is an important step to understand the mechanism underlying this disease by uncovering its related genes. In this study, a graphic method was proposed to identify novel glioma related genes based on known glioma related genes. A weighted graph was constructed according to the protein-protein interaction information retrieved from STRING and the well-known shortest path algorithm was employed to discover novel genes. The following analysis suggests that some of them are related to the biological process of glioma, proving that our method was effective in identifying novel glioma related genes. We hope that the proposed method would be applied to study other diseases and provide useful information to medical workers, thereby designing effective treatments of different diseases.

  20. Concurrent thermochemoradiotherapy for brain high-grade glioma

    Energy Technology Data Exchange (ETDEWEB)

    Ryabova, A. I., E-mail: ranigor@mail.ru; Novikov, V. A.; Startseva, Zh. A.; Bober, E. E.; Frolova, I. G. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); Choinzonov, E. L. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); Siberian State Medical University, Tomsk, 634050 (Russian Federation); Gribova, O. V. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); National Research Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation); Baranova, A. V. [National Research Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation)

    2016-08-02

    Despite the achievements in the current strategies for treatment, the prognosis in malignant glioma patients remains unsatisfactory. Hyperthermia is currently considered to be the most effective and universal modifier of radiotherapy and chemotherapy. Preliminary treatment outcomes for 28 patients with newly diagnosed (23) and recurrent (5) high-grade gliomas were presented. All the patients received multimodality treatment including surgery, thermoche-moradiotherapy followed by 4 cycles of adjuvant chemotherapy. All the patients endured thermochemoradiotherapy well. A complication, limited skin burn (II stage), was diagnosed in two cases and treated conservatively without treatment interruption. A month after thermochemoradiotherapy the results were as follows: complete regression was achieved in 4 cases, partial regression in 4 cases, stable disease in 14 cases and disease progression in 6 cases (one of them is pseudo-progression). After completing the adjuvant chemotherapy 2 more patients demonstrated complete response and 1 patient had disease progression. Introduction of local hyperthermia in multimodal therapy of malignant glioma does not impair the combined modality treatment tolerability of patients with malignant gliomas. A small number of studied patients and short follow-up time do not allow making reliable conclusions about the impact of local hyperthermia on the treatment outcomes; however, there is a tendency towards the increase in disease-free survival in the patients with newly diagnosed malignant gliomas.

  1. The molecular biology of WHO grade II gliomas.

    Science.gov (United States)

    Marko, Nicholas F; Weil, Robert J

    2013-02-01

    The WHO grading scheme for glial neoplasms assigns Grade II to 5 distinct tumors of astrocytic or oligodendroglial lineage: diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, pleomorphic xanthoastrocytoma, and pilomyxoid astrocytoma. Although commonly referred to collectively as among the "low-grade gliomas," these 5 tumors represent molecularly and clinically unique entities. Each is the subject of active basic research aimed at developing a more complete understanding of its molecular biology, and the pace of such research continues to accelerate. Additionally, because managing and predicting the course of these tumors has historically proven challenging, translational research regarding Grade II gliomas continues in the hopes of identifying novel molecular features that can better inform diagnostic, prognostic, and therapeutic strategies. Unfortunately, the basic and translational literature regarding the molecular biology of WHO Grade II gliomas remains nebulous. The authors' goal for this review was to present a comprehensive discussion of current knowledge regarding the molecular characteristics of these 5 WHO Grade II tumors on the chromosomal, genomic, and epigenomic levels. Additionally, they discuss the emerging evidence suggesting molecular differences between adult and pediatric Grade II gliomas. Finally, they present an overview of current strategies for using molecular data to classify low-grade gliomas into clinically relevant categories based on tumor biology.

  2. Epo is involved in angiogenesis in human glioma.

    Science.gov (United States)

    Nico, Beatrice; Annese, Tiziana; Guidolin, Diego; Finato, Nicoletta; Crivellato, Enrico; Ribatti, Domenico

    2011-03-01

    In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreactivity of tumor cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human glioma specimens, and the effect of anti-Epo antibody on glioma-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane (CAM) has been investigated. Results show that: (1) Epo/EpoR expression correlates with angiogenesis, (2) in the CAM assay, tumor bioptic specimens induce a strong angiogenic response, comparable to that induced by VEGF, and (3) an anti-Epo antibody co-administered with tumor bioptic specimens significantly inhibits the angiogenic response. These findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by glioma tumor cells and it affects glioma vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner. Moreover, as demonstrated by in vivo experiments, Epo is responsible for the strong angiogenic response induced by human glioma bioptic specimens, because an anti-Epo antibody is able to significantly inhibit this response.

  3. A Graphic Method for Identification of Novel Glioma Related Genes

    Directory of Open Access Journals (Sweden)

    Yu-Fei Gao

    2014-01-01

    Full Text Available Glioma, as the most common and lethal intracranial tumor, is a serious disease that causes many deaths every year. Good comprehension of the mechanism underlying this disease is very helpful to design effective treatments. However, up to now, the knowledge of this disease is still limited. It is an important step to understand the mechanism underlying this disease by uncovering its related genes. In this study, a graphic method was proposed to identify novel glioma related genes based on known glioma related genes. A weighted graph was constructed according to the protein-protein interaction information retrieved from STRING and the well-known shortest path algorithm was employed to discover novel genes. The following analysis suggests that some of them are related to the biological process of glioma, proving that our method was effective in identifying novel glioma related genes. We hope that the proposed method would be applied to study other diseases and provide useful information to medical workers, thereby designing effective treatments of different diseases.

  4. Targeting the erythropoietin receptor on glioma cells reduces tumour growth

    Energy Technology Data Exchange (ETDEWEB)

    Peres, Elodie A.; Valable, Samuel [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Guillamo, Jean-Sebastien [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Departement de Neurologie, CHU de Caen (France); Marteau, Lena [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Bernaudin, Jean-Francois [Service d' Histologie-Biologie Tumorale, ER2UPMC, Universite Paris 6, Hopital Tenon, Paris (France); Roussel, Simon [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Lechapt-Zalcman, Emmanuele [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Service d' Anatomie Pathologique, CHU de Caen (France); Bernaudin, Myriam [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France); Petit, Edwige, E-mail: epetit@cyceron.fr [CERVOxy team ' Hypoxia and cerebrovascular pathophysiology' , UMR 6232 CI-NAPS, Universite de Caen Basse-Normandie, Universite Paris-Descartes, CNRS, CEA. G.I.P. CYCERON, Caen (France)

    2011-10-01

    Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

  5. Concurrent thermochemoradiotherapy for brain high-grade glioma

    Science.gov (United States)

    Ryabova, A. I.; Novikov, V. A.; Choinzonov, E. L.; Gribova, O. V.; Startseva, Zh. A.; Bober, E. E.; Frolova, I. G.; Baranova, A. V.

    2016-08-01

    Despite the achievements in the current strategies for treatment, the prognosis in malignant glioma patients remains unsatisfactory. Hyperthermia is currently considered to be the most effective and universal modifier of radiotherapy and chemotherapy. Preliminary treatment outcomes for 28 patients with newly diagnosed (23) and recurrent (5) high-grade gliomas were presented. All the patients received multimodality treatment including surgery, thermoche-moradiotherapy followed by 4 cycles of adjuvant chemotherapy. All the patients endured thermochemoradiotherapy well. A complication, limited skin burn (II stage), was diagnosed in two cases and treated conservatively without treatment interruption. A month after thermochemoradiotherapy the results were as follows: complete regression was achieved in 4 cases, partial regression in 4 cases, stable disease in 14 cases and disease progression in 6 cases (one of them is pseudo-progression). After completing the adjuvant chemotherapy 2 more patients demonstrated complete response and 1 patient had disease progression. Introduction of local hyperthermia in multimodal therapy of malignant glioma does not impair the combined modality treatment tolerability of patients with malignant gliomas. A small number of studied patients and short follow-up time do not allow making reliable conclusions about the impact of local hyperthermia on the treatment outcomes; however, there is a tendency towards the increase in disease-free survival in the patients with newly diagnosed malignant gliomas.

  6. 丙泊酚对大鼠胶质瘤细胞侵袭和迁移能力的影响及ADAR2-AMPA受体GluR2通路在其中的作用%Effects of propofol on invasion and migration of glioma cells in rats and the role of ADAR2-AMPA receptor GluR2 pathway

    Institute of Scientific and Technical Information of China (English)

    王欣悦; 王海云; 王国林; 杨卓; 张涛

    2016-01-01

    目的 评价丙泊酚对大鼠胶质瘤细胞侵袭和迁移能力的影响及腺苷脱氨酶(ADAR2)-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)受体GluR2通路在其中的作用.方法 传代培养大鼠C6胶质瘤细胞,采用随机数字表法分为4组(n=24):对照组(C组)、丙泊酚组(P组)、阴性siRNA转染+丙泊酚组(NP组)和ADAR2-siRNA转染+丙泊酚组(AP组).C组正常培养;NP组和AP组分别将阴性siRNA或ADAR2-siRNA转染至细胞内,48 h后处理同P组;P组加入丙泊酚,终浓度1.2 μg/ml,孵育6h后换为正常培养液,继续培养18h.采用MTT比色分析法检测细胞活力,Transwell侵袭实验测定侵袭细胞数,细胞划痕实验测定迁移率,Western blot法检测胞核ADAR2和胞膜GluR2的表达.结果 与C组比较,P组和NP组细胞活力、侵袭细胞数和迁移率降低,胞核A-DAR2及胞膜GluR2表达上调(P<0.05);与P组比较,AP组细胞活力、侵袭细胞数和迁移率升高,胞核ADAR2及胞膜GluR2表达下调(P<0.05);与NP组比较,AP组细胞活力、侵袭细胞数和迁移率升高,胞核ADAR2及胞膜GluR2表达下调(P<0.05).结论 丙泊酚可抑制大鼠胶质瘤细胞的侵袭和迁移能力,其机制与激活ADAR2-AMPA受体GluR2通路有关.%Objective To evaluate the effects of propofol on the invasion and migration of glioma cells in the rats and the role of adenosine deaminase acting on RNA 2 (ADAR2)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit glutamate 2 (GluR2) pathway.Methods C6 glioma cells were subcuhured and randomly divided into 4 groups (n =24 each) using a random number table:control group (group C);propofol group (group P);negative siRNA transfection + propofol group (group NP);ADAR2-siRNA transfection + propofol group (group AP).The cells were cultured in the common culture medium in group C.In NP and AP groups,negative siRNA and ADAR2-siRNA were transfected into the cells,respectively,and 48 h later the other procedures were similar

  7. Relapse of herpes encephalitis induced by temozolomide-based chemoradiation in a patient with malignant glioma.

    Science.gov (United States)

    Okada, Masaki; Miyake, Keisuke; Shinomiya, Aya; Kawai, Nobuyuki; Tamiya, Takashi

    2013-02-01

    The authors report on a case of concurrent herpes simplex encephalitis (HSE) and malignant glioma. The co-occurrence of HSE and malignant glioma is very rare, but it can occur during glioma treatment. Both radiotherapy and chemoradiation with temozolomide can induce viral reactivation, leading to HSE relapse. Careful observation for HSE is necessary when administering chemoradiation to patients with a history of HSE. Antiviral therapy for HSE must be initiated immediately, and the chemoradiation for glioma should be stopped; however, it is not clear what antitumor therapy is optimal when HSE co-occurs during the treatment of glioma.

  8. Increasing of Blood-Brain Tumor Barrier Permeability through Transcellular and Paracellular Pathways by Microbubble-Enhanced Diagnostic Ultrasound in a C6 Glioma Model

    Science.gov (United States)

    Zhang, Jinlong; Liu, Heng; Du, Xuesong; Guo, Yu; Chen, Xiao; Wang, Shunan; Fang, Jingqin; Cao, Peng; Zhang, Bo; Liu, Zheng; Zhang, Weiguo

    2017-01-01

    Most of the anticancer agents cannot be efficiently delivered into the brain tumor because of the existence of blood-brain tumor barrier (BTB). The objective of this study was to explore the effect of microbubble-enhanced diagnostic ultrasound (MEUS) on the BTB permeability and the possible mechanism. Glioma-bearing rats were randomized into three groups as follows: the microbubble-enhanced continued diagnostic ultrasound (MECUS) group; the microbubble-enhanced intermittent diagnostic ultrasound (MEIUS) group and the control group. The gliomas were insonicated through the skull with a diagnostic ultrasound and injected with microbubbles through the tail veins. Evans Blue (EB) and dynamic contrast-enhanced-MRI were used to test changes in the BTB permeability. Confocal laser scanning microscopy was used to observe the deposition of the EB in the tumor tissues. The distribution and expression of junctional adhesion molecule-A (JAM-A) and calcium-activated potassium channels (KCa channels) were detected by a Western blot, qRT-PCR, and immunohistochemical staining. In the MEUS groups, the EB extravasation (11.0 ± 2.2 μg/g in MECUS group and 17.9 ± 2.3 μg/g in MEIUS group) exhibited a significant increase compared with the control group (5.3 ± 0.9 μg/g). The MEIUS group had more EB extravasation than the MECUS group. The Ktrans value of the dynamic contrast-enhanced-MRI in the MEUS groups was higher than that of the control group and correlated strongly with the EB extravasation in the tumor (R2 = 0.97). This showed that the Ktrans value might be a non-invasive method to evaluate the BTB permeability in rat glioma after microbubble-enhanced ultrasound treatment.Western blot, qRT-PCR and immunohistochemical staining revealed that MEUS increased the KCa channels expression and reduced JAM-A expression in glioma. This change was more obvious in the MEIUS group than in the MECUS group. The results demonstrated that MEUS effectively increased the BTB permeability in

  9. Glioma-initiating cells and molecular pathology: implications for therapy.

    Science.gov (United States)

    Natsume, Atsushi; Kinjo, Sayano; Yuki, Kanako; Kato, Takenori; Ohno, Masasuke; Motomura, Kazuya; Iwami, Kenichiro; Wakabayashi, Toshihiko

    2011-02-01

    There is now compelling evidence that gliomas harbor a small population of cells, termed glioma-initiating cells (GICs), characterized by their ability to undergo self-renewal and initiate tumorigenesis. The development of therapeutic strategies targeted toward GIC signaling may improve the treatment of malignant gliomas. The characterization of GICs provides a clue to elucidating histological heterogeneity and treatment failure. The role of the stem cell marker CD133 in the initiation and progression of brain tumors is still uncertain. Here, we review some of the signaling mechanisms involved in GIC biology, such as phosphatase and tensin homolog (PTEN), sonic hedgehog, Notch, and WNT signaling pathways, maternal embryonic leucine-zipper kinase (MELK), BMI1, and Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling. In addition, we discuss the role of microRNAs in GICs by focusing on microRNA-21 regulation by type I interferon.

  10. Targeting autophagy to sensitive glioma to temozolomide treatment.

    Science.gov (United States)

    Yan, Yuanliang; Xu, Zhijie; Dai, Shuang; Qian, Long; Sun, Lunquan; Gong, Zhicheng

    2016-02-02

    Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, the efficacy of TMZ is often limited by the development of resistance. Recently, studies have found that TMZ treatment could induce autophagy, which contributes to therapy resistance in glioma. To enhance the benefit of TMZ in the treatment of glioblastomas, effective combination strategies are needed to sensitize glioblastoma cells to TMZ. In this regard, as autophagy could promote cell survival or autophagic cell death, modulating autophagy using a pharmacological inhibitor, such as chloroquine, or an inducer, such as rapamycin, has received considerably more attention. To understand the effectiveness of regulating autophagy in glioblastoma treatment, this review summarizes reports on glioblastoma treatments with TMZ and autophagic modulators from in vitro and in vivo studies, as well as clinical trials. Additionally, we discuss the possibility of using autophagy regulatory compounds that can sensitive TMZ treatment as a chemotherapy for glioma treatment.

  11. Boldine: a potential new antiproliferative drug against glioma cell lines.

    Science.gov (United States)

    Gerhardt, Daniéli; Horn, Ana Paula; Gaelzer, Mariana Maier; Frozza, Rudimar Luiz; Delgado-Cañedo, Andrés; Pelegrini, Alessandra Luiza; Henriques, Amélia T; Lenz, Guido; Salbego, Christianne

    2009-12-01

    Malignant gliomas are the most common and devastating primary tumors of the central nervous system. Currently no efficient treatment is available. This study evaluated the effect and underlying mechanisms of boldine, an aporphine alkaloid of Peumus boldus, on glioma proliferation and cell death. Boldine decreased the cell number of U138-MG, U87-MG and C6 glioma lines at concentrations of 80, 250 and 500 muM. We observed that cell death caused by boldine was cell-type specific and dose-dependent. Exposure to boldine for 24 h did not activate key mediators of apoptosis. However, it induced alterations in the cell cycle suggesting a G(2)/M arrest in U138-MG cells. Boldine had no toxic effect on non-tumor cells when used at the same concentrations as those used on tumor cells. Based on these results, we speculate that boldine may be a promising compound for evaluation as an anti-cancer agent.

  12. MR imaging of optic chiasmatic glioma

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Seong Sook; Lee, Ho Kyu; Kim, Hyun Jin; Ryu, Meung Sun; Goo, Hyun Woo; Yoon, Chong Hyun; Choi, Choong Gon; Suh, Dae Chul; Ra, Young Shin; Khang, Shin Kwang [University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2002-08-01

    To evaluate the MR findings of optic chiasmatic glioma (OCG). MR images were reviewed in 14 patients with histologically proven OCGs and one with neurofibromatosis type 1 (male: female=8:7, mean age=8.5 years.) Tumors were evaluated retrospectively with respect to their size, involvement of the optic pathway, transverse/vertical diameter ratio based on the coronal plane, signal intensities, enhancement pattern, and the presence of a cyst or calcification. Tumors was measured 1.7-5.5 (mean, 3.3) cm in maximum diameter. In ten patients, the optic tracts were involved, and in three, the optic nerves. In 12 patients, tumors had a transverse/vertical diameter ratio of over one, and showed iso (n=5) or low signal intensity (n=10) compared with gray matter at T1-weighted imaging and high signal intensity (n=15) at T2-weighted imaging. Cyst formations were ween in eight patients, and tumors were enhanced strongly and homogeneously in nine and peripherally in four. In seven three was associated hydrocephalus, and in one, calcification. OCG is a suprasellar tumor which can extend into the optic pathway, has a transverse/vertical diameter ratio of more than one, and shows strong and homogeneous enhancement. These MR imaging findings are useful for the differentiation of OCG from other suprasellar tumors.

  13. Epigenetic aberrations and therapeutic implications in gliomas.

    Science.gov (United States)

    Natsume, Atsushi; Kondo, Yutaka; Ito, Motokazu; Motomura, Kazuya; Wakabayashi, Toshihiko; Yoshida, Jun

    2010-06-01

    Almost all cancer cells have multiple epigenetic abnormalities, which combine with genetic changes to affect many cellular processes, including cell proliferation and invasion, by silencing tumor-suppressor genes. In this review, we focus on the epigenetic mechanisms of DNA hypomethylation and CpG island hypermethylation in gliomas. Aberrant hypermethylation in promoter CpG islands has been recognized as a key mechanism involved in the silencing of cancer-associated genes and occurs at genes with diverse functions related to tumorigenesis and tumor progression. Such promoter hypermethylation can modulate the sensitivity of glioblastomas to drugs and radiotherapy. As an example, the methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter is a specific predictive biomarker of tumor responsiveness to chemotherapy with alkylating agents. Further, we reviewed reports on pyrosequencing - a simple technique for the accurate and quantitative analysis of DNA methylation. We believe that the quantification of MGMT methylation by pyrosequencing might enable the selection of patients who are most likely to benefit from chemotherapy. Finally, we also evaluated the potential of de novo NY-ESO-1, the most immunogenic cancer/testis antigen (CTA) discovered thus far, as an immunotherapy target. The use of potent epigenetics-based therapy for cancer cells might restore the abnormally regulated epigenomes to a more normal state through epigenetic reprogramming. Thus, epigenetic therapy may be a promising and potent treatment for human neoplasia.

  14. Autophagy contributes to gefitinib-induced glioma cell growth inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Cheng-Yi [Department of Surgery, Fong-Yuan Hospital, Taichung 420, Taiwan (China); Graduate Institute of Pharmaceutical Science and Technology, Central Taiwan University of Science and Technology, Taichung 406, Taiwan (China); Kuan, Yu-Hsiang [Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan (China); Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 402, Taiwan (China); Ou, Yen-Chuan; Li, Jian-Ri [Division of Urology, Taichung Veterans General Hospital, Taichung 407, Taiwan (China); Wu, Chih-Cheng [Department of Anesthesiology, Taichung Veterans General Hospital, Taichung 407, Taiwan (China); Department of Financial and Computational Mathematics, Providence University, Taichung 433, Taiwan (China); Pan, Pin-Ho [Department of Pediatrics, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan (China); Chen, Wen-Ying [Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan (China); Huang, Hsuan-Yi [Department of Surgery, Fong-Yuan Hospital, Taichung 420, Taiwan (China); Chen, Chun-Jung, E-mail: cjchen@vghtc.gov.tw [Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan (China); Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan (China); Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan (China); Center for General Education, Tunghai University, Taichung 407, Taiwan (China); Department of Nursing, HungKuang University, Taichung 433, Taiwan (China)

    2014-09-10

    Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation. - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK.

  15. Molecular subtypes of glioblastoma are relevant to lower grade glioma.

    Directory of Open Access Journals (Sweden)

    Xiaowei Guan

    Full Text Available Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas.Gene expression array, single nucleotide polymorphism (SNP array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson. Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP was assigned using prediction models by Fine et al.Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs.GBM gene-expression and methylation based subtypes are relevant for GII/III s and associate with overall survival differences. A better understanding of the association between these subtypes and GII/IIIs could further knowledge regarding prognosis and mechanisms of glioma progression.

  16. Progress of temozolomide in the treatment of recurrent high-grade gliomas

    Directory of Open Access Journals (Sweden)

    LI Jin-duo

    2013-12-01

    Full Text Available High-grade gliomas are central nervous system malignancies which are difficult to treat. Surgery, temozolomide combined with radiotherapy postoperatively and adjuvant chemotherapy with temozolomide have been established as the standard treatment options for high-grade gliomas. Nevertheless, the prognosis of patients with high-grade gliomas remains poor. At present, there is no standard therapy for recurrent or relapsed high-grade gliomas. Temozolomide is still an effective drug for the treatment of recurrent high-grade gliomas. According to the characteristics of patients, there have been many kinds of temozolomide administration and other treatments in combination. Individual therapy were paid more attention, so that the patients with high-grade gliomas recurrence could get greater survival benefit. This paper aims to introduce the progress of temozolomide in the treatment of recurrent high-grade gliomas in recent years.

  17. CREB1 regulates glucose transport of glioma cell line U87 by targeting GLUT1.

    Science.gov (United States)

    Chen, Jiaying; Zhang, Can; Mi, Yang; Chen, Fuxue; Du, Dongshu

    2017-06-23

    Glioma is stemmed from the glial cells in the brain, which is accounted for about 45% of all intracranial tumors. The characteristic of glioma is invasive growth, as well as there is no obvious boundary between normal brain tissue and glioma tissue, so it is difficult to resect completely with worst prognosis. The metabolism of glioma is following the Warburg effect. Previous researches have shown that GLUT1, as a glucose transporter carrier, affected the Warburg effect, but the molecular mechanism is not very clear. CREB1 (cAMP responsive element-binding protein1) is involved in various biological processes, and relevant studies confirmed that CREB1 protein regulated the expression of GLUT1, thus mediating glucose transport in cells. Our experiments mainly reveal that the CREB1 could affect glucose transport in glioma cells by regulating the expression of GLUT1, which controlled the metabolism of glioma and affected the progression of glioma.

  18. [Arteriovenous malformation-glioma association: study of four cases].

    Science.gov (United States)

    Borges, Lia Raquel R; Malheiros, Suzana M F; Pelaez, Maria Paula; Stávale, João Norberto; Santos, Adrialdo J; Carrete, Henrique; Nogueira, Roberto Gomes; Ferraz, Fernando A P; Gabbai, Alberto A

    2003-06-01

    We reviewed the clinical presentation, imaging and histopathologic findings in 4 patients with the diagnosis of arteriovenous malformation associated with glioma that were operated on from 1991 to 2000 in our institution. Four patients (2 males; age between 15 and 52 years) presented with progressive headache with clinical evidence of intracranial hypertension (in 3) and partial seizures (in 1). CT scan showed a brain tumor without any detectable pathologic vessels. Histologic examination revealed astrocytic tumors associated with arteriovenous malformation. No patient presented the vascular component intermixed with the tumor. The arteriovenous-glioma association is rare and must be identified by a clear demarcation between the malformation and the tumor.

  19. Diagnostic and prognostic value of IDH1 mutation in gliomas

    Directory of Open Access Journals (Sweden)

    YANG Yan-wu

    2012-12-01

    Full Text Available Objective To discuss the significance of IDH1 mutation for diagnosis and prognosis of gliomas through detecting of IDH1 mutation in supratentorial glioma cells. Methods IDH1 genes of postoperative pathological samples obtained from 315 patients with supratentorial gliomas (3 cases of WHO Ⅰ, 95 cases of WHO Ⅱ, 37 cases of WHO Ⅲ and 180 cases of WHO Ⅳ were collected for DNA extraction, on which PCR amplification and direct sequencing were done. At the same time, multiple-factor analysis was used on those patients' age, sex, tumor location, excision extension, Karnofsky Performance Status (KPS and progression-free survival time or median survival time, to investigate the influence of IDH1 mutation on the prognosis of patients. Results A total of 112 gene mutations among 315 cases (35.56% were found and they were all R132H type of mutations. Mutation rates in WHOⅡ, Ⅲ and Ⅳ gliomas were 72.63% (69/95, 24.32% (9/37 and 18.89% (34/180 respectively, which were significantly different (P = 0.000, for all. Among patients with IDH1 mutations in WHOⅣ gliomas, there were 18 cases of primary glioblastoma and 16 cases of secondary glioblastoma, the mutation rates of which were 11.39% (18/158 and 72.73% (16/22, respectively. The latter was much higher than the former and the difference was statistically significant ( χ 2 = 23.654,P = 0.001. Survival analysis revealed that IDH1 mutation presented notable effect on the prognosis of patients with gliomas. Conclusion IDH1 mutation can happen in WHO Ⅱ, Ⅲ and Ⅳ gliomas, and the mutation rates of WHOⅡ gliomas and secondary glioblastomas of WHO Ⅳ are higher than others. The survival time of patients are remarkably influenced by IDH1 mutation, and the prognosis of patient with IDH1 mutation is good, which may suggest that IDH1 mutation is an important diagnostic and prognostic biomarker in different grades of gliomas.

  20. Ionizing radiation augments glioma tropism of mesenchymal stem cells.

    Science.gov (United States)

    Thomas, Jonathan G; Parker Kerrigan, Brittany C; Hossain, Anwar; Gumin, Joy; Shinojima, Naoki; Nwajei, Felix; Ezhilarasan, Ravesanker; Love, Patrice; Sulman, Erik P; Lang, Frederick F

    2017-03-31

    OBJECTIVE Mesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs. METHODS To assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7-2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA. RESULTS Transwell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC

  1. The functional role of Notch signaling in human gliomas

    DEFF Research Database (Denmark)

    Stockhausen, Marie-Thérése; Kristoffersen, Karina; Poulsen, Hans Skovgaard

    2010-01-01

    have been referred to as brain cancer stem cells (bCSC), as they share similarities to normal neural stem cells in the brain. The Notch signaling pathway is involved in cell fate decisions throughout normal development and in stem cell proliferation and maintenance. The role of Notch in cancer is now...... firmly established, and recent data implicate a role for Notch signaling also in gliomas and bCSC. In this review, we explore the role of the Notch signaling pathway in gliomas with emphasis on its role in normal brain development and its interplay with pathways and processes that are characteristic...

  2. Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling.

    Science.gov (United States)

    a Dzaye, Omar Dildar; Hu, Feng; Derkow, Katja; Haage, Verena; Euskirchen, Philipp; Harms, Christoph; Lehnardt, Seija; Synowitz, Michael; Wolf, Susanne A; Kettenmann, Helmut

    2016-05-01

    Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133(+ )GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133(-) GL261 cells. In IL-6(-/-) mice, only tumors formed by CD133(+ )cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context.

  3. Immunotherapeutic targeting of shared melanoma-associated antigens in a murine glioma model.

    Science.gov (United States)

    Prins, Robert M; Odesa, Sylvia K; Liau, Linda M

    2003-12-01

    Immune-based treatments for central nervous system gliomas have traditionally lagged behind those of more immunogenic tumors such as melanoma. The relative paucity of defined glioma-associated antigens that can be targeted by the immune system may partially account for this situation. Antigens present on melanomas have been extensively characterized, both in humans and in murine preclinical models. Melanocytes and astrocytes are both derived embryologically from the neural ectoderm. Their neoplastic counterparts, malignant melanomas and gliomas, have been shown in humans to share common antigens at the RNA level. However, little is known concerning whether gliomas can be targeted by immune-based strategies that prime T cells to epitopes from melanoma-associated antigens (MAAs). In this study, we provide evidence that two common murine glioma cell lines (GL26 and GL261) express the melanoma antigens gp100 and tyrosinase-related protein 2 (TRP-2). To understand the immunogenicity of murine gliomas to CD8(+) T cells, we examined the ability of a MAA-specific CTL cell line to lyse the glioma cells, as well as the in vivo expansion of MAA-specific CD8(+) T cells in animals harboring gliomas. Both glioma cell lines were lysed by a human gp100-specific CTL cell line in vitro. Mice harboring s.c. GL26 gliomas possessed TRP-2-specific CD8(+) T cells, providing further evidence that these gliomas express the protein products in the context of MHC class I. Furthermore, MAA peptide-pulsed dendritic cells could prime T cells that specifically recognize GL26 glioma cells in vitro. Lastly, mice that were prevaccinated with human gp100 and TRP-2 peptide-pulsed dendritic cells had significantly extended survival when challenged with tumor cells in the brain, resulting in >50% long-term survival. These results suggest that shared MAAs on gliomas can be targeted immunotherapeutically, pointing the way to a new potential treatment option for patients with malignant gliomas.

  4. Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas.

    Science.gov (United States)

    Savaskan, N E; Seufert, S; Hauke, J; Tränkle, C; Eyüpoglu, I Y; Hahnen, E

    2011-01-06

    Malignant glioma represents one of the most aggressive and lethal human neoplasias. A hallmark of gliomas is their rapid proliferation and destruction of vital brain tissue, a process in which excessive glutamate release by glioma cells takes center stage. Pharmacologic antagonism with glutamate signaling through ionotropic glutamate receptors attenuates glioma progression in vivo, indicating that glutamate release by glioma cells is a prerequisite for rapid glioma growth. Glutamate has been suggested to promote glioma cell proliferation in an autocrine or paracrine manner, in particular by activation of the (RS)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) subtype of glutamate receptors. Here, we dissect the effects of glutamate secretion on glioma progression. Glioma cells release glutamate through the amino-acid antiporter system X(c)(-), a process that is mechanistically linked with cystine incorporation. We show that disrupting glutamate secretion by interfering with the system X(c)(-) activity attenuates glioma cell proliferation solely cystine dependently, whereas glutamate itself does not augment glioma cell growth in vitro. Neither AMPA receptor agonism nor antagonism affects glioma growth in vitro. On a molecular level, AMPA insensitivity is concordant with a pronounced transcriptional downregulation of AMPA receptor subunits or overexpression of the fully edited GluR2 subunit, both of which block receptor activity. Strikingly, AMPA receptor inhibition in tumor-implanted brain slices resulted in markedly reduced tumor progression associated with alleviated neuronal cell death, suggesting that the ability of glutamate to promote glioma progression strictly requires the tumor microenvironment. Concerning a potential pharmacotherapy, targeting system X(c)(-) activity disrupts two major pathophysiological properties of glioma cells, that is, the induction of excitotoxic neuronal cell death and incorporation of cystine required for

  5. Immunohistochemical evaluation of tissue factor, fibrin/fibrinogen and D-dimers in canine gliomas.

    Science.gov (United States)

    de la Fuente, Cristian; Pumarola, Martí; Blasco, Ester; Fernández, Francisco; Viu, Judit; Añor, Sònia

    2014-06-01

    In human gliomas, tissue factor (TF) is overexpressed, associated with the grade of malignancy and influences tumour biology. Intra-tumoural fibrin/fibrinogen deposition and activation of the fibrinolytic system also play a role in tumour cell proliferation and angiogenesis. The first aim of the present study was to investigate TF expression and the presence of fibrin/fibrinogen and D-dimers in canine glioma biopsies, graded according to the World Health Organization (WHO) classification of tumours of the central nervous system. The second aim was to investigate the occurrence of intravascular thrombosis (IVT) in canine gliomas, as a potential histological marker of glioma type or grade of malignancy. An immunohistochemical study using antibodies against TF, fibrin/fibrinogen and D-dimers was performed with 24 glioma samples, including 15 oligodendrogliomas, 6 astrocytomas and 3 mixed gliomas. Immunohistochemical data were statistically analysed to determine whether there was any relationship between glioma type and grade of malignancy. All gliomas were moderate to strongly positive for TF and the staining score was significantly higher (P = 0.04) in high-grade (III or IV) than in low-grade (II) gliomas. Intra-tumoural fibrin/fibrinogen deposition was detected in all tumour biopsies assessed, and D-dimers were detected in 17/24 gliomas. IVT was a frequent finding, but was not linked to a specific glioma type or malignancy grade. TF expression, fibrin/fibrinogen deposition, extravascular fibrinolytic system activation and IVT occur in canine gliomas. Canine glioma might be a suitable model for studying coagulation and fibrinolysis as potential therapeutic targets for human gliomas.

  6. Comparative evaluation of gadoteridol versus gadopentetate dimeglumine for contrast-enhanced MRI in a rat brain glioma model at 1.5 and 3.0 T%钆特醇及钆喷替酸葡甲胺在1.5、3.0 TMR下鼠脑胶质瘤模型增强扫描中的应用比较研究

    Institute of Scientific and Technical Information of China (English)

    艾飞; Val M Runge; John N Morelli; Lan.Vu; Jeremy Cannel; Alan T Loynachan; 漆剑频; 李小明

    2010-01-01

    计学意义(t值分别为31.503、5.137,P值均<0.05),而两者CE均值差异无统计学意义(t=2.033,P>0.05).结论 利用鼠脑胶质瘤模型,在1.5及3.0 T MR下注射钆特醇和Gd-DTPA行增强扫描,两者增强效果无明显差异;3.0 T MR下注射钆特醇行增强扫描,效果明显优于在1.5 T条件下使用;3.0 T MR下使用半剂量钆特醇与在1.5 T下使用标准剂量增强效果相仿,同样能取得满意的增强效果.因此,使用钆特醇可在保证增强效果的同时,在一定程度上降低使用MRI对比剂的风险,增加安全性.%Objective To compare gadoteridol and gadopentetate dimeglumine (Gd-DTPA) with respect to lesion enhancement in a rat brain glioma model at 1.5 and 3.0 T. Methods Glioma cells were injected into the brains of 42 male CDF ( Fisher 344) rats through implanted cannula to create Glioma animal model. One week after implantation, all rats were randomly divided in to four groups which included 12,10,10,10 rats. The comparisons included the contrast effect of gadoteridol versus gadopentetate dimeglumine at both 1.5 and 3.0 T. In addition, gadoteridol alone was evaluated by comparing the standard dose at both two field strengths and half dose at 3.0 T to a standard full dose at 1.5 T. Two MRI scans for different contrast agent injections were performed in each animal model with an interval of 24 hours. T1 -weighted images were analyzed pre-contrast and at five time points ( 1, 3, 5, 7 and 9 min) post-contrast with respect to lesion signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and contrast enhancement (CE). Student t test was used for statistics. Results The mean SNR, CNR, and CE were respectively 54. 4 ± 3. 2, 17.0 ± 3.3 and 20. 8 ± 3.4 with gadopentetate dimeglumine versus 53.2 ± 3.2, 17.2 ± 3. 1 and 20. 8 ± 3.2 with gadoteridol at 1.5 T at every postcontrast time point ( t = 2. 247, 0. 403, 0. 076, P > 0. 05 ). The mean SNR, CNR, and CE were respectively 94.8 ± 7.1, 38.0 ± 6.0 and 45.0 ± 6.3 with

  7. Critical Neural Networks in Awake Surgery for Gliomas

    Science.gov (United States)

    KINOSHITA, Masashi; MIYASHITA, Katsuyoshi; TSUTSUI, Taishi; FURUTA, Takuya; NAKADA, Mitsutoshi

    2016-01-01

    From the embarrassing character commonly infiltrating eloquent brain regions, the surgical resection of glioma remains challenging. Owing to the recent development of in vivo visualization techniques for the human brain, white matter regions can be delineated using diffusion tensor imaging (DTI) as a routine clinical practice in neurosurgery. In confirmation of the results of DTI tractography, a direct electrical stimulation (DES) substantially influences the investigation of cortico-subcortical networks, which can be identified via specific symptoms elicited in the concerned white matter tracts (eg., the arcuate fascicle, superior longitudinal fascicles, inferior fronto-occipital fascicle, inferior longitudinal fascicle, frontal aslant tract, sensori-motor tracts, optic radiation, and so forth). During awake surgery for glioma using DES, it is important to identify the anatomo-functional structure of white matter tracts to identify the surgical boundaries of brain regions not only to achieve maximal resection of the glioma but also to maximally preserve quality of life. However, the risk exists that neurosurgeons may be misled by the inability of DTI to visualize the actual anatomy of the white matter fibers, resulting in inappropriate decisions regarding surgical boundaries. This review article provides information of the critical neuronal network that is necessary to identify and understand in awake surgery for glioma, with special references to white matter tracts and the author’s experiences. PMID:27250817

  8. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma.

    Science.gov (United States)

    Bhat, Krishna P L; Salazar, Katrina L; Balasubramaniyan, Veerakumar; Wani, Khalida; Heathcock, Lindsey; Hollingsworth, Faith; James, Johanna D; Gumin, Joy; Diefes, Kristin L; Kim, Se Hoon; Turski, Alice; Azodi, Yasaman; Yang, Yuhui; Doucette, Tiffany; Colman, Howard; Sulman, Erik P; Lang, Frederick F; Rao, Ganesh; Copray, Sjef; Vaillant, Brian D; Aldape, Kenneth D

    2011-12-15

    Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression and aberrant osteoblastic and chondrocytic differentiation in a TEAD-dependent fashion. Using chromatin immunoprecipitation (ChIP), we show that TAZ is directly recruited to a majority of MES gene promoters in a complex with TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with platelet-derived growth factor-B (PDGF-B) resulted in high-grade tumors with MES features in a murine model of glioma. Our studies uncover a direct role for TAZ and TEAD in driving the MES differentiation of malignant glioma.

  9. Human pontine glioma cells can induce murine tumors

    NARCIS (Netherlands)

    Caretti, V.; Sewing, A.C.; Lagerweij, T.; Schellen, P.; Bugiani, M.; Jansen, M.H.; Vuurden, D.G. van; Navis, A.C.; Horsman, I.; Vandertop, W.P.; Noske, D.P.; Wesseling, P.; Kaspers, G.J.L.; Nazarian, J.; Vogel, H.; Hulleman, E.; Monje, M.; Wurdinger, T.

    2014-01-01

    Diffuse intrinsic pontine glioma (DIPG), with a median survival of only 9 months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop

  10. Mutant tristetraprolin: a potent inhibitor of malignant glioma cell growth

    Science.gov (United States)

    Malignant gliomas rely on the production of certain critical growth factors including VEGF, interleukin (IL)-6 and IL-8, to fuel rapid tumor growth, angiogenesis, and treatment resistance. Post-transcriptional regulation through adenine and uridine-rich elements of the 3' untranslated region is one ...

  11. Levetiracetam improves verbal memory in high-grade glioma patients

    NARCIS (Netherlands)

    de Groot, Marjolein; Douw, Linda; Sizoo, Eefje M; Bosma, Ingeborg; Froklage, Femke E; Heimans, Jan J; Postma, Tjeerd J; Klein, Martin; Reijneveld, Jaap C

    2013-01-01

    BACKGROUND: Treatment of high-grade glioma (HGG) patients with anti-epileptic drugs (AEDs) has met with various side effects, such as cognitive deterioration. The cognitive effects of both older and newer AEDs in HGG patients are largely unknown. The aim of this study was to determine the effect of

  12. Targeted therapies for malignant gliomas: novel agents, same barrier

    NARCIS (Netherlands)

    Lin, F.

    2013-01-01

    Malignant gliomas are common and devastating brain malignancies. Despite this extensive treatment the mean overall survival is still only 14.6 months and more effective treatments are urgently needed. Targeted therapy holds the promise for the new generation of chemotherapy due to the selectively ta

  13. Glioma surgery in eloquent areas : can we preserve cognition?

    NARCIS (Netherlands)

    Satoer, Djaina; Visch-Brink, Evy; Dirven, Clemens; Vincent, Arnaud

    2015-01-01

    BACKGROUND: Cognitive preservation is crucial in glioma surgery, as it is an important aspect of daily life functioning. Several studies claimed that surgery in eloquent areas is possible without causing severe cognitive damage. However, this conclusion was relatively ungrounded due to the lack of e

  14. Glioma surgery in eloquent areas: can we preserve cognition?

    NARCIS (Netherlands)

    D.D. Satoer (Djaina); E.G. Visch-Brink (Evy); C.M.F. Dirven (Clemens); A. Vincent (Audrey)

    2016-01-01

    textabstractBackground: Cognitive preservation is crucial in glioma surgery, as it is an important aspect of daily life functioning. Several studies claimed that surgery in eloquent areas is possible without causing severe cognitive damage. However, this conclusion was relatively ungrounded due to t

  15. Gliomas and the vascular fragility of the blood brain barrier

    Directory of Open Access Journals (Sweden)

    Luiz Gustavo eDubois

    2014-12-01

    Full Text Available Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB. By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM, characterized by a highly heterogeneous cell population (including tumor stem cells, extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the blood brain barrier and the concerns that arise when this barrier is affected.

  16. An unusual cystic appearance of disseminated low-grade gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Huang, T.; Zimmerman, R.A. [Dept. of Radiology, Children' s Hospital of Philadelphia, PA (United States); Perilongo, G. [Dipt. di Pediatria, Univ. di Padova (Italy); Kaufman, B.A. [Dept. of Neurosurgery, St Louis Children' s Hospital, St Louis, MO (United States); Holden, K.R. [Division of Pediatric Neurology, Room 511, Children' s Hospital, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425-2232 (United States); Carollo, C. [Division of Neuroradiology, Regione Veneto, Azienda Ospedalieri di Padova, Universita di Padova, Via Giustiniani 3, 35 128 Padua (Italy); Kling Chong, W.K. [Dept. of Radiology, Great Ormond Street Hospital for Children, London (United Kingdom)

    2001-10-01

    We report five cases of pediatric disseminated low-grade gliomas of the brainstem or spinal cord that exhibited an unusual, cystic pattern. Leptomeningeal disease was present in three of these at diagnosis, and was detected shortly afterwards in the other two. Four patients are alive up to 5 years later, following minimal to no intervention, while one is dead. (orig.)

  17. Glioma surgery in eloquent areas : can we preserve cognition?

    NARCIS (Netherlands)

    Satoer, Djaina; Visch-Brink, Evy; Dirven, Clemens; Vincent, Arnaud

    2015-01-01

    BACKGROUND: Cognitive preservation is crucial in glioma surgery, as it is an important aspect of daily life functioning. Several studies claimed that surgery in eloquent areas is possible without causing severe cognitive damage. However, this conclusion was relatively ungrounded due to the lack of

  18. Glioma surgery in eloquent areas: can we preserve cognition?

    NARCIS (Netherlands)

    D.D. Satoer (Djaina); E.G. Visch-Brink (Evy); C.M.F. Dirven (Clemens); A. Vincent (Audrey)

    2016-01-01

    markdownabstract__Background:__ Cognitive preservation is crucial in glioma surgery, as it is an important aspect of daily life functioning. Several studies claimed that surgery in eloquent areas is possible without causing severe cognitive damage. However, this conclusion was relatively ungrounded

  19. Prognostic Marker before Treatment of Patients with Malignant Glioma

    Directory of Open Access Journals (Sweden)

    Norbert Galldiks

    2012-11-01

    Full Text Available The purpose of this positron emission tomography (PET study was to compare the prognostic value of pretreatment volume of [11C] methionine (MET uptake and semiquantitative MET uptake ratio in patients with malignant glioma. The study population comprised 40 patients with malignant glioma. Pretreatment magnetic resonance imaging (MRI and MET-PET imaging were performed before the initiation of glioma treatment in all patients. The pretreatment MET uptake ratios and volumes were assessed. To create prognostically homogeneous subgroups, patients′ pretreatment prognostic factors were stratified according to the six classes of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA. Univariate and multivariate analyses were performed to determine significant prognostic factors. Survival analyses identified the pretreatment volume of MET uptake and a higher RTOG RPA class as significant predictors. In contrast, pretreatment maximum areas of contrast enhancement on MRI and semiquantitative MET uptake ratios could not be identified as significant prognostic factors. The patients′ outcomes and Karnofsky Performance Scale scores were significantly correlated with pretreatment volume of MET uptake but not with semiquantitative MET uptake ratio. The data suggest that pretreatment volumetry of MET uptake but not the semiquantitative MET uptake ratio is a useful biologic prognostic marker in patients with malignant glioma.

  20. Growth hormone and cancer: GH production and action in glioma?

    Science.gov (United States)

    Lea, Robert W; Dawson, Timothy; Martinez-Moreno, Carlos G; El-Abry, Nasra; Harvey, Steve

    2015-09-01

    The hypersecretion of pituitary growth hormone (GH) is associated with an increased risk of cancer, while reducing pituitary GH signaling reduces this risk. Roles for pituitary GH in cancer are therefore well established. The expression of the GH gene is, however, not confined to the pituitary gland and it is now known to occur in many extrapituitary tissues, in which it has local autocrine or paracrine actions, rather than endocrine function. It is, for instance, expressed in cancers of the prostate, lung, skin, endometrium and colon. The oncogenicity of autocrine GH may also be greater than that induced by endocrine or exogenous GH, as higher concentrations of GHR antagonists are required to inhibit its actions. This may reflect the fact that autocrine GH is thought to act at intracellular receptors directly after synthesis, in compartments not readily accessible to endocrine (or exogenous) GH. The roles and actions of extrapituitary GH in cancer may therefore differ from those of pituitary GH. The possibility that GH may be expressed and act in glioma tumors was therefore examined by immunohistochemistry. These results demonstrate, for the first time, the presence of abundant GH- and GH receptor (GHR-) immunoreactivity in glioma, in which they were co-localized in cytoplasmic but not nuclear compartments. These results demonstrate that glioma differs from most cancers in lacking nuclear GHRs, but GH is nevertheless likely to have autocrine or paracrine actions in the induction and progression of glioma.

  1. Convection-enhanced Delivery of Therapeutics for Malignant Gliomas

    Science.gov (United States)

    SAITO, Ryuta; TOMINAGA, Teiji

    2017-01-01

    Convection-enhanced delivery (CED) circumvents the blood–brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future. PMID:27980285

  2. Gliomas and the vascular fragility of the blood brain barrier

    Science.gov (United States)

    Dubois, Luiz Gustavo; Campanati, Loraine; Righy, Cassia; D’Andrea-Meira, Isabella; Spohr, Tania Cristina Leite de Sampaio e; Porto-Carreiro, Isabel; Pereira, Claudia Maria; Balça-Silva, Joana; Kahn, Suzana Assad; DosSantos, Marcos F.; Oliveira, Marcela de Almeida Rabello; Ximenes-da-Silva, Adriana; Lopes, Maria Celeste; Faveret, Eduardo; Gasparetto, Emerson Leandro; Moura-Neto, Vivaldo

    2014-01-01

    Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the BBB and the concerns that arise when this barrier is affected. PMID:25565956

  3. A Neuroblastoma × Glioma Hybrid Cell Line with Morphine Receptors

    Science.gov (United States)

    Klee, Werner A.; Nirenberg, Marshall

    1974-01-01

    A neuroblastoma × glioma hybrid cell line with well-developed neural properties was found that has high-affinity morphine receptors. The average cell contains approximately 3 × 106 receptors. In contrast, parent cells and other neuroblastoma or hybrid cell lines tested had few or no morphine receptors. PMID:4530316

  4. Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy

    Directory of Open Access Journals (Sweden)

    Gregory K Friedman

    2013-02-01

    Full Text Available While glioblastoma multiforme (GBM is the most common adult malignant brain tumor, GBMs in childhood represent less than 10% of pediatric malignant brain tumors and are phenotypically and molecularly distinct from adult GBMs. Similar to adult patients, outcomes for children with high-grade gliomas (HGGs remain poor. Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies. Poor outcomes have been attributed to a subpopulation of chemotherapy and radiotherapy resistant cells, termed ‘glioma stem cells’ (GSCs, ‘glioma progenitor cells’, or ‘glioma-initiating cells', which have the ability to initiate and maintain the tumor and to repopulate the recurring tumor after conventional therapy. Future innovative therapies for pediatric HGGs must be able to eradicate these therapy-resistant GSCs. Oncolytic herpes simplex viruses, genetically engineered to be safe for normal cells and to express diverse foreign anti-tumor therapeutic genes, have been demonstrated in preclinical studies to infect and kill GSCs and tumor cells equally while sparing normal brain cells. In this review, we discuss the unique aspects of pediatric GSCs, including markers to identify them, the microenvironment they reside in, signaling pathways that regulate them, mechanisms of cellular resistance, and approaches to target GSCs, with a focus on the promising therapeutic, genetically engineered oncolytic herpes simplex virus (HSV.

  5. Epileptic seizures in patients with glioma: A single centre- based ...

    African Journals Online (AJOL)

    Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights ... Results: Preoperative seizures were noted in 33.8 % of glioma patients. ..... adverse effects and in any case, it is important to ... data or proper documentation. .... brain tumour-related epilepsy: seizure control, safety,.

  6. Senescence from glioma stem cell differentiation promotes tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Ouchi, Rie [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Okabe, Sachiko; Migita, Toshiro [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Nakano, Ichiro [Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35233 (United States); Seimiya, Hiroyuki, E-mail: hseimiya@jfcr.or.jp [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan)

    2016-02-05

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  7. [Gliomas and BRCA genes mutations: fortuitous association or imputability?].

    Science.gov (United States)

    Girardstein-Boccara, Laura; Mari, Véronique; Met-Domestici, Marie; Burel-Vandenbos, Fanny; Berthet, Pascaline; Paquis, Philippe; Frenay, Marc Paul; Lebrun-Frenay, Christine

    2014-09-01

    BRCA is a tumor suppressor gene implicated in the major mechanisms of cellular stability in every type of cell. Its mutations are described in numerous cancers, mainly breast and ovarian in women. It was also found an increase of lifetime risk of pancreas, colon, prostate cancer or lymphoma in men carriers. We report the cases of two female patients aged 40 and 58-years-old female patients and one 35-years-old male patient, with brain or medullar gliomas, carriers of a germline mutation of BRCA gene. Those gliomas were particularly aggressive and were not responding to the standard treatment, with chemo and radiotherapy. The very unusual characteristics in location and evolutive profile of these central nervous system tumors raise the question of a genetical underlying mechanism, maybe linked to the BRCA gene mutation that carry these patients. In addition, a non-fortuitous association between germline mutation of BRCA and occurrence of a glioma can be evoked according to the embryological, epidemiological and biomolecular findings noted in the literature. Other clinical and experimental studies are necessary to precise the physiopathological link existing between BRCA mutations and the occurrence of a glioma; this could have therapeutical and clinical implications in the future.

  8. Levetiracetam improves verbal memory in high-grade glioma patients

    NARCIS (Netherlands)

    de Groot, Marjolein; Douw, Linda; Sizoo, Eefje M; Bosma, Ingeborg; Froklage, Femke E; Heimans, Jan J; Postma, Tjeerd J; Klein, Martin; Reijneveld, Jaap C

    BACKGROUND: Treatment of high-grade glioma (HGG) patients with anti-epileptic drugs (AEDs) has met with various side effects, such as cognitive deterioration. The cognitive effects of both older and newer AEDs in HGG patients are largely unknown. The aim of this study was to determine the effect of

  9. Expression and Prognostic Significance of p53 in Glioma Patients: A Meta-analysis.

    Science.gov (United States)

    Jin, Yueling; Xiao, Weizhong; Song, Tingting; Feng, Guangjia; Dai, Zhensheng

    2016-07-01

    Glioma is a brain tumor deriving from the neoplastic glial cells or neuroglia. Due to its resistance to anticancer drugs and different disease progress of individuals, patients with high-grade glioma are difficult to completely cure, leading to a poor prognosis and low overall survival. Therefore, there is an urgent need to look for prognostic and diagnostic indicators that can predict glioma grades. P53 is one of the widely studied biomarkers in human glioma. The purpose of this study was to comprehensively evaluate the significance of p53 expression in glioma grades and overall survival. We searched commonly used electronic databases to retrieve related articles of p53 expression in glioma. Overall, a total of 21 studies including 1322 glioma patients were finally screened out. We observed that the frequency of p53 immuno-positivity was higher in high-grade patients than that in low-grade category (63.8 vs. 41.6 %), and our statistic analysis indicated that p53 expression was associated with pathological grade of glioma (OR 2.93, 95 % CI 1.87-4.60, P p53 expression in patients with glioma. In conclusion, our results suggested that p53 immunohistochemical expression might have an effective usefulness in predicting the prognosis in patients with glioma.

  10. Upregulation of B23 promotes tumor cell proliferation and predicts poor prognosis in glioma

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Jianguo [Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu Province (China); Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu Province (China); Sun, Jie; Yang, Liu; Yan, Yaohua; Shi, Wei; Shi, Jinlong; Huang, Qingfeng; Chen, Jian [Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu Province (China); Lan, Qing, E-mail: lanqingsj@163.com [Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu Province (China)

    2015-10-09

    B23 (also known as Nucleophosmin, NPM, numatrin or NO38) is a ubiquitously expressed phosphoprotein belonging to the nucleoplasmin family of chaperones. In this study we intended to investigate the clinical significance of B23 expression in human glioma and its biological function in glioma cells. Western blot and immunohistochemistry analysis showed that B23 was overexpressed in glioma tissues and glioma cell lines. In addition, the expression level of B23 was positively correlated with glioma pathological grade and Ki-67 expression. Kaplan–Meier analysis revealed that a higher B23 expression in patients with glioma was associated with a poorer prognosis. In vitro, after the release of glioma cell lines from serum starvation, the expression of B23 was upregulated, as well as PCNA (Proliferating Cell Nuclear Antigen) and cyclin A. In addition, knockdown of B23 by small interfering RNA transfection diminished the expression of PCNA, cyclin D1 and arrested cell growth at G1 phase. Taken together, our results implied that B23 could be a candidate prognostic biomarker as well as a potential therapeutical target of glioma. - Highlights: • B23 expression increased as the malignant degree of glioma increased, which was consistent with Ki-67 expression. • High expression of B23 could be a strong determinant of poor prognosis in glioma. • B23 may be involved in the proliferation of glioma in a cell-cycle-dependent pathway. • Knockdown of B23 expression by siRNA could affect the progression of glioma. • B23 may be a potential prognosis biomarker and a possible therapeutic target for glioma.

  11. Slit2 inhibits glioma cell invasion in the brain by suppression of Cdc42 activity.

    Science.gov (United States)

    Yiin, Jia-Jean; Hu, Bo; Jarzynka, Michael J; Feng, Haizhong; Liu, Kui-Wei; Wu, Jane Y; Ma, Hsin-I; Cheng, Shi-Yuan

    2009-12-01

    Acquisition of insidious invasiveness by malignant glioma cells involves multiple genetic alterations in signaling pathways. Slit2, a chemorepulsive factor, controls cell migration of neuronal and glial cells during development and inhibits chemotaxic migration of various types of cells in vitro. However, the role of Slit2 in vitro remains controversial, and the biological significance of Slit2 expression in cancer cell invasion in vivo has not yet been determined. In the present study, we characterized the effects of Slit2 expression on the migration and invasion of invasive glioma cells in vitro and in vivo. By reverse transcriptase polymerase chain reaction (PCR) analyses, Slit2 was found to be expressed at lower levels in primary glioma specimens and invasive glioma cells compared with normal human brain cells and astrocytes. Ectopic expression of Slit2 or treatment with recombinant Slit2 on glioma cells attenuates cell migration and invasion through inhibition of Cdc42 activity in vitro. Cellular depletion of Robo1, a cognate receptor for Slit2, prevented Slit2 inhibition of Cdc42 activity and glioma cell migration. In vivo, expression of Slit2 by invasive SNB19 glioma cells markedly inhibited glioma cell infiltration into the brain of mice. Moreover, impediment of glioma cell invasion by Slit2 did not affect the expression of N-cadherin and beta-catenin in glioma cells. These results provide the first evidence demonstrating that Slit2-Robo1 inhibits glioma invasion through attenuating Cdc42 activity in vitro and in the brain. Understanding the mechanisms of Slit2-Robo1 inhibition of glioma cell invasion will foster new treatments for malignant gliomas.

  12. Association between Prediagnostic Allergy-Related Serum Cytokines and Glioma.

    Directory of Open Access Journals (Sweden)

    Judith Schwartzbaum

    Full Text Available Allergy is inversely related to glioma risk. To determine whether prediagnostic allergy-related serum proteins are associated with glioma, we conducted a nested case-control study of seven cytokines (IL4, IL13, IL5, IL6, IL10, IFNG, TGFB2, two soluble cytokine receptors (sIL4RA, sIL13RA2 and three allergy-related transcription factors (FOXP3, STAT3, STAT6 using serum specimens from the Janus Serum Bank Cohort in Oslo, Norway. Blood donors subsequently diagnosed with glioma (n = 487 were matched to controls (n = 487 on age and date of blood draw and sex. We first estimated individual effects of the 12 serum proteins and then interactions between IL4 and IL13 and their receptors using conditional logistic regression. We next tested equality of case-control inter-correlations among the 12 serum proteins. We found that TGFB2 is inversely related to glioblastoma (Odds Ratio (OR = 0.87, 95% Confidence Interval (CI = 0.76, 0.98. In addition, ≤ 5 years before diagnosis, we observed associations between IL4 (OR = 0.82, 95% CI = 0.66, 1.01, sIL4RA (OR = 0.80, 95% CI = 0.65, 1.00, their interaction (OR = 1.06, 95% CI = 1.01, 1.12 and glioblastoma. This interaction was apparent > 20 years before diagnosis (IL4-sIL4RA OR = 1.20, 95% CI = 1.05, 1.37. Findings for glioma were similar. Case correlations were different from control correlations stratified on time before diagnosis. Five years or less before diagnosis, correlations among case serum proteins were weaker than were those among controls. Our findings suggest that IL4 and sIL4RA reduce glioma risk long before diagnosis and early gliomagenesis affects circulating immune function proteins.

  13. ECHOGRAPHIC PICTURE OF OPTIC NERVE GLIOMA IN NEUROFIBROMATOSIS TYPE-1

    Directory of Open Access Journals (Sweden)

    Biljana Kuzmanović

    2002-12-01

    Full Text Available Background. Authors want to present echographic picture of orbital part of low-grade pilocytic astrocytoma involving the optic nerve and/or chiasm and optic tract (optic pathway glioma or visual pathway glioma.Methods. 4 children with neurofibromatosis type-1 complicated with optic pathway glioma diagnosed earlier with magnetic resonance were examined by ultrasound. Standardised A-scan technique was used for optic nerve width measurement. The 30° test and B-scan (axial, transverse and longitudinal sections of both eyes and orbits were performed as well.Results. The optic nerve diameter in our cases ranged from 4.48 to 8.5 mm. Two children had the left side optic pathway glioma, one boy had the right side optic pathway glioma and in one tumour was bilateral. The transversal section of the nerve revealed dark oval and in more perpendicular sections round void of the nerve. As the beam is swept towards the orbital apex void becomes more fusiform. The nerve and its sheaths are markedly widened. An abnormal increase in reflectivity and irregularity of the spike’s pattern is exhibited as well. No calcification along the sheaths is noticed. The transverse section of the tumour demonstrated an »inverse doughnut« sign. The outer whiter outline of the widened sheaths surrounds an inner darker circle. The longitudinal section revealed the optic nerve head continuing into the widened optic nerve. The 30° test was negative. The differential diagnosis of meningeoma, optic neuritis and orbital cysticercosis should be considered.Conclusions. Ultrasound as a cheap, safe, easily repeatable imaging method should become a method of choice for screening optic nerve tumours in neurofibromatosis type-1, especially in children, as well as for follow-up after treatment.

  14. Innate immune functions of microglia isolated from human glioma patients

    Directory of Open Access Journals (Sweden)

    Grimm Elizabeth

    2006-03-01

    Full Text Available Abstract Background Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; however, it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. We therefore undertook a novel characterization of the innate immune phenotype and function of freshly isolated human glioma-infiltrating microglia (GIM. Methods GIM were isolated by sequential Percoll purification from patient tumors immediately after surgical resection. Flow cytometry, phagocytosis and tumor cytotoxicity assays were used to analyze the phenotype and function of these cells. Results GIM expressed significant levels of Toll-like receptors (TLRs, however they do not secrete any of the cytokines (IL-1β, IL-6, TNF-α critical in developing effective innate immune responses. Similar to innate macrophage functions, GIM can mediate phagocytosis and non-MHC restricted cytotoxicity. However, they were statistically less able to mediate tumor cytotoxicity compared to microglia isolated from normal brain. In addition, the expression of Fas ligand (FasL was low to absent, indicating that apoptosis of the incoming lymphocyte population may not be a predominant mode of immunosuppression by microglia. Conclusion We show for the first time that despite the immunosuppressive environment of human gliomas, GIM are capable of innate immune responses such as phagocytosis, cytotoxicity and TLR expression but yet are not competent in secreting key cytokines. Further understanding of these innate immune functions could play a critical role in understanding and developing effective immunotherapies to malignant human gliomas.

  15. Mesenchymal stem cells deliver synthetic microRNA mimics to glioma cells and glioma stem cells and inhibit their cell migration and self-renewal.

    Science.gov (United States)

    Lee, Hae Kyung; Finniss, Susan; Cazacu, Simona; Bucris, Efrat; Ziv-Av, Amotz; Xiang, Cunli; Bobbitt, Kevin; Rempel, Sandra A; Hasselbach, Laura; Mikkelsen, Tom; Slavin, Shimon; Brodie, Chaya

    2013-02-01

    MicroRNAs (miRNAs) have emerged as potential cancer therapeutics; however, their clinical use is hindered by lack of effective delivery mechanisms to tumor sites. Mesenchymal stem cells (MSCs) have been shown to migrate to experimental glioma and to exert anti-tumor effects by delivering cytotoxic compounds. Here, we examined the ability of MSCs derived from bone marrow, adipose tissue, placenta and umbilical cord to deliver synthetic miRNA mimics to glioma cells and glioma stem cells (GSCs). We examined the delivery of miR-124 and miR-145 mimics as glioma cells and GSCs express very low levels of these miRNAs. Using fluorescently labeled miRNA mimics and in situ hybridization, we demonstrated that all the MSCs examined delivered miR-124 and miR-145 mimics to co-cultured glioma cells and GSCs via gap junction- dependent and independent processes. The delivered miR-124 and miR-145 mimics significantly decreased the luciferase activity of their respected reporter target genes, SCP-1 and Sox2, and decreased the migration of glioma cells and the self-renewal of GSCs. Moreover, MSCs delivered Cy3-miR-124 mimic to glioma xenografts when administered intracranially. These results suggest that MSCs can deliver synthetic exogenous miRNA mimics to glioma cells and GSCs and may provide an efficient route of therapeutic miRNA delivery in vivo.

  16. Fusions of Dendritic Cells and C6 Cells Transfected with TGF-β1 Antisense in Treatment of Intracranial Gliomas

    Institute of Scientific and Technical Information of China (English)

    Jin Gui-shan; Liu Fu-sheng; Chai Qi; Wang Jian-jao; Li Jun-hua

    2007-01-01

    Objective: To investigate the immunotherapy efficacy of fusion cells (dendritic-C6anti-TGF-β1 cells) in the treatment of intracranial gliomas. Methods: Dendritic cells were isolated from rat bone-marrow precursors stimulated in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and Interleukin-4 (IL-4). C6anti-TGF-β1 cells originally from C6 cell line of a rat glioblastoma were transfected with plasmid of TGF-β1 anti-sense gene. Fusions of dendritic cells and C6anti-TGF-β1 cells were prepared by polyethylene glycol (PEG). The DC/C6anti-TGF-β1 fusion cells were observed and confirmed by light microscopy and scanning electron microscopy. Experimental rats were divided into three groups at random: C6 cells (Ⅰ), dendritic-C6anti-TGF-β1 fusion cells and C6 cells (Ⅱ) and IMDM medium only (Ⅲ). The cells were injected into right parietal lobe region of the rat with stereotaxic technique. Histology, tumor necrosis and survival time were evaluated. Results: Compared with the rats that received C6 cells (survival median time was less than 20 days, tumor region was seen in all fields of observed), the rats injected with dendritic-C6anti-TGF-β1 fusion cells and C6 cells got a more prolonged life span (more than 59 days), as well as less tumor region (5.01%-6.2%). There was no tumor necrosis, but some glias were seen in surroundings. All rats were survived and no necrosis was observed in negative control group. Statistical analysis showed that group Ⅱ had significant difference compared with group Ⅰ. Conclusions: Dendritic-C6anti-TGF-β1 fusion cells could prolong the life span of rats, providing a strategy to achieve an antitumor response against tumors in the central nervous system.

  17. S100B-p53 disengagement by pentamidine promotes apoptosis and inhibits cellular migration via aquaporin-4 and metalloproteinase-2 inhibition in C6 glioma cells.

    Science.gov (United States)

    Capoccia, Elena; Cirillo, Carla; Marchetto, Annalisa; Tiberi, Samanta; Sawikr, Youssef; Pesce, Marcella; D'Alessandro, Alessandra; Scuderi, Caterina; Sarnelli, Giovanni; Cuomo, Rosario; Steardo, Luca; Esposito, Giuseppe

    2015-06-01

    S100 calcium-binding protein B (S100B) is highly expressed in glioma cells and promotes cancer cell survival via inhibition of the p53 protein. In melanoma cells, this S100B-p53 interaction is known to be inhibited by pentamidine isethionate, an antiprotozoal agent. Thus, the aim of the present study was to evaluate the effect of pentamidine on rat C6 glioma cell proliferation, migration and apoptosis in vitro. The change in C6 cell proliferation following treatment with pentamidine was determined by performing a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide-formazan assay. Significant dose-dependent decreases in proliferation were observed at pentamidine concentrations of 0.05 µM (58.5±5%; Ppentamidine was associated with a significant increase in apoptosis versus the untreated cells, as determined by DNA fragmentation assays, immunofluorescence analysis of C6 chromatin using Hoechst staining, and immunoblot analysis of B-cell lymphoma-2 (Bcl-2)-associated X protein (100%, Ppentamidine significantly upregulated the protein expression levels of p53 (681±87.5%, Ppentamidine compared with untreated cells (88±4.2%, Ppentamidine and S100B-p53 inhibitors may represent a novel approach for the treatment of glioma.

  18. The relation of consciousness level and cerebral blood flow in glioma and meningioma

    Energy Technology Data Exchange (ETDEWEB)

    Oyama, Hirofumi; Niwa, Masahiro; Kida, Yoshihisa; Tanaka, Takayuki; Maezawa, Satoshi; Kobayashi, Tatsuya [Komaki City Hospital, Nagoya (Japan)

    1997-03-01

    The relation between the consciousness level and cerebral blood flow (CBF) was analyzed in 17 cases of glioma and 6 cases of meningioma. CBF was in normal range in the alert groups of patients with glioma and meningioma. By contrast, CBF decreased generally not only in the affected side, but also in the non-affected side in the drowsy patient group with glioma. Widespread infiltration of glioma was seen in 4 cases of 6 drowsy cases. CBF increased after the partial resection of the tumor in 2 cases of glioma. Thus the disturbance of consciousness level was attributable to diffuse hypofunction accompanying the diffuse infiltration of glioma and the decrease of cerebral perfusion pressure caused by the increased intracranial pressure. (author)

  19. Neural progenitor and hemopoietic stem cells inhibit the growth of low-differentiated glioma.

    Science.gov (United States)

    Baklaushev, V P; Grinenko, N F; Savchenko, E A; Bykovskaya, S N; Yusubalieva, G M; Viktorov, I V; Bryukhovetskii, A S; Bryukhovetskii, I S; Chekhonin, V P

    2012-02-01

    The effects of neural progenitor and hemopoietic stem cells on C6 glioma cells were studied in in vivo and in vitro experiments. Considerable inhibition of proliferation during co-culturing of glioma cells with neural progenitor cells was revealed by quantitative MTT test and bromodeoxyuridine incorporation test. Labeled neural progenitor and hemopoietic stem cells implanted into the focus of experimental cerebral glioma C6 survive in the brain of experimental animals for at least 7 days, migrate with glioma cells, and accumulate in the peritumoral space. Under these conditions, neural progenitor cells differentiate with the formation of long processes. Morphometric analysis of glioma cells showed that implantation of neural progenitor and hemopoietic stem cells is accompanied by considerable inhibition of the growth of experimental glioma C6 in comparison with the control. The mechanisms of tumor-suppressive effects of neural and hemopoietic stem cells require further investigation.

  20. Expression of metastasis-associated protein 3 in human brain glioma related to tumor prognosis.

    Science.gov (United States)

    Shan, Shouqin; Hui, Guangyan; Hou, Fanggao; Shi, Hua; Zhou, Guoqing; Yan, Han; Wang, Lu; Liu, Jinfeng

    2015-10-01

    Glioma represents a disparate group of tumors characterized by high invasion ability, and therefore it is of clinical significance to identify molecular markers and therapeutic targets for better clinical management. Previously, metastasis-associated protein family (MTA) is considered to promote tumor cell invasion and metastasis of human malignancies. Recently, the newly identified MTA3 has been shown to play conflicting roles in human malignancies, while the expression pattern and potential clinical significance of MTA3 in human glioma have not been addressed yet. In the present study, we investigated the protein expression of MTA3 by immunohistochemistry assay and analyzed its association with glioma prognosis in 186 cases of patients. Results showed that MTA3 expression was decreased in glioma compared with that in normal brain (P human glioma and negatively associated with prognosis of patients, suggesting that MTA3 may play a tumor suppressor role in glioma.

  1. Light-controlled inhibition of malignant glioma by opsin gene transfer

    Science.gov (United States)

    Yang, F; Tu, J; Pan, J-Q; Luo, H-L; Liu, Y-H; Wan, J; Zhang, J; Wei, P-F; Jiang, T; Chen, Y-H; Wang, L-P

    2013-01-01

    Glioblastomas are aggressive cancers with low survival rates and poor prognosis because of their highly proliferative and invasive capacity. In the current study, we describe a new optogenetic strategy that selectively inhibits glioma cells through light-controlled membrane depolarization and cell death. Transfer of the engineered opsin ChETA (engineered Channelrhodopsin-2 variant) gene into primary human glioma cells or cell lines, but not normal astrocytes, unexpectedly decreased cell proliferation and increased mitochondria-dependent apoptosis, upon light stimulation. These optogenetic effects were mediated by membrane depolarization-induced reductions in cyclin expression and mitochondrial transmembrane potential. Importantly, the ChETA gene transfer and light illumination in mice significantly inhibited subcutaneous and intracranial glioma growth and increased the survival of the animals bearing the glioma. These results uncover an unexpected effect of opsin ion channels on glioma cells and offer the opportunity for the first time to treat glioma using a light-controllable optogenetic approach. PMID:24176851

  2. Methionine and cystine double deprivation stress suppresses glioma proliferation via inducing ROS/autophagy.

    Science.gov (United States)

    Liu, Huailei; Zhang, Weiguang; Wang, Kaikai; Wang, Xiaoxiong; Yin, Fei; Li, Chenguang; Wang, Chunlei; Zhao, Boxian; Zhong, Chen; Zhang, Jiakang; Peng, Fei; Bi, Yunke; Shen, Chen; Hou, Xu; Zhang, Daming; Liu, Yaohua; Ai, Jing; Zhao, Shiguang

    2015-01-22

    Cancer cells are highly dependent on methionine and cystine (Met-Cys) for survival and proliferation. However, the molecular mechanism is not fully clear. The present study is to investigate the effects of Met-Cys deprivation on glioma cells proliferation. The results showed that Met-Cys double deprivation had synergistic action on elevating ROS level, decreased GSH level and inhibition of glioma cell proliferation. Moreover, both of them deprivation triggered autophagy of glioma cells both in vitro and in vivo. Importantly, Met-Cys double restriction diet inhibited growth of glioma. These results provided a new regulation mechanism of Met-Cys metabolism on affecting glioma cell proliferation, suggesting that targeting Met-Cys metabolism may be a potential strategy for glioma therapy.

  3. A three-dimensional collagen scaffold cell culture system for screening anti-glioma therapeutics

    Science.gov (United States)

    Lv, Donglai; Yu, Shi-cang; Ping, Yi-fang; Wu, Haibo; Zhao, Xilong; Zhang, Huarong; Cui, Youhong; Chen, Bing; Zhang, Xia; Dai, Jianwu

    2016-01-01

    Three-dimensional (3D) culture, which can simulate in vivo microenvironments, has been increasingly used to study tumor cell biology. Since most preclinical anti-glioma drug tests still rely on conventional 2D cell culture, we established a collagen scaffold for 3D glioma cell culture. Glioma cells cultured on these 3D scaffolds showed greater degree of dedifferentiation and quiescence than cells in 2D culture. 3D-cultured cells also exhibited enhanced resistance to chemotherapeutic alkylating agents, with a much higher proportion of glioma stem cells and upregulation of O6-methylguanine DNA methyltransferase (MGMT). Importantly, tumor cells in 3D culture showed chemotherapy resistance patterns similar to those observed in glioma patients. Our results suggest that 3D collagen scaffolds are promising in vitro research platforms for screening new anti-glioma therapeutics. PMID:27486877

  4. Chordoid glioma with intraventricular dissemination: A case report with perfusion MR imaging features

    Energy Technology Data Exchange (ETDEWEB)

    Ki, So Yeon; Kim, Seul Kee; Heo, Tae Wook; Baek, Byung Hyun; Kim, Hyung Seok; Yoon, Woong [Chonnam National University Medical School, Chonnam National University Hospital, Gwangju (Korea, Republic of)

    2016-02-15

    Chordoid glioma is a rare low grade tumor typically located in the third ventricle. Although a chordoid glioma can arise from ventricle with tumor cells having features of ependymal differentiation, intraventricular dissemination has not been reported. Here we report a case of a patient with third ventricular chordoid glioma and intraventricular dissemination in the lateral and fourth ventricles. We described the perfusion MR imaging features of our case different from a previous report.

  5. Diffusion kurtosis imaging can efficiently assess the glioma grade and cellular proliferation

    OpenAIRE

    Jiang, Rifeng; Jiang, Jingjing; Zhao, Lingyun; Zhang, Jiaxuan; Zhang, Shun; Yao, Yihao; Yang, Shiqi; Shi, Jingjing; Shen, Nanxi; Su, Changliang; Zhang, Ju; Zhu, Wenzhen

    2015-01-01

    Conventional diffusion imaging techniques are not sufficiently accurate for evaluating glioma grade and cellular proliferation, which are critical for guiding glioma treatment. Diffusion kurtosis imaging (DKI), an advanced non-Gaussian diffusion imaging technique, has shown potential in grading glioma; however, its applications in this tumor have not been fully elucidated. In this study, DKI and diffusion weighted imaging (DWI) were performed on 74 consecutive patients with histopathologicall...

  6. MGMT testing-the challenges for biomarker-based glioma treatment

    OpenAIRE

    Wick, W; Weller, M; Van Den Bent, M.; Sanson, M; Weiler, M.; von Deimling, A.; Plass, C; Hegi, M.; Platten, M.; Reifenberger, G.

    2014-01-01

    Many patients with malignant gliomas do not respond to alkylating agent chemotherapy. Alkylator resistance of glioma cells is mainly mediated by the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in glioma cells compromises this DNA repair mechanism and increases chemosensitivity. MGMT promoter methylation is, therefore, a strong prognostic biomarker in paediatric and adult patients with glioblastoma treated wit...

  7. Silencing of WNK2 is associated with upregulation of MMP2 and JNK in gliomas

    OpenAIRE

    Costa, Angela Margarida; Pinto, Filipe; Martinho, Olga; Oliveira, Maria José; Jordan, Peter; Reis,R.M.

    2014-01-01

    Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix (ECM), thus assisting invasion. Upregulation of MMPs, frequently reported in gliomas, is associated with aggressive behavior. WNK2 is a tumor suppressor gene expressed in normal brain, and silenced by promoter methylation in gliomas. Patients without WNK2 exhibited poor prognosis, and its downregulation was associated with increased glioma cell invasion. Here we showed that MMP2 expression and activity ...

  8. Pharmacokinetics of BPA in gliomas with ultrasound induced blood-brain barrier disruption as measured by microdialysis.

    Directory of Open Access Journals (Sweden)

    Feng-Yi Yang

    Full Text Available The blood-brain barrier (BBB can be transiently disrupted by focused ultrasound (FUS in the presence of microbubbles for targeted drug delivery. Previous studies have illustrated the pharmacokinetics of drug delivery across the BBB after sonication using indirect visualization techniques. In this study, we investigated the in vivo extracellular kinetics of boronophenylalanine-fructose (BPA-f in glioma-bearing rats with FUS-induced BBB disruption by microdialysis. After simultaneous intravenous administration of BPA and FUS exposure, the boron concentration in the treated brains was quantified by inductively coupled plasma mass spectroscopy. With FUS, the mean peak concentration of BPA-f in the glioma dialysate was 3.6 times greater than without FUS, and the area under the concentration-time curve was 2.1 times greater. This study demonstrates that intracerebral microdialysis can be used to assess local BBB transport profiles of drugs in a sonicated site. Applying microdialysis to the study of metabolism and pharmacokinetics is useful for obtaining selective information within a specific brain site after FUS-induced BBB disruption.

  9. Curcumin delivery by methoxy polyethylene glycol-poly(caprolactone) nanoparticles inhibits the growth of C6 glioma cells

    Institute of Scientific and Technical Information of China (English)

    Junfei Shao; Donghui Zheng; Zhifeng Jiang; Huae Xu; Yong Hu; Xiaolin Li; Xiaowei Lu

    2011-01-01

    As a potential anticancer agent, curcumin (Cum) has been reported for its chemopreventive and chemotherapeutic activity in a series of cancers through influencing cell cycle arrest, differentiation, apoptosis, etc. Therefore, the potential activity against various cancers of Cure raises the possibility of its application as a novel model drug in nanopartiele-based delivery systems. The current study reported a spherical core-shell structure curcumin-loaded nanoparticle (Cum-np) formed by amphllic methoxy polyethylene glycolpoly(caprolactone) (mPEG-PCL) block copolymers. Characterization tests indicated that Cum was incorporated into mPEG-PCL-based nanoparticles with high encapsulation efficiency due to its lipophilicity. The incorporated Cum could be released from Cum-np in a sustained manner. Cum was effectively transported into the cells by nanoparticles through endocytosis and localized around the nuclei in the cytoplasms. In vitro studies proved that the cytotoxicity of Cum-np would be pro-apoptosis effect against rat C6 glioma cell line in a dose-dependent manner. The present results suggest that Cum-np could be a potential useful chemotherapeutic formulation for malignant glioma therapy. Moreover, the development of traditional Chinese medicine with nanoscale drug formation warrants more intensive research for its clinical applications.

  10. Glioma-targeted superparamagnetic iron oxide nanoparticles as drug-carrying vehicles for theranostic effects

    Science.gov (United States)

    Xu, He-Lin; Mao, Kai-Li; Huang, Yin-Ping; Yang, Jing-Jing; Xu, Jie; Chen, Pian-Pian; Fan, Zi-Liang; Zou, Shuang; Gao, Zheng-Zheng; Yin, Jia-Yu; Xiao, Jian; Lu, Cui-Tao; Zhang, Bao-Lin; Zhao, Ying-Zheng

    2016-07-01

    Multifunctional nanoparticles capable of the specific delivery of therapeutics to diseased cells and the real-time imaging of these sites have the potential to improve cancer treatment through personalized therapy. In this study, we have proposed a multifunctional nanoparticle that integrate magnetic targeting, drug-carrier functionality and real-time MRI imaging capabilities in one platform for the theranostic treatment of tumors. The multifunctional nanoparticle was designed with a superparamagnetic iron oxide core and a multifunctional shell composed of PEG/PEI/polysorbate 80 (Ps 80) and was used to encapsulate DOX. DOX-loaded multifunctional nanoparticles (DOX@Ps 80-SPIONs) with a Dh of 58.0 nm, a zeta potential of 28.0 mV, and a drug loading content of 29.3% presented superior superparamagnetic properties with a saturation magnetization (Ms) of 24.1 emu g-1. The cellular uptake of DOX@Ps 80-SPIONs by C6 cells under a magnetic field was significantly enhanced over that of free DOX in solution, resulting in stronger in vitro cytotoxicity. The real-time therapeutic outcome of DOX@Ps 80-SPIONs was easily monitored by MRI. Furthermore, the negative contrast enhancement effect of the nanoparticles was confirmed in glioma-bearing rats. Prussian blue staining and ex vivo DOX fluorescence assays showed that the magnetic Ps 80-SPIONs and encapsulated DOX were delivered to gliomas by imposing external magnetic fields, indicating effective magnetic targeting. Due to magnetic targeting and Ps 80-mediated endocytosis, DOX@Ps 80-SPIONs in the presence of a magnetic field led to the complete suppression of glioma growth in vivo at 28 days after treatment. The therapeutic mechanism of DOX@Ps 80-SPIONs acted by inducing apoptosis through the caspase-3 pathway. Finally, DOX@Ps 80-SPIONs' safety at therapeutic dosage was verified using pathological HE assays of the heart, liver, spleen, lung and kidney. Multifunctional SPIONs could be used as potential carriers for the

  11. Retinoids in the treatment of glioma: a new perspective

    Directory of Open Access Journals (Sweden)

    Mawson AR

    2012-08-01

    Full Text Available Anthony R MawsonDepartment of Health Policy and Management, School of Health Sciences, College of Public Service, Jackson State University, Jackson, MS, USAAbstract: Primary brain tumors are among the top ten causes of cancer-related deaths in the US. Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors diagnosed in adults each year and are associated with high morbidity and mortality. Despite optimal treatment, the prognosis for patients with gliomas remains poor. The use of retinoids (vitamin A and its congeners in the treatment of certain tumors was originally based on the assumption that these conditions were associated with an underlying deficiency of vitamin A and that supplementation with pharmacological doses would correct the deficiency. Yet the results of retinoid treatment have been only modestly beneficial and usually short-lived. Studies also indicate that vitamin A excess and supplementation have pro-oxidant effects and are associated with increased risks of mortality from cancer and other diseases. The therapeutic role of vitamin A in cancer thus remains uncertain and a new perspective on the facts is needed. The modest and temporary benefits of retinoid treatment could result from a process of feedback inhibition, whereby exogenous retinoid temporarily inhibits the endogenous synthesis of these compounds. In fact, repeated and/or excessive exposure of the tissues to endogenous retinoic acid may contribute to carcinogenesis. Gliomas, in particular, may result from an imbalance in retinoid receptor expression initiated by environmental factors that increase the endogenous production of retinoic acid in glia. At the receptor level, it is proposed that this imbalance is characterized by excessive expression of retinoic acid receptor-α(RARα and reduced expression of retinoic acid receptor-β (RARβ. This suggests a potential new treatment strategy for gliomas, possibly even at a

  12. In vitro enhancement of dendritic cell-mediated anti-glioma immune response by graphene oxide

    Science.gov (United States)

    Wang, Wei; Li, Zhongjun; Duan, Jinhong; Wang, Chen; Fang, Ying; Yang, Xian-Da

    2014-06-01

    Malignant glioma has extremely poor prognosis despite combination treatments with surgery, radiation, and chemotherapy. Dendritic cell (DC)-based immunotherapy may potentially serve as an adjuvant treatment of glioma, but its efficacy generally needs further improvement. Here we explored whether graphene oxide (GO) nanosheets could modulate the DC-mediated anti-glioma immune response in vitro, using the T98G human glioma cell line as the study model. Pulsing DCs with a glioma peptide antigen (Ag) generated a limited anti-glioma response compared to un-pulsed DCs. Pulsing DCs with GO alone failed to produce obvious immune modulation effects. However, stimulating DCs with a mixture of GO and Ag (GO-Ag) significantly enhanced the anti-glioma immune reaction ( p < 0.05). The secretion of interferon gamma (IFN-γ) by the lymphocytes was also markedly boosted by GO-Ag. Additionally, the anti-glioma immune response induced by GO-Ag appeared to be target-specific. Furthermore, at the concentration used in this study, GO exhibited a negligible effect on the viability of the DCs. These results suggested that GO might have potential utility for boosting a DC-mediated anti-glioma immune response.

  13. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.

    Science.gov (United States)

    Bandopadhayay, Pratiti; Ramkissoon, Lori A; Jain, Payal; Bergthold, Guillaume; Wala, Jeremiah; Zeid, Rhamy; Schumacher, Steven E; Urbanski, Laura; O'Rourke, Ryan; Gibson, William J; Pelton, Kristine; Ramkissoon, Shakti H; Han, Harry J; Zhu, Yuankun; Choudhari, Namrata; Silva, Amanda; Boucher, Katie; Henn, Rosemary E; Kang, Yun Jee; Knoff, David; Paolella, Brenton R; Gladden-Young, Adrianne; Varlet, Pascale; Pages, Melanie; Horowitz, Peleg M; Federation, Alexander; Malkin, Hayley; Tracy, Adam A; Seepo, Sara; Ducar, Matthew; Van Hummelen, Paul; Santi, Mariarita; Buccoliero, Anna Maria; Scagnet, Mirko; Bowers, Daniel C; Giannini, Caterina; Puget, Stephanie; Hawkins, Cynthia; Tabori, Uri; Klekner, Almos; Bognar, Laszlo; Burger, Peter C; Eberhart, Charles; Rodriguez, Fausto J; Hill, D Ashley; Mueller, Sabine; Haas-Kogan, Daphne A; Phillips, Joanna J; Santagata, Sandro; Stiles, Charles D; Bradner, James E; Jabado, Nada; Goren, Alon; Grill, Jacques; Ligon, Azra H; Goumnerova, Liliana; Waanders, Angela J; Storm, Phillip B; Kieran, Mark W; Ligon, Keith L; Beroukhim, Rameen; Resnick, Adam C

    2016-03-01

    Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

  14. Mechanism of SEMA3B gene silencing and clinical significance in glioma.

    Science.gov (United States)

    Pang, C H; Du, W; Long, J; Song, L J

    2016-03-18

    The aim of the current study was to explore mechanisms of SEMA3B gene expression and its clinical significance in glioma, and provide a theoretical foundation for investigating individualized treatment in glioma. Paraffin-embedded tissues from 43 patients with a confirmed clinical diagnosis of glioma following neurosurgery at the First Affiliated Hospital of Zhengzhou University from December 2013 to April 2014 were selected randomly. An additional three normal brain tissues were obtained following encephalic decompression excision due to acute craniocerebral injury in the same period, which were used as the control group. Immunohistochemical staining for vascular endothelial growth factor was performed on the glioma tissues from the 43 patients. Genomic DNA was extracted for bisulfate conversion and sequencing. SEMA3B was fully expressed in the three normal brain tissues, and incompletely expressed in the 43 glioma tissues, with a lack of expression in 48.8% (21/43) of samples. Moreover, 58% of high-grade gliomas (grade III and IV) lacked SEMA3B expression, which was significantly more than those that lacked expression (20%) in low-grade gliomas (grade I and II), indicating that, as the clinical pathological grade increased, SEMA3B expression decreased. The occurrence and development of malignant tumors is a product of multiple genes and other factors. Here, we provide theoretical basis for glioma development and prognosis involving DNA-methylation driven silencing of SEMA3B, and thus, SEMA3B is a potential target for directed treatments against glioma.

  15. Adhesion molecules and the extracellular matrix as drug targets for glioma.

    Science.gov (United States)

    Shimizu, Toshihiko; Kurozumi, Kazuhiko; Ishida, Joji; Ichikawa, Tomotsugu; Date, Isao

    2016-04-01

    The formation of tumor vasculature and cell invasion along white matter tracts have pivotal roles in the development and progression of glioma. A better understanding of the mechanisms of angiogenesis and invasion in glioma will aid the development of novel therapeutic strategies. The processes of angiogenesis and invasion cause the production of an array of adhesion molecules and extracellular matrix (ECM) components. This review focuses on the role of adhesion molecules and the ECM in malignant glioma. The results of clinical trials using drugs targeted against adhesion molecules and the ECM for glioma are also discussed.

  16. Increased Expression of microRNA-17 Predicts Poor Prognosis in Human Glioma

    Directory of Open Access Journals (Sweden)

    Shengkui Lu

    2012-01-01

    Full Text Available Aim. To investigate the clinical significance of microRNA-17 (miR-17 expression in human gliomas. Methods. Quantitative real-time polymerase chain reaction (qRT-PCR analysis was used to characterize the expression patterns of miR-17 in 108 glioma and 20 normal brain tissues. The associations of miR-17 expression with clinicopathological factors and prognosis of glioma patients were also statistically analyzed. Results. Compared with normal brain tissues, miR-17 expression was significantly higher in glioma tissues (P<0.001. In addition, the increased expression of miR-17 in glioma was significantly associated with advanced pathological grade (P=0.006 and low Karnofsky performance score (KPS, P=0.01. Moreover, Kaplan-Meier survival and Cox regression analyses showed that miR-17 overexpression (P=0.008 and advanced pathological grade (P=0.02 were independent factors predicting poor prognosis for gliomas. Furthermore, subgroup analyses showed that miR-17 expression was significantly associated with poor overall survival in glioma patients with high pathological grades (for grade III~IV: P<0.001. Conclusions. Our data offer the convinced evidence that the increased expression of miR-17 may have potential value for predicting poor prognosis in glioma patients with high pathological grades, indicating that miR-17 may contribute to glioma progression and be a candidate therapeutic target for this disease.

  17. The effects of CD147 on the cell proliferation, apoptosis, invasion, and angiogenesis in glioma.

    Science.gov (United States)

    Yin, Haoyuan; Shao, Ying; Chen, Xuan

    2017-01-01

    To analyze the effects of extracellular matrix metalloproteinase inducer (CD147) on glioma proliferation, apoptosis, invasion, and angiogenesis. Tissue samples were obtained from 101 glioma cases while normal brain tissues were obtained from 30 brain injury cases. Immunohistochemical assay was performed to detect the expressions of CD147, CD34, and VEGF in tissue samples. QRT-PCR was performed to detect the relative expression of CD147 mRNA in human glioma cell lines. CD147 siRNA was transfected into glioma cell line U251. Cell proliferation, apoptosis, invasion, and angiogenesis were tested by MTT, flow cytometry, Transwell assay, and vasculogenic mimicry assay, respectively. Expressions of relative proteins were analyzed with western blot. CD147 was positively expressed with the percentage of 0, 37.5, 44.8, 67.9, and 85.7 % in normal tissues and glioma tissues with WHO grades I-IV, respectively, and the scores of MVDand VEGF were associated with the expression of CD147. CD147 was significantly upregulated in the human glioma cell lines (P CD147 suppressed cell proliferation, blocked cell cycle, induced apoptosis, inhibited cell invasion and angiogenesis in glioma cells in vitro. The expression of CD147 was significantly associated with WHO tumor grade and angiogenesis; silencing of CD147 contributed to inhibition of glioma proliferation, invasion, and angiogenesis. Our study provided firm evidence that CD 147 is a potential glioma target for anti-angiogenic therapies.

  18. Enhanced transfection of brain tumor suppressor genes by photochemical internalization

    Science.gov (United States)

    Chou, Chih H.; Sun, Chung-Ho; Zhou, Yi-Hong; Madsen, Steen J.; Hirschberg, Henry

    2011-03-01

    One of many limitations for cancer gene therapy is the inability of the therapeutic gene to transfect a sufficient number of tumor cells. Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. The utility of PCI for the delivery of a tumor suppressor gene (PAX-6) was investigated in monolayers and spheroids consisting of F98 rat glioma cells.

  19. CDK4 amplification is an alternative mechanism to p16 gene homozygous deletion in glioma cell lines

    National Research Council Canada - National Science Library

    He, J; Allen, J R; Collins, V P; Allalunis-Turner, M J; Godbout, R; Day, 3rd, R S; James, C D

    1994-01-01

    ... those established from malignant gliomas. Here we have examined 32 glioma cell lines for amplification-associated overexpression of the CDK4 gene as an alternative mechanism for abrogating the growth-regulatory effects of p16...

  20. Armodafinil in Reducing Cancer-Related Fatigue in Patients With High Grade Glioma | Division of Cancer Prevention

    Science.gov (United States)

    This randomized phase III trial studies armodafinil to see how well it works in reducing cancer-related fatigue in patients with high grade glioma. Armodafinil may help relieve fatigue in patients with high grade glioma. |

  1. Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma

    National Research Council Canada - National Science Library

    Tina Y Huang; Andrea Piunti; Rishi R Lulla; Jin Qi; Craig M Horbinski; Tadanori Tomita; C David James; Ali Shilatifard; Amanda M Saratsis

    2017-01-01

    Diffuse midline gliomas (including diffuse intrinsic pontine glioma, DIPG) are highly morbid glial neoplasms of the thalamus or brainstem that typically arise in young children and are not surgically resectable...

  2. Fenofibrate dose not protect glioma cells from irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Ro, Jae Lim; Kim, Won Dong; Park, Woo Yoon [Radiation Oncology, Chungbuk National University College of Medicine, Jeonju (Korea, Republic of)

    2012-04-15

    Fenofibrate(FF) is a ligand for peroxisome proliferator-activated receptor (PPAR) α and used clinically as a hypolipidemic drug. FF has been reported to have a radioprotective effect of newborn cells in the dentate gyrus 1) and inhibit radiation-induced microglial pro-inflammatory response 2). However, if FF also protect tumor cells, it can not be used clinically during radiotherapy. Thus, we're interested in whether FF has an radioprotective effect of brain tumor cells or not Although the radiosensitive G0/G1 phase cells were increased, radiosensitization by FF was not observed in three human glioma cells. This may be due to counterbalance of radiosensitizing and radioprotecting proteins increased by FF. Taken together, FF neither radiosensitize nor radioprotect glioma cells, so it can be used to protect normal neural cells from radiation damage.

  3. Dianhydrogalactitol and radiation therapy. Treatment of supratentorial glioma.

    Science.gov (United States)

    Eagan, R T; Childs, D S; Layton, D D; Laws, E R; Bisel, H F; Holbrook, M A; Fleming, T R

    1979-05-11

    Dianhydrogalactitol was the most active of 177 agents tested against a mouse ependymoblastoma tumor. We conducted a prospectively randomized trial comparing whole-brain irradiation alone vs identical irradiation plus dianhydrogalactitol in 42 patients with grade 3 and 4 supratentorial astrocytomas. Patients receiving dianhydrogalactitol in addition to irradiation had a significantly longer median survival time (67 vs 35 weeks) than did patients receiving only irradiation. The major toxic effect of dianhydrogalactitol is hematologic suppression of a cumulative nature. Dianhydrogalactitol may play an important role (in conjunction with radiation therapy) in the initial treatment of patients with supratentorial glioma. Our data may indicate that the mouse ependymoblastoma system is a useful screen for agents to be used in the treatment of human glioma.

  4. Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers.

    LENUS (Irish Health Repository)

    Jansen, Michael

    2010-07-01

    Over the past 10 years, there has been an increasing use of molecular markers in the assessment and management of adult malignant gliomas. Some molecular signatures are used diagnostically to help pathologists classify tumours, whereas others are used to estimate prognosis for patients. Most crucial, however, are those markers that are used to predict response to certain therapies, thereby directing clinicians to a particular treatment while avoiding other potentially deleterious therapies. Recently, large-scale genome-wide surveys have been used to identify new biomarkers that have been rapidly developed as diagnostic and prognostic tools. Given these developments, the pace of discovery of new molecular assays will quicken to facilitate personalised medicine in the setting of malignant glioma.

  5. Role of Dicer on tumorigenesis in glioma cells

    Institute of Scientific and Technical Information of China (English)

    Anling Zhang; Lei Han; Guangxiu Wang; Zhifan Jia; Peiyu Pu; Chunsheng Kang

    2010-01-01

    Micro RNAs(miRNAs)are non-coding,single-stranded RNAs that regulate target gene expression by repressing translation or promoting RNA cleavage.Recent studies show that miRNA expression is globally decreased in some human tumors.Dicer is an essential component of the miRNA processing machinery.To determine whether global reduction of miRNA effects tumorigenesis,small interfering RNA were designed to target Dicer to restrain whole miRNA expression in the glioblastoma cell line-TJ905.With effective knock-down of Dicer,tumor cells were invasive and proliferative,and globally impaired miRNA processing enhanced proliferation and invasiveness of glioma cells in vitro.Suppression of Dicer expression resulted in a more aggressive glioma phenotype,which suggests that global reduction of miRNA expression could have an oncogenic role in glioblastoma cells.

  6. SVM-based glioma grading: Optimization by feature reduction analysis.

    Science.gov (United States)

    Zöllner, Frank G; Emblem, Kyrre E; Schad, Lothar R

    2012-09-01

    We investigated the predictive power of feature reduction analysis approaches in support vector machine (SVM)-based classification of glioma grade. In 101 untreated glioma patients, three analytic approaches were evaluated to derive an optimal reduction in features; (i) Pearson's correlation coefficients (PCC), (ii) principal component analysis (PCA) and (iii) independent component analysis (ICA). Tumor grading was performed using a previously reported SVM approach including whole-tumor cerebral blood volume (CBV) histograms and patient age. Best classification accuracy was found using PCA at 85% (sensitivity=89%, specificity=84%) when reducing the feature vector from 101 (100-bins rCBV histogram+age) to 3 principal components. In comparison, classification accuracy by PCC was 82% (89%, 77%, 2 dimensions) and 79% by ICA (87%, 75%, 9 dimensions). For improved speed (up to 30%) and simplicity, feature reduction by all three methods provided similar classification accuracy to literature values (∼87%) while reducing the number of features by up to 98%.

  7. In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma.

    Directory of Open Access Journals (Sweden)

    Susanna J E Veringa

    Full Text Available Pediatric high-grade gliomas (pHGG, including diffuse intrinsic pontine gliomas (DIPG, are the leading cause of cancer-related death in children. While it is clear that surgery (if possible, and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.

  8. Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy

    Directory of Open Access Journals (Sweden)

    Gregory J. Baker

    2014-07-01

    Full Text Available As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM, and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.

  9. Functionally-defined Therapeutic Targets in Diffuse Intrinsic Pontine Glioma

    Science.gov (United States)

    Grasso, Catherine S.; Tang, Yujie; Truffaux, Nathalene; Berlow, Noah E.; Liu, Lining; Debily, Marie-Anne; Quist, Michael J.; Davis, Lara E.; Huang, Elaine C.; Woo, Pamelyn J; Ponnuswami, Anitha; Chen, Spenser; Johung, Tessa B.; Sun, Wenchao; Kogiso, Mari; Du, Yuchen; Lin, Qi; Huang, Yulun; Hütt-Cabezas, Marianne; Warren, Katherine E.; Dret, Ludivine Le; Meltzer, Paul S.; Mao, Hua; Quezado, Martha; van Vuurden, Dannis G.; Abraham, Jinu; Fouladi, Maryam; Svalina, Matthew N.; Wang, Nicholas; Hawkins, Cynthia; Nazarian, Javad; Alonso, Marta M.; Raabe, Eric; Hulleman, Esther; Spellman, Paul T.; Li, Xiao-Nan; Keller, Charles; Pal, Ranadip; Grill, Jacques; Monje, Michelle

    2015-01-01

    Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNAseq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated efficacy in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat with histone demethylase inhibitor GSKJ4 revealed synergy. Together, these data suggest a promising therapeutic strategy for DIPG. PMID:25939062

  10. Multimodal imaging in cerebral gliomas and its neuropathological correlation

    Energy Technology Data Exchange (ETDEWEB)

    Gempt, Jens, E-mail: jens.gempt@lrz.tum.de [Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München (Germany); Soehngen, Eric [Abteilung für Neuroradiologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München (Germany); Abteilung für Neuropathologie des Instituts für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Ismaninger Str. 22, 81675 München (Germany); Förster, Stefan [Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München (Germany); Ryang, Yu-Mi [Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München (Germany); Schlegel, Jürgen [Abteilung für Neuropathologie des Instituts für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Ismaninger Str. 22, 81675 München (Germany); and others

    2014-05-15

    Introduction: Concerning the preoperative clinical diagnostic work-up of glioma patients, tumor heterogeneity challenges the oncological therapy. The current study assesses the performance of a multimodal imaging approach to differentiate between areas in malignant gliomas and to investigate the extent to which such a combinatorial imaging approach might predict the underlying histology. Methods: Prior to surgical resection, patients harboring intracranial gliomas underwent MRIs (MR-S, PWI) and {sup 18}F-FET-PETs. Intratumoral and peritumoral biopsy targets were defined, by MRI only, by FET-PET only, and by MRI and FET-PET combined, and biopsied prior to surgical resection and which then received separate histopathological examinations. Results: In total, 38 tissue samples were acquired (seven glioblastomas, one anaplastic astrocytoma, one anaplastic oligoastrocytoma, one diffuse astrocytoma, and one oligoastrocytoma) and underwent histopathological analysis. The highest mean values of Mib1 and CD31 were found in the target point “T’ defined by MRI and FET-PET combined. A significant correlation between NAA/Cr and PET tracer uptake (−0.845, p < 0.05) as well as Cho/Cr ratio and cell density (0.742, p < 0.05) and NAA/Cr ratio and MIB-1 (−0761, p < 0.05) was disclosed for this target point, though not for target points defined by MRI and FET-PET alone. Conclusion: Multimodal-imaging-guided stereotactic biopsy correlated more with histological malignancy indices, such as cell density and MIB-1 labeling, than targets that were based solely on the highest amino acid uptake or contrast enhancement on MRI. The results of our study indicate that a combined PET-MR multimodal imaging approach bears potential benefits in detecting glioma heterogeneity.

  11. Efficacy and toxicity of postoperative temozolomide radiochemotherapy in malignant glioma

    Energy Technology Data Exchange (ETDEWEB)

    Kocher, M.; Kunze, S.; Eich, H.T.; Semrau, R.; Mueller, R.P. [Dept. of Radiation Oncology, Univ. of Cologne (Germany)

    2005-03-01

    Purpose: to evaluate the feasibility, safety and efficacy of daily temozolomide concurrent with postoperative radiotherapy in malignant glioma. Patients and methods: from 11/1999 to 03/2003, n = 81 patients aged 15-72 years (median 52 years, karnofsky score 80-100% in 83%) suffering from primary glioblastoma (n = 47), anaplastic astrocytoma (n = 6), anaplastic oligodendroglioma (n = 16), and recurrent glioma (n = 12) were treated. Patients with primary gliomas received a combination of postoperative radiotherapy (60 Gy/1.8- to 2.0-Gy fractions) and daily oral temozolomide (75 mg/m{sup 2}) at all irradiation days (30-33 doses), while recurrent tumors were treated with 45-60 Gy and temozolomide. Initially, 6/81 patients had daily temozolomide doses of 50 mg/m{sup 2}. Results: in total, 70/81 patients (86%) completed both radio- and chemotherapy. Grade 1 nausea/vomiting was seen in 28%, grade 2 in 11%, grade 3 in 1%. Antiemetics were applied in 41%. Hematologic toxicities were observed as follows: leukopenia grade 3/4 1%, lymphopenia grade 3/4 46%, thrombopenia grade 3/4 1%. Two patients under dexamethasone suffered herpes encephalitis after one and 16 doses of temozolomide (75 mg/m{sup 2}). Median survival was 15 months for glioblastoma. In oligodendroglioma patients, a 4-year survival rate of 78% was observed. Conclusion: postoperative radiochemotherapy with 30-33 daily doses of temozolomide (75 mg/m{sup 2}) is safe in patients with malignant glioma. The combined schedule is effective in oligodendroglioma patients and may prolong survival in glioblastoma. Effort should be taken to minimize corticosteroid doses, since both steroids and temozolomide lead to immunosuppression. (orig.)

  12. Involvement of the kynurenine pathway in human glioma pathophysiology.

    Directory of Open Access Journals (Sweden)

    Seray Adams

    Full Text Available The kynurenine pathway (KP is the principal route of L-tryptophan (TRP catabolism leading to the production of kynurenine (KYN, the neuroprotectants, kynurenic acid (KYNA and picolinic acid (PIC, the excitotoxin, quinolinic acid (QUIN and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+. The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1, indoleamine 2,3-dioxygenase-2 (IDO-2 and tryptophan 2,3-dioxygenase (TDO-2 initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1 cultured human glioma cells and 2 plasma from patients with glioblastoma (GBM. Our data revealed that interferon-gamma (IFN-γ stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU, kynurenine hydroxylase (KMO and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD and kynurenine aminotransferase-I (KAT-I expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18 compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD(+, which is necessary for energy production and DNA repair.

  13. Tumor infiltrating immune cells in gliomas and meningiomas.

    Science.gov (United States)

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Miranda, David; Ruiz, Laura; Sousa, Pablo; Ciudad, Juana; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2016-03-01

    Tumor-infiltrating immune cells are part of a complex microenvironment that promotes and/or regulates tumor development and growth. Depending on the type of cells and their functional interactions, immune cells may play a key role in suppressing the tumor or in providing support for tumor growth, with relevant effects on patient behavior. In recent years, important advances have been achieved in the characterization of immune cell infiltrates in central nervous system (CNS) tumors, but their role in tumorigenesis and patient behavior still remain poorly understood. Overall, these studies have shown significant but variable levels of infiltration of CNS tumors by macrophage/microglial cells (TAM) and to a less extent also lymphocytes (particularly T-cells and NK cells, and less frequently also B-cells). Of note, TAM infiltrate gliomas at moderate numbers where they frequently show an immune suppressive phenotype and functional behavior; in contrast, infiltration by TAM may be very pronounced in meningiomas, particularly in cases that carry isolated monosomy 22, where the immune infiltrates also contain greater numbers of cytotoxic T and NK-cells associated with an enhanced anti-tumoral immune response. In line with this, the presence of regulatory T cells, is usually limited to a small fraction of all meningiomas, while frequently found in gliomas. Despite these differences between gliomas and meningiomas, both tumors show heterogeneous levels of infiltration by immune cells with variable functionality. In this review we summarize current knowledge about tumor-infiltrating immune cells in the two most common types of CNS tumors-gliomas and meningiomas-, as well as the role that such immune cells may play in the tumor microenvironment in controlling and/or promoting tumor development, growth and control.

  14. Cortical and Subcortical Structural Plasticity Associated with the Glioma Volumes in Patients with Cerebral Gliomas Revealed by Surface-Based Morphometry

    Directory of Open Access Journals (Sweden)

    Jinping Xu

    2017-06-01

    Full Text Available Postlesional plasticity has been identified in patients with cerebral gliomas by inducing a large functional reshaping of brain networks. Although numerous non-invasive functional neuroimaging methods have extensively investigated the mechanisms of this functional redistribution in patients with cerebral gliomas, little effort has been made to investigate the structural plasticity of cortical and subcortical structures associated with the glioma volume. In this study, we aimed to investigate whether the contralateral cortical and subcortical structures are able to actively reorganize by themselves in these patients. The compensation mechanism following contralateral cortical and subcortical structural plasticity is considered. We adopted the surface-based morphometry to investigate the difference of cortical and subcortical gray matter (GM volumes in a cohort of 14 healthy controls and 13 patients with left-hemisphere cerebral gliomas [including 1 patients with World Health Organization (WHO I, 8 WHO II, and 4 WHO III]. The glioma volume ranges from 5.1633 to 208.165 cm2. Compared to healthy controls, we found significantly increased GM volume of the right cuneus and the left thalamus, as well as a trend toward enlargement in the right globus pallidus in patients with cerebral gliomas. Moreover, the GM volumes of these regions were positively correlated with the glioma volumes of the patients. These results provide evidence of cortical and subcortical enlargement, suggesting the usefulness of surface-based morphometry to investigate the structural plasticity. Moreover, the structural plasticity might be acted as the compensation mechanism to better fulfill its functions in patients with cerebral gliomas as the gliomas get larger.

  15. Carboxyl terminus of Hsp70-interacting protein (CHIP) contributes to human glioma oncogenesis.

    Science.gov (United States)

    Xu, Tao; Zhou, Quan; Zhou, Jingxu; Huang, Yan; Yan, Yong; Li, Weiqing; Wang, Chunlin; Hu, Guohan; Lu, Yicheng; Chen, Juxiang

    2011-05-01

    Malignant glioma is the most common adult primary brain tumor, and the mechanism of its oncogenesis is poorly understood. Growing evidence has shown that E3 ubiquitin ligases can promote tumorgenesis of glioma. CHIP is an E3 ubiquitin ligase that can induce ubiquitylation and degradation of many tumor-related proteins, and it has been reported to act as an upstream regulator in breast cancer; however, its role in human gliomas has not been evaluated yet. In this study, the expression of CHIP in glioma tissues was studied using immunohistochemistry. CHIP expression in glioma cells was studied by real-time RT-PCR, western blot and double immunofluorescence staining. The role of CHIP in glioma oncogenesis was investigated by lentivirus-mediated RNA interference (RNAi) and overexpression in vitro and in vivo. We showed CHIP expression in glioma samples was related to tumor grades, with stronger staining in high-grade gliomas than in low-grade gliomas. Knocking down of CHIP suppressed proliferation, colony formation of U251 and U87 glioma cells, while overexpression of CHIP resulted in enhanced proliferation and colony formation in vitro. In a nude mouse xenograft model, intratumoral injection of CHIP RNAi lentivirus significantly delayed tumor growth. In contrast, overexpression of CHIP resulted in enhanced tumor growth in vivo. After CHIP RNAi, both survivin mRNA and protein were decreased, while CHIP overexpression induced increased mRNA and protein levels of survivin. This is the first study demonstrating CHIP contributes to oncogenesis of glioma. © 2011 Japanese Cancer Association.

  16. Cluster Analysis and Significance of Novel Genes Related to Molecular Classification of Glioma

    Institute of Scientific and Technical Information of China (English)

    Juxiang Chen; Yicheng Lu; Guohan Hu; Kehua Sun; Chun Luo; Meiqing Lou; Kang Ying; Yao Li

    2005-01-01

    OBJECTIVE To screen differentially expressed genes in the development of human glioma and establish a primary molecular classification of glioma based on gene expression using cDNA microarrays.METHODS Brain specimens were obtained from 18 patients with glioma, 10males and 8 females, ages 14~62 with an average age of 44.4. The total RNAs of these glioma specimens and two specimens of donated brain of normal adults were extracted. BioStarH140S microarrays (including 8,347old genes and 5,592 novel genes) were adopted and hybridized with probes which were prepared from the total RNAs. Differentially expressed genes between normal tissues and glioma tissues were assayed after scanning cDNA microarrays with ScanArray4000. Northern hybridization and in situ hybridization (ISH) were used to identify functions of novel genes. Those differentially expressed genes were studied with a Hierarchical method and molecular classification of glioma was preliminary carried out.RESULTS Among the 13,939 target genes, there were 1,200 (8.61%)differentially expressed genes, of which 395 (2.83%) were novel genes. A total of 348 genes were up-regulated and 852 genes were down-regulated in the gliomas. The results of bioinformatical analysis, Northern hybridization and ISH revealed that those novel genes were highly associated with gliomas. There were multiple genes, such as the MAP gene、cytoskeleton & matrix motility genes, etc, which were of relevance to classification by the Hierarchical method. Molecular classification of glioma using a Hierarchical cluster was in accordance with pathology and suggested a molecular process of tumorigenesis and development.CONCLUSION Multiple genes play important roles in development of glioma. cDNA microarray technology is a powerful technique in screening for differentially expressed genes between two different kinds of tissues. Further analysis of gene expression and novel genes would be helpful to understand the molecular mechanism of glioma

  17. Ionizing radiation improves glioma-specific targeting of superparamagnetic iron oxide nanoparticles conjugated with cmHsp70.1 monoclonal antibodies (SPION-cmHsp70.1)

    Science.gov (United States)

    Shevtsov, Maxim A.; Nikolaev, Boris P.; Ryzhov, Vyacheslav A.; Yakovleva, Ludmila Y.; Marchenko, Yaroslav Y.; Parr, Marina A.; Rolich, Valerij I.; Mikhrina, Anastasiya L.; Dobrodumov, Anatolii V.; Pitkin, Emil; Multhoff, Gabriele

    2015-12-01

    The stress-inducible 72 kDa heat shock protein Hsp70 is known to be expressed on the membrane of highly aggressive tumor cells including high-grade gliomas, but not on the corresponding normal cells. Membrane Hsp70 (mHsp70) is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. Herein, we conjugated the Hsp70-specific antibody (cmHsp70.1) which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor-specific targeting before and after ionizing irradiation. In vitro experiments demonstrated the selectivity of SPION-cmHsp70.1 conjugates to free and mHsp70 in different tumor cell types (C6 glioblastoma, K562 leukemia, HeLa cervix carcinoma) in a dose-dependent manner. High-resolution MRI (11 T) on T2-weighted images showed the retention of the conjugates in the C6 glioma model. Accumulation of SPION-cmHsp70.1 nanoparticles in the glioma resulted in a nearly 2-fold drop of values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M2 measurements showed a 7-fold increase in the tumor-to-background (normal brain) uptake ratio of SPION-cmHsp70.1 conjugates in glioma-bearing rats in comparison to SPIONs. This accumulation within Hsp70-positive glioma was further enhanced after a single dose (10 Gy) of ionizing radiation. Elevated accumulation of the magnetic conjugates in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents in brain tumors.The stress-inducible 72 kDa heat shock protein Hsp70 is known to be expressed on the membrane of highly aggressive tumor cells including high-grade gliomas, but not on the corresponding normal cells. Membrane Hsp70 (mHsp70) is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy

  18. The ketogenic diet for the treatment of malignant glioma.

    Science.gov (United States)

    Woolf, Eric C; Scheck, Adrienne C

    2015-01-01

    Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an effective method to improve current therapies. Indeed, metabolism has been a focus of cancer research in the last few years, as many pathways long associated with tumor growth have been found to intersect metabolic pathways in the cell. The ketogenic diet (high fat, low carbohydrate and protein), caloric restriction, and fasting all cause a metabolic change, specifically, a reduction in blood glucose and an increase in blood ketones. We, and others, have demonstrated that these metabolic changes improve survival in animal models of malignant gliomas and can potentiate the anti-tumor effect of chemotherapies and radiation treatment. In this review we discuss the use of metabolic alteration for the treatment of malignant brain tumors.

  19. Role of Inflammation and Oxidative Stress Mediators in Gliomas

    Directory of Open Access Journals (Sweden)

    Alfredo Conti

    2010-04-01

    Full Text Available Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.

  20. Radiochemotherapy of malignant glioma in adults. Clinical experiences

    Energy Technology Data Exchange (ETDEWEB)

    Kortmann, R.D.; Jeremic, B.; Plasswilm, L.; Bamberg, M. [Dept. for Radiation Oncology, Univ. of Tuebingen (Germany); Weller, M. [Dept. of Neurology, Univ. of Tuebingen (Germany)

    2003-04-01

    Background: Standard treatment in patients with malignant glioma consists of surgery and postoperative radiotherapy. A high early recurrence rate, particularly in glioblastoma, has led to the investigation of additional chemotherapy. Material and Methods: Recent results of radiochemotherapy published in the literature were reviewed with respect to outcome in phase II and III trials. Based on these experiences, aspects of future strategies were discussed. Results: 3 decades of intensive research had, unfortunately, little impact on the overall results. While early prospective studies established adjuvant nitrosoureas, particularly BCNU, as suitable adjuvant to surgery and postoperative radiotherapy, further studies largely concentrated on combined chemotherapeutic protocols, mostly procarbazine, CCNU and vincristine (PCV), which was shown to prolong survival in anaplastic astrocytoma. The recent MRC study, however, showed no effect for adjuvant PCV in grade III and IV malignant glioma. Only in high-grade glioma with an oligodendroglial component, additional chemotherapy may be of a decisive benefit. The introduction of newer drugs such as paclitaxel, temozolomide, or gemcitabine demonstrated no decisive advantage. Different modes of application and sequencing of radiotherapy and chemotherapy are presently actively investigated, but failed to substantially improve outcome. Conclusions: Therefore, search for newer and more effective drugs continues, as well as for ''optimal'' administration and sequencing, especially from the standpoint of accompanying acute and late toxicity. Finally, recent endeavors focused on basic research such as angiogenesis, migration and invasion, or induction of cell differentiation, but these strategies are still away from broader clinical investigation. (orig.)

  1. ASYMMETRIC CELL DIVISION: IMPLICATIONS FOR GLIOMA DEVELOPMENT AND TREATMENT

    Science.gov (United States)

    Lewis, Kate Marie; Petritsch, Claudia

    2014-01-01

    Glioma is a heterogeneous disease process with differential histology and treatment response. It was previously thought that the histological features of glial tumors indicated their cell of origin. However, the discovery of continuous neuro-gliogenesis in the normal adult brain and the identification of brain tumor stem cells within glioma have led to the hypothesis that these brain tumors originate from multipotent neural stem or progenitor cells, which primarily divide asymmetrically during the postnatal period. Asymmetric cell division allows these cell types to concurrently self-renew whilst also producing cells for the differentiation pathway. It has recently been shown that increased symmetrical cell division, favoring the self-renewal pathway, leads to oligodendroglioma formation from oligodendrocyte progenitor cells. In contrast, there is some evidence that asymmetric cell division maintenance in tumor stem-like cells within astrocytoma may lead to acquisition of treatment resistance. Therefore cell division mode in normal brain stem and progenitor cells may play a role in setting tumorigenic potential and the type of tumor formed. Moreover, heterogeneous tumor cell populations and their respective cell division mode may confer differential sensitivity to therapy. This review aims to shed light on the controllers of cell division mode which may be therapeutically targeted to prevent glioma formation and improve treatment response. PMID:25530875

  2. Dipeptidyl peptidase IV in two human glioma cell lines

    Directory of Open Access Journals (Sweden)

    A Sedo

    2009-12-01

    Full Text Available There is growing evidence that dipeptidyl peptidase IV [DPP-IV, EC 3.4.14.5] takes part in the metabolism of biologically active peptides participating in the regulation of growth and transformation of glial cells. However, the knowledge on the DPP-IV expression in human glial and glioma cells is still very limited. In this study, using histochemical and biochemical techniques, the DPP-IV activity was demonstrated in two commercially available human glioma cell lines of different transformation degree, as represented by U373 astrocytoma (Grade III and U87 glioblastoma multiforme (Grade IV lines. Higher total activity of the enzyme, as well as its preferential localisation in the plasma membrane, was observed in U87 cells. Compared to U373 population, U87 cells were morphologically more pleiomorphic, they were cycling at lower rate and expressing less Glial Fibrillary Acidic Protein. The data revealed positive correlation between the degree of transformation of cells and activity of DPP-IV. Great difference in expression of this enzyme, together with the phenotypic differences of cells, makes these lines a suitable standard model for further 57 studies of function of this enzyme in human glioma cells.

  3. Fluorescence and image guided resection in high grade glioma.

    Science.gov (United States)

    Panciani, Pier Paolo; Fontanella, Marco; Schatlo, Bawarjan; Garbossa, Diego; Agnoletti, Alessandro; Ducati, Alessandro; Lanotte, Michele

    2012-01-01

    The extent of resection in high grade glioma is increasingly been shown to positively effect survival. Nevertheless, heterogeneity and migratory behavior of glioma cells make gross total resection very challenging. Several techniques were used in order to improve the detection of residual tumor. Aim of this study was to analyze advantages and limitations of fluorescence and image guided resection. A multicentric prospective study was designed to evaluate the accuracy of each method. Furthermore, the role of 5-aminolevulinc acid and neuronavigation were reviewed. Twenty-three patients harboring suspected high grade glioma, amenable to complete resection, were enrolled. Fluorescence and image guides were used to perform surgery. Multiple samples were obtained from the resection cavity of each lesion according to 5-ALA staining positivity and boundaries as delineated by neuronavigation. All samples were analyzed by a pathologist blinded to the intra-operative labeling. Decision-making based on fluorescence showed a sensitivity of 91.1% and a specificity of 89.4% (pimage-guided resection accuracy was low (sensitivity: 57.8%; specificity: 57.4%; p=0.346). We observed that the sensitivity of 5-ALA can be improved by the combined use of neuronavigation, but this leads to a significant reduction in specificity. Thus, the use of auxiliary techniques should always be subject to critical skills of the surgeon. We advocate a large-scale study to further improve the assessment of multimodal approaches.

  4. Bromelain reversibly inhibits invasive properties of glioma cells.

    Science.gov (United States)

    Tysnes, B B; Maurer, H R; Porwol, T; Probst, B; Bjerkvig, R; Hoover, F

    2001-01-01

    Bromelain is an aqueous extract from pineapple stem that contains proteinases and exhibits pleiotropic therapeutic effects, i.e., antiedematous, antiinflammatory, antimetastatic, antithrombotic, and fibrinolytic activities. In this study, we tested bromelain's effects on glioma cells to assess whether bromelain could be a potential contributor to new antiinvasive strategies for gliomas. Several complementary assays demonstrated that bromelain significantly and reversibly reduced glioma cell adhesion, migration, and invasion without affecting cell viability, even after treatment periods extending over several months. Immunohistochemistry and immunoblotting experiments demonstrated that alpha3 and beta1 integrin subunits and hyaluronan receptor CD44 protein levels were reduced within 24 hours of bromelain treatment. These effects were not reflected at the RNA level because RNA profiling did not show any significant effects on gene expression. Interestingly, metabolic labelling with 35-S methionine demonstrated that de novo protein synthesis was greatly attenuated by bromelain, in a reversible manner. By using a transactivating signaling assay, we found that CRE-mediated signaling processes were suppressed. These results indicate that bromelain exerts its antiinvasive effects by proteolysis, signaling cascades, and translational attenuation.

  5. Bromelain Reversibly Inhibits Invasive Properties of Glioma Cells

    Directory of Open Access Journals (Sweden)

    Berit B. Tysnes

    2001-01-01

    Full Text Available Bromelain is an aqueous extract from pineapple stem that contains proteinases and exhibits pleiotropic therapeutic effects, i.e., antiedematous, antiinflammatory, antimetastatic, antithrombotic, fibrinolytic activities. In this study, we tested bromelain's effects on glioma cells to assess whether bromelain could be a potential contributor to new antiinvasive strategies for gliomas. Several complementary assays demonstrated that bromelain significantly and reversibly reduced glioma cell adhesion, migration, invasion without affecting cell viability, even after treatment periods extending over several months. Immunohistochemistry and immunoblotting experiments demonstrated that a3 and α1 integrin subunits and hyaluronan receptor CD44 protein levels were reduced within 24 hours of bromelain treatment. These effects were not reflected at the RNA level because RNA profiling did not show any significant effects on gene expression. Interestingly, metabolic labelling with 35-S methionine demonstrated that de novo protein synthesis was greatly attenuated by bromelain, in a reversible manner. By using a transactivating signaling assay, we found that CRE-mediated signaling processes were suppressed. These results indicate that bromelain exerts its antiinvasive effects by proteolysis, signaling cascades, translational attenuation.

  6. Second Surgery in Insular Low-Grade Gliomas

    Directory of Open Access Journals (Sweden)

    Tamara Ius

    2015-01-01

    Full Text Available Background. Given the technical difficulties, a limited number of works have been published on insular gliomas surgery and risk factors for tumor recurrence (TR are poorly documented. Objective. The aim of the study was to determine TR in adult patients with initial diagnosis of insular Low-Grade Gliomas (LGGs that subsequently underwent second surgery. Methods. A consecutive series of 53 patients with insular LGGs was retrospectively reviewed; 23 patients had two operations for TR. Results. At the time of second surgery, almost half of the patients had experienced progression into high-grade gliomas (HGGs. Univariate analysis showed that TR is influenced by the following: extent of resection (EOR (P<0.002, ΔVT2T1 value (P<0.001, histological diagnosis of oligodendroglioma (P=0.017, and mutation of IDH1 (P=0.022. The multivariate analysis showed that EOR at first surgery was the independent predictor for TR (P<0.001. Conclusions. In patients with insular LGG the EOR at first surgery represents the major predictive factor for TR. At time of TR, more than 50% of cases had progressed in HGG, raising the question of the oncological management after the first surgery.

  7. Targeted therapy in the treatment of malignant gliomas

    Directory of Open Access Journals (Sweden)

    Rimas V Lukas

    2009-05-01

    Full Text Available Rimas V Lukas1, Adrienne Boire2, M Kelly Nicholas1,2 1Department of Neurology; 2Department of Medicine, University of Chicago, Chicago, IL, USAAbstract: Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In addition, we will discuss strategies that target the extracellular matrix in which these cells reside as well as angiogenesis, a process emerging as central to tumor development and growth. Finally, we will briefly touch on the role of neural stem cells as both potential targets as well as delivery vectors for other therapies. Interdependence between these varied pathways, both in maintaining health and in causing disease, is clear. Thus, attempts to easily classify some targeted therapies are problematic.Keywords: glioma, EGFR, mTOR, HDAC, Ras, angiogenesis

  8. Post-treatment imaging of high-grade gliomas

    Directory of Open Access Journals (Sweden)

    Darshana Sanghvi

    2015-01-01

    Full Text Available Current standard of care for treatment of newly diagnosed high grade gliomas is surgery followed by concomitant radiotherapy (RT and chemotherapy (CT with temozolomide (TMZ. Recently, bevacizumab, an anti - angiogenic agent has also been approved for treatment of recurrent gliomas. Baseline imaging after excision is optimally obtained in the first 24 hours. When baseline postoperative imaging is delayed beyond 24 hours, subacute hemorrhage, subacute ischemia and inflammation at the resection margins render differentiation from residual tumor challenging. Radiation necrosis is a well recognized entity and is differentiated from recurrence based on morphology on structural imaging, presence of lipid - lactate complexes with lack of choline on spectroscopy and low normalized cerebral blood volume (CBV ratios at perfusion imaging. Novel chemotherapies have lead to the occurrence of interesting but sometimes confusing post treatment imaging appearances including the phenomena of ′pseudoprogression′ and ′pseudoresponse′. Pseudoprogression refers to transient, self resolving focal enhancement mediated by TMZ-induced increased vascular permeability and local inflammatory response. Pathologically, these lesions do not have viable tumor. The lesions stabilize or regress without further treatment and are usually clinically asymptomatic. Pseudoresponse refers to rapid regression of enhancement, perfusion, mass effect and midline shift caused by the anti - angiogenic effect of bevacizumab. It is termed pseudoresponse since biological tumor persists as non-enhancing altered signal. It is important for radiologists to be aware of these entities seen on post treatment imaging of gliomas, as misinterpretation may lead to inappropriate management decisions and prognostication.

  9. Atypical crossmodal emotional integration in patients with gliomas.

    Science.gov (United States)

    Luherne-du Boullay, Viviane; Plaza, Monique; Perrault, Annabelle; Capelle, Laurent; Chaby, Laurence

    2014-11-01

    The relevance of emotional perception in interpersonal relationships and social cognition has been well documented. Although brain diseases might impair emotional processing, studies concerning emotional recognition in patients with brain tumours are relatively rare. The aim of this study was to explore emotional recognition in patients with gliomas in three conditions (visual, auditory and crossmodal) and to analyse how tumour-related variables (notably, tumour localisation) and patient-related variables influence emotion recognition. Twenty six patients with gliomas and 26 matched healthy controls were instructed to identify 5 basic emotions and a neutral expression, which were displayed through visual, auditory and crossmodal stimuli. Relative to the controls, recognition was weakly impaired in the patient group under both visual and auditory conditions, but the performances were comparable in the crossmodal condition. Additional analyses using the 'race model' suggest differences in multisensory emotional integration abilities across the groups, which were potentially correlated with the executive disorders observed in the patients. These observations support the view of compensatory mechanisms in the case of gliomas that might preserve the quality of life and help maintain the normal social and professional lives often observed in these patients. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Evaluation of radiation effects against C6 glioma in combination with vaccinia virus-p53 gene therapy

    Science.gov (United States)

    Gridley, D. S.; Andres, M. L.; Li, J.; Timiryasova, T.; Chen, B.; Fodor, I.; Nelson, G. A. (Principal Investigator)

    1998-01-01

    The primary objective of this study was to evaluate the antitumor effects of recombinant vaccinia virus-p53 (rVV-p53) in combination with radiation therapy against the C6 rat glioma, a p53 deficient tumor that is relatively radioresistant. VV-LIVP, the parental virus (Lister strain), was used as a control. Localized treatment of subcutaneous C6 tumors in athymic mice with either rVV-p53 or VV-LIVP together with tumor irradiation resulted in low tumor incidence and significantly slower tumor progression compared to the agents given as single modalities. Assays of blood and spleen indicated that immune system activation may account, at least partly, for the enhance tumor inhibition seen with combined treatment. No overt signs of treatment-related toxicity were noted.

  11. Orphan nuclear receptor Nur77 is required for the differentiation of C6 glioma cells induced by cholera toxin

    Institute of Scientific and Technical Information of China (English)

    Dong XU; Yi-jun HUANG; Yan LI; Wei YIN; Guang-mei YAN

    2009-01-01

    Aim: To investigate a possible regulator gene involved in the cholera toxin-induced differentiation of rat C6 glioma cells. Methods: The global changes in the mRNA expression pattern induced by cholera toxin were analyzed using gene chip microarray. The selected gene was then silenced by RNA interference or overexpressed with an ORF plasmid to determine its necessity in this process. Results: Nur77, a member of the orphan nuclear receptor family (NR4A), was markedly up-regulated during the process of differentiation. Furthermore, RNAi of nur77 attenuated the induction effect of cholera toxin on C6 cells, whereas overexpression of nur77 led to similarly differentiated behavior, including morphologic and biomarker changes, as well as cell cycle arrest. Conclusion: Nur77 participated actively and essentially as an important regulator in the cholera toxin-induced differentiation of C6 cells.

  12. Gliomas do nervo óptico: estudo de 11 casos Optic nerve gliomas: a study of 11 cases

    Directory of Open Access Journals (Sweden)

    Luiz Fernando Bleggi Torres

    1996-06-01

    Full Text Available Os gliomas do nervo óptico podem apresentar-se esporadicamente ou como componentes da neurofibromatose. São neoplasias raras, correspondendo a 2 a 5% dos tumores intracranianos e cerca de 6% dos tumores intra-orbitários. No presente estudo, analisamos 11 casos de glioma de nervo óptico diagnosticados em Curitiba num período de 25 anos, sendo 10 pacientes do sexo feminino e 1 do sexo masculino. As idades variaram de 3 a 25 anos; 6 pacientes apresentavam idades inferiores a 15 anos. Dos casos desta série, 27,3% (n=3 apresentavam associação com neurofibromatose. Quanto à localização dos tumores, em 5 pacientes a lesão estava restrita ao nervo óptico e no restante havia extensão para o quiasma óptico, região supra-selar, lobo frontal ou temporal. Todos os pacientes tinham astrocitoma pilocítico.Optic nerve gliomas may occur alone or as components of neurofibromatosis. They are rare tumors accounting for 2 to 5% of all intracranial tumors and 6% of the intra-orbitary neoplasms. The authors present 11 cases of optic nerve glioma diagnosed in Curitiba in the last 25 years. Out of these 11 patients there were 10 women and only 1 man. The ages ranged from 3 to 25 years old, and 6 patients were under 15 years. In this series, 27,3% (n=3 of the cases were associated with neurofibromatosis. Five patients had their tumors restricted to the optic nerve while the others had either extension to the optic chiasm, supra-selar region, frontal or temporal lobe. All the patients had pilocytic astrocytomas.

  13. Research on the tetraethylammonium inhibit the proliferation of glioma cells%钾通道阻滞剂四乙胺诱导胶质瘤细胞增殖抑制作用的实验研究

    Institute of Scientific and Technical Information of China (English)

    陈刚; 张磊; 王玉春; 刘波; 王凯; 王晓民; 付立旗

    2015-01-01

    目的:研究钾离子通道阻滞剂四乙胺(T EA )在体外是否具有抗胶质瘤作用,对胶质瘤细胞是否具有抑制肿瘤细胞增殖的作用。方法四甲基噻唑蓝比色法(MTT 法)观察 TEA对胶质瘤细胞生长、增殖的影响。结果 MTT法发现 TEA可显著抑制胶质瘤细胞株的生长,且呈时间和剂量依赖性。结论 T EA在体外可显著抑制C6与9L胶质瘤细胞株增殖,其作用机制可能和细胞凋亡有关。%Objective To study wheather tetraethylammonium (TEA) could inhibit the proliferation of rat glioma cells in vitro ,and investigate the role of inhibiting the proliferation of glioma cells .Methods Effect of TEA on the growth of glioma cells was observed by methyl thiazolyl tetrazolium (MTT ) method . Results MTT results showed that TEA could inhibit the growth of glioma cells ,furthermore ,time and dose were dependent .Conclusions TEA can significantly inhibit the growth of C6 and 9L glioma cells line in vitro ,the mechanism may be related with cell apoptosis .

  14. Bone marrow-derived mesenchymal stem cells to glioma directional migration and DAPI markers%骨髓间充质干细胞向脑胶质瘤定向迁移及其DAPI标记的研究

    Institute of Scientific and Technical Information of China (English)

    程鹏; 胡宜; 刘云会

    2012-01-01

    OBJECTIVE: To investigate the migrating potential of bone marrow-derived mesenchymal stem cells (BMSCs) towards C6 glioma and the application value of DAPI in the tracking and migration of BMSCs towards glioma in vivo. METHODS: BMSCs were isolated,cultured,passaged and purified in vitro by direct adhesion method. Using Tran-swell inserts technique,in vitro model was established and the migration of BMSCs towards C6 glioma was studied. The rat C6 glioma model was established by stereotactic procedure. After being marked with DAPI,BMSCs were injected into collateral internal carotid artery of rats bearing glioma to study their tropism for C6 glioma in vivo and evaluated the application of DAPI in this process, RESULTS: BMSCs were successive subcultured and purified by direct adhesion method. The results of in vitro migration assay showed that BMSCs could migrate through the polycarbonate filter towards C6 cells. The average number of migrating BMSCs was (32. 1 ± 10. 5)/HP. ( × 400) . The nucleus of BMSCs labeled by DA-PI presented blue fluorescence,and all of the cells were labeled by DAPL After being injected into internal carotid artery, BMSCs could survive in the brain of rats bearing glioma,and showed extensive tropism for C6 glioma and scattered around the blood vessels within the tumor. CONCLUSIONS:DAPI can be used for the tracking of BMSCs in vivo. BMSCs have the ability to penetrate blood tumor barrier and migrate towards C6 glioma,and infusion through internal carotid artery is an effective way for their transplantation.%目的:探讨骨髓间充质干细胞(BSMCs)向C6胶质瘤定向迁移的能力以及DAPI用于BMSCs向胶质瘤体内迁移示踪的价值.方法:直接贴壁法分离培养纯化BMSCs.利用Transwell小室建立体外迁移模型检测BMSCs向C6胶质瘤细胞定向迁移的能力.立体定向法建立大鼠C6胶质瘤模型,利用DAPI体外标记培养、纯化的BMSCs,经荷瘤侧颈内动脉灌注,观察BMSCs向C6胶质瘤组织的

  15. Conditional astroglial Rictor overexpression induces malignant glioma in mice.

    Directory of Open Access Journals (Sweden)

    Tariq Bashir

    Full Text Available BACKGROUND: Hyperactivation of the mTORC2 signaling pathway has been shown to contribute to the oncogenic properties of gliomas. Moreover, overexpression of the mTORC2 regulatory subunit Rictor has been associated with increased proliferation and invasive character of these tumor cells. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether Rictor overexpression was sufficient to induce glioma formation in mice, we inserted a Cre-lox-regulated human Rictor transgene into the murine ROSA26 locus. This floxed Rictor strain was crossed with mice expressing the Cre recombinase driven from the glial fibrillary acidic protein (GFAP promoter whose expression is limited to the glial cell compartment. Double transgenic GFAP-Cre/Rictor(loxP/loxP mice developed multifocal infiltrating glioma containing elevated mTORC2 activity and typically involved the subventricular zone (SVZ and lateral ventricle. Analysis of Rictor-dependent signaling in these tumors demonstrated that in addition to elevated mTORC2 activity, an mTORC2-independent marker of cortical actin network function, was also elevated. Upon histological examination of the neoplasms, many displayed oligodendroglioma-like phenotypes and expressed markers associated with oligodendroglial lineage tumors. To determine whether upstream oncogenic EGFRvIII signaling would alter tumor phenotypes observed in the GFAP-Cre/Rictor(loxP/loxP mice, transgenic GFAP-EGFRvIII; GFAP-Cre/Rictor(loxP/loxP mice were generated. These mice developed mixed astrocytic-oligodendroglial tumors, however glioma formation was accelerated and correlated with increased mTORC2 activity. Additionally, the subventricular zone within the GFAP-Cre/Rictor(loxP/loxP mouse brain was markedly expanded, and a further proliferation within this compartment of the brain was observed in transgenic GFAP-EGFRvIII; GFAP-Cre/Rictor(loxP/loxP mice. CONCLUSION/SIGNIFICANCE: These data collectively establish Rictor as a novel oncoprotein and support

  16. Conditional Astroglial Rictor Overexpression Induces Malignant Glioma in Mice

    Science.gov (United States)

    Bashir, Tariq; Cloninger, Cheri; Artinian, Nicholas; Anderson, Lauren; Bernath, Andrew; Holmes, Brent; Benavides-Serrato, Angelica; Sabha, Nesrin; Nishimura, Robert N.; Guha, Abhijit; Gera, Joseph

    2012-01-01

    Background Hyperactivation of the mTORC2 signaling pathway has been shown to contribute to the oncogenic properties of gliomas. Moreover, overexpression of the mTORC2 regulatory subunit Rictor has been associated with increased proliferation and invasive character of these tumor cells. Methodology/Principal Findings To determine whether Rictor overexpression was sufficient to induce glioma formation in mice, we inserted a Cre-lox-regulated human Rictor transgene into the murine ROSA26 locus. This floxed Rictor strain was crossed with mice expressing the Cre recombinase driven from the glial fibrillary acidic protein (GFAP) promoter whose expression is limited to the glial cell compartment. Double transgenic GFAP-Cre/RictorloxP/loxP mice developed multifocal infiltrating glioma containing elevated mTORC2 activity and typically involved the subventricular zone (SVZ) and lateral ventricle. Analysis of Rictor-dependent signaling in these tumors demonstrated that in addition to elevated mTORC2 activity, an mTORC2-independent marker of cortical actin network function, was also elevated. Upon histological examination of the neoplasms, many displayed oligodendroglioma-like phenotypes and expressed markers associated with oligodendroglial lineage tumors. To determine whether upstream oncogenic EGFRvIII signaling would alter tumor phenotypes observed in the GFAP-Cre/RictorloxP/loxP mice, transgenic GFAP-EGFRvIII; GFAP-Cre/RictorloxP/loxP mice were generated. These mice developed mixed astrocytic-oligodendroglial tumors, however glioma formation was accelerated and correlated with increased mTORC2 activity. Additionally, the subventricular zone within the GFAP-Cre/RictorloxP/loxP mouse brain was markedly expanded, and a further proliferation within this compartment of the brain was observed in transgenic GFAP-EGFRvIII; GFAP-Cre/RictorloxP/loxP mice. Conclusion/Significance These data collectively establish Rictor as a novel oncoprotein and support the role of dysregulated

  17. Galectin-1-mediated biochemical controls of melanoma and glioma aggressive behavior

    Institute of Scientific and Technical Information of China (English)

    Florence; Lefranc; Véronique; Mathieu; Robert; Kiss

    2011-01-01

    Gliomas and melanomas are associated with dismal prognosis because of their marked intrinsic resistance to proapoptotic stimuli,such as conventional chemotherapy and radiotherapy,as well as their ability to escape immune cell attacks.In addition,gliomas and melanomas display pronounced neoangiogenesis.Galectin-1 is a hypoxia-sensitive protein,which is abundantly secreted by glioma and melanoma cells,which displays marked proangiogenic effects.It also provides immune tolerogenic environments to melanoma and glioma cells through the killing of activated T cells that attack these tumor cells.Galectin-1 protects glioma and melanoma cells against cytotoxic insults(including chemotherapy and radiotherapy) through a direct role in the unfolded protein response.Altogether,these facts clearly point to galectin-1 as an important target to be combated in gliomas and melanomas in order to:(1) weaken the defenses of these two types of cancers against radiotherapy,chemotherapy and immunotherapy/vaccine therapy;and(2) reinforce antiangiogenic therapies.In the present article,we review the biochemical and molecular biology-related pathways controlled by galectin-1,which are actually beneficial for melanoma and glioma cells,and therefore detrimental for melanoma and glioma patients.

  18. Mitochondrial DNA copy number in whole blood and glioma risk: A case control study.

    Science.gov (United States)

    Shen, Jie; Song, Renduo; Lu, Zhimin; Zhao, Hua

    2016-12-01

    Alterations in mitochondrial DNA (mtDNA) copy number are observed in human gliomas. However, whether variations in mtDNA copy number in whole blood play any role in glioma carcinogenesis is still largely unknown. In current study with 395 glioma patients and 425 healthy controls, we intended to investigate the association between mtDNA copy number in whole blood and glioma risk. Overall, we found that levels of mtDNA copy number were significantly higher in glioma cases than healthy controls (mean: 1.48 vs. 1.32, P copy number were inversely correlated with age (P copy number than their counterparts (P = 0.02, P copy number levels were associated with a 1.63-fold increased risk of glioma (adjusted odds ratio (OR) = 1.63, 95% confidence interval (CI) = 1.23-2.14). In further quartile analysis, study subjects who had highest levels of mtNDA copy number had 1.75-fold increased risk of gliomas (adjOR = 1.75, 95%CI = 1.18-2.61). In brief, our findings support the role of mtDNA copy number in the glioma carcinogenesis. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Gene expression profiles of gliomas in formalin-fixed paraffin-embedded material

    NARCIS (Netherlands)

    A.M. Gravendeel (Lonneke); J.J. de Rooi (Johan); P.H.C. Eilers (Paul); M.J. van den Bent (Martin); P.A.E. Sillevis Smitt (Peter); P.J. French (Pim)

    2012-01-01

    textabstractBackground: We have recently demonstrated that expression profiling is a more accurate and objective method to classify gliomas than histology. Similar to most expression profiling studies, our experiments were performed using fresh frozen (FF) glioma samples whereas most archival sample

  20. Suppression of Glioma-Cell Survival by Antisense and Dominant-Negative AKT2 RNA

    Institute of Scientific and Technical Information of China (English)

    Peiyu Pu; Chunsheng Kang; Jie Li; Guangxiu Wang

    2005-01-01

    OBJECTIVE Overexpression of growth factors and their receptors such as PDGF, FGF, VEGF, IGF, EGF, TGFα etc. Play a critical role in the development and progression of malignant gliomas. AKT, one of the most potent downstream signaling effectors of these growth factor receptors is usually overactivated in malignant gliomas. The present study was undertaken to investigate the effects of antisense and dominant negative AKT2 RNA on the survival of glioma cells with overexpression of AKT2.METHODS Antisense and dominant negative AKT2 constructs (AS-AKT2,DN-AKT2) were transfected into human glioblastoma cell line TJ905 with overexpression of AKT2. Using Western blotting, MTT assay, Ki67 labeling index (Ki67 LI), flow cytometry and the TUNEL method, the expression of AKT2 and GFAP, the proliferation rate and apoptosis of glioma cells transfected with AS-AKT2 or DN-AKT2 were compared to those characteristics of parental and glioma cells transfected with an empty vector.RESULTS Cell proliferation was inhibited in glioma cells transfected with ASAKT2 and DN-AKT2 RNA, while GFAP expression and apoptosis were markedly increased in those cells.CONCLUSION AKT is an important mediator in the growth signaling pathway of malignant gliomas and is a potential promising therapeutic target for malignant gliomas.

  1. Hyperbaric oxygen promotes malignant glioma cell growth and inhibits cell apoptosis.

    Science.gov (United States)

    Wang, Yong-Gang; Zhan, Yi-Ping; Pan, Shu-Yi; Wang, Hai-Dong; Zhang, Dun-Xiao; Gao, Kai; Qi, Xue-Ling; Yu, Chun-Jiang

    2015-07-01

    Glioblastoma multiforme (GBM) is the most frequently diagnosed intracranial malignant tumor in adults. Clinical studies have indicated that hyperbaric oxygen may improve the prognosis and reduce complications in glioma patients; however, the specific mechanism by which this occurs remains unknown. The present study investigated the direct effects of hyperbaric oxygen stimulation on glioma by constructing an intracranial transplanted glioma model in congenic C57BL/6J mice. Bioluminescent imaging (BLI) was used to assess the growth of intracranial transplanted GL261-Luc glioma cells in vivo, while flow cytometric and immunohistochemical assays were used to detect and compare the expression of the biomarkers, Ki-67, CD34 and TUNEL, reflecting the cell cycle, apoptosis and angiogenesis. BLI demonstrated that hyperbaric oxygen promoted the growth of intracranially transplanted GL261-Luc glioma cells in vivo. Flow cytometric analysis indicated that hyperbaric oxygen promoted GL261-Luc glioma cell proliferation and also prevented cell cycle arrest. In addition, hyperbaric oxygen inhibited the apoptosis of the transplanted glioma cells. Immunohistochemical analysis also indicated that hyperbaric oxygen increased positive staining for Ki-67 and CD34, while reducing staining for TUNEL (a marker of apoptosis). The microvessel density was significantly increased in the hyperbaric oxygen treatment group compared with the control group. In conclusion, hyperbaric oxygen treatment promoted the growth of transplanted malignant glioma cells in vivo and also inhibited the apoptosis of these cells.

  2. Alisertib and Fractionated Stereotactic Radiosurgery in Treating Patients With Recurrent High Grade Gliomas

    Science.gov (United States)

    2016-10-19

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymal Giant Cell Astrocytoma; Recurrent Adult Brain Tumor

  3. A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma.

    Science.gov (United States)

    Song, Ye; Hu, Zheng; Long, Hao; Peng, Yuping; Zhang, Xi'an; Que, Tianshi; Zheng, Shihao; Li, Zhiyong; Wang, Gang; Yi, Liu; Liu, Zhen; Fang, Weiyi; Qi, Songtao

    2014-09-01

    HDGF is overexpressed in gliomas as compared to normal brain. We therefore analyzed the molecular mechanisms of HDGF action in gliomas. HDGF was downregulated in normal brain tissue as compared to glioma specimens at both the mRNA and the protein levels. In glioma samples, increased HDGF expression was associated with disease progression. Knocking down HDGF expression not only significantly decreased cellular proliferation, migration, invasion, and tumorigenesis, but also markedly enhanced TMZ-induced cytotoxicity and apoptosis in glioma cells. Mechanistic analyses revealed that CCND1, c-myc, and TGF-β were downregulated after stable HDGF knockdown in the U251 and U87 glioma cells. HDGF knockdown restored E-cadherin expression and suppressed mesenchymal cell markers such as vimentin, β-catenin, and N-cadherin. The expression of cleaved caspase-3 increased, while Bcl-2 decreased in each cell line following treatment with shHDGF and TMZ, as compared to TMZ alone. Furthermore, RNAi-based knockdown study revealed that HDGF is probably involved in the activation of both the PI3K/Akt and the TGF-β signaling pathways. Together, our data suggested that HDGF regulates glioma cell growth, apoptosis and epithelial-mesenchymal transition (EMT) probably through the Akt and the TGF-β signaling pathways. These results provide evidence that targeting HDGF or its downstream targets may lead to novel therapies for gliomas.

  4. Pontine glioma extending to the ipsilateral cavernous sinus and Meckel's cave: MR appearance.

    Science.gov (United States)

    Yuh, W T; Nguyen, H D; Mayr, N A; Follett, K A

    1992-01-01

    The authors describe an exophytic glioma of the pons that grew into the Meckel's cave and cavernous sinus in a 75-year-old man. Pontine gliomas should be included in the differential diagnosis of a hyperintense, complex cystic mass seen along the distribution of cranial nerve V.

  5. Radiosensitizing potential of the selective cyclooygenase-2 (COX-2) inhibitor meloxicam on human glioma cells

    NARCIS (Netherlands)

    Bijnsdorp, Irene; Berg, van den Jaap; Kuipers, Gitta; Wedekind, Laurine; Slotman, Ben; Rijn, van Johannes; Lafleur, M.; Sminia, Peter

    2007-01-01

    The COX-2 protein is frequently overexpressed in human malignant gliomas. This expression has been associated with their aggressive growth characteristics and poor prognosis for patients. Targeting the COX-2 pathway might improve glioma therapy. In this study, the effects of the selective COX-2 in

  6. Interleukin-2 expression and glioma cell proliferation following Vaceinia vector gene transfection in vivo

    Institute of Scientific and Technical Information of China (English)

    Xiaogang Wang; Xuezhong Wei; Jiangqiu Liu

    2008-01-01

    BACKGROUND: The effectiveness of gene therapy is closely related to the efficiency of vector transfection and expression.OBJECTIVE: This study was designed to transfect a human brain glioma cell line with recombinant Vaccinia virus expressing the interleukin-2 (rVV-IL-2) gene, and to observe IL-2 expression and glioma cell proliferation potential after transfection. DESIGN: Experimental observation. SETTING: Department of Neurosurgery, Shenyang Military Area Command of Chinese PLA. MATERIALS: The rVV-IL-2 vectors were obtained through homologous recombination and screening in the Second Military Medical University of Chinese PLA. The human brain glioma cell line and IL-2-dependent cells were produced by the Second Military Medical University of Chinese PLA. Human IL-2 was produced by Genzyme Corporation. MAIN OUTCOME MEASURES: IL-2 expression at different time points after transfection of human brain glioma cells with varying MOI of Vaccinia viral vectors; in vitro proliferation capacity of human brain glioma cells among the 4 groups. RESULTS: IL-2 expression was detectable 4 hours after Vaccinia viral vector transfection and reached 300 kU/L by 8 hours. There was no significant difference in the proliferating rate of human brain glioma cells among the 4 groups (P > 0.05).CONCLUSION: Vaccinia viral vectors can transfect human brain glioma cells in vitro and express high levels of IL-2. Vaccinia virus and high IL-2 expression do not influence the proliferation rate of human brain glioma cells in vitro.

  7. Expression and prognostic value of the WEE1 kinase in gliomas

    DEFF Research Database (Denmark)

    Music, Darija; Dahlrot, Rikke Hedegaard; Hermansen, Simon Kjær

    2016-01-01

    to irradiation and temozolomide. However, expression level and prognostic potential of WEE1 protein in gliomas remain uninvestigated. In this study, glioma samples from 235 patients across all four WHO grades were analyzed by immunohistochemistry. Using image analysis, we calculated the area fraction of WEE1...

  8. Malignant glioma of the optic chiasm eight years after radiotherapy for prolactinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hufnagel, T.J.; Kim, J.H.; Lesser, R.; Miller, J.M.; Abrahams, J.J.; Piepmeier, J.; Manuelidis, E.E.

    1988-12-01

    A 41-year-old man had rapidly progressive visual loss caused by a malignant glioma that developed in the optic chiasm eight years after radiation therapy for a recurrent prolactinoma. Radiation-induced glioma should be considered as a cause of progressive visual loss in patients who have received irradiation in the region of the sella turcica.

  9. Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance.

    Science.gov (United States)

    Shahi, M H; Farheen, S; Mariyath, M P M; Castresana, J S

    2016-11-01

    Chemoresistance is a common hurdle for the proper treatment of gliomas. The role of Shh-Gli1 signaling in glioma progression has been reported. However, its role in glioma chemoresistance has not been well studied yet. In this work, we found that Shh-Gli1 signaling regulates the expression of one stem cell marker, BMI1 (B cell-specific Moloney murine leukemia virus), in glioma. Interestingly, we also demonstrated high expression of MRP1 (multi-drug resistance protein 1) in glioma. MRP1 expression was decreased by BMI1 siRNA and Shh-Gli1 cell signaling specific inhibitor GANT61 in our experiments. GANT61 very efficiently inhibited cell colony growth in glioma cell lines, compared to temozolomide. Moreover, a synergic effect of GANT61 and temozolomide drastically decreased the LD50 of temozolomide in the cell colony experiments. Therefore, our results suggest that there is a potential nexus of Shh-Gli1-BMI1 cell signaling to regulate MRP1 and to promote chemoresistance in glioma. Henceforth, our study opens the possibility of facing new targets, Gli1 and BMI1, for the effective treatment of glioma suppression of chemoresistance with adjuvant therapy of GANT61 and temozolomide.

  10. The epidemiology of glioma in adults: a "state of the science" review.

    Science.gov (United States)

    Ostrom, Quinn T; Bauchet, Luc; Davis, Faith G; Deltour, Isabelle; Fisher, James L; Langer, Chelsea Eastman; Pekmezci, Melike; Schwartzbaum, Judith A; Turner, Michelle C; Walsh, Kyle M; Wrensch, Margaret R; Barnholtz-Sloan, Jill S

    2014-07-01

    Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O⁶-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine-phosphate-guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults.

  11. MiR-661 inhibits glioma cell proliferation, migration and invasion by targeting hTERT

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zhen, E-mail: lizhen7111@163.com [Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, 110004 (China); Liu, Yun-hui; Diao, Hong-yu [Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, 110004 (China); Ma, Jun [Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, Liaoning Province, 110001 (China); Yao, Yi-long [Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, 110004 (China)

    2015-12-25

    In this study, we analyzed the functional role of miR-661 in glioma cell proliferation, migration and invasion. We found that overexpression of miR-661 obviously suppressed the proliferation, migration and invasion of glioma cells. MiRNA target prediction algorithms implied that hTERT is a candidate target gene for miR-661. A fluorescent reporter assay confirmed that miR-661 could lead to hTERT gene silencing by recognizing and specifically binding to the predicted site of the hTERT mRNA 3′ untranslated region (3′UTR) specifically. Furthermore, hTERT knockdown significantly decreased the growth and viability of glioma cells. These results indicate that miR-661 can inhibit glioma cell proliferation, migration and invasion by targeting hTERT. - Highlights: • MiR-661 was downregulated in glioma tissues and functional as a tumor suppressor. • MiR-661 modulates cell proliferation, invasion and migration of glioma cells. • MiR-661 directly target hTERT in glioma cells. • MiR-661 inhibits glioma cell tumorgenesis by targeting hTERT.

  12. Delta-24-RGD oncolytic adenovirus elicits anti-glioma immunity in an immunocompetent mouse model

    NARCIS (Netherlands)

    H. Jiang (Hao); K. Clise-Dwyer (Karen); K.E. Ruisaard (Kathryn); X. Fan (Xuejun); W. Tian (Weihua); J. Gumin (Joy); M.L.M. Lamfers (Martine); A. Kleijn (Anne); F.F. Lang (Frederick); S. Yung (Sun); L.M. Vence (Luis); C. Gomez-Manzano (Candelaria); J. Fueyo (Juan)

    2014-01-01

    textabstractBackground: Emerging evidence suggests anti-cancer immunity is involved in the therapeutic effect induced by oncolytic viruses. Here we investigate the effect of Delta-24-RGD oncolytic adenovirus on innate and adaptive anti-glioma immunity. Design: Mouse GL261-glioma model was set up in

  13. Hedgehog signaling sensitizes glioma stem cells to endogenous nano-irradiation

    NARCIS (Netherlands)

    Morgenroth, Agnieszka; Vogg, Andreas T J; Ermert, Katja; Zlatopolskiy, Boris; Mottaghy, Felix M

    2014-01-01

    The existence of therapy resistant glioma stem cells is responsible for the high recurrence rate and incurability of glioblastomas. The Hedgehog pathway activity plays an essential role for self-renewal capacity and survival of glioma stem cells. We examined the potential of the Sonic hedgehog ligan

  14. Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk

    DEFF Research Database (Denmark)

    Amirian, E Susan; Zhou, Renke; Wrensch, Margaret R

    2016-01-01

    BACKGROUND: Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Gliom...

  15. Influence of serum and albumin on the in vitro anandamide cytotoxicity toward C6 glioma cells assessed by the MTT cell viability assay: implications for the methodology of the MTT tests.

    Science.gov (United States)

    Bilmin, Krzysztof; Kopczyńska, Beata; Grieb, Paweł

    2013-01-01

    Anandamide (AEA), an endogenous ligand of cannabinoid CB1 and CB2 receptors, which also binds transient receptor potential vanilloid type 1 receptor (TRPV1), has been shown to display substantial selective cytotoxicity toward some cancer cell lines in vitro, although the relevant data are not consistent. In the present study, we employed the MTT test to assess short-term cytotoxicity of AEA on C6 rat glioma cell culture. When anandamide was administered to the culture medium with foetal bovine serum (FBS), no cytotoxic effect was observed following 24 h exposure of the glioma cells to micromolar concentrations of AEA. However, if no serum was present in the medium, micro-to-submicromolar concentrations of AEA induced dose-dependent cytotoxicity clearly detectable after 24 h. Control experiments made it possible to exclude significant interference of serum with the MTT test per se. Bovine serum albumin mimicked the effect of FBS. We conclude that the apparent inhibition of short-term cytotoxicity of AEA toward C6 rat glioma cells in vitro is caused by binding AEA to serum proteins such as albumin. Taking into account that blood serum or albumin is practically always present in cell culture media, we discuss implications of binding substances to serum proteins for methodology and interpretation of in vitro cytotoxicity testing.

  16. Contributions of aryl hydrocarbon receptor genetic variants to the risk of glioma and PAH-DNA adducts.

    Science.gov (United States)

    Gu, Aihua; Ji, Guixiang; Jiang, Tao; Lu, Ailin; You, Yongping; Liu, Ning; Luo, Chengzhang; Yan, Wei; Zhao, Peng

    2012-08-01

    The aryl hydrocarbon receptor (AHR) gene is involved in the response to polycyclic aromatic hydrocarbon (PAH) exposure. To investigate the hypothesis that the genetic variants in the AHR gene might be a causal genetic susceptibility to PAH-DNA adduct formation and glioma risk, we conducted a case-control study of 384 glioma cases and 384 cancer-free controls to explore the association between six common single-nucleotide polymorphisms of the AHR gene and glioma risk. Using PAH-DNA adducts as biomarkers, we then evaluated the association between PAH-DNA adduct levels and glioma risk based on a tissue microarray including 11 controls and 77 glioma patients. We further explored the contributions of the glioma risk-associated AHR polymorphisms to the levels of PAH-DNA adducts in glioma tissues based on 77 glioma patients. We found that PAH-DNA adduct staining existed in normal brain tissues and grades I-IV gliomas, and the staining intensity was significantly associated with the glioma grade. Two AHR polymorphisms (rs2066853 and rs2158041) demonstrated significant association with glioma risk. Intriguingly, we also found statistically significant associations between these two variants and PAH-DNA adduct levels in glioma tissue. These data suggest the contributions of AHR rs2066853 and rs2158041 to glioma risk and the PAH-DNA adduct levels, which shed new light on gene-environment interactions in the etiology of glioma. Further studies with a larger sample size and ethnically diverse populations are required to elucidate the potential biological mechanism for, as well as the impact of, the susceptibility to glioma due to genetic variants of AHR.

  17. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    Energy Technology Data Exchange (ETDEWEB)

    Massi, Paola [Department of Pharmacology, Chemotherapy and Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan (Italy); Valenti, Marta; Solinas, Marta; Parolaro, Daniela, E-mail: daniela.parolaro@uninsubria.it [Department of Structural and Functional Biology, Section of Pharmacology, Center of Neuroscience, University of Insubria, Via A. da Giussano 10, 20152 Busto Arsizio, Varese (Italy)

    2010-05-26

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells.

  18. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Paola Massi

    2010-05-01

    Full Text Available Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells.

  19. Stathmin expression in glioma-derived microvascular endothelial cells: a novel therapeutic target.

    Science.gov (United States)

    Dong, Baijing; Mu, Luyan; Qin, Xiangying; Qiao, Wanchen; Liu, Xiaodong; Yang, Liming; Xue, Li; Rainov, Nikolai G; Liu, Xiaoqian

    2012-03-01

    The purpose of this study was to investigate stathmin expression and its mechanisms of action in GDMEC. Microvascular endothelial cells were isolated from human gliomas (n=68) and normal brain specimans (n=20), and purified by magnetic beads coated with anti-CD105 antibody. The expression of stathmin mRNA and protein were detected by RT-PCR and western blotting, respectively. Stathmin expression was silenced by application of specific siRNA in high grade GDMEC. The proliferation, apoptosis and invasion behavior of GDMEC were investigated. The stathmin positive rate of endothelial cells in normal brain, grade I-II glioma and grade III-IV glioma was 20, 66 and 95.5%, respectively (Pstathmin, cell viability was reduced, the apoptosis rate increased and the migration of vascular endothelial cells was suppressed significantly (Pstathmin suppressed neoangiogenesis of glioma and provides a potential target for glioma treatment.

  20. Natural killer cells eradicate galectin-1-deficient glioma in the absence of adaptive immunity.

    Science.gov (United States)

    Baker, Gregory J; Chockley, Peter; Yadav, Viveka Nand; Doherty, Robert; Ritt, Michael; Sivaramakrishnan, Sivaraj; Castro, Maria G; Lowenstein, Pedro R

    2014-09-15

    Natural killer (NK) cells safeguard against early tumor formation by destroying transformed target cells in a process referred to as NK immune surveillance. However, the immune escape mechanisms used by malignant brain tumors to subvert this innate type of immune surveillance remain unclear. Here we show that malignant glioma cells suppress NK immune surveillance by overexpressing the β-galactoside-binding lectin galectin-1. Conversely, galectin-1-deficient glioma cells could be eradicated by host NK cells before the initiation of an antitumor T-cell response. In vitro experiments demonstrated that galectin-1-deficient GL26-Cit glioma cells are ∼3-fold more sensitive to NK-mediated tumor lysis than galectin-1-expressing cells. Our findings suggest that galectin-1 suppression in human glioma could improve patient survival by restoring NK immune surveillance that can eradicate glioma cells. Cancer Res; 74(18); 5079-90. ©2014 AACR. ©2014 American Association for Cancer Research.

  1. Application of iron oxide nanoparticles in glioma imaging and therapy: from bench to bedside

    Science.gov (United States)

    Liu, Heng; Zhang, Jun; Chen, Xiao; Du, Xue-Song; Zhang, Jin-Long; Liu, Gang; Zhang, Wei-Guo

    2016-04-01

    Gliomas are the most common primary brain tumors and have a very dismal prognosis. However, recent advancements in nanomedicine and nanotechnology provide opportunities for personalized treatment regimens to improve the poor prognosis of patients suffering from glioma. This comprehensive review starts with an outline of the current status facing glioma. It then provides an overview of the state-of-the-art applications of iron oxide nanoparticles (IONPs) to glioma diagnostics and therapeutics, including MR contrast enhancement, drug delivery, cell labeling and tracking, magnetic hyperthermia treatment and magnetic particle imaging. It also addresses current challenges associated with the biological barriers and IONP design with an emphasis on recent advances and innovative approaches for glioma targeting strategies. Opportunities for future development are highlighted.

  2. Matrine inhibits the invasive properties of human glioma cells by regulating epithelial‑to‑mesenchymal transition.

    Science.gov (United States)

    Wang, Zhongwei; Wu, Yi; Wang, Yali; Jin, Yingying; Ma, Xiulong; Zhang, Yang; Ren, Hongtao

    2015-05-01

    Matrine is reported to be effective in tumor therapies; however, the anti‑metastatic effect and molecular mechanism(s) of matrine on glioma remain poorly understood. Therefore, the purpose of this study was to assess the effects of matrine on glioma and the associated mechanism(s). In the study, we demonstrated that matrine inhibited the proliferation of glioma cells. We also observed that matrine inhibited the migration and invasion of glioma cells at non‑toxic concentrations. Matrine also decreased the expression of E‑cadherin and increased the expression of N‑cadherin. These results suggest that the anti‑metastatic effect of matrine may be correlated with epithelial‑to‑mesenchymal transition (EMT). Moreover, matrine could reduce the phosphorylation levels of p38 and AKT proteins. In conclusion, these results suggest matrine may be a potential alternative against invasive glioma cells via the p38 MAPK and AKT signaling‑dependent inhibition of EMT.

  3. Comprehensive RNA-seq transcriptomic profiling in the malignant progression of gliomas

    Science.gov (United States)

    Zhao, Zheng; Meng, Fanlin; Wang, Wen; Wang, Zheng; Zhang, Chuanbao; Jiang, Tao

    2017-01-01

    Gliomas are the most common and lethal intracranial tumours. RNA sequencing technologies and advanced data analyses recently enabled the characterization of transcriptomic information, including protein-coding gene expression, non-coding gene expression, alternative splicing, and fusion gene detection, to facilitate detection of diseases and altered phenotypes. As a part of the Chinese Glioma Genome Atlas (CGGA) project, our aim was to delineate comprehensive transcriptome profiling in the malignant progression of human gliomas. Three hundred twenty five gliomas with different grades were collected over the past twelve years. Using the Illumina HiSeq 2,000 system, over 92 million high quality 101-bp paired-end reads were generated per sample, yielding a total of 30 billion reads. This comprehensive dataset will be useful to deepen the comprehensive understanding of gliomas, providing an opportunity to generate new therapies, diagnoses, and preventive strategies. PMID:28291232

  4. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas

    Directory of Open Access Journals (Sweden)

    Torres-Trejo Alejandro

    2007-12-01

    Full Text Available Abstract Background The prognosis for malignant gliomas remains dismal. We addressed the safety, feasibility and preliminary clinical activity of the vaccinations using autologous glioma cells and interleukin (IL-4 gene transfected fibroblasts. Methods In University of Pittsburgh Cancer Institute (UPCI protocol 95-033, adult participants with recurrent glioblastoma multiforme (GBM or anaplastic astrocytoma (AA received gross total resection (GTR of the recurrent tumors, followed by two vaccinations with autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector admixed with irradiated autologous glioma cells. In UPCI 99-111, adult participants with newly diagnosed GBM or AA, following GTR and radiation therapy, received two intradermal vaccinations with the TFG-IL4-Neo-TK-transfected fibroblasts admixed with type-1 dendritic cells (DC loaded with autologous tumor lysate. The participants were evaluated for occurrence of adverse events, immune response, and clinical response by radiological imaging. Results and Discussion In UPCI 95-033, only 2 of 6 participants received the vaccinations. Four other participants were withdrawn from the trial because of tumor progression prior to production of the cellular vaccine. However, both participants who received two vaccinations demonstrated encouraging immunological and clinical responses. Biopsies from the local vaccine sites from one participant displayed IL-4 dose-dependent infiltration of CD4+ as well as CD8+ T cells. Interferon (IFN-γ Enzyme-Linked Immuno-SPOT (ELISPOT assay in another human leukocyte antigen (HLA-A2+ participant demonstrated systemic T-cell responses against an HLA-A2-restricted glioma-associated antigen (GAA epitope EphA2883–891. Moreover, both participants demonstrated clinical and radiological improvement with no evidence of allergic encephalitis, although both participants eventually succumbed with the tumor recurrence. In 99-111, 5 of 6 enrolled participants

  5. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells.

    Science.gov (United States)

    Lin, Hua; Patel, Shaan; Affleck, Valerie S; Wilson, Ian; Turnbull, Douglass M; Joshi, Abhijit R; Maxwell, Ross; Stoll, Elizabeth A

    2017-01-01

    Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells. We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention. We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma. Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

  6. Perampanel in Drug-Resistant Epilepsy with Gliomas Seizure Response to Perampanel in Drug-resistant Epilepsy with Gliomas: Early Observations

    OpenAIRE

    Vecht, Charles; Duran-Peña, Alberto; Houillier, Caroline; Durand, Thomas; Capelle, Laurent; Huberfeld, Gilles

    2017-01-01

    International audience; Drug-resistant epilepsy (DRE) occurs commonly in gliomas, possibly due to a shared mechanism of AMPA-activation involving both seizure activity and tumor growth. We tested the AMPA-receptor blocker perampanel (PER) in patients with DRE in low- and high-grade gliomas. Seizure response was defined as 50% drop in seizure frequency or as seizure-freedom. Cognitive function was examined by computerized test on cognitive speed (CTCS), which is sensitive to the type of cognit...

  7. 氧自由基与脑胶质瘤瘤周水肿关系的实验研究%Relationship Between Oxygen Free Radical and Peritumor Edema in Glioma

    Institute of Scientific and Technical Information of China (English)

    赵心同; 赵洪洋; 姚东晓; 王海均

    2011-01-01

    目的:探讨自由基和脑胶质瘤瘤周水肿的关系.方法:体外培养大鼠C6脑胶质瘤细胞株,采用立体定向技术将细胞株接种在右侧尾状核,建立大鼠脑胶质瘤模型,共60只,术后5天将荷瘤大鼠随机分为3组(EDA高剂量组,EDA低剂量组和对照组),每组各20只,每组10只用来测定荷瘤大鼠瘤周脑组织含水量、SOD活性及MDA含量,剩余10只用来观察荷瘤大鼠生存时间.结果:EDA干预组荷瘤大鼠瘤周脑组织含水量下降,SOD活性增高,MDA含量下降,以EDA高剂量组更为显著.各组荷瘤大鼠瘤周脑组织含水量与SOD活性呈负相关,而与MDA含量呈正相关.且EDA组荷瘤大鼠生存时间延长.结论:由基参与大鼠脑胶质瘤瘤周水肿的形成,自由基清除剂能够减轻大鼠脑胶质瘤瘤周脑组织水肿.%Objective: To investigate the relationship between oxygen free radical and peritumor edema in glioma. Methods: The rat C6 glioma cells were cultivated in vitro. The suspention of C6 glioma cells was stereotaxically injected into right caudate to establish rat C6 glioma model. After surgery, all rat glioma models were randomly classified into 3 groups (edaravone-trteated group in high dose,edaravone-trteated group in low dose and control group). Each group had twenty rats. Ten rats from each group were used to determine the moisture content in peritumor brain tissues, SOD activity and the content of MDA. The other 10 rats were used to detect the survival time after surgery. Results: The decreased moisture and MDA contents in peritumor brain tissues and increased SOD activity were found in edaravune-treated group, especially in high dose. The survival time was longer in edaravone-treated group than that of control group.Conclusion: Oxygen free radical is involved in the formation of peritumor edema in glioma, and the free radical scavenger may reduce the peritumor edema in glioma.

  8. The indolinone MAZ51 induces cell rounding and G2/M cell cycle arrest in glioma cells without the inhibition of VEGFR-3 phosphorylation: involvement of the RhoA and Akt/GSK3β signaling pathways.

    Directory of Open Access Journals (Sweden)

    Joo-Hee Park

    Full Text Available MAZ51 is an indolinone-based molecule originally synthesized as a selective inhibitor of vascular endothelial growth factor receptor (VEGFR-3 tyrosine kinase. This study shows that exposure of two glioma cell lines, rat C6 and human U251MG, to MAZ51 caused dramatic shape changes, including the retraction of cellular protrusions and cell rounding. These changes were caused by the clustering and aggregation of actin filaments and microtubules. MAZ51 also induced G2/M phase cell cycle arrest. This led to an inhibition of cellular proliferation, without triggering significant cell death. These alterations induced by MAZ51 occurred with similar dose- and time-dependent patterns. Treatment of glioma cells with MAZ51 resulted in increased levels of phosphorylated GSK3β through the activation of Akt, as well as increased levels of active RhoA. Interestingly, MAZ51 did not affect the morphology and cell cycle patterns of rat primary cortical astrocytes, suggesting it selectively targeted transformed cells. Immunoprecipitation-western blot analyses indicated that MAZ51 did not decrease, but rather increased, tyrosine phosphorylation of VEGFR-3. To confirm this unanticipated result, several additional experiments were conducted. Enhancing VEGFR-3 phosphorylation by treatment of glioma cells with VEGF-C affected neither cytoskeleton arrangements nor cell cycle patterns. In addition, the knockdown of VEGFR-3 in glioma cells did not cause morphological or cytoskeletal alterations. Furthermore, treatment of VEGFR-3-silenced cells with MAZ51 caused the same alterations of cell shape and cytoskeletal arrangements as that observed in control cells. These data indicate that MAZ51 causes cytoskeletal alterations and G2/M cell cycle arrest in glioma cells. These effects are mediated through phosphorylation of Akt/GSK3β and activation of RhoA. The anti-proliferative activity of MAZ51 does not require the inhibition of VEGFR-3 phosphorylation, suggesting that it is

  9. Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer

    Science.gov (United States)

    Andersson, Ulrika; Wibom, Carl; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Armstrong, Georgina N.; Shete, Sanjay; Lau, Ching C.; Bainbridge, Matthew N.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Lai, Rose; Il'yasova, Dora; Houlston, Richard S.; Schildkraut, Joellen; Bernstein, Jonine L.; Olson, Sara H.; Jenkins, Robert B.; Lachance, Daniel H.; Wrensch, Margaret; Davis, Faith G.; Merrell, Ryan; Johansen, Christoffer; Sadetzki, Siegal; Bondy, Melissa L.; Melin, Beatrice S.; Adatto, Phyllis; Morice, Fabian; Payen, Sam; McQuinn, Lacey; McGaha, Rebecca; Guerra, Sandra; Paith, Leslie; Roth, Katherine; Zeng, Dong; Zhang, Hui; Yung, Alfred; Aldape, Kenneth; Gilbert, Mark; Weinberger, Jeffrey; Colman, Howard; Conrad, Charles; de Groot, John; Forman, Arthur; Groves, Morris; Levin, Victor; Loghin, Monica; Puduvalli, Vinay; Sawaya, Raymond; Heimberger, Amy; Lang, Frederick; Levine, Nicholas; Tolentino, Lori; Saunders, Kate; Thach, Thu-Trang; Iacono, Donna Dello; Sloan, Andrew; Gerson, Stanton; Selman, Warren; Bambakidis, Nicholas; Hart, David; Miller, Jonathan; Hoffer, Alan; Cohen, Mark; Rogers, Lisa; Nock, Charles J; Wolinsky, Yingli; Devine, Karen; Fulop, Jordonna; Barrett, Wendi; Shimmel, Kristen; Ostrom, Quinn; Barnett, Gene; Rosenfeld, Steven; Vogelbaum, Michael; Weil, Robert; Ahluwalia, Manmeet; Peereboom, David; Staugaitis, Susan; Schilero, Cathy; Brewer, Cathy; Smolenski, Kathy; McGraw, Mary; Naska, Theresa; Rosenfeld, Steven; Ram, Zvi; Blumenthal, Deborah T.; Bokstein, Felix; Umansky, Felix; Zaaroor, Menashe; Cohen, Avi; Tzuk-Shina, Tzeela; Voldby, Bo; Laursen, René; Andersen, Claus; Brennum, Jannick; Henriksen, Matilde Bille; Marzouk, Maya; Davis, Mary Elizabeth; Boland, Eamon; Smith, Marcel; Eze, Ogechukwu; Way, Mahalia; Lada, Pat; Miedzianowski, Nancy; Frechette, Michelle; Paleologos, Nina; Byström, Gudrun; Svedberg, Eva; Huggert, Sara; Kimdal, Mikael; Sandström, Monica; Brännström, Nikolina; Hayat, Amina; Tihan, Tarik; Zheng, Shichun; Berger, Mitchel; Butowski, Nicholas; Chang, Susan; Clarke, Jennifer; Prados, Michael; Rice, Terri; Sison, Jeannette; Kivett, Valerie; Duo, Xiaoqin; Hansen, Helen; Hsuang, George; Lamela, Rosito; Ramos, Christian; Patoka, Joe; Wagenman, Katherine; Zhou, Mi; Klein, Adam; McGee, Nora; Pfefferle, Jon; Wilson, Callie; Morris, Pagan; Hughes, Mary; Britt-Williams, Marlin; Foft, Jessica; Madsen, Julia; Polony, Csaba; McCarthy, Bridget; Zahora, Candice; Villano, John; Engelhard, Herbert; Borg, Ake; Chanock, Stephen K; Collins, Peter; Elston, Robert; Kleihues, Paul; Kruchko, Carol; Petersen, Gloria; Plon, Sharon; Thompson, Patricia; Johansen, C.; Sadetzki, S.; Melin, B.; Bondy, Melissa L.; Lau, Ching C.; Scheurer, Michael E.; Armstrong, Georgina N.; Liu, Yanhong; Shete, Sanjay; Yu, Robert K.; Aldape, Kenneth D.; Gilbert, Mark R.; Weinberg, Jeffrey; Houlston, Richard S.; Hosking, Fay J.; Robertson, Lindsay; Papaemmanuil, Elli; Claus, Elizabeth B.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Sloan, Andrew E.; Barnett, Gene; Devine, Karen; Wolinsky, Yingli; Lai, Rose; McKean-Cowdin, Roberta; Il'yasova, Dora; Schildkraut, Joellen; Sadetzki, Siegal; Yechezkel, Galit Hirsh; Bruchim, Revital Bar-Sade; Aslanov, Lili; Sadetzki, Siegal; Johansen, Christoffer; Kosteljanetz, Michael; Broholm, Helle; Bernstein, Jonine L.; Olson, Sara H.; Schubert, Erica; DeAngelis, Lisa; Jenkins, Robert B.; Yang, Ping; Rynearson, Amanda; Andersson, Ulrika; Wibom, Carl; Henriksson, Roger; Melin, Beatrice S.; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Merrell, Ryan; Lada, Patricia; Wrensch, Margaret; Wiencke, John; Wiemels, Joe; McCoy, Lucie; McCarthy, Bridget J.; Davis, Faith G.

    2014-01-01

    Background Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes. PMID:24723567

  10. Probing the Bi-directional Interaction Between Microglia and Gliomas in a Tumor Microenvironment on a Microdevice.

    Science.gov (United States)

    Gu, Rui; Zhang, Xu; Zhang, Ge; Tao, Tingting; Yu, Haibo; Liu, Lianqing; Dou, Ying; Li, Aiping; Qin, Jianhua

    2017-02-24

    It has been proven that microglia are involved in both early and late stages of glioma progression and contribute substantially to the tumor mass of gliomas. Because no appropriate in vitro or in vivo investigative approach is available, the dynamic interaction between microglia and gliomas during tumor formation remains unclear. In this study, three types of microfluidic assay were developed to examine the outcomes of the dynamic interaction between microglia and gliomas. Co-migration assay and two-dimensional cell co-culture assay have been used to show that microglial BV-2 cells migrate toward C6 glioma cells and inhibit tumor growth during the early stage of tumorigenesis. However, in three-dimensional cell spheres (three-dimensional cell co-culture assay) that contain a large amount of glioma cells, mimicking the late stage of glioma growth, the phagocytosis of microglia was suppressed, which suggests that glioma cells could reeducate classically activated microglia into a tumor-promoting state at some point during tumor progression. Notably, we found that microglia could contribute to tumor invasion and acquisition of the epithelial-mesenchymal transition phenotype in the glioma microenvironment during the early stage and the late stage of tumor progression. In conclusion, we have developed a potential quantitative method for in vitro study of glioma immunity and provided evidence for the duality of glioma-associated microglia.

  11. Relation of Cystatin C and Cathepsin B Expression to the Pathological Grade and Invasion of Human Gliomas

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    OBJECTIVE To explore the relation of cystatin C and cathepsin B expression to the pathological grade and invasion of human gliomas.METHODS A immunohistochemical method was used to detect the expression of cystatin C and cathepsin B in 57 glioma samples.RESULTS The expression of cystatin C in high-grade (Grade Ⅲ~Ⅳ )gliomas was significantly weaker than that in low-grade(Grade Ⅰ~Ⅱ, P=0.0001).On the other hand, the expression of cathepsin B in high-grade gliomas was significantly stronger than that in low-grade (P=0.0001). Cystatin C expression correlated inversely with cathepsin B expression in gliomas (P=0.01).CONCLUSION Cystatin C and cathepsin B expression is related to the pathological grade and invasion of gliomas. Combining detection of cystatin C and cathepsin B expressions might provide significant information for clinical assessment of maglignant phenotypes and invasion of gliomas.

  12. Expression and significance of P53 protein and MDM-2 protein in human gliomas

    Institute of Scientific and Technical Information of China (English)

    WANG An-liu; LIU Zhao-xia; LI Guang; ZHANG Li-wei

    2011-01-01

    Background P53 is one of the most studied tumor suppressors in the cancer research, and over 50% of human tumors carry P53 mutations. MDM-2 is amplified and/or ove