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Sample records for c6 rat glioma

  1. Ketamine suppresses the proliferation of rat C6 glioma cells.

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    Niwa, Hidetomo; Furukawa, Ken-Ichi; Seya, Kazuhiko; Hirota, Kazuyoshi

    2017-10-01

    The present study investigated the effects of N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, on the growth of gliomas. To analyze the effects of ketamine treatment, rat C6 glioma cells arising from astrocytes, and RNB cells representing non-malignant astrocytes, were examined. In ketamine-treated C6 cells, the gene expression changes associated with cell proliferation following ketamine treatment were evaluated using a cDNA microarray. A cell proliferation assay was performed to analyze the dose-dependent proliferation of C6 glioma and RNB cells following culture (72 h) with ketamine treatment (0-100 µM). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed following cell incubation with/without ketamine, to confirm if the ketamine-induced cell death of C6 glioma and RNB cells were due to apoptosis. In addition, cell proliferation and TUNEL assays were performed following cell incubations with a selective NMDAR antagonist, D-2-amino-5-phosphonovaleric acid (D-AP5). Analysis of the cDNA microarray indicated that the growth of C6 glioma cells were suppressed by the effects of ketamine. Furthermore, results of the proliferation assay confirmed that ketamine treatment inhibited C6 cell proliferation, most notably at a dose of 30 µM (n=7, 66.4%; Pcells, with a significant effect on the rate of death observed at all tested concentrations (3, 10, 30 and 100 µM). Results of the aforementioned proliferation and TUNEL assay experiments were reproduced when ketamine was replaced with a selective NMDAR antagonist, D-AP5. However, the NMDARantagonist-induced effects were not observed in RNB cell cultures. Although it would be premature to apply the results from the present study to human cases, these results indicated that ketamine is an anesthetic candidate providing potential benefit for glioma resection.

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

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    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.

  3. Evaluation of rat C6 malignant glioma using spectral computed tomography.

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    Liu, Jianli; Zhou, Junlin; Li, Jie; Zhang, Lingyan; Zhang, Peili; Liu, Bin

    2017-08-01

    To investigate the use of multi-parameter spectral computed tomography (CT) for the evaluation of rat C6 glioma, 15 male Wistar rats were seeded with C6 glioma cells into the right basal ganglia and scanned 12 days later using spectral CT. Brain sections corresponding to scanned regions were immunostained for proliferation marker protein Ki67 (Ki67). Pearson's correlation coefficients between spectral CT parameters and Ki67 expression were determined. Thirteen rats survived 12 days and developed tumors. Optimal contrast-to-noise ratio achieved was 65 keV. Brain regions containing liquefactive necrosis, solid tumor, peripheral tumor and normal tissue differed significantly with regard to the spectral curve slope (0.24±0.46, 1.81±1.09, 0.8±0.43 and 0.11±0.27, respectively; Pspectral curve slope (r=0.821; PSpectral CT can detect microstructural changes within malignant gliomas and potentially provide important information regarding tumor proliferation and the extent of the invasion.

  4. Cinnamon polyphenols regulate S100β, sirtuins, and neuroactive proteins in rat C6 glioma cells.

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    Qin, Bolin; Panickar, Kiran S; Anderson, Richard A

    2014-02-01

    Increasing evidence suggests that cinnamon has many health benefits when used in herbal medicine and as a dietary ingredient. The aim of this study was to investigate the effects of an aqueous extract of cinnamon, high in type A polyphenols, on molecular targets in rat C6 glioma cells that underlie their protective effects. C6 rat glioma cells were seeded in 35-mm culture dishes or six-well plates, then were incubated with cinnamon polyphenols at doses of 10 and 20 μg/mL for 24 h. The targeting protein expression, secretion, and phosphorylation were evaluated by immunoprecitation/immunoblotting and immunofluorescence imaging. Cinnamon polyphenols significantly enhanced secretion of S100β, a Ca(2+)-binding protein, and increased intracellular S100β expression after 24 h of incubation, in rat C6 glioma cells. Cinnamon polyphenols also enhanced protein levels of sirtuin 1, 2, and 3, deacetylases important in cell survival, and the tumor suppressor protein, p53, and inhibited the inflammatory factors, tumor necrosis factor alpha, and phospho-p65, a subunit of nuclear factor-κβ. Cinnamon polyphenols also up-regulated levels of phospho-p38, extracellular signal-regulated protein and mitogen-activated protein and kinase-activated protein kinases that may be important for prosurvival functions. Our results indicate that the effects of cinnamon polyphenols on upregulating prosurvival proteins, activating mitogen-activated protein kinase pathways, and decreasing proinflammatory cytokines may contribute to their neuroprotective effects. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Enhancement effect of cytotoxicity response of silver nanoparticles combined with thermotherapy on C6 rat glioma cells.

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    Wang, Rui; Chen, Chunmei; Yang, Weizhong; Shi, Songsheng; Wang, Chunhua; Chen, Jing

    2013-06-01

    The present studies reveal that silver nanoparticles (AgNPs) can induce apoptosis and enhance radio-sensitivity on cancer cells. In this paper, we mainly investigated the effect of AgNPs on rat glioma C6 cells upon the combination treatment of hyperthermia treatment (HTT). AgNPs were synthesized by a polyol process and the mean size was 15 nm. The particles showed dose-dependent cytotoxicity on C6 cells from the experimental data. Besides, we found that heating cells could enhance the contents of cell uptake of AgNPs. From the survival curves, AgNPs showed the ability to enhance thermo-sensitivity on C6 cells. Our results revealed that AgNPs could have a potential application in enhancing effect on HTT induced killing of glioma cells.

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

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    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

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

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    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.

  8. C6 glioma cell invasion and migration of rat brain after neural homografting: ultrastructure.

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    Bernstein, J J; Goldberg, W J; Laws, E R; Conger, D; Morreale, V; Wood, L R

    1990-04-01

    C6 tumor cells (10(6] were grafted as suspensions into freshly made implantation pockets in rat host cerebral cortex. Specimens were prepared for transmission and scanning electron microscopy 1 to 7 days postimplantation (DPI). By 3 DPI vacuolated C6 cells had migrated on or invaded the host brain. C6 cells were observed on the glia limitans on the surface of the brain, in the corpus callosum, subependymal space, and perivascular space and had invaded the cortex under the implantation pocket. In addition to the tumor mass that was observed under the implantation pocket, by 7 DPI individual C6 cells had migrated into the corpus callosum and internal capsule. Migrated C6 cells were observed in a perineuronal position in the hippocampus and other gray matter structures inferior to the corpus callosum. Micropockets were found around each C6 cell and the processes of these cells had replaced host parenchyma. The preferred routes of migration were on basal lamina and parallel and intersecting nerve fiber bundles. Invasion occurred through gray and white matter. The movement of homografted C6 cells in the brain suggests that these cells actively migrate as individual cells in addition to invading as a mass.

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

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    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.

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

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    Yeung, Timothy Pok Chi; Kurdi, Maher; Wang, Yong; Al-Khazraji, Baraa; Morrison, Laura; Hoffman, Lisa; Jackson, Dwayne; Crukley, Cathie; Lee, Ting-Yim; Bauman, Glenn; Yartsev, Slav

    2014-01-01

    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. 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. 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 Pstereotactic 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 (Pstereotactic 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.

  11. 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

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    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

  12. Gene Therapy with HSV1-sr39TK/GCV Exhibits a Stronger Therapeutic Efficacy Than HSV1-TK/GCV in Rat C6 Glioma Cells

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    Lei-qing Li

    2013-01-01

    Full Text Available Although the combination of herpes simplex virus type 1 (HSV-1 thymidine kinase (TK with ganciclovir (GCV has been shown as a promising suicide gene treatment strategy for glioma, the almost immunodepressive dose of GCV required for its adequate in vivo efficacy has hampered its further clinical application. Therefore, In order to reduce the GCV dose required, we aim to compare the therapeutic efficacy of HSV1-sr39TK, an HSV1-TK mutant with increased GCV prodrug catalytic activity, with wildtype TK in C6 glioma cells. Accordingly, rat C6 glioma cells were first transfected with pCDNA-TK and pCDNA-sr39TK, respectively, and the gene transfection efficacy was verified by immunocytochemistry and western blot analysis. Then the in vivo sensitivity of these transfected C6-TK and C6-sr39TK cells to GCV was determined by 3-(4,5-dimethylthiahiazo-(-z-y1-3,5-di-phenytetrazoliumromide (MTT colorimetric assay and Hoechst-propidium iodide (PI staining. Finally, a subcutaneously C6 xenograft tumor model was established in the nude mice to test the in vitro efficacy of TK/GCV gene therapy. Our results showed that, as compared with wildtype TK, HSV1-sr39TK/GCV demonstrated a stronger therapeutic efficacy against C6 glioma both in vitro and in vivo, which, by reducing the required GCV dose, might warrant its future use in the treatment of glioma under clinical setting.

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

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    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.

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

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    Timothy Pok Chi Yeung

    Full Text Available 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.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.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.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.

  15. Functional Changes of Dendritic Cells in C6 Glioma-Bearing Rats That Underwent Combined Argon-Helium Cryotherapy and IL-12 Treatment.

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    Li, Ming; Cui, Yao; Li, Xiqing; Guo, Yanwu; Wang, Bin; Zhang, Jiadong; Xu, Jian; Han, Shuangyin; Shi, Xiwen

    2016-08-01

    The aim of this study was to explore changes in tumor tissues of glioma-bearing rats that underwent argon-helium cryoablation as well as changes in antitumor immunity before and after combined interleukin 12 treatment. Two hundred sixty Wistar rats were randomly divided into a blank control group, intravenous injection interleukin-12 group, cryotherapy group, and cryotherapy + intravenous injection group. C6 glioma cells proliferated in vitro were implanted subcutaneously on the backs of rats to establish C6 glioma-bearing animal models. Each group underwent the corresponding treatments, and morphological changes in tumor tissues were examined using hematoxylin-eosin staining. CD11c staining was examined using immunohistochemistry, and differences in dendritic cells and T-cell subsets before and after treatment were analyzed using flow cytometry. The control group showed no statistical changes in terms of tumor tissue morphology and cellular immunity, cryotherapy group, and cryotherapy + intravenous injection group, among which the count for the cryotherapy + intravenous injection group was significantly higher than those of all other groups. In the argon-helium cryotherapy group, tumor cells were damaged and dendritic cell markers were positive. The number of CD11c+ and CD86+ cells increased significantly after the operation as did the cytokine interferon-γ level (P < .01), suggesting a shift toward Th1-type immunity. Combined treatment of argon-helium cryoablation and interleukin 12 for gliomas not only effectively injured tumor tissues but also boosted immune function and increased antitumor ability. Therefore, this approach is a promising treatment measure for brain gliomas. © The Author(s) 2015.

  16. Intracellular labeling and quantification process by magnetic resonance imaging using iron oxide magnetic nanoparticles in rat C6 glioma cell line

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    Edson Amaro Junior

    2012-06-01

    Full Text Available 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 T1 and T2weighted 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 relaxivities of the aminosilane-coated magnetic nanoparticles with a hydrodynamic diameter of 50nm to a 3-T field were r1=(6.1±0.3×10-5 ms-1mL/μg, r2=(5.3±0.1× 10-4 ms-1mL/μg, with a ratio of r2 / r1 ≅ 9. The iron uptake in the cells was calculated by analyzing the relaxation rates (R1 and R2 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 r2 / r1 ≅ 9 indicates that these magnetic nanoparticles are ideal for quantification by magnetic resonance imaging with T2-weighted imaging techniques.

  17. Alterations of the Blood-Brain Barrier and Regional Perfusion in Tumor Development: MRI Insights from a Rat C6 Glioma Model.

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    Monika Huhndorf

    Full Text Available Angiogenesis and anti-angiogenetic medications play an important role in progression and therapy of glioblastoma. In this context, in vivo characterization of the blood-brain-barrier and tumor vascularization may be important for individual prognosis and therapy optimization.We analyzed perfusion and capillary permeability of C6-gliomas in rats at different stages of tumor-growth by contrast enhanced MRI and dynamic susceptibility contrast (DSC MRI at 7 Tesla. The analyses included maps of relative cerebral blood volume (CBV and signal recovery derived from DSC data over a time period of up to 35 days after tumor cell injections.In all rats tumor progression was accompanied by temporal and spatial changes in CBV and capillary permeability. A leakage of the blood-brain barrier (slow contrast enhancement was observed as soon as the tumor became detectable on T2-weighted images. Interestingly, areas of strong capillary permeability (fast signal enhancement were predominantly localized in the center of the tumor. In contrast, the tumor rim was dominated by an increased CBV and showed the highest vessel density compared to the tumor center and the contralateral hemisphere as confirmed by histology.Substantial regional differences in the tumor highlight the importance of parameter maps in contrast or in addition to region-of-interest analyses. The data vividly illustrate how MRI including contrast-enhanced and DSC-MRI may contribute to a better understanding of tumor development.

  18. Alterations of the Blood-Brain Barrier and Regional Perfusion in Tumor Development: MRI Insights from a Rat C6 Glioma Model.

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    Huhndorf, Monika; Moussavi, Amir; Kramann, Nadine; Will, Olga; Hattermann, Kirsten; Stadelmann, Christine; Jansen, Olav; Boretius, Susann

    2016-01-01

    Angiogenesis and anti-angiogenetic medications play an important role in progression and therapy of glioblastoma. In this context, in vivo characterization of the blood-brain-barrier and tumor vascularization may be important for individual prognosis and therapy optimization. We analyzed perfusion and capillary permeability of C6-gliomas in rats at different stages of tumor-growth by contrast enhanced MRI and dynamic susceptibility contrast (DSC) MRI at 7 Tesla. The analyses included maps of relative cerebral blood volume (CBV) and signal recovery derived from DSC data over a time period of up to 35 days after tumor cell injections. In all rats tumor progression was accompanied by temporal and spatial changes in CBV and capillary permeability. A leakage of the blood-brain barrier (slow contrast enhancement) was observed as soon as the tumor became detectable on T2-weighted images. Interestingly, areas of strong capillary permeability (fast signal enhancement) were predominantly localized in the center of the tumor. In contrast, the tumor rim was dominated by an increased CBV and showed the highest vessel density compared to the tumor center and the contralateral hemisphere as confirmed by histology. Substantial regional differences in the tumor highlight the importance of parameter maps in contrast or in addition to region-of-interest analyses. The data vividly illustrate how MRI including contrast-enhanced and DSC-MRI may contribute to a better understanding of tumor development.

  19. Simple and effective preparation of nano-pulverized curcumin by femtosecond laser ablation and the cytotoxic effect on C6 rat glioma cells in vitro.

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    Tagami, Tatsuaki; Imao, Yukino; Ito, Shunsuke; Nakada, Akiko; Ozeki, Tetsuya

    2014-07-01

    The pulverization of poorly water-soluble drugs and drug candidates into nanoscale particles is a simple and effective means of increasing their pharmacological effect. Consequently, efficient methods for pulverizing compounds are being developed. Femtosecond lasers, which emit ultrashort laser pulses, can be used to generate nanoscale particles without heating and are finding in various fields, including pharmaceutical science. Laser ablation holds promise as a novel top-down pulverization method for obtaining drug nanoparticles. We used a poorly water-soluble compound, curcumin (diferuloyl methane), to understand the characteristics of femtosecond laser pulverization. Various factors such as laser strength, laser scan speed, and the buffer solution affected the size of the curcumin particles. The minimum curcumin particle size was approximately 500 nm; the particle size was stable after 30 days. In vitro studies suggested that curcumin nanoparticles exhibited a cytotoxic effect on C6 rat glioma cells, and remarkable intracellular uptake of the curcumin nanoparticles was observed. The results suggest that femtosecond laser ablation is a useful approach for preparing curcumin nanoparticles that exhibit remarkable therapeutic effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Cinnamon polyphenols attenuate the hydrogen peroxide-induced down regulation of S100β secretion by regulating sirtuin 1 in C6 rat glioma cells.

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    Qin, Bolin; Panickar, Kiran S; Anderson, Richard A

    2014-04-25

    It is well established that the brain is particularly susceptible to oxidative damage due to its high consumption of oxygen. The objective of this study was to investigate the protective effects of a water soluble polyphenol-rich extract of cinnamon and the possible mechanisms, under conditions of oxidative stress-induced by hydrogen peroxide, in rat C6 glioma cells. After 24h of H2O2 incubation, the secretion and intracellular expression of S100β were determined by immunoprecitation/immunoblotting and immunofluorescence imaging. Cinnamon polyphenols (CP) counteracted the oxidative effects of H2O2 on S100β secretion and expression. CP also enhanced the impaired protein levels of sirtuins 1, 2, and 3, which are deacetylases important in cell survival. H2O2 also induced the overexpression of the proinflammatory factors, TNF-α, phospho-NF-κB p65, as well as of Bcl-xl, Bax and Caspase-3, which are all the members of the Bcl-2 family. CP not only suppressed the expression of these proteins but also attenuated the phosphorylation induced by H2O2. CP also upregulated the decreased Bcl-2 protein levels in H2O2 treated C6 cells. The effects of CP on H2O2-induced downregulation of S100β secretion were blocked by SIRT1 siRNA demonstrating that SIRT1 plays a regulatory role in CP-mediated prevention by H2O2. These data demonstrate that Cinnamon polyphenols may exert neuroprotective effects in glial cells by the regulation of Bcl-2 family members and enhancing SIRT1 expression during oxidative stress. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. 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.

  2. Extract from mistletoe, Viscum album L., reduces Hsp27 and 14-3-3 protein expression and induces apoptosis in C6 rat glioma cells.

    Science.gov (United States)

    Uçar, E Ö; Arda, N; Aitken, A

    2012-08-24

    Extracts of mistletoe (Viscum album) are intensively used in complementary medicine, but their mechanisms are not fully understood in most cases, and the effects on metabolism have not been investigated in detail. However, some biologically active natural products are well known to provoke unexpected cellular responses. They reduce overexpression of heat shock proteins (Hsps) in cancer cells. The aim of the current study was to determine whether methanolic extract of V. album, which possesses antioxidant activity, has an effect on expression levels of Hsp27 and 14-3-3 proteins in a C6 glioma cell line. For the first time, the apoptosis-inducing effect of this extract was also determined via caspase-3 activation in the cells. Overexpression of Hsps was induced by heat shock at 42°C for 1 h. Expression levels of Hsp27 and 14-3-3 proteins were determined using Western blot analysis. The apoptosis-inducing effect was also evaluated via caspase-3 activation in C6 glioma cells. Pretreatment of the cells with a nontoxic dose (100 μg/mL) of V. album extract before heat shock significantly reduced expression levels of Hsp27 (73%) and 14-3-3β (124%), 14-3-3γ (23%), and 14-3-3ζ (84%) proteins. Pretreatment with the extract before heat shock increased apoptosis via caspase-3 activation (60%) in C6 glioma cells. This result suggested that the methanolic extract of V. album downregulates expression of Hsp27 and 14-3-3 chaperone proteins and induces apoptosis, which warrants further exploration as a potential bioactive compound for cancer therapy.

  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. In vitro study of haematoporphyrin monomethyl ether-mediated sonodynamic effects on C6 glioma cells.

    Science.gov (United States)

    Li, Jian-hua; Song, Da-yong; Xu, Yong-gang; Huang, Zheng; Yue, Wu

    2008-09-01

    To study the cytotoxicity induced by haematoporphyrin monomethyl ether (HMME)-mediated sonodynamic therapy (SDT) on C6 glioma cells. The potent photosensitizer HMME was used as the sensitizer. Rat C6 glioma cells were incubated with HMME (10 microg/mL) in the dark for 2 h and then subjected to ultrasound treatment at 1.0 MHz and 0.5 W/cm2 for 2 min. The growth inhibition rate at different time points after SDT was determined by MTT assay. The apoptotic rate and cell circle profiles were examined with flow cytometry. Fine structures were observed with transmission electron microscope (TEM). The sonodynamic effect on the glioma cells was also studied in the absence or presence of various reactive oxygen species (ROS) scavengers. The growth inhibition rate of C6 glioma cells after SDT significantly increased. SDT also increased the apoptosis and proliferation rate (APR). TEM examination showed the morphological features of apoptosis or necrosis. The addition of NaN(3) showed a strong protective effect again SDT. Our data indicated that SDT could kill C6 glioma cells in vitro and possibility through induction of apoptosis and necrosis. Singlet oxygen ((1)O2) may play an important role in SDT.

  5. 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.

  6. [Study in the killing effect of Myxoma virus to C6 glioma cell in vitro].

    Science.gov (United States)

    Zang, Meng; Zhang, Qiu-Sheng; Liang, Shi-Jie; Ji, Tao; Lin, Heng-Zhou; Li, Wei-Ping

    2012-02-01

    To evaluate the susceptibility of C6 glioma cells to Myxoma virus and the killing effect of Myxoma virus to the C6 glioma cells in vitro. C6 glioma cells were infected with myxoma virus, used death virus as the negative control, 5-FU as the positive control, DEMD as blank control. The number of living cells were counted every 24 h, and Western-Blot method, inverted microscope and MTT assay were applicated to observe the cell morphology and survival rate in each group. The cell number were decreased rapidly in virus effected group and 5-FU group, with significant differences to the negative and blank control groups. And cells in virus effected group appeared cytopathic effect. C6 glioma cells were susceptible to myxoma virus and myxoma virus had killing effect to C6 glioma cells in vitro.

  7. Fluorine-18-deoxyglucose positron emission tomography/computed tomography with Ki67 and GLUT-1 immunohistochemistry for evaluation of the radiosensitization effect of oleanolic acid on C6 rat gliomas.

    Science.gov (United States)

    Zhang, Yu; Xu, Huiqin; Wang, Hui; Yu, Wenjing; Zhao, Xuefeng; Xue, Yangyang

    2015-01-01

    The aim of this study was to investigate the radiosensitization effect of oleanolic acid (OA) in an in-vivo C6 rat glioma model using fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) and Ki67 and glucose transporter-1 (GLUT-1) immunohistochemistry(IHC) and evaluate the utility of 18F-FDG PET/CT in assessing early changes after radiotherapy. Tumor-bearing rats were divided into four groups: the control group (group A), the OA group(group B), the radiotherapy group (group C), and the OA combined with radiotherapy group (group D). 18F-FDG PET/CT images were obtained to monitor the tumor/muscle (T/M) ratio of 18F-FDG uptake before treatment,1 day after treatment, and 7 days after treatment. Tumor volume changes were also assessed, and hematoxylin and eosin staining and Ki67 and GLUT-1 IHC staining were also carried out. Before treatment, there were no obvious differences between the T/M ratios (F=0.147, P=0.931)and tumor volumes (F=0.177, P=0.911) among the four groups. At day 1 after treatment, statistical differences were observed in the T/M ratios (F=2.891, P=0.05), with decreased values in groups C and D compared with group A(tCA=2.354, tDA=2.356, PGLUT-1 in the four groups (F=16.667, 22.082, and 39.555,PGLUT-1, and our study also found a significant relationship between the expression of Ki67 and the expression of GLUT-1. OA has a radiosensitization effect on C6 rat glioma tumors in vivo, detected using 18F-FDG PET/CT and Ki67 and GLUT-1 IHC staining. 18F-FDG PET/CT is a potentially sensitive tool for the evaluation of early changes after radiotherapy.

  8. Effect of Aspirin and Indomethacin on Prostaglandin E2 Synthesis in C6 Glioma Cells

    OpenAIRE

    Hwang, Shiuh-Lin; Lee, Kung-Shing; Lin, Chih-Lung; Lieu, Ann-Shung; Cheng, Chi-Yun; Loh, Joon-Khim; Hwang, Yan-Fen; Su, Yu-Feng; Howng, Shen-Long

    2004-01-01

    Prostaglandin E2 (PGE2) plays an important role in immunosuppression and tumor growth. PGE2 inhibitors such as aspirin and indomethacin suppress experimental tumor growth. Little is known of the relationship between PGE2 synthesis in brain tumors and the dose of aspirin or indomethacin. The present study was undertaken to evaluate the effect of different doses of aspirin and indomethacin on PGE2 synthesis in C6 glioma cells. C6 glioma cells were incubated with different concentrations (2, 4, ...

  9. Visualization of experimental glioma C6 by MRI with magnetic nanoparticles conjugated with monoclonal antibodies to vascular endothelial growth factor.

    Science.gov (United States)

    Abakumov, M A; Shein, S A; Vishvasrao, H; Nukolova, N V; Sokol'ski-Papkov, M; Sandalova, T O; Gubskii, I L; Grinenko, N F; Kabanov, A V; Chekhonin, V P

    2012-12-01

    We developed a method for obtaining iron oxide nanoparticles and their conjugation with monoclonal antibodies to vascular endothelial growth factor. The resultant vector nanoparticles were low-toxic and the antibodies retained their immunochemical activity after conjugation. The study was carried out on rats with intracranial glioma C6 on day 14 after its implantation. The intravenously injected nanoparticles visualized the brain tumor in contrast to nanoparticles conjugated with nonspecific immunoglobulins that did not accumulate in the tumor.

  10. Uptake and Toxicity of Copper Oxide Nanoparticles in C6 Glioma Cells.

    Science.gov (United States)

    Joshi, Arundhati; Rastedt, Wiebke; Faber, Kathrin; Schultz, Aaron G; Bulcke, Felix; Dringen, Ralf

    2016-11-01

    Copper oxide nanoparticles (CuO-NPs) are frequently used for many technical applications, but are also known for their cell toxic potential. In order to investigate a potential use of CuO-NPs as a therapeutic drug for glioma treatment, we have investigated the consequences of an application of CuO-NPs on the cellular copper content and cell viability of C6 glioma cells. CuO-NPs were synthesized by a wet-chemical method and were coated with dimercaptosuccinic acid and bovine serum albumin to improve colloidal stability in physiological media. Application of these protein-coated nanoparticles (pCuO-NPs) to C6 cells caused a strong time-, concentration- and temperature-dependent copper accumulation and severe cell death. The observed loss in cellular MTT-reduction capacity, the loss in cellular LDH activity and the increase in the number of propidium iodide-positive cells correlated well with the specific cellular copper content. C6 glioma cells were less vulnerable to pCuO-NPs compared to primary astrocytes and toxicity of pCuO-NPs to C6 cells was only observed for incubation conditions that increased specific cellular copper contents above 20 nmol copper per mg protein. Both cellular copper accumulation as well as the pCuO-NP-induced toxicity in C6 cells were prevented by application of copper chelators, but not by endocytosis inhibitors, suggesting that liberation of copper ions from the pCuO-NPs is the first step leading to the observed toxicity of pCuO-NP-treated glioma cells.

  11. Effect of Aspirin and Indomethacin on Prostaglandin E2 Synthesis in C6 Glioma Cells

    Directory of Open Access Journals (Sweden)

    Shiuh-Lin Hwang

    2004-01-01

    Full Text Available Prostaglandin E2 (PGE2 plays an important role in immunosuppression and tumor growth. PGE2 inhibitors such as aspirin and indomethacin suppress experimental tumor growth. Little is known of the relationship between PGE2 synthesis in brain tumors and the dose of aspirin or indomethacin. The present study was undertaken to evaluate the effect of different doses of aspirin and indomethacin on PGE2 synthesis in C6 glioma cells. C6 glioma cells were incubated with different concentrations (2, 4, and 8 μM of aspirin and indomethacin for 1, 2, 4, 6, 8, 12, and 24 hours. Intracellular PGE2 concentration was measured by enzyme immunoassay. Each concentration of aspirin and indomethacin effectively inhibited PGE2 synthesis. Concentrations of 2, 4, and 8 μM of aspirin significantly inhibited PGE2 production at 6, 4, and 1 hours, respectively, and the inhibition persisted for more than 24 hours (p 0.05. Indomethacin 8 μM was effective at 1 hour and the inhibition persisted beyond 24 hours (p < 0.05. Our study demonstrates that aspirin and indomethacin inhibit PGE2 synthesis in C6 glioma cells and that low-dose aspirin is as effective as high-dose aspirin. This study may encourage future clinical use of low-dose aspirin in the prevention or treatment of brain tumors.

  12. 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.

  13. 27-Hydroxycholesterol regulates cholesterol synthesis and transport in C6 glioma cells.

    Science.gov (United States)

    An, Yu; Zhang, Dan-Di; Yu, Huan-Ling; Ma, Wei-Wei; Lu, Yan-Hui; Liu, Quan-Ri; Xiao, Rong

    2017-03-01

    The oxysterol 27-Hydroxycholesterol (27-OHC) is a major cholesterol metabolite that can cross the blood brain barrier (BBB) from peripheral circulation to the brain. Currently, the role of 27-OHC on cholesterol homeostasis in astrocytes and the underlying mechanisms are not defined. Since all brain cholesterol is essentially synthesized in brain itself and astrocytes as net producers of cholesterol are essential for normal brain function, here we investigated the effects of 27-OHC on cholesterol synthesis and transport in C6 glioma cells. C6 cells were treated with 5, 10 and 20μM 27-OHC for 24h and the cell viability and apoptosis, the cholesterol levels and metabolism-related mediators, genes and proteins were subsequently assessed using cell-counting kit (CCK)-8, Amplex red, ELISA, real-time PCR and Western blot, respectively. We found that 27-OHC decreased cholesterol levels by down-regulating the expression of sterol-regulated element binding protein-1 (SREBP-1a), 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low density lipoprotein receptor (LDLR) and promoted cholesterol transport by up-regulating the expression of peroxisome proliferator-activated receptors-γ (PPAR-γ), liver X receptor-α (LXR-α), ATP-binding cassette transporter protein family member A1 (ABCA1) and apolipoprotein E (ApoE)genes. Our results suggested that 27-OHC may represent a sensitive modulator of cholesterol metabolism disorder by suppressing cholesterol synthesis and stimulating cholesterol transport in astrocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Hydrophobic fractal surface from glycerol tripalmitate and the effects on C6 glioma cell growth.

    Science.gov (United States)

    Zhang, Shanshan; Chen, Xuerui; Yu, Jing; Hong, Biyuan; Lei, Qunfang; Fang, Wenjun

    2016-06-01

    To provide a biomimic environment for glial cell culture, glycerol tripalmitate (PPP) has been used as a raw material to prepare fractal surfaces with different degrees of hydrophobicity. The spontaneous formation of the hydrophobic fractal surfaces was monitored by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The surface morphologies were observed by a scanning electron microscope (SEM), and then the fractal dimension (FD) values of the surfaces were determined with the box-counting method. C6 glioma cells were cultured and compared on different hydrophobic PPP surfaces and poly-L-lysine (PLL)-coated surface. The cell numbers as a function of incubation time on different surfaces during the cell proliferation process were measured, and the cell morphologies were observed under a fluorescence microscope. Influences of hydrophobic fractal surfaces on the cell number and morphology were analyzed. The experimental results show that the cell proliferation rates decrease while the cell morphology complexities increase with the growth of the fractal dimensions of the PPP surfaces. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Endogenous expression of histamine H1 receptors functionally coupled to phosphoinositide hydrolysis in C6 glioma cells: regulation by cyclic AMP.

    OpenAIRE

    Peakman, M C; Hill, S. J.

    1994-01-01

    1. The effects of histamine receptor agonists and antagonists on phospholipid hydrolysis in rat-derived C6 glioma cells have been investigated. 2. Histamine H1 receptor-stimulation caused a concentration-dependent increase in the accumulation of total [3H]-inositol phosphates in cells prelabelled with [3H]-myo-inositol. The rank order of agonist potencies was histamine (EC50 = 24 microM) > N alpha-methylhistamine (EC50 = 31 microM) > 2-thiazolylethylamine (EC50 = 91 microM). 3. The response t...

  16. [Effects of myxoma virus on gliomas of rats models in vivo].

    Science.gov (United States)

    Zhang, Qiu-Sheng; Zhang, Meng; Liang, Shi-Jie; Lin, Heng-Zhou; Ji, Tao; Li, Wei-Ping

    2012-04-01

    To explore the in vivo effects of myxoma virus (MV) on gliomas of rat model. Methods C6 glioma cells were implanted into the frontal lobe of SD rats using stereotactic methods to establish animal models of glioma. C6 glioma cells were implanted into the frontal lobe of SD rats using stereotactic methods to establish animal models of glioma. Models were divided into 4 groups randomly after tumor growth was affirmed, and MV, 5-FU, MV + 5-FU, and denatured myxoma virus (DV) were implanted into the tumors using stereotactic methods, bodyweight, tumor size, expression of glial fibrillary acidic protein (GFAP), Akt of each model were observed. The gliomas in all SD rats were established successfully. And tumor growth in MV, 5-FU, MV + 5-FU were significantly decreased as compared with DV group after injection, sizes of some tumors were lessened, and GFAP expression decreased in MV, 5-FU and MV +5-FU groups. The expression of PI3k, Akt and mTOR were decreased in MV and MV +5-FU groups. C6 glioma SD rat models could be established successfully using stereotactic methods. MV may enhance biological activity of chemotherapeutic drugs on tumor cells of animal models in vivo by regulating some genes of PI3K-Akt-mTOR signal pathway.

  17. Generation of Brain Microvascular Endothelial-Like Cells from Human Induced Pluripotent Stem Cells by Co-Culture with C6 Glioma Cells.

    Directory of Open Access Journals (Sweden)

    Haruka Minami

    Full Text Available The blood brain barrier (BBB is formed by brain microvascular endothelial cells (BMECs and tightly regulates the transport of molecules from blood to neural tissues. In vitro BBB models from human pluripotent stem cell (PSCs-derived BMECs would be useful not only for the research on the BBB development and function but also for drug-screening for neurological diseases. However, little is known about the differentiation of human PSCs to BMECs. In the present study, human induced PSCs (iPSCs were differentiated into endothelial cells (ECs, and further maturated to BMECs. Interestingly, C6 rat glioma cell-conditioned medium (C6CM, in addition to C6 co-culture, induced the differentiation of human iPSC-derived ECs (iPS-ECs to BMEC-like cells, increase in the trans-endothelial electrical resistance, decreased in the dextran transport and up-regulation of gene expression of tight junction molecules in human iPS-ECs. Moreover, Wnt inhibitors attenuated the effects of C6CM. In summary, we have established a simple protocol of the generation of BMEC-like cells from human iPSCs, and have demonstrated that differentiation of iPS-ECs to BMEC-like cells is induced by C6CM-derived signals, including canonical Wnt signals.

  18. Modeling and quantifying biochemical changes in C6 tumor gliomas by Fourier transform infrared imaging.

    Science.gov (United States)

    Beljebbar, Abdelilah; Amharref, Nadia; Lévèques, Antoine; Dukic, Sylvain; Venteo, Lydie; Schneider, Laurence; Pluot, Michel; Manfait, Michel

    2008-11-15

    The purpose of the study was to investigate molecular changes associated with glioma tissues using FT-IR microspectroscopic imaging (FT-IRM). A multivariate statistical analysis allowed one to successfully discriminate between normal, tumoral, peri-tumoral, and necrotic tissue structures. Structural changes were mainly related to qualitative and quantitative changes in lipid content, proteins, and nucleic acids that can be used as spectroscopic markers for this pathology. We have developed a spectroscopic model of glioma to quantify these chemical changes. The model constructed includes individual FT-IR spectra of normal and glioma brain constituents such as lipids, DNA, and proteins (measured on delipidized tissue). Modeling of FT-IR spectra yielded fit coefficients reflecting the chemical changes associated with a tumor. Our results demonstrate the ability of FT-IRM to assess the importance and distribution of each individual constituent and its variation in normal brain structures as well as in the different pathological states of glioma. We demonstrated that (i) cholesterol and phosphatidylethanolamine contributions are highest in corpus callosum and anterior commissure but decrease gradually towards the cortex surface as well as in the tumor, (ii) phosphatidylcholine contribution is highest in the cortex and decreases in the tumor, (iii) galactocerebroside is localized only in white, but not in gray matter, and decreases in the vital tumor region while the necrosis area shows a higher concentration of this cerebroside, (iv) DNA and oleic acid increase in the tumor as compared to gray matter. This approach could, in the future, contribute to enhance diagnostic accuracy, improve the grading, prognosis, and play a vital role in therapeutic strategy and monitoring.

  19. Platelet-derived growth factor BB promotes the migration of bone marrow-derived mesenchymal stem cells towards C6 glioma and up-regulates the expression of intracellular adhesion molecule-1.

    Science.gov (United States)

    Cheng, Peng; Gao, Zhi-Qiang; Liu, Yun-Hui; Xue, Yi-Xue

    2009-02-13

    Recent studies have indicated that bone marrow-derived mesenchymal stem cells (BMSCs) have the capacity of migrating towards gliomas. However, few data are available about the molecular mechanism responsible for this migratory capacity. The aim of our study was to investigate the role of platelet-derived growth factor BB (PDGFBB) in the migration of BMSCs towards C6 glioma and evaluate the effect of PDGFBB on the migrating capacity and intercellular adhesion molecule-1 (ICAM-1) expression of BMSCs. The chemokinetic activity of BMSCs in response to C6 glioma-conditioned medium and recombinant rat PDGFBB was analyzed by in vitro migration assay. The effect of PDGFBB on the expression of ICAM-1 was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. Our data showed that C6 glioma-conditioned medium significantly increased the migration of BMSCs, which could be partially blocked by a PDGFBB neutralizing antibody. Recombinant rat PDGFBB enhanced the migration of BMSCs in a concentration-dependent way from 5 to 50ng/ml. Moreover, RT-PCR and immunofluorescence showed that 12h of 20ng/ml PDGFBB incubation could up-regulate the ICAM-1 expression of BMSCs. Our data also revealed that SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK), significantly decreased the PDGFBB-induced migration and ICAM-1 expression of BMSCs. These results demonstrate that PDGFBB contributes to the migration of BMSCs towards C6 glioma and up-regulates the expression of ICAM-1, and that p38MAPK is an important signaling molecule correlating with the signal transduction of PDGFBB-induced migration and ICAM-1 expression of BMSCs.

  20. Imbalance of Ca2+ and K+ fluxes in C6 glioma cells after PDT measured with scanning ion-selective electrode technique.

    Science.gov (United States)

    Hu, Sheng-Li; Du, Peng; Hu, Rong; Li, Fei; Feng, Hua

    2014-05-01

    Photodynamic therapy (PDT) possesses the capacity to lead to death of C6 glioma in vitro and in vivo. The purpose of this study was to investigate whether Ca(2+) and K(+) homeostasis of C6 glioma cells were affected by PDT. C6 glioma cells were randomly divided into five groups: control group, Hematoporphyrin derivative (HpD) group (10 mg/l, without irradiation), PDT group (HpD 10 mg/l + irradiation), PDT&6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) group (HpD 10 mg/l + CNQX 50 mol/l + irradiation), and HpD&CNQX group (HpD 10 mg/l + CNQX 50 mol/l, without irradiation). Glioma cells in PDT and PDT&CNQX group were subjected to PDT. Cells in PDT&CNQX group were administered α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist CNQX prior to PDT on C6 glioma cells. The changes of Ca(2+) and K(+) fluxes were studied by using a non-invasive scanning ion-selective electrode technique (SIET). Morphology of C6 cells was observed with optical microscopy. PDT induced Ca(2+) influx and K(+) efflux significantly, which resulted in death of C6 cells. When AMPA glutamate receptor antagonist CNQX was applied, Ca(2+) influx and K(+) efflux were partly blocked up and viability of C6 cells increased. These results indicate that Ca(2+) influx and K(+) efflux may correlate with the treatment effects of PDT on C6 glioma cells.

  1. Endogenous expression of histamine H1 receptors functionally coupled to phosphoinositide hydrolysis in C6 glioma cells: regulation by cyclic AMP.

    Science.gov (United States)

    Peakman, M C; Hill, S J

    1994-12-01

    1. The effects of histamine receptor agonists and antagonists on phospholipid hydrolysis in rat-derived C6 glioma cells have been investigated. 2. Histamine H1 receptor-stimulation caused a concentration-dependent increase in the accumulation of total [3H]-inositol phosphates in cells prelabelled with [3H]-myo-inositol. The rank order of agonist potencies was histamine (EC50 = 24 microM) > N alpha-methylhistamine (EC50 = 31 microM) > 2-thiazolylethylamine (EC50 = 91 microM). 3. The response to 0.1 mM histamine was antagonized in a concentration-dependent manner by the H1-antagonists, mepyramine (apparent Kd = 1 nM) and (+)-chlorpheniramine (apparent Kd = 4 nM). In addition, (-)-chlorpheniramine was more than two orders of magnitude less potent than its (+)-stereoisomer. 4. Elevation of intracellular cyclic AMP accumulation with forskolin (10 microM, EC50 = 0.3 microM), isoprenaline (1 microM, EC50 = 4 nM) or rolipram (0.5 mM), significantly reduced the histamine-mediated (0.1 mM) inositol phosphate response by 37%, 43% and 26% respectively. In contrast, 1,9-dideoxyforskolin did not increase cyclic AMP accumulation and had no effect on the phosphoinositide response to histamine. 5. These data indicate the presence of functionally coupled, endogenous histamine H1 receptors in C6 glioma cells. Furthermore, the results also indicate that H1 receptor-mediated phospholipid hydrolysis is inhibited by the elevation of cyclic AMP levels in these cells.

  2. ROS enhancement by silicon nanoparticles in X-ray irradiated aqueous suspensions and in glioma C6 cells

    Energy Technology Data Exchange (ETDEWEB)

    David Gara, Pedro M. [CITOMA, Fundacion Avanzar, Instituto de Terapia Radiante S.A., CIO La Plata (Argentina); Garabano, Natalia I. [University of Buenos Aires, Departamento de Quimica Biologica, Facultad de Ciencias Exactas y Naturales, UBA (Argentina); Llansola Portoles, Manuel J. [UNLP, INIFTA, Departamento de Quimica, Facultad de Ciencias Exactas (Argentina); Moreno, M. Sergio [Centro Atomico Bariloche (Argentina); Dodat, Diego; Casas, Oscar R. [CITOMA, Fundacion Avanzar, Instituto de Terapia Radiante S.A., CIO La Plata (Argentina); Gonzalez, Monica C., E-mail: gonzalez@inifta.unlp.edu.ar [UNLP, INIFTA, Departamento de Quimica, Facultad de Ciencias Exactas (Argentina); Kotler, Monica L., E-mail: kotler@qb.fcen.uba.ar [University of Buenos Aires, Departamento de Quimica Biologica, Facultad de Ciencias Exactas y Naturales, UBA (Argentina)

    2012-03-15

    The capability of silicon nanoparticles to increase the yield of reactive species upon 4 MeV X-ray irradiation of aqueous suspensions and C6 glioma cell cultures was investigated. ROS generation was detected and quantified using several specific probes. The particles were characterized by FTIR, XPS, TEM, DLS, luminescence, and adsorption spectroscopy before and after irradiation to evaluate the effect of high energy radiation on their structure. The total concentration of O{sub 2}{sup Bullet -}/HO{sub 2}{sup Bullet}, HO{sup Bullet}, and H{sub 2}O{sub 2} generated upon 4-MeV X-ray irradiation of 6.4 {mu}M silicon nanoparticle aqueous suspensions were on the order of 10 {mu}M per Gy, ten times higher than that obtained in similar experiments but in the absence of particles. Cytotoxic {sup 1}O{sub 2} was generated only in irradiation experiments containing the particles. The particle surface became oxidized to SiO{sub 2} and the luminescence yield reduced with the irradiation dose. Changes in the surface morphology did not affect, within the experimental error, the yields of ROS generated per Gy. X-ray irradiation of glioma C6 cell cultures with incorporated silicon nanoparticles showed a marked production of ROS proportional to the radiation dose received. In the absence of nanoparticles, the cells showed no irradiation-enhanced ROS generation. The obtained results indicate that silicon nanoparticles of <5 nm size have the potential to be used as radiosensitizers for improving the outcomes of cancer radiotherapy. Their capability of producing {sup 1}O{sub 2} upon X-ray irradiation opens novel approaches in the design of therapy strategies.

  3. A two-step synthetic strategy to obtain a water-soluble derivative of curcumin with improved antioxidant capacity and in vitro cytotoxicity in C6 glioma cells.

    Science.gov (United States)

    Landeros, José M; Belmont-Bernal, Fernando; Pérez-González, Alma Teresa; Pérez-Padrón, Mario Israel; Guevara-Salazar, Patricia; González-Herrera, Irma Gabriela; Guadarrama, Patricia

    2017-02-01

    A novel water-soluble derivative of curcumin (Cur-[G-2]-OH) was designed and synthesized from accessible raw materials in only two steps with an overall yield of 80%. The modification of curcumin phenol groups with second-generation polyester dendrons (dendronization) as a strategy to achieve an optimal hydrophilic/hydrophobic balance allows the complete water solubilization of the new curcumin derivative (5mg/ml) at room temperature. The therapeutic potential of Cur-[G-2]-OH was investigated in terms of antioxidant capacity, intracellular uptake and cytotoxicity in both rat glioblastoma cells and normal human dermal fibroblasts. Although the phenolic groups of curcumin were locked by dendronization, Cur-[G-2]-OH exhibited antioxidant capacity in water that was even higher than curcumin in dimethylsulfoxide (DMSO). This compound showed a steady cellular uptake contrasted with curcumin, which has a saturation capture at high concentrations. Combined with improved stability, this property seems to allow the intracellular accumulation of Cur-[G-2]-OH. Furthermore, the new compound exhibited increased cytotoxicity in rat C6 glioma cells in a time- and concentration-dependent manner, whereas in normal human fibroblasts, its IC50 value was >600μM versus the IC50 of curcumin found between 100 and 200μM. Surprisingly, Cur-[G-2]-OH drives cell death of C6 cells by a different mechanism of apoptosis triggered by curcumin. Together, these results suggest that curcumin dendronization could promote molecular and cellular mechanisms that are different from those induced by curcumin, presumably due to structural factors and not only for improved water solubility. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Evaluation of N-[(11)C]methyl-AMD3465 as a PET tracer for imaging of CXCR4 receptor expression in a C6 glioma tumor model.

    Science.gov (United States)

    Hartimath, S V; van Waarde, A; Dierckx, R A J O; de Vries, E F J

    2014-11-03

    The chemokine receptor CXCR4 and its ligand CXCL12 play an important role in tumor progression and metastasis. CXCR4 receptors are expressed by many cancer types and provide a potential target for treatment. Noninvasive detection of CXCR4 may aid diagnosis and improve therapy selection. It has been demonstrated in preclinical studies that positron emission tomography (PET) with a radiolabeled small molecule could enable noninvasive monitoring of CXCR4 expression. Here, we prepared N-[(11)C]methyl-AMD3465 as a new PET tracer for CXCR4. N-[(11)C]Methyl-AMD3465 was readily prepared by N-methylation with [(11)C]CH3OTf. The tracer was obtained in a 60 ± 2% yield (decay corrected), the purity of the tracer was >99%, and specific activity was 47 ± 14 GBq/μmol. Tracer stability was tested in vitro using liver microsomes and rat plasma; excellent stability was observed. The tracer was evaluated in rat C6 glioma and human PC-3 cell lines. In vitro cellular uptake of N-[(11)C]methyl-AMD3465 was receptor mediated. The effect of transition metal ions (Cu(2+), Ni(2+), and Zn(2+)) on cellular binding was examined in C6 cells, and the presence of these ions increased the cellular binding of the tracer 9-, 7-, and 3-fold, respectively. Ex vivo biodistribution and PET imaging of N-[(11)C]methyl-AMD3465 were performed in rats with C6 tumor xenografts. Both PET and biodistribution studies demonstrated specific accumulation of the tracer in the tumor (SUV 0.6 ± 0.2) and other CXCR4 expressing organs, such as lymph node (1.5 ± 0.2), liver (8.9 ± 1.0), bone marrow (1.0 ± 0.3), and spleen (1.0 ± 0.1). Tumor uptake was significantly reduced (66%, p tracer injection. Our data demonstrated that N-[(11)C]methyl-AMD3465 is capable of detecting physiologic CXCR4 expression in tumors and other CXCR4 expressing tissues. These results warrant further evaluation of N-[(11)C]methyl-AMD3465 as a potential PET tracer for CXCR4 receptor imaging.

  5. Induction of cell cycle arrest at G1 and S phases and cAMP-dependent differentiation in C6 glioma by low concentration of cycloheximide

    Directory of Open Access Journals (Sweden)

    Zhang Samuel S

    2010-12-01

    Full Text Available Abstract Background Differentiation therapy has been shown effective in treatment of several types of cancer cells and may prove to be effective in treatment of glioblastoma multiforme, the most common and most aggressive primary brain tumor. Although extensively used as a reagent to inhibit protein synthesis in mammalian cells, whether cycloheximide treatment leads to glioma cell differentiation has not been reported. Methods C6 glioma cell was treated with or without cycloheximide at low concentrations (0.5-1 μg/ml for 1, 2 and 3 days. Cell proliferation rate was assessed by direct cell counting and colony formation assays. Apoptosis was assessed by Hoechst 33258 staining and FACS analysis. Changes in several cell cycle regulators such as Cyclins D1 and E, PCNA and Ki67, and several apoptosis-related regulators such as p53, p-JNK, p-AKT, and PARP were determined by Western blot analysis. C6 glioma differentiation was determined by morphological characterization, immunostaining and Western blot analysis on upregulation of GFAP and o p-STAT3 expression, and upregulation of intracellular cAMP. Results Treatment of C6 cell with low concentration of cycloheximide inhibited cell proliferation and depleted cells at both G2 and M phases, suggesting blockade at G1 and S phases. While no cell death was observed, cells underwent profound morphological transformation that indicated cell differentiation. Western blotting and immunostaining analyses further indicated that changes in expression of several cell cycle regulators and the differentiation marker GFAP were accompanied with cycloheximide-induced cell cycle arrest and cell differentiation. Increase in intracellular cAMP, a known promoter for C6 cell differentiation, was found to be elevated and required for cycloheximide-promoted C6 cell differentiation. Conclusion Our results suggest that partial inhibition of protein synthesis in C6 glioma by low concentration of cycloheximide induces cell cycle

  6. Fibroblast growth factor-2 up-regulates the expression of nestin through the Ras–Raf–ERK–Sp1 signaling axis in C6 glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Kai-Wei [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China); Huang, Yuan-Li [Department of Biotechnology, College of Health Science, Asia University, Taichung 413, Taiwan (China); Wong, Zong-Ruei; Su, Peng-Han [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China); Huang, Bu-Miin [Department of Cell Biology and Anatomy, National Cheng-Kung University, Tainan 701, Taiwan (China); Ju, Tsai-Kai [Instrumentation Center, National Taiwan University, Taipei 106, Taiwan (China); Technology Commons, College of Life Science, National Taiwan University, Taipei 106, Taiwan (China); Yang, Hsi-Yuan, E-mail: hyhy@ntu.edu.tw [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China)

    2013-05-17

    Highlights: •Nestin expression in C6 glioma cells is induced by FGF-2. •Nestin expression is induced by FGF-2 via de novo RNA and protein synthesis. •The FGFR inhibitor SU5402 blocks the FGF-2-induced nestin expression. •The mRNA of FGFR1 and 3 are detected in C6 glioma cells. •Ras–Raf–ERK–Sp1 signaling pathway is responsibe for FGF-2-induced nestin expression. -- Abstract: Nestin is a 240-kDa intermediate filament protein expressed mainly in neural and myogenic stem cells. Although a substantial number of studies have focused on the expression of nestin during development of the central nervous system, little is known about the factors that induce and regulate its expression. Fibroblast growth factor-2 (FGF-2) is an effective mitogen and stimulates the proliferation and differentiation of a subset of nestin-expressing cells, including neural progenitor cells, glial precursor cells, and smooth muscle cells. To assess whether FGF-2 is a potent factor that induces the expression of nestin, C6 glioma cells were used. The results showed that nestin expression was up-regulated by FGF-2 via de novo RNA and protein synthesis. Our RT-PCR results showed that C6 glioma cells express FGFR1/3, and FGFRs is required for FGF-2-induced nestin expression. Further signaling analysis also revealed that FGF-2-induced nestin expression is mediated through FGFR–MAPK–ERK signaling axis and the transcriptional factor Sp1. These findings provide new insight into the regulation of nestin in glial system and enable the further studies on the function of nestin in glial cells.

  7. Tumor resection cavity administered iodine-131-labeled antitenascin 81C6 radioimmunotherapy in patients with malignant glioma: neuropathology aspects

    Energy Technology Data Exchange (ETDEWEB)

    McLendon, Roger E. [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States)]. E-mail: mclen001@mc.duke.edu; Akabani, Gamal [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States); Friedman, Henry S. [Department of Pediatrics, Duke University Medical Center, Durham, NC 27710 (United States); Reardon, David A. [Department of Medicine, Duke University Medical Center, Durham, NC 27710 (United States); Cleveland, Linda [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Cokgor, Ilkcan [Department of Pediatrics, Duke University Medical Center, Durham, NC 27710 (United States); Herndon, James E. [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710 (United States); Wikstrand, Carol [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Boulton, Susan T. [Department of Surgery, Duke University Medical Center, Durham, NC 27710 (United States); Friedman, Allan H. [Department of Surgery, Duke University Medical Center, Durham, NC 27710 (United States); 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)

    2007-05-15

    Introduction: The neurohistological findings in patients treated with targeted {beta} emitters such as {sup 131}I are poorly described. We report a histopathologic analysis from patients treated with combined external beam therapy and a brachytherapy consisting of a {sup 131}I-labeled monoclonal antibody (mAb) injected into surgically created resection cavities during brain tumor resections. Methods: Directed tissue samples of the cavity walls were obtained because of suspected tumor recurrence from 28 patients. Samples and clinical follow-up were evaluated on all patients (Group A) based on total radiation dose received and a subset of these (n=18; Group B, proximal therapy subset) who had received external beam therapy within {<=}3 months of mAb therapy and undergoing 26 biopsies over 37 months. Histologic outcomes were 'proliferative glioma,' 'quiescent glioma' and negative for neoplasm. Statistical analysis was used to assess the casual relation between total absorbed dose ({sup 131}I-mAb+external beam) and histologic diagnosis. Results: The lesions observed after {sup 131}I-mAb therapy were qualitatively similar to those reported for other types of radiation therapy; however, the high localized dose rate and absorbed doses produced by the short range of {sup 131}I {beta} particles seem to have resulted in an earlier necrotic reaction in the tumor bed. Among all 28 (Group A) patients, median survival from tissue analysis after mAb therapy depended on histopathology and total radiation absorbed dose. Median survival for patients with tissue classified as proliferative glioma, quiescent glioma and negative for neoplasm were 3.5, 15 and 27.5 months, respectively. Without categorization, total dose was a significant predictor of survival (P<.002) where patients with higher doses had better prognoses. For example, median survival in patients receiving a total radiation dose greater than 86 Gy was 19 months compared with 7 months for those

  8. Identification of valid endogenous control genes for determining gene expression in C6 glioma cell line treated with conditioned medium from adipose-derived stem cell.

    Science.gov (United States)

    Iser, I C; de Campos, R P; Bertoni, A P S; Wink, M R

    2015-10-01

    There is growing evidence that mesenchymal stem cells (MSCs) can be important players in the tumor microenvironment. They can affect the glioma progression through the modulation of different genes. This modulation can be evaluated through a very useful model, treating the tumor cells with MSC-conditioned medium. However, for an accurate and reliable gene expression analysis, normalization of gene expression data against reference genes is a prerequisite. We performed a systematic review in an attempt to find a reference gene to use when analyzing gene expression in C6 glioma cells lines. Considering that we were not able to find a reference gene originated by an appropriate validation, in this study we evaluated candidate genes to be used as reference gene in C6 cells under different treatments with adipose-derived stem cells conditioned medium (CM-ADSCs). β-actin (ACTB); glyceraldehyde-3-phosphate dehydrogenase (GAPDH); hypoxanthine-guanine phosphoribosyltransferase I (HPRT-1); TATA box binding protein (TBP) and beta-2-microglobulin (B2M) were evaluated by real-time reverse transcription PCR (RT-qPCR). The mean Cq, the maximum fold change (MFC) and NormFinder software were used for reference gene evaluation and selection. The GAPDH and ACTB genes have been the most widely used reference genes to normalize among the different investigated genes in our review, however, controversially these genes underwent a substantial variability among the genes evaluated in the present work. Individually, TBP gene was more stable when compared with other genes analyzed and the combination of TBP and HPRT-1 was even more stable. These results evidence the importance of appropriate validation of reference genes before performing qPCR experiments. Besides, our data will contribute with researchers that work analyzing the role of ADSCs in glioma microenvironment through gene expression. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  9. Preparation and characterization of realgar nanoparticles and their inhibitory effect on rat glioma cells.

    Science.gov (United States)

    An, Yan-li; Nie, Fang; Wang, Zi-yu; Zhang, Dong-sheng

    2011-01-01

    Our objective was to prepare a new nano-sized realgar particle and characterize its anti-tumor effect on tumor cells. Nanoparticles were prepared by coprecipitation and were detected by transmission electron microscopy, scanning electron microscopy, energy dispersive spectrometry (EDS), and dynamic light scattering. An anti-proliferative effect of realgar nanoparticles on rat glioma (C6) cells was determined by the MTT assay. Cell cycle and apoptosis rates were observed by flow cytometry. Apoptosis-related gene expression was detected by immunofluorescence staining. Realgar nanoparticles were successfully prepared. The particles were spherical, with an average diameter of approximately 80 nm, and contained arsenic and sulfur elements. Realgar nanoparticles inhibited C6 cell proliferation and induced apoptosis in a dose- and time-dependent manner. Treatment of C6 cells with realgar nanoparticles significantly increased the proportions of cells in S and G2/M phases, decreased the proportion of cells in G0/G1 phase, downregulated Bcl-2 expression, and substantially upregulated Bax expression. Realgar nanoparticles significantly inhibited C6 glioma cell proliferation and promoted cell apoptosis by inducing the upregulation of Bax and downregulation of Bcl-2 expression. Realgar nanoparticles are a promising in vitro anti-cancer strategy and may be applicable for human cancer therapy studies.

  10. Relationship between the Size of Magnetic Nanoparticles and Efficiency of MRT Imaging of Cerebral Glioma in Rats.

    Science.gov (United States)

    Semkina, A S; Abakumov, M A; Abakumov, A M; Nukolova, N V; Chekhonin, V P

    2016-06-01

    BSA-coated Fe3O4 nanoparticles with different hydrodynamic diameters (36±4 and 85±10 nm) were synthesized, zeta potential and T2 relaxivity were determined, and their morphology was studied by transmission electron microscopy. Studies on rats with experimental glioma C6 showed that smaller nanoparticles more effectively accumulated in the tumor and circulated longer in brain vessels. Optimization of the hydrodynamic diameter improves the efficiency of MRT contrast agent.

  11. Exposure of C6 glioma cells to Pb(II) increases the phosphorylation of p38{sup MAPK} and JNK1/2 but not of ERK1/2

    Energy Technology Data Exchange (ETDEWEB)

    Posser, Thais; Rossi, Francesco M.; Oliveira, Camila S.; Leal, Rodrigo B. [Universidade Federal de Santa Catarina, Departamento de Bioquimica, Centro de Ciencias Biologicas, Florianopolis, SC (Brazil); Mendes de Aguiar, Claudia B.N.; Garcez, Ricardo C.; Trentin, Andrea G. [Universidade Federal de Santa Catarina, Departamento de Biologia Celular, Embriologia e Genetica, Centro de Ciencias Biologicas, Florianopolis, SC (Brazil); Moura Neto, Vivaldo [Universidade Federal do Rio de Janeiro, Departamento de Anatomia, Centro de Ciencias da Saude, Rio de Janeiro, RJ (Brazil)

    2007-06-15

    Pb(II) is a neurotoxic pollutant that produces permanent cognitive deficits in children. Pb(II) can modulate cell signaling pathways and cell viability in a variety of cell types. However, these actions are not well demonstrated on glial cells, which represent an important target for metals into the central nervous system. The present work was undertaken to determine the ability of Pb(II) in modulating the activity of mitogen activated protein kinases (MAPKs) in cultures of C6 rat glioma cells, a useful functional model for the study of astrocytes. Additionally, cell viability was analyzed by measurement of MTT reduction. Cells were exposed to lead acetate 0.1, 1, 10 {mu}M for 24 and 48 h. MAPKs activation - in particular ERK1/2, p38{sup MAPK} and JNK1/2 - were analyzed by western blotting. Results showed that 10 {mu}M Pb(II) treatment for 24 h caused a discrete stimulation of p38{sup MAPK} phosphorylation. However, 1 and 10 {mu}M Pb(II) treatment for 48 h provoked a significant stimulation in the phosphorylation state of p38{sup MAPK} and JNK1/2. The phosphorylation state of ERK1/2 was not modified by any Pb(II) treatment. Moreover, data indicate that at 48 h treatment even 1 {mu}M Pb(II) can be cytotoxic, causing impairment on cell viability. Therefore, depending on a long incubation period, a significant concomitant activation of p38{sup MAPK} and JNK1/2 by Pb(II) took place in parallel with the impairment of C6 glioma cells viability. (orig.)

  12. 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.

  13. Astrocyte activation and neurotoxicity: A study in different rat brain regions and in rat C6 astroglial cells.

    Science.gov (United States)

    Goswami, Poonam; Gupta, Sonam; Joshi, Neeraj; Sharma, Sharad; Singh, Sarika

    2015-07-01

    The present study was conducted to investigate the effect of rotenone on astrocytes activation, their viability and its effect on neuronal death in different brain regions. Rotenone was injected in rat brain by intracerebroventricularly (bilateral) route at dose of 6 μg and 12 μg. In vitro C6 cells were treated with rotenone at concentration of 0.1, 0.25, 0.5, 1 and 2 μM. Rotenone administration to rat brain caused significant astrocytes activation in frontal cortex, cerebellum, cerebellar nucleus, substantia nigra, hypothalamus and hippocampus regions of the rat brain. Rotenone administration also led to significant degeneration of cells in all the studied regions along with altered nuclear morphology assessed by hematoxylin-eosin and cresyl violet staining. Histological staining showed the significantly decreased number of cells in all the studied regions except cerebellar nucleus in dose and time dependant manner. Rotenone administration in the rat brain also caused significant decrease in glutathione levels and augmented nitrite levels. In vitro treatment of rotenone to astrocytic C6 cells caused significantly increased expression of glial fibrillar acidic protein (GFAP) and decreased viability in dose and time dependent manner. Rotenone treatment to C6 cells exhibited significant generation of reactive oxygen species, augmented nitrite level, impaired mitochondrial activity, apoptotic chromatin condensation and DNA damage in comparison to control cells. Findings showed that oxidative stress play a considerable role in rotenone induced astrocyte death that was attenuated with co-treatment of antioxidant melatonin. In conclusion, results showed that rotenone caused significant astrocytes activation, altered nuclear morphology, biochemical alteration and apoptotic cell death in different rat brain regions. In vitro observations in C6 cells showed that rotenone treatment exhibited oxidative stress mediated apoptotic cell death, which was attenuated with co

  14. Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells

    OpenAIRE

    Gonz?lez, A; Mart?nez-Campa, C; Mediavilla, M D; Alonso-Gonz?lez, C; S?nchez-Barcel?, E J; Cos, S

    2007-01-01

    Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on oestrogen-dependent tumours. Recently, it has been described that melatonin, on the basis of its antioxidant properties, inhibits the growth of glioma cells. Glioma cells express oestrogen receptors and have the ability to synthesise oestrogens from androgens. In the present study, we demonstrate that pharmacological concentrations of melatonin decreases the growth of C6 glioma cells and reduces the local bios...

  15. 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.

  16. Antiproliferative activity of Juglone derivatives on rat glioma.

    Science.gov (United States)

    Pavan, Valeria; Ribaudo, Giovanni; Zorzan, Maira; Redaelli, Marco; Pezzani, Raffaele; Mucignat-Caretta, Carla; Zagotto, Giuseppe

    2017-03-01

    Malignant gliomas are aggressive and life-threatening tumours that still show a poor prognosis: the current therapeutic approach based on surgical resection and chemotherapy combined with radiotherapy does not provide a satisfactory chance of long-term survival to patients. Natural bioactive compounds represent a precious source of molecules with antiproliferative activity, potentially effective also against glioma cells. Among these, Juglone is a known allelopathic compound extracted from the eastern black walnut (Juglans nigra) whose antimitotic effect has been extensively described in mammalian cells. We investigated the antiproliferative effect of a synthetic derivative of this natural compound, 2-(2,4-dihydroxyphenyl)-8-hydroxy-1,4-naphthoquinone (DiNAF), in rat glioma cells. We compared this molecule and its effect with the natural reference compound and with newly synthesised derivatives to build a preliminar structure-activity relationship. Biological assays and NMR-based redox experiments confirmed that DiNAF is a promising lead and supported the hypothesis of a redox mechanism underlying its cytotoxic activity.

  17. Effective transvascular drug delivery to glioma in rats by using a pulsed laser-induced photomechanical wave (Conference Presentation)

    Science.gov (United States)

    Akutsu, Yusuke; Sato, Shunichi; Tomiyama, Arata; Tsunoi, Yasuyuki; Kawauchi, Satoko; Mori, Kentaro; Terakawa, Mitsuhiro

    2016-03-01

    Glioma is one of the most aggressive cancers, for which efficacy of conventional chemotherapy is often limited due to the blood-tumor barrier (BTB). Thus, the development of a method for enhancing the BTB permeability is strongly desired. In this study, we applied a photomechanical wave (PMW), which was generated by the irradiation of a light-absorbing material with a nanosecond laser pulse, to transiently open the BTB in a rat intracranial glioma model using C6 cells. A tumor was grown in the both hemispheres, and a solution of Evans blue (EB), as a test drug, was injected into the tail vein. Thereafter, we applied a PMW generated at a laser fluence of 0.2 J/cm2 (averaged peak pressure, ~27 MPa), 0.4 J/cm2 (~54 MPa) or 0.6 J/cm2 (~78MPa), to one hemisphere through the cranial window, while the other hemisphere served as a control. Four hours later, the rat was perfused, and we compared intensity distributions of EB fluorescence between the both hemispheres. Intensities of EB fluorescence both in the peritumoral and tumor core regions were increased with increasing the laser fluence, but hemorrhage was observed at the highest fluence. Thus, 0.4 J/cm2 would be optimum for efficient and safe BTB opening. On the basis of fluorescence microscopy with the use of enhanced green fluorescent protein-expressing C6 cells, we confirmed that a drug was delivered into targeted glioma cells in the peritumoral region. These results show the validity of the present transvascular drug delivery method to glioma.

  18. In vivo measurement of gadolinium concentration in a rat glioma model by monochromatic quantitative computed tomography: comparison between gadopentetate dimeglumine and gadobutrol.

    Science.gov (United States)

    Le Duc, Géraldine; Corde, Stéphanie; Charvet, Anne-Marie; Elleaume, Hélène; Farion, Régine; Le Bas, Jean-François; Estève, François

    2004-07-01

    Monochromatic quantitative computed tomography allows a nondestructive and quantitative measurement of gadolinium (Gd) concentration. This technique was used in the C6 rat glioma model to compare gadopentetate dimeglumine and gadobutrol. Rats bearing late-stage gliomas received 2.5 mmol/kg (392.5 mg Gd/kg) of gadopentetate dimeglumine (n = 5) and gadobutrol (n = 6) intravenously before the imaging session performed at the European Synchrotron Radiation Facility. Monochromatic quantitative computed tomography enabled in vivo follow-up of Gd concentration as a function of time in specified regions of interest. Surprisingly, after gadobutrol injection, Gd concentrations in the center and periphery of the tumor were higher than those after gadopentetate injection, although identical in normal and contralateral area of the brain. The in vivo assessment of absolute Gd concentrations revealed differences in gadobutrol and gadopentetate dimeglumine behaviors in tumoral tissues despite injections in the same conditions. These differences might be attributed to different characteristics of the contrast agents.

  19. Influence of rat progenitor neurogenic cells supernatant on glioma 101.8 cells in vitro

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    Liubich L. D.

    2015-06-01

    Full Text Available Aim. To evaluate the influence of the rat progenitor neurogenic cells supernatant (RPNS on the transplantable rat malignant brain glioma cells (strain 101.8 under conditions of cultivation. Methods. Primary cultures were obtained from glioma 101.8 fragments (n = 12 and intact brain of newborn rats (n = 9. RPNS was received from neurogenic cell suspensions of fetal rat brain on 8–11th (E8-11 and 12–16th (E12-16 days of gestation. Results: RPNS (E8-11 as well as RPNS (E12-16 showed a cytotoxic effect on the glioma 101.8 cells in short-term cultures, the level of which was dose-dependent and intensified with increasing duration of incubation. RPNS (E12-16 had a more pronounced cytotoxic action on the cells of glioma 101.8 compared with RPNS (E8-11. The cytotoxic index (CI of RPNS (E12-16 on the glioma 101.8 cells was significantly higher than CI determined in cell suspensions of normal rat brain (CI was (91.99 ± 2.37 % and (22.9 ± 4.97 % respectively over 48 h incubation with RPNS. After RPNS (E8-11 influence on the glioma 101.8 primary cultures the signs of dose-dependent cytotoxic effects were observed: the thinning of growth areas, appearance of dystrophic and necrobiotic changes in tumor cells and decreasing of a mitotic index. These features were strengthened under the RPNS (E12-16 influence. Conclusions. Fetal RPNS showed dose-dependent cytotoxic and antiproliferative effects on the cultivated glioma 101.8 cells, which were intensified with the increasing of rat brain gestational age and lengthening of the incubation duration. A prerequisite for such effects is likely the NPC ability to produce the substances with antitumor activity.

  20. Transcriptional and post-transcriptional down-regulation of cyclin D1 contributes to C6 glioma cell differentiation induced by forskolin.

    Science.gov (United States)

    He, Songmin; Zhu, Wenbo; Zhou, Yuxi; Huang, Yijun; Ou, Yanqiu; Li, Yan; Yan, Guangmei

    2011-09-01

    Malignant gliomas are the most common and lethal intracranial tumors, and differentiation therapy shows great potential to be a promising candidate for their treatment. Here, we have elaborated that a PKA activator, forskolin, represses cell growth via cell cycle arrest in the G0/G1 phase and induces cell differentiation characteristic with elongated processes and restoration of GFAP expression. In mechanisms, we verified that forskolin significantly diminishes the mRNA and protein level of a key cell cycle regulator cyclin D1, and maintenance of low cyclin D1 expression level was required for forskolin-induced proliferation inhibition and differentiation by gain and loss of function approaches. In addition, that forskolin down-regulated the cyclin D1 by proteolytic (post-transcriptional) mechanisms was dependent on GSK-3β activation at Ser9. The pro-differentiation activity of forskolin and related molecular mechanisms imply that forskolin can be developed into a candidate for the future in differentiation therapy of glioma, and cyclin D1 is a promising target for pro-differentiation strategy. Copyright © 2011 Wiley-Liss, Inc.

  1. Gamma-linolenic acid inhibits both tumour cell cycle progression and angiogenesis in the orthotopic C6 glioma model through changes in VEGF, Flt1, ERK1/2, MMP2, cyclin D1, pRb, p53 and p27 protein expression

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    Colquhoun Alison

    2009-03-01

    Full Text Available Abstract Background Gamma-linolenic acid is a known inhibitor of tumour cell proliferation and migration in both in vitro and in vivo conditions. The aim of the present study was to determine the mechanisms by which gamma-linolenic acid (GLA osmotic pump infusion alters glioma cell proliferation, and whether it affects cell cycle control and angiogenesis in the C6 glioma in vivo. Methods Established C6 rat gliomas were treated for 14 days with 5 mM GLA in CSF or CSF alone. Tumour size was estimated, microvessel density (MVD counted and protein and mRNA expression measured by immunohistochemistry, western blotting and RT-PCR. Results GLA caused a significant decrease in tumour size (75 ± 8.8% and reduced MVD by 44 ± 5.4%. These changes were associated with reduced expression of vascular endothelial growth factor (VEGF (71 ± 16% and the VEGF receptor Flt1 (57 ± 5.8% but not Flk1. Expression of ERK1/2 was also reduced by 27 ± 7.7% and 31 ± 8.7% respectively. mRNA expression of matrix metalloproteinase-2 (MMP2 was reduced by 35 ± 6.8% and zymography showed MMP2 proteolytic activity was reduced by 32 ± 8.5%. GLA altered the expression of several proteins involved in cell cycle control. pRb protein expression was decreased (62 ± 18% while E2F1 remained unchanged. Cyclin D1 protein expression was increased by 42 ± 12% in the presence of GLA. The cyclin dependent kinase inhibitors p21 and p27 responded differently to GLA, p27 expression was increased (27 ± 7.3% while p21 remained unchanged. The expression of p53 was increased (44 ± 16% by GLA. Finally, the BrdU incorporation studies found a significant inhibition (32 ± 11% of BrdU incorporation into the tumour in vivo. Conclusion Overall the findings reported in the present study lend further support to the potential of GLA as an inhibitor of glioma cell proliferation in vivo and show it has direct effects upon cell cycle control and angiogenesis. These effects involve changes in protein

  2. Effect of Guiqiyiyuan ointment on bystander effect in rat models of 12C6+ beam radiation damage

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    Jian-qing LIANG

    2017-11-01

    Full Text Available Objective To investigate the bystander effect injury to lung-heart-liver-spleen caused by 12C6+ beam radiation, and explore the prevention and treatment effect of Guiqiyiyuan ointment on the injury and its mechanism. Methods Ninety healthy male Wistar rats were randomly divided into 3 groups: NC group (normal control, normal saline 2ml/kg, n=30, SR group (simple radiation, 8Gy, 2ml/kg, n=30, GO group (Guiqiyiyuan ointment 11.83g/kg, radiation, 8Gy, n=30. All the rats received intragastric administration for 7 days. The right side of the lung was modeled by 12C6+ beam radiation. After modeling, the rats were killed at 48h. The heart, liver and spleen were taken. The malonaldehyde (MDA, glutathione (GSH, glutathione peroxidase (GSH-Px, superoxide dismutase (SOD contents were measured by colorimetry, DNA methylation rate was assayed by ELISA, and the expressions of Dnmt1, Dnmt3a and Dnmt3b were detected by immunohistochemistry. Results Compared with NC group, the contents of SOD, GSH and GSH-Px decreased (P<0.01, MDA increased (P<0.01, the level of DNA methylation decreased (P<0.01, and the expressions of Dnmt1, Dnmt3a and Dnmt3b increased in SR group (P<0.01. Compared with SR group, the contents of SOD, GSH and GSH-Px increased (P<0.01, MDA decreased (P<0.01, the level of DNA methylation increased (P<0.01, and the expressions of Dnmt1, Dnmt3a and Dnmt3b decreased in GO group (P<0.01. Dnmt1, Dnmt3a and Dnmt3b proteins were expressed in the cytoplasm of myocardial cells, hepatocytes and peripheral B cells of the white pulp in spleen, in all the groups. The color of NC group was light brown-brown, showing a weak positive expression. The color of SR group was brown-brown, showing a strong positive expression. The color of GO group was light brown-tan, showing a moderate positive expression. Conclusion The Guiqiyiyuan ointment can reduce the bystander effect caused by the 12C6+ beam radiation, and its mechanism is related to improving the oxidative

  3. Antiproliferative activity of some novel platinum complexes on C6 ...

    African Journals Online (AJOL)

    MCF-7) and glioma cells (C6). IC50 values of the three compounds were lower in the cisplatin-resistant cell type C6 cell lines than in MCF-7 cells. Key words: Cisplatin, antiproliferative activity, breast cancer cells (MCF-7), glioma cells (C6), IC50.

  4. The extrinsic and intrinsic apoptotic pathways are involved in manganese toxicity in rat astrocytoma C6 cells.

    Science.gov (United States)

    Alaimo, Agustina; Gorojod, Roxana M; Kotler, Mónica L

    2011-08-01

    Manganese (Mn) is a trace element known to be essential for maintaining the proper function and regulation of many biochemical and cellular reactions. However, chronic exposure to high levels of Mn in occupational or environmental settings can lead to its accumulation in the brain resulting in a degenerative brain disorder referred to as Manganism. Astrocytes are the main Mn store in the central nervous system and several lines of evidence implicate these cells as major players in the role of Manganism development. In the present study, we employed rat astrocytoma C6 cells as a sensitive experimental model for investigating molecular mechanisms involved in Mn neurotoxicity. Our results show that C6 cells undergo reactive oxygen species-mediated apoptotic cell death involving caspase-8 and mitochondrial-mediated pathways in response to Mn. Exposed cells exhibit typical apoptotic features, such as chromatin condensation, cell shrinkage, membrane blebbing, caspase-3 activation and caspase-specific cleavage of the endogenous substrate poly (ADP-ribose) polymerase. Participation of the caspase-8 dependent pathway was assessed by increased levels of FasL, caspase-8 activation and Bid cleavage. The involvement of the mitochondrial pathway was demonstrated by the disruption of the mitochondrial membrane potential, the opening of the mitochondrial permeability transition pore, cytochrome c release, caspase-9 activation and the increased mitochondrial levels of the pro-apoptotic Bcl-2 family proteins. In addition, our data also shows for the first time that mitochondrial fragmentation plays a relevant role in Mn-induced apoptosis. Taking together, these findings contribute to a deeper elucidation of the molecular signaling mechanisms underlying Mn-induced apoptosis. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Thrombin has a bimodal effect on glioma cell growth.

    OpenAIRE

    Schafberg, H.; Nowak, G.; Kaufmann, R.

    1997-01-01

    Using rat glioma C6 cells as a model, we have found a bimodal effect of alpha-thrombin on cell growth. In C6 cells treated with alpha-thrombin at concentrations from 0.02 nM to 1.0 nM, inhibition of cell proliferation was noted. Because the thrombin receptor agonist peptide TRAP-6 also induced inhibition of cell proliferation and the thrombin receptor antagonist peptide T1 prevented the inhibitory effect of alpha-thrombin on C6 glioma cell growth, thrombin receptor involvement in antiprolifer...

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

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    Nina P Connolly

    Full Text Available 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

  7. 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

  8. Brain pharmacokinetics of ganciclovir in rats with orthotopic BT4C glioma.

    Science.gov (United States)

    Gynther, Mikko; Kääriäinen, Tiina M; Hakkarainen, Jenni J; Jalkanen, Aaro J; Petsalo, Aleksanteri; Lehtonen, Marko; Peura, Lauri; Kurkipuro, Jere; Samaranayake, Haritha; Ylä-Herttuala, Seppo; Rautio, Jarkko; Forsberg, Markus M

    2015-01-01

    Ganciclovir (GCV) is an essential part of the Herpes simplex virus thymidine kinase (HSV-tk) gene therapy of malignant gliomas. The purpose of this study was to investigate the brain pharmacokinetics and tumor uptake of GCV in the BT4C rat glioma model. GCV's brain and tumor uptakes were investigated by in vivo microdialysis in rats with orthotopic BT4C glioma. In addition, the ability of GCV to cross the blood-brain barrier and tumor vasculature was assessed with in situ rat brain perfusion. Finally, the extent to which GCV could permeate across the BT4C glioma cell membrane was assessed in vitro. The areas under the concentration curve of unbound GCV in blood, brain extracellular fluid (ECF), and tumor ECF were 6157, 1658, and 4834 μM⋅min, respectively. The apparent maximum unbound concentrations achieved within 60 minutes were 46.9, 11.8, and 25.8 μM in blood, brain, and tumor, respectively. The unbound GCV concentrations in brain and tumor after in situ rat brain perfusion were 0.41 and 1.39 nmol/g, respectively. The highly polar GCV likely crosses the fenestrated tumor vasculature by paracellular diffusion. Thus, GCV is able to reach the extracellular space around the tumor at higher concentrations than that in healthy brain. However, GCV uptake into BT4C cells at 100 μM was only 2.1 pmol/mg of protein, and no active transporter-mediated disposition of GCV could be detected in vitro. In conclusion, the limited efficacy of HSV-tk/GCV gene therapy may be due to the poor cellular uptake and rapid elimination of GCV. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

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

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    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

  10. Sea Buckthorn Leaf Extract Inhibits Glioma Cell Growth by Reducing Reactive Oxygen Species and Promoting Apoptosis.

    Science.gov (United States)

    Kim, Sung-Jo; Hwang, Eunmi; Yi, Sun Shin; Song, Ki Duk; Lee, Hak-Kyo; Heo, Tae-Hwe; Park, Sang-Kyu; Jung, Yun Joo; Jun, Hyun Sik

    2017-08-01

    Hippophae rhamnoides L., also known as sea buckthorn (SBT), possesses a wide range of biological and pharmacological activities. However, the underlying mechanism is largely unknown. The present study examined whether SBT leaf extract could inhibit proliferation and promote apoptosis of rat glioma C6 cells. The results revealed that the treatment with SBT leaf extract inhibited proliferation of rat C6 glioma cells in a dose-dependent manner. SBT-induced reduction of C6 glioma cell proliferation and viability was accompanied by a decrease in production of reactive oxygen species (ROS), which are critical for the proliferation of tumor cells. SBT treatment not only significantly upregulated the expression of the pro-apoptotic protein Bcl-2-associated X (Bax) but also promoted its localization in the nucleus. Although increased expression and nuclear translocation of Bax were observed in SBT-treated C6 glioma cells, the induced nuclear morphological change was distinct from that of typical apoptotic cells in that most of SBT-treated cells were characterized by convoluted nuclei with cavitations and clumps of chromatin. All of these results suggest that SBT leaf extract could inhibit the rapid proliferation of rat C6 glioma cells, possibly by inducing the early events of apoptosis. Thus, SBT may serve as a potential therapeutic candidate for the treatment of glioma.

  11. Differential inhibitory effects of 2-azafluorenones on PI-PLC activation but not on PC-PLC- or PC-PLD-activation induced by histamine, PAF, PMA or A23187 in C6 glioma cells.

    Science.gov (United States)

    Wang, Hai-Long; Wang, Li-Chuan; Wei, Jiann-Wu

    2013-02-28

    In this study, C6 glioma cells were used to test the effects of 2-azafluorenone and its related compounds on membrane phosphatidylinositol (PI) and phosphatidylcholine (PC) turnover. An increase of [³H]-labeled inositol phosphate (IP1) formation by histamine (100 μM) or A23187 (100 nM) via the activation of phosphatidylinositol-specific phospholipase C (PI-PLC) to breakdown labeled substrate was observed, and this effect could be partially blocked by about half at 100 μM of 2-azafluorenones. Histamine induced the increase of IP1 formation, but failed to cause an increase in extracellularly releasing of [3H]choline metabolites, or intracellular accumulation of [³H]phosphscholine. However, platelet activation factor (PAF) from 0.2 to 1 μM, and phorbol 12-myristate-13-acetate (PMA) at 1 μM caused an increase in extracellularly releasing of [³H]choline metabolites, and intracellular accumulation of [³H]phosphocholine via the activation on phosphatidylcholine (PC)-PLC. These responses of PAF and PMA were not affected by 2-azafluorenone or 4-methyl-2-azafluorenone even at high concentration (10⁻⁴ M). A23187 induced an increase of intracellular [³H]choline release via the activation of PCphospholipase D (PLD). This increasing effect of 100 nM A23187 was not affected by 2-azafluorenone or 4-methyl-2-azafluorenone even at a high concentration of 10⁻⁴ M. In summary, the inhibitory effect of 2-azafluorenone and its related compound 4-methyl-2-azafluorenone was observed selectively on PIPLC, but not on PC-PLC or PC-PLD based on changes of products after the activation of these enzymes.

  12. 5-Aminolevulinic acid-mediated sonosensitization of rat RG2 glioma cells in vitro

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    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.

  13. PLC-dependent intracellular Ca2+ release was associated with C6-ceramide-induced inhibition of Na+ current in rat granule cells.

    Science.gov (United States)

    Liu, Zheng; Fei, Xiao-Wei; Fang, Yan-Jia; Shi, Wen-Jie; Zhang, Yu-Qiu; Mei, Yan-Ai

    2008-09-01

    In this report, the effects of C(6)-ceramide on the voltage-gated inward Na(+) currents (I(Na)), two types of main K(+) current [outward rectifier delayed K(+) current (I(K)) and outward transient K(+) current (I(A))], and cell death in cultured rat cerebellar granule cells were investigated. At concentrations of 0.01-100 microM, ceramide produced a dose-dependent and reversible inhibition of I(Na) without alteration of the steady-state activation and inactivation properties. Treatment with C(2)-ceramide caused a similar inhibitory effect on I(Na). However, dihydro-C(6)-ceramide failed to modulate I(Na). The effect of C(6)-ceramide on I(Na) was abolished by intracellular infusion of the Ca(2+)-chelating agent, 1,2-bis (2-aminophenoxy) ethane-N, N, N9, N9-tetraacetic acid, but was mimicked by application of caffeine. Blocking the release of Ca(2+) from the sarcoplasmic reticulum with ryanodine receptor blocker induced a gradual increase in I(Na) amplitude and eliminated the effect of ceramide on I(Na). In contrast, the blocker of the inositol 1,4,5-trisphosphate-sensitive Ca(2+) receptor did not affect the action of C(6)-ceramide. Intracellular application of GTPgammaS also induced a gradual decrease in I(Na) amplitude, while GDPbetaS eliminated the effect of C(6)-ceramide on I(Na). Furthermore, the C(6)-ceramide effect on I(Na) was abolished after application of the phospholipase C (PLC) blockers and was greatly reduced by the calmodulin inhibitors. Fluorescence staining showed that C(6)-ceramide decreased cell viability and blocking I(Na) by tetrodotoxin did not mimic the effect of C(6)-ceramide, and inhibiting intracellular Ca(2+) release by dantrolene could not decrease the C(6)-ceramide-induced cell death. We therefore suggest that increased PLC-dependent Ca(2+) release through the ryanodine-sensitive Ca(2+) receptor may be responsible for the C(6)-ceramide-induced inhibition of I(Na), which does not seem to be associated with C(6)-ceramide-induced granule

  14. Fasting enhances the response of glioma to chemo- and radiotherapy.

    Science.gov (United States)

    Safdie, Fernando; Brandhorst, Sebastian; Wei, Min; Wang, Weijun; Lee, Changhan; Hwang, Saewon; Conti, Peter S; Chen, Thomas C; Longo, Valter D

    2012-01-01

    Glioma, including anaplastic astrocytoma and glioblastoma multiforme (GBM) are among the most commonly diagnosed malignant adult brain tumors. GBM is a highly invasive and angiogenic tumor, resulting in a 12 to 15 months median survival. The treatment of GBM is multimodal and includes surgical resection, followed by adjuvant radio-and chemotherapy. We have previously reported that short-term starvation (STS) enhances the therapeutic index of chemo-treatments by differentially protecting normal cells against and/or sensitizing tumor cells to chemotoxicity. To test the effect of starvation on glioma cells in vitro, we treated primary mouse glia, murine GL26, rat C6 and human U251, LN229 and A172 glioma cells with Temozolomide in ad lib and STS mimicking conditions. In vivo, mice with subcutaneous or intracranial models of GL26 glioma were starved for 48 hours prior to radio- or chemotherapy and the effects on tumor progression and survival were measured. Starvation-mimicking conditions sensitized murine, rat and human glioma cells, but not primary mixed glia, to chemotherapy. In vivo, starvation for 48 hours, which causes a significant reduction in blood glucose and circulating insulin-like growth factor 1 (IGF-1) levels, sensitized both subcutaneous and intracranial glioma models to radio-and chemotherapy. Starvation-induced cancer sensitization to radio- or chemotherapy leads to extended survival in the in vivo glioma models tested. These results indicate that fasting and fasting-mimicking interventions could enhance the efficacy of existing cancer treatments against aggressive glioma in patients.

  15. 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 ...

  16. Direct and indirect interactions between antidepressant drugs and CYP2C6 in the rat liver during long-term treatment.

    Science.gov (United States)

    Daniel, W A; Haduch, A; Syrek, M; Boksa, J

    2006-12-01

    The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2C6 measured as a rate of warfarin 7-hydroxylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally (i.p.) for one day or two weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone at 10 mg/kg i.p.; desipramine, fluoxetine, sertraline at 5mg/kg i.p.; mirtazapine at 3mg/kg i.p.), in the absence of the antidepressants in vitro. Some of the investigated antidepressant drugs added to liver microsomes of control rats inhibited the rate of 7-hydroxylation of warfarin. The obtained K(i) values indicated that nefazodone and fluoxetine were the most potent inhibitors of the studied reaction (K(i)=13 and 23microM, respectively), while tricyclic antidepressants and sertraline were weak in this respect (K(i)=70-127microM). A one-day (i.e. 24h) exposure to fluoxetine and mirtazapine resulted in a significant increase in the rate of the 7-hydroxylation of warfarin in rat liver microsomes. The other studied antidepressants did not significantly affect the rate of the CYP2C6-specific reaction. After two-week treatment with the investigated antidepressants, the increase in CYP2C6 activity observed after 24-h exposure to fluoxetine and mirtazapine was more pronounced. Moreover, unlike after one-day exposure, imipramine and sertraline significantly increased the activity of the enzyme. The other tricyclic antidepressants or nefazodone did not produce any significant effect when administered in vivo. The above-described enhancement of CYP2C6 activity correlated positively with the simultaneously observed increases in the enzyme protein level

  17. Novel antitumor effect of carboplatin delivered by intracerebral microinfusion in a rat malignant glioma model.

    Science.gov (United States)

    Tange, Yuichi; Miyazaki, Masahiro; Iwata, Junko; Aiko, Yasuhisa; Sakamoto, Shinichi; Mori, Kentaro

    2009-12-01

    Carboplatin loaded osmotic mini-pumps were implanted in 24 9L malignant glioma-bearing rats to investigate the implications of direct intracerebral microinfusion. Carboplatin using 0.1 mg/ml (low dose group) or 1.0 mg/ml (high dose group) with eight rats in each group, or 5% D-glucose (control group) in eight rats were infused at 1 microl/hr for 7 days. The tumor volume was serially measured by magnetic resonance (MR) imaging with gadolinium as the enhanced area, and the survival periods and histological findings were also examined. Separately, to examine the effects of intracerebral carboplatin infusion on vascular permeability, tumor-bearing rats received intravenous administration of 2% Evans blue at 21 days after infusion. The high dose group showed transient increase of enhanced volume at 21 days associated with mass effect, and significantly decreased tumor volume at 28 and 35 days compared with the control and low dose groups. The high dose group showed significant longer survival time than the control and low dose groups. Histological examination of the high dose group at 21 days showed the central tumor necrotic area around the infusion site and Evans blue leakage into the surrounding enhanced rim and the necrotic core. Therefore, leakage of plasma fluid into the necrotic area was considered to be the cause of apparent transient swelling. The present study demonstrated quantitatively using MR imaging that intracerebral carboplatin microinfusion significantly inhibited the rapid growth of experimental rat glioma but that the high dose required carries the risk of transient swelling of the target tumor.

  18. Quantitative multiparametric MRI assessment of glioma response to radiotherapy in a rat model.

    Science.gov (United States)

    Hong, Xiaohua; Liu, Li; Wang, Meiyun; Ding, Kai; Fan, Ying; Ma, Bo; Lal, Bachchu; Tyler, Betty; Mangraviti, Antonella; Wang, Silun; Wong, John; Laterra, John; Zhou, Jinyuan

    2014-06-01

    The inability of structural MRI to accurately measure tumor response to therapy complicates care management for patients with gliomas. The purpose of this study was to assess the potential of several noninvasive functional and molecular MRI biomarkers for the assessment of glioma response to radiotherapy. Fourteen U87 tumor-bearing rats were irradiated using a small-animal radiation research platform (40 or 20 Gy), and 6 rats were used as controls. MRI was performed on a 4.7 T animal scanner, preradiation treatment, as well as at 3, 6, 9, and 14 days postradiation. Image features of the tumors, as well as tumor volumes and animal survival, were quantitatively compared. Structural MRI showed that all irradiated tumors still grew in size during the initial days postradiation. The apparent diffusion coefficient (ADC) values of tumors increased significantly postradiation (40 and 20 Gy), except at day 3 postradiation, compared with preradiation. The tumor blood flow decreased significantly postradiation (40 and 20 Gy), but the relative blood flow (tumor vs contralateral) did not show a significant change at most time points postradiation. The amide proton transfer weighted (APTw) signals of the tumor decreased significantly at all time points postradiation (40 Gy), and also at day 9 postradiation (20 Gy). The blood flow and APTw maps demonstrated tumor features that were similar to those seen on gadolinium-enhanced T1-weighted images. Tumor ADC, blood flow, and APTw were all useful imaging biomarkers by which to predict glioma response to radiotherapy. The APTw signal was most promising for early response assessment in this model. © The Author(s) 2013. 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.

  19. TWIST is Expressed in Human Gliomas, Promotes Invasion

    Directory of Open Access Journals (Sweden)

    Maria C. Elias

    2005-09-01

    Full Text Available TWIST is a basic helix-loop-helix (bHLH transcription factor that regulates mesodermal development, promotes tumor cell metastasis, and, in response to cytotoxic stress, enhances cell survival. Our screen for bHLH gene expression in rat C6 glioma revealed TWIST. To delineate a possible oncogenic role for TWIST in the human central nervous system (CNS, we analyzed TWIST message, protein expression in gliomas, normal brain. TWIST was detected in the large majority of human glioma-derived cell lines, human gliomas examined. Increased TWIST mRNA levels were associated with the highest grade gliomas, increased TWIST expression accompanied transition from low grade to high grade in vivo, suggesting a role for TWIST in promoting malignant progression. In accord, elevated TWIST mRNA abundance preceded the spontaneous malignant transformation of cultured mouse astrocytes hemizygous for p53. Overexpression of TWIST protein in a human glioma cell line significantly enhanced tumor cell invasion, a hallmark of high-grade gliomas. These findings support roles for TWIST both in early glial tumorigenesis, subsequent malignant progression. TWIST was also expressed in embryonic, fetal human brain, in neurons, but not glia, of mature brain, indicating that, in gliomas, TWIST may promote the functions also critical for CNS development or normal neuronal physiology.

  20. Glioma morphology and tumor-induced vascular alterations revealed in 7 rodent glioma models by in vivo magnetic resonance imaging and angiography

    Science.gov (United States)

    Doblas, Sabrina; He, Ting; Saunders, Debbie; Pearson, Jamie; Hoyle, Jessica; Smith, Nataliya; Lerner, Megan; Towner, Rheal A.

    2010-01-01

    Purpose To evaluate the added value of non-contrast-enhanced magnetic resonance angiography (MRA) to conventional MR imaging for a detailed characterization of different rodent glioma models. Materials and Methods Intracerebral tumor cell implantation and chemical induction methods were implemented to obtain rat C6, 9L/LacZ, F98, RG2 and ENU-induced glioma models, a human U87 MG tumor model as well as a mouse GL261 glioma model. MR assessments were regularly conducted on a 7 Tesla Bruker BioSpin system. The tumor border sharpness and growth characteristics of each glioma model were assessed from T2-weighted images. Neovascularization and vascular alterations inherent to each model were characterized by assessing absolute blood volumes, vessel density, length and diameter using Mathematica and Amira software. Results 9L/LacZ and ENU gliomas both presented flaws that hinder their use as reliable brain tumor models. C6 gliomas were slightly invasive and induced moderate vascular alterations, whereas GL261 tumors dramatically altered the brain vessels in the glioma region. F98, RG2 and U87 are infiltrative models which produced dramatic vascular alterations. Conclusion MRI and MRA provided crucial in vivo information to identify a distinctive “fingerprint” for each of our 7 rodent glioma models. PMID:20677250

  1. Multifunctional upconversion nanoparticles for targeted dual-modal imaging in rat glioma xenograft.

    Science.gov (United States)

    Yang, Lin; Shao, Bin; Zhang, Xiangtong; Cheng, Qian; Lin, Tie; Liu, Enzhong

    2016-09-01

    Achieving a radiographic gross total resection in high-grade gliomas improves overall survival. Many technologies such as intraoperative microscope, intraoperative ultrasound, fluorescence imaging, and intraoperative magnetic resonance imaging have been applied to improve tumor resection. However, most commercial available magnetic resonance imaging contrast agents have limited permeability across the blood-brain barrier and are cleared rapidly from circulation. Fluorescence imaging discriminates tumor from normal tissue and provides a promising new strategy to maximize sage surgical resection of tumor. However, the penetration depth of fluorescence imaging is generally low. In this study, a new type of magnetite NaGdF4:Yb(3+),Er(3+),Li(+)@NaGdF4 (UCNPs) core-shell nanoparticles, coated with SiO2 and further functionalized with glioma and blood-brain barrier targeting motifs, was prepared for dual-modal in vivo upconversion imaging and magnetic resonance imaging. The as-prepared multifunctional upconversion nanoparticles (UCNPs@SiO2-CX-Lf) were biocompatible, showed strong upconversion luminescence under excitation of 980 nm, and provided high signal-to-noise ratio in vivo. Moreover, UCNPs@SiO2-CX-Lf nanoparticles showed a high relaxivity of 1.25 S(-1 )mM(-1) and were successfully applied as contrast agent for magnetic resonance imaging in tumor xenograft rat model with prolonged tumor signal enhancement. In vivo and magnetic resonance imaging Upconversion Luminescence (UCL) imaging results indicated that these particles can across the blood-brain barrier, bind to glioma, gave bright UCL signal and T1 magnetic resonance imaging contrast. Targeted UCL and magnetic resonance imaging dual-modal in vivo imaging using Yb(3+)/Er(3+)/Li(+) codoped NaGdF4 core-shell nanostructure can serve as a platform technology for the next generation of intraoperative probes for image-guided tumor resection. © The Author(s) 2016.

  2. 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.

  3. Biodisposition and metabolism of [{sup 18}F]fluorocholine in 9L glioma cells and 9L glioma-bearing fisher rats

    Energy Technology Data Exchange (ETDEWEB)

    Bansal, Aditya; Harris, Robert A. [Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Indianapolis, IN (United States); Shuyan, Wang; Hara, Toshiko [Indiana University School of Medicine, Department of Radiology, Indianapolis, IN (United States); DeGrado, Timothy R. [Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, Indianapolis, IN (United States); Indiana University School of Medicine, Department of Radiology, Indianapolis, IN (United States)

    2008-06-15

    [{sup 18}F]Fluorocholine ([{sup 18}F]FCH) was developed as an analog of [{sup 11}C]choline for tumor imaging; however, its metabolic handling remains ill defined. In this study, the metabolism of [{sup 18}F]FCH is evaluated in cultured 9L glioma cells and Fisher 344 rats bearing 9L glioma tumors. 9L glioma cells were incubated with [{sup 18}F]FCH and [{sup 14}C]choline under normoxic and hypoxic (1% O{sub 2}) conditions and analyzed for metabolic fate. [{sup 18}F]FCH and [{sup 14}C]choline kinetics and metabolism were studied in Fisher 344 rats bearing subcutaneous 9L tumors. [{sup 18}F]FCH and [{sup 14}C]choline were similarly metabolized in 9L cells in both normoxic and hypoxic conditions over a 2-h incubation period. In normoxia, radioactivity was predominantly in phosphorylated form for both tracers after 5-min incubation. In hypoxia, the tracers remained mainly in nonmetabolized form at early timepoints (<20 min). Slow dephosphorylation of intracellular [{sup 18}F]phosphofluorocholine (0.043-0.060 min{sup -1}) and [{sup 14}C]phosphocholine (0.072-0.088 min{sup -1}) was evidenced via efflux measurements. In rat, both [{sup 18}F]FCH and [{sup 14}C]choline showed high renal and hepatic uptake. Blood clearance of both tracers was rapid with oxidative metabolites, [{sup 18}F]fluorobetaine and [{sup 14}C]betaine, representing the majority of radiolabel in plasma after 5 min postinjection. Oxidation (in liver) and lipid incorporation (in lung) were somewhat slower for [{sup 18}F]FCH relative to [{sup 14}C]choline. The majority of radiolabel in hypoxic subcutaneous tumor, as in hypoxic cultured 9L cells, was found as nonmetabolized [{sup 18}F]FCH and [{sup 14}C]choline. [{sup 18}F]FCH mimics choline uptake and metabolism by 9L glioma cells and tumors. However, subtle changes in biodistribution, oxidative metabolism, dephosphorylation, lipid incorporation, and renal excretion show moderate effects of the presence of the radiofluorine atom in [{sup 18}F]FCH. The

  4. Biodisposition and metabolism of [18F]fluorocholine in 9L glioma cells and 9L glioma-bearing Fisher rats

    Science.gov (United States)

    Bansal, Aditya; Shuyan, Wang; Hara, Toshiko; Harris, Robert A.; DeGrado, Timothy R.

    2008-01-01

    Purpose [18F]Fluorocholine [18F]FCH) was developed as an analog of [11C]choline for tumor imaging, however, its metabolic handling remains ill-defined. In this study, the metabolism of [18F]FCH is evaluated in cultured 9L glioma cells and Fisher 344 rats bearing 9L glioma tumors. Methods 9L glioma cells were incubated with [18F]FCH and [14C]choline under normoxic and hypoxic (1% O2) conditions and analyzed for metabolic fate. [18F]FCH and [14C]choline kinetics and metabolism were studied in Fisher 344 rats bearing subcutaneous 9L tumors. Results [18F]FCH and [14C]choline were similarly metabolized in 9L cells in both normoxic and hypoxic conditions over a 2 hr incubation period. In normoxia, radioactivity was predominantly in phosphorylated form for both tracers after 5 min incubation. In hypoxia, the tracers remained mainly in nonmetabolized form at early timepoints (< 20 min). Slow dephosphorylation of intracellular [18F]phosphofluorocholine (0.043–0.060 min−1) and [14C]phosphocholine (0.072–0.088 min−1) was evidenced via efflux measurements. In rat, both [18F]FCH and [14C]choline showed high renal and hepatic uptake. Blood clearance of both tracers was rapid with oxidative metabolites, [18F]fluorobetaine and [14C]betaine, representing the majority of radiolabel in plasma after 5 min post-injection. Oxidation (in liver) and lipid incorporation (in lung) were somewhat slower for [18F]FCH relative to [14C]choline. The majority of radiolabel in hypoxic subcutaneous tumor, as in hypoxic cultured 9L cells, was found as nonmetabolized [18F]FCH and [14C]choline. Conclusions [18F]FCH mimics choline uptake and metabolism by 9L glioma cells and tumors. However, subtle changes in biodistribution, oxidative metabolism, dephosphorylation, lipid incorporation and renal excretion show moderate effects of the presence of the radiofluorine atom in [18F]FCH. The decrease in phosphorylation of exogenous choline by cancer cells should be considered in interpretation of PET

  5. 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...

  6. The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals.

    Science.gov (United States)

    Wang, Yahua; Ying, Xue; Xu, Haolun; Yan, Helu; Li, Xia; Tang, Hui

    2017-01-01

    Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood-brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposomes in order to improve the drug delivery system onto the glioma cells and induce the apoptosis of glioma stem cells afterward. In this experiment, curcumin was chosen to kill gliomas, while quinacrine was used to induce apoptosis of the glioma stem cells. Also, p-aminophenyl-α-D-mannopyranoside could facilitate the transport of liposomes across the blood-brain barrier and finally target the brain glioma cells. The cell experiments in vitro indicated that the targeted liposomes could significantly improve the anti-tumor effects of the drugs, while enhancing the uptake effects, apoptosis effects, and endocytic effects of C6 glioma cells and C6 glioma stem cells. Given the animal experiments in vivo, we discovered that the targeted liposomes could obviously increase the survival period of brain glioma-bearing mice and inhibit the growth of gliomas. In summary, curcumin and quinacrine liposomes modified with p-aminophenyl-α-D-mannopyranoside is a potential preparation to treat brain glioma cells and brain glioma stem cells.

  7. Decreased MiR-17 in glioma cells increased cell viability and migration by increasing the expression of Cyclin D1, p-Akt and Akt.

    Directory of Open Access Journals (Sweden)

    Guangwei Sun

    Full Text Available The activating mutations of micro RNA (miR-17 have been revealed in tumors such as human non-Hodgkin's lymphoma and T cell leukemia. However, it is unclear about the role of miR-17 in glioma cells. The current study aimed to investigate effects of miR-17 mimics or inhibitor on the viability and migration of rat glioma C6 cells, and explore possible mechanisms.The expression of miR-17 in rat glioma C6 cells and normal brain tissue was detected by quantitative PCR. Protein expression of Cyclin D1 in rat glioma C6 cells and normal brain tissue was measured by Western Blot. Glioma C6 cells were transfected with MiR-17 mimics or inhibitor. Cells that were not transfected (Lipofectamine only and cells that were transfected with nonsense RNA negative control served as control. MTT assay was utilized to detect cell viability, and cell wound scratch assay was utilized to examine the migration index. In addition, protein expression of Cyclin D1, p-Akt and Akt in MiR-17 mimics or inhibitor-transfected glioma C6 cells was detected by Western Blot. This study had been approved by the Medical Ethics Committee of the First Affiliated Hospital of Soochow University. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.The expression of miR-17 was significantly lower, whereas the expression of Cyclin D1 was significantly higher in glioma C6 cells compared to normal brain tissue. MiR-17 mimics decreased the viability and migration of glioma C6 cells markedly at 48 h. In addition, MiR-17 inhibitor increased the viability and migration of glioma C6 cells at 24 and 48 h. The protein expression of Cyclin D1, p-Akt and Akt in glioma C6 cells decreased after transfection with miR-17 mimics for 72 h, and increased after transfection with miR-17 inhibitor for 72 h.The reduced miR-17 levels in glioma cells increased cell viability and migration, which correlates with increased expression of Cyclin D1, p

  8. 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.

  9. The impact of tumor nitric oxide production on VEGFA expression and tumor growth in a zebrafish rat glioma xenograft model.

    Directory of Open Access Journals (Sweden)

    Nadhir Yousfi

    Full Text Available To investigate the effect of nitric oxide on tumor development, we established a rat tumor xenograft model in zebrafish embryos. The injected tumor cells formed masses in which nitric oxide production could be detected by the use of the cell-permeant DAF-FM-DA (diaminofluorophore 4-amino-5-methylamino-2'-7'-difluorofluorescein diacetate and DAR-4M-AM (diaminorhodamine-4M. This method revealed that nitric oxide production could be co-localized with the tumor xenograft in 46% of the embryos. In 85% of these embryos, tumors were vascularized and blood vessels were observed on day 4 post injection. Furthermore, we demonstrated by qRT-PCR that the transplanted glioma cells highly expressed Nos2, Vegfa and Cyclin D1 mRNA. In the xenografted embryos we also found increased zebrafish vegfa expression. Glioma and zebrafish derived Vegfa and tumor Cyclin D1 expression could be down regulated by the nitric oxide scavenger 2-(4-Carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide or CPTIO. We conclude that even if there is a heterogeneous nitric oxide production by the xenografted glioma cells that impacts Vegfa and Cyclin D1 expression levels, our results suggest that reduction of nitric oxide levels by nitric oxide scavenging could be an efficient approach to treat glioma.

  10. 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. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. T11TS immunotherapy repairs PI3K-AKT signaling in T-cells: Clues toward enhanced T-cell survival in rat glioma model.

    Science.gov (United States)

    Chaudhuri, Suhnrita; Singh, Manoj K; Bhattacharya, Debanjan; Datta, Ankur; Hazra, Iman; Mondal, Somnath; Faruk Sk Md, Omar; Ronsard, Larance; Ghosh, Tushar K; Chaudhuri, Swapna

    2018-02-01

    Malignant glioma is the most fatal of astrocytic lineage tumors despite therapeutic advances. Onset and progression of gliomas is accompanied by severe debilitation of T-cell defense and T-cell survival. One of the chief contributors to T-cell survival downstream of activation is the PI3K-AKT pathway. Our prior studies showed that the novel immunotherapeutic molecule T11-target structure (T11TS) blocks T-cell apoptosis in glioma. We also showed activation of immunological synapse components and calcineurin-NFAT pathway following T11TS immunotherapy of glioma-bearing rats. This lead to investigations whether such T-cell activation upon T11TS therapy translates into activation of downstream PI3K/AKT signals which may be related to observed blockade of T-cell apoptosis. For the purpose, we assessed by flowcytometry and immunoblotting, expressions of PI3K, PDK1, AKT, p-AKT, and PTEN in splenic T-cells of normal, experimentally-induced glioma-bearing rats and glioma-bearing rats receiving first, second and third doses of T11TS. We also determined comparative nuclear translocation of NF-κB across groups. We found significant increases in T-cell expressions of PDK1, PI3K, and p-AKT in T11TS-treated animal groups compared to sharp downregulations in glioma. AKT levels remained unchanged across groups. PTEN levels declined sharply after T11TS immunotherapy. T11TS also caused enhanced NF-κB translocation to the T-cell nucleus compared to glioma group. Results showed heightened activation of the PI3K-AKT pathway in glioma-bearing rats following T11TS immunotherapy. These results illustrate the novel role of T11TS immunotherapy in ameliorating the PI3K pathway in T-cells in glioma-bearing animals to enhance T-cell survival, according greater defense against glioma. The study thus has far-reaching clinical outcomes. © 2017 Wiley Periodicals, Inc.

  12. Dynamic-contrast-enhanced-MRI with extravasating contrast reagent: Rat cerebral glioma blood volume determination

    Science.gov (United States)

    Li, Xin; Rooney, William D.; Várallyay, Csanád G.; Gahramanov, Seymur; Muldoon, Leslie L.; Goodman, James A.; Tagge, Ian J.; Selzer, Audrey H.; Pike, Martin M.; Neuwelt, Edward A.; Springer, Charles S.

    2010-10-01

    The accurate mapping of the tumor blood volume (TBV) fraction ( vb) is a highly desired imaging biometric goal. It is commonly thought that achieving this is difficult, if not impossible, when small molecule contrast reagents (CRs) are used for the T1-weighted (Dynamic-Contrast-Enhanced) DCE-MRI technique. This is because angiogenic malignant tumor vessels allow facile CR extravasation. Here, a three-site equilibrium water exchange model is applied to DCE-MRI data from the cerebrally-implanted rat brain U87 glioma, a tumor exhibiting rapid CR extravasation. Analyses of segments of the (and the entire) DCE data time-course with this "shutter-speed" pharmacokinetic model, which admits finite water exchange kinetics, allow TBV estimation from the first-pass segment. Pairwise parameter determinances were tested with grid searches of 2D parametric error surfaces. Tumor blood volume ( vb), as well as ve (the extracellular, extravascular space volume fraction), and Ktrans (a CR extravasation rate measure) parametric maps are presented. The role of the Patlak Plot in DCE-MRI is also considered.

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model.

    Science.gov (United States)

    Singleton, W G; Collins, A M; Bienemann, A S; Killick-Cole, C L; Haynes, H R; Asby, D J; Butts, C P; Wyatt, M J; Barua, N U; Gill, S S

    2017-01-01

    The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood-brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls. Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P<0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination. CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic.

  18. Pharmacokinetic changes induced by focused ultrasound in glioma-bearing rats as measured by dynamic contrast-enhanced MRI.

    Science.gov (United States)

    Yang, Feng-Yi; Ko, Chia-En; Huang, Sheng-Yao; Chung, I-Fang; Chen, Gin-Shin

    2014-01-01

    Focused ultrasound (FUS) combined with microbubbles has been shown to be a noninvasive and targeted drug delivery technique for brain tumor treatment. The purpose of this study was to measure the kinetics of Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) in glioma-bearing rats in the presence of FUS-induced blood-brain barrier disruption (BBB-D) by magnetic resonance imaging (MRI). A total of ten glioma-bearing rats (9-12 weeks, 290-340 g) were used in this study. Using dynamic contrast-enhanced (DCE)-MRI, the spatial permeability of FUS-induced BBB-D was evaluated and the kinetic parameters were calculated by a general kinetic model (GKM). The results demonstrate that the mean Ktrans of the sonicated tumor (0.128±0.019 at 20 min and 0.103±0.023 at 24 h after sonication, respectively) was significantly higher than (2.46-fold at 20 min and 1.78-fold at 24 h) that of the contralateral (non-sonicated) tumor (0.052±0.019 at 20 min and 0.058±0.012 at 24 h after sonication, respectively). In addition, the transfer constant Ktrans in the sonicated tumor correlated strongly with tissue EB extravasation (R = 0.95), which suggests that DCE-MRI may reflect drug accumulation in the brain. Histological observations showed no macroscopic damage except for a few small erythrocyte extravasations. The current study demonstrates that DCE-MRI can monitor the dynamics of the FUS-induced BBB-D process and constitutes a useful tool for quantifying BBB permeability in tumors.

  19. 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

  20. Conjugation of functionalized SPIONs with transferrin for targeting and imaging brain glial tumors in rat model.

    Directory of Open Access Journals (Sweden)

    Weili Jiang

    Full Text Available Currently, effective and specific diagnostic imaging of brain glioma is a major challenge. Nanomedicine plays an essential role by delivering the contrast agent in a targeted manner to specific tumor cells, leading to improvement in accurate diagnosis by good visualization and specific demonstration of tumor cells. This study investigated the preparation and characterization of a targeted MR contrast agent, transferrin-conjugated superparamagnetic iron oxide nanoparticles (Tf-SPIONs, for brain glioma detection. MR imaging showed the obvious contrast change of brain glioma before and after administration of Tf-SPIONs in C6 glioma rat model in vivo on T2 weighted imaging. Significant contrast enhancement of brain glioma could still be clearly seen even 48 h post injection, due to the retention of Tf-SPIONs in cytoplasm of tumor cells which was proved by Prussian blue staining. Thus, these results suggest that Tf-SPIONs could be a potential targeting MR contrast agent for the brain glioma.

  1. Polyoxygenated 24,28-epoxyergosterols inhibiting the proliferation of glioma cells from sea anemone Anthopleura midori.

    Science.gov (United States)

    Yu, Siran; Ye, Xuewei; Chen, Lu; Lian, Xiao-Yuan; Zhang, Zhizhen

    2014-10-01

    Eleven sterols (1-11) and one carotenoid (12) were isolated and identified from sea anemone Anthopleura midori. Compounds 1-6 are rare polyoxygenated ergosterols with a 24,28-epoxy moiety. The structures of these epoxyergosterols were determined by NMR and HRESIMS analyses as well as their chemical-physical properties. Epoxyergosterols 1 and 2 were found to be new natural products and 3-6 are new compounds. Bioactive assay showed that compounds 1, 2, 3, 5, 7, 8, 11, and 12 inhibited the proliferation of rat glioma C6 and human glioma U251 cells with IC50 in a range of 2.41-80.45 μM. Further investigation suggested that 1 and 3 induced apoptosis in glioma cells and 1 blocked U251 cells at the G0/G1 phase. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. 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 < 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). 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.

  3. 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.

  4. Dihydroxy-2,5 benzenesulphonate (dobesilate) elicits growth arrest and apoptosis in glioma cells.

    Science.gov (United States)

    Cuevas, P; Díaz-González, D; Giménez-Gallego, G; Dujovny, M

    2005-12-01

    Dihydroxy-2,5 benzenesulphonate (dobesilate) is used as an oral agent for treatment of vascular complications of diabetic retinopathy. We previously showed that blockade of fibroblast growth factor (FGF) driving angiogenesis with dobesilate inhibited new blood vessel formation in a mouse gelatine plug assay. In the present study we assessed the effects of dobesilate in rat glioma cells. Rat C6 cells line were grown as adherent cells in Dulbecco modified Eagle medium supplemented with 1% (v/v) fetal bovine serum and antibiotics. Calcium dobesilate was added in independent experiments at the following concentrations: 10, 25, 50, 75 and 100 microM, and cells were incubated for 24 hours. Effects of dobesilate in glioma cell proliferation and survival were assessed using crystal violet staining and TUNEL assay, respectively. Incubation of glioma cells with dobesilate for 24 hours concentration-dependently decreased cell proliferation with an apparent IC50 of 25 microM, and this antiproliferative effect was related to a significant increase in glioma cell apoptosis. The results suggest that dobesilate is a promising candidate leading to the development of a new adjuvant therapeutic strategy for gliomas.

  5. AMOG/beta2 and glioma invasion: does loss of AMOG make tumour cells run amok?

    Science.gov (United States)

    Senner, V; Schmidtpeter, S; Braune, S; Püttmann, S; Thanos, S; Bartsch, U; Schachner, M; Paulus, W

    2003-08-01

    The beta2 subunit of Na,K-ATPase, initially described as adhesion molecule on glia (AMOG), has been shown to mediate neurone-astrocyte adhesion as well as neural cell migration in vitro. We have investigated the expression of AMOG/beta2 in human gliomas and its effect on glioma cell adhesion and migration. Compared to normal astrocytes of human brain, AMOG/beta2 expression levels of neoplastic astrocytes were down-regulated in biopsy specimens and inversely related to the grade of malignancy. One rat and four human glioma cell lines showed complete loss of AMOG. To investigate the function of AMOG/beta2, its expression was re-established by transfecting an expression plasmid into AMOG/beta2-negative C6 rat glioma cells. In vitro assays revealed increased adhesion and decreased migration on matrigel of AMOG/beta2-positive cells as compared to their AMOG/beta2-negative counterparts. We conclude that increasing loss of AMOG/beta2 during malignant progression parallels and may underlie the extensive invasion pattern of malignant gliomas.

  6. Survival Analysis of F98 Glioma Rat Cells Following Minibeam or Broad-Beam Synchrotron Radiation Therapy

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    Prezado Yolanda

    2011-04-01

    Full Text Available Abstract Background In the quest of a curative radiotherapy treatment for gliomas new delivery modes are being explored. At the Biomedical Beamline of the European Synchrotron Radiation Facility (ESRF, a new spatially-fractionated technique, called Minibeam Radiation Therapy (MBRT is under development. The aim of this work is to compare the effectiveness of MBRT and broad-beam (BB synchrotron radiation to treat F98 glioma rat cells. A dose escalation study was performed in order to delimit the range of doses where a therapeutic effect could be expected. These results will help in the design and optimization of the forthcoming in vivo studies at the ESRF. Methods Two hundred thousand F98 cells were seeded per well in 24-well plates, and incubated for 48 hours before being irradiated with spatially fractionated and seamless synchrotron x-rays at several doses. The percentage of each cell population (alive, early apoptotic and dead cells, where either late apoptotic as necrotic cells are included was assessed by flow cytometry 48 hours after irradiation, whereas the metabolic activity of surviving cells was analyzed on days 3, 4, and 9 post-irradiation by using QBlue test. Results The endpoint (or threshold dose from which an important enhancement in the effectiveness of both radiation treatments is achieved obtained by flow cytometry could be established just before 12 Gy in the two irradiation schemes, whilst the endpoints assessed by the QBlue reagent, taking into account the cell recovery, were set around 18 Gy in both cases. In addition, flow cytometric analysis pointed at a larger effectiveness for minibeams, due to the higher proportion of early apoptotic cells. Conclusions When the valley doses in MBRT equal the dose deposited in the BB scheme, similar cell survival ratio and cell recovery were observed. However, a significant increase in the number of early apoptotic cells were found 48 hours after the minibeam radiation in comparison with

  7. Cellular host responses to gliomas.

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    Joseph Najbauer

    Full Text Available BACKGROUND: Glioblastoma multiforme (GBM is the most aggressive type of malignant primary brain tumors in adults. Molecular and genetic analysis has advanced our understanding of glioma biology, however mapping the cellular composition of the tumor microenvironment is crucial for understanding the pathology of this dreaded brain cancer. In this study we identified major cell populations attracted by glioma using orthotopic rodent models of human glioma xenografts. Marker-specific, anatomical and morphological analyses revealed a robust influx of host cells into the main tumor bed and tumor satellites. METHODOLOGY/PRINCIPAL FINDINGS: Human glioma cell lines and glioma spheroid orthotopic implants were used in rodents. In both models, the xenografts recruited large numbers of host nestin-expressing cells, which formed a 'network' with glioma. The host nestin-expressing cells appeared to originate in the subventricular zone ipsilateral to the tumor, and were clearly distinguishable from pericytes that expressed smooth muscle actin. These distinct cell populations established close physical contact in a 'pair-wise' manner and migrated together to the deeper layers of tumor satellites and gave rise to tumor vasculature. The GBM biopsy xenografts displayed two different phenotypes: (a low-generation tumors (first in vivo passage in rats were highly invasive and non-angiogenic, and host nestin-positive cells that infiltrated into these tumors displayed astrocytic or elongated bipolar morphology; (b high-generation xenografts (fifth passage had pronounced cellularity, were angiogenic with 'glomerulus-like' microvascular proliferations that contained host nestin-positive cells. Stromal cell-derived factor-1 and its receptor CXCR4 were highly expressed in and around glioma xenografts, suggesting their role in glioma progression and invasion. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a robust migration of nestin-expressing host cells to glioma, which

  8. Sweet Taste Receptors in Normal and Pathological Rat Brain

    OpenAIRE

    YI, Chenju

    2011-01-01

    The mammalian sweet taste receptors (T1Rs) are G protein-coupled receptor complexes, which have recently been proposed to be associated with the brain glucose sensor. Here, we investigated the expression of sweet taste receptors T1R1 and T1R3 in normal and pathological rat brain, including tissue libraries of C6 rat glioma and rat brain of middle cerebral artery occlusion (MCAO), by immunohistological methods. The results demonstrated that neurons located in different brain regions, including...

  9. Evaluation of a novel sodium borocaptate-containing unnatural amino acid as a boron delivery agent for neutron capture therapy of the F98 rat glioma.

    Science.gov (United States)

    Futamura, Gen; Kawabata, Shinji; Nonoguchi, Naosuke; Hiramatsu, Ryo; Toho, Taichiro; Tanaka, Hiroki; Masunaga, Shin-Ichiro; Hattori, Yoshihide; Kirihata, Mitsunori; Ono, Koji; Kuroiwa, Toshihiko; Miyatake, Shin-Ichi

    2017-01-23

    Boron neutron capture therapy (BNCT) is a unique particle radiation therapy based on the nuclear capture reactions in boron-10. We developed a novel boron-10 containing sodium borocaptate (BSH) derivative, 1-amino-3-fluorocyclobutane-1-carboxylic acid (ACBC)-BSH. ACBC is a tumor selective synthetic amino acid. The purpose of this study was to assess the biodistribution of ACBC-BSH and its therapeutic efficacy following Boron Neutron Capture Therapy (BNCT) of the F98 rat glioma. We evaluated the biodistribution of three boron-10 compounds, ACBC-BSH, BSH and boronophenylalanine (BPA), in vitro and in vivo, following intravenous (i.v.) administration and intratumoral (i.t.) convection-enhanced delivery (CED) in F98 rat glioma bearing rats. For BNCT studies, rats were stratified into five groups: untreated controls, neutron-irradiation controls, BNCT with BPA/i.v., BNCT with ACBC-BSH/CED, and BNCT concomitantly using BPA/i.v. and ACBC-BSH/CED. In vitro, ACBC-BSH attained higher cellular uptake F98 rat glioma cells compared with BSH. In vivo biodistribution studies following i.v. administration and i.t. CED of ACBC-BSH attained significantly higher boron concentrations than that of BSH, but much lower than that of BPA. However, following convection enhanced delivery (CED), ACBC-BSH attained significantly higher tumor concentrations than BPA. The i.t. boron-10 concentrations were almost equal between the ACBC-BSH/CED group and BPA/i.v. group of rats. The tumor/brain boron-10 concentration ratio was higher with ACBC-BSH/CED than that of BPA/i.v. group. Based on these data, BNCT studies were carried out in F98 glioma bearing rats using BPA/i.v. and ACBC-BSH/CED as the delivery agents. The corresponding mean survival times were 37.4 ± 2.6d and 44.3 ± 8.0d, respectively, and although modest, these differences were statistically significant. Our findings suggest that further studies are warranted to evaluate ACBC-BSH/CED as a boron delivery agent.

  10. 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

  11. Caffeine inhibits migration in glioma cells through the ROCK-FAK pathway.

    Science.gov (United States)

    Chen, Ying; Chou, Wei-Chung; Ding, You-Ming; Wu, Ya-Chieh

    2014-01-01

    Glioma is the most malignant brain tumor that has the ability to migrate and invade the CNS. In this study, we investigated the signaling mechanism of caffeine on the migration of glioma cells. The effect of caffeine on cell migration was evaluated using Transwell and wound healing assays. The expression of the focal adhesion complex as it related to cell migration was assayed using Western blotting and immunostaining. Caffeine decreased the migration of rat C6 and human U87MG glioma cells and down-regulated the expression of phosphorylated focal adhesion kinase (p-FAK) and p-paxillin. Caffeine also decreased p-FAK staining at the edge of glioma cells and disassembled actin stress fibers. Additionally, caffeine elevated expression of phosphorylated myosin light chain (p-MLC), an effect that could be blocked by Y27632, a rho-associated protein kinase (ROCK) inhibitor, but not myosin light chain kinase inhibitor, ML-7. Y27632 also inhibited the caffeine-reduced expression of p-FAK and p-paxillin as well as cell migration. Caffeine decreased the migration of glioma cell through the ROCK-focal adhesion complex pathway; this mechanism may be useful as part of clinical therapy in the future. © 2014 S. Karger AG, Basel

  12. Caffeine Inhibits Migration in Glioma Cells through the ROCK-FAK Pathway

    Directory of Open Access Journals (Sweden)

    Ying Chen

    2014-06-01

    Full Text Available Aims: Glioma is the most malignant brain tumor that has the ability to migrate and invade the CNS. In this study, we investigated the signaling mechanism of caffeine on the migration of glioma cells. Methods: The effect of caffeine on cell migration was evaluated using Transwell and wound healing assays. The expression of the focal adhesion complex as it related to cell migration was assayed using Western blotting and immunostaining. Results: Caffeine decreased the migration of rat C6 and human U87MG glioma cells and down-regulated the expression of phosphorylated focal adhesion kinase (p-FAK and p-paxillin. Caffeine also decreased p-FAK staining at the edge of glioma cells and disassembled actin stress fibers. Additionally, caffeine elevated expression of phosphorylated myosin light chain (p-MLC, an effect that could be blocked by Y27632, a rho-associated protein kinase (ROCK inhibitor, but not myosin light chain kinase inhibitor, ML-7. Y27632 also inhibited the caffeine-reduced expression of p-FAK and p-paxillin as well as cell migration. Conclusion: Caffeine decreased the migration of glioma cell through the ROCK-focal adhesion complex pathway; this mechanism may be useful as part of clinical therapy in the future.

  13. 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

  14. Endothelial Cell Implantation and Survival within Experimental Gliomas

    Science.gov (United States)

    Lal, Bachchu; Indurti, Ravi R.; Couraud, Pierre-Olivier; Goldstein, Gary W.; Laterra, John

    1994-10-01

    The delivery of therapeutic genes to primary brain neoplasms opens new opportunities for treating these frequently fatal tumors. Efficient gene delivery to tissues remains an important obstacle to therapy, and this problem has unique characteristics in brain tumors due to the blood-brain and blood-tumor barriers. The presence of endothelial mitogens and vessel proliferation within solid tumors suggests that genetically modified endothelial cells might efficiently transplant to brain tumors. Rat brain endothelial cells immortalized with the adenovirus E1A gene and further modified to express the β-galactosidase reporter were examined for their ability to survive implantation to experimental rat gliomas. Rats received 9L, F98, or C6 glioma cells in combination with endothelial cells intracranially to caudate/putamen or subcutaneously to flank. Implanted endothelial cells were identified by β-galactosidase histochemistry or by polymerase chain reaction in all tumors up to 35 days postimplantation, the latest time examined. Implanted endothelial cells appeared to cooperate in tumor vessel formation and expressed the brain-specific endothelial glucose transporter type 1 as identified by immunohistochemistry. The proliferation of implanted endothelial cells was supported by their increased number within tumors between postimplantation days 14 and 21 (P = 0.015) and by their expression of the proliferation antigen Ki67. These findings establish that genetically modified endothelial cells can be stably engrafted to growing gliomas and suggest that endothelial cell implantation may provide a means of delivering therapeutic genes to brain neoplasms and other solid tumors. In addition, endothelial implantation to brain may be useful for defining mechanisms of brain-specific endothelial differentiation.

  15. 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.)

  16. Histologic classification of gliomas

    NARCIS (Netherlands)

    Perry, Arie; Wesseling, Pieter|info:eu-repo/dai/nl/157872866

    2016-01-01

    Gliomas form a heterogeneous group of tumors of the central nervous system (CNS) and are traditionally classified based on histologic type and malignancy grade. Most gliomas, the diffuse gliomas, show extensive infiltration in the CNS parenchyma. Diffuse gliomas can be further typed as astrocytic,

  17. Dobesilate inhibits the activation of signal transducer and activator of transcription 3, and the expression of cyclin D1 and bcl-XL in glioma cells.

    Science.gov (United States)

    Cuevas, P; Díaz-González, D; Sánchez, I; Lozano, R M; Giménez-Gallego, G; Dujovny, M

    2006-03-01

    Because fibroblast growth factor (FGF) causes the intracellular accumulation of activated signal transducer and activator of transcription 3 (STAT3), we assessed whether dobesilate, a synthetic FGF inhibitor that has been reported to show antiproliferative and proapoptotic activities in glioma cell cultures, down-regulates the STAT3 signaling pathway in growing cultures of those cells. Because STAT3 signaling pathway plays pleiotropic roles in tumor proliferation, maintenance of STAT3 in its inactive state may prevent glioma growth and spreading. Rat glioma C6 cells were treated with dobesilate and cultures were evaluated immunocytochemically for STAT3 activation and enhancement of the expression rate of cyclin D1 and bcl-XL. Dobesilate abrogates the accumulation of activated STAT3 in glioma cells. The decrease in the intracellular levels of activated STAT3 by the dobesilate treatment runs parallel with a significant attenuation of cyclin D1 and bcl-XL expression. Treatment with inhibitors of FGF down-regulates the STAT3 signaling pathway. These alterations could be correlated to the already observed inhibition of cell proliferation and promotion of apoptosis in glioma cell cultures by dobesilate. The reported results may open new avenues for developing new treatments against these tumors.

  18. Skeletal muscle and glioma oxygenation by carbogen inhalation in rats: a longitudinal study by EPR oximetry using single-probe implantable oxygen sensors.

    Science.gov (United States)

    Hou, Huagang; Khan, Nadeem; Lariviere, Jean; Hodge, Sassan; Chen, Eunice Y; Jarvis, Lesley A; Eastman, Alan; Williams, Benjamin B; Kuppusamy, Periannan; Swartz, Harold M

    2014-01-01

    The feasibility of EPR oximetry using a single-probe implantable oxygen sensor (ImOS) was tested for repeated measurement of pO₂ in skeletal muscle and ectopic 9L tumors in rats. The ImOS (50 mm length) were constructed using nickel-chromium alloy wires, with lithium phthalocyanine (LiPc, oximetry probe) crystals loaded in the sensor loop and coated with AF 2400(®) Teflon. These ImOS were implanted into the skeletal muscle in the thigh and subcutaneous 9L tumors. Dynamic changes in tissue pO₂ were assessed by EPR oximetry at baseline, during tumor growth, and repeated hyperoxygenation with carbogen breathing. The mean skeletal muscle pO₂ of normal rats was stable and significantly increased during carbogen inhalation in experiments repeated for 12 weeks. The 9L tumors were hypoxic with a tissue pO₂ of 12.8 ± 6.4 mmHg on day 1; however, the response to carbogen inhalation varied among the animals. A significant increase in the glioma pO₂ was observed during carbogen inhalation on day 9 and day 14 only. In summary, EPR oximetry with ImOS allowed direct and longitudinal oxygen measurements in deep muscle tissue and tumors. The heterogeneity of 9L tumors in response to carbogen highlights the need to repeatedly monitor pO₂ to confirm tumor oxygenation so that such changes can be taken into account in planning therapies and interpreting results.

  19. A Spectroscopic Survey of Electronic Transitions of C$_6$H, $^{13}$C$_6$H, and C$_6$D

    CERN Document Server

    Bacalla, Xavier; Linnartz, Harold; Ubachs, Wim; Zhao, Dongfeng

    2016-01-01

    Electronic spectra of C$_6$H are measured in the $18\\,950-21\\,100$ cm$^{-1}$ domain using cavity ring-down spectroscopy of a supersonically expanding hydrocarbon plasma. In total, 19 (sub)bands of C$_6$H are presented, all probing the vibrational manifold of the B$^2\\Pi$ electronically excited state. The assignments are guided by electronic spectra available from matrix isolation work, isotopic substitution experiments (yielding also spectra for $^{13}$C$_6$H and C$_6$D), predictions from ab initio calculations as well as rotational fitting and vibrational contour simulations using the available ground state parameters as obtained from microwave experiments. Besides the $0_0^0$ origin band, three non-degenerate stretching vibrations along the linear backbone of the C$_6$H molecule are assigned: the $\

  20. 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 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. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary

  1. Comparison of intracerebral delivery of carboplatin and photon irradiation with an optimized regimen for boron neutron capture therapy of the F98 rat glioma

    Energy Technology Data Exchange (ETDEWEB)

    Barth, Rolf F., E-mail: rolf.barth@osumc.edu [Department of Pathology, Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210 (United States); Yang Weilian; Huo Tianyao [Department of Pathology, Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210 (United States); Riley, Kent J.; Binns, Peter J. [Nuclear Reactor Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Grecula, John C., E-mail: john.grecula@osumc.edu [James Cancer Hospital and Solove Research Institute, Department of Radiation Oncology, Ohio State University, Columbus, OH, 43210 (United States); Gupta, Nilendu, E-mail: nilendu.gupta@osumc.edu [James Cancer Hospital and Solove Research Institute, Department of Radiation Oncology, Ohio State University, Columbus, OH, 43210 (United States); Rousseau, Julia, E-mail: julia.rousseau@yahoo.fr [INSERM, U836, Institute of Neurosciences, Grenoble (France); Elleaume, Helene, E-mail: h.elleaume@esrf.fr [INSERM, U836, Institute of Neurosciences, Grenoble (France)

    2011-12-15

    In this report we have summarized our studies to optimize the delivery of boronophenylalanine (BPA) and sodium borocaptate (BSH) for boron neutron capture therapy (BNCT) of F98 glioma bearing rats. These results have been compared to a chemoradiotherapeutic approach using the same tumor model. The best survival data from our BNCT studies were obtained using a combination of BPA and sodium borocaptate BSH administered via the internal carotid artery, in combination with blood-brain barrier disruption (BBB-D). This treatment resulted in a mean survival time (MST) of 140 d with a 25% cure rate. The other approach combined intracerebral administration of carboplatin by either convection enhanced delivery (CED) or Alzet pump infusion, followed by external beam photon irradiation. This resulted in MSTs of 83 d and 112 d, respectively, with a cure rate of 40% for the latter. However, a significant problem that must be solved for both BNCT and this new chemoradiotherapeutic approach is how to improve drug uptake and microdistribution within the tumor.

  2. Exploring the therapeutic efficacy of glioma vaccines based on allo- and syngeneic antigens and distinct immunological costimulation activators

    NARCIS (Netherlands)

    Stathopoulos, A.; Pretto, C.; Devillers, L.; Pierre, D.; Hofman, F.M.; Epstein, A.L.; Farghadani, H.; Kruse, C.A.; Jadus, M.R.; Chen, T.C.; Schijns, V.E.J.C.

    2012-01-01

    The efficacy of a various immunotherapeutic immunisation strategies for malignant glioma brain cancer was evaluated in the syngeneic CNS-1 Lewis rat glioma model. A prototype glioma cancer vaccine, which was composed of multivalent antigens derived from allogeneic and syngeneic cells and lysates,

  3. 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.

  4. Water extract from the leaves of Withania somnifera protect RA differentiated C6 and IMR-32 cells against glutamate-induced excitotoxicity.

    Directory of Open Access Journals (Sweden)

    Hardeep Kataria

    Full Text Available Glutamate neurotoxicity has been implicated in stroke, head trauma, multiple sclerosis and neurodegenerative disorders. Search for herbal remedies that may possibly act as therapeutic agents is an active area of research to combat these diseases. The present study was designed to investigate the neuroprotective role of Withania somnifera (Ashwagandha, also known as Indian ginseng, against glutamate induced toxicity in the retinoic acid differentiated rat glioma (C6 and human neuroblastoma (IMR-32 cells. The neuroprotective activity of the Ashwagandha leaves derived water extract (ASH-WEX was evaluated. Cell viability and the expression of glial and neuronal cell differentiation markers was examined in glutamate challenged differentiated cells with and without the presence of ASH-WEX. We demonstrate that RA-differentiated C6 and IMR-32 cells, when exposed to glutamate, undergo loss of neural network and cell death that was accompanied by increase in the stress protein HSP70. ASH-WEX pre-treatment inhibited glutamate-induced cell death and was able to revert glutamate-induced changes in HSP70 to a large extent. Furthermore, the analysis on the neuronal plasticity marker NCAM (Neural cell adhesion molecule and its polysialylated form, PSA-NCAM revealed that ASH-WEX has therapeutic potential for prevention of neurodegeneration associated with glutamate-induced excitotoxicty.

  5. Water extract from the leaves of Withania somnifera protect RA differentiated C6 and IMR-32 cells against glutamate-induced excitotoxicity.

    Science.gov (United States)

    Kataria, Hardeep; Wadhwa, Renu; Kaul, Sunil C; Kaur, Gurcharan

    2012-01-01

    Glutamate neurotoxicity has been implicated in stroke, head trauma, multiple sclerosis and neurodegenerative disorders. Search for herbal remedies that may possibly act as therapeutic agents is an active area of research to combat these diseases. The present study was designed to investigate the neuroprotective role of Withania somnifera (Ashwagandha), also known as Indian ginseng, against glutamate induced toxicity in the retinoic acid differentiated rat glioma (C6) and human neuroblastoma (IMR-32) cells. The neuroprotective activity of the Ashwagandha leaves derived water extract (ASH-WEX) was evaluated. Cell viability and the expression of glial and neuronal cell differentiation markers was examined in glutamate challenged differentiated cells with and without the presence of ASH-WEX. We demonstrate that RA-differentiated C6 and IMR-32 cells, when exposed to glutamate, undergo loss of neural network and cell death that was accompanied by increase in the stress protein HSP70. ASH-WEX pre-treatment inhibited glutamate-induced cell death and was able to revert glutamate-induced changes in HSP70 to a large extent. Furthermore, the analysis on the neuronal plasticity marker NCAM (Neural cell adhesion molecule) and its polysialylated form, PSA-NCAM revealed that ASH-WEX has therapeutic potential for prevention of neurodegeneration associated with glutamate-induced excitotoxicty.

  6. 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

  7. Focal brainstem gliomas

    Science.gov (United States)

    Sabbagh, Abdulrahman J.; Alaqeel, Ahmed M.

    2015-01-01

    Improved neuronavigation guidance as well as intraoperative imaging and neurophysiologic monitoring technologies have enhanced the ability of neurosurgeons to resect focal brainstem gliomas. In contrast, diffuse brainstem gliomas are considered to be inoperable lesions. This article is a continuation of an article that discussed brainstem glioma diagnostics, imaging, and classification. Here, we address open surgical treatment of and approaches to focal, dorsally exophytic, and cervicomedullary brainstem gliomas. Intraoperative neuronavigation, intraoperative neurophysiologic monitoring, as well as intraoperative imaging are discussed as adjunctive measures to help render these procedures safer, more acute, and closer to achieving surgical goals. PMID:25864061

  8. UPA-sensitive ACPP-conjugated nanoparticles for multi-targeting therapy of brain glioma.

    Science.gov (United States)

    Zhang, Bo; Zhang, Yujie; Liao, Ziwei; Jiang, Ting; Zhao, Jingjing; Tuo, Yanyan; She, Xiaojian; Shen, Shun; Chen, Jun; Zhang, Qizhi; Jiang, Xinguo; Hu, Yu; Pang, Zhiqing

    2015-01-01

    Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory. Therefore, drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits. In the present study, we developed a multi-targeting drug delivery system modified with uPA-activated cell-penetrating peptide (ACPP) for the treatment of brain glioma (ANP). In vitro experiments demonstrated nanoparticles (NP) decorated with cell-penetrating peptide (CPP) or ACPP could significantly improve nanoparticles uptake by C6 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel (PTX) was loaded. In vivo imaging experiment revealed that ANP accumulated more specifically in brain glioma site than NP decorated with or without CPP. Brain slides further showed that ACPP contributed to more nanoparticles accumulation in glioma site, and ANP could co-localize not only with glioma parenchyma cells, but also with stroma cells including neo-vascular cells and tumor associated macrophages. The pharmacodynamics results demonstrated ACPP could significantly improve the therapeutic benefits of nanoparticles by significantly prolonging the survival time of glioma bearing mice. In conclusion, the results suggested that nanoparticles modified with uPA-sensitive ACPP could reach multiple types of cells in glioma tissues and provide a novel strategy for glioma targeted therapy.

  9. 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

  10. Epidemiology of glioma

    DEFF Research Database (Denmark)

    Rasmussen, Birthe Krogh; Hansen, Steinbjørn; Laursen, René J

    2017-01-01

    In this national population-based study of glioma, we present epidemiologic data on incidence, demographics, survival, clinical characteristics and symptoms, and evaluate the association of specific indicators with the grade of glioma. We included 1930 patients registered in the Danish Neuro...

  11. Genetic alterations in Glioma

    NARCIS (Netherlands)

    L.B.C. Bralten (Linda); P.J. French (Pim)

    2011-01-01

    textabstractGliomas 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

  12. Nano Size Effects of TiO2 Nanotube Array on the Glioma Cells Behavior

    OpenAIRE

    Xiangxin Xue; Anhua Wu; Dongyong Zhang; Ang Tian; Xiaofei Qin; He Yang

    2012-01-01

    In order to investigate the interplay between the cells and TiO2 nanotube array, and to explore the ability of cells to sense the size change in nano-environment, we reported on the behavior of glioma C6 cells on nanotube array coatings in terms of proliferation and apoptosis. The behavior of glioma C6 cells was obviously size-dependent on the coatings; the caliber with 15 nm diameter provided effective spacing to improve the cells proliferation and enhanced the cellular activities. C6 cells&...

  13. Uptake of {sup 18}F-fluorocholine, {sup 18}F-fluoro-ethyl-L-tyrosine and {sup 18}F-fluoro-2-deoxyglucose in F98 gliomas in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Spaeth, Nicolas; Treyer, Valerie; Weber, Bruno; Buck, Alfred [University Hospital, Raemistrasse 100, 8091, PET Center, Division of Nuclear Medicine, Zuerich (Switzerland); Wyss, Matthias T. [University Hospital, Raemistrasse 100, 8091, PET Center, Division of Nuclear Medicine, Zuerich (Switzerland); PSI and USZ, Paul Scherrer Institute, Zurich, Zurich (Switzerland); Pahnke, Jens [University Hospital, Department of Pathology, Zurich, Zurich (Switzerland); Biollaz, Gregoire [University Hospital, Section of Clinical Immunology, Zurich, Zurich (Switzerland); Lutz, Amelie; Goepfert, Kerstin [University Hospital, Institute of Diagnostic Radiology, Zurich, Zurich (Switzerland); Westera, Gerrit [PSI and USZ, Paul Scherrer Institute, Zurich, Zurich (Switzerland)

    2006-06-15

    The positron emission tomography (PET) tracers {sup 18}F-fluoro-ethyl-L-tyrosine (FET), {sup 18}F-fluorocholine (N,N-dimethyl-N-[{sup 18}F]fluoromethyl-2-hydroxyethylammonium (FCH)) and {sup 18}F-fluoro-2-deoxyglucose (FDG) are used in the diagnosis of brain tumours. The aim of this study was threefold: (a) to assess the uptake of the different tracers in the F98 rat glioma, (b) to evaluate the impact of blood-brain barrier (BBB) disruption and microvessel density (MVD) on tracer uptake and (c) to compare the uptake in the tumours to that in the radiation injuries (induced by proton irradiation of healthy rats) of our previous study. F98 gliomas were induced in 26 rats. The uptake of FET, FCH and FDG was measured using autoradiography and correlated with histology, disruption of the BBB and MVD. The mean FET, FCH and FDG standardised uptake values (SUVs) in the tumour and the contralateral normal cortex (in parentheses) were 4.19{+-}0.86 (1.32{+-}0.26), 2.98{+-}0.58 (0.51{+-}0.11) and 11.02{+-}3.84 (4.76{+-}1.77) respectively. MVD was significantly correlated only with FCH uptake. There was a trend towards a negative correlation between the degree of BBB disruption and FCH uptake and a trend towards a positive correlation with FET uptake. The ratio of the uptake in tumours to that in the radiation injuries was 1.97 (FCH), 2.71 (FET) and 2.37 (FDG). (orig.)

  14. Effects of anticancer drugs on glia-glioma brain tumor model characterized by acoustic impedance microscopy

    Science.gov (United States)

    Soon, Thomas Tiong Kwong; Chean, Tan Wei; Yamada, Hikari; Takahashi, Kenta; Hozumi, Naohiro; Kobayashi, Kazuto; Yoshida, Sachiko

    2017-07-01

    An ultrasonic microscope is a useful tool for observing living tissue without chemical fixation or histochemical processing. Two-dimensional (2D) acoustic impedance microscopy developed in our previous study for living cell observation was employed to visualize intracellular changes. We proposed a brain tumor model by cocultivating rat glial cells and C6 gliomas to quantitatively analyze the effects of two types of anticancer drugs, cytochalasin B (CyB) and temozolomide (TMZ), when they were applied. We reported that CyB treatment (25 µg/ml, T = 90 min) significantly reduced the acoustic impedance of gliomas and has little effect on glial cells. Meanwhile, TMZ treatment (2 mg/ml, T = 90 min) impacted both cells equally, in which both cells’ acoustic impedances were decreased. As CyB targets the actin filament polymerization of the cells, we have concluded that the decrease in acoustic impedance was in fact due to actin filament depolymerization and the data can be quantitatively assessed for future studies in novel drug development.

  15. Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway.

    Directory of Open Access Journals (Sweden)

    Kimberleve Rolón-Reyes

    Full Text Available Glioblastoma is one of the most aggressive and fatal brain cancers due to the highly invasive nature of glioma cells. Microglia infiltrate most glioma tumors and, therefore, make up an important component of the glioma microenvironment. In the tumor environment, microglia release factors that lead to the degradation of the extracellular matrix and stimulate signaling pathways to promote glioma cell invasion. In the present study, we demonstrated that microglia can promote glioma migration through a mechanism independent of extracellular matrix degradation. Using western blot analysis, we found upregulation of proline rich tyrosine kinase 2 (Pyk2 protein phosphorylated at Tyr579/580 in glioma cells treated with microglia conditioned medium. This upregulation occurred in rodent C6 and GL261 as well as in human glioma cell lines with varying levels of invasiveness (U-87MG, A172, and HS683. siRNA knock-down of Pyk2 protein and pharmacological blockade by the Pyk2/focal-adhesion kinase (FAK inhibitor PF-562,271 reversed the stimulatory effect of microglia on glioma migration in all cell lines. A lower concentration of PF-562,271 that selectively inhibits FAK, but not Pyk2, did not have any effect on glioma cell migration. Moreover, with the use of the CD11b-HSVTK microglia ablation mouse model we demonstrated that elimination of microglia in the implanted tumors (GL261 glioma cells were used for brain implantation by the local in-tumor administration of Ganciclovir, significantly reduced the phosphorylation of Pyk2 at Tyr579/580 in implanted tumor cells. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 signaling pathway in glioma cells.

  16. Childhood Brain Stem Glioma Treatment

    Science.gov (United States)

    ... factors for brain stem glioma include: Having certain genetic disorders , such as neurofibromatosis type 1 (NF1). The signs and symptoms of brain stem glioma are not the same in every child. Signs ...

  17. Thermotherapy-induced reduction in glioma invasiveness is mediated by tumor necrosis factor-alpha.

    Science.gov (United States)

    Qin, L J; Zhang, T; Jia, Y S; Zhang, Y B; Zhang, Y X; Wang, H T

    2015-10-02

    Thermotherapy has been proven to be effective for the treatment of various tumors, including glioma. We determined whether tumor necrosis factor-alpha (TNF-α) is involved in the regulation of the biological processes of glioma development. Reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry were used to investigate the levels of TNF-α mRNA and heat shock factor-1 (HSF1) protein, respectively, in glioma cells. Radioimmunoassay was used to dynamically monitor the contents of TNF-α in the nutrient fluid of C6 cells after thermotherapy treatment. Crystal violet staining was used to determine glioma invasiveness. The most obvious increases in HSF1 protein and TNF-α mRNA in C6 cells were observed at 30 and 60 min after thermotherapy, respectively. In addition, the radioactivity of TNF-α in the culture fluid of the C6 cells reached a peak after 120 min of thermotherapy. In addition, glioma invasiveness decreased and the concentration of TNF-α reached a maximum after 120 min of thermotherapy. Our results show that the decrease in thermotherapy-mediated glioma invasiveness is due to the accelerated release of TNF-α, which could promote the release of HSF1 from neurospongioma cells.

  18. Activation of endogenous p53 by combined p19Arf gene transfer and nutlin-3 drug treatment modalities in the murine cell lines B16 and C6

    Directory of Open Access Journals (Sweden)

    Zanatta Daniela B

    2010-06-01

    Full Text Available Abstract Background Reactivation of p53 by either gene transfer or pharmacologic approaches may compensate for loss of p19Arf or excess mdm2 expression, common events in melanoma and glioma. In our previous work, we constructed the pCLPG retroviral vector where transgene expression is controlled by p53 through a p53-responsive promoter. The use of this vector to introduce p19Arf into tumor cells that harbor p53wt should yield viral expression of p19Arf which, in turn, would activate the endogenous p53 and result in enhanced vector expression and tumor suppression. Since nutlin-3 can activate p53 by blocking its interaction with mdm2, we explored the possibility that the combination of p19Arf gene transfer and nutlin-3 drug treatment may provide an additive benefit in stimulating p53 function. Methods B16 (mouse melanoma and C6 (rat glioma cell lines, which harbor p53wt, were transduced with pCLPGp19 and these were additionally treated with nutlin-3 or the DNA damaging agent, doxorubicin. Viral expression was confirmed by Western, Northern and immunofluorescence assays. p53 function was assessed by reporter gene activity provided by a p53-responsive construct. Alterations in proliferation and viability were measured by colony formation, growth curve, cell cycle and MTT assays. In an animal model, B16 cells were treated with the pCLPGp19 virus and/or drugs before subcutaneous injection in C57BL/6 mice, observation of tumor progression and histopathologic analyses. Results Here we show that the functional activation of endogenous p53wt in B16 was particularly challenging, but accomplished when combined gene transfer and drug treatments were applied, resulting in increased transactivation by p53, marked cell cycle alteration and reduced viability in culture. In an animal model, B16 cells treated with both p19Arf and nutlin-3 yielded increased necrosis and decreased BrdU marking. In comparison, C6 cells were quite susceptible to either treatment, yet

  19. Inhibition of proliferation and induction of differentiation of glioma cells with Datura stramonium agglutinin.

    Science.gov (United States)

    Sasaki, T; Yamazaki, K; Yamori, T; Endo, T

    2002-10-07

    We found that a lectin, Datura stramonium agglutinin, induced irreversible differentiation in C6 glioma cells. The differentiated cells had long processes, a low rate of proliferation and a high content of glial fibrillary acidic protein. When the medium was replaced with Datura stramonium agglutinin-free medium after 1 h, cell proliferation continued to be inhibited. Experiments with several other lectins indicated that both recognition of linear N-acetyllactosamine repeats and recognition of multiantennary units of cell-surface glycans were required for the inhibition of C6 proliferation. Proliferation of four human glial tumour cells was also inhibited by Datura stramonium agglutinin. Further, these differentiated human glial tumour cells had long processes and a high content of glial fibrillary acidic protein similar to differentiated C6 glioma cells. Taken together, these observations suggest that Datura stramonium agglutinin may be useful as a new therapy for treating glioma without side effects. Copyright 2002 Cancer Research UK

  20. Molecular Neuropathology of Gliomas

    Directory of Open Access Journals (Sweden)

    Guido Reifenberger

    2009-01-01

    Full Text Available Gliomas are the most common primary human brain tumors. They comprise a heterogeneous group of benign and malignant neoplasms that are histologically classified according to the World Health Organization (WHO classification of tumors of the nervous system. Over the past 20 years the cytogenetic and molecular genetic alterations associated with glioma formation and progression have been intensely studied and genetic profiles as additional aids to the definition of brain tumors have been incorporated in the WHO classification. In fact, first steps have been undertaken in supplementing classical histopathological diagnosis by the use of molecular tests, such as MGMT promoter hypermethylation in glioblastomas or detection of losses of chromosome arms 1p and 19q in oligodendroglial tumors. The tremendous progress that has been made in the use of array-based profiling techniques will likely contribute to a further molecular refinement of glioma classification and lead to the identification of glioma core pathways that can be specifically targeted by more individualized glioma therapies.

  1. Angiogenesis in gliomas.

    Directory of Open Access Journals (Sweden)

    Elzbieta Czykier

    2008-02-01

    Full Text Available Brain gliomas are characterized by invasive growth and neovascularisation potential. Angiogenesis plays a major role in the progression of gliomas and its determination has a great prognostic value. The aim of the study was to assess the vascularisation of chosen brain gliomas and to estimate how it is correlated with tumour histological type, malignancy grade, location and size, and with age and sex of patients. Tumour vascularisation analysis was based on the determination of microvascular proliferation (MVP and microvessel density (MVD. Microvascular proliferation was measured with immunohistochemical methods using mouse monoclonal antibodies to detect cell proliferation antigens. The following antibodies were used Ki-67 and PCNA (DAKO. Identification of vessels was performed by CD31 antibody and anti-human von Willebrand factor (DAKO. The highest microvascular proliferation and microvascular density were observed in multiform glioblastomas and the lowest in oligodendrogliomas. Significant correlation was observed between the vascularisation and malignancy grade.

  2. Human gliomas contain morphine

    DEFF Research Database (Denmark)

    Olsen, Peter; Rasmussen, Mads; Zhu, Wei

    2005-01-01

    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 endogeno...... of the solutions used in the study nor was it present as a residual material in blank HPLC runs. CONCLUSIONS: Morphine is present in human gliomas, suggesting that it may exert an action that effects tumour physiology/pathology.......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...

  3. Nasal Glioma: Case report

    Directory of Open Access Journals (Sweden)

    Ozgur Surmelioglu

    2011-02-01

    Full Text Available Nasal gliomas are rare, benign, congenital tumors that are thought to be result of abnormality in embryonic development. Three types of clinical presentations have been recognized; extranasal, intranasal and combined. Clinically, these masses are non-pulsatile, gray or purple lesions that obstruct the nasal cavity and cause deformity extranasaly. Histologically, they are made up of astrocytic cells, fibrous and vascular connective tissue that is covered with nasal respiratory mucosa. Treatment of the nasal glioma requires a multidisciplinary approach including an radiologist, neurosurgeon and otorhinolaryngologist. Radiological investigation should be performed to describe intracranial extension. In this case, a 2 years old boy with nasal mass that was diagnosed as nasal glioma is reported. . [Cukurova Med J 2011; 36(1.000: 34-36

  4. 26 CFR 1.414(c)-6 - Effective date.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Effective date. 1.414(c)-6 Section 1.414(c)-6 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.414(c)-6 Effective date. (a) General...

  5. Astrocyte Elevated Gene-1 (AEG-1): a novel target for human glioma therapy

    Science.gov (United States)

    Emdad, Luni; Sarkar, Devanand; Lee, Seok-Geun; Su, Zhao Zhong; Yoo, Byoung Kwon; Dash, Rupesh; Yacoub, Adly; Fuller, Christine E.; Shah, Khalid; Dent, Paul; Bruce, Jeffrey N.; Fisher, Paul B.

    2011-01-01

    Malignant gliomas including glioblastoma multiforme (GBM) and anaplastic astrocytomas are the most common primary brain tumors. Despite multimodal treatment including surgery, chemotherapy and radiation, median survival for patients with GBMs is only 12–15 months. Identifying molecules critical for glioma progression is crucial for devising effective targeted therapy. In the present study, we investigated the potential contribution of Astrocyte Elevated Gene-1 (AEG-1) in gliomagenesis and explored the possibility of AEG-1 as a therapeutic target for malignant glioma. We analyzed the expression levels of AEG-1 in 9 normal brain tissues and 98 brain tumor patient samples by Western blot analysis and immunohistochemistry. AEG-1 expression was significantly elevated in > 90% of diverse human brain tumor samples including GBMs and astrocytic tumors, and also in human glioma cell lines as compared to normal brain tissues and normal astrocytes. Knockdown of AEG-1 by siRNA inhibited cell viability, cloning efficiency, invasive ability of U87 human glioma cells and 9L rat gliosarcoma cells. We also found that matrix metalloproteases (MMP-2 and MMP-9) are involved in AEG-1-mediated invasion of glioma cells. In an orthotopic nude mouse brain tumor model using primary human GBM12 tumor cells, AEG-1 siRNA significantly suppressed glioma cell growth in vivo. Taken together these provocative results indicate that AEG-1 may play a crucial role in the pathogenesis of glioma and that AEG-1 could represent a viable potential target for malignant glioma therapy. PMID:20053777

  6. Connexin 43-targeted T1 contrast agent for MRI diagnosis of glioma.

    Science.gov (United States)

    Abakumova, Tatiana; Abakumov, Maxim; Shein, Sergey; Chelushkin, Pavel; Bychkov, Dmitry; Mukhin, Vladimir; Yusubalieva, Gaukhar; Grinenko, Nadezhda; Kabanov, Alexander; Nukolova, Natalia; Chekhonin, Vladimir

    2016-01-01

    Glioblastoma multiforme is the most aggressive form of brain tumor. Early and accurate diagnosis of glioma and its borders is an important step for its successful treatment. One of the promising targets for selective visualization of glioma and its margins is connexin 43 (Cx43), which is highly expressed in reactive astrocytes and migrating glioma cells. The purpose of this study was to synthesize a Gd-based contrast agent conjugated with specific antibodies to Cx43 for efficient visualization of glioma C6 in vivo. We have prepared stable nontoxic conjugates of monoclonal antibody to Cx43 and polylysine-DTPA ligands complexed with Gd(III), which are characterized by higher T1 relaxivity (6.5 mM(-1) s(-1) at 7 T) than the commercial agent Magnevist® (3.4 mM(-1) s(-1)). Cellular uptake of Cx43-specific T1 contrast agent in glioma C6 cells was more than four times higher than the nonspecific IgG-contrast agent, as detected by flow cytometry and confocal analysis. MRI experiments showed that the obtained agents could markedly enhance visualization of glioma C6 in vivo after their intravenous administration. Significant accumulation of Cx43-targeted contrast agents in glioma and the peritumoral zone led not only to enhanced contrast but also to improved detection of the tumor periphery. Fluorescence imaging confirmed notable accumulation of Cx43-specific conjugates in the peritumoral zone compared with nonspecific IgG conjugates at 24 h after intravenous injection. All these features of Cx43-targeted contrast agents might be useful for more precise diagnosis of glioma and its borders by MRI. Copyright © 2015 John Wiley & Sons, Ltd.

  7. A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas

    Science.gov (United States)

    2017-01-30

    Pilomyxoid Astrocytoma; Pilocytic Astrocytoma; Glioma, Astrocytic; Optic Nerve Glioma; Pleomorphic Xanthoastrocytoma; Glioblastoma Multiforme; Anaplastic Astrocytoma; Gliosarcoma; Diffuse Intrinsic Pontine Glioma; DIPG; Low-grade Glioma; Brainstem Glioma

  8. Mitochondrial Dysfunction in Gliomas

    Czech Academy of Sciences Publication Activity Database

    Katsetos, C.D.; Anni, H.; Dráber, Pavel

    2013-01-01

    Roč. 20, č. 3 (2013), s. 216-227 ISSN 1071-9091 R&D Projects: GA MŠk LH12050 Institutional support: RVO:68378050 Keywords : gliomas * mitochondrial dysfunction * microtubule proteins Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.883, year: 2013

  9. Metabolic Reprogramming in Glioma

    Science.gov (United States)

    Strickland, Marie; Stoll, Elizabeth A.

    2017-01-01

    Many cancers have long been thought to primarily metabolize glucose for energy production—a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilize other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumor. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumor environment. Mutations in the tumor suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumor biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid

  10. The classical photoactivated drug 8-methoxypsoralen and related compounds are effective without UV light irradiation against glioma cells.

    Science.gov (United States)

    de Oliveira, Diêgo Madureira; Ferreira Lima, Rute Maria; Clarencio, Jorge; Velozo, Eudes da Silva; de Amorim, Ilza Alves; Andrade da Mota, Tales Henrique; Costa, Silvia Lima; Silva, Fábio Pittella; El-Bachá, Ramon Dos Santos

    2016-10-01

    Currently, there is no effective therapy for high grade gliomas. 8-Methoxypsoralen (8-MOP) is a compound used in the treatment of skin diseases combined with UV light irradiation. In this work, rat glioma C6 cells, normal astrocytes and human glioblastoma GL-15 cells comprised an in vitro model to evaluate the antitumor activity of 8-MOP. We found that 8-MOP promoted a time- and concentration-dependent reduction of cell viability in tumor, but not in normal cells. This effect was more evident in log-phase growing culture, indicating antiproliferative activity, which was confirmed by colony formation assay. Long-term effect of 8-MOP at low concentration was also attested. The concentrations used in the tests (0.02-0.4 mM) were lower than plasmatic concentration found in patients. Despite the treatment leads to considerable morphological changes and apoptosis when used at high concentrations, 8-MOP did not promote cell cycle arrest, change in migration pattern neither necrosis. In addition, we evaluated the effect of 8-MOP in MDA-MB-231, CT-26 and SCC-3 cell lines, derived from other kind of primary tumors, and found that CT-26 cells did not respond to 8-MOP treatment, indicating that this compound does not act through a generic mechanism. Coumarin derivatives structurally related to 8-MOP were screened for its antitumor potential and presented different patterns of biological activity, and then it was possible to suggest the relevance of 8-MOP molecular structure for antiproliferative action. Therefore, 8-MOP, a drug with an outstanding record of safety, and related coumarins are good prototypes for development of a new class of anti-glioma drugs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. 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 Garnier

    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...... that the primary glioma spheroid area was constant or decreasing after implantation, with a clear increase in the number of invading cells over time. In contrast, the U87MG spheroid area increased after implantation, with no convincing tumor cell invasion. High levels of Bmi-1 and nestin were found in all...... spheroids, whereas high levels of Sox2 and low to moderate levels of CD133 were only found in the primary spheroids. In conclusion, the invasion of gliomas is preserved using primary glioma spheroids. Some stem cell features are preserved as well, making this model useful in drug development elucidating...

  12. The Role of Fascin in the Migration and Invasiveness of Malignant Glioma Cells

    Directory of Open Access Journals (Sweden)

    Jeong Hyun Hwang

    2008-02-01

    Full Text Available Malignant glioma is the most common primary brain tumor, and its ability to invade the surrounding brain parenchyma is a leading cause of tumor recurrence and treatment failure. Whereas the molecular mechanisms of glioma invasion are incompletely understood, there is growing evidence that cytoskeletal-matrix interactions contribute to this process. Fascin, an actin-bundling protein, induces parallel actin bundles in cell protrusions and increases cell motility in multiple human malignancies. The role of fascin in glioma invasion remains unclear. We demonstrate that fascin is expressed in a panel of human malignant glioma cell lines, and downregulation of fascin expression in glioma cell lines by small interfering RNA (siRNA is associated with decreased cellular attachment to extracellular matrix (ECM and reduced migration. Using immunofluorescence analysis, we show that fascin depletion results in a reduced number of filopodia as well as altered glioma cell shape. In vitro invasiveness of U251, U87, and SNB19 glioma cells was inhibited by fascin siRNA treatment by 52.2%, 40.3%, and 23.8% respectively. Finally, we show a decreased invasiveness of U251-GFP cells by fascin knockdown in an ex vivo rat brain slice model system. This is the first study to demonstrate a role for fascin in glioma cell morphology, motility, and invasiveness.

  13. Cyt c6-3: A New Isoform of Photosynthetic Cyt c6 Exclusive to Heterocyst-Forming Cyanobacteria.

    Science.gov (United States)

    Torrado, Alejandro; Valladares, Ana; Puerto-Galán, Leonor; Hervás, Manuel; Navarro, José A; Molina-Heredia, Fernando P

    2017-02-01

    All known cyanobacteria contain Cyt c6, a small soluble electron carrier protein whose main function is to transfer electrons from the Cyt b6f complex to PSI, although it is also involved in respiration. We have previously described a second isoform of this protein, the Cyt c6-like, whose function remains unknown. Here we describe a third isoform of Cyt c6 (here called Cytc6-3), which is only found in heterocyst-forming filamentous cyanobacteria. Cyt c6-3 is expressed in vegetative cells but is specifically repressed in heterocysts cells under diazotrophic growth conditions. Although there is a close structural similarity between Cyt c6-3 and Cyt c6 related to the general protein folding, Cyt c6-3 presents differential electrostatic surface features as compared with Cyt c6, its expression is not copper dependent and has a low reactivity towards PSI. According to the different expression pattern, functional reactivity and structural properties, Cyt c6-3 has to play an as yet to be defined regulatory role related to heterocyst differentiation. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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

    African Journals Online (AJOL)

    TCNS may be of therapeutic importance in the treatment of malignant glioma. REFERENCES. 1. Ng SS, Gao Y, Chau DH. A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide. Cancer Gene. Ther 2007; 14: 561-572. 2. Stiles CD, Rowitch DH. Glioma ...

  15. Canine spinal cord glioma.

    Science.gov (United States)

    Rissi, Daniel R; Barber, Renee; Burnum, Annabelle; Miller, Andrew D

    2017-01-01

    Spinal cord glioma is uncommonly reported in dogs. We describe the clinicopathologic and diagnostic features of 7 cases of canine spinal cord glioma and briefly review the veterinary literature on this topic. The median age at presentation was 7.2 y. Six females and 1 male were affected and 4 dogs were brachycephalic. The clinical course lasted from 3 d to 12 wk, and clinical signs were progressive and associated with multiple suspected neuroanatomic locations in the spinal cord. Magnetic resonance imaging of 6 cases revealed T2-weighted hyperintense lesions with variable contrast enhancement in the spinal cord. All dogs had a presumptive clinical diagnosis of intraparenchymal neoplasia or myelitis based on history, advanced imaging, and cerebrospinal fluid analysis. Euthanasia was elected in all cases because of poor outcome despite anti-inflammatory or immunosuppressive treatment or because of poor prognosis at the time of diagnosis. Tumor location during autopsy ranged from C1 to L6, with no clear predilection for a specific spinal cord segment. The diagnosis was based on histopathology and the immunohistochemistry expression of glial fibrillary acidic protein, oligodendrocyte lineage transcription factor 2, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, neuron-specific enolase, synaptophysin, and Ki-67. Diagnoses consisted of 4 cases of oligodendroglioma, 2 cases of gliomatosis cerebri, and 1 astrocytoma. This case series further defines the clinicopathologic features of canine spinal glioma and highlights the need for comprehensive immunohistochemistry in addition to routine histopathology to confirm the diagnosis of these tumors.

  16. 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...... that the primary glioma spheroid area was constant or decreasing after implantation, with a clear increase in the number of invading cells over time. In contrast, the U87MG spheroid area increased after implantation, with no convincing tumor cell invasion. High levels of Bmi-1 and nestin were found in all...

  17. Isomerisation of c4-c6 aldoses with zeolites

    DEFF Research Database (Denmark)

    2014-01-01

    The present invention relates to isomerization of C4-C6 aldoses to their corresponding C4-C6 ketoses. In particular, the invention concerns isomerization of C4-C6 aldoses over solid zeolite catalysts free of any metals other than aluminum, in the presence of suitable solvent(s) at suitable elevat...... in the catalyst. The ketoses obtained are used as sweeteners in the food and/or brewery industry, or treated to obtain downstream platform chemicals such as lactic acid, HMF, levulinic acid, furfural, MMHB, and the like....

  18. [Possibility of overcoming ACNU resistance in ACNU-resistant sublines of rat brain tumors in vitro by a calmodulin inhibitor].

    Science.gov (United States)

    Yoshida, T; Shimizu, K; Mogami, H; Sakamoto, Y; Egawa, T

    1987-02-01

    A calmodulin inhibitor, trifluoperazine, was found to enhance the cytotoxicity of ACNU in vitro in rat C6 glioma, 9L gliosarcoma and their ACNU-resistant sublines (C6/ACNU and 9L/ACNU). Uptake and retention of ACNU in these cells were studied with [14C]ACNU in the absence or presence of trifluoperazine. The results indicated that intracellular uptake and retention of ACNU in C6 and 9L cells were larger than those in C6/ACNU and 9L/ACNU cells, and that trifluoperazine increased the cellular uptake and retention of ACNU in C6 and 9L, especially in C6/ACNU and 9L/ACNU cells. The amounts of ACNU in C6/ACNU and 9L/ACNU cells reached almost the same level as those detected in C6 and 9L cells. When trifluoperazine were added along with ACNU to the culture in vitro at a concentration of 10 and 20 microM, ACNU resistance was completely overcome. Furthermore, treatment of C6 and C6/ACNU cells with 20 microM trifluoperazine did not change the cellular uptake rate of [14C]AIB (alpha-aminoisobutyric acid), which might indicate that the membrane permeability of the cells was kept intact during the drug treatment. The same phenomenon was observed in 9L and 9L/ACNU cells. It might be concluded that the enhanced effect of cytotoxicity of ACNU in ACNU-resistant rat brain tumor cells presented in this study is presumably due to the increase of intracellular concentration of ACNU resulting from the inhibition of the efflux of ACNU by trifluoperazine from the resistant cells. It was also suggested that ACNU resistance in malignant brain tumors could be overcome by combination chemotherapy with ACNU and calmodulin inhibitors.

  19. Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Hanna Stedt

    2012-01-01

    Full Text Available Malignant glioma is a severe cancer with a poor prognosis. Local occurrence and rare metastases of malignant glioma make it a suitable target for gene therapy. Several studies have demonstrated the importance of Src kinase in different cancers. However, these studies have focused mainly on Src-deficient mice or pharmacological inhibitors of Src. In this study we have used Src small hairpin RNAs (shRNAs in a lentiviral backbone to mimic a long-term stable treatment and determined the role of Src in tumor tissues. Efficacy of Src shRNAs was confirmed in vitro demonstrating up to 90% target gene inhibition. In a mouse malignant glioma model, Src shRNA tumors were almost 50-fold smaller in comparison to control tumors and had significantly reduced vascularity. In a syngenic rat intracranial glioma model, Src shRNA-transduced tumors were smaller and these rats had a survival benefit over the control rats. In vivo treatment was enhanced by chemotherapy and histone deacetylase inhibition. Our results emphasise the importance of Src in tumorigenesis and demonstrate that it can be efficiently inhibited in vitro and in vivo in two independent malignant glioma models. In conclusion, Src is a potential target for RNA interference-mediated treatment of malignant glioma.

  20. Bioactive triterpenoid saponins and phenolic compounds against glioma cells.

    Science.gov (United States)

    Ye, Xuewei; Yu, Siran; Liang, Ying; Huang, Haocai; Lian, Xiao-Yuan; Zhang, Zhizhen

    2014-11-15

    A total of 54 natural origin compounds were evaluated for their activity in inhibiting the proliferation of glioma cells. Results showed that four Aesculus polyhydroxylated triterpenoid saponins (3-6), six Gleditsia triterpenoid saponins (7-12), and five phenolic compounds (43-46, 51) had dose-dependent activity suppressing the proliferation of both C6 and U251 cells. Structure-activity relationship analysis suggested that the acetyl group at C-28 for the Aesculus saponins and the monoterpenic acid moiety for the Gleditsia saponins could be critical for the activity of these active compounds. Aesculioside H (4), gleditsioside A (7), and feuric acid 3,4-dihydroxyphenethyl ester (FADPE, 46) were the three most active compounds from the different types of the active compounds and induced apoptosis and necrosis in glioma cells. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. 26 CFR 1.663(c)-6 - Effective dates.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Effective dates. 1.663(c)-6 Section 1.663(c)-6... Effective dates. Sections 1.663(c)-1 through 1.663(c)-5 are applicable for estates and qualified revocable... date that section 1307 of the Tax Reform Act of 1997 became effective but before December 28, 1999, the...

  2. Bystander killing effect of tymidine kinase gene-transduced adult bone marrow stromal cells with ganciclovir on malignant glioma cells.

    Science.gov (United States)

    Mori, Kentaro; Iwata, Junko; Miyazaki, Masahiro; Osada, Hideo; Tange, Yuichi; Yamamoto, Takuji; Aiko, Yasuhisa; Tamura, Masaru; Shiroishi, Toshihiko

    2010-01-01

    Transduction of the suicide gene of Herpes simplex virus thymidine kinase (Hsv-tk) into glioma cells or neural stem cells combined with pro-drug ganciclovir (GCV) treatment has been effective to treat experimental glioma in the rat through the bystander effect. Bone marrow stromal cells (MSCs) in the adult bone marrow have tropism for brain tumors and act as tumor stromal cells. Whether adult MSCs expressing Hsv-tk can also act as effector cells of the bystander killing effect on murine glioma cells was investigated. In vitro study of co-culture between 9L/LacZ (9L) glioma cells and Hsv-tk-transduced MSCs (MSCs/tk(+)) followed by GCV administration in the culture medium resulted in apparent nuclear morphological changes in the 9L glioma cells surrounding the MSCs/tk(+). 9L glioma cell survival in the presence of MSCs/tk(+) and GCV treatment was quantitatively measured and showed significant decrease of 9L glioma cell proliferation with higher MSCs/tk(+) ratio and GCV concentration. Intracerebral co-inoculation experiments in Fisher rats used 9L glioma cells and either MSCs/tk(+) or Hsv-tk-non-transduced MSCs (MSCs/tk(-)) followed by intraperitoneal injection of GCV (100 mg/kg, daily for 7 days). The animals co-inoculated with 9L glioma cells and MSCs/tk(+) showed significant retardation of tumor growth and prolongation of survival time compared with the animals with 9L glioma cells and MSCs/tk(-). Quantitative findings were established of the novel effects of adult MSCs/tk(+) as effector cells of the bystander killing effect on glioma cells.

  3. 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

  4. Volumetric Properties of the Mixture Cyclohexene C6H10 + C6H12 Cyclohexane (VMSD1211, LB4459_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexene C6H10 + C6H12 Cyclohexane (VMSD1211, LB4459_V)' providing data from direct low-pressure dilatometric measurement of molar excess volume at variable mole fraction and constant temperature.

  5. 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

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

    Science.gov (United States)

    Maurer, Gabriele D; Brucker, Daniel P; Bähr, Oliver; Harter, Patrick N; Hattingen, Elke; Walenta, Stefan; Mueller-Klieser, Wolfgang; Steinbach, Joachim P; Rieger, Johannes

    2011-07-26

    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. 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. 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. 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 target non-oxidative pathways.

  7. Cannabinoids and gliomas.

    Science.gov (United States)

    Velasco, Guillermo; Carracedo, Arkaitz; Blázquez, Cristina; Lorente, Mar; Aguado, Tania; Haro, Amador; Sánchez, Cristina; Galve-Roperh, Ismael; Guzmán, Manuel

    2007-08-01

    Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances--the endocannabinoids--that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

  8. Review - Synthesis and superconducting properties of CaC6

    Directory of Open Access Journals (Sweden)

    Nicolas Emery, Claire Herold, Jean-François Mareche and Philippe Lagrange

    2008-01-01

    Full Text Available Among the superconducting graphite intercalation compounds, CaC6 exhibits the highest critical temperature Tc=11.5 K. Bulk samples of CaC6 are obtained by immersing highly oriented pyrographite pieces in a well-chosen liquid Li–Ca alloy for 10 days at 350 °C. The crystal structure of CaC6 belongs to the { m R}ar{3}{ m m} space group. In order to study the superconducting properties of CaC6, magnetisation was measured as a function of temperature and direction of magnetic field applied parallel or perpendicular to the c-axis. Meissner effect was evidenced, as well as a type II superconducting behaviour and a small anisotropy. In agreement with calculations, experimental results obtained from various techniques suggest that a classical electron-phonon mechanism is responsible for the superconductivity of CaC6. Application of high pressure increases the Tc up to 15.1 K at 8 GPa.

  9. Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses

    OpenAIRE

    Fulci, Giulia; Breymann, Laura; Gianni, Davide; Kurozomi, Kazuhiko; Rhee, Sarah S.; Yu, Jianhua; Kaur, Balveen; Louis, David N.; Weissleder, Ralph; Caligiuri, Michael A.; Chiocca, E. Antonio

    2006-01-01

    Clinical trials are testing oncolytic viruses (OVs) as therapies for cancer. We have shown that animals that have brain tumors and are treated with a herpes simplex virus (HSV)-derived OV live significantly longer when cyclophosphamide (CPA) is preadministered. Here, we explore the mechanisms behind this finding. In a syngeneic rat glioma model, intratumoral HSV administration is associated with rapid increase of natural killer cells, microglia/macrophages (CD68+ and CD163+), and IFN-γ. Pretr...

  10. A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost.

    Science.gov (United States)

    Reardon, David A; Zalutsky, Michael R; Akabani, Gamal; Coleman, R Edward; Friedman, Allan H; Herndon, James E; McLendon, Roger E; Pegram, Charles N; Quinn, Jennifer A; Rich, Jeremy N; Vredenburgh, James J; Desjardins, Annick; Guruangan, Sridharan; Boulton, Susan; Raynor, Renee H; Dowell, Jeanette M; Wong, Terence Z; Zhao, Xiao-Guang; Friedman, Henry S; Bigner, Darell D

    2008-04-01

    The purpose of this study was to determine the feasibility and assess the efficacy and toxicity, among newly diagnosed malignant glioma patients, of administering (131)I-labeled murine antitenascin monoclonal antibody 81C6 ((131)I-81C6) into a surgically created resection cavity (SCRC) to achieve a patient-specific, 44-Gy boost to the 2-cm SCRC margin. A radioactivity dose of (131)I-81C6 calculated to achieve a 44-Gy boost to the SCRC was administered, followed by conventional external beam radiotherapy (XRT) and chemotherapy. Twenty-one patients were enrolled in the study: 16 with glioblastoma multiforme (GBM) and 5 with anaplastic astrocytoma. Twenty patients received the targeted 44-Gy boost (+/-10%) to the SCRC. Attributable toxicity was mild and limited to reversible grade 3 neutropenia or thrombocytopenia (n = 3; 14%), CNS wound infections (n = 3; 14%), and headache (n = 2; 10%). With a median follow-up of 151 weeks, median overall survival times for all patients and those with GBM are 96.6 and 90.6 weeks, respectively; 87% of GBM patients are alive at 1 year. It is feasible to consistently achieve a 44-Gy boost dose to the SCRC margin with patient-specific dosing of (131)I-81C6. Our study regimen ((131)I-81C6 + XRT + temozolomide) was well tolerated and had encouraging survival. To determine if selection of good-prognosis patients affects outcome associated with this approach, the U.S. Food and Drug Administration has approved a trial randomizing newly diagnosed GBM patients to either our study regimen or standard XRT plus temozolomide.

  11. Bioactivatable, membrane-permeant analogs of cyclic nucleotides as biological tools for growth control of C6 glioma cells

    NARCIS (Netherlands)

    Bartsch, M; Zorn-Kruppa, M; Kuhl, N; Genieser, HG; Schwede, F; Jastorff, B

    In the present study, the cAMP analogs 8-bromocAMP (8-BrcAMP), N6-2OdibutyrylcAMP (DBcAMP) and 8-parachlorophenylthiocAMP (8-CPTcAMP), as well as the corresponding cAMPacetoxymethyl (AM)esterprodrugs were tested in a HPLC study for their membrane permeability, intracellular accumulation and

  12. The protective effect of fermented Curcuma longa L. on memory dysfunction in oxidative stress-induced C6 gliomal cells, proinflammatory-activated BV2 microglial cells, and scopolamine-induced amnesia model in mice.

    Science.gov (United States)

    Eun, Cheong-Su; Lim, Jong-Soon; Lee, Jihye; Lee, Sam-Pin; Yang, Seun-Ah

    2017-07-17

    Curcuma longa L. is a well-known medicinal plant that has been used for its anti-cancer, neuroprotective, and hepatoprotective effects. However, the neuroprotective effect of fermented C. longa (FCL) has not been reported. Therefore, in this study, the effectiveness of FCL for the regulation of memory dysfunction was investigated in two brain cell lines (rat glioma C6 and murine microglia BV2) and scopolamine-treated mice. C. longa powder was fermented by 5% Lactobacillus plantarum K154 containing 2% (w/v) yeast extract at 30 °C for 72 h followed by sterilization at 121 °C for 15 min. The protective effects of fermented C. longa (FCL) on oxidative stress induced cell death were analyzed by MTT assay in C6 cells. The anti-inflammatory effects of FCL were investigated by measuring the production of nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) as well as the expression levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated BV2 cells. The step-through passive avoidance test, Morris water maze test, acetylcholinesterase (AChE) activity, and expression of cAMP response element-binding protein (CREB) and brain-derived neurotropic factor (BDNF) were employed to determine the effects of FCL on scopolamine-induced memory deficit in mice. The contents of curcuminoids were analyzed through LC/MS. Pretreatment with FCL effectively prevented the cell death induced by oxidative stress in C6 cells. Moreover, FCL inhibited the production NO and PGE 2 via the inhibition of iNOS and COX-2 expression in BV2 cells. FCL significantly attenuated scopolamine-induced memory impairment in mice and prevented scopolamine-induced AChE activity in the hippocampus. Additionally, FCL reversed the reduction of CREB and BDNF expression. The curcuminoids content in FCL was 1.44%. FCL pretreatment could alleviate scopolamine-induced memory impairment in mice, as well as oxidative stress and inflammation in C6 and BV2 cells, respectively. Thus, FCL might be a

  13. Differential activation of catalase expression and activity by PPAR agonists: Implications for astrocyte protection in anti-glioma therapy☆

    Science.gov (United States)

    Khoo, Nicholas K.H.; Hebbar, Sachin; Zhao, Weiling; Moore, Steven A.; Domann, Frederick E.; Robbins, Mike E.

    2013-01-01

    Glioma survival is dismal, in part, due to an imbalance in antioxidant expression and activity. Peroxisome proliferator-activated receptor (PPAR) agonists have antineoplastic properties which present new redox-dependent targets for glioma anticancer therapies. Herein, we demonstrate that treatment of primary cultures of normal rat astrocytes with PPAR agonists increased the expression of catalase mRNA protein, and enzymatic activity. In contrast, these same agonists had no effect on catalase expression and activity in malignant rat glioma cells. The increase in steady-state catalase mRNA observed in normal rat astrocytes was due, in part, to de novo mRNA synthesis as opposed to increased catalase mRNA stability. Moreover, pioglitazone-mediated induction of catalase activity in normal rat astrocytes was completely blocked by transfection with a PPARγ-dominant negative plasmid. These data suggest that defects in PPAR-mediated signaling and gene expression may represent a block to normal catalase expression and induction in malignant glioma. The ability of PPAR agonists to differentially increase catalase expression and activity in normal astrocytes but not glioma cells suggests that these compounds might represent novel adjuvant therapeutic agents for the treatment of gliomas. PMID:24024139

  14. Volumetric Properties of the Mixture Benzene C6H6 + C6H12 Cyclohexane (VMSD1221, LB3969_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Benzene C6H6 + C6H12 Cyclohexane (VMSD1221, LB3969_V)' providing data from direct dilatometric measurement of molar excess volume at variable mole fraction and constant pressure and temperature, in the single-phase region(s).

  15. Volumetric Properties of the Mixture Cyclohexene C6H10 + C6H12 Cyclohexane (VMSD1112, LB4460_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexene C6H10 + C6H12 Cyclohexane (VMSD1112, LB4460_V)' providing data by calculation of mass density in the single-phase region(s) from low-pressure dilatometric measurements of the molar excess volume at variable mole fraction and constant temperature.

  16. Formation and stabilization of C6- by radiative electron attachment

    Science.gov (United States)

    Chandrasekaran, Vijayanand; Prabhakaran, Aneesh; Kafle, Bhim; Rubinstein, Hilel; Heber, Oded; Rappaport, Michael; Toker, Yoni; Zajfman, Daniel

    2017-03-01

    Radiative electron attachment (REA) plays an important role in forming molecular anions in various astrophysical environments. In this work, we determined the rate coefficient for the formation of C6- by REA based on a detailed balance approach. C6- ions are stored in an electrostatic ion beam trap and are photoexcited above their adiabatic detachment energy (4.18 eV). Due to fast internal conversion and intramolecular vibrational redistribution, photoexcitation leads to the formation of temporary negative ions (TNIs), the same as those one formed by the electron attachment. Absolute vibrational autodetachment and recurrent (or Poincaré) fluorescence (RF) rate coefficients have already been reported [V. Chandrasekaran et al., J. Phys. Chem. Lett. 5, 4078 (2014)]. Knowing the branching ratios of the various competing rate coefficients is decisive to the understanding of the formation probability of anions via REA. The radiative stabilization rate of C6-, shown to be dominated by RF, was determined to be 5 × 104 s-1 at the electron detachment energy, i.e., at least a factor of 100 faster than the stabilization by infrared transitions. The RF is found to very effectively stabilize the TNI formed by electron attachment. Using detailed balance to link the measured delayed detachment rate to the rate of electron attachment, we estimate the REA rate leading to the formation of C6- to be 3 × 10-7 cm3 s-1 at 300 K in agreement with theory (1.7 × 10-7 cm3 s-1 [R. Terzieva and E. Herbst, Int. J. Mass Spectrom. 201, 135 (2000)]). Such a high rate for REA to C6 indicates that REA may play a prominent role in the formation of anions in the interstellar medium.

  17. Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells

    Directory of Open Access Journals (Sweden)

    Iida Hiroki

    2011-06-01

    Full Text Available Abstract Background Peripheral-type benzodiazepine receptor (PBR expression levels are low in normal human brain, but their levels increase in inflammation, brain injury, neurodegenerative states and gliomas. It has been reported that PBR functions as an immunomodulator. The mechanisms of action of midazolam, a benzodiazepine, in the immune system in the CNS remain to be fully elucidated. We previously reported that interleukin (IL-1β stimulates IL-6 synthesis from rat C6 glioma cells and that IL-1β induces phosphorylation of inhibitory kappa B (IκB, p38 mitogen-activated protein (MAP kinase, stress-activated protein kinase (SAPK/c-Jun N-terminal kinase (JNK, extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription (STAT3. It has been shown that p38 MAP kinase is involved in IL-1β-induced IL-6 release from these cells. In the present study, we investigated the effect of midazolam on IL-1β-induced IL-6 release from C6 cells, and the mechanisms of this effect. Methods Cultured C6 cells were stimulated by IL-1β. IL-6 release from C6 cells was measured using an enzyme-linked immunosorbent assay, and phosphorylation of IκB, the MAP kinase superfamily, and STAT3 was analyzed by Western blotting. Results Midazolam, but not propofol, inhibited IL-1β-stimulated IL-6 release from C6 cells. The IL-1β-stimulated levels of IL-6 were suppressed by wedelolactone (an inhibitor of IκB kinase, SP600125 (an inhibitor of SAPK/JNK, and JAK inhibitor I (an inhibitor of JAK 1, 2 and 3. However, IL-6 levels were not affected by PD98059 (an inhibitor of MEK1/2. Midazolam markedly suppressed IL-1β-stimulated STAT3 phosphorylation without affecting the phosphorylation of p38 MAP kinase, SAPK/JNK or IκB. Conclusion These results strongly suggest that midazolam inhibits IL-1β-induced IL-6 release in rat C6 glioma cells via suppression of STAT3 activation. Midazolam may affect immune system function in the CNS.

  18. 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.

  19. 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.

  20. The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals

    OpenAIRE

    Wang,Yahua; Ying,Xue; Xu,Haolun; Yan,Helu; Li,Xia; Tang,Hui

    2017-01-01

    Yahua Wang, Xue Ying, Haolun Xu, Helu Yan, Xia Li, Hui Tang Key Laboratory of Xinjiang Phytomedicine Resources and Modernization of TCM, School of Pharmaceutical Sciences, Shihezi University, Shihezi, Xinjiang, People’s Republic of China Abstract: Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood–brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposom...

  1. 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 Arg132 of IDH1 and Arg172 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. PMID:26188014

  2. 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.

  3. 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...

  4. Increasing the efficacy of antitumor glioma vaccines by photodynamic therapy and local injection of allogeneic glioma cells

    Science.gov (United States)

    Christie, Catherine E.; Peng, Qian; Madsen, Steen J.; Uzal, Francisco A.; Hirschberg, Henry

    2016-03-01

    Immunotherapy of brain tumors involves the stimulation of an antitumor immune response. This type of therapy can be targeted specifically to tumor cells thus sparing surrounding normal brain. Due to the presence of the blood-brain barrier, the brain is relatively isolated from the systemic circulation and, as such, the initiation of significant immune responses is more limited than other types of cancers. The purpose of this study was to show that the efficacy of tumor primed antigen presenting macrophage vaccines could be increased by: (1) PDT of the priming tumor cells, and (2) injection of allogeneic glioma cells directly into brain tumors. Experiments were conducted in an in vivo brain tumor model using Fisher rats and BT4C (allogeneic) and F98 (syngeneic) glioma cells. Preliminary results showed that vaccination alone had significantly less inhibitory effect on F98 tumor growth compared to the combination of vaccination and allogeneic cell (BT4C) injection.

  5. 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.

  6. Structure of C6H12 films on graphite

    OpenAIRE

    Razafitianamaharavo, A.; Convert, P.; Coulomb, J.P.; Croset, B.; Dupont-Pavlovsky, N.

    1989-01-01

    An X-ray and neutron scattering study of C6H12 adsorbed on graphite has been performed from 77 to 260 K. In the monolayer range, three solids have been observed ; they exhibit, in order of increasing density, a commensurate √7 . √7 structure (S1), an incommensurate hexagonal structure (S 2)' and a centered rectangular structure (S3 ). The melting temperature has been located at 240 K, and a tentative phase diagram has been proposed. Only one layer is adsorbed at 77 K before 3D condensation, w...

  7. 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...

  8. 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.

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

    African Journals Online (AJOL)

    Purpose: To investigate the effect of tricyclic neovibsanin scaffold (TCNS) on cell viability, colony formation capacity and induction of apoptosis in glioma cells. Methods: 3-(4, 5-Dimethylthiazol-2-yl) 2, 5-diphe¬nyltetrazolium bromide (MTT) assay was used to analyze the effect of TCNS on cell proliferation. Light microscopic ...

  10. F3 peptide-functionalized PEG-PLA nanoparticles co-administrated with tLyp-1 peptide for anti-glioma drug delivery.

    Science.gov (United States)

    Hu, Quanyin; Gu, Guangzhi; Liu, Zhongyang; Jiang, Mengyin; Kang, Ting; Miao, Deyu; Tu, Yifan; Pang, Zhiqing; Song, Qingxiang; Yao, Lei; Xia, Huimin; Chen, Hongzhan; Jiang, Xinguo; Gao, Xiaoling; Chen, Jun

    2013-01-01

    The development of a drug delivery strategy which can mediate efficient tumor targeting together with high cellular internalization and extensive vascular extravasation is essential and important for glioma treatment. To achieve this goal, F3 peptide that specifically bind to nucleolin, which is highly expressed on the surface of both glioma cells and endothelial cells of glioma angiogenic blood vessels, is utilized to decorate a nanoparticulate drug delivery system to realize glioma cell and neovasculature dual-targeting and efficient cellular internalization. Tumor homing and penetrating peptide, tLyp-1 peptide, which contains the motif of (R/K)XX(R/K) and specially binds to neuropilin is co-administrated to improve the penetration of the nanoparticles across angiogenic vasculature into glioma parenchyma. The F3 conjugation via a maleimide-thiol coupling reaction was confirmed by XPS analysis with 1.03% nitrogen detected on the surface of the functionalized nanoparticles. Enhanced cellular interaction with C6 cells, improved penetration in 3D multicell tumor spheroids, and increased cytotoxicity of the loaded paclitaxel were achieved by the F3-functionalized nanoparticles (F3-NP). Following co-administration with tLyp-1 peptide, F3-NP displayed enhanced accumulation at the tumor site and deep penetration into the glioma parenchyma and achieved the longest survival in mice bearing intracranial C6 glioma. The findings here clearly indicated that the strategy by co-administrating a tumor homing and penetrating peptide with functionalized nanoparticles dual-targeting both glioma cells and neovasculature could significantly improve the anti-glioma drug delivery, which also hold a great promise for chemotherapy of other hard-to-cure cancers. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Effects of cutting parameters during turning 100C6 steel

    Directory of Open Access Journals (Sweden)

    Chibane H.

    2010-06-01

    Full Text Available The objective of the paper is to evaluate the effects of cutting parameters in terms of cutting speed, depth of cut and feed rate on the influence of the surface roughness, consumed power, cutting time and tool vibrations during turning process. The material chosen in this case was 100C6 steel in dry conditions. The effects of the selected process parameters have been investigated using full factorial design of experiments (33 and the multiple linear regression (MLR. Thus, first-order empirical models were established. Analysis of variance (ANOVA was employed to check the validity of the developed models within the limits of the factors that were being investigated and to test the significance of the above parameters. Results indicate that the feed rate is the only significant factor affecting the surface roughness. The cutting speed and feed rate are the most influential factors on cutting time. Estimated tool vibrations are functions of cutting speed, feed rate and depth of cut in decreasing order. Finally, the models obtained can be used for determination of optimal settings of cuttings parameters and this methodology should help us to obtain the best process parameters for dry turning of 100C6 steel.

  12. Nano Size Effects of TiO2 Nanotube Array on the Glioma Cells Behavior

    Directory of Open Access Journals (Sweden)

    Xiangxin Xue

    2012-12-01

    Full Text Available In order to investigate the interplay between the cells and TiO2 nanotube array, and to explore the ability of cells to sense the size change in nano-environment, we reported on the behavior of glioma C6 cells on nanotube array coatings in terms of proliferation and apoptosis. The behavior of glioma C6 cells was obviously size-dependent on the coatings; the caliber with 15 nm diameter provided effective spacing to improve the cells proliferation and enhanced the cellular activities. C6 cells’ biological behaviors showed many similar tendencies to many phorocytes; the matching degree of geometry between nanotube and integrin defined that a spacing of 15 nm was optimal for inducing signals to nucleus, which results in achieving maximum activity of glioma cells. In addition, the immune behavior of cells was studied, a variety of inflammatory mediator’s gene expression levels were controlled by the nanoscale dimension, the expressions of IL-6 and IL-10 were higher on 30 nm than on 15 nm nanotube.

  13. Nano size effects of TiO2 nanotube array on the glioma cells behavior.

    Science.gov (United States)

    Yang, He; Qin, Xiaofei; Tian, Ang; Zhang, Dongyong; Xue, Xiangxin; Wu, Anhua

    2012-12-21

    In order to investigate the interplay between the cells and TiO(2) nanotube array, and to explore the ability of cells to sense the size change in nano-environment, we reported on the behavior of glioma C6 cells on nanotube array coatings in terms of proliferation and apoptosis. The behavior of glioma C6 cells was obviously size-dependent on the coatings; the caliber with 15 nm diameter provided effective spacing to improve the cells proliferation and enhanced the cellular activities. C6 cells' biological behaviors showed many similar tendencies to many phorocytes; the matching degree of geometry between nanotube and integrin defined that a spacing of 15 nm was optimal for inducing signals to nucleus, which results in achieving maximum activity of glioma cells. In addition, the immune behavior of cells was studied, a variety of inflammatory mediator's gene expression levels were controlled by the nanoscale dimension, the expressions of IL-6 and IL-10 were higher on 30 nm than on 15 nm nanotube.

  14. Malignant glioma after bombshell injury.

    Science.gov (United States)

    Troost, D; Tulleken, C A

    1984-01-01

    A case of post-traumatic glioma is presented. The patient, wounded in the head in World War II by a bombshell, developed symptoms of an intracranial tumor in 1982. Histopathologically the tumor was an astrocytoma grade III. The tumor was in direct continuity with an old abscess membrane.

  15. C-6 regioselective bromination of methyl indolyl-3-acetate.

    Science.gov (United States)

    Suárez-Castillo, Oscar R; Meléndez-Rodríguez, Myriam; Beiza-Granados, Lidia; Cano-Escudero, Indira C; Morales-Ríos, Martha S; Joseph-Nathan, Pedro

    2011-04-01

    An efficient route to natural occurring methyl 6-bromoindolyl-3-acetate 1c from methyl indolyl-3-acetate 3 was achieved in 3 steps and 68% overall yield. Thus, in order to regioselectively brominate 3 at the C6-position, introduction of electron withdrawing substituents at N1 and C8 was affected to give intermediate 4 in 82% yield. Bromination of 4 with 8 equiv of bromine in CCl4 and washings with aqueous Na2SO3 gave 5 in 86% yield, which was N- and C-decarbomethoxylated by treatment with NaCN in DMSO, affording 1c in 97% yield. The regioselectivity of bromination was evidenced by NMR spectroscopy and X- ray diffraction analysis.

  16. Modulation of Fatty Acids and Interleukin-6 in Glioma Cells by South American Tea Extracts and their Phenolic Compounds.

    Science.gov (United States)

    Cittadini, María C; García-Estévez, Ignacio; Escribano-Bailón, M Teresa; Rivas-Gonzalo, Julián C; Valentich, Mirta A; Repossi, Gastón; Soria, Elio A

    2017-12-21

    Dietary phenolic compounds are plant metabolites with beneficial effects on the central nervous system. Thus, our aim was to identify anti-inflammatory compounds from South American plants on glia, which regulates neuro-immune response. The compounds were extracted from Lantana grisebachii (LG), Aspidosperma quebracho-blanco (AQB), and Ilex paraguariensis (IP) teas and identified by HPLC-DAD-MS. Extracts (0-200 µg/ml) were tested on human T98-G and rat C6 glioma lines. Cellular viability (by the resazurin assay), fatty acid profile (by gas chromatography) and pro-inflammatory interleukin-6 release (IL-6 by ELISA) were determined. Data were analyzed by partial least-square regression to discriminate bioactive compounds. Twenty-one compounds were determined in LG, mainly iridoids, which were linked to ω-3 and ω-6 polyunsaturated fatty acids, but not to IL-6 release. Thirty-one compounds were found in AQB, mostly hydroxybenzoic derivatives, which were positively related to IL-6 release. Twenty-three compounds were identified in IP, including caffeoylquinic derivatives and mainly chlorogenic acid. They increased the ω-7 palmitoleic fatty acid, which was related to IL-6 decrease. These results enhances phytochemical knowledge of widely available plants, and suggest the lipid-related anti-inflammatory activity of IP phenolic compounds, which give nutritional relevance to the tea.

  17. Survival and low grade glioma: the emergence of genetic information

    OpenAIRE

    Claus, Elizabeth B.; Walsh, Kyle M.; Wiencke, John; Molinaro, Annette M.; Wiemels, Joseph L.; Schildkraut, Joellen M.; Bondy, Melissa L.; Berger, Mitchel; Jenkins, Robert; Wrensch, Margaret

    2015-01-01

    Significant gaps exist in our understanding of the causes and clinical management of glioma. One of the biggest gaps is how best to manage low grade (World Health Organization (WHO) grade II) glioma patients. Low grade glioma is a uniformly fatal disease of young adults (mean age 41 years) with survival averaging approximately 7 years. Although low grade glioma patients have better survival than patients with high grade (WHO grade III/IV) glioma, all low grade gliomas eventually progress to h...

  18. 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.

  19. 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.

  20. [Intraoperative diagnosis of cerebral gliomas].

    Science.gov (United States)

    Konovalov, A N

    1980-01-01

    At the Burdenko Institute for Neurosurgery in Moscow, the following methods are used for the demarkation of cerebral gliomas: Beta-radiometry, rheometry = measurement of th electrical resistance of the cerebral tissue, staining of the tumour prior to the surgical intervention by means of a Serbinenko catheter, puncture biopsy as well as thermometry. The most frequently used techniques are beta-radiometry and rheometry. The methods are simple in application and the results are reliable. The accuracy of the localisation of a cerebral glioma by means of beta-radiometry is 98 per cent. For the impedance measurement a frequency of 1000 Hz is used. Liquids show the lowest and fibrous meningiomas the highest electrical resistance values. On an average the resistance of cerebral tumours is half as high as that of the average normal brain tissue. In almost all operations one tries to obtain an information about the extent and position of the glioma by means of brain puncture. A special needle probe has been designed to obtain tissue pieces for histological examinations. Experience has also been gained with ultrasonic probing and with temperature measurements of tumour and brain tissue. the interior of the tumours shows a 0.5 to 3 degrees C higher temperature.

  1. 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

  2. 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...

  3. Solvent effect on infrared spectra of methyl methacrylate in CCl 4/C 6H 14, CHCl 3/C 6H 14 and C 2H 5OH/C 6H 14 binary solvent systems

    Science.gov (United States)

    Zheng, Jianping; Liu, Qing; Zhang, Hui; Fang, Danjun

    2004-11-01

    Research of methyl methacrylate (MMA) in three kinds of binary solvent systems (CCl 4/C 6H 14, CHCl 3/C 6H 14 and C 2H 5OH/C 6H 14) on the infrared (IR) spectra was reported. Two types of carbonyl stretching vibration bands for MMA in CHCl 3/C 6H 14 or C 2H 5OH/C 6H 14 mixtures were found with the changing of the mole fraction of CHCl 3 (X CHCl3) or C 2H 5OH (X C 2H 5OH ). The carbonyl stretching vibration bands at lower frequencies in the above two mixtures were attributed to the formation of hydrogen bonding between MMA and CHCl 3 or C 2H 5OH. While in CCl 4/C 6H 14 mixtures there was only one type of carbonyl stretching vibration band of MMA. Good linear correlations between the frequencies of CO or CC stretching vibration band of MMA and X CCl 4, X CHCl3 or X C 2H 5OH were found, respectively. The solute-solvent interactions in the three different binary solvent systems were discussed in detail.

  4. Production of lactic acid from C6-polyols by alkaline hydrothermal reactions

    Energy Technology Data Exchange (ETDEWEB)

    Zhou Huazhen; Jin Fangming; Wu Bing; Cao Jianglin; Duan Xiaokun [State Key Laboratory of Pollution Control and Resources Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China); Kishita, Atsushi, E-mail: fmjin@tongji.edu.c [Graduate School of Environmental Studies, Tohoku University, Sendai 980-8579 (Japan)

    2010-03-01

    Production of lactic acid from C6-polyols (Mannitol) under alkaline hydrothermal conditions was investigated. Experiments were performed to examine the difference in the production of lactic acid between C6-polyols and C3-polyols (glycerine), as well as C6-aldoses (glucose). Results showed that the yield of lactic acid from C6-polyols was lower than that from both glycerine and glucose. It indicated that long chain polyols might follow a different reaction pathway from that of glycerine. Further investigation is needed to clarify the reaction mechanism and improve the relatively low lactic acid acid yield from C6-polyols.

  5. Angiocentric Glioma: The Infiltrative Glioma with Ependymal Differentiation.

    Science.gov (United States)

    Ersen, Ayca; Canda, M Serefettin; Men, Suleyman; Yucesoy, Kemal; Kalemci, Orhan; Canda, Tulay

    2017-01-01

    Angiocentric glioma is an epileptogenic, infiltrative, low grade glial tumor, with ependymal and astrocytic differentiation, most commonly seen in young adults and the pediatric age group. Herein we report a case of 21-year-old male patient who presented with fever and pharmaco-resistant seizures. Computed tomography revealed an iso-dense mass lesion in the gyrus rectus of the left frontal lobe. On magnetic resonance imaging the mass was hyperintense on both T1- and T2-weighted images with no contrast enhancement. Histopathological examination revealed monomorphous tumor cells diffusely infiltrating the neuropil with circumferential, radial, or longitudinal angiocentric alignment and subpial aggregation with perpendicular alignment of the cells to the pial surface. Among central nervous system tumors with ependymal differentiation, this distinct entity is the one with an infiltrating growth pattern. In spite of the infiltrating pattern, it does not seem to have a potential for aggressive behavior.

  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. Improving Seroreactivity-Based Detection of Glioma

    Directory of Open Access Journals (Sweden)

    Nicole Ludwig

    2009-12-01

    Full Text Available Seroreactivity profiling emerges as valuable technique for minimal invasive cancer detection. Recently, we provided first evidence for the applicability of serum profiling of glioma using a limited number of immunogenic antigens. Here, we screened 57 glioma and 60 healthy sera for autoantibodies against 1827 Escherichia coli expressed clones, including 509 in-frame peptide sequences. By a linear support vector machine approach, we calculated mean specificity, sensitivity, and accuracy of 100 repetitive classifications. We were able to differentiate glioma sera from sera of the healthy controls with a specificity of 90.28%, a sensitivity of 87.31% and an accuracy of 88.84%. We were also able to differentiate World Health Organization grade IV glioma sera from healthy sera with a specificity of 98.45%, a sensitivity of 80.93%, and an accuracy of 92.88%. To rank the antigens according to their information content, we computed the area under the receiver operator characteristic curve value for each clone. Altogether, we found 46 immunogenic clones including 16 in-frame clones that were informative for the classification of glioma sera versus healthy sera. For the separation of glioblastoma versus healthy sera, we found 91 informative clones including 26 in-frame clones. The best-suited in-frame clone for the classification glioma sera versus healthy sera corresponded to the vimentin gene (VIM that was previously associated with glioma. In the future, autoantibody signatures in glioma not only may prove useful for diagnosis but also offer the prospect for a personalized immune-based therapy.

  8. Low grade glioma: An Update for Radiologists

    OpenAIRE

    Larsen, J; Wharton, S. B.; Romanowski, C.; McKevitt, F.M.; Bridgewater, C.; Zaki, H; Hoggard, N.

    2017-01-01

    With the recent publication of a new World Health Organization (WHO) brain tumour classification that reflects increased understanding of glioma tumour genetics there is a need for radiologists to understand the changes and their implications for patient management. There has also been an increasing trend for adopting earlier, more aggressive surgical approaches to low grade glioma treatment. We will summarise these changes, give some context to the increased role of tumour genetics and discu...

  9. 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.

  10. 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.

  11. Aberrant Signaling Pathways in Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Nakada, Mitsutoshi, E-mail: nakada@ns.m.kanazawa-u.ac.jp; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan); Teng, Lei [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan); Department of Neurosurgery, The First Clinical College of Harbin Medical University, Nangang, Harbin 150001 (China); Pyko, Ilya V.; Hamada, Jun-Ichiro [Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641 (Japan)

    2011-08-10

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies.

  12. Testosterone attenuates morpho-functional alterations by 2-methoxyestradiol exposure and induces differentiation in C6 cells.

    Science.gov (United States)

    Manca, Paolo; Chisu, Valentina

    2011-06-01

    2-Methoxyestradiol (2ME) is a cytotoxic drug that interacts with tubulin and alters microtubule dynamics. It has been reported that testosterone (T) has a neuroprotective effect against oxidative stress and induces differentiation in mouse C1300 neuroblastoma cells. Here, we investigated the ability of T to attenuate the cytotoxic effects of 2ME and to induce cell differentiation in an immortalized rat glial cell line, known as C6. C6 cells were exposed for 5 days to 5 µM 2ME, 50 nM T, or both. We evaluated the morphological changes, growth rate, vitality, catalase activity, and glial fibrillary acidic protein (GFAP) immunoreactivity in control and treated C6 cells. Western blot analyses were used to quantify expression of tyrosinated tubulin (Tyr-Tub), acetylated tubulin (Acet-Tub), total α-tubulin (TOT-Tub), and GFAP. After 2ME exposure, the cells displayed a globular, shrunken shape, and retraction or absence of cytoplasmic processes; moreover, 2ME treatment significantly decreased cell growth, cell viability, catalase activity, and expression of both Tyr-Tub and Acet-Tub. However, when T was added, the cells exhibited a glial-like shape, elongated cell processes, and enhanced cell growth, cell vitality, catalase activity, and GFAP immunoreactivity. Densitometric values of Tyr-Tub, Acet-Tub, and GFAP increased significantly when T was present, while Tot-Tub values were unaltered. These results indicate that, in C6 cells, T: (i) attenuated the morpho-functional changes caused by 2ME exposure; (ii) induced glial differentiation; and (iii) exerted a direct action on the microtubule system. Copyright © 2010 Wiley-Liss, Inc.

  13. Tesmilifene modifies brain endothelial functions and opens the blood-brain/blood-glioma barrier.

    Science.gov (United States)

    Walter, Fruzsina R; Veszelka, Szilvia; Pásztói, Mária; Péterfi, Zoltán A; Tóth, András; Rákhely, Gábor; Cervenak, László; Ábrahám, Csongor S; Deli, Mária A

    2015-09-01

    Tesmilifene, a tamoxifen analog with antihistamine action, has chemopotentiating properties in experimental and clinical cancer studies. In our previous works, tesmilifene increased the permeability of the blood-brain barrier (BBB) in animal and culture models. Our aim was to investigate the effects of tesmilifene on brain microvessel permeability in the rat RG2 glioma model and to reveal its mode of action in brain endothelial cells. Tesmilifene significantly increased fluorescein extravasation in the glioma. Short-term treatment with tesmilifene reduced the resistance and increased the permeability for marker molecules in a rat triple co-culture BBB model. Tesmilifene also affected the barrier integrity in brain endothelial cells co-cultured with RG2 glioblastoma cells. Tesmilifene inhibited the activity of P-glycoprotein and multidrug resistance-associated protein-1 efflux pumps and down-regulated the mRNA expression of tight junction proteins, efflux pumps, solute carriers, and metabolic enzymes important for BBB functions. Among the possible signaling pathways that regulate BBB permeability, tesmilifene activated the early nuclear translocation of NFκB. The MAPK/ERK and PI3K/Akt kinase pathways were also involved. We demonstrate for the first time that tesmilifene increases permeability marker molecule extravasation in glioma and inhibits efflux pump activity in brain endothelial cells, which may have therapeutic relevance. Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood-brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood-brain barrier functions, which may have therapeutic relevance. © 2015 International Society for Neurochemistry.

  14. Adenoviral vector-mediated gene transfer: timing of wild-type p53 gene expression in vivo and effect of tumor transduction on survival in a rat glioma brachytherapy model.

    Science.gov (United States)

    Bampoe, J; Glen, J; Hubbard, S L; Salhia, B; Shannon, P; Rutka, J; Bernstein, M

    2000-08-01

    This study sought to investigate modification of the radiation response in a rat 9L brain tumor model in vivo by the wild-type p53 gene (wtp53). Determination of the timing and dose of radiation therapy required the assessment of the duration of the effect of wtp53 expression on 9L tumors after in vivo transfection. Anesthetized male F-344 rats each were stereotactically inoculated with 4 x 10(4) 9L gliosarcoma cells through a skull screw into the cerebrum in the right frontal region. Twelve-day-old tumors were inoculated through the screw with recombinant adenoviral vectors under isoflurane anaesthesia: control rats with Ad5/RSV/GL2 (carrying the luciferase gene), and study rats with Ad5CMV-p53 (carrying the wtp53 gene). Brain tumors removed at specific times after transfection were measured, homogenized, and lysed and wtp53 expression determined by Western blot analysis. Four groups of nine rats were, subsequently, implanted with iodine-125 seeds 15 days post-tumor inoculation to give a minimum tumor dose of 40 or 60 Gy. We demonstrated transfer of wtp53 into rat 9L tumors in vivo using the Ad5CMV-p53 vector. The expression of wtp53 was demonstrated to be maximum between days 1 and 3 post-vector inoculation. Tumors expressing wtp53 were smaller than controls transfected with Ad5/RSV/GL2 but this difference was not statistically significant. Radiation made a significant difference to the survival of tumor-bearing rats. Moreover, wtp53 expression conferred a significant additional survival advantage. The expression of wtp53 significantly improves the survival of irradiated tumor-bearing rats in our model.

  15. A rare case of cervical facet joint and synovial cyst at C5/C6.

    Science.gov (United States)

    Phan, Kevin; Mobbs, Ralph J

    2016-07-01

    Lumbar synovial cysts are uncommon, and particularly rare at cervical levels. We report a 40-year-old woman who presented with pain distribution in the typical C6 dermatome. MRI revealed a right-sided large extradural cystic lesion adjacent to the C5/C6 facet joint that was hyperintense on T2-weighted MRI and hypointense on T1-weighted MRI. The patient underwent posterior cervical surgery at the C5/C6 level which involved posterior decompressive unilateral laminotomy and excision of the C5/C6 facet joint cyst. Following complete facetectomy of the right C5/C6 facet joint and exposure of the C6 nerve throughout its foraminal course, instrumented fusion was performed. Following the procedure, the patient had an uneventful recovery with relief of her radicular symptoms at follow-up clinical review. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. 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. © 2016 International Society of Neuropathology.

  17. Cognitive functioning early after surgery of gliomas in eloquent areas

    NARCIS (Netherlands)

    Satoer, Djaina; Vork, Judith; Visch-Brink, Evy; Smits, Marion; Dirven, Clemens; Vincent, Arnaud

    2012-01-01

    OBJECT: Patients with gliomas frequently have cognitive deficits, and surgery can exacerbate these deficits. Preoperative assessment is therefore crucial in patients undergoing surgery for glioma in eloquent areas, because the proximity of functional areas increases the risk of permanent

  18. Glioma

    Science.gov (United States)

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

  19. Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses.

    Science.gov (United States)

    Fulci, Giulia; Breymann, Laura; Gianni, Davide; Kurozomi, Kazuhiko; Rhee, Sarah S; Yu, Jianhua; Kaur, Balveen; Louis, David N; Weissleder, Ralph; Caligiuri, Michael A; Chiocca, E Antonio

    2006-08-22

    Clinical trials are testing oncolytic viruses (OVs) as therapies for cancer. We have shown that animals that have brain tumors and are treated with a herpes simplex virus (HSV)-derived OV live significantly longer when cyclophosphamide (CPA) is preadministered. Here, we explore the mechanisms behind this finding. In a syngeneic rat glioma model, intratumoral HSV administration is associated with rapid increase of natural killer cells, microglia/macrophages (CD68+ and CD163+), and IFN-gamma. Pretreatment with CPA enhances HSV replication and oncolysis and reduces an HSV-mediated increase in CD68+ and CD163+ cells and intratumoral IFN-gamma. Molecular imaging shows CPA pretreatment to inhibit HSV-induced infiltration of tumor-associated phagocytic cells. Our results reveal molecular and cellular mechanisms that inhibit intratumoral spread of HSV and suggest a therapeutic path for improving the efficacy of virotherapy as a treatment for cancer.

  20. Draft Genome Sequence of Acinetobacter johnsonii C6, an Environmental Isolate Engaging in Interspecific Metabolic Interactions

    DEFF Research Database (Denmark)

    Kaas, Rolf Sommer; Mordhorst, Hanne; Leekitcharoenphon, Pimlapas

    2017-01-01

    Acinetobacter johnsonii C6 originates from creosote-polluted groundwater and performs ecological and evolutionary interactions with Pseudomonas putida in biofilms. The draft genome of A. johnsonii C6 is 3.7 Mbp and was shaped by mobile genetic elements. It reveals genes facilitating the biodegrad......Acinetobacter johnsonii C6 originates from creosote-polluted groundwater and performs ecological and evolutionary interactions with Pseudomonas putida in biofilms. The draft genome of A. johnsonii C6 is 3.7 Mbp and was shaped by mobile genetic elements. It reveals genes facilitating...

  1. Reaction of Cl atoms with C6F13CH2OH, C6F13CHO, and C3F7CHO.

    Science.gov (United States)

    Solignac, G; Mellouki, A; Le Bras, G; Barnes, I; Benter, Th

    2006-04-06

    The Cl atom initiated oxidation of C(6)F(13)CH(2)OH, C(6)F(13)CHO, and C(3)F(7)CHO was investigated at 298 K and 1000 mbar pressure of air in a photoreactor using in situ Fourier transform infrared (FTIR) analysis. The rate coefficient for the reaction Cl + C(6)F(13)CH(2)OH (reaction 2) was measured using a relative method: k(2) = (6.5 +/- 0.8) x 10(-13) cm(3) molecule(-1) s(-1). C(6)F(13)CHO was detected as the major primary product, while CO and CF(2)O were found to be the major secondary products. A fitting procedure applied to the concentration-time profiles of C(6)F(13)CHO provided a production yield of (1.0 +/- 0.2) for this aldehyde in reaction 2, and the rate coefficient for the reaction Cl + C(6)F(13)CHO (reaction 4) was k(4) = (2.8 +/- 0.7) x 10(-12) cm(3) molecule(-1) s(-1). A high CO yield observed in the oxidation of C(6)F(13)CH(2)OH, (52 +/- 1)%, is attributed to the Cl atom initiated oxidation of C(6)F(13)CHO. High CO yields, (61 +/- 2)% and (85 +/- 5)%, were also measured in the Cl atom initiated oxidation of C(3)F(7)CHO in air and nitrogen, respectively. These high CO yields suggest the occurrence of a decomposition reaction of the perfluoroacyl, C(6)F(13)CO, and C(3)F(7)CO radicals to form CO which will compete with the combination reaction of these radicals with oxygen to form perfluoroacyl peroxy radicals in the presence of air. The latter radicals C(n)F(2)(n)(+1)CO(O)(2) (n = 6-12), through their reaction with HO(2) radicals, are currently considered as a possible source of persistent perfluorocarboxylic acids which have been detected in the environment. The consequences of the present results would be a reduction of the strength of this potential source of carboxylic acids in the atmosphere.

  2. 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 IDH mutated gliomas (21 % versus 1 %, p IDH mutations and loss of ATRX expression. In two patients, the same IDH mutation was demonstrated in the glioma and in a cartilaginous tumor. In contrast to sporadic IDH mutated gliomas, no enchondromatosis glioma harbored a 1p/19q co-deletion (0/6 versus 59/123, p = 0.03). The characteristics of gliomas in patients with enchondromatosis suggest that these tumors, as cartilaginous tumors, result from somatic IDH 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.

  3. Oncolytic adenoviruses: A thorny path to glioma cure

    OpenAIRE

    Ulasov, I.V.; Borovjagin, A.V.; Schroeder, B.A.; Baryshnikov, A.Y.

    2014-01-01

    Glioblastoma Multiforme (GBM) is a rapidly progressing brain tumor. Despite the relatively low percentage of cancer patients with glioma diagnoses, recent statistics indicate that the number of glioma patients may have increased over the past decade. Current therapeutic options for glioma patients include tumor resection, chemotherapy, and concomitant radiation therapy with an average survival of approximately 16 months. The rapid progression of gliomas has spurred the development of novel tr...

  4. Treg infiltration in glioma: a hurdle for antiglioma immunotherapy.

    Science.gov (United States)

    Vandenberk, Lien; Van Gool, Stefaan W

    2012-07-01

    Tregs play a crucial role in glioma-mediated immunosuppression; hence, tackling the Treg population in patients with malignant glioma could improve the clinical success rate of antiglioma immunotherapy. Therefore, it is of high importance to elucidate the mechanisms responsible for Treg recruitment and retention within the glioma microenvironment. The current paper demonstrates that, in addition to preferential chemoattraction, glioma-derived soluble factors can also induce preferential Treg proliferation and survival. These data identify new targets for Treg modulating strategies.

  5. 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.)

  6. Inhibition of CYP4A by a novel flavonoid FLA-16 prolongs survival and normalizes tumor vasculature in glioma.

    Science.gov (United States)

    Wang, Chenlong; Li, Ying; Chen, Honglei; Zhang, Jie; Zhang, Jing; Qin, Tian; Duan, Chenfan; Chen, Xuewei; Liu, Yanzhuo; Zhou, Xiaoyang; Yang, Jing

    2017-08-28

    Glioblastomas rapidly become refractory to anti-VEGF therapies. We previously showed that cytochrome P450 (CYP) 4A-derived 20-hydroxyeicosatetraenoic acid (20-HETE) promotes angiogenesis. Here, we tested whether a novel flavonoid (FLA-16) prolongs survival and normalizes tumor vasculature in glioma through CYP4A inhibition. FLA-16 improved survival, reduced tumor burden, and normalized vasculature, accompanied with the decreased secretion of 20-HETE, VEGF and TGF-β in tumor-associated macrophages (TAMs) and endothelial progenitor cells (EPCs) in C6 and U87 gliomas. FLA-16 attenuated vascular abnormalization induced by co-implantation of GL261 glioma cells with CYP4A10(high) macrophages or EPCs. Mechanistically, the conditional medium from TAMs and EPCs treated with FLA-16 enhanced the migration of pericyte cells, and decreased the proliferation and migration of endothelial cells, which were reversed by CYP4A overexpression or exogenous addition of 20-HETE, VEGF and TGF-β. Furthermore, FLA-16 prevented crosstalk between TAMs and EPCs during angiogenesis. These results suggest that CYP4A inhibition by FLA-16 prolongs survival and normalizes vasculature in glioma through decreasing production of TAMs and EPCs-derived VEGF and TGF-β. This may represent a potential therapeutic strategy to overcome resistance to anti-VEGF treatment by effects on vessels and immune cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Bromelain Reversibly Inhibits Invasive Properties of Glioma Cells

    OpenAIRE

    Tysnes, Berit B; Maurer, H Rainer; Porwol, Torsten; Probst, Beatrice; Bjerkvig, Rolf; Hoover, Frank

    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 a...

  8. Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells.

    Science.gov (United States)

    Kruczyk, Marcin; Przanowski, Piotr; Dabrowski, Michal; Swiatek-Machado, Karolina; Mieczkowski, Jakub; Wallerman, Ola; Ronowicz, Anna; Piotrowski, Arkadiusz; Wadelius, Claes; Kaminska, Bozena; Komorowski, Jan

    2014-11-01

    Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune regulation. Only a small fraction of those genes has been proven to be direct STAT3 targets. In gliomas, STAT3 can play tumor suppressive or oncogenic roles depending on the tumor genetic background with target genes being largely unknown. We used chromatin immunoprecipitation, promoter microarrays and deep sequencing to assess the genome-wide occupancy of phospho (p)-Stat3 and epigenetic modifications of H3K4me3 and H3ac in C6 glioma cells. This combined assessment identified a list of 1200 genes whose promoters have both Stat3 binding sites and epigenetic marks characteristic for actively transcribed genes. The Stat3 and histone markings data were also intersected with a set of microarray data from C6 glioma cells after inhibition of Jak2/Stat3 signaling. Subsequently, we found 284 genes characterized by p-Stat3 occupancy, activating histone marks and transcriptional changes. Novel genes were screened for their potential involvement in oncogenesis, and the most interesting hits were verified by ChIP-PCR and STAT3 knockdown in human glioma cells. Non-random association between silent genes, histone marks and p-Stat3 binding near transcription start sites was observed, consistent with its repressive role in transcriptional regulation of target genes in glioma cells with specific genetic background. Copyright © 2014. Published by Elsevier B.V.

  9. Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations

    Science.gov (United States)

    2018-02-05

    Advanced Malignant Solid Neoplasm; Glioblastoma; Grade II Glioma; IDH1 Gene Mutation; IDH2 Gene Mutation; Recurrent Cholangiocarcinoma; Recurrent Glioma; Recurrent Malignant Solid Neoplasm; WHO Grade III Glioma

  10. Volumetric Properties of the Mixture Nitrobenzene C6H5NO2 + C6H12 Cyclohexane (VMSD1212, LB3420_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Nitrobenzene C6H5NO2 + C6H12 Cyclohexane (VMSD1212, LB3420_V)' providing data by calculation of molar excess volume from low-pressure density measurements at variable mole fraction and constant temperature.

  11. Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H15N Dipropylamine (VMSD1111, LB3520_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H15N Dipropylamine (VMSD1111, LB3520_V)' providing data from direct low-pressure measurement of mass density at variable mole fraction and constant temperature, in the single-phase region(s).

  12. Vapor-Liquid Equilibrium in the Mixture Cyclohexene C6H10 + C6H12 Cyclohexane (EVLM1231, LB5705_E)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'vapor-liquid Equilibrium in the Mixture Cyclohexene C6H10 + C6H12 Cyclohexane (EVLM1231, LB5705_E)' providing data from direct measurement of temperature and mole fraction in vapor phase at variable mole fraction in liquid phase and constant pressure.

  13. Heat of Mixing and Solution of Cyclohexane C6H12 + C6H14O Dipropyl ether (HMSD1111, LB4069_H)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Heat of Mixing and Solution of Cyclohexane C6H12 + C6H14O Dipropyl ether (HMSD1111, LB4069_H)' providing data from direct low-pressure calorimetric measurement of molar excess enthalpy at variable mole fraction and constant temperature.

  14. Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H15N Triethylamine (VMSD1212, LB3445_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H15N Triethylamine (VMSD1212, LB3445_V)' providing data by calculation of molar excess volume from low-pressure density measurements at variable mole fraction and constant temperature.

  15. Heat of Mixing and Solution of Cyclohexane C6H12 + C6H14O Diisopropyl ether (HMSD1111, LB3915_H)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Heat of Mixing and Solution of Cyclohexane C6H12 + C6H14O Diisopropyl ether (HMSD1111, LB3915_H)' providing data from direct low-pressure calorimetric measurement of molar excess enthalpy at variable mole fraction and constant temperature.

  16. Heat of Mixing and Solution of Cyclohexane C6H12 + C6H18N3OP Phosphoric tris(dimethylamide) (HMSD1111, LB3769_H)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Heat of Mixing and Solution of Cyclohexane C6H12 + C6H18N3OP Phosphoric tris(dimethylamide) (HMSD1111, LB3769_H)' providing data from direct low-pressure calorimetric measurement of molar excess enthalpy at variable mole fraction and constant temperature.

  17. Volumetric Properties of the Mixture Bromobenzene C6H5Br + C6H12 Cyclohexane (VMSD1111, LB3734_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Bromobenzene C6H5Br + C6H12 Cyclohexane (VMSD1111, LB3734_V)' providing data from direct low-pressure measurement of mass density at variable mole fraction and constant temperature, in the single-phase region(s).

  18. Volumetric Properties of the Mixture Nitrobenzene C6H5NO2 + C6H12 Cyclohexane (VMSD1111, LB3157_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Nitrobenzene C6H5NO2 + C6H12 Cyclohexane (VMSD1111, LB3157_V)' providing data from direct low-pressure measurement of mass density at variable mole fraction and constant temperature, in the single-phase region(s).

  19. Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H14O Diisopropyl ether (VMSD1112, LB3862_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H14O Diisopropyl ether (VMSD1112, LB3862_V)' providing data by calculation of mass density in the single-phase region(s) from low-pressure dilatometric measurements of the molar excess volume at variable mole fraction and constant temperature.

  20. Heat of Mixing and Solution of 2-Methylpyridine C6H7N + C6H12 Hex-1-ene (HMSD1111, LB3864_H)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Heat of Mixing and Solution of 2-Methylpyridine C6H7N + C6H12 Hex-1-ene (HMSD1111, LB3864_H)' providing data from direct low-pressure calorimetric measurement of molar excess enthalpy at variable mole fraction and constant temperature.

  1. Volumetric Properties of the Mixture Bromobenzene C6H5Br + C6H12 Cyclohexane (VMSD1212, LB3251_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Bromobenzene C6H5Br + C6H12 Cyclohexane (VMSD1212, LB3251_V)' providing data by calculation of molar excess volume from low-pressure density measurements at variable mole fraction and constant temperature.

  2. Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H14O Diisopropyl ether (VMSD1211, LB3553_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H14O Diisopropyl ether (VMSD1211, LB3553_V)' providing data from direct low-pressure dilatometric measurement of molar excess volume at variable mole fraction and constant temperature.

  3. Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H14O Hexan-1-ol (VMSD1212, LB4546_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H14O Hexan-1-ol (VMSD1212, LB4546_V)' providing data by calculation of molar excess volume from low-pressure density measurements at variable mole fraction and constant temperature.

  4. Volumetric Properties of the Mixture Nitrobenzene C6H5NO2 + C6H12 Cyclohexane (VMSD1111, LB3475_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Nitrobenzene C6H5NO2 + C6H12 Cyclohexane (VMSD1111, LB3475_V)' providing data from direct low-pressure measurement of mass density at variable mole fraction and constant temperature, in the single-phase region(s).

  5. Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H14O Diisopropyl ether (VMSD1211, LB3859_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H14O Diisopropyl ether (VMSD1211, LB3859_V)' providing data from direct low-pressure dilatometric measurement of molar excess volume at variable mole fraction and constant temperature.

  6. Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H15N Triethylamine (VMSD1111, LB3514_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H15N Triethylamine (VMSD1111, LB3514_V)' providing data from direct low-pressure measurement of mass density at variable mole fraction and constant temperature, in the single-phase region(s).

  7. Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H15N Dipropylamine (VMSD1212, LB3462_V)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture Cyclohexane C6H12 + C6H15N Dipropylamine (VMSD1212, LB3462_V)' providing data by calculation of molar excess volume from low-pressure density measurements at variable mole fraction and constant temperature.

  8. Heat of Mixing and Solution of 2-Methylpyridine C6H7N + C6H12 Cyclohexane (HMSD1111, LB3828_H)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Heat of Mixing and Solution of 2-Methylpyridine C6H7N + C6H12 Cyclohexane (HMSD1111, LB3828_H)' providing data from direct low-pressure calorimetric measurement of molar excess enthalpy at variable mole fraction and constant temperature.

  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. 26 CFR 1.381(c)(6)-1 - Depreciation method.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 4 2010-04-01 2010-04-01 false Depreciation method. 1.381(c)(6)-1 Section 1.381... (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(6)-1 Depreciation method. (a) Carryover... corporation which computes its allowance for the depreciation of the property under section 167(b)(2), (3), or...

  11. Tissue Proteome Analysis of Different Grades of Human Gliomas Provides Major Cues for Glioma Pathogenesis.

    Science.gov (United States)

    Gollapalli, Kishore; Ghantasala, Saicharan; Atak, Apurva; Rapole, Srikanth; Moiyadi, Aliasgar; Epari, Sridhar; Srivastava, Sanjeeva

    2017-05-01

    Gliomas are heterogeneous and most commonly occurring brain tumors. Blood-brain barrier restricts the entry of brain tumor proteins into blood stream thus limiting the usage of serum or plasma for proteomic analysis. Our study aimed at understanding the molecular basis of aggressiveness of various grades of brain tumors using isobaric tagging for relative and absolute quantification (iTRAQ) based mass spectrometry. Tissue proteomic analysis of various grades of gliomas was performed using four-plex iTRAQ. We labeled five sets (each set consists of control, grade-II, III, and IV tumor samples) of individual glioma patients using iTRAQ reagents. Significantly altered proteins were subjected to bioinformatics analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID). Various metabolic pathways like glycolysis, TCA-cycle, electron transport chain, lactate metabolism, and blood coagulation pathways were majorly observed to be perturbed in gliomas. Most of the identified proteins involved in redox reactions, protein folding, pre-messenger RNA (mRNA) processing, antiapoptosis, and blood coagulation were found to be upregulated in gliomas. Transcriptomics data of glioblastoma multiforme (GBM), low-grade gliomas (LGGs), and controls were downloaded from The Cancer Genome Atlas (TCGA) data portal and further analyzed using BRB-Array tools. Expression levels of a few significantly altered proteins like lactate dehydrogenase, alpha-1 antitrypsin, fibrinogen alpha chain, nucleophosmin, annexin A5, thioredoxin, ferritin light chain, thymosin beta-4-like protein 3, superoxide dismutase-2, and peroxiredoxin-1 and 6 showed a positive correlation with increasing grade of gliomas thereby offering an insight into molecular basis behind their aggressive nature. Several proteins identified in different grades of gliomas are potential grade-specific markers, and perturbed pathways provide comprehensive overview of molecular cues involved in glioma

  12. 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

  13. Selective induction of apoptosis in glioma tumour cells by a Gynostemma pentaphyllum extract.

    Science.gov (United States)

    Schild, L; Chen, B H; Makarov, P; Kattengell, K; Heinitz, K; Keilhoff, G

    2010-07-01

    At low concentration H(2)O(2) is an important signal molecule in proliferation of tumour cells. We report about a study investigating the effect of an ethanolic extract from Gynostemma pentaphyllum on proliferation of C6 glioma tumour cells and cellular H(2)O(2) concentration. The proliferation of these cells was maximal at about 1 muM extracellular H(2)O(2). HPLC-finger prints of the extract revealed a set of saponines as essential components. In C6 glioma cells the extract caused increase in super oxide dismutase (SOD) activity, in the amount of SOD protein, and in cellular H(2)O(2) concentration. It inhibited cell proliferation and induced activation of caspase 3 as indication of apoptosis. No effect of the extract was observed on the proliferation of astrocytes of a primary cell culture. From these findings we suggest that the ethanolic extract from Gynostemma pentaphyllum may selectively shift the H(2)O(2) concentration to toxic levels exclusively in tumour cells due to increased SOD activity. It may have a high potency in cancer therapy and cancer prophylaxis. (c) 2010 Elsevier GmbH. All rights reserved.

  14. Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy

    DEFF Research Database (Denmark)

    Khan, Z.; Knecht, Wolfgang; Willer, Mette

    2010-01-01

    The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen....... In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT...... suicide gene therapy system in combination with stem cell mediated gene delivery promises new treatment of malignant gliomas....

  15. miR-21 Is Linked to Glioma Angiogenesis

    DEFF Research Database (Denmark)

    Hermansen, Simon Kjær; Nielsen, Boye Schnack; Aaberg-Jessen, Charlotte

    2016-01-01

    MicroRNA-21 (miR-21) is the most consistently over-expressed microRNA (miRNA) in malignant gliomas. We have previously reported that miR-21 is upregulated in glioma vessels and subsets of glioma cells. To better understand the role of miR-21 in glioma angiogenesis and to characterize miR-21-posit...... with the six markers. These findings suggest that miR-21 is linked to glioma angiogenesis, that miR-21 is unlikely to regulate PTEN, and that miR-21-positive tumor cells do not possess stem cell characteristics....

  16. Steroid hormones affect binding of the sigma ligand {sup 11}C-SA4503 in tumour cells and tumour-bearing rats

    Energy Technology Data Exchange (ETDEWEB)

    Rybczynska, Anna A.; Elsinga, Philip H.; Sijbesma, Jurgen W.; Jong, Johan R. de; Vries, Erik F. de; Dierckx, Rudi A.; Waarde, Aren van [University of Groningen, Nuclear Medicine and Molecular Imaging, University of Groningen Medical Center, Groningen (Netherlands); Ishiwata, Kiichi [Tokyo Metropolitan Institute of Gerontology, Positron Medical Center, Tokyo (Japan)

    2009-07-15

    Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist {sup 11}C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. {sup 11}C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. Binding of {sup 11}C-SA4503 to C6 cells was increased ({proportional_to}50%) upon removal and decreased ({proportional_to}60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC{sub 50} progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of {sup 11}C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. The binding of {sup 11}C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids. (orig.)

  17. 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

  18. Tumor-specific contrast agent based on ferric oxide superparamagnetic nanoparticles for visualization of gliomas by magnetic resonance tomography.

    Science.gov (United States)

    Abakumov, M A; Grinenko, N F; Baklaushev, V P; Sandalova, T O; Nukolova, N V; Semyonova, A V; Sokol'ski-Papkov, M; Vishvasrao, H; Kabanov, A V; Chekhonin, V P

    2012-05-01

    The aim of this study was to create vector superparamagnetic nanoparticles for tumor cell visualization in vivo by magnetic resonance tomography. A method for obtaining superparamagnetic nanoparticles based on ferric oxide with the magnetic nucleus diameter of 12 ± 3 nm coated with BSA and forming stable water dispersions was developed. The structure and size of the nanoparticles were studied by transmissive electron microscopy, dynamic light scattering, and x-ray phase analysis. Their T2 relaxivity was comparable with that of the available commercial analog. Low cytotoxicity of these nanoparticles was demonstrated by MTT test on primary and immortalized cell cultures. The nanoparticles were vectorized by monoclonal antibodies to connexin 43 (Cx43). Specific binding of vectorized nanoparticles to C6 glioma Cx43-positive cell membranes was demonstrated. Hence, vector biocompatible nanoparticles with high relaxivity, fit for use as MRT contrast for the diagnosis of poorly differentiated gliomas, were created.

  19. Evaluation of N-[C-11]Methyl-AMD3465 as a PET Tracer for Imaging of CXCR4 Receptor Expression in a C6 Glioma Tumor Model

    NARCIS (Netherlands)

    Hartimath, S. V.; van Waarde, A.; Dierckx, R. A. J. O.; de Vries, E. F. J.

    2014-01-01

    The chemokine receptor CXCR4 and its ligand CXCL12 play an important role in tumor progression and metastasis. CXCR4 receptors are expressed by many cancer types and provide a potential target for treatment. Noninvasive detection of CXCR4 may aid diagnosis and improve therapy selection. It has been

  20. [Guidelines for the radiotherapy of gliomas].

    Science.gov (United States)

    Feuvret, L; Antoni, D; Biau, J; Truc, G; Noël, G; Mazeron, J-J

    2016-09-01

    Gliomas are the most frequent primary brain tumours. Treating these tumours is difficult because of the proximity of organs at risk, infiltrating nature, and radioresistance. Clinical prognostic factors such as age, Karnofsky performance status, tumour location, and treatments such as surgery, radiation therapy, and chemotherapy have long been recognized in the management of patients with gliomas. Molecular biomarkers are increasingly evolving as additional factors that facilitate diagnosis and therapeutic decision-making. These practice guidelines aim at helping in choosing the best treatment, in particular radiation therapy. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  1. Reactions of metallic Li or LiC6 with organic solvents for lithium ion battery

    Science.gov (United States)

    Nakajima, Tsuyoshi; Hirobayashi, Yuki; Takayanagi, Yuki; Ohzawa, Yoshimi

    2013-12-01

    DSC (Differential Scanning Calorimetry) study has been made on the reactions of metallic Li or LiC6 with organic solvents for lithium ion battery. Ethylene carbonate (EC) more easily reacts with metallic Li and LiC6 than propylene carbonate (PC). This may be because formation of lithium alkyl carbonate is more difficult for PC than EC. On the other hand, diethyl carbonate (DEC), ethyl methyl carbonate (EMC) and dimethyl carbonate (DMC) react with Li in the same manner. Reactions of Li and LiC6 with organic solvents have been discussed based on the results of quantum calculation.

  2. Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma.

    Science.gov (United States)

    Wicks, Robert T; Azadi, Javad; Mangraviti, Antonella; Zhang, Irma; Hwang, Lee; Joshi, Avadhut; Bow, Hansen; Hutt-Cabezas, Marianne; Martin, Kristin L; Rudek, Michelle A; Zhao, Ming; Brem, Henry; Tyler, Betty M

    2015-01-01

    3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPA's inability to cross the blood-brain-barrier and DCA's dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed. Cytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT). 3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%. Intracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. 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

    family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies...... and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain...... tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically...

  4. 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

  5. Stability of corticosteroids under anaerobic conditions. C6 and C9 fluorine-containing corticosteroids

    NARCIS (Netherlands)

    Dekker, D.; Buijs, D.J.

    The decomposition of corticosteroids due to a fluorine atom at C6 and/or C9 is investigated. Chromatographic properties, the isolation and the structure elucidation of decomposition products are given.

  6. A regioselective alkylation at the C-6 hydroxyl group of erythromycin A-oxime derivatives

    OpenAIRE

    HOSANG MASTER; SINGH DHARMENDRA

    2005-01-01

    Erythromycin A contains five hydroxyl groups. The regioselective alkylation at the C-6 hydroxyl group was achieved to an extent ofmore than 97% when a 9-O-substituted erythromycin A-9-oxime was employed as the substrate.

  7. Comparison of C5 and C6 Aqua-MODIS Dark Target Aerosol Validation

    Science.gov (United States)

    Munchak, Leigh A.; Levy, Robert C.; Mattoo, Shana

    2014-01-01

    We compare C5 and C6 validation to compare the C6 10 km aerosol product against the well validated and trusted aerosol product on global and regional scales. Only the 10 km aerosol product is evaluated in this study, validation of the new C6 3 km aerosol product still needs to be performed. Not all of the time series has processed yet for C5 or C6, and the years processed for the 2 products is not exactly the same (this work is preliminary!). To reduce the impact of outlier observations, MODIS is spatially averaged within 27.5 km of the AERONET site, and AERONET is temporatally averaged within 30 minutes of the MODIS overpass time. Only high quality (QA = 3 over land, QA greater than 0 over ocean) pixels are included in the mean.

  8. Exploration of sensory impairments associated with C6 and C7 radiculopathies.

    Science.gov (United States)

    Rainville, James; Laxer, Eric; Keel, John; Pena, Enrique; Kim, David; Milam, R Alden; Carkner, Eric

    2016-01-01

    Cervical radiculopathy is a common disorder caused by compression of the cervical nerve roots and is characterized by arm pain and altered sensory-motor function. Incongruity in the locations of C6 and C7 dermatomes in competing versions of historical dermatome maps has plagued interpretation of impaired sensation associated with C6 and C7 radiculopathies. Magnetic resonance imaging (MRI) allows accurate identification of the C6 or C7 nerve root compression and therefore makes it possible to explore sensory findings that are associated with compression of specific nerve root. This study compared the locations of impaired sensation in subjects with cervical radiculopathy from MRI-confirmed C6 and C7 nerve root compression. Case series was used for this study. A total of 122 subjects with symptoms suggestive of cervical radiculopathy were recruited by 11 spine specialist from 5 practice locations. Of these, 30 subjects had MRI-confirmed C6 and 40 subjects C7 radiculopathy. Standardized pinprick sensory examination of the forearm and hand of every subject was performed, and the locations of sensory impairments were recorded. Sensory examination was performed before reviewing MRI results or performing motor or reflex examination. Areas of impaired sensation were recorded on drawings of the palmar and dorsal forearm and hand, and translated using a grid into 36 specific areas for analysis. Chi-square was used to compare frequencies of findings for each grid area for C6 and C7 radiculopathies. Power analysis suggested that a minimum of 27 subjects in each group were needed to detect a 30 percentage point difference in frequency of sensory impairments. Significance was set at ≤.05. Approximately 80% of subjects had impaired sensation in at least 1 grid area, most often in the distal forearm and hand, and many had findings in multiple areas. There was nearly complete overlap for locations of impaired sensation for C6 and C7 radiculopathy, and the frequencies of impaired

  9. C6 Peptide-Based Multiplex Phosphorescence Analysis (PHOSPHAN) for Serologic Confirmation of Lyme Borreliosis.

    Science.gov (United States)

    Pomelova, Vera G; Korenberg, Edward I; Kuznetsova, Tatiana I; Bychenkova, Tatiana A; Bekman, Natalya I; Osin, Nikolay S

    2015-01-01

    A single-tier immunoassay using the C6 peptide of VlsE (C6) from Borrelia burgdorferi sensu stricto (Bb) has been proposed as a potential alternative to conventional two-tier testing for the serologic diagnosis of Lyme disease in the United States and Europe. To evaluate the performance of C6 peptide based multiplex Phosphorescence Analysis (PHOSPHAN) for the serologic confirmation of Lyme borreliosis (LB) in Russian patients. Serum samples (n = 351) were collected from 146 patients with erythema migrans (EM); samples from 131 of these patients were taken several times prior to treatment and at different stages of recovery. The control group consisted of 197 healthy blood donors and 31 patients with other diseases, all from the same highly endemic region of Russia. All samples were analyzed by PHOSPHAN for IgM and IgG to Bb C6, recombinant OspC and VlsE proteins, and C6 peptides from B. garinii and B. afzelii. IgM and IgG to Bb C6 were identified in 43 and 95 out of 131 patients (32.8 and 72.5%, respectively); seroconversion of IgM antibodies was observed in about half of the patients (51.2%), and of IgG antibodies, in almost all of them (88.4%). Additional detection of OspC-IgM and VlsE-IgM or IgG to C6 from B. garinii or B. afzelii did not contribute significantly to the overall sensitivity of the multiplex immunoassay. The multiplex phosphorescence immunoassay is a promising method for simultaneously revealing the spectrum of antibodies to several Borrelia antigens. Detection of IgM and IgG to Bb C6 in the sera of EM patients provides effective serologic confirmation of LB and, with high probability, indicates an active infection process.

  10. Glia to glioma: A wrathful journey

    Directory of Open Access Journals (Sweden)

    Krishnendu Ghosh

    2017-05-01

    Full Text Available Glial cells, unlike neurons in the brain, can undergo cellular division to maintain their functional continuity. However, sometimes this divisional attribute gets uncontrolled, which breaches tissue organization and transforms tissues into neoplasm. The proliferative abnormality of neuroglia results in one of the most dreaded neoplasm amounting to 30% of all brain tumors—the glioma. The abnormal proliferation, high level of progression and invasive potential makes glioma one of the most lethal killers in its class. The pathological scenario becomes more moribund owing to poor prognosis and high mortality rate of the menace. Conventional onco-therapies yield dismal results compared to other soft tissue tumors. In time, with the advent of newer trends of prognosis and treatment modalities in the field of oncology, a hope for betterment is expected, but not yet achieved. These advancements would fetch some better results with proper and minute understanding of the biology of glioma, both at physiological as well as molecular level. In the present context, we have tried to document an insight to glioma biology that can serve as a primer to understand this lethal killer and its killing spree, with some approaches to combat its carnage.

  11. 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

  12. Surgical strategies for glioma involving language areas.

    Science.gov (United States)

    Zhang, Zhong; Jiang, Tao; Xie, Jian; Liu, Fu-sheng; Li, Shou-wei; Qiao, Hui; Wang, Zhong-cheng

    2008-09-20

    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. 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. 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. 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. Glioma virus therapies between bench and bedside

    Science.gov (United States)

    Kaufmann, Johanna K.; Chiocca, E. Antonio

    2014-01-01

    Despite extensive research, current glioma therapies are still unsatisfactory, and novel approaches are pressingly needed. In recent years, both nonreplicative viral vectors and replicating oncolytic viruses have been developed for brain cancer treatment, and the mechanistic background of their cytotoxicity has been unveiled. A growing number of clinical trials have convincingly established viral therapies to be safe in glioma patients, and maximum tolerated doses have generally not been reached. However, evidence for therapeutic benefit has been limited: new generations of therapeutic vectors need to be developed in order to target not only tumor cells but also the complex surrounding microenvironment. Such therapies could also direct long-lasting immune responses toward the tumor while reducing early antiviral reactions. Furthermore, viral delivery methods are to be improved and viral spread within the tumor will have to be enhanced. Here, we will review the outcome of completed glioma virus therapy trials as well as highlight the ongoing clinical activities. On this basis, we will give an overview of the numerous strategies to enhance therapeutic efficacy of new-generation viruses and novel treatment regimens. Finally, we will conclude with approaches that may be crucial to the development of successful glioma therapies in the future. PMID:24470549

  14. 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...

  15. Microwave spectrum and structure of C 6 H 5 CCH\\ctdot H 2 S complex

    Science.gov (United States)

    Goswami, Mausumi; Arunan, E.

    2011-07-01

    Rotational spectra of C 6H 5CCH⋯H 2S, C 6H 5CCH⋯H 234S, C 6H 5CCH⋯HDS, C 6H 5CCH⋯D 2S and C 6H 5CCD⋯H 2S complexes have been observed using a pulsed nozzle Fourier transform microwave spectrometer. The observed spectrum is consistent with a structure in which hydrogen sulfide is located over the phenyl ring π cloud and the distance between the centers of masses of the two monomers is 3.74 ± 0.01 Å. In the complex, the H 2S unit is shifted from the phenyl ring center towards the acetylene group. The vibrationally averaged structure has an effective C s symmetry. Ab initio calculations were performed at MP2/aug-cc-pVDZ level of theory to locate the possible geometries of the complex. The calculations reveal the experimentally observed structure to be more stable than a coplanar arrangement of the monomers, which was observed for the C 6H 5CCH⋯H 2O complex. Atoms in molecule theoretical analysis shows the presence of S-H⋯π hydrogen bond. For the parent isotopologue, each transition frequency was found to split into two resulting from an interchange of the equivalent hydrogens of H 2S unit in the complex.

  16. 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.

  17. 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Imaging of gliomas with Cis-4-[{sup 18}F]fluoro-L-proline

    Energy Technology Data Exchange (ETDEWEB)

    Langen, Karl-J. E-mail: k.j.langen@fz-juelich.de; Jarosch, Michael; Hamacher, Kurt; Muehlensiepen, Heinz; Weber, Friedrich; Floeth, Frank; Pauleit, Dirk; Herzog, Hans; Coenen, Heinz H

    2004-01-01

    Tumor imaging with cis-4-[{sup 18}F]fluoro-L-proline (cis-FPro) was compared to that of L-[{sup 3}H]proline and L-[{sup 3}H]methionine in F98 rat gliomas by dual-tracer autoradiography. All tracers exhibited high accumulation in the tumors but in the normal brain significant uptake was observed for L-[{sup 3}H]methionine only. Tumor extent on autoradiograms with L-[{sup 3}H]proline and L-[{sup 3}H]methionine was identical to that of histological staining while autoradiograms of cis-FPro showed diffuse uptake in the penumbra of some tumors. First PET studies in 7 patients with cerebral gliomas demonstrated accumulation of cis-FPro in tumor areas with enhancement of Gd-DTPA on MR scans. Uptake of cis-FPro in normal brain tissue was negligible. In one patient with a glioblastoma accumulation of cis-FPro was also found in two brain areas without enhancement of Gd-DTPA on MR scans. Control of MRI suggested tumor growth in these areas at further follow up. Our results indicate that in most gliomas increased cis-FPro uptake is restricted to areas with disruption of the BBB which limits its clinical utility.

  19. Imaging of gliomas with Cis-4-[18F]fluoro-L-proline.

    Science.gov (United States)

    Langen, Karl J; Jarosch, Michael; Hamacher, Kurt; Mühlensiepen, Heinz; Weber, Friedrich; Floeth, Frank; Pauleit, Dirk; Herzog, Hans; Coenen, Heinz H

    2004-01-01

    Tumor imaging with cis-4-[18F]fluoro-L-proline (cis-FPro) was compared to that of L-[3H]proline and L-[3H]methionine in F98 rat gliomas by dual-tracer autoradiography. All tracers exhibited high accumulation in the tumors but in the normal brain significant uptake was observed for L-[3H]methionine only. Tumor extent on autoradiograms with L-[3H]proline and L-[3H]methionine was identical to that of histological staining while autoradiograms of cis-FPro showed diffuse uptake in the penumbra of some tumors. First PET studies in 7 patients with cerebral gliomas demonstrated accumulation of cis-FPro in tumor areas with enhancement of Gd-DTPA on MR scans. Uptake of cis-FPro in normal brain tissue was negligible. In one patient with a glioblastoma accumulation of cis-FPro was also found in two brain areas without enhancement of Gd-DTPA on MR scans. Control of MRI suggested tumor growth in these areas at further follow up. Our results indicate that in most gliomas increased cis-FPro uptake is restricted to areas with disruption of the BBB which limits its clinical utility.

  20. C6/36 Aedes albopictus cells have a dysfunctional antiviral RNA interference response.

    Directory of Open Access Journals (Sweden)

    Doug E Brackney

    2010-10-01

    Full Text Available Mosquitoes rely on RNA interference (RNAi as their primary defense against viral infections. To this end, the combination of RNAi and invertebrate cell culture systems has become an invaluable tool in studying virus-vector interactions. Nevertheless, a recent study failed to detect an active RNAi response to West Nile virus (WNV infection in C6/36 (Aedes albopictus cells, a mosquito cell line frequently used to study arthropod-borne viruses (arboviruses. Therefore, we sought to determine if WNV actively evades the host's RNAi response or if C6/36 cells have a dysfunctional RNAi pathway. C6/36 and Drosophila melanogaster S2 cells were infected with WNV (Flaviviridae, Sindbis virus (SINV, Togaviridae and La Crosse virus (LACV, Bunyaviridae and total RNA recovered from cell lysates. Small RNA (sRNA libraries were constructed and subjected to high-throughput sequencing. In S2 cells, virus-derived small interfering RNAs (viRNAs from all three viruses were predominantly 21 nt in length, a hallmark of the RNAi pathway. However, in C6/36 cells, viRNAs were primarily 17 nt in length from WNV infected cells and 26-27 nt in length in SINV and LACV infected cells. Furthermore, the origin (positive or negative viral strand and distribution (position along viral genome of S2 cell generated viRNA populations was consistent with previously published studies, but the profile of sRNAs isolated from C6/36 cells was altered. In total, these results suggest that C6/36 cells lack a functional antiviral RNAi response. These findings are analogous to the type-I interferon deficiency described in Vero (African green monkey kidney cells and suggest that C6/36 cells may fail to accurately model mosquito-arbovirus interactions at the molecular level.

  1. Fine and hyperfine collisional excitation of C6H by He

    Science.gov (United States)

    Walker, Kyle M.; Lique, François; Dawes, Richard

    2018-01-01

    Hydrogenated carbon chains have been detected in interstellar and circumstellar media and accurate modelling of their abundances requires collisional excitation rate coefficients with the most abundant species. Among them, the C6H molecule is one of the most abundant towards many lines of sight. Hence, we determined fine and hyperfine-resolved rate coefficients for the excitation of C6H(X2Π) due to collisions with He. We present the first interaction potential energy surface for the C6H-He system, obtained from highly correlated ab initio calculations and characterized by a large anisotropy due to the length of the molecule. We performed dynamical calculations for transitions among the first fine structure levels (up to J = 30.5) of both spin-orbit manifolds of C6H using the close-coupling method, and rate coefficients are determined for temperatures ranging from 5 to 100 K. The largest rate coefficients for even ΔJ transitions conserve parity, while parity-breaking rate coefficients are favoured for odd ΔJ. Spin-orbit changing rate coefficients are several orders of magnitude lower than transitions within a single manifold. State-to-state hyperfine-resolved cross-sections for the first levels (up to J = 13.5) in the Ω = 3/2 spin-orbit manifold are deduced using recoupling techniques. Rate coefficients are obtained and the propensity rule ΔJ = ΔF is seen. These new data will help determine the abundance of C6H in astrophysical environments such as cold dense molecular clouds, star-forming regions and circumstellar envelopes, and will help in the interpretation of the puzzling C6H-/C6H abundance ratios deduced from observations.

  2. Use of tricyclic antidepressants and risk of glioma

    DEFF Research Database (Denmark)

    Pottegård, Anton; García Rodríguez, Luis Alberto; Rasmussen, Lotte

    2016-01-01

    BACKGROUND: A protective effect of tricyclic antidepressants (TCAs) against gliomas has been suggested by a small number of studies. We investigated this putative association in a nationwide setting. METHODS: Using a case-control design, we identified all patients with histologically verified...... glioma (cases) in Denmark between 2000 and 2012 and matched these 1 : 20 to population controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) for glioma associated with long-term (⩾3 years) use of TCAs. Similar analyses were performed for selective serotonin reuptake...... inhibitors (SSRIs). RESULTS: We identified 3767 glioma cases and 75 340 population controls. Long-term use of TCAs was inversely associated with risk of glioma (OR 0.72, 95% CI: 0.41-1.25). Long-term SSRI use was not associated with glioma risk (OR 0.93, 95% CI: 0.75-1.16). CONCLUSIONS: Our study indicated...

  3. Withania somnifera Suppresses Tumor Growth of Intracranial Allograft of Glioma Cells.

    Science.gov (United States)

    Kataria, Hardeep; Kumar, Sushil; Chaudhary, Harshita; Kaur, Gurcharan

    2016-08-01

    Gliomas are the most frequent type of primary brain tumor in adults. Their highly proliferative nature, complex cellular composition, and ability to escape therapies have confronted investigators for years, hindering the advancement toward an effective treatment. Agents that are safe and can be administered as dietary supplements have always remained priority to be most feasible for cancer therapy. Withania somnifera (ashwagandha) is an essential ingredient of Ayurvedic preparations and is known to eliminate cancer cells derived from a variety of peripheral tissues. Although our previous studies have addressed the in vitro anti-proliferative and differentiation-inducing properties of ashwagandha on neuronal cell lines, in vivo studies validating the same are lacking. While exploring the mechanism of its action in vitro, we observed that the ashwagandha water extract (ASH-WEX) induced the G2/M phase blockade and caused the activation of multiple pro-apoptotic pathways, leading to suppression of cyclin D1, bcl-xl, and p-Akt, and reduced the expression of polysialylated form of neural cell adhesion molecule (PSA-NCAM) as well as the activity of matrix metalloproteinases. ASH-WEX reduced the intracranial tumor volumes in vivo and suppressed the tumor-promoting proteins p-nuclear factor kappa B (NF-κB), p-Akt, vascular endothelial growth factor (VEGF), heat shock protein 70 (HSP70), PSA-NCAM, and cyclin D1 in the rat model of orthotopic glioma allograft. Reduction in glial fibrillary acidic protein (GFAP) and upregulation of mortalin and neural cell adhesion molecule (NCAM) expression specifically in tumor-bearing tissue further indicated the anti-glioma efficacy of ASH-WEX in vivo. Combining this enhanced understanding of the molecular mechanisms of ASH-WEX in glioma with in vivo model system offers new opportunities to develop therapeutic strategy for safe, specific, and effective formulations for treating brain tumors.

  4. Deregulated expression of the clock genes in gliomas.

    Science.gov (United States)

    Chen, Z; Liu, P; Li, C; Luo, Y; Chen, I; Liang, W; Chen, X; Feng, Y; Xia, H; Wang, F

    2013-02-01

    Growing evidence shows that the deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of genes controlling circadian rhythm in glioma cells have not been explored. Using reverse transcription polymerase chain reaction and immunohistochemistry techniques, we examined the expression of the most important clock genes, clock, in 67 gliomas.Our results revealed that asynchronized expression of the clock gene was found in cancerous tissues in comparison with paired non-cancerous tissues. The expression levels of clock mRNA in grade III or IV glioma was significantly different from the surrounding non-tumor tissues (P  0.05). The intensity of immunoactivity for Clock in highgrade gliomas was significantly higher than that of low-grade gliomas (r = -0.403, P 5 0.012 ,  0.05). The expression of PCNA (Proliferating Cell Nuclear Antigen) protein in highgrade gliomas was significantly higher than that of low-grade gliomas (P control of normal circadian rhythm, thus benefiting the survival of glioma cells and promoting carcinogenesis.

  5. Malignant clinical features of anaplastic gliomas without IDH mutation.

    Science.gov (United States)

    Shibahara, Ichiyo; Sonoda, Yukihiko; Shoji, Takuhiro; Kanamori, Masayuki; Saito, Ryuta; Inoue, Tomoo; Kawaguchi, Tomohiro; Yamashita, Yoji; Watanabe, Takashi; Kumabe, Toshihiro; Watanabe, Mika; Suzuki, Hiroyoshi; Tominaga, Teiji

    2015-01-01

    Diagnosis of WHO grade III anaplastic gliomas does not always correspond to its clinical outcome because of the isocitrate dehydrogenase (IDH) gene status. Anaplastic gliomas without IDH mutation result in a poor prognosis, similar to grade IV glioblastomas. However, the malignant features of anaplastic gliomas without IDH mutation are not well understood. The aim of this study was to examine anaplastic gliomas, in particular those without IDH mutation, with regard to their malignant features, recurrence patterns, and association with glioma stem cells. We retrospectively analyzed 86 cases of WHO grade III anaplastic gliomas. Data regarding patient characteristics, recurrence pattern, and prognosis were obtained from medical records. We examined molecular alterations such as IDH mutation, 1p19q loss, TP53 mutation, MGMT promoter methylation, Ki67 labeling index, and CD133, SOX2, and NESTIN expression. Of the 86 patients with anaplastic gliomas, 58 carried IDH mutation, and 40 experienced recurrence. The first recurrence was local in 25 patients and distant in 15. Patients without IDH mutation exhibited significantly higher CD133 and SOX2 expression (P = .025 and .020, respectively) and more frequent distant recurrence than those with IDH mutation (P = .022). Patients with anaplastic gliomas without IDH mutation experienced distant recurrence and exhibited glioma stem cell markers, indicating that this subset may share some malignant characteristics with glioblastomas. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  6. IGFBP2 expression predicts IDH-mutant glioma patient survival.

    Science.gov (United States)

    Huang, Lin Eric; Cohen, Adam L; Colman, Howard; Jensen, Randy L; Fults, Daniel W; Couldwell, William T

    2017-01-03

    Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas. Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis. Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear. Through comparative analyses of 286 cases of IDH-wildtype and IDH-mutant lower-grade glioma from a TCGA data set, we report that IDH-mutant gliomas have increased expression of tumor-suppressor genes (NF1, PTEN, and PIK3R1) and decreased expression of oncogenes(AKT2, ARAF, ERBB2, FGFR3, and PDGFRB) and glioma progression genes (FOXM1, IGFBP2, and WWTR1) compared with IDH-wildtype gliomas. Furthermore, each of these genes is prognostic in overall gliomas; however, within the IDH-mutant group, none remains prognostic except IGFBP2 (encodinginsulin-like growth factor binding protein 2). Through validation in an independent cohort, we show that patients with low IGFBP2 expressiondisplay a clear advantage in overall and disease-free survival, whereas those with high IGFBP2 expressionhave worse median survival than IDH-wildtype patients. These observations hold true across different histological and molecular subtypes of lower-grade glioma. We propose therefore that an unexpected biological consequence of IDH mutations in glioma is to ameliorate patient survival by promoting tumor-suppressor signaling while inhibiting that of oncogenes, particularly IGFBP2.

  7. Sunitinib in Treating Patients With Recurrent Malignant Gliomas

    Science.gov (United States)

    2016-01-29

    Adult Anaplastic Astrocytoma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pineal Gland Astrocytoma

  8. C5 and C6 human dermatomes: a clinical, electromyographical, imaging and surgical findings.

    Science.gov (United States)

    Faleiros, Antonio Tadeu de Souza; Resende, Luiz Antonio de Lima; Zanini, Marco Antonio; Castro, Heloisa Amélia de Lima; Gabarra, Roberto Colichio

    2009-06-01

    There is substantial controversy in literature about human dermatomes. In this work, C5 and C6 superior limb dermatomes were studied. The method consisted of comparing clinical signs and symptoms with conduction studies, electromyographical data, neurosurgical findings, and imaging findings obtained by computerized tomography (CT) or magnetic resonance imaging (MRI), for each patient. Data analysis from superior members in 18 patients suggests that C5 is located in the lateral aspect of the shoulder and arm, and C6 in the lateral aspect of the forearm and 1st, 2nd, and 3rd fingers. To our knowledge this is the first time that C5 and C6 human dermatomes have been studied by all the following methods together: clinical, electromyographical, CT and MR imaging, and surgical findings.

  9. PICquant: a quantitative platform to measure differential peptide abundance using dual-isotopic labeling with 12C6- and 13C6-phenyl isocyanate.

    Science.gov (United States)

    Lyons, Charles E; Victor, Ken G; Moshnikov, Sergey A; Bachmann, Lorin M; Baras, Alexander S; Dettmann, Kathleen M; Cross, Janet V; Templeton, Dennis J

    2011-02-01

    We have developed a complete system for the isotopic labeling, fractionation, and automated quantification of differentially expressed peptides that significantly facilitates candidate biomarker discovery. We describe a new stable mass tagging reagent pair, (12)C(6)- and (13)C(6)-phenyl isocyanate (PIC), that offers significant advantages over currently available tags. Peptides are labeled predominantly at their amino termini and exhibit elution profiles that are independent of label isotope. Importantly, PIC-labeled peptides have unique neutral-mass losses upon CID fragmentation that enable charge state and label isotope identification and, thereby, decouple the sequence identification from the quantification of candidate biomarkers. To exploit these properties, we have coupled peptide fractionation protocols with a Thermo LTQ-XL LC-MS(2) data acquisition strategy and a suite of automated spectrum analysis software that identifies quantitative differences between labeled samples. This approach, dubbed the PICquant platform, is independent of protein sequence identification and excludes unlabeled peptides that otherwise confound biomarker discovery. Application of the PICquant platform to a set of complex clinical samples showed that the system allows rapid identification of peptides that are differentially expressed between control and patient groups.

  10. The interaction of C6H6 and C6H12 with noble metal surfaces: electronic level alignment and the origin of the interface dipole.

    Science.gov (United States)

    Bagus, Paul S; Hermann, Klaus; Wöll, Christof

    2005-11-08

    The electronic interaction of two molecules, the aromatic benzene (C6H6) and the saturated hydrocarbon cyclohexane (C6H12) with a Cu(111) surface, have been determined using precise, ab initio electronic structure calculations. For the interaction of these adsorbates with the substrate, we present a detailed analysis and decomposition of various individual chemical mechanisms that contribute. A novel aspect of this analysis is the use of charge-density difference contour plots to graphically display the chemistry. A wave-function-based approach was used in order to avoid problems when the presently most commonly employed approach, density-functional theory, is applied to weakly chemisorbed molecules, where the interaction is dominated by van der Waals forces. The present information are not only relevant with regard to understanding the chemistry going on when molecules are adsorbed on a Cu surface but also have important consequences with regard to charge injection in molecular electronic devices, e.g., organic field-effect transistors and organic light-emitting diodes.

  11. Elimination of C-6-hydrogen during the formation of ecdysteroids from cholesterol in Locusta migratoria ovaries

    Energy Technology Data Exchange (ETDEWEB)

    Fujimoto, Y.; Hiramoto, M.; Kakinuma, K.; Ikekawa, N. (Tokyo Institute of Technology (Japan))

    1989-03-01

    Being administered to Locusta migratoria adult females, (6-{sup 3}H, 4-{sup 14}C)cholesterol was incorporated into ecdysone and 2-deoxyecdysone. The ratio of {sup 3}H/{sup 14}C of the two ecdysteroids isolated from newly laid eggs revealed that C-6-hydrogen of cholesterol was eliminated during the conversion to ecdysteroids in the ovaries of the insects. Thus, a hypothetical mechanism involving migration of the C-6-hydrogen to the C-5 position in the formation of A/B cis junction turned out to be less likely.

  12. Double Insertion of Coordinated Phosphanylalkyne Ligands into a Pt-C(6)F(5) Bond.

    Science.gov (United States)

    Charmant; Forniés; Gómez; Lalinde; Moreno; Orpen; Solano

    1999-10-18

    Enhanced reactivity is shown by uncoordinated C identical withC bonds in the proximity of a metal in phosphanylacetylene complexes. cis-[Pt(C(6)F(5))(2)(thf)(2)] reacts with [M(C(6)F(5))(2)(PPh(2)C identical withCPh)(2)] (M=Pt, Pd) to form binuclear complexes containing the novel 2,3-bis(diphenylphosphanyl)-1,3-butadien-1-yl bridging ligand. Substitution of the solvent ligands with, for example, PPh(2)H (see picture) provides species that could be characterized by X-ray crystallography.

  13. 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.

  14. Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

    Science.gov (United States)

    2017-10-23

    Childhood Cerebral Anaplastic Astrocytoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma

  15. Radiotherapeutic alternatives for previously irradiated recurrent gliomas

    Directory of Open Access Journals (Sweden)

    Schulz-Ertner Daniela

    2007-08-01

    Full Text Available Abstract Re-irradiation for recurrent gliomas has been discussed controversially in the past. This was mainly due to only marginal palliation while being associated with a high risk for side effects using conventional radiotherapy. With modern high-precision radiotherapy re-irradiation has become a more wide-spread, effective and well-tolerated treatment option. Besides external beam radiotherapy, a number of invasive and/or intraoperative radiation techniques have been evaluated in patients with recurrent gliomas. The present article is a review on the available methods in radiation oncology and summarizes results with respect to outcome and side effects in comparison to clinical results after neurosurgical resection or different chemotherapeutic approaches.

  16. Nanotechnology Applications for Diffuse Intrinsic Pontine Glioma.

    Science.gov (United States)

    Bredlau, Amy Lee; Dixit, Suraj; Chen, Chao; Broome, Ann-Marie

    2017-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) are invariably fatal tumors found in the pons of elementary school aged children. These tumors are grade II-IV gliomas, with a median survival of less than 1 year from diagnosis when treated with standard of care (SOC) therapy. Nanotechnology may offer therapeutic options for the treatment of DIPGs. Multiple nanoparticle formulations are currently being investigated for the treatment of DIPGs. Nanoparticles based upon stable elements, polymer nanoparticles, and organic nanoparticles are under development for the treatment of brain tumors, including DIPGs. Targeting of nanoparticles is now possible as delivery techniques that address the difficulty in crossing the blood brain barrier (BBB) are developed. Theranostic nanoparticles, a combination of therapeutics and diagnostic nanoparticles, improve imaging of the cancerous tissue while delivering therapy to the local region. However, additional time and attention should be directed to developing a nanoparticle delivery system for treatment of the uniformly fatal pediatric disease of DIPG.

  17. Semiautomatic Segmentation of Glioma on Mobile Devices

    OpenAIRE

    Ya-Ping Wu; Yu-Song Lin; Wei-Guo Wu; Cong Yang; Jian-Qin Gu; Yan Bai; Mei-Yun Wang

    2017-01-01

    Brain tumor segmentation is the first and the most critical step in clinical applications of radiomics. However, segmenting brain images by radiologists is labor intense and prone to inter- and intraobserver variability. Stable and reproducible brain image segmentation algorithms are thus important for successful tumor detection in radiomics. In this paper, we propose a supervised brain image segmentation method, especially for magnetic resonance (MR) brain images with glioma. This paper uses...

  18. Nanomedicines and the future of glioma

    OpenAIRE

    Lalatsa, Aikaterini; Moreira Leite, Diana; Pilkington, Geoffrey John

    2015-01-01

    There is a higher incidence of brain tumours in the UK than the world average for both men (8.1 per 100,000), and women (5.3 per 100,000). Malignant gliomas are the most common primary brain tumours of which glioblastoma (GBM) is the most prevalent. GBM is also known to be the most biologically aggressive and cellularly heterogeneous and is highly diffusively infiltrative in nature which renders surgical excision impossible without causing significant neurological deficit. Typically, followin...

  19. Maintenance of Stemlike Glioma Cells and Microglia in an Organotypic Glioma Slice Model.

    Science.gov (United States)

    Raju, E N Sanjaya; Kuechler, Jan; Behling, Susanne; Sridhar, Susmita; Hirseland, Eileen; Tronnier, Volker; Zechel, Christina

    2015-10-01

    The therapeutic resistance of gliomas is, at least in part, due to stemlike glioma cells (SLGCs), which self-renew, generate the bulk of tumor cells, and sustain tumor growth. SLGCs from glioblastomas (GB) have been studied in cell cultures or mouse models, whereas little is known about SLGCs from lower grade gliomas. To compare cell and organotypic slice cultures from GBs and lower grade gliomas and study the maintenance of SLGCs. Cells and tissue slices from astrocytomas, oligodendrogliomas, oligoastrocytomas, and GBs were cultivated in (1) serum-free medium supplemented with the growth factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), (2) medium containing 10% serum plus EGF and bFGF (F+GF medium), or (3) medium containing 10% fetal calf serum (F medium). Maintenance of cells and cytoarchitecture was addressed, using several candidate SLGC markers (Nestin, Sox2, CD133, CD44, CD49f/integrin α6, and Notch) as well as CD31 (endothelial cells), ionized calcium-binding adapter molecule 1 (microglia), and vimentin. Cell vitality was determined. SLGCs were present in tissue slices from lower and higher grade gliomas. Preservation of the cytoarchitecture in slices was possible for >3 weeks. Maintenance of SLGCs required the presence of EGF/bFGF in cell and slice cultures, in which F+GF appeared superior to N medium. Constraints were observed regarding the preservation of the microglia but not of the endothelial cells. Maintenance of the microglia was improved by addition of the cytokine macrophage colony-stimulating factor. Medium supplemented with serum and growth factors EGF, bFGF, and macrophage colony-stimulating factor permits the preservation of SLGCs and non-SLGCs in the original glioma microenvironment.

  20. Pseudoprogression after glioma therapy: an update.

    Science.gov (United States)

    Galldiks, Norbert; Kocher, Martin; Langen, Karl-Josef

    2017-11-01

    Initial diagnostics and follow-up of gliomas is usually based on contrast-enhanced MRI. However, the capacity of standard MRI to differentiate neoplastic tissue from posttherapeutic effects such as pseudoprogression is limited. Advanced neuroimaging methods may provide relevant additional information, which allow for a more accurate diagnosis especially in clinically equivocal situations. This review article focuses predominantly on PET using radiolabeled amino acids and advanced MRI techniques such as perfusion-weighted imaging (PWI) and summarizes the efforts of these methods regarding the identification of pseudoprogression after glioma therapy. Areas covered: The current literature on pseudoprogression in the field of brain tumors, with a focus on gliomas is summarized. A literature search was performed using the terms 'pseudoprogression', 'temozolomide', 'glioblastoma', 'PET', 'PWI', 'radiochemotherapy', and derivations thereof. Expert commentary: The present literature provides strong evidence that PWI MRI and amino acid PET can be of great value by providing valuable additional diagnostic information in order to overcome the diagnostic challenge of pseudoprogression. Despite various obstacles such as the still limited availability of amino acid PET and the lack of standardization of PWI, the diagnostic improvement probably results in relevant benefits for brain tumor patients and justifies a more widespread use of these diagnostic tools.

  1. 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.

  2. Exploratory catalyst screening studies on the liquefaction of model humins from C6 sugars

    NARCIS (Netherlands)

    Wang, Y.; Agarwal, S.; Tang, Z.; Heeres, H. J.

    2017-01-01

    A catalyst screening study is reported on the liquefaction of humins, the solid byproducts from C6 sugar biorefineries for levulinic acid and 5-hydroxymethylfurfural production. Experiments were carried out in a batch reactor using an artificial model of humin derived from glucose with isopropanol

  3. Mode of action of pectin lyase A of Aspergillus niger on differently C6-substituted oligogalacturonides

    NARCIS (Netherlands)

    Alebeek, van G.J.W.M.; Christensen, T.M.I.E.; Schols, H.A.; Mikkelsen, J.D.; Voragen, A.G.J.

    2002-01-01

    A thorough investigation of the mode of action of Aspergillus niger (4M-147) pectin lyase A (PLA) on differently C6-substituted oligogalacturonides is described. PLA appeared to be very specific for fully methyl-esterified oligogalacturonides: removal of the methyl-ester or changing the type of

  4. Structural and electronic properties of lithium intercalated graphite LiC6

    CSIR Research Space (South Africa)

    Kganyago, KR

    2003-11-01

    Full Text Available The lattice properties and electronic structure of graphite and LiC6 within the most widely used density-functional theory implementation, the local density approximation (LDA) are calculated. Improvements to the LDA in the form of a generalized...

  5. Probability density fittings of corrosion test-data: Implications on C 6 ...

    Indian Academy of Sciences (India)

    In this study, corrosion test-data of steel-rebar in concrete were subjected to the fittings of the Normal, Gumbel and the Weibull probability distribution functions. This was done to investigate the suitability of the results of the fitted test-data, by these distributions, for modelling the effectiveness of C6H15NO3, triethanolamine ...

  6. LINE EMISSION FROM C6+, O8++LI ELECTRON-CAPTURE COLLISIONS

    NARCIS (Netherlands)

    OLSON, RE; PASCALE, J; HOEKSTRA, R

    1992-01-01

    Electron capture cross sections to nl sublevels have been calculated for 1-10 keV u-1 collisions of C6+ and O8+ projectiles on a Li target. The classical trajectory Monte Carlo method has been employed with the initial phase distributions for the Li(2s) target obtained from Hartree-Fock

  7. 40 CFR 721.524 - Alcohols, C6-12, ethoxylated, reaction product with maleic anhydride.

    Science.gov (United States)

    2010-07-01

    ... AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant... chemical substance identified generically as alcohols, C6-12, ethoxylated, reaction product with maleic... provisions of subpart A of this part apply to this section except as modified by this paragraph. (1...

  8. C6 deficiency does not alter intrinsic regeneration speed after peripheral nerve crush injury

    NARCIS (Netherlands)

    Sta, M.; Cappaert, N. L. M.; Ramekers, D.; Ramaglia, V.; Wadman, W. J.; Baas, F.

    2014-01-01

    Peripheral nerve injury leads to Wallerian degeneration, followed by regeneration, in which functionality and morphology of the nerve are restored. We previously described that deficiency for complement component C6, which prevents formation of the membrane attack complex, slows down degeneration

  9. Analytical system for stable carbon isotope measurements of low molecular weight (C2-C6) hydrocarbons

    NARCIS (Netherlands)

    Zuiderweg, A.T.; Holzinger, R.; Roeckmann, T.

    2011-01-01

    We present setup, testing and initial results from a new automated system for stable carbon isotope ratio measurements on C2 to C6 atmospheric hydrocarbons. The inlet system allows analysis of trace gases from air samples ranging from a few liters for urban samples and samples with high mixing

  10. Correlated linear response calculations of the C6 dispersion coefficients of hydrogen halides

    Czech Academy of Sciences Publication Activity Database

    Sauer, S. P. A.; Paidarová, Ivana

    2007-01-01

    Roč. 3, 2-4 (2007), s. 399-421 ISSN 1574-0404 R&D Projects: GA AV ČR IAA401870702 Institutional research plan: CEZ:AV0Z40400503 Keywords : hydrogen halides * C6 dospersion coefficients * van der Waals coefficients * polarizability at imaginary frequences * SOPPA Subject RIV: CF - Physical ; Theoretical Chemistry

  11. Thiyl radical interaction with pyrimidine C5-C6 double bond.

    Science.gov (United States)

    Wójcik, Aleksandra; Naumov, Sergej; Marciniak, Bronisław; Hermann, Ralf; Brede, Ortwin

    2005-08-11

    Addition and elimination interaction of thiyl radicals with the C5-C6 double bond in pyrimidines was studied by the pulse radiolysis technique in aqueous solution with the use of different monitoring systems. For this purpose, p-thiocresol, cysteamine hydrochloride, and mercaptoethanol were used. The rate constants of addition and elimination of thiyl radicals were determined by applying the modified version of ACUCHEM (computer program for modeling complex reaction systems). Aliphatic thiyl radicals add to the pyrimidine C5-C6 double bond with k = 1.0-3.0 x 10(7) dm3 mol(-1) s(-1), whereas elimination takes place with k = 0.7-2.0 x 10(5) s(-1). Quantum chemical calculations at the B3LYP/6-31G(d)/PCM level show that the addition should occur at the C6 position of the pyrimidine ring and that the energy of interaction between thiyl radicals and the pyrimidine double bond C5-C6 is low.

  12. Lactoferrin conjugated iron oxide nanoparticles for targeting brain glioma cells in magnetic particle imaging

    Science.gov (United States)

    Tomitaka, Asahi; Arami, Hamed; Gandhi, Sonu; Krishnan, Kannan M.

    2015-10-01

    Magnetic Particle Imaging (MPI) is a new real-time imaging modality, which promises high tracer mass sensitivity and spatial resolution directly generated from iron oxide nanoparticles. In this study, monodisperse iron oxide nanoparticles with median core diameters ranging from 14 to 26 nm were synthesized and their surface was conjugated with lactoferrin to convert them into brain glioma targeting agents. The conjugation was confirmed with the increase of the hydrodynamic diameters, change of zeta potential, and Bradford assay. Magnetic particle spectrometry (MPS), performed to evaluate the MPI performance of these nanoparticles, showed no change in signal after lactoferrin conjugation to nanoparticles for all core diameters, suggesting that the MPI signal is dominated by Néel relaxation and thus independent of hydrodynamic size difference or presence of coating molecules before and after conjugations. For this range of core sizes (14-26 nm), both MPS signal intensity and spatial resolution improved with increasing core diameter of nanoparticles. The lactoferrin conjugated iron oxide nanoparticles (Lf-IONPs) showed specific cellular internalization into C6 cells with a 5-fold increase in MPS signal compared to IONPs without lactoferrin, both after 24 h incubation. These results suggest that Lf-IONPs can be used as tracers for targeted brain glioma imaging using MPI.

  13. 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.

  14. ABCG2 is related with the grade of glioma and resistance to mitoxantone, a chemotherapeutic drug for glioma.

    Science.gov (United States)

    Jin, Yao; Bin, Zhang Quan; Qiang, Huang; Liang, Chu; Hua, Chen; Jun, Dong; Dong, Wang Ai; Qing, Lan

    2009-10-01

    The aim of this study is to explore if ABCG2 is related to the grade of glioma and resistance to chemotherapeutic drug for glioma. The ABCG2 expression and distribution among glioma tissues of different grades and other samples were examined using tissue microarray technique. The enhancement of sensitivity of CD133+ glioma stem cells to chemotherapeutic agent, mitoxantone through addition of ABCG2 competitive inhibitor nicardipine was testified by MTT assay and FACS analysis. The positive immunostaining of ABCG2 was observed in less than 10% of low-grade gliomas (3/31 in grade I + II) and in more than 40% of high-grade gliomas (16/37 in grade III + IV), which was statistically different (chi (2) = 10.710, P = 0.0011). In samples consisting of glioma stem cells (CD133+), the positive-straining rate was 100% (4/4), while in CD133- fraction, no positive staining was observed. A simultaneous treatment of CD133+ tumor cells with concentration-dependent mitoxantone (10(-5)-1 microM) and 2.5/5.0 microM nicardipine resulted in synergistic cytotoxicity. The apoptotic rate of CD133+ cells treated with mitoxantone plus nicardipine was significantly higher than that treated with mitoxantone alone (58.54 +/- 7.06% vs. 30.7 +/- 3.79%, P level of ABCG2 is positively associated with the increasing pathological grade of glioma (poor cell differentiation). ABCG2 plays a key role in glioma cells resistance to mitoxantone, chemotherapeutic drug for glioma. Thus, inhibition of ABCG2 protein activity by nicardipine in glioma can sensitize it to mitoxantone, which may lead to better treatment strategies for cancers.

  15. Deregulated expression of the Per1 and Per2 in human gliomas.

    Science.gov (United States)

    Xia, He-chun; Niu, Zhan-feng; Ma, Hui; Cao, Shuan-zhu; Hao, Shao-cai; Liu, Zhong-tao; Wang, Fan

    2010-05-01

    Growing evidence shows that the deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of genes controlling circadian rhythm in glioma cells have not been explored. Using reverse transcription polymerase chain reaction and immunohistochemistry techniques, we examined the expression of two important clock genes, Per1 and Per2, in 33 gliomas. In this study, out of 33 gliomas, 28 were Per1-positive, and 23 were Per2-positive. The expression levels of Per1 and Per2 in glioma cells were significantly different from the surrounding non-glioma cells (P0.05). While there was no difference in the intensity of immunoactivity for Per2 between high-grade gliomas and low-grade gliomas (r=-0.330, P=0.061), the expression level of Per1 in high-grade gliomas was significantly lower than that in low-grade gliomas(r=-0.433, P=0.012). In this study, we found that the expression of Per1 and Per2 in glioma cells was much lower than in the surrounding non-glioma cells. Therefore, we suggest that disturbances in Per1 and Per2 expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells. Differential expression of circadian clock genes in glioma and non-glioma cells may provide a molecular basis for the chemotherapy of gliomas.

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

    African Journals Online (AJOL)

    Purpose: To elucidate the outcomes of treatment and epidemiology of epilepsy related to glioma in a single center in Chinese patients. Methods: Prescription medicines usage and clinical data were collected from medical records of 119 patients with gliomas between August 2009 and September 2015. Fisher's exact and ...

  17. The functional role of Notch signaling in human gliomas

    DEFF Research Database (Denmark)

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

    2010-01-01

    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...

  18. Dexamethasone inhibits the HSV-tk/ ganciclovir bystander effect in malignant glioma cells

    Directory of Open Access Journals (Sweden)

    Jolois Olivier

    2005-04-01

    Full Text Available Abstract Background HSV-tk/ ganciclovir (GCV gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed. Methods Stable clones of TK-expressing U87, C6 and LN18 cells were generated and their bystander effect on wild type cells was assessed. The effects of dexamethasone on cell proliferation and sensitivity to ganciclovir were assessed with a thymidine incorporation assay and a MTT test. Gap junction mediated intercellular communication was assessed with microinjections and FACS analysis of calcein transfer. The effect of dexamethasone treatment on the sensitivity of TK-expressing to FAS-dependent apoptosis in the presence or absence of ganciclovir was assessed with an MTT test. Western blot was used to evidence the effect of dexamethasone on the expression of Cx43, CD95, CIAP2 and BclXL. Results Dexamethasone significantly reduced the bystander effect in TK-expressing C6, LN18 and U87 cells. This inhibition results from a reduction of the gap junction mediated intercellular communication of these cells (GJIC, from an inhibition of their growth and thymidine incorporation and from a modulation of the apoptotic cascade. Conclusion The overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment in vitro. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment.

  19. Dexamethasone inhibits the HSV-tk/ ganciclovir bystander effect in malignant glioma cells

    Science.gov (United States)

    Robe, Pierre A; Nguyen-Khac, Minh; Jolois, Olivier; Rogister, Bernard; Merville, Marie-Paule; Bours, Vincent

    2005-01-01

    Background HSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed. Methods Stable clones of TK-expressing U87, C6 and LN18 cells were generated and their bystander effect on wild type cells was assessed. The effects of dexamethasone on cell proliferation and sensitivity to ganciclovir were assessed with a thymidine incorporation assay and a MTT test. Gap junction mediated intercellular communication was assessed with microinjections and FACS analysis of calcein transfer. The effect of dexamethasone treatment on the sensitivity of TK-expressing to FAS-dependent apoptosis in the presence or absence of ganciclovir was assessed with an MTT test. Western blot was used to evidence the effect of dexamethasone on the expression of Cx43, CD95, CIAP2 and BclXL. Results Dexamethasone significantly reduced the bystander effect in TK-expressing C6, LN18 and U87 cells. This inhibition results from a reduction of the gap junction mediated intercellular communication of these cells (GJIC), from an inhibition of their growth and thymidine incorporation and from a modulation of the apoptotic cascade. Conclusion The overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment in vitro. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment. PMID:15804364

  20. Molecular and Genetic Determinants of Glioma Cell Invasion

    Directory of Open Access Journals (Sweden)

    Kenta Masui

    2017-12-01

    Full Text Available A diffusely invasive nature is a major obstacle in treating a malignant brain tumor, “diffuse glioma”, which prevents neurooncologists from surgically removing the tumor cells even in combination with chemotherapy and radiation. Recently updated classification of diffuse gliomas based on distinct genetic and epigenetic features has culminated in a multilayered diagnostic approach to combine histologic phenotypes and molecular genotypes in an integrated diagnosis. However, it is still a work in progress to decipher how the genetic aberrations contribute to the aggressive nature of gliomas including their highly invasive capacity. Here we depict a set of recent discoveries involving molecular genetic determinants of the infiltrating nature of glioma cells, especially focusing on genetic mutations in receptor tyrosine kinase pathways and metabolic reprogramming downstream of common cancer mutations. The specific biology of glioma cell invasion provides an opportunity to explore the genotype-phenotype correlation in cancer and develop novel glioma-specific therapeutic strategies for this devastating disease.

  1. IDH1 and IDH2 Mutations in Gliomas

    Science.gov (United States)

    Cohen, Adam; Holmen, Sheri; Colman, Howard

    2014-01-01

    Mutations in isocitrate dehydrogenase (IDH) 1 and 2, originally discovered in 2009, occur in the vast majority of low grade gliomas and secondary high grade gliomas. These mutations, which occur early in gliomagenesis, change the function of the enzymes, causing them to produce 2-hydroxyglutarate, a possible oncometabolite, and to not produce NADPH. IDH mutations are oncogenic, although whether the mechanism is through alterations in hydroxylases, redox potential, cellular metabolism, or gene expression is not clear. The mutations also drive increased methylation in gliomas. Gliomas with mutated IDH1 and IDH2 have improved prognosis compared to gliomas with wild-type IDH. Mutated IDH can now be detected by immunohistochemistry and magnetic resonance spectroscopy. No drugs currently target mutated IDH, although this remains an area of active research. PMID:23532369

  2. Functional roles of enhancer of zeste homolog 2 in gliomas.

    Science.gov (United States)

    Yin, Yatao; Qiu, Shuwei; Peng, Ying

    2016-01-15

    Gliomas are the most common and lethal type of primary malignant brain tumor. Due to the infiltrative nature and high resistance to standard first line treatment with combinations of radiation and chemotherapy, the prognosis of patient is very poor. Recently, accumulated evidence suggests that enhancer of zeste homolog 2 (EZH2) serves as an oncogene and is involved in multiple glioma cell processes, including cell cycle, invasion, glioma stem cell maintenance, drug and radiotherapy resistance and so on. In this review, we will focus on updating current knowledge of EZH2 in gliomas. Moreover, the regulation of EZH2 by microRNAs and long non-coding RNAs and the therapeutic strategies targeting EZH2 for gliomas will also be discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Scientific Impact of MODIS C5 Calibration Degradation and C6+ Improvements

    Science.gov (United States)

    Lyapustin, A.; Wang, Y.; Xiong, X.; Meister, G.; Platnick, S.; Levy, R.; Franz, B.; Korkin, S.; Hilker, T.; Tucker, J.; hide

    2014-01-01

    The Collection 6 (C6) MODIS (Moderate Resolution Imaging Spectroradiometer) land and atmosphere data sets are scheduled for release in 2014. C6 contains significant revisions of the calibration approach to account for sensor aging. This analysis documents the presence of systematic temporal trends in the visible and near-infrared (500 m) bands of the Collection 5 (C5) MODIS Terra and, to lesser extent, in MODIS Aqua geophysical data sets. Sensor degradation is largest in the blue band (B3) of the MODIS sensor on Terra and decreases with wavelength. Calibration degradation causes negative global trends in multiple MODIS C5 products including the dark target algorithm's aerosol optical depth over land and Ångstrom exponent over the ocean, global liquid water and ice cloud optical thickness, as well as surface reflectance and vegetation indices, including the normalized difference vegetation index (NDVI) and enhanced vegetation index (EVI). As the C5 production will be maintained for another year in parallel with C6, one objective of this paper is to raise awareness of the calibration-related trends for the broad MODIS user community. The new C6 calibration approach removes major calibrations trends in the Level 1B (L1B) data. This paper also introduces an enhanced C6C calibration of the MODIS data set which includes an additional polarization correction (PC) to compensate for the increased polarization sensitivity of MODIS Terra since about 2007, as well as detrending and Terra- Aqua cross-calibration over quasi-stable desert calibration sites. The PC algorithm, developed by the MODIS ocean biology processing group (OBPG), removes residual scan angle, mirror side and seasonal biases from aerosol and surface reflectance (SR) records along with spectral distortions of SR. Using the multiangle implementation of atmospheric correction (MAIAC) algorithm over deserts, we have also developed a detrending and cross-calibration method which removes residual decadal trends on

  4. Biocytin and biotin uptake into NB2a neuroblastoma and C6 astrocytoma cells.

    Science.gov (United States)

    Baur, Barbara; Suormala, Terttu; Baumgartner, E Regula

    2002-01-25

    Uptake of biocytin and biotin was investigated in cultured transformed variants of neuronal (NB2a neuroblastoma) and glial (C6 astrocytoma) CNS cells. NB2a cells took up both compounds but biocytin was transported more efficiently than biotin in the nanomolar concentration range. In NB2a cells a single transport mechanism was found for biocytin with different kinetic parameters in the presence of high extracellular Na+ (Km 0.4 microM, Vmax 20 pmol/min/mg), K+ (Km 1.7 microM, Vmax 32 pmol/min/mg), or choline+ (Km 0.1 microM, Vmax 5 pmol/min/mg). Two transport systems (Km1 17 microM, Vmax1 53 pmol/min/mg; Km2 314 microM, Vmax2 360 pmol/min/mg) were identified for biotin with only system 1 being Na+-dependent. Biocytin uptake was competitively inhibited by excess biotin but not vice versa. Inhibition studies with structural analogs indicated different specificities for biotin and biocytin uptake. Biocytin uptake into C6 cells was hardly detectable whereas biotin was taken up by diffusion (kD 0.6 microl/min/mg) and a single saturable mechanism (Km 70 microM, Vmax 119 pmol/min/mg) at high extracellular Na+. High extracellular K+ enhanced biotin diffusion into C6 cells. Inhibition studies with structural analogs revealed a less specific biotin uptake mechanism in C6 than in NB2a cells. Biocytin normalized deficient biotin-dependent propionyl-CoA carboxylase activity within 4 h in biotin-deficient NB2a cells whereas in C6 cells reactivation was biocytin is only poorly transported into C6 cells. Specific biocytin uptake into NB2a cells is to our knowledge the first demonstration of a carrier-mediated transport mechanism for this compound. Neuronal biocytin uptake might contribute to the pathogenesis of biotinidase deficiency where biocytin is present in elevated levels.

  5. Combination of anti-VEGF therapy and temozolomide in two experimental human glioma models.

    Science.gov (United States)

    Grossman, Rachel; Brastianos, Harry; Blakeley, Jaishri O; Mangraviti, Antonella; Lal, Bachchu; Zadnik, Patti; Hwang, Lee; Wicks, Robert T; Goodwin, Rory C; Brem, Henry; Tyler, Betty

    2014-01-01

    Anti-angiogenic agents, such as bevacizumab (BEV), can induce normalization of the blood brain barrier, which may influence the penetration and activity of a co-administered cytotoxic drug. However, it is unknown whether this effect is associated with a benefit in overall survival. This study employed intracranial human glioma models to evaluate the effect of BEV alone and in combination with temozolomide (TMZ) and/or radiation therapy (XRT) on overall survival. One hundred eight male athymic rats were intracranially injected with either U251 or U87 human glioma. Ten or eleven days after tumor inoculation, animals bearing U251 and U87, respectively, were treated with: TMZ alone (50 mg/kg for 5 consecutive days, P.O.), BEV alone (15 mg/kg, I.V.), a combination of TMZ and BEV, or a combination of TMZ, BEV, and a single fraction of XRT (20 Gy). Controls received no treatment. The U87 experiment was repeated and the relationship between survival and the extent of anti-angiogenesis via anti-laminin antibodies for the detection of blood vessels was assessed. In both U87 glioma experiments, all of the treatment groups had a statistically significant increase in survival as compared to the control groups. Also, for both U87 experiments the combination groups of TMZ and BEV had significantly better survival when compared to either treatment administered alone, with 75% of animals demonstrating long-term survival (LTS) (defined as animals alive 120 days after tumor implantation) in one experiment and 25% LTS in the repeat experiment. In the U251 glioma experiment, all treated groups (except BEV alone) had significantly improved survival as compared to controls with minimal statistical variance among groups. The percent vessel area was lowest in the group of animals treated with BEV alone. The addition of BEV to TMZ and/or XRT had variable effect on prolonging survival in the two human glioma models tested with reduced tumor vascularity in groups treated with BEV. These

  6. PJ-34 inhibits PARP-1 expression and ERK phosphorylation in glioma-conditioned brain microvascular endothelial cells.

    Science.gov (United States)

    Motta, Carla; D'Angeli, Floriana; Scalia, Marina; Satriano, Cristina; Barbagallo, Davide; Naletova, Irina; Anfuso, Carmelina Daniela; Lupo, Gabriella; Spina-Purrello, Vittoria

    2015-08-15

    Inhibitors of PARP-1(Poly(ADP-ribose) polymerase-1) act by competing with NAD(+), the enzyme physiological substrate, which play a protective role in many pathological conditions characterized by PARP-1 overactivation. It has been shown that PARP-1 also promotes tumor growth and progression through its DNA repair activity. Since angiogenesis is an essential requirement for these activities, we sought to determine whether PARP inhibition might affect rat brain microvascular endothelial cells (GP8.3) migration, stimulated by C6-glioma conditioned medium (CM). Through wound-healing experiments and MTT analysis, we demonstrated that PARP-1 inhibitor PJ-34 [N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide] abolishes the migratory response of GP8.3 cells and reduces their viability. PARP-1 also acts in a DNA independent way within the Extracellular-Regulated-Kinase (ERK) signaling cascade, which regulates cell proliferation and differentiation. By western analysis and confocal laser scanning microscopy (LSM), we analyzed the effects of PJ-34 on PARP-1 expression, phospho-ERK and phospho-Elk-1 activation. The effect of MEK (mitogen-activated-protein-kinase-kinase) inhibitor PD98059 (2-(2-Amino-3-methoxyphenyl)-4 H-1-benzopyran-4-one) on PARP-1 expression in unstimulated and in CM-stimulated GP8.3 cells was analyzed by RT-PCR. PARP-1 expression and phospho-ERK activation were significantly reduced by treatment of GP8.3 cells with PJ-34 or PD98059. By LSM, we further demonstrated that PARP-1 and phospho-ERK are coexpressed and share the same subcellular localization in GP8.3 cells, in the cytoplasm as well as in nucleoplasm. Based on these data, we propose that PARP-1 and phospho-ERK interact in the cytosol and then translocate to the nucleus, where they trigger a proliferative response. We also propose that PARP-1 inhibition blocks CM-induced endothelial migration by interfering with ERK signal-transduction pathway. Copyright © 2015 Elsevier B.V. All rights

  7. 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.

  8. 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.

    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

  9. 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.

  10. Design, Synthesis and Biological Evaluation of C(6-Modified Celastrol Derivatives as Potential Antitumor Agents

    Directory of Open Access Journals (Sweden)

    Kaiyong Tang

    2014-07-01

    Full Text Available New six C6-celastrol derivatives were designed, synthesized, and evaluated for their in vitro cytotoxic activities against nine human cancer cell lines (BGC-823, H4, Bel7402, H522, Colo 205, HepG2 and MDA-MB-468. The results showed that most of the compounds displayed potent inhibition against BGC823, H4, and Bel7402, with IC50s of 1.84–0.39 μM. The best compound NST001A was tested in an in vivo antitumor assay on nude mice bearing Colo 205 xenografts, and showed significant inhibition of tumor growth at low concentrations. Therefore, celastrol C-6 derivatives are potential drug candidates for treating cancer.

  11. Electrocatalytic investigation of light-induced electron transfer between cytochrome c6 and photosystem I.

    Science.gov (United States)

    Proux-Delrouyre, Vanessa; Demaille, Christophe; Leibl, Winfried; Sétif, Pierre; Bottin, Hervé; Bourdillon, Christian

    2003-11-12

    A light-activated electron-transfer chain was assembled using solubilized cyanobacterial photosystem I as photoactive enzyme, cytochrome c(6) (also from cyanobacteria) as electron donor, and methyl viologen as electron acceptor. The photocatalytic activity of the ensemble was measured by direct and reversible electrochemistry of cytochrome c(6) at a surface-modified gold electrode. Analysis of the electrochemical response with an appropriate model for the reaction mechanism allowed the relation of the overall catalytic reaction rate to the individual steps of the catalytic cycle. Second-order rate constants were determined for the first time under steady-state conditions. The results validate this approach as an efficient method for the study of electron transfer between photoactive enzymes and their redox partners.

  12. Preparation of Poly (MA-alt--olefin-C 6, 8, 12, 18)/Silica ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Chemical Sciences; Volume 127; Issue 11. Preparation of Poly(MA-alt--olefin-C6,8,12,18)/Silica Nanohybrids via in situ generated nanofillers for use as a dual function organonanofiller. Deni̇z Demi̇rcan Günay Ki̇barer Zaki̇r M O Rzayev. Articles Volume 127 Issue 11 November 2015 pp ...

  13. Cervical pedicle screw fixation at C6 and C7 A cadaveric study

    Directory of Open Access Journals (Sweden)

    Ye Li

    2015-01-01

    Conclusion: The intersection of the horizontal line through the midpoint of the transverse process root and vertical line through the intersection of the posterolateral and posterior planes of the isthmus can be used as an entry point for C6 and C7 pedicle screw fixation. The screws should be inserted at 60 or 90° with the posterolateral isthmus in the horizontal plane and at 75° with the posterior isthmus in the sagittal plane. The LSC should not exceed 30 mm.

  14. Isolation of Rickettsia felis in the Mosquito Cell Line C6/36

    OpenAIRE

    Horta, Maurício C.; LABRUNA, Marcelo B; Durigon, Edison L.; Schumaker, Teresinha T. S.

    2006-01-01

    We report the isolation and establishment of Rickettsia felis in the C6/36 cell line. Rickettsial growth was intense, always with 90 to 100% of cells being infected after few weeks. The rickettsial isolate was confirmed by testing infected cells by PCR and sequencing fragments of three major Rickettsia genes (gltA, ompB, and the 17-kDa protein gene).

  15. Monitoring climatic changes and carbon cycle in canyons and caves: the C6 project.

    OpenAIRE

    Madonia, P.

    2008-01-01

    The acronym C6 means "Climatic Changes and Carbon Cycle in Canyons and Caves". It is a monitoring project, for the evaluation of climate change signals, based on measuring sites located inside canyons and caves; it merged in the year 2005, under the scientific supervision of the Palermo Branch of the Italian National Institute for Geophysics and Volcanology (I.N.G.V.), two different monitoring programs active since 1999. The choice of these environments is based on their morpholog...

  16. The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium.

    Science.gov (United States)

    Amirian, E Susan; Armstrong, Georgina N; Zhou, Renke; Lau, Ching C; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Il'yasova, Dora; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S; Jenkins, Robert B; Lachance, Daniel; Olson, Sara H; Bernstein, Jonine L; Merrell, Ryan T; Wrensch, Margaret R; Davis, Faith G; Lai, Rose; Shete, Sanjay; Amos, Christopher I; Scheurer, Michael E; Aldape, Kenneth; Alafuzoff, Irina; Brännström, Thomas; Broholm, Helle; Collins, Peter; Giannini, Caterina; Rosenblum, Marc; Tihan, Tarik; Melin, Beatrice S; Bondy, Melissa L

    2016-01-15

    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 collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

    Science.gov (United States)

    Nakae, Shunsuke; Sasaki, Hikaru; Hayashi, Saeko; Hattori, Natsuki; Kumon, Masanobu; Nishiyama, Yuya; Adachi, Kazuhide; Nagahisa, Shinya; Hayashi, Takuro; Inamasu, Joji; Abe, Masato; Hasegawa, Mitsuhiro; Hirose, Yuichi

    2015-01-01

    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.

  18. 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.

  19. Emerging microtubule targets in glioma therapy

    Czech Academy of Sciences Publication Activity Database

    Katsetos, C.D.; Reginato, M.J.; Baas, P.W.; D'Agostino, L.; Legido, A.; Tuszynski, J. A.; Dráberová, Eduarda; Dráber, Pavel

    2015-01-01

    Roč. 22, č. 1 (2015), s. 49-72 ISSN 1071-9091 R&D Projects: GA MŠk LH12050; GA MZd NT14467 Grant - others:GA AV ČR M200521203PIPP; NIH(US) R01 NS028785; Philadelphia Health Education Corporation (PHEC)–St. Christopher’s Hospital for Children Reunified Endowment (C.D.K.)(US) 323256 Institutional support: RVO:68378050 Keywords : glioma tumorigenesis * glioblastoma * tubulin * microtubules Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.303, year: 2015

  20. Mean Diffusional Kurtosis in Patients with Glioma

    DEFF Research Database (Denmark)

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

    2015-01-01

    with regard to glioma grading, compare it to conventional DKI and compare the diagnostic accuracy of mean kurtosis (MK’) to that of the widely used mean diffusivity (MD). Material and Methods: MK’ and MD were measured in the contrast-enhancing tumor core, the peri-focal hyperintensity on T2FLAIR...... significance and accuracy (AUCMK’=886; AUCMD=0.876; pMK’=0.003; pMD=0.004). The mean MK’ in all tissue types was comparable to those obtained by conventional DKI. Conclusion: The DKI approach used here is considerably faster than conventional DKI methods, while yielding comparable results. It can...

  1. Prognostic value of Musashi-1 in gliomas

    DEFF Research Database (Denmark)

    Dahlrot, Rikke H; Hansen, Steinbjørn; Herrstedt, Jørn

    2013-01-01

    and hence poor prognosis. Samples of 241 gliomas diagnosed between 2005 and 2009 were stained with an anti-Musashi-1 antibody using a fluorescent staining protocol followed by automated image acquisition and processing. Musashi-1 area fraction and intensity in cytoplasm and in nuclei were quantified...... by systematic random sampling in 2 % of the vital tumor area. In WHO grade III tumors high levels of Musashi-1 were associated with poor survival in multivariate analysis (HR 3.39, p = 0.02). We identified a sub-population of glioblastoma (GBM) patients with high levels of Musashi-1 and a superior prognosis (HR...

  2. A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas

    Science.gov (United States)

    2017-11-07

    Adult Anaplastic Astrocytoma; Recurrent Grade III Glioma; Recurrent Grade IV Glioma; Adult Anaplastic Oligodendroglioma; Adult Brain Tumor; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Recurrent Adult Brain Tumor; Adult Anaplastic Oligoastrocytoma; Recurrent High Grade Glioma

  3. 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

  4. 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.

  5. Correlation of immune phenotype with IDH mutation in diffuse glioma.

    Science.gov (United States)

    Berghoff, Anna Sophie; Kiesel, Barbara; Widhalm, Georg; Wilhelm, Dorothee; Rajky, Orsolya; Kurscheid, Sebastian; Kresl, Philip; Wöhrer, Adelheid; Marosi, Christine; Hegi, Monika E; Preusser, Matthias

    2017-10-19

    Tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) are targets of immune checkpoint inhibitors. Forty-three World Health Organization (WHO) grade II/III gliomas (39 IDH-mutant [mut], 4 IDH-wildtype [wt]) and 14 IDH-mut glioblastomas (GBM) were analyzed for TIL (CD3+; PD1+) infiltration and PD-L1 expression. Results were compared with the data of a previously published series of 117 IDH-wt glioblastomas. PD-L1 gene expression levels were evaluated in 677 diffuse gliomas grades II-IV from The Cancer Genome Atlas (TCGA) database. TIL and PD-L1 expression were observed in approximately half of WHO grade II/III gliomas. IDH-wt status was associated with significantly higher TIL infiltration and PD-L1 expression among all (grades II-IV) cases (n = 174, P IDH-wt compared with IDH-mut samples (LGG: N = 516; P = 1.933e-11, GBM: N = 161; P IDH-mut gliomas had higher PD-L1 gene promoter methylation levels than IDH-wt gliomas (P IDH mutation status. IDH-wt gliomas display a more prominent TIL infiltration and higher PD-L1 expression than IDH-mut cases. Mechanistically this may be at least in part due to differential PD-L1 gene promoter methylation levels. Our findings may be relevant for immune modulatory treatment strategies in glioma patients.

  6. 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.

  7. Constitutive Activation of Raf-1 Induces Glioma Formation in Mice

    Directory of Open Access Journals (Sweden)

    Yelena Lyustikman

    2008-05-01

    Full Text Available In human glioblastoma multiforme (GBM, RAS activity is upregulated in the majority of the tumors. Furthermore, the levels of phospho-mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK, a downstream effector of RAS, are also increased. In mice, activated KRas cooperates with the loss of INK4a-ARF locus or with activated Akt to induce gliomas, confirming an important role for this pathway in glioma biology. However, to correctly target therapies against the RAS signaling pathway, it is necessary to identify the effectors that contribute to RAS-mediated gliomagenesis. In this study, we investigated the contribution of RAF signaling in glioma oncogenesis. We find that the levels of RAF-1 and BRAF proteins and RAF kinase activity are increased in human GBM samples. We confirm the importance of this finding by demonstrating a causal role for a constitutively active Raf-1 mutant in glioma formation in mice. Specifically, we find that activated Raf-1 cooperates with Arf loss or Akt activation to generate gliomas similar to activated KRas under the same conditions. Our study suggests that the oncogenic effect of KRas in glioma formation may be transduced at least in part through Raf signaling and that therapeutic targeting of this pathway may be beneficial in glioma treatment.

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

    Science.gov (United States)

    Nevo, Ido; Woolard, Kevin; Cam, Maggie; Li, Aiguo; Webster, Joshua D; Kotliarov, Yuri; Kim, Hong Sug; Ahn, Susie; Walling, Jennifer; Kotliarova, Svetlana; Belova, Galina; Song, Hua; Bailey, Rolanda; Zhang, Wei; Fine, Howard A

    2014-01-01

    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.

  9. Association between adult height, genetic susceptibility and risk of glioma

    Science.gov (United States)

    Kitahara, Cari M; Wang, Sophia S; Melin, Beatrice S; Wang, Zhaoming; Braganza, Melissa; Inskip, Peter D; Albanes, Demetrius; Andersson, Ulrika; Beane Freeman, Laura E; Buring, Julie E; Carreón, Tania; Feychting, Maria; Gapstur, Susan M; Gaziano, J Michael; Giles, Graham G; Hallmans, Goran; Hankinson, Susan E; Henriksson, Roger; Hsing, Ann W; Johansen, Christoffer; Linet, Martha S; McKean-Cowdin, Roberta; Michaud, Dominique S; Peters, Ulrike; Purdue, Mark P; Rothman, Nathaniel; Ruder, Avima M; Sesso, Howard D; Severi, Gianluca; Shu, Xiao-Ou; Stevens, Victoria L; Visvanathan, Kala; Waters, Martha A; White, Emily; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Hoover, Robert; Fraumeni, Joseph F; Chatterjee, Nilanjan; Yeager, Meredith; Chanock, Stephen J; Hartge, Patricia; Rajaraman, Preetha

    2012-01-01

    Background Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease. Methods We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case–control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. Results Among men, we found a positive association between height and glioma risk (≥190 vs 170–174 cm, pooled OR = 1.70, 95% CI: 1.11–2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17–3.38; P-trend = 0.02). Among women, these associations were less clear (≥175 vs 160–164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70–1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77–2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk. Conclusion An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease. PMID:22933650

  10. 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.

  11. 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.

  12. The proteomic landscape of glioma stem-like cells

    Directory of Open Access Journals (Sweden)

    Cheryl F. Lichti

    2015-09-01

    Full Text Available Glioma stem-like cells (GSCs are hypothesized to provide a repository of cells in tumors that can self-replicate and are radio- and chemo-resistant. GSC lines, representing several glioma subtypes, have been isolated and characterized at the transcript level. We sought to characterize 35 GSC lines at the protein level using label-free quantitative proteomics. Resulting relative fold changes were used to drive unsupervised hierarchical clustering for the purpose of classifying the cell lines based on proteomic profiles. Bioinformatics analysis identified synoviolin, serine/arginine-rich splicing factor 2, symplekin, and IL-5 as molecules of interest in progression and/or treatment of glioma.

  13. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

    Science.gov (United States)

    Brat, Daniel J; Verhaak, Roel G W; Aldape, Kenneth D; Yung, W K Alfred; Salama, Sofie R; Cooper, Lee A D; Rheinbay, Esther; Miller, C Ryan; Vitucci, Mark; Morozova, Olena; Robertson, A Gordon; Noushmehr, Houtan; Laird, Peter W; Cherniack, Andrew D; Akbani, Rehan; Huse, Jason T; Ciriello, Giovanni; Poisson, Laila M; Barnholtz-Sloan, Jill S; Berger, Mitchel S; Brennan, Cameron; Colen, Rivka R; Colman, Howard; Flanders, Adam E; Giannini, Caterina; Grifford, Mia; Iavarone, Antonio; Jain, Rajan; Joseph, Isaac; Kim, Jaegil; Kasaian, Katayoon; Mikkelsen, Tom; Murray, Bradley A; O'Neill, Brian Patrick; Pachter, Lior; Parsons, Donald W; Sougnez, Carrie; Sulman, Erik P; Vandenberg, Scott R; Van Meir, Erwin G; von Deimling, Andreas; Zhang, Hailei; Crain, Daniel; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Troy; Sherman, Mark; Yena, Peggy; Black, Aaron; Bowen, Jay; Dicostanzo, Katie; Gastier-Foster, Julie; Leraas, Kristen M; Lichtenberg, Tara M; Pierson, Christopher R; Ramirez, Nilsa C; Taylor, Cynthia; Weaver, Stephanie; Wise, Lisa; Zmuda, Erik; Davidsen, Tanja; Demchok, John A; Eley, Greg; Ferguson, Martin L; Hutter, Carolyn M; Mills Shaw, Kenna R; Ozenberger, Bradley A; Sheth, Margi; Sofia, Heidi J; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean Claude; Ayala, Brenda; Baboud, Julien; Chudamani, Sudha; Jensen, Mark A; Liu, Jia; Pihl, Todd; Raman, Rohini; Wan, Yunhu; Wu, Ye; Ally, Adrian; Auman, J Todd; Balasundaram, Miruna; Balu, Saianand; Baylin, Stephen B; Beroukhim, Rameen; Bootwalla, Moiz S; Bowlby, Reanne; Bristow, Christopher A; Brooks, Denise; Butterfield, Yaron; Carlsen, Rebecca; Carter, Scott; Chin, Lynda; Chu, Andy; Chuah, Eric; Cibulskis, Kristian; Clarke, Amanda; Coetzee, Simon G; Dhalla, Noreen; Fennell, Tim; Fisher, Sheila; Gabriel, Stacey; Getz, Gad; Gibbs, Richard; Guin, Ranabir; Hadjipanayis, Angela; Hayes, D Neil; Hinoue, Toshinori; Hoadley, Katherine; Holt, Robert A; Hoyle, Alan P; Jefferys, Stuart R; Jones, Steven; Jones, Corbin D; Kucherlapati, Raju; Lai, Phillip H; Lander, Eric; Lee, Semin; Lichtenstein, Lee; Ma, Yussanne; Maglinte, Dennis T; Mahadeshwar, Harshad S; Marra, Marco A; Mayo, Michael; Meng, Shaowu; Meyerson, Matthew L; Mieczkowski, Piotr A; Moore, Richard A; Mose, Lisle E; Mungall, Andrew J; Pantazi, Angeliki; Parfenov, Michael; Park, Peter J; Parker, Joel S; Perou, Charles M; Protopopov, Alexei; Ren, Xiaojia; Roach, Jeffrey; Sabedot, Thaís S; Schein, Jacqueline; Schumacher, Steven E; Seidman, Jonathan G; Seth, Sahil; Shen, Hui; Simons, Janae V; Sipahimalani, Payal; Soloway, Matthew G; Song, Xingzhi; Sun, Huandong; Tabak, Barbara; Tam, Angela; Tan, Donghui; Tang, Jiabin; Thiessen, Nina; Triche, Timothy; Van Den Berg, David J; Veluvolu, Umadevi; Waring, Scot; Weisenberger, Daniel J; Wilkerson, Matthew D; Wong, Tina; Wu, Junyuan; Xi, Liu; Xu, Andrew W; Yang, Lixing; Zack, Travis I; Zhang, Jianhua; Aksoy, B Arman; Arachchi, Harindra; Benz, Chris; Bernard, Brady; Carlin, Daniel; Cho, Juok; DiCara, Daniel; Frazer, Scott; Fuller, Gregory N; Gao, JianJiong; Gehlenborg, Nils; Haussler, David; Heiman, David I; Iype, Lisa; Jacobsen, Anders; Ju, Zhenlin; Katzman, Sol; Kim, Hoon; Knijnenburg, Theo; Kreisberg, Richard Bailey; Lawrence, Michael S; Lee, William; Leinonen, Kalle; Lin, Pei; Ling, Shiyun; Liu, Wenbin; Liu, Yingchun; Liu, Yuexin; Lu, Yiling; Mills, Gordon; Ng, Sam; Noble, Michael S; Paull, Evan; Rao, Arvind; Reynolds, Sheila; Saksena, Gordon; Sanborn, Zack; Sander, Chris; Schultz, Nikolaus; Senbabaoglu, Yasin; Shen, Ronglai; Shmulevich, Ilya; Sinha, Rileen; Stuart, Josh; Sumer, S Onur; Sun, Yichao; Tasman, Natalie; Taylor, Barry S; Voet, Doug; Weinhold, Nils; Weinstein, John N; Yang, Da; Yoshihara, Kosuke; Zheng, Siyuan; Zhang, Wei; Zou, Lihua; Abel, Ty; Sadeghi, Sara; Cohen, Mark L; Eschbacher, Jenny; Hattab, Eyas M; Raghunathan, Aditya; Schniederjan, Matthew J; Aziz, Dina; Barnett, Gene; Barrett, Wendi; Bigner, Darell D; Boice, Lori; Brewer, Cathy; Calatozzolo, Chiara; Campos, Benito; Carlotti, Carlos Gilberto; Chan, Timothy A; Cuppini, Lucia; Curley, Erin; Cuzzubbo, Stefania; Devine, Karen; DiMeco, Francesco; Duell, Rebecca; Elder, J Bradley; Fehrenbach, Ashley; Finocchiaro, Gaetano; Friedman, William; Fulop, Jordonna; Gardner, Johanna; Hermes, Beth; Herold-Mende, Christel; Jungk, Christine; Kendler, Ady; Lehman, Norman L; Lipp, Eric; Liu, Ouida; Mandt, Randy; McGraw, Mary; Mclendon, Roger; McPherson, Christopher; Neder, Luciano; Nguyen, Phuong; Noss, Ardene; Nunziata, Raffaele; Ostrom, Quinn T; Palmer, Cheryl; Perin, Alessandro; Pollo, Bianca; Potapov, Alexander; Potapova, Olga; Rathmell, W Kimryn; Rotin, Daniil; Scarpace, Lisa; Schilero, Cathy; Senecal, Kelly; Shimmel, Kristen; Shurkhay, Vsevolod; Sifri, Suzanne; Singh, Rosy; Sloan, Andrew E; Smolenski, Kathy; Staugaitis, Susan M; Steele, Ruth; Thorne, Leigh; Tirapelli, Daniela P C; Unterberg, Andreas; Vallurupalli, Mahitha; Wang, Yun; Warnick, Ronald; Williams, Felicia; Wolinsky, Yingli; Bell, Sue; Rosenberg, Mara; Stewart, Chip; Huang, Franklin; Grimsby, Jonna L; Radenbaugh, Amie J; Zhang, Jianan

    2015-06-25

    Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most

  14. Analysis on Biomechanical Characteristics of Post-operational Vertebral C5-C6 Segments

    Directory of Open Access Journals (Sweden)

    Heqiang Tian

    2016-03-01

    Full Text Available Both anterior cervical decompression and fusion (ACDF and artificial cervical disc replacement (ACDR have obvious advantages in the treatment of cervical spondylosis. To analyze the operation results, it is absolutely necessary to study the biomechanics of the movement range of post-operational vertebral C5-C6 segments, especially the biomechanical characteristics in cervical tissues in actual movements. In this study, using the human vertebral 3D graph gained by imaging diagnosis (CT, a vertebral solid model is established by the 3D reconstruction algorithm and reverse engineering technology. After that, with cervical soft tissue structure added to the solid model and set with a joint contact mechanism, a finite element model with a complete, accurate cervical C5-C6 kinematic unit is constructed, based on relevant physiological anatomical knowledge. This model includes vertebral segments, an intervertebral disc, ligament and zygopophysis in the cervical C5-C6 kinematic unit. In the created vertebral finite element model, the model is amended, referring to ACDF and ACDR, and the load and constraint are applied to a normal group, a fusion group and a displacement group, so as to analyze the biomechanical characteristics of the cervical vertebra after ACDF and ACDR. By comparing the finite element simulation results of different surgeries, this paper is intended to evaluate the functions and biomechanical behaviors of the post-operational vertebra, and explore the influence of the operation on the biomechanical stability of the cervical vertebra. This will provide theoretical guidance for implementation and optimization of ACDF and ACDR.

  15. Customer exposure to MTBE, TAME, C6 alkyl methyl ethers, and benzene during gasoline refueling.

    Science.gov (United States)

    Vainiotalo, S; Peltonen, Y; Ruonakangas, A; Pfäffli, P

    1999-01-01

    We studied customer exposure during refueling by collecting air samples from customers' breathing zone. The measurements were carried out during 4 days in summer 1996 at two Finnish self-service gasoline stations with "stage I" vapor recovery systems. The 95-RON (research octane number) gasoline contained approximately 2.7% methyl tert-butyl ether (MTBE), approximately 8.5% tert-amyl methyl ether (TAME), approximately 3.2% C6 alkyl methyl ethers (C6 AMEs), and 0.75% benzene. The individual exposure concentrations showed a wide log-normal distribution, with low exposures being the most frequent. In over 90% of the samples, the concentration of MTBE was higher (range MTBE values were well below the short-term (15 min) threshold limits set for occupational exposure (250-360 mg/m3). At station A, the geometric mean concentrations in individual samples were 3.9 mg/m3 MTBE and 2. 2 mg/m3 TAME. The corresponding values at station B were 2.4 and 1.7 mg/m3, respectively. The average refueling (sampling) time was 63 sec at station A and 74 sec at station B. No statistically significant difference was observed in customer exposures between the two service stations. The overall geometric means (n = 167) for an adjusted 1-min refueling time were 3.3 mg/m3 MTBE and 1.9 mg/m3 TAME. Each day an integrated breathing zone sample was also collected, corresponding to an arithmetic mean of 20-21 refuelings. The overall arithmetic mean concentrations in the integrated samples (n = 8) were 0.90 mg/m3 for benzene and 0.56 mg/m3 for C6 AMEs calculated as a group. Mean MTBE concentrations in ambient air (a stationary point in the middle of the pump island) were 0.16 mg/m3 for station A and 0.07 mg/m3 for station B. The mean ambient concentrations of TAME, C6 AMEs, and benzene were 0.031 mg/m3, approximately 0.005 mg/m3, and approximately 0.01 mg/m3, respectively, at both stations. The mean wind speed was 1.4 m/sec and mean air temperature was 21 degreesC. Of the gasoline refueled during the

  16. Il programma di monitoraggio C6: Climatic Changes and Carbon Cycle in Canyons and Caves

    OpenAIRE

    Madonia, P.

    2006-01-01

    L'acronimo C6 sta per "Climatic Changes and Carbon Cycle in Canyons and Caves". E' un progetto di monitoraggio dei parametri climatici e dell'anidride carbonica, nato come tale nel 2005, ma che ha raggruppato al proprio interno attività di monitoraggio ambientale promosse da gestori di aree protette ed associazioni sportivo-ambientali sin dal 1999. Allo stato attuale sono attivi 6 siti di misura, disposti lungo un transetto Sud-Nord nell'areale mediterraneo, dalla Giordania sino all’Appennino...

  17. Hydrostatic pressure testing of graphite/epoxy cylinder C6-1

    Energy Technology Data Exchange (ETDEWEB)

    Blake, H.W.; Starbuck, J.M.

    1992-07-01

    This report details the design, fabrication, and testing of IM6 graphite cylinder C6-1, which achieved a record pressure in hydrotest without failure. Included are the details of the cylinder construction, the design calculations for stress and buckling, and the cylinder failure predictions. Also provided are the design details of the metal end closures including the design calculations for the linear tapered end plugs. Finally, the test data and observations from the hydrotest are summarized. This work is performed under the Oak Ridge National Laboratory, Laboratory Directed Research and Development Program. The project is funded by the Director as a three-year project.

  18. Semiautomatic Segmentation of Glioma on Mobile Devices

    Directory of Open Access Journals (Sweden)

    Ya-Ping Wu

    2017-01-01

    Full Text Available Brain tumor segmentation is the first and the most critical step in clinical applications of radiomics. However, segmenting brain images by radiologists is labor intense and prone to inter- and intraobserver variability. Stable and reproducible brain image segmentation algorithms are thus important for successful tumor detection in radiomics. In this paper, we propose a supervised brain image segmentation method, especially for magnetic resonance (MR brain images with glioma. This paper uses hard edge multiplicative intrinsic component optimization to preprocess glioma medical image on the server side, and then, the doctors could supervise the segmentation process on mobile devices in their convenient time. Since the preprocessed images have the same brightness for the same tissue voxels, they have small data size (typically 1/10 of the original image size and simple structure of 4 types of intensity value. This observation thus allows follow-up steps to be processed on mobile devices with low bandwidth and limited computing performance. Experiments conducted on 1935 brain slices from 129 patients show that more than 30% of the sample can reach 90% similarity; over 60% of the samples can reach 85% similarity, and more than 80% of the sample could reach 75% similarity. The comparisons with other segmentation methods also demonstrate both efficiency and stability of the proposed approach.

  19. A clinically isolated syndrome: butterfly glioma mimic

    Directory of Open Access Journals (Sweden)

    Ramshekhar Menon

    2015-01-01

    Full Text Available The report explores a unique and treatable "butterfly"- glioma mimic and the neuroimaging characteristics that help to diagnose this entity. A 35-year-old patient presented with subacute-onset, progressive frontal lobe dysfunction followed by features of raised intracranial pressure. Neuroimaging features were consistent with a "butterfly" lesion that favored the possibility of a gliomatosis cerebri with significant edema and marked corpus callosum and fornix thickening. Contrast-enhanced and perfusion images revealed a confluent tumefactive lesion with a characteristic "broken-ring" pattern of enhancement, mass-effect and low perfusion; features favoring an alternative inflammatory pathology. This was peculiar as calloso-forniceal involvement of this nature has not been previously reported in inflammatory demyelinating mass lesions. This was confirmed as a tumefactive demyelination on histopathology. Following treatment, on clinical and imaging follow-up, significant resolution was evident suggesting a monophasic illness. This case highlights the stringent clinico-radiological-pathological approach required in the evaluation and management of butterfly lesions despite the striking imaging appearances. Tumefactive demyelination in this patient represents a clinically isolated syndromic presentation of an inflammatory pathology that can resemble gliomatosis cerebri. These "butterfly"-glioma mimics are scarcely reported in the literature, are eminently treatable with variable prognosis and prone for relapse.

  20. 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.

  1. Gene Therapy and Targeted Toxins for Glioma

    Science.gov (United States)

    Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

    2011-01-01

    The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

  2. Photodynamic therapy of recurrent cerebral glioma

    Science.gov (United States)

    Zhu, Shu-Gan; Wu, Si-En; Chen, Zong-Qian; Sun, Wei

    1993-03-01

    Photodynamic therapy (PDT) was performed on 11 cases of recurrent cerebral glioma, including 3 cases of recurrent glioblastoma, 7 of recurrent anaplastic astrocytoma, and 1 recurrent ependymoma. Hematoporphyrin derivative (HPD) was administered intravenously at a dose of 4 - 7 mg/kg 5 - 24 hours before the operation. All patients underwent a craniotomy with a nearly radical excision of the tumor following which the tumor bed was irradiated with 630 nm laser light emitting either an argon pumped dye laser or frequency double YAG pumped dye laser for 30 to 80 minutes with a total dose of 50 J/cm2 (n equals 1), 100 J/cm2 (n equals 2), 200 J/cm2 (n equals 7), and 300 J/cm2 (n equals 1). The temperature was kept below 37 degree(s)C by irrigation. Two patients underwent postoperative radiotherapy. There was no evidence of increased cerebral edema, and no other toxicity by the therapy. All patients were discharged from the hospital within 15 days after surgery. We conclude that PDT using 4 - 7 mg/kg of HPD and 630 nm light with a dose of up to 300 J/cm2 can be used as an adjuvant therapy with no additional complications. Adjuvant PDT in the treatment of recurrent glioma is better than simple surgery.

  3. Deregulated expression of cry1 and cry2 in human gliomas.

    Science.gov (United States)

    Luo, Yong; Wang, Fan; Chen, Lv-An; Chen, Xiao-Wei; Chen, Zhi-Jun; Liu, Ping-Fei; li, Fen-Fen; Li, Cai-Yan; Liang, Wu

    2012-01-01

    Growing evidence shows that deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of gene chnages controlling circadian rhythm in glioma cells have not been explored. Using real time polymerase chain reaction and immunohistochemistry techniques, we examined the expression of two important clock genes, cry1 and cry2, in 69 gliomas. In this study, out of 69 gliomas, 38 were cry1-positive, and 51 were cry2-positive. The expression levels of cry1 and cry2 in glioma cells were significantly different from the surrounding non-glioma cells (P0.05) but there was a difference in the intensity of immunoactivity for cry 2 between high-grade gliomas and low-grade gliomas (r=-0.384, P=0.021). In this study, we found that the expression of cry1 and cry2 in glioma cells was much lower than in the surrounding non-glioma cells. Therefore, we suggest that disturbances in cry1 and cry2 expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells. Differential expression of circadian clock genes in glioma and non-glioma cells may provide a molecular basis for the chemotherapy of gliomas.

  4. Creatine CEST MRI for Differentiating Gliomas with Different Degrees of Aggressiveness.

    Science.gov (United States)

    Cai, Kejia; Tain, Rong-Wen; Zhou, Xiaohong Joe; Damen, Frederick C; Scotti, Alessandro M; Hariharan, Hari; Poptani, Harish; Reddy, Ravinder

    2017-04-01

    Creatine (Cr) is a major metabolite in the bioenergetic system. Measurement of Cr using conventional MR spectroscopy (MRS) suffers from low spatial resolution and relatively long acquisition times. Creatine chemical exchange saturation transfer (CrCEST) magnetic resonance imaging (MRI) is an emerging molecular imaging method for tissue Cr measurements. Our previous study showed that the CrCEST contrast, obtained through multicomponent Z-spectral fitting, was lower in tumors compared to normal brain, which further reduced with tumor progression. The current study was aimed to investigate if CrCEST MRI can also be useful for differentiating gliomas with different degrees of aggressiveness. Intracranial 9L gliosarcoma and F98 glioma bearing rats with matched tumor size were scanned with a 9.4 T MRI scanner at two time points. CEST Z-spectra were collected using a customized sequence with a frequency-selective rectangular saturation pulse (B1 = 50 Hz, duration = 3 s) followed by a single-shot readout. Z spectral data were fitted pixel-wise with five Lorentzian functions, and maps of CrCEST peak amplitude, linewidth, and integral were produced. For comparison, single-voxel proton MR spectroscopy ((1)H-MRS) was performed to quantify and compare the total Cr concentration in the tumor. CrCEST contrasts decreased with tumor progression from weeks 3 to 4 in both 9L and F98 phenotypes. More importantly, F98 tumors had significantly lower CrCEST integral compared to 9L tumors. On the other hand, integrals of other Z-spectral components were unable to differentiate both tumor progression and phenotype with limited sample size. Given that F98 is a more aggressive tumor than 9L, this study suggests that CrCEST MRI may help differentiate gliomas with different aggressiveness.

  5. Cerebral Connectivity and High-grade Gliomas: Evolving Concepts of Eloquent Brain in Surgery for Glioma

    Directory of Open Access Journals (Sweden)

    Sanjay Konakondla

    2017-02-01

    Full Text Available Technological advances in imaging the human brain help us map and understand the intricacies of cerebral connectivity. Current techniques and specific imaging sequences, however, do come with limitations. Image resolution, variability of techniques and interpretation of images across institutions are just a few concerns. In the setting of high-grade gliomas, understanding how these pathways are affected during tumor growth, surgical resection, and in the brain plasticity presents an even greater challenge. Clinical symptoms, tumor growth, and intraoperative electrical stimulation are important peri-operative considerations to assist in determining neuronal re-wiring and establish a basis of anatomic and functional correlation. The application of functional mapping coupled with the understanding of the natural history of gliomas and implications of neural plasticity, is critical in achieving the goals of maximal tumor resection while minimizing post operative deficits and improving quality of life.

  6. Ca intercalated bilayer graphene as a thinnest limit of superconducting C6Ca.

    Science.gov (United States)

    Kanetani, Kohei; Sugawara, Katsuaki; Sato, Takafumi; Shimizu, Ryota; Iwaya, Katsuya; Hitosugi, Taro; Takahashi, Takashi

    2012-11-27

    Success in isolating a 2D graphene sheet from bulky graphite has triggered intensive studies of its physical properties as well as its application in devices. Graphite intercalation compounds (GICs) have provided a platform of exotic quantum phenomena such as superconductivity, but it is unclear whether such intercalation is feasible in the thinnest 2D limit (i.e., bilayer graphene). Here we report a unique experimental realization of 2D GIC, by fabricating calcium-intercalated bilayer graphene C(6)CaC(6) on silicon carbide. We have investigated the structure and electronic states by scanning tunneling microscopy and angle-resolved photoemission spectroscopy. We observed a free-electron-like interlayer band at the Brillouin-zone center, which is thought to be responsible for the superconductivity in 3D GICs, in addition to a large π* Fermi surface at the zone boundary. The present success in fabricating Ca-intercalated bilayer graphene would open a promising route to search for other 2D superconductors as well as to explore its application in devices.

  7. Covalent functionalization of octagraphene with magnetic octahedral B6- and non-planar C6- clusters

    Science.gov (United States)

    Chigo-Anota, E.; Cárdenas-Jirón, G.; Salazar Villanueva, M.; Bautista Hernández, A.; Castro, M.

    2017-10-01

    The interaction between the magnetic boron octahedral (B6-) and non-planar (C6-) carbon clusters with semimetal nano-sheet of octa-graphene (C64H24) in the gas phase is studied by means of DFT calculations. These results reveal that non-planar-1 (anion) carbon cluster exhibits structural stability, low chemical reactivity, magnetic (1.0 magneton bohr) and semiconductor behavior. On the other hand, there is chemisorption phenomena when the stable B6- and C6- clusters are absorbed on octa-graphene nanosheets. Such absorption generates high polarity and the low-reactivity remains as on the individual pristine cases. Electronic charge transference occurs from the clusters toward the nanosheets, producing a reduction of the work function for the complexes and also induces a magnetic behavior on the functionalized sheets. The quantum descriptors obtained for these systems reveal that they are feasible candidates for the design of molecular circuits, magnetic devices, and nano-vehicles for drug delivery.

  8. Immunohistochemical detection of CD10 with monoclonal antibody 56C6 on paraffin sections.

    Science.gov (United States)

    Kaufmann, O; Flath, B; Späth-Schwalbe, E; Possinger, K; Dietel, M

    1999-01-01

    We tested a total of 174 paraffin-embedded hematolymphoid neoplasias to determine whether CD10 can be specifically and sensitivity detected on paraffin sections using monoclonal antibody 56C6 after epitope retrieval. For 32 cases, results of CD10 detection by immunohistochemistry were compared with flow cytometric data. In only 1 case of follicle center lymphoma, divergent staining results were found with the detection of CD10 by flow cytometry but not by immunohistochemistry. Altogether, 22 of 28 follicle center lymphomas, 2 of 6 hairy cell leukemias, 14 of 34 diffuse large B-cell lymphomas, 3 of 3 Burkitt lymphomas, 4 of 5 precursor B-lineage acute lymphoblastic leukemias, and 2 of 4 T-lymphoblastic lymphomas were CD10+. Decalcification of bone marrow biopsy specimens did not diminish the staining intensity. All other cases, including 10 acute myeloid leukemias and a range of low-grade B-cell lymphomas, were CD10-. CD10 is reliably detectable with antibody 56C6 on paraffin sections using epitope retrieval. The antibody is especially useful for the subclassification of acute leukemias and low-grade B-cell lymphomas.

  9. Rationalizing thermal reactions of C6Lix negative electrode with nonaqueous electrolyte

    Science.gov (United States)

    Mukai, Kazuhiko; Inoue, Takao; Hasegawa, Madoka

    2017-10-01

    Exothermic reactions at elevated temperatures (T) between Li-intercalated C6Lix negative electrodes and nonaqueous electrolytes play a crucial role in the thermal runaway of lithium-ion batteries. However, despite intensive studies so far, the origin of the reactions has not been fully understood, particularly from the viewpoint of a material balance. In this paper, we performed differential scanning calorimetry (DSC) analyses up to 450 °C for samples with x = 0.22, 0.45, 0.67, and 0.89, which were prepared from a graphited mesophase-pitch-based carbon fiber. The DSC profiles for C6Lix with 1 M LiPF6 dissolved in ethylene carbonate (EC)/diethylene carbonate (DEC) solution (EC/DEC = 3/7 by volume) were found to be divided into four different T regions regardless of x. That is, Region (I) below 150 °C, Region (II) for 150 °C < T ≤ 240 °C, Region (III) for 240 °C < T ≤ 270 °C, and Region (IV) above 270 °C. By combining with results for X-ray diffraction measurements and scanning electron microscopic analyses, we have rationalized the change in enthalpy (ΔH) of each Region taking into account the given material balance. Strategies for inhibiting the thermal runaway of LIBs are also discussed.

  10. Primary and submovement control of aiming in C6 tetraplegics following posterior deltoid transfer.

    Science.gov (United States)

    Robinson, Mark A; Elliott, Digby; Hayes, Spencer J; Barton, Gabor J; Bennett, Simon J

    2014-07-23

    Upper limb motor control in fast, goal-directed aiming is altered in tetraplegics following posterior-deltoid musculotendinous transfer. Specifically, movements have similar end-point accuracy but longer duration and lower peak velocity than those of age-matched, neurotypical controls. Here, we examine in detail the interplay between primary movement and submovement phases in five C6 tetraplegic and five control participants. Aiming movements were performed in two directions (20 cm away or toward), with or without vision. Trials that contained a submovement phase (i.e., discontinuity in velocity, acceleration or jerk) were identified. Discrete kinematic variables were then extracted on the primary and submovements phases. The presence of submovements did not differ between the tetraplegic (68%) and control (57%) groups, and almost all submovements resulted from acceleration and jerk discontinuities. Tetraplegics tended to make a smaller amplitude primary movement, which had lower peak velocity and greater spatial variability at peak velocity. This was followed by a larger amplitude and longer duration secondary submovement. Peak velocity of primary movement was not related to submovement incidence. Together, the primary and submovement phases of both groups were equally effective in reducing end-point error. C6 tetraplegic participants exhibit some subtle differences in measures of motor behaviour compared to control participants, but importantly feedforward and feedback processes work effectively in combination to achieve accurate goal-directed aiming.

  11. The Crystal Structure of a Phenyliminomethyldicyclopentadienyltitanium(III) Complex, Cp2Ti-η2-C6H5CN-2,6-(CH3)2C6H3

    NARCIS (Netherlands)

    Bolhuis, F. van; Boer, E.J.M. de; Teuben, J.H.

    1979-01-01

    The crystal structure of Cp2TiC6H5CN-2,6-(CH3)2C6H3 is reported. The iminoacyl ligand is η2-coordinated at the metal (Ti—C 2.096(4), Ti—N 2.149(4) Å). The cyclopentadienyl ligands show the normal bent Cp2Ti structure.

  12. Preclinical evaluation of spatial frequency domain-enabled wide-field quantitative imaging for enhanced glioma resection

    Science.gov (United States)

    Sibai, Mira; Fisher, Carl; Veilleux, Israel; Elliott, Jonathan T.; Leblond, Frederic; Roberts, David W.; Wilson, Brian C.

    2017-07-01

    5-Aminolevelunic acid-induced protoporphyrin IX (PpIX) fluorescence-guided resection (FGR) enables maximum safe resection of glioma by providing real-time tumor contrast. However, the subjective visual assessment and the variable intrinsic optical attenuation of tissue limit this technique to reliably delineating only high-grade tumors that display strong fluorescence. We have previously shown, using a fiber-optic probe, that quantitative assessment using noninvasive point spectroscopic measurements of the absolute PpIX concentration in tissue further improves the accuracy of FGR, extending it to surgically curable low-grade glioma. More recently, we have shown that implementing spatial frequency domain imaging with a fluorescent-light transport model enables recovery of two-dimensional images of [PpIX], alleviating the need for time-consuming point sampling of the brain surface. We present first results of this technique modified for in vivo imaging on an RG2 rat brain tumor model. Despite the moderate errors in retrieving the absorption and reduced scattering coefficients in the subdiffusive regime of 14% and 19%, respectively, the recovered [PpIX] maps agree within 10% of the point [PpIX] values measured by the fiber-optic probe, validating its potential as an extension or an alternative to point sampling during glioma resection.

  13. Nasal glioma with psammomatous calcification- An unusual presentation

    Directory of Open Access Journals (Sweden)

    Rana Sherwani

    2014-03-01

    Full Text Available Congenital midline swellings of nose are encountered rarely, and nasal gliomas constitute about 5% of such lesions. Various theories have been suggested to explain the pathogenesis. Imaging preferably by MRI is mandated to study the extent and to rule out intracranial extension. Clinically, these masses are firm and incompressible. Histologically, they are made up of astrocytes and neuroglial cells, embedded in fibrous and vascular connective tissue. The mainstay of treatment is conservative surgical excision because nasal gliomas are slow-growing, rarely recurrent, and have no malignant potential. We present a case of congenital extranasal glioma with psammomatous calcification and without any intracranial extension in an eighteen month old boy.--------------------------------------------Cite this article as: Sherwani RK, Akhtar K, Ray PS, Ahmad SS. Nasal glioma with psammomatous calcification- An unusual presentation. Int J  Cancer Ther Oncol 2014; 2(2:02027. DOI: 10.14319/ijcto.0202.7

  14. Role of radiotherapy for high grade gliomas management.

    Science.gov (United States)

    Caruso, C; Carcaterra, M; Donato, V

    2013-06-01

    We have analyzed the therapeutic standard options for high grade gliomas, with particular attention to the different radiation therapy modalities and techniques and their application considering the natural history of the disease. Of the several therapeutic options, surgical resection remains the initial treatment of choice for patients with high grade glioma; of all adjuvant treatments tested, radiotherapy offers the greatest magnitude of survival benefit, so radiotherapy, which must be started within 6 weeks of surgery, is mandatory for practically all patients with high grade gliomas. In this paper we perform an overview considering the integration between the different therapeutic modalities, with particular attention to the radiation therapy role in the management of high grade gliomas.

  15. Immunotherapy Approaches for Malignant Glioma From 2007 to 2009

    Science.gov (United States)

    Sampson, John H.

    2012-01-01

    Malignant glioma is a deadly disease for which there have been few therapeutic advances over the past century. Although previous treatments were largely unsuccessful, glioma may be an ideal target for immune-based therapy. Recently, translational research led to several clinical trials based on tumor immunotherapy to treat patients with malignant glioma. Here we review 17 recent glioma immunotherapy clinical trials, published over the past 3 years. Various approaches were used, including passive transfer of naked and radiolabeled antibodies, tumor antigen-specific peptide immunization, and the use of patient tumor cells with or without dendritic cells as vaccines. We compare and discuss the current state of the art of clinical immunotherapy treatment, as well as its limited successes, pitfalls, and future potential. PMID:20424975

  16. Cytomegalovirus as an oncomodulatory agent in the progression of glioma.

    Science.gov (United States)

    Joseph, Gabriel P; McDermott, Ryan; Baryshnikova, Maria A; Cobbs, Charles S; Ulasov, Ilya V

    2017-01-01

    Glioblastoma multiforme (GBM) is the most aggressive neoplastic brain tumor in humans with a median survival of less than 2 years. It is therefore critical to understand the mechanism of glioma progression and to identify future targets for intervention. We investigate the mechanisms of cytomegalovirus as an oncomodulatory agent implicated in glioma progression, as well as immunosuppression. This review provides a comprehensive evaluation of recent investigative developments concerning the role of CMV in cellular processes during glioma growth. The manners in which CMV and its viral products interact with regulatory cellular signaling pathways in the host are of primary interest. Here, we examine some of the most significant oncomodulatory effects that CMV can confer in brain tumors, including the inhibition of apoptosis and promoting the growth of glioma stem cells, which are tightly linked to tumor survival and recurrence. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Erlotinib and Temsirolimus in Treating Patients With Recurrent Malignant Glioma

    Science.gov (United States)

    2015-05-29

    Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymal Giant Cell Astrocytoma; Recurrent Adult Brain Tumor

  18. MRI in Glioma Immunotherapy: Evidence, Pitfalls, and Perspectives

    Directory of Open Access Journals (Sweden)

    Domenico Aquino

    2017-01-01

    Full Text Available Pseudophenomena, that is, imaging alterations due to therapy rather than tumor evolution, have an important impact on the management of glioma patients and the results of clinical trials. RANO (response assessment in neurooncology criteria, including conventional MRI (cMRI, addressed the issues of pseudoprogression after radiotherapy and concomitant chemotherapy and pseudoresponse during antiangiogenic therapy of glioblastomas (GBM and other gliomas. The development of cancer immunotherapy forced the identification of further relevant response criteria, summarized by the iRANO working group in 2015. In spite of this, the unequivocal definition of glioma progression by cMRI remains difficult particularly in the setting of immunotherapy approaches provided by checkpoint inhibitors and dendritic cells. Advanced MRI (aMRI may in principle address this unmet clinical need. Here, we discuss the potential contribution of different aMRI techniques and their indications and pitfalls in relation to biological and imaging features of glioma and immune system interactions.

  19. Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells

    Energy Technology Data Exchange (ETDEWEB)

    Morioka, Norimitsu, E-mail: mnori@hiroshima-u.ac.jp; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

    2016-01-08

    Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. - Highlights: • Rev-erbα mRNA and Rev-erbβ mRNA are expressed in C6 astroglial cells. • TNF increases the expression of CCL2, IL-6, MMP-9 and iNOS mRNA. • REV-ERB activation inhibits CCL2 mRNA and MMP-9 mRNA expression. • HDAC3 activity is involved in the inhibitory effect of REV-ERB on MMP-9 induction.

  20. Molecular Subtyping of Tumors from Patients with Familial Glioma.

    Science.gov (United States)

    Ruiz, Vanessa Y; Praska, Corinne E; Armstrong, Georgina; Kollmeyer, Thomas M; Yamada, Seiji; Decker, Paul A; Kosel, Matthew L; Eckel-Passow, Jeanette E; Consortium, The Gliogene; Lachance, Daniel H; Bainbridge, Matthew N; Melin, Beatrice S; Bondy, Melissa L; Jenkins, Robert B

    2017-10-10

    Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on IDH mutation and 1p/19q co-deletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas, and that tumors in the same family should have the same molecular subtype. Participants in the FG study (Gliogene) provided samples for germline DNA analysis. Formalin-fixed, paraffin-embedded (FFPE) tumor was obtained for a subset of FG cases, and DNA was extracted. We analyzed tissue from 75 families, including 10 families containing a second affected family member. Copy number variation (CNV) data was obtained using a first-generation Affymetrix molecular inversion probe (MIP) array. Samples from 62 of 75 (83%) FG cases could be classified into the 3 subtypes. The prevalence of the molecular subtypes was: 30 (48%) IDH-wild type, 21 (34%) IDH-mutant non-codeleted, and 11 (19%) IDH-mutant and 1p/19q-codeleted. This distribution of molecular subtypes was not statistically different from that of sporadic gliomas (p=0.54). Of 10 paired FG samples, molecular subtypes were concordant for 7 (κ=0.59): 3 IDH-mutant non-codeleted, 2 IDH-wild type, and 2 IDH-mutant and 1p/19q-codeleted gliomas. Our data suggest that within individual families, patients develop gliomas of the same molecular subtype. However, we did not observe differences in the prevalence of the molecular subtypes in FG compared with sporadic gliomas. These observations provide further insight about the distribution of molecular subtypes in FG.

  1. Thromboxane synthase regulates the migratory phenotype of human glioma cells.

    OpenAIRE

    Giese, A.; Hagel, C; Kim, E L; Zapf, S.; Djawaheri, J.; Berens, M. E.; M. Westphal

    1999-01-01

    The capacity of glial tumor cells to migrate and diffusely infiltrate normal brain compromises surgical eradication of the disease. Identification of genes associated with invasion may offer novel strategies for anti-invasive therapies. The gene for TXsyn, an enzyme of the arachidonic acid pathway, has been identified by differential mRNA display as being overexpressed in a glioma cell line selected for migration. In this study TXsyn mRNA expression was found in a large panel of glioma cell l...

  2. Utility of multiparametric 3-T MRI for glioma characterization

    Energy Technology Data Exchange (ETDEWEB)

    Roy, Bhaswati; Gupta, Rakesh K. [Fortis Memorial Research Institute, Department of Radiology and Imaging, Gurgaon, Haryana (India); Maudsley, Andrew A.; Sheriff, Sulaiman [University of Miami, Department of Radiology, Miami (United States); Awasthi, Rishi; Mohakud, Sudipta [Sanjay Gandhi Postgraduate Institute of Medical Sciences, Department of Radiodiagnosis, Lucknow (India); Gu, Meng; Spielman, Daniel M. [Stanford University, Department of Radiology, Standford (United States); Husain, Nuzhat [Ram Manohar Lohia Institute of Medical Sciences, Department of Pathology, Lucknow (India); Behari, Sanjay [Sanjay Gandhi Postgraduate Institute of Medical Sciences, Department of Neurosurgery, Lucknow (India); Pandey, Chandra M. [Sanjay Gandhi Postgraduate Institute of Medical Sciences, Department of Biostatistics and Health Informatics, Lucknow (India); Rathore, Ram K.S. [Indian Institute of Technology, Department of Mathematics and Statistics, Kanpur (India); Alger, Jeffry R. [UCLA School of Medicine, Department of Radiological Sciences, Los Angeles (United States)

    2013-05-15

    Accurate grading of cerebral glioma using conventional structural imaging techniques remains challenging due to the relatively poor sensitivity and specificity of these methods. The purpose of this study was to evaluate the relative sensitivity and specificity of structural magnetic resonance imaging and MR measurements of perfusion, diffusion, and whole-brain spectroscopic parameters for glioma grading. Fifty-six patients with radiologically suspected untreated glioma were studied with T1- and T2-weighted MR imaging, dynamic contrast-enhanced MR imaging, diffusion tensor imaging, and volumetric whole-brain MR spectroscopic imaging. Receiver-operating characteristic analysis was performed using the relative cerebral blood volume (rCBV), apparent diffusion coefficient, fractional anisotropy, and multiple spectroscopic parameters to determine optimum thresholds for tumor grading and to obtain the sensitivity, specificity, and positive and negative predictive values for identifying high-grade gliomas. Logistic regression was performed to analyze all the parameters together. The rCBV individually classified glioma as low and high grade with a sensitivity and specificity of 100 and 88 %, respectively, based on a threshold value of 3.34. On combining all parameters under consideration, the classification was achieved with 2 % error and sensitivity and specificity of 100 and 96 %, respectively. Individually, CBV measurement provides the greatest diagnostic performance for predicting glioma grade; however, the most accurate classification can be achieved by combining all of the imaging parameters. (orig.)

  3. Lysyl oxidase genetic variants and the prognosis of glioma.

    Science.gov (United States)

    Han, Song; Feng, Sizhe; Yuan, Guanqian; Dong, Tao; Gao, Dandan; Liang, Guobiao; Wei, Xuezhong

    2014-03-01

    Lysyl oxidase (LOX) is a copper-dependent amine oxidase that plays important roles in the development and homeostasis of primary brain tumors such as glioma. The aim of this study was to investigate whether polymorphisms in the LOX gene were associated with susceptibility to glioma. We tested two functional polymorphisms of LOX, -22G/C and 473G/A, and compared them between 466 glioma cases and 502 healthy controls in the Chinese population. Results showed that the prevalence of 473AA genotype was significantly increased in cases than in controls (p = 0.001). Individuals who carried 473A allele had a 1.44-fold of increased risk for glioma than those with 473G allele (p = 0.002). In addition, when analyzing the survival time of glioma patients with LOX 473G/A polymorphism, cases with AA genotype had significantly shorter survival time compared to the patients carrying G allele (25.0 months vs 43.0 months, p = 0.0009). These results suggested that polymorphism in LOX gene was associated with increased susceptibility to glioma and could be used as prognostic factor for this malignancy. © 2013 APMIS. Published by John Wiley & Sons Ltd.

  4. 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.

  5. Gamma-glutamylcyclotransferase promotes the growth of human glioma cells by activating Notch-Akt signaling

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Shang-Hang; Yu, Ning; Liu, Xi-Yao; Tan, Guo-Wei; Wang, Zhan-Xiang, E-mail: md_wzx7189@163.com

    2016-03-18

    Glioma as an aggressive type tumor is rapidly growing and has become one of the leading cause of cancer-related death worldwide. γ-Glutamylcyclotransferase (GGCT) has been shown as a diagnostic marker in various cancers. To reveal whether there is a correlation between GGCT and human glioma, GGCT expression in human glioma tissues and cell lines was first determined. We found that GGCT expression was up-regulated in human glioma tissues and cell lines. Further, we demonstrate that GGCT knockdown inhibits glioma cell T98G and U251 proliferation and colony formation, whereas GGCT overexpression leads to oppose effects. GGCT overexpression promotes the expression of Notch receptors and activates Akt signaling in glioma cells, and Notch-Akt signaling is activated in glioma tissues with high expression of GGCT. Finally, we show that inhibition of Notch-Akt signaling with Notch inhibitor MK-0752 blocks the effects of GGCT on glioma proliferation and colony formation. In conclusion, GGCT plays a critical role in glioma cell proliferation and may be a potential cancer therapeutic target. - Highlights: • GGCT expression is up-regulated in human glioma tissues and cell lines. • GGCT promotes glioma cell growth and colony formation. • GGCT promotes the activation of Notch-Akt signaling in glioma cells and tissues. • Notch inhibition blocks the role of GGCT in human glioma cells.

  6. Mosquito cell line C6/36 shows resistence to Cyt1Aa6

    Czech Academy of Sciences Publication Activity Database

    Zhang, L.; Huang, E.; Tang, B.; Guan, X.; Gelbič, Ivan

    2012-01-01

    Roč. 50, č. 4 (2012), s. 265-269 ISSN 0019-5189 R&D Projects: GA MŠk 2B08003 Grant - others:National Nature Science Foundation of China(CN) 31071745; Science Foundation of the Ministry of Education of China(CN) 20093515110010; Science Foundation of the Ministry of Education of China(CN) 20093515120010; Transformation Fund for Agricultural Science and Technology Achievements(CN) 2010GB2C400212; Fujian Colleges and Universities for the Development of the West Strait(CN) 0b08b005 Institutional research plan: CEZ:AV0Z50070508 Keywords : Bacillus thuringiensis * C6/36 cells * indirect immunofluorescence assay Subject RIV: ED - Physiology Impact factor: 1.195, year: 2012 http://nopr.niscair.res.in/bitstream/123456789/13748/1/IJEB%2050(4)%20265-269.pdf

  7. Upper limb reinnervation in C6 tetraplegia using a triple nerve transfer: case report.

    Science.gov (United States)

    van Zyl, Natasha; Hahn, Jodie B; Cooper, Catherine A; Weymouth, Michael D; Flood, Stephen J; Galea, Mary P

    2014-09-01

    Restoration of elbow extension, grasp, key pinch, and release are major goals in low-level tetraplegia. Traditionally, these functions are achieved using tendon transfers. In this case these goals were achieved using nerve transfers. We present a 21-year-old man with a C6 level of tetraplegia. The left upper limb was treated 6 months after injury with a triple nerve transfer. A teres minor nerve branch to long head of triceps nerve branch, brachialis nerve branch to anterior interosseous nerve, and supinator nerve branch to posterior interosseous nerve transfer were used successfully to reconstruct elbow extension, key pinch, grasp, and release simultaneously. Copyright © 2014 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

  8. Charge density waves in the graphene sheets of the superconductor CaC(6).

    Science.gov (United States)

    Rahnejat, K C; Howard, C A; Shuttleworth, N E; Schofield, S R; Iwaya, K; Hirjibehedin, C F; Renner, Ch; Aeppli, G; Ellerby, M

    2011-11-29

    Graphitic systems have an electronic structure that can be readily manipulated through electrostatic or chemical doping, resulting in a rich variety of electronic ground states. Here we report the first observation and characterization of electronic stripes in the highly electron-doped graphitic superconductor, CaC(6), by scanning tunnelling microscopy and spectroscopy. The stripes correspond to a charge density wave with a period three times that of the Ca superlattice. Although the positions of the Ca intercalants are modulated, no displacements of the carbon lattice are detected, indicating that the graphene sheets host the ideal charge density wave. This provides an exceptionally simple material-graphene-as a starting point for understanding the relation between stripes and superconductivity. Furthermore, our experiments suggest a strategy to search for superconductivity in graphene, namely in the vicinity of striped 'Wigner crystal' phases, where some of the electrons crystallize to form a superlattice.

  9. Comparing MODIS C6 'Deep Blue' and 'Dark Target' Aerosol Data

    Science.gov (United States)

    Hsu, N. C.; Sayer, A. M.; Bettenhausen, C.; Lee, J.; Levy, R. C.; Mattoo, S.; Munchak, L. A.; Kleidman, R.

    2014-01-01

    The MODIS Collection 6 Atmospheres product suite includes refined versions of both 'Deep Blue' (DB) and 'Dark Target' (DT) aerosol algorithms, with the DB dataset now expanded to include coverage over vegetated land surfaces. This means that, over much of the global land surface, users will have both DB and DT data to choose from. A 'merged' dataset is also provided, primarily for visualization purposes, which takes retrievals from either or both algorithms based on regional and seasonal climatologies of normalized difference vegetation index (NDVI). This poster present some comparisons of these two C6 aerosol algorithms, focusing on AOD at 550 nm derived from MODIS Aqua measurements, with each other and with Aerosol Robotic Network (AERONET) data, with the intent to facilitate user decisions about the suitability of the two datasets for their desired applications.

  10. Unilateral hyperplasia of the left posterior arch and associated vertebral schisis at C6 level

    Energy Technology Data Exchange (ETDEWEB)

    Esposito, Giuseppe; Bonis, Pasquale de; Tamburrini, Gianpiero; Massimi, Luca; Rocco, Concezio di [Catholic University, School of Medicine, Department of Pediatric Neurosurgery, Rome (Italy); Byvaltsev, Vadim [Irkutsk Railway Clinical Hospital, Department of Neurosurgery, Irkutsk (Russian Federation); Leone, Antonio [Catholic University, School of Medicine, Department of Bioimaging and Radiological Sciences, Rome (Italy)

    2009-12-15

    We report on a 5-year-old girl with unilateral hyperplasia of the left posterior arch of C6 associated with spina bifida occulta at the same level. Anteroposterior and lateral radiographs of the cervical spine showed hypertrophy of the left lamina as well as overgrowth and elongation of the left spinous process of the sixth cervical vertebra. Computed tomography (CT) examination better depicted this congenital variant and clearly showed the associated schisis of the posterior arch at the same level. Magnetic resonance (MR) imaging examination ruled out other spinal anomalies. The neck pain, the young age of the patient and the local aesthetic abnormality contributed to the surgical indication. To the best of our knowledge, this is the first case in the English literature of unilateral hyperplasia of a posterior cervical arch. Only one previous study has reported a similar congenital anomaly, but it was limited to the left side of the spinous process. (orig.)

  11. Upscattering of ultracold neutrons from the polymer [C6H12]n

    Science.gov (United States)

    Sharapov, E. I.; Morris, C. L.; Makela, M.; Saunders, A.; Adamek, Evan R.; Broussard, L. J.; Cude-Woods, C. B.; Fellers, Deion E.; Geltenbort, Peter; Hartl, M.; Hasan, S. I.; Hickerson, K. P.; Hogan, G.; Holley, A. T.; Lavelle, C. M.; Liu, Chen-Yu; Mendenhall, M. P.; Ortiz, J.; Pattie, R. W., Jr.; Phillips, D. G., II; Ramsey, J.; Salvat, D. J.; Seestrom, S. J.; Shaw, E.; Sjue, Sky; Sondheim, W. E.; VornDick, B.; Wang, Z.; Womack, T. L.; Young, A. R.; Zeck, B. A.

    2013-12-01

    It is generally accepted that the main cause of ultracold neutron (UCN) losses in storage traps is upscattering to the thermal energy range by hydrogen adsorbed on the surface of the trap walls. However, the data on which this conclusion is based are poor and contradictory. Here we report a measurement, performed at the Los Alamos National Laboratory UCN source, of the average energy of the flux of upscattered neutrons after the interaction of UCN with hydrogen bound in the semicrystalline polymer PMP (trade name TPX), [C6H12]n. Our analysis, performed with the mcnp code which applies the neutron-scattering law to UCN upscattered by bound hydrogen in semicrystalline polyethylene, [C2H4]n, leads us to a flux average energy value of 26±3 meV, in contradiction to previously reported experimental values of 10 to 13 meV and in agreement with the theoretical models of neutron heating implemented in mcnp.

  12. Enzymatic Hydrolysis of Pretreated Fibre Pressed Oil Palm Frond by using Sacchariseb C6

    Science.gov (United States)

    Hashim, F. S.; Yussof, H. W.; Zahari, M. A. K. M.; Rahman, R. A.; Illias, R. M.

    2017-06-01

    Enzymatic hydrolysis becomes a prominent technology for conversion of cellulosic biomass to its glucose monomers that requires an action of cellulolytic enzymes in a sequential and synergistic manner. In this study, the effect of agitation speed, glucan loading, enzyme loading, temperature and reaction time on the production of glucose from fibre pressed oil palm frond (FPOPF) during enzymatic hydrolysis was screened by a half factorial design 25-1 using Response Surface Methodology (RSM). The FPOPF sample was first delignified by alkaline pretreatment at 4.42 (w/v) sodium hydroxide for an hour prior to enzymatic hydrolysis using commercial cellulase enzyme, Sacchariseb C6. The effect of enzymatic hydrolysis on the structural of FPOPF has been evaluated by Scanning Electron Microscopy (SEM) analysis. Characterization of raw FPOPF comprised of 4.5 extractives, 40.7 glucan, 26.1 xylan, 26.2 lignin and 1.8 ash, whereas for pretreated FPOPF gave 0.3 extractives, 61.4 glucan, 20.4 xylan, 13.3 lignin and 1.3 ash. From this study, it was found that the best enzymatic hydrolysis condition yielded 33.01 ± 0.73 g/L of glucose when performed at 200 rpm of agitation speed, 60 FPU/mL of enzyme loading, 4 (w/w) of glucan loading, temperature at 55 □ and 72 hours of reaction time. The model obtained was significant with p-value determination (R2) from ANOVA study was 0.9959. Overall, it can be concluded that addition of Sacchariseb C6 during enzymatic hydrolysis from pretreated FPOPF produce high amount of glucose that enhances it potential for industrial application. This glucose can be further used to produce high-value products.

  13. The analysis of deregulated expression and methylation of the PER2 genes in gliomas

    National Research Council Canada - National Science Library

    Wang Fan; Xiaowei Chen; Caiyan Li; Yongluo; Lvan Chen; Pingfei Liu; Zhijun Chen

    2014-01-01

    .... However, the molecular mechanisms of genes controlling circadian rhythm in glioma cells have not been explored and differential expression of the circadian clock genes in glioma and non-tumor cells...

  14. Proton Beam Radiation Therapy in Treating Patients With Low Grade Gliomas

    Science.gov (United States)

    2015-12-14

    Adult Brain Tumor; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Grade II Meningioma; Adult Melanocytic Lesion; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pineal Gland Astrocytoma; Adult Pineocytoma; Recurrent Adult Brain Tumor

  15. Epigenetic modification in gliomas: role of the histone methyltransferase EZH2.

    Science.gov (United States)

    Bian, Er-Bao; Li, Jia; He, Xiao-Jun; Zong, Gang; Jiang, Tao; Li, Jun; Zhao, Bing

    2014-10-01

    Gliomas are characterized by increased anaplasia, malignization, proliferation and invasion. They exhibit high resistance to standard treatment with combinations of radiotherapy and chemotherapy. They are currently the most common primary malignancy tumors in the brain that is related to a high mortality rate. Recently, increasing evidence suggests that EZH2 is involved in a number of glioma cell processes, including proliferation, apoptosis, invasion and angiogenesis. In this review, we emphasize the role of EZH2 in gliomas. We also address that EZH2 interacting with DNA methylation mediates transcriptional repression of specific genes in gliomas, and the regulation of EZH2 by microRNAs in gliomas. Although the exact role of EZH2 in gliomas has not been fully elucidated, to understand the role of EZH2 proteins in epigenetic modification will provide valuable insights into the causes of gliomas, and pave the way to the potential future applications of EZH2 in the treatment of gliomas.

  16. Structural Stability and Electronic Properties of Na2C6O6 for a Rechargeable Sodium-ion Battery

    Science.gov (United States)

    Yamashita, Tomoki; Fujii, Akihiro; Momida, Hiroyoshi; Oguchi, Tamio

    2014-03-01

    Sodium-ion batteries have been explored as a promising alternative to lithium-ion batteries owing to a significant advantage of a natural abundance of sodium. Recently, it has been reported that disodium rhodizonate, Na2C6O6, exhibit good electrochemical properties and cycle performance as a minor-metal free organic cathode for sodium-ion batteries. However, its crystal structures during discharge/charge cycle still remain unclear. In this work, we theoretically propose feasible crystal structures of Na2+xC6O6 using first principles calculations. A structural phase transition has been found: Na4C6O6 has a different C6O6 packing arrangement from Na2C6O6. Electronic structures of Na2+xC6O6 during discharge/charge cycle are also discussed. Our predictions could be the key to understanding the discharge/charge process of Na2C6O6. Supported by MEXT program ``Elements Strategy Initiative to Form Core Rersearch Center'' (since 2012), MEXT; Ministry of Education Culture, Sports, Science and Technology, Japan.

  17. Irreversible blockade of the high and low affinity ( sup 3 H) naloxone binding sites by C-6 derivatives of morphinane-6-ones

    Energy Technology Data Exchange (ETDEWEB)

    Krizsan, D. (EGIS Pharmaceutical Works, Budapest (Hungary)); Varga, E.; Benyhe, S.; Szucs, M.; Borsodi, A. (Biological Research Center of the Hungarian Academy of Sciences, Szeged (Hungary)); Hosztafi, S. (Alkaloida Chemical Works, Tiszavasvari (Hungary))

    1991-01-01

    C-6 derivatives-hydrazones, phenylhydrazones, dinitrophenylhydrazones, oximes and semicarbazones - of morphinane-6-ones were synthesized and their binding characteristics were studied on rat brain membranes. The dihydromorphinone and oxymorphone derivatives compete for the ({sup 3}H)naloxone binding sites with high affinity, while the dihydrocodeinone and oxycodone derivatives are less potent. The affinity of the new compounds is decreased for the delta sites as compared to the parent ligands. The ligands bearing bulky substituents also bind with low affinity to the kappa sites. The modification decreased the Na{sup +}-index of compounds indicating their mixed agonist-antagonist character. The dihydromorphinone derivatives are all capable to block irreversibly the high affinity binding site of ({sup 3}H)naloxone, whereas the dihydrocodeinone derivatives block irreversibly the low affinity site. A possible mechanism for the inhibition is suggested.

  18. Childhood Brain Stem Glioma Treatment (PDQ®)—Health Professional Version

    Science.gov (United States)

    Childhood brain stem glioma presents as a diffuse intrinsic pontine glioma (DIPG; a fast-growing tumor that is difficult to treat and has a poor prognosis) or a focal glioma (grows more slowly, is easier to treat, and has a better prognosis). Learn about the diagnosis, cellular classification, staging, treatment, and clinical trials for pediatric brain stem glioma in this expert-reviewed summary.

  19. 3D organic Na4C6O6/graphene architecture for fast sodium storage with ultralong cycle life.

    Science.gov (United States)

    Gu, Jianan; Gu, Yue; Yang, Shubin

    2017-11-23

    Sodium-ion batteries (SIBs) have aroused increasing interest as one of the most promising replacements for lithium-ion batteries (LIBs). Here, a novel organic-inorganic 3D Na 4 C 6 O 6 -graphene architecture was successfully fabricated from commercial Na 2 C 6 O 6 and for the first time applied for sodium storage. Hence, the 3D Na 4 C 6 O 6 -graphene architecture exhibits a high reversible capacity, good cyclic performance and high-rate capability for sodium storage.

  20. Human ClC-6 is a late endosomal glycoprotein that associates with detergent-resistant lipid domains.

    Directory of Open Access Journals (Sweden)

    Sofie Ignoul

    Full Text Available BACKGROUND: The mammalian CLC protein family comprises nine members (ClC-1 to -7 and ClC-Ka, -Kb that function either as plasma membrane chloride channels or as intracellular chloride/proton antiporters, and that sustain a broad spectrum of cellular processes, such as membrane excitability, transepithelial transport, endocytosis and lysosomal degradation. In this study we focus on human ClC-6, which is structurally most related to the late endosomal/lysomal ClC-7. PRINCIPAL FINDINGS: Using a polyclonal affinity-purified antibody directed against a unique epitope in the ClC-6 COOH-terminal tail, we show that human ClC-6, when transfected in COS-1 cells, is N-glycosylated in a region that is evolutionary poorly conserved between mammalian CLC proteins and that is located between the predicted helices K and M. Three asparagine residues (N410, N422 and N432 have been defined by mutagenesis as acceptor sites for N-glycosylation, but only two of the three sites seem to be simultaneously N-glycosylated. In a differentiated human neuroblastoma cell line (SH-SY5Y, endogenous ClC-6 colocalizes with LAMP-1, a late endosomal/lysosomal marker, but not with early/recycling endosomal markers such as EEA-1 and transferrin receptor. In contrast, when transiently expressed in COS-1 or HeLa cells, human ClC-6 mainly overlaps with markers for early/recycling endosomes (transferrin receptor, EEA-1, Rab5, Rab4 and not with late endosomal/lysosomal markers (LAMP-1, Rab7. Analogously, overexpression of human ClC-6 in SH-SY5Y cells also leads to an early/recycling endosomal localization of the exogenously expressed ClC-6 protein. Finally, in transiently transfected COS-1 cells, ClC-6 copurifies with detergent-resistant membrane fractions, suggesting its partitioning in lipid rafts. Mutating a juxtamembrane string of basic amino acids (amino acids 71-75: KKGRR disturbs the association with detergent-resistant membrane fractions and also affects the segregation of ClC-6

  1. Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma.

    Science.gov (United States)

    Fathi, Amir T; Nahed, Brian V; Wander, Seth A; Iafrate, A John; Borger, Darrell R; Hu, Ranliang; Thabet, Ashraf; Cahill, Daniel P; Perry, Ashley M; Joseph, Christelle P; Muzikansky, Alona; Chi, Andrew S

    2016-02-01

    Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated. In this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort. We found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type. Our finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management. Patients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management. ©AlphaMed Press.

  2. 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

  3. Monte Carlo studies of isomers, structures, and properties in benzene-cyclohexane clusters: computation strategy and application to the dimer and trimer, (C6H6)(C6H12)n, n = 1-2.

    Science.gov (United States)

    Easter, David C; Terrell, David A; Roof, Jessica A

    2005-02-03

    Low-temperature isomeric energies, structures, and properties of benzene-cyclohexane clusters are investigated via Monte Carlo simulations. The Monte Carlo strategy is first documented and then applied to (C(6)H(6))(C(6)H(12)) and (C(6)H(6))(C(6)H(12))(2) using four different potential energy surfaces. Results identify a single parallel-displaced dimer isomer. MP2 optimizations and frequency calculations support the Monte Carlo dimer structure and identify the van der Waals mode observed in vibronic spectra. Caloric simulations identify two temperatures where structural transitions occur and imply an experimental temperature below 10 K for dimers in cold supersonic expansions. The (C(6)H(6))(C(6)H(12))(2) studies identify eight independent trimer isomers: three form parallel-stacked (sandwich) arrangements with the two cyclohexane moieties related through a D(6)(h) transformation. The remaining five trimer isomers are trigonal, with no overall symmetry. Caloric studies indicate that the sandwich and trigonal isomeric classes coexist independently below 60 K, consistent with trimer vibronic spectra that contain two independent van der Waals progressions.

  4. [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.

  5. 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 ...

  6. A glioma classification scheme based on coexpression modules of EGFR and PDGFRA

    NARCIS (Netherlands)

    Y. Sun (Yingyu); W. Zhang (Wei); D. Chen (Dongfeng); H. Lv (Hui); J. Zheng (Junxiong); H. Lilljebjörnd (Henrik); L. Ran (Liang); T.X. Bao (Tang Xue); C. Soneson (Charlotte); H. Olov Sjögren (Hans); L.G. Salford (Leif); J. Ji (Jianguang); P.J. Frenc (Pim); T. Fioretose (Thoas); T. Jiang (Tao); X. Fan (Xiaolong)

    2014-01-01

    textabstractWe hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were

  7. 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.

  8. Modeling the degradation mechanisms of C6/LiFePO4 batteries

    Science.gov (United States)

    Li, Dongjiang; Danilov, Dmitri L.; Zwikirsch, Barbara; Fichtner, Maximilian; Yang, Yong; Eichel, Rüdiger-A.; Notten, Peter H. L.

    2018-01-01

    A fundamental electrochemical model is developed, describing the capacity fade of C6/LiFePO4 batteries as a function of calendar time and cycling conditions. At moderate temperatures the capacity losses are mainly attributed to Li immobilization in Solid-Electrolyte-Interface (SEI) layers at the anode surface. The SEI formation model presumes the availability of an outer and inner SEI layers. Electron tunneling through the inner SEI layer is regarded as the rate-determining step. The model also includes high temperature degradation. At elevated temperatures, iron dissolution from the positive electrode and the subsequent metal sedimentation on the negative electrode influence the capacity loss. The SEI formation on the metal-covered graphite surface is faster than the conventional SEI formation. The model predicts that capacity fade during storage is lower than during cycling due to the generation of SEI cracks induced by the volumetric changes during (dis)charging. The model has been validated by cycling and calendar aging experiments and shows that the capacity loss during storage depends on the storage time, the State-of-Charge (SoC), and temperature. The capacity losses during cycling depend on the cycling current, cycling time, temperature and cycle number. All these dependencies can be explained by the single model presented in this paper.

  9. Superconducting graphene sheets in CaC6 enabled by phonon-mediated interband interactions.

    Science.gov (United States)

    Yang, S-L; Sobota, J A; Howard, C A; Pickard, C J; Hashimoto, M; Lu, D H; Mo, S-K; Kirchmann, P S; Shen, Z-X

    2014-03-20

    There is a great deal of fundamental and practical interest in the possibility of inducing superconductivity in a monolayer of graphene. But while bulk graphite can be made to superconduct when certain metal atoms are intercalated between its graphene sheets, the same has not been achieved in a single layer. Moreover, there is a considerable debate about the precise mechanism of superconductivity in intercalated graphite. Here we report angle-resolved photoelectron spectroscopy measurements of the superconducting graphite intercalation compound CaC6 that distinctly resolve both its intercalant-derived interlayer band and its graphene-derived π* band. Our results indicate the opening of a superconducting gap in the π* band and reveal a substantial contribution to the total electron-phonon-coupling strength from the π*-interlayer interband interaction. Combined with theoretical predictions, these results provide a complete account for the superconducting mechanism in graphite intercalation compounds and lend support to the idea of realizing superconducting graphene by creating an adatom superlattice.

  10. Analytical system for stable carbon isotope measurements of low molecular weight (C2-C6 hydrocarbons

    Directory of Open Access Journals (Sweden)

    T. Röckmann

    2011-06-01

    Full Text Available We present setup, testing and initial results from a new automated system for stable carbon isotope ratio measurements on C2 to C6 atmospheric hydrocarbons. The inlet system allows analysis of trace gases from air samples ranging from a few liters for urban samples and samples with high mixing ratios, to many tens of liters for samples from remote unpolluted regions with very low mixing ratios. The centerpiece of the sample preparation is the separation trap, which is used to separate CO2 and methane from the compounds of interest. The main features of the system are (i the capability to sample up to 300 l of air, (ii long term (since May 2009 operational δ13C accuracy levels in the range 0.3–0.8 ‰ (1-σ, and (iii detection limits of order 1.5–2.5 ngC (collected amount of substance for all reported compounds. The first application of this system was the analysis of 21 ambient air samples taken during 48 h in August 2009 in Utrecht, the Netherlands. Results obtained are generally in good agreement with those from similar urban ambient air studies. Short sample intervals allowed by the design of the instrument help to illustrate the complex diurnal behavior of hydrocarbons in an urban environment, where diverse sources, dynamical processes, and chemical reactions are present.

  11. Genetic analysis of benzothiophene biodesulfurization pathway of Gordonia terrae strain C-6.

    Directory of Open Access Journals (Sweden)

    Wei Wang

    Full Text Available Sulfur can be removed from benzothiophene (BT by some bacteria without breaking carbon-carbon bonds. However, a clear mechanism for BT desulfurization and its genetic components have not been reported in literatures so far. In this study, we used comparative transcriptomics to study differential expression of genes in Gordonia terrae C-6 cultured with BT or sodium sulfate as the sole source of sulfur. We found that 135 genes were up-regulated with BT relative to sodium sulfate as the sole sulfur source. Many of these genes encode flavin-dependent monooxygenases, alkane sulfonate monooxygenases and desulfinase, which perform similar functions to those involved in the 4S pathway of dibenzothiophene (DBT biodesulfurization. Three of the genes were found to be located in the same operon, designated bdsABC. Cell extracts of pET28a-bdsABC transfected E. coli Rosetta (DE3 converted BT to a phenolic compound, identified as o-hydroxystyrene. These results advance our understanding of enzymes involved in the BT biodesulfurization pathway.

  12. Generation of C6+ in a spark-discharge coupled laser plasma

    Science.gov (United States)

    Balki, Oguzhan; Rahman, Md. Mahmudur; Xiao, Shu; Elsayed-Ali, Hani E.

    2017-11-01

    By coupling a spark discharge into a laser-generated carbon plasma, fully-stripped carbon ions with a relatively low laser pulse energy are observed. When spark-discharge energy of ∼ 750 mJ is coupled to the carbon plasma generated by ∼ 50 mJ laser pulse (wavelength 1064 nm, pulse width 8 ns, intensity 5 × 109 W /cm2), enhancement in the total ion charge by a factor of ∼ 6 is observed, along with the increase of maximum charge state from C4+ to C6+. Spark coupling to the laser plasma significantly reduces the laser pulse energy required to generate highly-charged ions. Compared to the laser carbon plasma alone, the spark discharge increases the intensity of the spectral emission of carbon lines, the electron density ne, and the electron temperature Te. The effective ion plasma temperature associated with translational motion along the plume axis Tieff is calculated from the ion time-of-flight signal.

  13. Physical properties of new cerium palladium phosphide with C6Cr23-type structure

    Directory of Open Access Journals (Sweden)

    T. Abe

    2014-01-01

    Full Text Available We have found that a cerium palladium phosphide crystallizes into a C6Cr23-type structure with atomic disorder. Prepared polycrystalline samples show a homogeneity range in the ternary Ce–Pd–P phase diagram. The physical properties of the highest-quality sample of Ce2.4Pd20.7P5.9 were investigated by measuring the magnetization, electrical resistivity and specific heat. No pronounced phase transition was observed down to 0.5 K. The Kondo screening of localized 4f electrons in metallic Ce2.4Pd20.7P5.9 appears to be weaker than that in the isostructural compounds of Ce3Pd20Si6 and Ce3Pd20Ge6. By a comparative study of Ce2.4Pd20.7P5.9 and Ce3Pd20X6 (X = Si, Ge, the competition between the Kondo temperature and ordering temperatures including the quadrupolar ordering temperature is briefly discussed.

  14. Brd1 gene in maize encodes a brassinosteroid C-6 oxidase.

    Directory of Open Access Journals (Sweden)

    Irina Makarevitch

    Full Text Available The role of brassinosteroids in plant growth and development has been well-characterized in a number of plant species. However, very little is known about the role of brassinosteroids in maize. Map-based cloning of a severe dwarf mutant in maize revealed a nonsense mutation in an ortholog of a brassinosteroid C-6 oxidase, termed brd1, the gene encoding the enzyme that catalyzes the final steps of brassinosteroid synthesis. Homozygous brd1-m1 maize plants have essentially no internode elongation and exhibit no etiolation response when germinated in the dark. These phenotypes could be rescued by exogenous application of brassinolide, confirming the molecular defect in the maize brd1-m1 mutant. The brd1-m1 mutant plants also display alterations in leaf and floral morphology. The meristem is not altered in size but there is evidence for differences in the cellular structure of several tissues. The isolation of a maize mutant defective in brassinosteroid synthesis will provide opportunities for the analysis of the role of brassinosteroids in this important crop system.

  15. Vascular permeability in the RG2 glioma model can be mediated by macropinocytosis and be independent of the opening of the tight junction.

    Science.gov (United States)

    Pernet-Gallay, Karin; Jouneau, Pierre-Henri; Bertrand, Anne; Delaroche, Julie; Farion, Régine; Rémy, Chantal; Barbier, Emmanuel L

    2017-04-01

    This study evaluates the extravasation pathways of circulating macromolecules in a rat glioma model (RG2) which was observed by both magnetic resonance imaging using ultrasmall superparamagnetic iron oxide and electron microscopy. Although magnetic resonance imaging signal enhancement was observed as soon as 10 min after injection (9.4% 2 h after injection), electron microscopy showed that endothelial cells were still tightly sealed. However, circulating immunoglobulin G and ultrasmall superparamagnetic iron oxide were found in large membrane compartments of endothelial cells, in the basal lamina (7.4 ± 1.2 gold particles/µm 2 in the tumor versus 0.38 ± 0.17 in healthy tissue, p = 1.4.10 -5 ) and between tumoral cells. Altogether, this strongly suggests an active transport mediated by macropinocytosis. To challenge this transport mechanism, additional rats were treated with amiloride, an inhibitor of macropinocytosis, leading to a reduction of membrane protrusions (66%) and of macropinosomes. Amiloride however also opened tumoral tight junctions allowing a larger extravasation of ultrasmall superparamagnetic iron oxide (magnetic resonance imaging signal enhancement of 35.7% 2 h after injection). Altogether, these results suggest that ultrasmall superparamagnetic iron oxide and immunoglobulin G in the RG2 glioma model follow an active extravasation pathway mediated by a macropinocytosis process. Amiloride also appears as a potential strategy to facilitate the extravasation of chemotherapeutic drugs in glioma.

  16. Quantitative analysis of mitotic Olig2 cells in adult human brain and gliomas: implications for glioma histogenesis and biology.

    Science.gov (United States)

    Rhee, Wootack; Ray, Sutapa; Yokoo, Hideaki; Hoane, Megan E; Lee, Chong C; Mikheev, Andrei M; Horner, Philip J; Rostomily, Robert C

    2009-04-01

    The capacity of adult human glial progenitor cells (AGPs), to proliferate and undergo multipotent differentiation, positions them as ideal candidate cells of origin for human gliomas. To investigate this potential role we identified AGPs as mitotically active Olig2 cells in nonneoplastic adult human brain and gliomas. We conservatively estimated that one in 5,000 human temporal lobe neocortical gray or subcortical white matter cells is mitotic. Extrapolating from a mean Olig2/Mib-1 labeling index (LI) of 52% and total cell number of 100 billion, we estimated the overall prevalence of mitotic Olig2 AGPs in nonneoplastic human brain parenchyma at 10 million. These data identify a large reservoir of Olig2 AGPs which could be potential targets for human gliomagenesis. The vast majority of mitotic cells in Grade II and Grade III gliomas of all histologic subtypes expressed Olig2 (mean LI 75%) but rarely S100B (LI 0.6%), identifying the Olig2 cell as a distinct contributor to the proliferating cell population of human gliomas of both oligodendroglial and astrocytic lineages. In the most malignant Grade IV glioma, or glioblastoma multiforme (GBM), the prevalence of Olig2/Mib-1 cells was significantly decreased (24.5%). The significantly lower Olig2/Mib-1 LI in GBMs suggests that a decrease in the prevalence of Olig2 cells to the total mitotic cell pool accompanies increasing malignancy. The novel framework provided by this quantitative and comparative analysis supports future studies to examine the histogenetic role of Olig2 AGPs in adult gliomas, their potential contribution to the tumor stroma and the molecular role of Olig2 in glioma pathogenesis. (c) 2008 Wiley-Liss, Inc.

  17. 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.

  18. The influence of feeding linoleic, gamma-linolenic and docosahexaenoic acid rich oils on rat brain tumor fatty acids composition and fatty acid binding protein 7 mRNA expression

    Directory of Open Access Journals (Sweden)

    Abdi Khosro

    2008-11-01

    Full Text Available Abstract Background Experimental studies indicate that gamma linolenic acid (GLA and docosahexaenoic acid (DHA may inhibit glioma cells growth but effects of oral consumption of these fatty acids on brain tumor fatty acid composition have not been determined in vivo. Methods GLA oil (GLAO; 72% GLA, DHA oil (DHAO; 73% DHA were fed to adult wistar rats (1 mL/rat/day starting one week prior to C6 glioma cells implantation and continued for two weeks after implantation. Control group were fed same amount of high linoleic acid safflower oil (74–77% linoleic acid. Fatty acid composition of tumor samples was determined in a set of 8–12 animals in each group and serum fatty acid in 6 animals per each group. Gene expression of tumor fatty acid binding protein 7 (FABP7, epidermal growth factor receptor (EGFR, peroxisome proliferator activated receptor γ (PPAR-γ and retinoid × receptor-α (RXR-α were determined in a set of 18 animals per group. Results DHAO feeding increased EPA of brain tumors and decreased ratio of n-6/n-3 fatty acids. Serum levels of EPA were also increased in DHAO group. A similar trend in serum and tumor levels of DHA were observed in DHAO group but it did not achieve statistical significance. GLAO increased serum concentration of GLA but had no significant effect on tumor GLA or dihomo-gamma linolenic acid (DGLA concentrations. Gene expression of FABP7 was up-regulated in tumors of DHAO group but no other significant effects were observed on EGFR, PPAR-γ or RXR-α expression, and expression of these genes in tumors of GLAO were not different from SFO group. Conclusion Dietary supplementation of DHA containing oil could be an effective way to increase levels of long chain n-3 fatty acids in brain tumors and this increase may be mediated partly by up-regulation of FABP7 expression.

  19. 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.

  20. Improved Adeno-associated Viral Gene Transfer to Murine Glioma.

    Science.gov (United States)

    Zolotukhin, I; Luo, D; Gorbatyuk, Os; Hoffman, Be; Warrington, Kh; Herzog, Rw; Harrison, Jk; Cao, O

    2013-04-29

    Glioblastoma (GBM) is a deadly primary brain tumor. Current treatment, consisting of surgical removal of the tumor mass followed by chemotherapy and/or radiotherapy, does not significantly prolong survival. Gene therapies for GBM are being developed in clinical trials, for example using adenoviral vectors. While adeno-associated virus (AAV) represents an alternative vector system, limited gene transfer to glioma cells has hampered its use. Here, we evaluated newly emerged variants of AAV capsid for gene delivery to murine glioma. We tested a mutant AAV2 capsid devoid of 3 surface-exposed tyrosine residues, AAV2 (Y444-500-730F), and a "shuffed" capsid (ShH19, containing sequences from several serotypes) that had previously been selected for enhanced glial gene delivery. AAV2 (Y-F) and ShH19 showed improved transduction of murine glioma GL261 cells in vitro by 2- to 6-fold, respectively, over AAV2. While AAV2 gene transfer to GL261 cells in established tumors in brains of syngeneic mice was undetectable, intratumoral injection of AAV2 (Y-F) or ShH19 resulted in local transduction of approximately 10% of tumor cells. In addition, gene transfer to neurons adjacent to the tumor was observed, while microglia were rarely transduced. Use of self-complementary vectors further increased transduction of glioma cells. Together, the data demonstrate the potential for improved AAV-based gene therapy for glioma using recently developed capsid variants.

  1. Expression of microRNA-184 in glioma.

    Science.gov (United States)

    Wu, Xiao-Ben; Yang, Wei; Fan, Gang; Lin, Wan-Run; Liu, Fang; Lu, Zhi-Ming

    2018-01-01

    The aim of the present study was to examine the expression of microRNA (miRNA)-184 in gliomas with different pathological grades, and its effect on survival prognosis. For the present study, 40 participants were selected with different pathological grades of glioma tissues with grade I (n=10), grade II (n=8), grade III (n=16), and grade IV (n=6). In addition, 10 cases of normal brain tissue (obtained by decompression because of traumatic brain injury) were selected. RT-PCR and immunohistochemical techniques were used to detect the expression level and intensity of miRNA-184 in different grades of glioma tissues. The length of survival of miRNA-184-positive patients was analyzed. miRNA-184 mRNA expression was found in normal tissues and tumor tissues, and the expression in tumor tissues was significant (P184 expression were observed among different grades (P184 expression increased with the increase of grade level. The differences in expression across grade levels was statistically significant (P184-positive expression was significantly shorter than that of the negative expression group (P184 is highly expressed in gliomas, which is positively correlated with pathological grade, and is not correlated with pathological type, and negatively correlated with survival time. Thus, miRNA-184 is a potentially important molecular marker for glioma.

  2. 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.

  3. 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......, CDKN2A-CDKN2B), 11q23.3 (rs498872, PHLDB1), and 20q13.33 (rs6010620, RTEL1) as determinants of glioma risk. The authors investigated whether there is interaction between the effects of allergy and these 5 variants on glioma risk. Data from 5 case-control studies carried out in Denmark, Finland, Sweden.......047), and between "any allergy" and rs6010620 (greater protective effect; interaction OR = 0.70, P = 0.017). Case-only analyses provided further support for atopy interactions for rs4977756 and rs498872. This study provides evidence for possible gene-environment interactions in glioma development....

  4. 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.

  5. 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.

  6. Glutamate and α-ketoglutarate: key players in glioma metabolism.

    Science.gov (United States)

    Maus, Andreas; Peters, Godefridus J

    2017-01-01

    Glioblastoma multiforme (GBM), or grade IV astrocytoma, is the most common type of primary brain tumor. It has a devastating prognosis with a 2-year-overall survival rate of only 26 % after standard treatment, which includes surgery, radiation, and adjuvant chemotherapy with temozolomide. Also lower grade gliomas are difficult to treat, because they diffusely spread into the brain, where extensive removal of tissue is critical. Better understanding of the cancer's biology is a key for the development of more effective therapy approaches. The discovery of isocitrate dehydrogenase (IDH) mutations in leukemia and glioma drew attention to specific metabolic aberrations in IDH-mutant gliomas. In the center of the metabolic alterations is α-ketoglutarate (αKG), an intermediate metabolite in the tricarboxylic acid (TCA) cycle, and the associated amino acid glutamate (Glu). This article highlights the role of these metabolites in glioma energy and lipid production and indicates possible weak spots of IDH-mutant and IDH-wt gliomas.

  7. Single-tier testing with the C6 peptide ELISA kit compared with two-tier testing for Lyme disease.

    Science.gov (United States)

    Wormser, Gary P; Schriefer, Martin; Aguero-Rosenfeld, Maria E; Levin, Andrew; Steere, Allen C; Nadelman, Robert B; Nowakowski, John; Marques, Adriana; Johnson, Barbara J B; Dumler, J Stephen

    2013-01-01

    For the diagnosis of Lyme disease, the 2-tier serologic testing protocol for Lyme disease has a number of shortcomings including low sensitivity in early disease; increased cost, time, and labor; and subjectivity in the interpretation of immunoblots. In this study, the diagnostic accuracy of a single-tier commercial C6 ELISA kit was compared with 2-tier testing. The results showed that the C6 ELISA was significantly more sensitive than 2-tier testing with sensitivities of 66.5% (95% confidence interval [CI] 61.7-71.1) and 35.2% (95% CI 30.6-40.1), respectively (P tier testing in sera from Lyme disease patients with early neurologic manifestations (88.6% versus 77.3%, P = 0.13) or arthritis (98.3% versus 95.6%, P = 0.38). The specificities of C6 ELISA and 2-tier testing in over 2200 blood donors, patients with other conditions, and Lyme disease vaccine recipients were found to be 98.9% and 99.5%, respectively (P tier testing, the C6 ELISA as a single-step serodiagnostic test provided increased sensitivity in early Lyme disease with comparable sensitivity in later manifestations of Lyme disease. The C6 ELISA had slightly decreased specificity. Future studies should evaluate the performance of the C6 ELISA compared with 2-tier testing in routine clinical practice. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Selective accumulation and strong photodynamic effects of a new photosensitizer, ATX-S10.Na (II), in experimental malignant glioma.

    Science.gov (United States)

    Yamamoto, Junkoh; Hirano, Toru; Li, Shaoyi; Koide, Masayo; Kohno, Eiji; Inenaga, Chikanori; Tokuyama, Tsutomu; Yokota, Naoki; Yamamoto, Seiji; Terakawa, Susumu; Namba, Hiroki

    2005-11-01

    We investigated the feasibility of a novel photosensitizer, ATX-S10.Na (II), in photodynamic therapy (PDT) for glioma. First, PDT was performed in various brain tumor cell lines in vitro. Cytotoxicity depended upon both drug concentration and laser energy and the 50% inhibitory concentration ranged from 3.5 to 20 microg/ml. Next, PDT was performed in the subcutaneous and intracranial 9L tumor models in Fischer rats using ATX-S10.Na (II) and light from a 670-nm diode laser delivered by intratumoral insertion of an optical fiber. The effect of PDT on brain tumors was evaluated using magnetic resonance imaging. Sequential changes of the ATX-S10.Na (II) concentrations were also measured quantitatively by fluorospectrometry up to 12 h after intravenous administration in rats with intracranial and subcutaneous tumors. The concentration of ATX-S10.Na (II) in the brain tumor reached a maximum at 2 h after administration and the tumor/normal brain concentration ratio was as high as 131 at 8 h. Intratumoral PDT for intracranial tumors irradiated at this timing showed an obvious anti-tumor effect without severe side effects. The present study demonstrated the highly selective accumulation of ATX-S10.Na (II) in tumor tissue and its potent photodynamic effect in an experimental malignant glioma model.

  9. Discrimination between glioma grades II and III in suspected low-grade gliomas using dynamic contrast-enhanced and dynamic susceptibility contrast perfusion MR imaging

    DEFF Research Database (Denmark)

    Falk, Anna; Fahlström, Markus; Rostrup, Egill

    2014-01-01

    grade II and grade III gliomas in histogram perfusion parameters was performed, and the areas under the curves (AUC) from the ROC analyses were evaluated. RESULTS: In DCE, the skewness of transfer constant (k(trans)) was found superior for differentiating grade II from grade III in all gliomas (AUC 0.......76). In DSC, the standard deviation of relative cerebral blood flow (rCBF) was found superior for differentiating grade II from grade III gliomas (AUC 0.80). CONCLUSIONS: Histogram parameters from k(trans) (DCE) and rCBF (DSC) could most efficiently discriminate between grade II and grade III gliomas....... that could best discriminate between grade II and III gliomas. METHODS: MRI (3 T) including morphological ((T2 fluid attenuated inversion recovery (FLAIR) and T1-weighted (T1W)+Gd)) and perfusion (DCE and DSC) sequences was performed in 39 patients with newly diagnosed suspected low-grade glioma after...

  10. Detections of Long Carbon Chains CH_{3}CCCCH, C_{6}H, LINEAR-C_{6}H_{2} and C_{7}H in the Low-Mass Star Forming Region L1527

    Science.gov (United States)

    Araki, Mitsunori; Takano, Shuro; Sakai, Nami; Yamamoto, Satoshi; Oyama, Takahiro; Kuze, Nobuhiko; Tsukiyama, Koichi

    2017-06-01

    Carbon chains in the warm carbon chain chemistry (WCCC) region has been searched in the 42-44 GHz region by using Green Bank 100 m telescope. Long carbon chains C_{7}H, C_{6}H, CH_{3}CCCCH, and linear-C_{6}H_{2} and cyclic species C_{3}H and C_{3}H_{2}O have been detected in the low-mass star forming region L1527, performing the WCCC. C_{7}H was detected for the first time in molecular clouds. The column density of C_{7}H is derived to be 6.2 × 10^{10} cm^{-2} by using the detected J = 24.5-23.5 and 25.5-24.5 rotational lines. The ^{2}Π_{1/2} electronic state of C_{6}H, locating 21.6 K above the ^{2}Π_{3/2} electronic ground state, and the K_a = 0 line of the para species of linear-C_{6}H_{2} were also detected firstly in molecular clouds. The column densities of the ^{2}Π_{1/2} and ^{2}Π_{3/2} states of C_{6}H in L1527 were derived to be 1.6 × 10^{11} and 1.1 × 10^{12} cm^{-2}, respectively. The total column density of linear-C_{6}H_{2} is obtained to be 1.86 × 10^{11} cm^{-2}. While the abundance ratios of carbon chains in between L1527 and the starless dark cloud Taurus Molecular Cloud-1 Cyanopolyyne Peak (TMC-1 CP) have a trend of decrease by extension of carbon-chain length, column densities of CH_{3}CCCCH and C_{6}H are on the trend. However, the column densities of linear-C_{6}H_{2}, and C_{7}H are as abundant as those of TMC-1 CP in spite of long carbon chain, i.e., they are not on the trend. The abundances of linear-C_{6}H_{2} and C_{7}H show that L1527 is rich for long carbon chains as well as TMC-1 CP.

  11. 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.

  12. Pokemon expression in malignant glioma: an application of bioinformatics methods.

    Science.gov (United States)

    Rovin, Richard A; Winn, Robert

    2005-10-15

    In this report the authors review the role of bioinformatics in the design of a research project in which the molecular genetics of malignant glioma were studied. A project to characterize Pokemon expression in malignant glioma was developed, refined, and implemented using bioinformatics methods. Using the resources available from the National Center for Biotechnology Information, the messenger RNA (mRNA) sequence for Pokemon was determined. With this information and online primer design tools, novel primers were designed that would specifically amplify Pokemon mRNA by using reverse transcription-polymerase chain reaction assays. The promise of bioinformatics is in the rapid and widespread dissemination and analysis of genomic information. This information is then used in research investigating the genetic basis of disease. In this paper the authors review the bioinformatics methods used in their study of Pokemon expression in malignant glioma.

  13. Novel therapeutic delivery approaches in development for pediatric gliomas.

    Science.gov (United States)

    Warren, Katherine E

    2013-09-01

    Pediatric gliomas are a heterogeneous group of diseases, ranging from relatively benign pilocytic astrocytomas with >90% 5-year survival, to glioblastomas and diffuse intrinsic pontine gliomas with low-grade gliomas, but many high-grade tumors are resistant to chemotherapy. A major obstacle and contributor to this resistance is the blood–brain barrier, which protects the CNS by limiting entry of potential toxins, including chemotherapeutic agents. Several novel delivery approaches that circumvent the blood–brain barrier have been developed, including some currently in clinical trials. This review describes several of these novel approaches to improve delivery of chemotherapeutic agents to their site of action at the tumor, in attempts to improve their efficacy and the prognosis of children with this disease.

  14. [Improved diagnostics of cerebral gliomas using FET PET].

    Science.gov (United States)

    Langen, Karl-Josef; Floeth, Frank W; Stoffels, Gabriele; Hamacher, Kurt; Coenen, Heinz H; Pauleit, Dirk

    2007-01-01

    Positron emission tomography (PET) using radiolabeled amino acids has shown great potential for more accurate diagnostics of cerebral gliomas. O-(2-[18F]Fluoroethyl)-L-tyrosine (FET) is a new tracer for PET which can be produced with high efficiency and distributed on a wide clinical scale in Germany. In a biopsy-controlled study, a significant improvement of the detection of true tumor extent of cerebral gliomas could be demonstrated by the combined use of FET PET and MRT in comparison with MRT alone. Advantages of FET PET are an improved guidance of biopsies, an improved planning of surgery and radiation therapy, and the differentiation of tumor recurrence from unspecific post-therapeutic tissue changes. Furthermore, FET PET appears to be particularly valuable in the prognosis of low-grade gliomas.

  15. FT-IR study on interactions between medroxyprogesterone acetate and solvent in CHCl3/cyclo-C6H12 and CCl4/cyclo-C6H12 binary solvent systems

    Science.gov (United States)

    Shi, Jie-hua; Fan, Chun-hui

    2012-09-01

    The intermolecular interactions between medroxyprogesterone acetate (MPA) and CHCl3 and CCl4 solvent in CHCl3/cyclo-C6H12 and CCl4/cyclo-C6H12 binary solvent systems have been studied by Fourier transform infrared spectroscopy (FT-IR). The experimental results showed that there are hydrogen bonding interactions between oxygen atoms of all carbonyl groups in MPA and hydrogen atom of CHCl3 so as to form 1:3 complex of MPA with CHCl3 and produce three new absorption bands at 1728.9-1736.1, 1712.7-1717.4 and 1661.9-1673.8 cm-1, respectively. And, 1:1 complex of MPA with CCl4 is formed in CCl4/cyclo-C6H12 binary solvent as a result of hydrogen bonding interaction between C3 carbonyl group and empty d-orbital in chlorine atom of CCl4 leading to producing new absorption band at 1673.2-1674.2 cm-1. However, all free carbonyl and associated carbonyl stretching vibrations of MPA in CHCl3/cyclo-C6H12 and CCl4/cyclo-C6H12 binary solvent systems shift to lower wavenumbers with the increasing of volume fraction of CHCl3 and CCl4 in binary solvent systems owing to the dipole-dipole interaction and the dipole-induced dipole interaction between MPA and solvents.

  16. Evaluation of the C6 Lyme Enzyme Immunoassay for the Diagnosis of Lyme Disease in Children and Adolescents.

    Science.gov (United States)

    Lipsett, Susan C; Branda, John A; McAdam, Alexander J; Vernacchio, Louis; Gordon, Caroline D; Gordon, Catherine R; Nigrovic, Lise E

    2016-10-01

    The commercially-available C6 Lyme enzyme immunoassay (EIA) has been approved to replace the standard whole-cell sonicate EIA as a first-tier test for the diagnosis of Lyme disease and has been suggested as a stand-alone diagnostic. However, the C6 EIA has not been extensively studied in pediatric patients undergoing evaluation for Lyme disease. We collected discarded serum samples from children and adolescents (aged ≤21 years) undergoing conventional 2-tiered testing for Lyme disease at a single hospital-based clinical laboratory located in an area endemic for Lyme disease. We performed a C6 EIA on all collected specimens, followed by a supplemental immunoblot if the C6 EIA result was positive but the whole-cell sonicate EIA result was negative. We defined a case of Lyme disease as either a clinician-diagnosed erythema migrans lesion or a positive standard 2-tiered serologic result in a patient with symptoms compatible with Lyme disease. We then compared the performance of the C6 EIA alone and as a first-tier test followed by immunoblot, with that of standard 2-tiered serology for the diagnosis of Lyme disease. Of the 944 specimens collected, 114 (12%) were from patients with Lyme disease. The C6 EIA alone had sensitivity similar to that of standard 2-tiered testing (79.8% vs 81.6% for standard 2-tiered testing; P = .71) with slightly lower specificity (94.2% vs 98.8% 2; P Lyme disease, the C6 EIA could guide initial clinical decision making, although a supplemental immunoblot should still be performed. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  17. 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.

  18. Anatomic mapping of molecular subtypes in diffuse glioma.

    Science.gov (United States)

    Tang, Qisheng; Lian, Yuxi; Yu, Jinhua; Wang, Yuanyuan; Shi, Zhifeng; Chen, Liang

    2017-09-15

    Tumor location served as an important prognostic factor in glioma patients was considered to postulate molecular features according to cell origin theory. However, anatomic distribution of unique molecular subtypes was not widely investigated. The relationship between molecular phenotype and histological subgroup were also vague based on tumor location. Our group focuses on the study of glioma anatomic location of distinctive molecular subgroups and histology subtypes, and explores the possibility of their consistency based on clinical background. We retrospectively reviewed 143 cases with both molecular information (IDH1/TERT/1p19q) and MRI images diagnosed as cerebral diffuse gliomas. The anatomic distribution was analyzed between distinctive molecular subgroups and its relationship with histological subtypes. The influence of tumor location, molecular stratification and histology diagnosis on survival outcome was investigated as well. Anatomic locations of cerebral diffuse glioma indicate varied clinical outcome. Based on that, it can be stratified into five principal molecular subgroups according to IDH1/TERT/1p19q status. Triple-positive (IDH1 and TERT mutation with 1p19q codeletion) glioma tended to be oligodendroglioma present with much better clinical outcome compared to TERT mutation only group who is glioblastoma inclined (median overall survival 39 months VS 18 months). Five molecular subgroups were demonstrated with distinctive locational distribution. This kind of anatomic feature is consistent with its corresponding histological subtypes. Each molecular subgroup in glioma has unique anatomic location which indicates distinctive clinical outcome. Molecular diagnosis can be served as perfect complementary tool for the precise diagnosis. Integration of histomolecular diagnosis will be much more helpful in routine clinical practice in the future.

  19. 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.

  20. Connectomic profile and clinical phenotype in newly diagnosed glioma patients

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    Jolanda Derks

    2017-01-01

    Full Text Available Gliomas are primary brain tumors, originating from the glial cells in the brain. In contrast to the more traditional view of glioma as a localized disease, it is becoming clear that global brain functioning is impacted, even with respect to functional communication between brain regions remote from the tumor itself. However, a thorough investigation of glioma-related functional connectomic profiles is lacking. Therefore, we constructed functional brain networks using functional MR scans of 71 glioma patients and 19 matched healthy controls using the automated anatomical labelling (AAL atlas and interregional Pearson correlation coefficients. The frequency distributions across connectivity values were calculated to depict overall connectomic profiles and quantitative features of these distributions (full-width half maximum (FWHM, peak position, peak height were calculated. Next, we investigated the spatial distribution of the connectomic profile. We defined hub locations based on the literature and determined connectivity (1 between hubs, (2 between hubs and non-hubs, and (3 between non-hubs. Results show that patients had broader and flatter connectivity distributions compared to controls. Spatially, glioma patients particularly showed increased connectivity between non-hubs and hubs. Furthermore, connectivity distributions and hub-non-hub connectivity differed within the patient group according to tumor grade, while relating to Karnofsky performance status and progression-free survival. In conclusion, newly diagnosed glioma patients have globally altered functional connectomic profiles, which mainly affect hub connectivity and relate to clinical phenotypes. These findings underscore the promise of using connectomics as a future biomarker in this patient population.

  1. Experimental immunotherapy for malignant glioma: lessons from two decades of research in the GL261 model.

    Science.gov (United States)

    Maes, Wim; Van Gool, Stefaan W

    2011-02-01

    Nearly twenty years of experimental immunotherapy for malignant glioma yielded important insights in the mechanisms governing glioma immunology. Still considered promising, it is clear that immunotherapy does not on its own represent the magic bullet in glioma therapy. In this review, we summarize the major immunotherapeutic achievements in the mouse GL261 glioma model, which has emerged as the gold standard syngeneic model for experimental glioma therapy. Gene therapy, monoclonal antibody treatment, cytokine therapy, cell transfer strategies and dendritic cell therapy were hereby considered. Apart from the considerable progress made in understanding glioma immunology in this model, we also addressed its most pertinent issues and shortcomings. Despite these, the GL261 model will remain indispensable in glioma research since it is a fast, highly reproducible and easy-to-establish model system.

  2. Convection-enhanced delivery of a hydrophilic nitrosourea ameliorates deficits and suppresses tumor growth in experimental spinal cord glioma models.

    Science.gov (United States)

    Ogita, Shogo; Endo, Toshiki; Sugiyama, Shinichiro; Saito, Ryuta; Inoue, Tomoo; Sumiyoshi, Akira; Nonaka, Hiroi; Kawashima, Ryuta; Sonoda, Yukihiko; Tominaga, Teiji

    2017-05-01

    Convection-enhanced delivery (CED) is a technique allowing local infusion of therapeutic agents into the central nervous system, circumventing the blood-brain or spinal cord barrier. To evaluate the utility of nimustine hydrochloride (ACNU) CED in controlling tumor progression in an experimental spinal cord glioma model. Toxicity studies were performed in 42 rats following the administration of 4 μl of ACNU CED into the mid-thoracic spinal cord at concentrations ranging from 0.1 to 10 mg/ml. Behavioral analyses and histological evaluations were performed to assess ACNU toxicity in the spinal cord. A survival study was performed in 32 rats following the implantation of 9 L cells into the T8 spinal cord. Seven days after the implantation, rats were assigned to four groups: ACNU CED (0.25 mg/ml; n = 8); ACNU intravenous (i.v.) (0.4 mg; n = 8); saline CED (n = 8); saline i.v. (n = 8). Hind limb movements were evaluated daily in all rats for 21 days. Tumor sizes were measured histologically. The maximum tolerated ACNU concentration was 0.25 mg/ml. Preservation of hind limb motor function and tumor growth suppression was observed in the ACNU CED (0.25 mg/ml) and ACNU i.v. groups. Antitumor effects were more prominent in the ACNU CED group especially in behavioral analyses (P < 0.05; log-rank test). ACNU CED had efficacy in controlling tumor growth and preserving neurological function in an experimental spinal cord tumor model. ACNU CED can be a viable treatment option for spinal cord high-grade glioma.

  3. microRNA-214-mediated UBC9 expression in glioma

    OpenAIRE

    Zhao, Zhiqiang; Tan, Xiaochao; Zhao, Ani; Zhu, Liyuan; Yin, Bin; Yuan, Jiangang; Qiang, Boqin; Peng, Xiaozhong

    2012-01-01

    It has been reported that ubiquitin-conjugating enzyme 9 (Ubc9), the unique enzyme2 in the sumoylation pathway, is up-regulated in many cancers. However, the expression and regulation of UBC9 in glioma remains unknown. In this study, we found that Ubc9 was up-regulated in glioma tissues and cell lines compared to a normal control. UBC9 knockdown by small interfering RNA (siRNA) affected cell proliferation and apoptosis in T98G cells. Further experiments revealed that microRNA (miR)-214 direct...

  4. Current and Future Gene Therapy for Malignant Gliomas

    Directory of Open Access Journals (Sweden)

    Kanzawa Takao

    2003-01-01

    Full Text Available Malignant gliomas are the most common neoplasm in the central nervous system. When treated with conventional treatments including surgery, irradiation, and chemotherapy, the average life expectancy of the most malignant type, glioblastoma multiforme is usually less than 1 year. Therefore, gene therapy is expected to be an effective and possibly curative treatment. Many gene therapeutic approaches have demonstrated efficacy in experimental animal models. However, the current clinical trials are disappointing. This review focuses on current therapeutic genes/vectors/delivery systems/targeting strategies in order to introduce updated trends and hopefully indicate prospective gene therapy for malignant gliomas.

  5. 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. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  6. Long non-coding RNA H19 regulates glioma angiogenesis and the biological behavior of glioma-associated endothelial cells by inhibiting microRNA-29a.

    Science.gov (United States)

    Jia, Peng; Cai, Heng; Liu, Xiaobai; Chen, Jiajia; Ma, Jun; Wang, Ping; Liu, Yunhui; Zheng, Jian; Xue, Yixue

    2016-10-28

    Long non-coding RNAs (lncRNAs) play crucial roles in the development and progression of glioma. Previous studies indicated that lncRNA H19 regulated tumor carcinogenesis, angiogenesis and metastasis. This study aimed to investigate its functional role in glioma-induced endothelial cell proliferation, migration and tube formation as well as its possible molecular mechanisms. H19 was up-regulated in microvessels from glioma tissues and glioma-associated endothelial cells (GEC) cultured in glioma conditioned medium. Knockdown of H19 suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro and meanwhile up-regulated the expression of miR-29a. Bioinformatics analysis and luciferase reporter assay defined that H19 mediated the above effects via directly binding to miR-29a. In addition, miR-29a targeted 3'-UTR region of vasohibin 2 (VASH2) and decreased its expression. VASH2 has been identified as an angiogenic factor. Knockdown of H19 also decreased the VASH2 expression by up-regulating miR-29a. In conclusion, the results indicated that knockdown of H19 suppressed glioma induced angiogenesis by inhibiting microRNA-29a, which may modulate the onset of glioma by regulating biological behaviors of glioma vascular endothelial cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. C5 and C6 human dermatomes: a clinical, electromyographical, imaging and surgical findings Dermátomos humanos C5 e C6: estudo clínico, eletromiográfico, de imagem e cirúrgico

    Directory of Open Access Journals (Sweden)

    Antonio Tadeu de Souza Faleiros

    2009-06-01

    Full Text Available There is substantial controversy in literature about human dermatomes. In this work, C5 and C6 superior limb dermatomes were studied. The method consisted of comparing clinical signs and symptoms with conduction studies, electromyographical data, neurosurgical findings, and imaging findings obtained by computerized tomography (CT or magnetic resonance imaging (MRI, for each patient. Data analysis from superior members in 18 patients suggests that C5 is located in the lateral aspect of the shoulder and arm, and C6 in the lateral aspect of the forearm and 1st, 2nd, and 3rd fingers. To our knowledge this is the first time that C5 and C6 human dermatomes have been studied by all the following methods together: clinical, electromyographical, CT and MR imaging, and surgical findings.Há controvérsias na literatura sobre os dermátomos humanos. Neste estudo os dermátomos do membro superior C5 e C6 foram analisados. O método consistiu em comparar os sinais e sintomas com achados eletromiográficos, de imagem e achados cirúrgicos. Análise dos dados do membro superior de 18 pacientes sugere que o dermátomo C5 esteja localizado na região lateral do ombro e braço, e o dermátomo C6 na região lateral do antebraço e 1º, 2º e 3º dedos da mão. Este é o primeiro estudo em que os dermátomos C5 e C6 foram avaliados pelos dados clínicos, eletromiográficos, de imagem e achados cirúrgicos.

  8. Serum stability and physicochemical characterization of a novel amphipathic peptide C6M1 for siRNA delivery.

    Directory of Open Access Journals (Sweden)

    Mousa Jafari

    Full Text Available The efficient delivery of nucleic acids as therapeutic agents is a major challenge in gene therapy. Peptides have recently emerged as a novel carrier for delivery of drugs and genes. C6M1 is a designed amphipathic peptide with the ability to form stable complexes with short interfering RNA (siRNA. The peptide showed a combination of random coil and helical structure in water but mainly adopted a helical conformation in the presence of anions or siRNA. Revealed by dynamic light scattering (DLS and microscopy techniques, the interaction of C6M1 and siRNA in water and HEPES led to complexes of ∼70 and ∼155 nm in size, respectively, but showed aggregates as large as ∼500 nm in PBS. The time-dependent aggregation of the complex in PBS was studied by DLS and fluorescence spectroscopy. At molar ratio of 15∶1, C6M1 was able to completely encapsulate siRNA; however, higher molar ratios were required to obtain stable complexes. Naked siRNA was completely degraded in 4 h in the solution of 50% serum; however C6M1 protected siRNA against serum RNase over the period of 24 h. Western blotting experiment showed ∼72% decrease in GAPDH protein level of the cells treated with C6M1-siRNA complexes while no significant knockdown was observed for the cells treated with naked siRNA.

  9. Inhibition of GlcNAc-Processing Glycosidases by C-6-Azido-NAG-Thiazoline and Its Derivatives

    Directory of Open Access Journals (Sweden)

    Jana Krejzová

    2014-03-01

    Full Text Available NAG-thiazoline is a strong competitive inhibitor of GH20 β-N-acetyl- hexosaminidases and GH84 β-N-acetylglucosaminidases. Here, we focused on the design, synthesis and inhibition potency of a series of new derivatives of NAG-thiazoline modified at the C-6 position. Dimerization of NAG-thiazoline via C-6 attached triazole linkers prepared by click chemistry was employed to make use of multivalency in the inhibition. Novel compounds were tested as potential inhibitors of β-N-acetylhexosaminidases from Talaromyces flavus, Streptomyces plicatus (both GH20 and β-N-acetylglucosaminidases from Bacteroides thetaiotaomicron and humans (both GH84. From the set of newly prepared NAG-thiazoline derivatives, only C-6-azido-NAG-thiazoline displayed inhibition activity towards these enzymes; C-6 triazole-substituted NAG-thiazolines lacked inhibition activity against the enzymes used. Docking of C-6-azido-NAG-thiazoline into the active site of the tested enzymes was performed. Moreover, a stability study with GlcNAc-thiazoline confirmed its decomposition at pH < 6 yielding 2-acetamido-2-deoxy-1-thio-α/β-D-glucopyranoses, which presumably dimerize oxidatively into S-S linked dimers; decomposition products of NAG-thiazoline are void of inhibitory activity.

  10. THE DISTRIBUTION OF COMMERCIAL CROWN ETHER DC18C6 AND THE EXTRACTION STUDY OF ALKALI AND EARTH ALKALI METALS

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    Bambang Rusdiarso

    2010-06-01

    Full Text Available Distribution of A and B isomers of crown-ether DC18C6 on their organic and water phases (chloride, nitrate and sulphocyanide salts and extraction of alkali and earth alkali metals has been studied. In LiCl 0.1 M environment, lithium extraction could be ignored. The presence of extracted potassium metal may affect the crown ether DC18C6 distribution albeit only a little. In KNO3 0.1 M environment, the distribution coefficient values (d were 6.1 and 10.3 for A and B isomers, respectively ; while in KCl  0.1 M environment the values were 4.9 and 11.8, respectively. In KSCN 0.1 M, d values for A and B isomers were 40.4 and 36.6, respectively, which were higher than the value obtained from both KNO3 and KCl  0.1 M environments. Caesium metal extraction using DC18C6 occurred weakly, up to only 5%. Strontium extraction using DC18C6 achieved better yield than the caesium extraction. The percentage of extraction increased under organic solvent according to the following: toluene (4% < chloroform (28% < TBP (35%.   Keywords: distribution, crown-ether DC18C6, extraction.

  11. Heat of Mixing and Solution of Hex-1-ene C6H12 + C6H18N3OP Phosphoric tris(dimethylamide) (HMSD1111, LB3772_H)

    Science.gov (United States)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume B 'Binary Liquid Systems of Nonelectrolytes II' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Heat of Mixing and Solution of Hex-1-ene C6H12 + C6H18N3OP Phosphoric tris(dimethylamide) (HMSD1111, LB3772_H)' providing data from direct low-pressure calorimetric measurement of molar excess enthalpy at variable mole fraction and constant temperature.

  12. Rare bilateral C6 spondylolysis and spondylolisthesis in an adolescent athlete: evaluation with magnetic resonance imaging and multidetector computerized tomography.

    Science.gov (United States)

    Amin, Mohammed F; Mollano, Anthony V; Weinstein, Stuart L; El-Khoury, George Y

    2006-10-01

    Case report. To show a rare case of cervical spondylolysis and spondylolisthesis secondary to bilateral stress fractures at the pedicle laminar junction of C6 in a 16-year-old athlete playing high school baseball. The patient presented with 3 months of neck pain and intermittent right arm radicular symptoms. Plain radiographs and multidetector computerized tomography (CT) of the cervical spines. Plain radiographs revealed loss of lower cervical lordosis. Multidetector CT indicated bilateral C6 spondylolysis. Magnetic resonance imaging showed bilateral marrow edema at the pedicle laminar junction of C6. Treatment included placing his neck in a Philadelphia collar for 6 weeks. Follow-up CT revealed progression of healing. Early diagnosis and appropriate management of these cases are important to promote healing.

  13. Respiratory cytochrome c oxidase can be efficiently reduced by the photosynthetic redox proteins cytochrome c6 and plastocyanin in cyanobacteria.

    Science.gov (United States)

    Navarro, José A; Durán, Raúl V; De la Rosa, Miguel A; Hervás, Manuel

    2005-07-04

    Plastocyanin and cytochrome c6 are two small soluble electron carriers located in the intrathylacoidal space of cyanobacteria. Although their role as electron shuttle between the cytochrome b6f and photosystem I complexes in the photosynthetic pathway is well established, their participation in the respiratory electron transport chain as donors to the terminal oxidase is still under debate. Here, we present the first time-resolved analysis showing that both cytochrome c6 and plastocyanin can be efficiently oxidized by the aa3 type cytochrome c oxidase in Nostoc sp. PCC 7119. The apparent electron transfer rate constants are ca. 250 and 300 s(-1) for cytochrome c6 and plastocyanin, respectively. These constants are 10 times higher than those obtained for the oxidation of horse cytochrome c by the oxidase, in spite of being a reaction thermodynamically more favourable.

  14. Synthesis and biological evaluation of novel C6-cyclo secondary amine substituted purine steroid-nucleosides analogues.

    Science.gov (United States)

    Huang, Li-Hua; Li, Yang; Xu, Hong-De; Zheng, Yong-Fei; Liu, Hong-Min

    2014-07-01

    Novel C6-cyclo secondary amine substituted purine steroid-nucleoside analogues (2-9) were efficiently synthesized through displacement of the C6 chloro on the purine ring of series 1 with versatile cyclic secondary amines, including pyrrolidines, piperidine, morpholine, and piperazines. All the newly-synthesized compounds were evaluated for their anticancer activity in vitro against Hela, PC-3 and MCF-7 cell lines. Among them, compounds 5c and 6b exhibited significant cytotoxicity on PC-3 cell lines. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. An analysis of 170 glioma patients and systematic review to investigate the association between IDH-1 mutations and preoperative glioma-related epilepsy.

    Science.gov (United States)

    Yang, Yuan; Mao, Qing; Wang, Xiang; Liu, Yanhui; Mao, Yunhe; Zhou, Qiao; Luo, Jiewen

    2016-09-01

    Seizure is a common presenting symptom of glioma, and many biomarkers have been suggested to be associated with preoperative seizure; however, the relationships between IDH (isocitrate dehydrogenase) mutations and glioma-related epilepsy only recently been studied. The authors aimed to examine the correlations between IDH mutations in glioma patients with preoperative seizures and tumor location. A series of 170 glioma samples were analyzed for IDH1 R132H mutations (amino acid change from arginine to histidine at codon 132) with immunohistochemistry (IHC) staining and for IDH mutations with direct DNA sequencing when the IHC results were negative. If either the IHC or direct DNA sequencing result was positive, the IDH status was defined as mutated. The results of the IDH mutation examinations were used to analyze the relationship between mutations and glioma-related epilepsy. The study population consisted of 64 (37.6%) World Health Organization (WHO) grade II gliomas, 58 (34.1%) grade III, and 48 (28.3%) grade IV gliomas. A total of 84 samples with IDH1 mutations were observed in our study, and 54 of these presented with seizures as the initial symptoms, whereas 28 of the patients with wild-type IDH status presented with seizures (p=0.043 for the WHO grade II gliomas, p=0.002 for the grade III gliomas and p=0.942 for the grade IV gliomas, chi-squared tests). Among the WHO grade II and III gliomas, IDH1 mutations were significantly associated with preoperative seizures, but no significant relationship between IDH mutations and preoperative seizures was found with glioblastoma multiforme. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. 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.

  17. Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy.

    Science.gov (United States)

    Khan, Zahidul; Knecht, Wolfgang; Willer, Mette; Rozpedowska, Elzbieta; Kristoffersen, Peter; Clausen, Anders Ranegaard; Munch-Petersen, Birgitte; Almqvist, Per M; Gojkovic, Zoran; Piskur, Jure; Ekström, Tomas J

    2010-06-01

    The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the nucleoside analog prodrug zidovudine (azidothymidine, AZT), which is known to penetrate the blood-brain barrier. An important feature of toTK1 is that it efficiently phosphorylates its substrate AZT not only to AZT monophosphate, but also to AZT diphosphate, with excellent kinetics. The efficiency of the toTK1/AZT system was confirmed when toTK1-transduced human glioblastoma (GBM) cells displayed a 500-fold increased sensitivity to AZT compared with wild-type cells. In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT suicide gene therapy system in combination with stem cell-mediated gene delivery promises new treatment of malignant gliomas.

  18. 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.

  19. Exploiting macrophages as targeted carrier to guide nanoparticles into glioma.

    Science.gov (United States)

    Pang, Liang; Qin, Jing; Han, Limei; Zhao, Wenjie; Liang, Jianming; Xie, Zhongyi; Yang, Pei; Wang, Jianxin

    2016-06-14

    The restriction of anti-cancer drugs entry to tumor sites in the brain is a major impediment to the development of new strategies for the treatment of glioma. Based on the finding that macrophages possess an intrinsic homing property enabling them to migrate to tumor sites across the endothelial barriers in response to the excretion of cytokines/chemokines in the diseased tissues, we exploited macrophages as 'Trojan horses' to carry drug-loading nanoparticles (NPs), pass through barriers, and offload them into brain tumor sites. Anticancer drugs were encapsulated in nanoparticles to avoid their damage to the cells. Drug loading NPs was then incubated with RAW264.7 cells in vitro to prepare macrophage-NPs (M-NPs). The release of NPs from M-NPs was very slow in medium of DMEM and 10% FBS and significantly accelerated when LPS and IFN-γ were added to mimic tumor inflammation microenvironment. The viability of macrophages was not affected when the concentration of doxorubicin lower than 25 μg/ml. The improvement of cellular uptake and penetration into the core of glioma spheroids of M-NPs compared with NPs was verified in in vitro studies. The tumor-targeting efficiency of NPs was also significantly enhanced after loading into macrophages in nude mice bearing intracranial U87 glioma. Our results provided great potential of macrophages as an active biocarrier to deliver anticancer drugs to the tumor sites in the brain and improve therapeutic effects of glioma.

  20. 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.

  1. Patterns of diagnostic marker assessment in adult diffuse glioma

    DEFF Research Database (Denmark)

    Woehrer, Adelheid; Kristensen, Bjarne W.; Vital, Anne

    2017-01-01

    markers to routine diagnostic use. Adult diffuse glioma is a prototypic example for a group of tumors that underwent substantial regrouping, and it represents a major workload for surgical neuropathologists. Hence, we conducted a survey among members of the European Confederation of Neuropathological...

  2. 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

  3. 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

  4. microRNA-214-mediated UBC9 expression in glioma.

    Science.gov (United States)

    Zhao, Zhiqiang; Tan, Xiaochao; Zhao, Ani; Zhu, Liyuan; Yin, Bin; Yuan, Jiangang; Qiang, Boqin; Peng, Xiaozhong

    2012-11-01

    It has been reported that ubiquitin-conjugating enzyme 9 (Ubc9), the unique enzyme2 in the sumoylation pathway, is up-regulated in many cancers. However, the expression and regulation of UBC9 in glioma remains unknown. In this study, we found that Ubc9 was up-regulated in glioma tissues and cell lines compared to a normal control. UBC9 knockdown by small interfering RNA (siRNA) affected cell proliferation and apoptosis in T98G cells. Further experiments revealed that microRNA (miR)-214 directly targeted the 3' untranslated region (UTR) of UBC9 and that there was an inverse relationship between the expression levels of miR-214 and UBC9 protein in glioma tissues and cells. miR-214 overexpression suppressed the endogenous UBC9 protein and affected T98G cell proliferation. These findings suggest that miR-214 reduction facilitates UBC9 expression and is involved in the regulation of glioma cell proliferation.

  5. microRNA-214-mediated UBC9 expression in glioma

    Directory of Open Access Journals (Sweden)

    Zhiqiang Zhao, Xiaochao Tan, Ani Zhao, Liyuan Zhu, Bin Yin, Jiangang Yuan, Boqin Qiang & Xiaozhong Peng*

    2012-11-01

    Full Text Available It has been reported that ubiquitin-conjugating enzyme 9 (Ubc9,the unique enzyme2 in the sumoylation pathway, is up-regulatedin many cancers. However, the expression and regulation ofUBC9 in glioma remains unknown. In this study, we found thatUbc9 was up-regulated in glioma tissues and cell lines comparedto a normal control. UBC9 knockdown by small interfering RNA(siRNA affected cell proliferation and apoptosis in T98G cells.Further experiments revealed that microRNA (miR-214 directlytargeted the 3' untranslated region (UTR of UBC9 and that therewas an inverse relationship between the expression levels ofmiR-214 and UBC9 protein in glioma tissues and cells. miR-214overexpression suppressed the endogenous UBC9 protein andaffected T98G cell proliferation. These findings suggest thatmiR-214 reduction facilitates UBC9 expression and is involvedin the regulation of glioma cell proliferation

  6. Insulator dysfunction and oncogene activation in IDH mutant gliomas.

    Science.gov (United States)

    Flavahan, William A; Drier, Yotam; Liau, Brian B; Gillespie, Shawn M; Venteicher, Andrew S; Stemmer-Rachamimov, Anat O; Suvà, Mario L; Bernstein, Bradley E

    2016-01-07

    Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.

  7. 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.

  8. Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy.

    Science.gov (United States)

    Friedman, Gregory K; Raborn, Joel; Kelly, Virginia M; Cassady, Kevin A; Markert, James M; Gillespie, G Yancey

    2013-01-01

    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 HGG must be able to eradicate these therapy-resistant GSCs. Oncolytic herpes simplex viruses (oHSV), 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 oHSV.

  9. Modeling of Malignant Glioma and Investigations into Novel Treatments

    NARCIS (Netherlands)

    R.K. Balvers (Rutger)

    2015-01-01

    markdownabstractAbstract With the advent of personalized medicine and large omics-based profiling studies into multiple diseases, new opportunities rise for the treatment of Malignant Glioma. This primary brain tumor remains unvariantly fatal and therefore urgently requires novel treatment

  10. 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.)

  11. miR-21 Is Linked to Glioma Angiogenesis

    DEFF Research Database (Denmark)

    Hermansen, Simon Kjær; Nielsen, Boye Schnack; Aaberg-Jessen, Charlotte

    2016-01-01

    MicroRNA-21 (miR-21) is the most consistently over-expressed microRNA (miRNA) in malignant gliomas. We have previously reported that miR-21 is upregulated in glioma vessels and subsets of glioma cells. To better understand the role of miR-21 in glioma angiogenesis and to characterize miR-21......-positive tumor cells, we systematically stained consecutive serial sections from ten astrocytomas for miR-21, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), phosphatase and tensin homolog (PTEN), octamer-binding transcription factor 4 (Oct4), sex-determining region Y box 2...... (Sox2) and CD133. We developed an image analysis-based co-localization approach allowing global alignment and quantitation of the individual markers, and measured the miR-21 in situ hybridization signal against the immunohistochemical staining of the six different markers. miR-21 significantly co...

  12. EXPLORING THE ANTITUMOR EFFECT OF VIRUS IN MALIGNANT GLIOMA.

    Science.gov (United States)

    Saha, Dipongkor; Ahmed, Seemin S; Rabkin, Samuel D

    Malignant gliomas are the most common type of primary malignant brain tumor with no effective treatments. Current conventional therapies (surgical resection, radiation therapy, temozolomide (TMZ), and bevacizumab administration) typically fail to eradicate the tumors resulting in the recurrence of treatment-resistant tumors. Therefore, novel approaches are needed to improve therapeutic outcomes. Oncolytic viruses (OVs) are excellent candidates as a more effective therapeutic strategy for aggressive cancers like malignant gliomas since OVs have a natural preference or have been genetically engineered to selectively replicate in and kill cancer cells. OVs have been used in numerous preclinical studies in malignant glioma, and a large number of clinical trials using OVs have been completed or are underway that have demonstrated safety, as well as provided indications of effective antiglioma activity. In this review, we will focus on those OVs that have been used in clinical trials for the treatment of malignant gliomas (herpes simplex virus, adenovirus, parvovirus, reovirus, poliovirus, Newcastle disease virus, measles virus, and retrovirus) and OVs examined preclinically (vesicular stomatitis virus and myxoma virus), and describe how these agents are being used.

  13. Convection-enhanced Delivery of Therapeutics for Malignant Gliomas.

    Science.gov (United States)

    Saito, Ryuta; Tominaga, Teiji

    2017-01-15

    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 promisin