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Sample records for activity improves glioblastoma

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

    Science.gov (United States)

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

    2014-01-01

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

  2. Glioblastoma

    Science.gov (United States)

    ... these tumors to contain cystic mineral, calcium deposits, blood vessels, or a mixed grade of cells. Glioblastomas are usually highly malignant—a large number of tumor cells are reproducing at any given time, and they are nourished by an ample blood supply. Dead cells may also be seen, especially ...

  3. Effect of alternative temozolomide schedules on glioblastoma O 6-methylguanine-DNA methyltransferase activity and survival

    OpenAIRE

    Robinson, C G; Palomo, J M; Rahmathulla, G; McGraw, M; Donze, J; L. Liu; Vogelbaum, M A

    2010-01-01

    Background: O 6-methylguanine-DNA methyltransferase (MGMT) expression in glioblastoma correlates with temozolomide resistance. Dose-intense temozolomide schedules deplete MGMT activity in peripheral blood mononuclear cells; however, no published data exist evaluating the effect of temozolomide schedules on intracranial tumour MGMT activity. Methods: Human glioblastoma cells (GBM43) with an unmethylated MGMT promoter were implanted intracranially in immunodeficient rodents. Three weeks later, ...

  4. Bevacizumab Improves Quality of Life in Patients with Recurrent Glioblastoma

    OpenAIRE

    Seema Nagpal; Griffith Harsh; Lawrence Recht

    2011-01-01

    Objective. To quantify the benefits in survival and quality of life in patients receiving bevacizumab (BEV) for recurrent glioblastoma (GBM). Methods. This is a retrospective study of 40 adult patients with recurrent GBM treated between 2005 and 2009 at a single institution. All patients had initial treatment with surge...

  5. Bevacizumab Improves Quality of Life in Patients with Recurrent Glioblastoma

    Directory of Open Access Journals (Sweden)

    Seema Nagpal

    2011-01-01

    Full Text Available Objective. To quantify the benefits in survival and quality of life in patients receiving bevacizumab (BEV for recurrent glioblastoma (GBM. Methods. This is a retrospective study of 40 adult patients with recurrent GBM treated between 2005 and 2009 at a single institution. All patients had initial treatment with surgery, radiation, and concurrent temozolomide, then monthly temozolomide. Over 250 charts were screened. Sufficient data was available for 20 patients treated with BEV and 20 patients who did not receive BEV at the time of recurrence. The independent living score (ILS, designed to reward long-term independent survival, was calculated for each patient. Results. The mean ILS was nearly double in the BEV group compared to the No-BEV group (15.0 versus 8.2, =0.002, t-test. Two months after initiation of therapy, the median steroid dose dropped by over 90% in patients treated with BEV, but doubled in the NoBEV group. Median survival from the time of recurrence was significantly affected: 10.6 months in the BEV group versus 4.2 months (<0.001, log rank survival in the NoBEV group. Conclusions. BEV increases independent living and lengthens overall survival after GBM recurrence. Reduction in steroid dose may contribute to prolonged independence.

  6. In-vitro suppression of metabolic activity in malignant human glioblastomas due to pulsed - low frequency electric potential exposures

    Science.gov (United States)

    Schlichting, Abby; Waynant, Ronald W.; Tata, Darrell B.

    2010-02-01

    The role of pulsed - low repetition frequency electric potential was investigated in suppressing the metabolic activities of aggressive human brain cancer cells. Twenty four hours post exposure the glioblastomas were found to be significantly inhibited in their metabolic activity. The findings herein reveal a near complete inhibition of glioblastoma's metabolic activity through selective applications of low frequency pulsed electric potentials.

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

    Science.gov (United States)

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

    2016-08-01

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

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

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

    2013-01-01

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

  9. New insights into the anticancer activity of carnosol: p53 reactivation in the U87MG human glioblastoma cell line.

    Science.gov (United States)

    Giacomelli, Chiara; Natali, Letizia; Trincavelli, Maria Letizia; Daniele, Simona; Bertoli, Alessandra; Flamini, Guido; Braca, Alessandra; Martini, Claudia

    2016-05-01

    Glioblastoma multiforme (GBM) is an aggressive brain tumour with high resistance to radio- and chemotherapy. As such, increasing attention has focused on developing new therapeutic strategies to improve treatment responses. Recently, attention has been shifted to natural compounds that are able to halt tumour development. Among them, carnosol (CAR), a phenolic diterpene present in rosemary, has become a promising molecule that is able to prevent certain types of solid cancer. However, no data are available on the effects of CAR in GBM. Here, CAR activity decreased the proliferation of different human glioblastoma cell lines, particularly cells that express wild type p53. The p53 pathway is involved in the control of apoptosis and is often impaired in GBM. Notably, CAR, through the dissociation of p53 from its endogenous inhibitor MDM2, was able to increase the intracellular p53 levels in GBM cells. Accordingly, functional reactivation of p53 was demonstrated by the stimulation of p53 target genes' transcription, the induction of apoptosis and cell cycle blockade. Most importantly, CAR produced synergistic effects with temozolomide (TMZ) and reduced the restoration of the tumour cells' proliferation after drug removal. Thus, for the first time, these data highlighted the potential use of the diterpene in the sensitization of GBM cells to chemotherapy through a direct re-activation of p53 pathway. Furthermore, progress has been made in delineating the biochemical mechanisms underlying the pro-apoptotic effects of this molecule. PMID:26939786

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

    Science.gov (United States)

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

    2014-02-01

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

  11. STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-02-10

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

  12. Inhibition of Multidrug resistance protein 1 (MRP1 improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

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    Amanda eTivnan

    2015-06-01

    Full Text Available Glioblastoma multiforme (GBM is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1 in high grade glioma, and it’s role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150µM, vincristine (100nM and etoposide (2µM. Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and Multidrug resistance protein 4 (MRP4 led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 hour period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients.

  13. Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme.

    Science.gov (United States)

    Tivnan, Amanda; Zakaria, Zaitun; O'Leary, Caitrín; Kögel, Donat; Pokorny, Jenny L; Sarkaria, Jann N; Prehn, Jochen H M

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150 μM), vincristine (100 nM), and etoposide (2 μM). Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein) led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and multidrug resistance protein 4 (MRP4) led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 h period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients. PMID:26136652

  14. EGFR as a therapeutic target in glioblastoma

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    David M Siebert

    2012-01-01

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

  15. BI-33BEVACIZUMAB-INDUCED HYPERTENSION IS A PREDICTIVE MARKER FOR IMPROVED OUTCOMES IN RECURRENT GLIOBLASTOMA

    OpenAIRE

    Zhong, Jim; Ali, Arif; Voloschin, Alfredo; Liu, Yuan; Curran, Walter; Crocker, Ian; Shu, Hui-Kuo

    2014-01-01

    PURPOSE: Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) approved for treatment of recurrent glioblastoma (GBM). Previous studies have demonstrated differential outcomes for patients treated with this agent for other tumors based on whether hypertension developed as a side effect. We conducted a single-institutional retrospective study analyzing survival outcomes for patients with recurrent GBM treated with bevacizumab based on whether patients develop...

  16. Tectal glioblastoma Glioblastoma tetal

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    Feres Chaddad Neto

    2007-12-01

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

  17. Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity

    International Nuclear Information System (INIS)

    Activation of Notch signaling contributes to glioblastoma multiform (GBM) tumorigenesis. However, the molecular mechanism that promotes the Notch signaling augmentation during GBM genesis remains largely unknown. Identification of new factors that regulate Notch signaling is critical for tumor treatment. The expression levels of RND3 and its clinical implication were analyzed in GBM patients. Identification of RND3 as a novel factor in GBM genesis was demonstrated in vitro by cell experiments and in vivo by a GBM xenograft model. We found that RND3 expression was significantly decreased in human glioblastoma. The levels of RND3 expression were inversely correlated with Notch activity, tumor size, and tumor cell proliferation, and positively correlated with patient survival time. We demonstrated that RND3 functioned as an endogenous repressor of the Notch transcriptional complex. RND3 physically interacted with NICD, CSL, and MAML1, the Notch transcriptional complex factors, promoted NICD ubiquitination, and facilitated the degradation of these cofactor proteins. We further revealed that RND3 facilitated the binding of NICD to FBW7, a ubiquitin ligase, and consequently enhanced NICD protein degradation. Therefore, Notch transcriptional activity was inhibited. Forced expression of RND3 repressed Notch signaling, which led to the inhibition of glioblastoma cell proliferation in vitro and tumor growth in the xenograft mice in vivo. Downregulation of RND3, however, enhanced Notch signaling activity, and subsequently promoted glioma cell proliferation. Inhibition of Notch activity abolished RND3 deficiency-mediated GBM cell proliferation. We conclude that downregulation of RND3 is responsible for the enhancement of Notch activity that promotes glioblastoma genesis

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Science.gov (United States)

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

    1987-01-01

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

  20. CDBG Public Improvements Activity

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

  1. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

    OpenAIRE

    Batchelor, Tracy T.; Gerstner, Elizabeth R.; Emblem, Kyrre E; Dan G Duda; Kalpathy-Cramer, Jayashree; Snuderl, Matija; Ancukiewicz, Marek; Polaskova, Pavlina; Pinho, Marco C.; Jennings, Dominique; Plotkin, Scott R.; Chi, Andrew S.; Eichler, April F.; Dietrich, Jorg; Hochberg, Fred H.

    2013-01-01

    This study demonstrates that antiangiogenic therapy increases tumor blood perfusion in a subset of newly diagnosed glioblastoma patients, and that it is these patients who survive longer when this expensive and potentially toxic therapy is combined with standard radiation and chemotherapy. This study provides fresh insights into the selection of glioblastoma patients most likely to benefit from antiangiogenic treatments.

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

    Science.gov (United States)

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

    2016-06-01

    Interferon-induced protein with tetratricopeptide repeat 1 (IFIT1) plays a key role in growth suppression and apoptosis promotion in cancer cells. Interferon was reported to induce the expression of IFIT1 and inhibit the expression of O-6-methylguanine-DNA methyltransferase (MGMT).This study aimed to investigate the expression of IFIT1, the correlation between IFIT1 and MGMT, and their impact on the clinical outcome in newly diagnosed glioblastoma. The expression of IFIT1 and MGMT and their correlation were investigated in the tumor tissues from 70 patients with newly diagnosed glioblastoma. The effects on progression-free survival and overall survival were evaluated. Of 70 cases, 57 (81.4%) tissue samples showed high expression of IFIT1 by immunostaining. The χ(2) test indicated that the expression of IFIT1 and MGMT was negatively correlated (r = -0.288, P = .016). Univariate and multivariate analyses confirmed high IFIT1 expression as a favorable prognostic indicator for progression-free survival (P = .005 and .017) and overall survival (P = .001 and .001), respectively. Patients with 2 favorable factors (high IFIT1 and low MGMT) had an improved prognosis as compared with others. The results demonstrated significantly increased expression of IFIT1 in newly diagnosed glioblastoma tissue. The negative correlation between IFIT1 and MGMT expression may be triggered by interferon. High IFIT1 can be a predictive biomarker of favorable clinical outcome, and IFIT1 along with MGMT more accurately predicts prognosis in newly diagnosed glioblastoma. PMID:26980050

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Li Li

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

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

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    Noel J. Aherne

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Stephen Shannon

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

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

    OpenAIRE

    Larson, Erik W.; Peterson, Halloran E.; Fairbanks, Robert K; Lamoreaux, Wayne T.; Mackay, Alexander R.; Call, Jason A.; Demakas, John J.; Cooke, Barton S; Lee, Christopher M

    2013-01-01

    The management of glioblastoma multiforme (GBM) is in most cases complex and must be specifically tailored to the needs of the patient with the goals of extended survival and improved quality of life. Despite advancements in therapy, treatment outcomes remain almost universally poor. Salvage treatment options for the recurrence of the disease is an area of intense study. The following case highlights the utility of Gamma Knife Radiosurgery (GKRS) as a salvage treatment. In this clinical situa...

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

    Directory of Open Access Journals (Sweden)

    Nam Phong Nguyen

    2013-11-01

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

  9. Neuronal Activity, Mitogens, and mTOR: Overcoming the Hurdles for the Treatment of Glioblastoma Multiforme

    OpenAIRE

    Maiese, Kenneth

    2015-01-01

    Glioblastoma multiforme (GBM) and other malignant gliomas are considered to be the most prevalent of primary malignant brain tumors. The incidence of these tumors per year is reported as 4.13 per 100,000 individuals per year. The median survival time following the diagnosis of GBM is approximately fifteen months in the setting of providing presently available treatments with surgical resection, radiation, and chemotherapy. Given these statistics, new strategies for the treatment of GBM and ot...

  10. Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma

    OpenAIRE

    Yamaki, Tomohiro; Suenaga, Yusuke; Iuchi, Toshihiko; Alagu, Jennifer; Takatori, Atsushi; Itami, Makiko; Araki, Akinobu; Ohira, Miki; Inoue, Masahiro; Kageyama, Hajime; Yokoi, Sana; Saeki, Naokatsu; Nakagawara, Akira

    2013-01-01

    Glioblastoma multiforme (GBM) is a highly invasive and chemoradioresistant brain malignancy. Temozolomide (TMZ), a DNA-alkylating agent, is effective against GBM and has become the standard first-line drug. However, the mechanism by which TMZ regulates the progression of GBM remains elusive. Here, we demonstrate that TMZ targets TAp63, a p53 family member, inducing its expression to suppress the progression of human GBM. High levels of TAp63 expression in GBM tissues after TMZ treatment was a...

  11. Glioblastoma stem cells resistant to temozolomide-induced autophagy

    Institute of Scientific and Technical Information of China (English)

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

    2009-01-01

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

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

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    Enfeng Wang

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

  13. Cell survival of glioblastoma grown in medium containing hydrogen peroxide and/or nitrite, or in plasma-activated medium.

    Science.gov (United States)

    Kurake, Naoyuki; Tanaka, Hiromasa; Ishikawa, Kenji; Kondo, Takashi; Sekine, Makoto; Nakamura, Kae; Kajiyama, Hiroaki; Kikkawa, Fumitaka; Mizuno, Masaaki; Hori, Masaru

    2016-09-01

    Non-equilibrium atmospheric pressure plasmas generate a high electron density (on the order of 10(16) electrons per cm(-3)) using Ar gas. Culture medium in air at room temperature was plasma-irradiated for several hundred seconds. Tens of micromolar hydrogen peroxide (H2O2) and millimolar levels of nitrous ion (NO2(-)) were detected in the plasma-irradiated culture medium (plasma activated medium; PAM) and selectively induced the apoptotic death of glioblastoma tumor cells, but did not kill normal mammary epithelial cells. A similar antitumor effect was induced by spiking the medium with comparable concentrations of H2O2 and NO2(-). The PAM remained still a somewhat difference that it should also be assessed for understanding other latent mechanisms. PMID:26820218

  14. Mesenchymal Migration as a Therapeutic Target in Glioblastoma

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    Jessie Zhong

    2010-01-01

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

  15. O6-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma

    Science.gov (United States)

    Bobola, Michael S.; Alnoor, Mohammad; Chen, John Y.-S.; Kolstoe, Douglas D.; Silbergeld, Daniel L.; Rostomily, Robert C.; Blank, A.; Chamberlain, Marc C.; Silber, John R.

    2014-01-01

    Background CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies. Methods We examined the relationship of MGMT activity in 91 GBMs and 84 AGs with progression-free survival (PFS) following alkylator therapy and with promoter methylation status determined by methylation-specific PCR (MSP). Results Cox regression analysis revealed that GBMs with high activity had a significantly greater risk for progression in dichotomous (P ≤ 0.001) and continuous (P ≤ 0.003) models, an association observed for different alkylator regimens, including concurrent chemo-radiation with temozolomide. Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors had significantly lower activity (P ≤ 0.005) and longer PFS (P ≤ 0.036) compared to unmethylated tumors, despite overlapping activities. PFS was also significantly greater in methylated vs. unmethylated GBMs with comparable activity (P ≤ 0.005), and among unmethylated tumors with less than median activity (P ≤ 0.026), suggesting that mechanisms in addition to MGMT promote alkylator resistance. Similar associations of MGMT activity with PFS and promoter methylation status were observed for AGs. Conclusions Our results provide strong support for the hypotheses that MGMT activity promotes alkylator resistance and reflects promoter methylation status in malignant gliomas. General significance MGMT activity is an attractive target for anti-resistance therapy regardless of methylation status. PMID:25558448

  16. Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

    OpenAIRE

    Tivnan, Amanda; Zakaria, Zaitun; O'Leary, Caitrín; Kögel, Donat; Pokorny, Jenny L.; Sarkaria, Jann N.; Prehn, Jochen H M

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30–40% response rate, many fall into the range of 10–20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB ...

  17. Inhibition of Multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

    OpenAIRE

    Amanda eTivnan; Zaitun eZakaria; Caitrin eO'Leary; Donat eKogel; Pokorny, Jenny L.; Sarkaria, Jann N.; Prehn, Jochen H M

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it’s role in BB...

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

    Science.gov (United States)

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

    2015-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Meurer Luise

    2006-09-01

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

  20. Piperlongumine selectively kills glioblastoma multiforme cells via reactive oxygen species accumulation dependent JNK and p38 activation.

    Science.gov (United States)

    Liu, Ju Mei; Pan, Feng; Li, Li; Liu, Qian Rong; Chen, Yong; Xiong, Xin Xin; Cheng, Kejun; Yu, Shang Bin; Shi, Zhi; Yu, Albert Cheung-Hoi; Chen, Xiao Qian

    2013-07-19

    Piperlongumine (PL), a natural alkaloid isolated from the long pepper, may have anti-cancer properties. It selectively targets and kills cancer cells but leaves normal cells intact. Here, we reported that PL selectively killed glioblastoma multiforme (GBM) cells via accumulating reactive oxygen species (ROS) to activate JNK and p38. PL at 20μM could induce severe cell death in three GBM cell lines (LN229, U87 and 8MG) but not astrocytes in cultures. PL elevated ROS prominently and reduced glutathione levels in LN229 and U87 cells. Antioxidant N-acetyl-L-cysteine (NAC) completely reversed PL-induced ROS accumulation and prevented cell death in LN229 and U87 cells. In LN229 and U87 cells, PL-treatment activated JNK and p38 but not Erk and Akt, in a dosage-dependent manner. These activations could be blocked by NAC pre-treatment. JNK and p38 specific inhibitors, SB203580 and SP600125 respectively, significantly blocked the cytotoxic effects of PL in LN229 and U87 cells. Our data first suggests that PL may have therapeutic potential for one of the most malignant and refractory tumors GBM. PMID:23796709

  1. Piperlongumine inhibits migration of glioblastoma cells via activation of ROS-dependent p38 and JNK signaling pathways.

    Science.gov (United States)

    Liu, Qian Rong; Liu, Ju Mei; Chen, Yong; Xie, Xiao Qiang; Xiong, Xin Xin; Qiu, Xin Yao; Pan, Feng; Liu, Di; Yu, Shang Bin; Chen, Xiao Qian

    2014-01-01

    Piperlongumine (PL) is recently found to kill cancer cells selectively and effectively via targeting reactive oxygen species (ROS) responses. To further explore the therapeutic effects of PL in cancers, we investigated the role and mechanisms of PL in cancer cell migration. PL effectively inhibited the migration of human glioma (LN229 or U87 MG) cells but not normal astrocytes in the scratch-wound culture model. PL did not alter EdU(+)-cells and cdc2, cdc25c, or cyclin D1 expression in our model. PL increased ROS (measured by DCFH-DA), reduced glutathione, activated p38 and JNK, increased IκBα, and suppressed NFκB in LN229 cells after scratching. All the biological effects of PL in scratched LN229 cells were completely abolished by the antioxidant N-acetyl-L-cysteine (NAC). Pharmacological administration of specific p38 (SB203580) or JNK (SP600125) inhibitors significantly reduced the inhibitory effects of PL on LN229 cell migration and NF κ B activity in scratch-wound and/or transwell models. PL prevented the deformation of migrated LN229 cells while NAC, SB203580, or SP600125 reversed PL-induced morphological changes of migrated cells. These results suggest potential therapeutic effects of PL in the treatment and prevention of highly malignant tumors such as glioblastoma multiforme (GBM) in the brain by suppressing tumor invasion and metastasis. PMID:24967005

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

    Directory of Open Access Journals (Sweden)

    Qian Rong Liu

    2014-01-01

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

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

    Science.gov (United States)

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

    2016-11-01

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

  4. Bevacizumab for the Treatment of Recurrent Glioblastoma

    OpenAIRE

    Chamberlain, Marc C.

    2011-01-01

    Despite advances in upfront therapy, the prognosis in the great majority of patients with glioblastoma (GBM) is poor as almost all recur and result in disease-related death. Glioblastoma are highly vascularized cancers with elevated expression levels of vascular endothelial growth factor (VEGF), the dominant mediator of angiogenesis. A compelling biologic rationale, a need for improved therapy, and positive results from studies of bevacizumab in other cancers led to the evaluation of bevacizu...

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

    Institute of Scientific and Technical Information of China (English)

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Naama Dror

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Yongsheng Li

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Erik W. Larson

    2013-01-01

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

  11. Multiple extraneural metastasis of glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    J. Undabeitia

    2015-04-01

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

  12. Stereotactic Radiosurgery for Glioblastoma.

    Science.gov (United States)

    Redmond, Kristin J; Mehta, Minesh

    2015-01-01

    Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and one of the most aggressive of all human cancers. GBM tumors are highly infiltrative and relatively resistant to conventional therapies. Aggressive management of GBM using a combination of surgical resection, followed by fractionated radiotherapy and chemotherapy has been shown to improve overall survival; however, GBM tumors recur in the majority of patients and the disease is most often fatal. There is a need to develop new treatment regimens and technological innovations to improve the overall survival of GBM patients. The role of stereotactic radiosurgery (SRS) for the treatment of GBM has been explored and is controversial. SRS utilizes highly precise radiation techniques to allow dose escalation and delivery of ablative radiation doses to the tumor while minimizing dose to the adjacent normal structures. In some studies, SRS with concurrent chemotherapy has shown improved local control with acceptable toxicities in select GBM patients. However, because GBM is a highly infiltrative disease, skeptics argue that local therapies, such as SRS, do not improve overall survival. The purpose of this article is to review the literature regarding SRS in both newly diagnosed and recurrent GBM, to describe SRS techniques, potential eligible SRS candidates, and treatment-related toxicities. In addition, this article will propose promising areas for future research for SRS in the treatment of GBM. PMID:26848407

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

    Science.gov (United States)

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

    2011-10-01

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

  14. Emerging Biomarkers in Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-08-22

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

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

    Science.gov (United States)

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

    2012-02-01

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

  16. Eosinophils in glioblastoma biology

    Directory of Open Access Journals (Sweden)

    Curran Colleen S

    2012-01-01

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

  17. P04.16THE BIOMARKER POTENTIAL OF MGMT PROTEIN EXPRESSION IN GLIOBLASTOMA IS IMPROVED BY EXCLUSION OF NON-TUMOR CELLS

    Science.gov (United States)

    Klitkou, J.; Dahlrot, R.H.; Hansen, S.; Kristensen, B.W.

    2014-01-01

    INTRODUCTION: Methylation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) gene promoter is predictive of benefit from temozolomide (TMZ) in glioblastoma (GBM). Non-tumor cells are numerous in GBMs and a potential source of bias in attempts to determine MGMT status by immunohistochemistry. The aim of the present study was to explore the prognostic potential of MGMT protein expression excluding these cells. METHOD: Immunofluorescence multiplexing and automated analysis were combined to quantify MGMT (green fluorescence) in tumor cell nuclei using image analysis algorithms. Microglia/macrophages, lymfocytes and vascular structures (red fluorescence) known to express MGMT were excluded from the analysis. The study included paraffin sections from 173 primary GBM's. RESULTS: High area fraction of tumor cell nuclei expressing MGMT was associated with poor prognosis (HR = 1.59, p = 0.005). Prognostic value of MGMT expression was particularly strong in patients treated with TMZ as first line therapy (HR = 2.31, p = 0.0003). The 2-year survival in this group was 44 % versus 7 % for patients with low and high expression respectively. Non-tumor cell nuclei often showed higher MGMT expression than adjacent tumor cells. Exclusion of these cells was shown to improve the prognostic value of MGMT expression. CONCLUSION: MGMT protein expression in tumor cell nuclei holds prognostic potential in GBM. Exclusion of non-tumor cells from the analysis is crucial to avoid false positives. The path to possible clinical implementation will require further testing in independent patient cohorts as well as development of a highly robust multiplexing assay with not yet defined cut-off levels.

  18. Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome

    Science.gov (United States)

    Weller, Michael; Nabors, Louis Burt; Gorlia, Thierry; Leske, Henning; Rushing, Elisabeth; Bady, Pierre; Hicking, Christine; Perry, James; Hong, Yong-Kil; Roth, Patrick; Wick, Wolfgang; Goodman, Simon L.; Hegi, Monika E.; Picard, Martin; Moch, Holger; Straub, Josef; Stupp, Roger

    2016-01-01

    Integrins αvβ3 and αvβ5 regulate angiogenesis and invasiveness in cancer, potentially by modulating activation of the transforming growth factor (TGF)-β pathway. The randomized phase III CENTRIC and phase II CORE trials explored the integrin inhibitor cilengitide in patients with newly diagnosed glioblastoma with versus without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. These trials failed to meet their primary endpoints. Immunohistochemistry was used to assess the levels of the target integrins of cilengitide, αvβ3 and αvβ5 integrins, of αvβ8 and of their putative target, phosphorylation of SMAD2, in tumor tissues from CENTRIC (n=274) and CORE (n=224). αvβ3 and αvβ5 expression correlated well in tumor and endothelial cells, but showed little association with αvβ8 or pSMAD2 levels. In CENTRIC, there was no interaction between the biomarkers and treatment for prediction of outcome. In CORE, higher αvβ3 levels in tumor cells were associated with improved progression-free survival by central review and with improved overall survival in patients treated with cilengitide. Integrins αvβ3, αvβ5 and αvβ8 are differentially expressed in glioblastoma. Integrin levels do not correlate with the activation level of the canonical TGF-β pathway. αvβ3 integrin expression may predict benefit from integrin inhibition in patients with glioblastoma lacking MGMT promoter methylation. PMID:26918452

  19. Coordination of glioblastoma cell motility by PKCι

    Directory of Open Access Journals (Sweden)

    Baldwin R Mitchell

    2010-09-01

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

  20. Motor activity improves temporal expectancy.

    Directory of Open Access Journals (Sweden)

    Lilian Fautrelle

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

  1. Motor activity improves temporal expectancy.

    Science.gov (United States)

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

    2015-01-01

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

  2. Irinotecan and Bevacizumab in Glioblastoma-A Review

    Directory of Open Access Journals (Sweden)

    1M. T. Shahid

    2014-03-01

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

  3. Improved Active Vibration Isolation Systems

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2005-01-01

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

  5. Layer-by-layer nanoencapsulation of camptothecin with improved activity.

    Science.gov (United States)

    Parekh, Gaurav; Pattekari, Pravin; Joshi, Chaitanya; Shutava, Tatsiana; DeCoster, Mark; Levchenko, Tatyana; Torchilin, Vladimir; Lvov, Yuri

    2014-04-25

    160 nm nanocapsules containing up to 60% of camptothecin in the core and 7-8 polyelectrolyte bilayers in the shell were produced by washless layer-by-layer assembly of heparin and block-copolymer of poly-l-lysine and polyethylene glycol. The outer surface of the nanocapsules was additionally modified with polyethylene glycol of 5 kDa or 20 kDa molecular weight to attain protein resistant properties, colloidal stability in serum and prolonged release of the drug from the capsules. An advantage of the LbL coated capsules is the preservation of camptothecin lactone form with the shell assembly starting at acidic pH and improved chemical stability of encapsulated drug at neutral and basic pH, especially in the presence of albumin that makes such formulation more active than free camptothecin. LbL nanocapsules preserve the camptothecin lactone form at pH 7.4 resulting in triple activity of the drug toward CRL2303 glioblastoma cell. PMID:24508806

  6. Radiation induced glioblastoma. A case report

    Energy Technology Data Exchange (ETDEWEB)

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

    2000-05-01

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

  7. P04.16THE BIOMARKER POTENTIAL OF MGMT PROTEIN EXPRESSION IN GLIOBLASTOMA IS IMPROVED BY EXCLUSION OF NON-TUMOR CELLS

    OpenAIRE

    Klitkou, J.; Dahlrot, R.H.; Hansen, S; Kristensen, B.W.

    2014-01-01

    INTRODUCTION: Methylation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) gene promoter is predictive of benefit from temozolomide (TMZ) in glioblastoma (GBM). Non-tumor cells are numerous in GBMs and a potential source of bias in attempts to determine MGMT status by immunohistochemistry. The aim of the present study was to explore the prognostic potential of MGMT protein expression excluding these cells. METHOD: Immunofluorescence multiplexing and automated analysis w...

  8. Bidirectional Contrast agent leakage correction of dynamic susceptibility contrast (DSC)-MRI improves cerebral blood volume estimation and survival prediction in recurrent glioblastoma treated with bevacizumab.

    OpenAIRE

    Ab, KL; Boxerman, JL; Lai, A.; Nghiemphu, PL; Pope, WB; Cloughesy, TF; Ellingson, BM

    2016-01-01

    To evaluate a leakage correction algorithm for T1 and T2* artifacts arising from contrast agent extravasation in dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) that accounts for bidirectional contrast agent flux and compare relative cerebral blood volume (CBV) estimates and overall survival (OS) stratification from this model to those made with the unidirectional and uncorrected models in patients with recurrent glioblastoma (GBM).We determined median rCBV within contras...

  9. Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity

    International Nuclear Information System (INIS)

    Cancer stem cells (CSCs) or tumor initiating cells (TICs) drive glioblastoma (GBM) development, invasiveness and drug resistance. Distinct molecular pathways might regulate CSC biology as compared to cells in the bulk tumor mass, representing potential therapeutic targets. Chemokine CXCL12 and its receptor CXCR4 control proliferation, invasion and angiogenesis in GBM cell lines and primary cultures, but little is known about their activity in GBM CSCs. We demonstrate that CSCs, isolated from five human GBMs, express CXCR4 and release CXCL12 in vitro, although different levels of expression and secretion were observed in individual cultures, as expected for the heterogeneity of GBMs. CXCL12 treatment induced Akt-mediated significant pro-survival and self-renewal activities, while proliferation was induced at low extent. The role of CXCR4 signaling in CSC survival and self-renewal was further demonstrated using the CXCR4 antagonist AMD3100 that reduced self-renewal and survival with greater efficacy in the cultures that released higher CXCL12 amounts. The specificity of CXCL12 in sustaining CSC survival was demonstrated by the lack of AMD3100-dependent inhibition of viability in differentiated cells derived from the same GBMs. These findings, although performed on a limited number of tumor samples, suggest that the CXCL12/CXCR4 interaction mediates survival and self-renewal in GBM CSCs with high selectivity, thus emerging as a candidate system responsible for maintenance of cancer progenitors, and providing survival benefits to the tumor

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

    OpenAIRE

    Hayley Patricia Ellis; Kathreena Mary Kurian

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common primary intrinsic central nervous system tumor and has an extremely poor overall survival with only 10% patients being alive after 5 years. There has been interesting preliminary evidence suggesting that diabetic patients receiving peroxisome proliferator-activated receptor gamma (PPARγ) agonists, a group of anti-diabetic, thiazolidinedione drugs, have an increased median survival for glioblastoma. Although thiazolidinediones are effective oral...

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

    Science.gov (United States)

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

    2015-11-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  13. Microarray Analysis in Glioblastomas

    Science.gov (United States)

    Bhawe, Kaumudi M.; Aghi, Manish K.

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Patel Sunil J

    2004-12-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-03-07

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

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

    Directory of Open Access Journals (Sweden)

    Roberto eWurth

    2014-05-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-01-11

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    F.S. Lizarte Neto

    2013-01-01

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

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

    Science.gov (United States)

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

    2016-08-28

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

  1. How I treat glioblastoma in older patients.

    Science.gov (United States)

    Mohile, Nimish A

    2016-01-01

    Glioblastoma, a WHO grade IV astrocytoma, is the most common primary malignant brain tumor in adults. It is characterized by molecular heterogeneity and aggressive behavior. Glioblastoma is almost always incurable and most older patients survive less than 6 months. Supportive care with steroids and anti-epileptic drugs is critical to improving and maintain quality of life. Young age, good performance status and methylation of the methyl guanyl methyl transferase promoter are important positive prognostic factors. Several recent clinical trials suggest that there is a subset of the elderly with prolonged survival that is comparable to younger patients. Treatment of glioblastoma in older patients includes maximal safe resection followed by either radiation, chemotherapy or combined modality therapy. Recent advances suggest that some patients can avoid radiation entirely and be treated with chemotherapy alone. Decisions about therapy are individual and based on a patient's performance status, family support and molecular features. Future work needs to better determine the role for comprehensive geriatric assessments in this patient population to better identify patients who may most benefit from aggressive therapies. PMID:26725536

  2. Glioblastoma with oligodendroglial components: glioblastoma or anaplastic oligodendroglial tumors.

    Science.gov (United States)

    Takeuchi, Hiroaki; Hosoda, Tetsuya; Kitai, Ryuhei; Kodera, Toshiaki; Arishima, Hidetaka; Tsunetoshi, Kenzo; Neishi, Hiroyuki; Yamauchi, Takahiro; Sato, Kazufumi; Imamura, Yoshiyuki; Itoh, Hiroshi; Kubota, Toshihiko; Kikuta, Ken-ichiro

    2012-07-01

    There have been some recent reports about glioblastoma with oligodendroglial (OG) components and malignant glioma with primitive neuroectodermal tumor (PNET)-like components. We investigated whether the presence and extent of OG components and PNET-like components influenced the prognosis in patients with glioblastoma. Eighty-six patients with glioblastoma were divided into an OG group (28 %), which revealed areas with a honeycomb appearance, and a non-OG group (72 %) without a honeycomb appearance. Patients with glioblastoma were also divided into a PNET group (27 %), which revealed areas with PNET-like features defined as neoplastic cells with high N/C ratios and hyperchromatic oval-carrot-shaped nuclei, and lacked the typical honeycomb appearance, and a non-PNET group (73 %) without PNET features. There were no significant differences in overall survival among the OG, the non-OG, the PNET, and the non-PNET groups. Two patients who survived longer than 36 months had both OG and PNET components with 1p or 19q loss of heterozygosity. Perinuclear halo, which is a characteristic feature of oligodendrogliomas, is an artifact of tissue fixation. Therefore, we should not readily use the term glioblastoma with OG components. PNET-like components, which are considered rare in malignant gliomas, may be frequently identified in glioblastomas. PMID:22527749

  3. Lactate levels with glioblastoma multiforme.

    Science.gov (United States)

    Kahlon, Arunpreet Singh; Alexander, Mariam; Kahlon, Arundeep; Wright, Jonathan

    2016-07-01

    A 37-year-old woman with known glioblastoma multiforme was admitted for treatment of new deep vein thrombosis. Anion gap and plasma lactate levels were found to be elevated. Magnetic resonance imaging of the brain showed a stable, advanced glioblastoma multiforme. All causes of lactic acidosis, including infections and medications, were ruled out. Aggressive tumors have been shown to produce lactate levels in minute quantities in their microenvironment, which helps them metastasize and evade immune response and even radiation. PMID:27365883

  4. Recurrent Glioblastoma: Where we stand

    OpenAIRE

    Sanjoy Roy; Debarshi Lahiri; Tapas Maji; Jaydip Biswas

    2015-01-01

    Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM) treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment w...

  5. Lactate levels with glioblastoma multiforme

    OpenAIRE

    Kahlon, Arunpreet Singh; Alexander, Mariam; Kahlon, Arundeep; Wright, Jonathan

    2016-01-01

    A 37-year-old woman with known glioblastoma multiforme was admitted for treatment of new deep vein thrombosis. Anion gap and plasma lactate levels were found to be elevated. Magnetic resonance imaging of the brain showed a stable, advanced glioblastoma multiforme. All causes of lactic acidosis, including infections and medications, were ruled out. Aggressive tumors have been shown to produce lactate levels in minute quantities in their microenvironment, which helps them metastasize and evade ...

  6. Neural Stem Cells and Glioblastoma

    OpenAIRE

    Rispoli, Rossella; Conti, Carlo; Celli, Paolo; Caroli, Emanuela; Carletti, Sandro

    2014-01-01

    Glioblastoma multiforme represents one of the most common brain cancers with a rather heterogeneous cellular composition, as indicated by the term “multiforme". Recent reports have described the isolation and identification of cancer neural stem cells from human adult glioblastoma multiforme, which possess the capacity to establish, sustain, and expand these tumours, even under the challenging settings posed by serial transplantation experiments. Our study focused on the distribution of neura...

  7. CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

    OpenAIRE

    Würth, Roberto; Bajetto, Adriana; Harrison, Jeffrey K.; Barbieri, Federica; Florio, Tullio

    2014-01-01

    Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascr...

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

    OpenAIRE

    Roberto eWurth; Adriana eBajetto; Harrison, Jeffrey K.; Federica eBarbieri; Tullio eFlorio

    2014-01-01

    Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells.Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascri...

  9. [Palliative care for glioblastoma].

    Science.gov (United States)

    Dieudonné, Nathalie; De Micheli, Rita; Hottinger, Andreas

    2016-04-27

    Patients with glioblastoma have a limited life expectancy and an impaired quality of life and they should be offered palliative care soon after the diagnosis is established. Still, only a quarter of patients aged over 65 return home or medical institution after completing treatments. Home care must be promoted by coordinating assistance and care, combining disciplines such as physiotherapy and ergotherapy, medical and nursing care and psychosocial support. Patients are at risk of mood, personality and behavioural disorders. Limited awareness of these troubles and their physical limitations alter their capacity of rehabilitation and social relationships. Isolation of relatives, exhaustion and misunderstandings should be prevented. The therapeutic goals should be discussed and determined upstream to anticipate difficulties and questions concerning end of life. PMID:27281945

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

    LENUS (Irish Health Repository)

    Rock, K

    2012-01-03

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

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

    LENUS (Irish Health Repository)

    2012-02-01

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

  12. IMPROVING CAUSE DETECTION SYSTEMS WITH ACTIVE LEARNING

    Data.gov (United States)

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2012-01-01

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

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

    OpenAIRE

    Ramanauskiene, Kristina; Raudonis, Raimondas; Majiene, Daiva

    2016-01-01

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

  15. Glioblastoma with spinal seeding

    Energy Technology Data Exchange (ETDEWEB)

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

    2004-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Kristina Ramanauskiene

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  18. 5-ALA based photodynamic management of glioblastoma

    Science.gov (United States)

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

    2014-03-01

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

  19. Physical Activity Improves Quality of Life

    Science.gov (United States)

    ... Workplace Food and Beverage Toolkit Physical activity improves quality of life Updated:Mar 2,2015 Do you want to ... illnesses and diseases associated with aging and maintains quality of life and independence longer for seniors So why not ...

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

    Directory of Open Access Journals (Sweden)

    Sri Hari Krishna Vellanki

    2009-08-01

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

  1. Corticosteroids compromise survival in glioblastoma.

    Science.gov (United States)

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

    2016-05-01

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

  2. Role of bevacizumab therapy in the management of glioblastoma

    Directory of Open Access Journals (Sweden)

    Scott J Peak

    2010-04-01

    Full Text Available Scott J Peak, Victor A LevinNeuro-Oncology Program, Department of Neurosurgery and Neuroscience, Kaiser Permanente, Redwood City, CA, USAAbstract: Glioblastoma is one of the most common primary brain tumors and one of the most difficult to treat. In population-based studies only 30% of patients will survive 1 year and in the most efficacious surgery, irradiation, and chemotherapy clinical trials approximately 20% will live 2 years. Bevacizumab is a recombinant, antivascular epidermal growth factor receptor (VEGF monoclonal antibody with 6 VEGF-binding residues that binds to VEGF, preventing VEGF from binding to its target, VEGFR-1 and VEGFR-2, on endothelial cells. Through its binding to VEGF ligands bevacizumab reduces tumor angiogenesis and vasogenic brain edema; the consequences are that bevacizumab reduces the rate of glioblastoma tumor growth and its associated tumoral edema, thereby improving quality of life and survival for patients suffering from cerebral glioblastoma. In this review, we will summarize the studies that led to the use of bevacizumab in glioblastoma and the potential side-effects and complications that can be associated with its use and, finally, new opportunities for drug combinations with bevacizumab.Keywords: chemotherapy, VEGF, edema, central nervous system

  3. Irinotecan and bevacizumab in recurrent glioblastoma multiforme

    DEFF Research Database (Denmark)

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

    2011-01-01

    BVZ and CPT-11 in recurrent GBM. Particular attention is placed on the literature and a discussion on whether treatment with BVZ and CPT-11 improves clinical outcome. Antiangiogenic treatment has led to difficulties when evaluating objective response by the conventional MacDonald criteria. In the......INTRODUCTION: Glioblastoma multiforme (GBM) is the most common high grade primary brain tumor in adults. Despite significant advances in treatment, the prognosis remains poor. Bevacizumab (BVZ) and irinotecan (CPT-11) are currently being investigated in the treatment of GBM patients. Although...... treatment with BVZ and irinotecan provides impressive response rates (RR), it is still uncertain if this treatment translates into improved clinical benefit in GBM patients. AREAS COVERED: This review discusses the clinical efficacy, safety and difficulties regarding response evaluation when treating with...

  4. Targeting EGFR for Treatment of Glioblastoma: Molecular Basis to Overcome Resistance

    OpenAIRE

    Taylor, Tiffany E.; Furnari, Frank B.; Cavenee, Webster K.

    2012-01-01

    Glioblastoma (glioblastoma multiforme; GBM; WHO Grade IV) accounts for the majority of primary malignant brain tumors in adults. Amplification and mutation of the epidermal growth factor receptor (EGFR) gene represent signature genetic abnormalities encountered in GBM. A range of potential therapies that target EGFR or its mutant constitutively active form, ΔEGFR, including tyrosine kinase inhibitors (TKIs), monoclonal antibodies, vaccines, and RNA-based agents, are currently in development o...

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

    Science.gov (United States)

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

    2011-10-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-05-08

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

  7. The Study of Glioblastoma Differentiation Possibility

    Directory of Open Access Journals (Sweden)

    Medyanik I.A.

    2014-06-01

    Full Text Available The aim of the investigation was to assess the possibility of glioblastoma differentiation using infrared spectroscopy, proton magnetic resonance spectroscopy and immunohistochemistry. Materials and Methods. 22 patients with glioblastomas and 21 patients with anaplastic astrocytomas were examined. All the patients underwent infrared spectroscopy of blood serum. 16 patients with glioblastomas were examined preoperatively and postoperatively, and in both cases 7 of them underwent proton magnetic resonance spectroscopy of tumors and identical peritumoral areas. All diagnoses were morphologically confirmed, and 10 cases with glioblastomas and 15 cases with anaplastic astrocytomas were confirmed by immunohistochemistry. Results. Glioblastoma differentiation (Grade IV into anaplastic astrocytomas (Grade III was revealed postoperatively, in total glioblastoma resection and confirmed by the findings of infrared spectroscopy in blood serum, proton magnetic resonance spectroscopy of identical peritumoral areas performed preoperatively and postoperatively, as well as by immunohistochemical investigation of peritumoral area. Conclusion. The complex of the techniques applied (infrared spectroscopy, proton magnetic resonance spectroscopy, immunohistochemistry enables to assess how effective and total the surgery was, and if it promoted glioblastoma differentiation postoperatively, and determine how the tumor will develop after the surgery: as glioblastoma — with early continuous tumor growth, or as anaplastic astrocytoma — with the longer recurrence-free period. The findings are in agreement with tissue theory of tumor genesis; and change the understanding of the role and significance of surgical resection of glioblastomas in tumor differentiation.

  8. Software Engineering Improvement Activities/Plan

    Science.gov (United States)

    2003-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2008-01-01

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

  10. Recurrent Glioblastoma: Where we stand

    Directory of Open Access Journals (Sweden)

    Sanjoy Roy

    2015-01-01

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

  11. Recurrent Glioblastoma: Where we stand.

    Science.gov (United States)

    Roy, Sanjoy; Lahiri, Debarshi; Maji, Tapas; Biswas, Jaydip

    2015-01-01

    Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM) treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment with targeted agents or cytotoxic chemotherapy, reirradiation, or radiosurgery. Research into novel therapies is investigating alternative temozolomide regimens, convection-enhanced delivery, immunotherapy, gene therapy, antiangiogenic agents, poly ADP ribose polymerase inhibitors, or cancer stem cell signaling pathways. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy. PMID:26981507

  12. Titanocene Difluorides with Improved Cytotoxic Activity

    OpenAIRE

    Eger, Silvia; Immel, Timo; Claffey, James; Müller-Bunz, Helge; Tacke, Matthias; Groth, Ulrich; Huhn, Thomas

    2010-01-01

    Titanocene difluorides can be obtained by halide metathesis of the respective titanocene dichlorides with trimethyltin fluoride (Me3SnF), giving access to a new class of cytotoxic active substances. Furthermore, an improved method for the synthesis of diaryl-substituted titanocene dichlorides is presented.

  13. Chimeric enzymes with improved cellulase activities

    Science.gov (United States)

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

    2015-03-31

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

  14. Targeting glioblastoma via intranasal administration of Ff bacteriophages

    Science.gov (United States)

    Dor-On, Eyal; Solomon, Beka

    2015-01-01

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

  15. Targeting glioblastoma via intranasal administration of Ff bacteriophages

    Directory of Open Access Journals (Sweden)

    Eyal eDor-On

    2015-05-01

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

  16. Spatiotemporal Evolution of the Primary Glioblastoma Genome.

    Science.gov (United States)

    Kim, Jinkuk; Lee, In-Hee; Cho, Hee Jin; Park, Chul-Kee; Jung, Yang-Soon; Kim, Yanghee; Nam, So Hee; Kim, Byung Sup; Johnson, Mark D; Kong, Doo-Sik; Seol, Ho Jun; Lee, Jung-Il; Joo, Kyeung Min; Yoon, Yeup; Park, Woong-Yang; Lee, Jeongwu; Park, Peter J; Nam, Do-Hyun

    2015-09-14

    Tumor recurrence following treatment is the major cause of mortality for glioblastoma multiforme (GBM) patients. Thus, insights on the evolutionary process at recurrence are critical for improved patient care. Here, we describe our genomic analyses of the initial and recurrent tumor specimens from each of 38 GBM patients. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor. In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk for TMZ-induced hypermutation for these tumors under the standard regimen. PMID:26373279

  17. Hypofractionated stereotactic radiation therapy for recurrent glioblastoma: single institutional experience

    OpenAIRE

    Ciammella, Patrizia; Podgornii, Ala; Galeandro, Maria; D’Abbiero, Nunziata; Pisanello, Anna; Botti, Andrea; Cagni, Elisabetta; Iori, Mauro; Iotti, Cinzia

    2013-01-01

    Background Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Tumor control and survival have improved with the use of radiotherapy (RT) plus concomitant and adjuvant chemotherapy, but the prognosis remain poor. In most cases the recurrence occurs within 7–9 months after primary treatment. Currently, many approaches are available for the salvage treatment of patients with recurrent GBM, including resection, re-irradiation or systemic agents, but no standard of care...

  18. Clonal evolution of glioblastoma under therapy.

    Science.gov (United States)

    Wang, Jiguang; Cazzato, Emanuela; Ladewig, Erik; Frattini, Veronique; Rosenbloom, Daniel I S; Zairis, Sakellarios; Abate, Francesco; Liu, Zhaoqi; Elliott, Oliver; Shin, Yong-Jae; Lee, Jin-Ku; Lee, In-Hee; Park, Woong-Yang; Eoli, Marica; Blumberg, Andrew J; Lasorella, Anna; Nam, Do-Hyun; Finocchiaro, Gaetano; Iavarone, Antonio; Rabadan, Raul

    2016-07-01

    Glioblastoma (GBM) is the most common and aggressive primary brain tumor. To better understand how GBM evolves, we analyzed longitudinal genomic and transcriptomic data from 114 patients. The analysis shows a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern, together with estimates of evolutionary rate, suggests that relapse-associated clones typically existed years before diagnosis. Fifteen percent of tumors present hypermutation at relapse in highly expressed genes, with a clear mutational signature. We find that 11% of recurrence tumors harbor mutations in LTBP4, which encodes a protein binding to TGF-β. Silencing LTBP4 in GBM cells leads to suppression of TGF-β activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-β pathway as a potential therapeutic target in GBM. PMID:27270107

  19. Ecological Factors Improving Efficiency of Business Activities

    OpenAIRE

    Kononova G. A.; Tsiganov V. V.

    2015-01-01

    The economic importance of optimizing the environmental situation from the perspective of an entrepreneur are assessed in the article. The classification of administrative decisions taken in the course of the business activities is proposed. The authors identified a group of solutions directly providing optimization of environment external to the enterprise, solutions that have an indirect positive impact on the environment and solutions that improve ecology of industrial premises. The nature...

  20. Glioblastoma Multiforme: Relationship to Subventricular Zone and Recurrence

    OpenAIRE

    Kimura, Margareth; Lee, Yeuh; Miller, Ryan; Castillo, Mauricio

    2013-01-01

    Neurogenesis in the adult mammalian brain is active in two areas: the subgranular zone in the dentate gyrus of the hippocampus and the subventricular zone. Cancer stem cells have been isolated from malignant brain tumors and it is widely believed they arise from transformed endogenous stem cells. We sought to determine if the initial location of glioblastoma (GB) as seen on conventional MRI and its relationship to the subventricular zone (SVZ) predicts the pattern of recurrence. We analyzed t...

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

    Directory of Open Access Journals (Sweden)

    Diana Aguilar-Morante

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

  2. Network Modeling Identifies Patient-specific Pathways in Glioblastoma

    Science.gov (United States)

    Tuncbag, Nurcan; Milani, Pamela; Pokorny, Jenny L.; Johnson, Hannah; Sio, Terence T.; Dalin, Simona; Iyekegbe, Dennis O.; White, Forest M.; Sarkaria, Jann N.; Fraenkel, Ernest

    2016-01-01

    Glioblastoma is the most aggressive type of malignant human brain tumor. Molecular profiling experiments have revealed that these tumors are extremely heterogeneous. This heterogeneity is one of the principal challenges for developing targeted therapies. We hypothesize that despite the diverse molecular profiles, it might still be possible to identify common signaling changes that could be targeted in some or all tumors. Using a network modeling approach, we reconstruct the altered signaling pathways from tumor-specific phosphoproteomic data and known protein-protein interactions. We then develop a network-based strategy for identifying tumor specific proteins and pathways that were predicted by the models but not directly observed in the experiments. Among these hidden targets, we show that the ERK activator kinase1 (MEK1) displays increased phosphorylation in all tumors. By contrast, protein numb homolog (NUMB) is present only in the subset of the tumors that are the most invasive. Additionally, increased S100A4 is associated with only one of the tumors. Overall, our results demonstrate that despite the heterogeneity of the proteomic data, network models can identify common or tumor specific pathway-level changes. These results represent an important proof of principle that can improve the target selection process for tumor specific treatments. PMID:27354287

  3. Nanoparticles of carbon allotropes inhibit glioblastoma multiforme angiogenesis in ovo

    DEFF Research Database (Denmark)

    Grodzik, Marta; Sawosz, Ewa; Wierzbicki, Mateusz;

    2011-01-01

    The objective of the study was to determine the effect of carbon nanoparticles produced by different methods on the growth of brain tumor and the development of blood vessels. Glioblastoma multiforme cells were cultured on the chrioallantoic membrane of chicken embryo and after 7 days of incubati...... antiangiogenic activity of carbon nanoparticles, making them potential factors for anticancer therapy.......The objective of the study was to determine the effect of carbon nanoparticles produced by different methods on the growth of brain tumor and the development of blood vessels. Glioblastoma multiforme cells were cultured on the chrioallantoic membrane of chicken embryo and after 7 days of incubation......, were treated with carbon nanoparticles administered in ovo to the tumor. Both types of nanoparticles significantly decreased tumor mass and volume, fibroblast growth factor-2 and vascular endothelial growth factor expression at the messenger ribonucleic acid level. The present results demonstrate...

  4. Current concepts in glioblastoma imaging

    Institute of Scientific and Technical Information of China (English)

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

    2012-01-01

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

  5. Evolving Molecular Genetics of Glioblastoma

    OpenAIRE

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

    2016-01-01

    Objective: To summary the recent advances in molecular research of glioblastoma (GBM) and current trends in personalized therapy of this disease. Data Sources: Data cited in this review were obtained mainly from PubMed in English up to 2015, with keywords “molecular”, “genetics”, “GBM”, “isocitrate dehydrogenase”, “telomerase reverse transcriptase”, “epidermal growth factor receptor”, “PTPRZ1-MET”, and “clinical treatment”. Study Selection: Articles regarding the morphological pathology of GB...

  6. Ecological Factors Improving Efficiency of Business Activities

    Directory of Open Access Journals (Sweden)

    Kononova G. A.

    2015-01-01

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

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  8. An update on the epigenetics of glioblastomas.

    Science.gov (United States)

    Ferreira, Wallax Augusto Silva; Pinheiro, Danilo do Rosário; Costa Junior, Carlos Antonio da; Rodrigues-Antunes, Symara; Araújo, Mariana Diniz; Leão Barros, Mariceli Baia; Teixeira, Adriana Corrêa de Souza; Faro, Thamirys Aline Silva; Burbano, Rommel Rodriguez; Oliveira, Edivaldo Herculano Correa de; Harada, Maria Lúcia; Borges, Bárbara do Nascimento

    2016-09-01

    Glioblastomas, also known as glioblastoma multiforme (GBM), are the most aggressive and malignant type of primary brain tumor in adults, exhibiting notable variability at the histopathological, genetic and epigenetic levels. Recently, epigenetic alterations have emerged as a common hallmark of many tumors, including GBM. Considering that a deeper understanding of the epigenetic modifications that occur in GBM may increase the knowledge regarding the tumorigenesis, progression and recurrence of this disease, in this review we discuss the recent major advances in GBM epigenetics research involving histone modification, glioblastoma stem cells, DNA methylation, noncoding RNAs expression, including their main alterations and the use of epigenetic therapy as a valid option for GBM treatment. PMID:27585647

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

    Directory of Open Access Journals (Sweden)

    Jian Tu

    2013-01-01

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

  10. Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma.

    Science.gov (United States)

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

    2016-07-01

    The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas. PMID:26443480

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

    OpenAIRE

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

    2015-01-01

    Background The use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-gly...

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

    Science.gov (United States)

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

    2014-02-01

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

  13. Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenografts.

    Science.gov (United States)

    Serrill, Jeffrey D; Wan, Xuemei; Hau, Andrew M; Jang, Hyo Sang; Coleman, Daniel J; Indra, Arup K; Alani, Adam W G; McPhail, Kerry L; Ishmael, Jane E

    2016-02-01

    Coibamide A is a cytotoxic lariat depsipeptide isolated from a rare cyanobacterium found within the marine reserve of Coiba National Park, Panama. Earlier testing of coibamide A in the National Cancer Institute in vitro 60 human tumor cell line panel (NCI-60) revealed potent anti-proliferative activity and a unique selectivity profile, potentially reflecting a new target or mechanism of action. In the present study we evaluated the antitumor activity of coibamide A in several functional cell-based assays and in vivo. U87-MG and SF-295 glioblastoma cells showed reduced migratory and invasive capacity and underwent G1 cell cycle arrest as, likely indirect, consequences of treatment. Coibamide A inhibited extracellular VEGFA secreted from U87-MG glioblastoma and MDA-MB-231 breast cancer cells with low nM potency, attenuated proliferation and migration of normal human umbilical vein endothelial cells (HUVECs) and selectively decreased expression of vascular endothelial growth factor receptor 2 (VEGFR2). We report that coibamide A retains potent antitumor properties in a nude mouse xenograft model of glioblastoma; established subcutaneous U87-MG tumors failed to grow for up to 28 days in response to 0.3 mg/Kg doses of coibamide A. However, the natural product was also associated with varied patterns of weight loss and thus targeted delivery and/or medicinal chemistry approaches will almost certainly be required to improve the toxicity profile of this unusual macrocycle. Finally, similarities between coibamide A- and apratoxin A-induced changes in cell morphology, decreases in VEGFR2 expression and macroautophagy signaling in HUVECs raise the possibility that both cyanobacterial natural products share a common mechanism of action. PMID:26563191

  14. Molecular heterogeneity in glioblastoma: potential clinical implications

    Directory of Open Access Journals (Sweden)

    Nicole Renee Parker

    2015-03-01

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

  15. Advanced case of glioblastoma multiforme and pregnancy

    OpenAIRE

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

    2015-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant form of the glial tumors. Advanced and treated GBM is rarely associated with pregnancy for many reasons. Glioblastoma multiforme presenting during pregnancy carries unique challenges to the patient, baby, family, and health care providers. We describe an unusual case of advanced GBM that was treated with maximum doses of chemotherapy and radiations, and she became pregnant and presented at eighteenth weeks of gestation. Her medica...

  16. Current data and strategy in glioblastoma multiforme

    OpenAIRE

    Iacob, G; Dinca, EB

    2009-01-01

    Glioblastoma multiforme (GBM) or astrocytoma grade Ⅳ on WHO classification is the most aggressive and the most frequent of all primary brain tumors. Glioblastoma is multiforme , resistant to therapeutic interventions illustrating the heterogeneity exhibited by this tumor in its every aspect, including clinical presentation, pathology, genetic signature. Current data and treatment strategy in GBM are presented focusing on basic science data and key clinical aspects like surgery, including pers...

  17. Strategies in Gene Therapy for Glioblastoma

    International Nuclear Information System (INIS)

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

  18. Strategies in Gene Therapy for Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-10-22

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

  19. Yes and PI3K bind CD95 to signal invasion of glioblastoma.

    Science.gov (United States)

    Kleber, Susanne; Sancho-Martinez, Ignacio; Wiestler, Benedict; Beisel, Alexandra; Gieffers, Christian; Hill, Oliver; Thiemann, Meinolf; Mueller, Wolf; Sykora, Jaromir; Kuhn, Andreas; Schreglmann, Nina; Letellier, Elisabeth; Zuliani, Cecilia; Klussmann, Stefan; Teodorczyk, Marcin; Gröne, Hermann-Josef; Ganten, Tom M; Sültmann, Holger; Tüttenberg, Jochen; von Deimling, Andreas; Regnier-Vigouroux, Anne; Herold-Mende, Christel; Martin-Villalba, Ana

    2008-03-01

    Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo. PMID:18328427

  20. TSPO Imaging in Glioblastoma Multiforme

    DEFF Research Database (Denmark)

    Jensen, Per; Feng, Ling; Law, Ian;

    2015-01-01

    -CLINDE is superior to (18)F-FET in predicting progression of glioblastoma multiforme (GBM) at follow-up. METHODS: Three patients with World Health Organization grade IV GBM were scanned with (123)I-CLINDE SPECT, (18)F-FET PET, and gadolinium-enhanced MR imaging. Molecular imaging data were compared with follow......-up gadolinium-enhanced MR images or contrast-enhanced CT scans. RESULTS: The percentage overlap between volumes of interest (VOIs) of increased (18)F-FET uptake and (123)I-CLINDE binding was variable (12%-42%). The percentage overlap of MR imaging baseline VOIs was greater for (18)F-FET (79%-93%) than (123)I...

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

    Science.gov (United States)

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

    2016-01-01

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

  2. Molecular network profiling of U373MG human glioblastoma cells following induction of apoptosis by novel marine-derived anti-cancer 1,2,3,4-tetrahydroisoquinoline alkaloids

    OpenAIRE

    Tabunoki Hiroko; Saito Naoki; Suwanborirux Khanit; Charupant Kornvika; Satoh Jun-ichi

    2012-01-01

    Abstract Background Glioblastoma is the most aggressive form of brain tumors showing resistance to treatment with various chemotherapeutic agents. The most effective way to eradicate glioblastoma requires the concurrent inhibition of multiple signaling pathways and target molecules involved in the progression of glioblastoma. Recently, we obtained a series of 1,2,3,4-tetrahydroisoquinoline alkaloids with potent anti-cancer activities, including ecteinascidin-770 (ET-770; the compound 1a) and ...

  3. Evaluation of tyrosine kinase inhibitor combinations for glioblastoma therapy.

    Directory of Open Access Journals (Sweden)

    Avadhut D Joshi

    Full Text Available Glioblastoma multiforme (GBM is the most common intracranial cancer but despite recent advances in therapy the overall survival remains about 20 months. Whole genome exon sequencing studies implicate mutations in the receptor tyrosine kinase pathways (RTK for driving tumor growth in over 80% of GBMs. In spite of various RTKs being mutated or altered in the majority of GBMs, clinical studies have not been able to demonstrate efficacy of molecular targeted therapies using tyrosine kinase inhibitors in GBMs. Activation of multiple downstream signaling pathways has been implicated as a possible means by which inhibition of a single RTK has been ineffective in GBM. In this study, we sought a combination of approved drugs that would inhibit in vitro and in vivo growth of GBM oncospheres. A combination consisting of gefitinib and sunitinib acted synergistically in inhibiting growth of GBM oncospheres in vitro. Sunitinib was the only RTK inhibitor that could induce apoptosis in GBM cells. However, the in vivo efficacy testing of the gefitinib and sunitinib combination in an EGFR amplified/PTEN wild type GBM xenograft model revealed that gefitinib alone could significantly improve survival in animals whereas sunitinib did not show any survival benefit. Subsequent testing of the same drug combination in a different syngeneic glioma model that lacked EGFR amplification but was more susceptible to sunitinib in vitro demonstrated no survival benefit when treated with gefitinib or sunitinib or the gefitinib and sunitinib combination. Although a modest survival benefit was obtained in one of two animal models with EGFR amplification due to gefitinib alone, the addition of sunitinib, to test our best in vitro combination therapy, did not translate to any additional in vivo benefit. Improved targeted therapies, with drug properties favorable to intracranial tumors, are likely required to form effective drug combinations for GBM.

  4. PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma.

    Science.gov (United States)

    Agnihotri, Sameer; Golbourn, Brian; Huang, Xi; Remke, Marc; Younger, Susan; Cairns, Rob A; Chalil, Alan; Smith, Christian A; Krumholtz, Stacey-Lynn; Mackenzie, Danielle; Rakopoulos, Patricia; Ramaswamy, Vijay; Taccone, Michael S; Mischel, Paul S; Fuller, Gregory N; Hawkins, Cynthia; Stanford, William L; Taylor, Michael D; Zadeh, Gelareh; Rutka, James T

    2016-08-15

    Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila Cancer Res; 76(16); 4708-19. ©2016 AACR. PMID:27325644

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

    Directory of Open Access Journals (Sweden)

    Azeem Arshad

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

  6. Effect of Corilagin on the Proliferation and NF-κB in U251 Glioblastoma Cells and U251 Glioblastoma Stem-Like Cells

    Directory of Open Access Journals (Sweden)

    Wen-Tao Yang

    2016-01-01

    Full Text Available Background. This study is to explore the effect of corilagin on the proliferation and NF-κB signaling pathway in U251 glioblastoma cells and U251 glioblastoma stem-like cells. Methods. CD133 positive U251 glioblastoma cells were separated by immunomagnetic beads to isolate glioblastoma stem-like cells. U251 cells and stem-like cells were intervened by different corilagin concentrations (0, 25, 50, and 100 μg/mL for 48 h, respectively. Cell morphology, cell counting kit-8 assay, flow cytometry, dual luciferase reporter assay, and a western blot were used to detect and analyze the cell proliferation and cell cycle and investigate the expression of IKBα protein in cytoplasm and NF-κB/p65 in nucleus. Results. Corilagin inhibited the cell proliferation of U251 cells and their stem-like cells and the inhibition role was stronger in U251 stem-like cells (P<0.05. The cell cycle was arrested at G2/M phase in the U251 cells following corilagin intervention; the proportion of cells in G2/M phase increased as the concentration of corilagin increased (P<0.05. The U251 stem-like cells were arrested at the S phase following treatment with corilagin; the proportion of cells in the S phase increased as the concentration of corilagin increased (P<0.05. The ratio of dual luciferase activities of U251 stem-like cells was lower than that of U251 cells in the same corilagin concentration. With increasing concentrations of corilagin, the IKBα expression in cytoplasm of U251 cells and U251 stem-like cells was increased, but the p65 expression in nucleus of U251 cells and U251 stem-like cells was decreased (P<0.05. Conclusion. Corilagin can inhibit the proliferation of glioblastoma cells and glioblastoma stem-like cells; the inhibition on glioblastoma stem-like cell proliferation is stronger than glioblastoma cells. This different result indicates that the effect of corilagin on U251 cells and U251 stem-like cells may have close relationships with mechanism of

  7. Effect of Corilagin on the Proliferation and NF-κB in U251 Glioblastoma Cells and U251 Glioblastoma Stem-Like Cells

    Science.gov (United States)

    Yang, Wen-Tao; Li, Gen-Hua; Li, Zheng-You; Feng, Song; Liu, Xue-Qin; Han, Guang-Kui; Zhang, Hao; Qin, Xian-Yun; Zhang, Ran; Nie, Quan-Min; Jin, Feng

    2016-01-01

    Background. This study is to explore the effect of corilagin on the proliferation and NF-κB signaling pathway in U251 glioblastoma cells and U251 glioblastoma stem-like cells. Methods. CD133 positive U251 glioblastoma cells were separated by immunomagnetic beads to isolate glioblastoma stem-like cells. U251 cells and stem-like cells were intervened by different corilagin concentrations (0, 25, 50, and 100 μg/mL) for 48 h, respectively. Cell morphology, cell counting kit-8 assay, flow cytometry, dual luciferase reporter assay, and a western blot were used to detect and analyze the cell proliferation and cell cycle and investigate the expression of IKBα protein in cytoplasm and NF-κB/p65 in nucleus. Results. Corilagin inhibited the cell proliferation of U251 cells and their stem-like cells and the inhibition role was stronger in U251 stem-like cells (P < 0.05). The cell cycle was arrested at G2/M phase in the U251 cells following corilagin intervention; the proportion of cells in G2/M phase increased as the concentration of corilagin increased (P < 0.05). The U251 stem-like cells were arrested at the S phase following treatment with corilagin; the proportion of cells in the S phase increased as the concentration of corilagin increased (P < 0.05). The ratio of dual luciferase activities of U251 stem-like cells was lower than that of U251 cells in the same corilagin concentration. With increasing concentrations of corilagin, the IKBα expression in cytoplasm of U251 cells and U251 stem-like cells was increased, but the p65 expression in nucleus of U251 cells and U251 stem-like cells was decreased (P < 0.05). Conclusion. Corilagin can inhibit the proliferation of glioblastoma cells and glioblastoma stem-like cells; the inhibition on glioblastoma stem-like cell proliferation is stronger than glioblastoma cells. This different result indicates that the effect of corilagin on U251 cells and U251 stem-like cells may have close relationships with mechanism of cell

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

    Directory of Open Access Journals (Sweden)

    Gloria Perazzoli

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

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

    Directory of Open Access Journals (Sweden)

    Celina Bihan

    2012-09-01

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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Michael Preukschas

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

  12. Successfully improving physical activity behavior after rehabilitation

    NARCIS (Netherlands)

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

    2007-01-01

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

  13. Molecular profiling in glioblastoma: prelude to personalized treatment.

    Science.gov (United States)

    Mladkova, Nikol; Chakravarti, Arnab

    2009-01-01

    The purpose of this review is to provide an up-to-date summary of the current knowledge and understanding of the molecular alterations and pathways relevant to the clinical outcome of glioblastoma patients and their potential use in designing personalized treatment for these patients. This article also discusses the potential of molecular profiling as a diagnostic modality, possible therapeutic implications of MGMT promoter methylation, the targeted inhibition of angiogenesis, and assessment of the tumor's molecular background with respect to PI3K/AKT pathway activation and associated molecules (EGFR, EGFRvIII, PTEN). PMID:19080742

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

    Directory of Open Access Journals (Sweden)

    Miyuki Uno

    2011-01-01

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

  15. Evolving Molecular Genetics of Glioblastoma

    Institute of Scientific and Technical Information of China (English)

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

    2016-01-01

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

  16. Management of glioblastoma multiforme in pregnancy.

    Science.gov (United States)

    Jayasekera, Bodiabaduge A P; Bacon, Andrew D; Whitfield, Peter C

    2012-06-01

    Glioblastoma multiforme presenting during pregnancy presents unique challenges to the clinician. In planning treatment, potential benefits to the mother must be balanced against the risks to the fetus. In addition, evidence relating to timing of surgery and the use of radiotherapy and chemotherapy in pregnancy is limited. Management of peritumoral edema and seizures in pregnancy is also complicated by the potential for drug-related teratogenic effects and adverse neonatal outcomes on the fetus. The general anesthetic used for surgery must factor obstetric and neurosurgical considerations. In this review article, the authors seek to examine the role, safety, and timing of therapies for glioblastoma in the context of pregnancy. This covers the use of radiotherapy and chemotherapy, timing of surgery, postoperative care, anesthetic considerations, and use of anticonvulsant medications and steroids. The authors hope that this will provide a framework for clinicians treating pregnant patients with glioblastomas. PMID:22404670

  17. Oncogenic Ras modulates p38 MAPK-mediated inflammatory cytokine production in glioblastoma cells.

    Science.gov (United States)

    Munoz, Lenka; Yeung, Yiu To; Grewal, Thomas

    2016-04-01

    Inflammation is an important factor promoting the progression of glioblastoma. In the present study we examined the contribution of Ras signaling and TNFα/IL-1β cytokines to the development of the glioblastoma inflammatory microenvironment. Enhanced activation of Ras through de-regulated activation of receptor tyrosine kinases, such as EGFR, PDGFR and cMet, is a hallmark of the majority of glioblastomas. Glioblastoma microenvironment contains high levels of TNFα and IL-1β, which mediate inflammation through induction of a local network of cytokines and chemokines. While many studies have focused on Ras- and TNFα/IL-1β-driven inflammation in isolation, little is known about the co-operation between these oncogenic and microenvironment-derived stimuli. Using constitutively active HRasG12V that mimics enhanced Ras activation, we demonstrate that elevated Ras activity in glioblastoma cells leads to up-regulation of IL-6 and IL-8. Furthermore, Ras synergizes with the microenvironment-derived TNFα and IL-1β resulting in amplified IL-6/IL-8 secretion. IL-8 secretion induced by Ras and TNFα/IL-1β is attenuated by inhibitors targeting Erk, JNK and p38 MAPK pathways. IL-6 secretion significantly decreased upon inhibition of JNK and p38 MAPK pathways. Interestingly, although constitutively active HRasG12V does not increase basal or TNFα/IL-1β stimulated p38 MAPK activity, HRasG12V increased the efficacy of the p38 MAPK inhibitor SB203580 to inhibit IL-1β-induced IL-6 secretion. In summary, oncogenic Ras co-operates with the microenvironment-derived TNFα/IL-1β to sustain inflammatory microenvironment, which was effectively attenuated via inhibition of p38 MAPK signaling. PMID:26794430

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

    Science.gov (United States)

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

    2016-01-01

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

  19. Glioblastoma multiforme: Effect of hypoxia and hypoxia inducible factors on therapeutic approaches

    Science.gov (United States)

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors. Hypoxic regions of glioblastoma exacerbate the prognosis and clinical outcomes of the patients as hypoxic tumor cells are resistant to chemo- and radiation therapy and are also protected by the malfunctional vasculature that developed due to hypoxia. Predominantly, hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF)/VEGF receptor, transforming growth factor-β, epidermal growth factor receptor and PI3 kinase/Akt signaling systems are involved in tumor progression and growth. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Abnormal vessel formation is crucial in generating pseudopalisading necrosis regions that protect cancer stem cells residing in that region from therapeutic agents and this facilitates the cancer stem cell niche to expand and contribute to cell proliferation and tumor growth. Therapeutic approaches that target hypoxia-induced factors, such as use of the monoclonal antibody against VEGF, bevacizumab, have been useful only in stabilizing the disease but failed to increase overall survival. Hypoxia-activated TH-302, a nitroimidazole prodrug of cytotoxin bromo-isophosphoramide mustard, appears to be more attractive due to its better beneficial effects in glioblastoma patients. A better understanding of the hypoxia-mediated protection of glioblastoma cells is required for developing more effective therapeutics.

  20. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity

    OpenAIRE

    Hegi, M E; L. Liu; Herman, J G; Stupp, R; Wick, W.; Weller, M.; Mehta, M P; Gilbert, M. R.

    2008-01-01

    Resistance to alkylating agents via direct DNA repair by O(6)-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overal...

  1. Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells.

    Science.gov (United States)

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

    2016-07-01

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

  2. Radiation and concomitant chemotherapy for patients with glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    Salvador Vill; Carme Bala; Slvia Comas

    2014-01-01

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

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

    Science.gov (United States)

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

    2014-05-01

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

  4. Signal transduction molecule patterns indicating potential glioblastoma therapy approaches

    Directory of Open Access Journals (Sweden)

    Cruceru ML

    2013-11-01

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

  5. Does gender matter in glioblastoma?

    Science.gov (United States)

    Verger, E; Valduvieco, I; Caral, Ll; Pujol, T; Ribalta, T; Viñolas, N; Boget, T; Oleaga, L; Blanco, Y; Graus, F

    2011-10-01

    BACKGROUND The clinical outcome of glioblastoma (GBM) patients who receive radiotherapy alone or with chemotherapy is well established. However, little is known about how many patients do not receive this treatment. We consider it is important to investigate why a proportion of operated patients do not receive further treatment after surgery. METHODS We reviewed all consecutive GBM patients operated on in our hospital between January 2000 and December 2008. RESULTS A total of 216 patients with GBM were identified. Fifty-five (25%) did not receive any treatment after surgery. Univariate analysis showed that factors associated with no further treatment after surgery were older than 60 years (p=0.002), of female gender (p=0.03), had a KPS<70 (p<0.001) and had had a biopsy (p<0.001). Multivariate analysis indicated that age =60 years and KPS <70 were independent predictors of no further treatment after surgery. Gender was not an independent variable. However, women in the whole series were older than 60 years (p=0.01), and they had a worse KPS (p=0.02) and more biopsies (p=0.04) than men. In the whole group, median survival time was 10.4 months for men (n=125) vs. 7.2 months for women (n=91), log rank p<0.04. This difference was not observed in the group that was treated after surgery. CONCLUSIONS One out of four patients could not be treated after surgery. Independent predictors were older age and low KPS. These poor risk variables were more frequent in women and their survival was therefore lower than men in our series. PMID:21975336

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

    Directory of Open Access Journals (Sweden)

    Hayley Patricia Ellis

    2014-03-01

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

  7. Wnt inhibitory factor-1 regulates glioblastoma cell cycle and proliferation.

    Science.gov (United States)

    Wu, Jun; Fang, Jiasheng; Yang, Zhuanyi; Chen, Fenghua; Liu, Jingfang; Wang, Yanjin

    2012-10-01

    Wnt proteins are powerful regulators of cell proliferation and differentiation, and activation of the Wnt signalling pathway is involved in the pathogenesis of several types of human tumours. Wnt inhibitory factor-1 (WIF-1) acts as a Wnt antagonist and tumour suppressor. Previous studies have shown that reducing expression of the WIF-1 gene aberrantly activates Wnt signalling and induces the development of certain types of cancers. In the present study, we examined the expression of WIF-1 in human primary glioblastoma multiforme (GBM) tumours. Studies using semiquantitative reverse transcription-polymerase chain reaction and immunohistochemical analysis revealed that WIF-1 expression is lower in human GBM than in normal brain tissue. To clarify the role of WIF-1, we transfected U251 human glioblastoma-derived cells, which do not express WIF-1, with the pcDNA3.1-WIF1 vector to restore WIF-1 expression. The results of cell proliferation, colony formation and apoptosis assays, as well as flow cytometry, indicate that exogenous WIF-1 has no effect on U251 cell apoptosis, but does arrest cells at the G(0)/G(1) phase and inhibit cell growth. Collectively, our data suggest that WIF-1 is a potent inhibitor of GBM growth. PMID:22901505

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

    Science.gov (United States)

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

    2015-10-13

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

  9. Current Studies of Immunotherapy on Glioblastoma.

    Science.gov (United States)

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

    2014-04-01

    Glioblastoma is a form of brain tumor with a very high morbidity and mortality. Despite decades of research, the best treatments currently in clinical practice only extend survival by a number of months. A promising alternative to conventional treatment for glioblastomas is immunotherapy. Although proposed over a century ago, the field of cancer immunotherapy has historically struggled to translate it into effective clinical treatments. Better understanding is needed of the various regulatory and co-stimulatory factors in the glioblastoma patient for more efficient immunotherapy treatments. The tumor microenvironment is anatomically shielded from normal immune-surveillance by the blood-brain barrier, irregular lymphatic drainage system, and it's in a potently immunosuppressive environment. Immunotherapy can potentially manipulate these forces effectively to enhance anti-tumor immune response and clinical benefit. New treatments utilizing the immune system show promise in terms of targeting and efficacy. This review article attempts to discuss current practices in glioblastoma treatment, the theory behind immunotherapy, and current research into various clinical trials. PMID:25346943

  10. Small cell glioblastoma or small cell carcinoma

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  11. Glioblastoma multiforme in the very elderly.

    Science.gov (United States)

    Connon, Felicity V; Rosenthal, Mark A; Drummond, Katherine

    2016-01-01

    Glioblastoma is the most malignant and most common primary brain tumour and is treated with resection followed by post-operative radiotherapy and chemotherapy. However, a significant amount of patients are older than 80 years, and such an approach may not be appropriate. Data on patients aged 80 or older with glioblastoma from two hospitals was collected using the CNS Tumour Database on the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD) system operated by BioGrid. Between 2008 and July 2011, 40 patients aged 80 years or older were diagnosed with glioblastoma. The median ECOG PS was 2 and the ASA score was 3. All 40 patients underwent surgery and 33% had a gross total resection. Only six patients (15%) had either post-operative radiotherapy or chemotherapy. The overall median survival was 4 months (range 0-18 months) and 28% of patients lived between 6 and 24 months. This is the largest reported cohort of very elderly patients with glioblastoma. Patients tolerated surgery but few went on to receive post-operative radiotherapy or chemotherapy. This patient population requires special attention and in particular would benefit from participation in suitable clinical trials to determine the best care regime. PMID:26208944

  12. MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib

    OpenAIRE

    Chahal, Manik; Xu, Yaoxian; Lesniak, David; Graham, Kathryn; Famulski, Konrad; Christensen, James G.; Aghi, Manish; Jacques, Amanda; Murray, David; Sabri, Siham; Abdulkarim, Bassam

    2010-01-01

    Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O6-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT-positive but not...

  13. Research reactor management. Safety improvement activities in HANARO

    International Nuclear Information System (INIS)

    Safety activities in HANARO have been continuously conducted to enhance its safe operation. Great effort has been placed on a normalization and improvement of the safety attitude of the regular staff and other employees working at the reactor and other experimental facilities. This paper introduces the activities on safety improvement that were performed over the last few years. (author)

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

    Science.gov (United States)

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

    2011-04-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  16. The tumor suppressive role of WIF1 in glioblastoma

    OpenAIRE

    Vassallo I.

    2013-01-01

    Expression based prediction of gene alterations identified WNT inhibitory factor I (WIF1) as a new candidate tumor suppressor gene involved in glioblastoma. WIF1 encodes a secreted WNT antagonist and it is strongly down-regulated in most glioblastoma as compared to normal brain both by genomic deletion and WIF1 promoter hypermethylation. WIF1 expression in glioblastoma cell lines inhibited cell proliferation in vitro and in vivo and strongly reduced migration capability. Interestingly, WIF1 e...

  17. Detection of MGMT promoter methylation in glioblastoma using pyrosequencing

    OpenAIRE

    Xie, Hao; Tubbs, Raymond; Yang, Bin

    2015-01-01

    Recent clinical trials on patients with glioblastoma revealed that O6-Methylguanine-DNA methyltransferase (MGMT) methylation status significantly predicts patient’s response to alkylating agents. In this study, we sought to develop and validate a quantitative MGMT methylation assay using pyrosequencing on glioblastoma. We quantified promoter methylation of MGMT using pyrosequencing on paraffin-embedded fine needle aspiration biopsy tissues from 43 glioblastoma. Using a 10% cutoff, MGMT methyl...

  18. PCDH10 is required for the tumorigenicity of glioblastoma cells

    International Nuclear Information System (INIS)

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

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

    Directory of Open Access Journals (Sweden)

    Lin YL

    2015-09-01

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

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

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which, despite combined modality treatment, reoccurs and is invariably fatal for affected patients. Recently, a member of the serine/threonine protein kinase D (PRKD) family, PRKD2, was shown to be a potent mediator of glioblastoma growth. Here we studied the role of PRKD2 in U87MG glioblastoma cell migration and invasion in response to sphingosine-1-phosphate (S1P), an activator of PRKD2 and a GBM mitogen. Time-lapse microscopy demonstrated that random cell migration was significantly diminished in response to PRKD2 silencing. The pharmacological PRKD family inhibitor CRT0066101 decreased chemotactic migration and invasion across uncoated or matrigel-coated Transwell inserts. Silencing of PRKD2 attenuated migration and invasion of U87MG cells even more effectively. In terms of downstream signaling, CRT0066101 prevented PRKD2 autophosphorylation and inhibited p44/42 MAPK and to a smaller extent p54/46 JNK and p38 MAPK activation. PRKD2 silencing impaired activation of p44/42 MAPK and p54/46 JNK, downregulated nuclear c-Jun protein levels and decreased c-JunS73 phosphorylation without affecting the NFκB pathway. Finally, qPCR array analyses revealed that silencing of PRKD2 downregulates mRNA levels of integrin alpha-2 and -4 (ITGA2 and -4), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and matrix metallopeptidase 1 (MMP1). Findings of the present study identify PRKD2 as a potential target to interfere with glioblastoma cell migration and invasion, two major determinants contributing to recurrence of glioblastoma after multimodality treatment. Highlights: • Sphingosine-1-phosphate induces glioma cell migration and invasion. • Part of the effects is mediated by protein kinase D2 (PRKD2) activation. • Inactivation of PRKD2 attenuates glioblastoma cell migration and invasion. • Both, RNAi and pharmacological inhibition of PRKD2 inhibits MAPK

  1. BI-14GENOMIC PROFILING OF A PREDICTIVE SIGNATURE FOR MET-TARGETED THERAPY IN GLIOBLASTOMA

    OpenAIRE

    Johnson, Jennifer; Ascierto, Maria Libera; Newsome, David; Mittal, Sandeep; Kang, Liang; Briggs, Michael; Tanner, Kirk; Michael E. Berens; Marincola, Francesco M.; Vande Woude, George F.; Xie, Qian

    2014-01-01

    The success of molecular targeted therapy against cancer depends on discovering the tumor driver genes and the molecular determinants that control the pathway activity. Glioblastoma (GBM) is one of the most devastating cancers due to its highly infiltrating nature, and MET pathway activation is a major cause of invasion in both primary and recurrent tumors. Because MET inhibitors are in clinical trials against GBM, there may be clinical utility from developing more effective patient enrollmen...

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

    Science.gov (United States)

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

    2015-11-01

    Aberrant hedgehog signaling contributes to the development of various malignancies, including glioblastoma (GBM). However, the potential mechanism of hedgehog signaling in GBM migration and invasion has remained to be elucidated. The present study showed that enhanced hedgehog signaling by recombinant human sonic hedgehog N‑terminal peptide (rhSHH) promoted the adhesion, invasion and migration of GBM cells, accompanied by increases in mRNA and protein levels of matrix metalloproteinase‑2 (MMP‑2) and MMP‑9. However, inhibition of hedgehog signaling with cyclopamine suppressed the adhesion, invasion and migration of GBM cells, accompanied by decreases in mRNA and protein levels of MMP‑2 and ‑9. Furthermore, it was found that MMP‑2- and MMP‑9-neutralizing antibodies or GAM6001 reversed the inductive effects of rhSHH on cell migration and invasion. In addition, enhanced hedgehog signaling by rhSHH increased AKT phosphorylation, whereas blockade of hedgehog signaling decreased AKT phosphorylations. Further experiments showed that LY294002, an inhibitor of phosphoinositide-3 kinase (PI3K), decreased rhSHH‑induced upregulation of MMP‑2 and ‑9. Finally, the protein expression of glioblastoma-associated oncogene 1 was positively correlated with levels of phosphorylated AKT as well as protein expressions of MMP‑2 and ‑9 in GBM tissue samples. In conclusion, the present study indicated that the hedgehog pathway regulates GBM-cell migration and invasion by increasing MMP-2 and MMP-9 production via the PI3K/AKT pathway. PMID:26299938

  3. Overview of Cellular Immunotherapy for Patients with Glioblastoma

    Directory of Open Access Journals (Sweden)

    Elodie Vauleon

    2010-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

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

  5. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme.

    Science.gov (United States)

    Bradshaw, Amy; Wickremsekera, Agadha; Tan, Swee T; Peng, Lifeng; Davis, Paul F; Itinteang, Tinte

    2016-01-01

    Glioblastoma multiforme (GBM), an aggressive tumor that typically exhibits treatment failure with high mortality rates, is associated with the presence of cancer stem cells (CSCs) within the tumor. CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells that drive tumor growth. Studies of many cancer types have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple GBM and glioblastoma cancer stem cell subtypes, making investigation and establishment of a universal treatment difficult. This review examines the current knowledge on the CSC markers SALL4, OCT-4, SOX2, STAT3, NANOG, c-Myc, KLF4, CD133, CD44, nestin, and glial fibrillary acidic protein, specifically focusing on their use and validity in GBM research and how they may be utilized for investigations into GBM's cancer biology. PMID:27148537

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

    Institute of Scientific and Technical Information of China (English)

    Linda Gordon Hjeljord; Arne Tronsmo

    2004-01-01

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

  7. Glioblastoma multiforme after radiotherapy for acromegaly

    Energy Technology Data Exchange (ETDEWEB)

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

    1983-07-01

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

  8. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme

    OpenAIRE

    Bradshaw, Amy; Wickremsekera, Agadha; Tan, Swee T.; Peng, Lifeng; Davis, Paul F.; Itinteang, Tinte

    2016-01-01

    Glioblastoma multiforme (GBM), an aggressive tumor that typically exhibits treatment failure with high mortality rates, is associated with the presence of cancer stem cells (CSCs) within the tumor. CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells that drive tumor growth. Studies of many cancer types have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is ...

  9. Detection of primary cilia in human glioblastoma

    OpenAIRE

    Sarkisian, Matthew R.; Siebzehnrubl, Dorit; Hoang-Minh, Lan; Deleyrolle, Loic; Silver, Daniel J.; Siebzehnrubl, Florian A.; Guadiana, Sarah M.; Srivinasan, Gayathri; Semple-Rowland, Susan; Harrison, Jeffrey K.; Steindler, Dennis A.; Brent A Reynolds

    2014-01-01

    Glioblastoma (GBM) is the most common malignant adult brain tumor and carries a poor prognosis due to primary and acquired resistance. While many cellular features of GBM have been documented, it is unclear if cells within these tumors extend a primary cilium, an organelle whose associated signaling pathways may regulate proliferation, migration, and survival of neural precursor and tumor cells. Using immunohistochemical and electron microscopy (EM) techniques, we screened human GBM tumor bio...

  10. Bevacizumab for the Treatment of Glioblastoma

    OpenAIRE

    Gil-Gil, Miguel J.; Carlos Mesia; Montserrat Rey; Jordi Bruna

    2013-01-01

    Glioblastoma (GBM) or grade IV glioma is the most common primary brain tumor in adults. Standard treatment median overall survival (OS) is only 14–15 months and less than 10% of patients will survive 5 years after diagnosis. There is no standard treatment in recurrent GBM and OS ranges from 3 to 9 months. GBM is 1 of the most vascularized human tumors and GBM cells produce vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF, has demonstrated ac...

  11. Reirradiation for recurrent glioblastoma by cyberknife

    International Nuclear Information System (INIS)

    This is a retrospective study to evaluate the outcomes of recurrent, previously irradiated glioblastoma treated with hypofractionated stereotactic radiotherapy using the CyberKnife (CK). 48 patients (20 male and 28 female, ages 21-78 years, median 61 years) with recurrent glioblastoma were analyzed. The period from conventional radiotherapy to CK treatment was 4 to 216 months (median 7 months). The dose of conventional radiotherapy was 40-70 Gy, median 65 Gy. Tumor volume ranged from 1.3 to 257 ml (median 45 ml). The marginal dose (D95) was 17-35 Gy (median 30 Gy) delivered in one to 7 sessions. Follow-up ranged from 4 to 17 months (median 7 months). Median survival from CK treatment was 7 months. No patient survived more than 17 months. CK retreatment for recurrent glioblastoma was palliative, contributing to the maintainenance of quality of life (QOL). A multidisciplinary approach for recurrent GBM, including a molecular targeting regimen and re-irradiation, is expected to prolong the performance status of patient. (author)

  12. Glioblastoma Stem Cells: A Neuropathologist's View

    Directory of Open Access Journals (Sweden)

    Roger E. McLendon

    2011-01-01

    Full Text Available Glioblastoma (WHO Grade IV is both the most common primary brain tumor and the most malignant. Advances in the understanding of the biology of the tumor are needed in order to obtain a clearer picture of the mechanisms driving these tumors. To neuropathologists, glioblastoma is a tumor that represents a complex system of migrating pleomorphic tumor cells, proliferating blood vessels, infiltrating inflammatory cells, and necrosis. This review will highlight how the glioma stem cell concept brings these elements together into a collective whole, interacting with microenvironmental influences in complex ways. Borrowing from chaos theory a vocabulary of “self organizing systems” and “complex adaptive systems” that seem useful in describing these pathologic features, a new paradigm of glioblastoma biology will be proposed that genetic changes should be understood in a three dimensional framework as they relate not only to the tumor cells themselves but also to the multicellular hierarchical unit, not isolated from, but responsive to, its local milieu. In this way we will come to better appreciate the impact our therapeutic interventions have on the regional phenotypic heterogeneity that exists within the tumor and the intercellular communications directing adaptation and progression.

  13. Patterns of Failure for Pediatric Glioblastoma Multiforme Following Radiation Therapy.

    Science.gov (United States)

    Shabason, Jacob E; Sutton, David; Kenton, Owen; Guttmann, David M; Lustig, Robert A; Hill-Kayser, Christine

    2016-08-01

    Despite aggressive multimodal therapy for pediatric glioblastoma multiforme (GBM), patient survival remains poor. This retrospective review of patients with GBM aims to evaluate the patterns of failure after radiation therapy (RT). The study included 14 pediatric patients treated with RT at the Children's Hospital of Philadelphia from 2007 to 2015. With a median follow-up of 16.9 months, 13 (92.9%) developed recurrent disease. Of recurrences, nine (69.2%) were in-field, three (23.1%) were marginal, and one (7.7%) was distant. The majority of patients treated with adjuvant radiation failed in the region of high-dose RT, indicating the need for improvements in local therapy. PMID:27128519

  14. Development of targeted therapies in treatment of glioblastoma

    Institute of Scientific and Technical Information of China (English)

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

    2015-01-01

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

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

    Science.gov (United States)

    Nelson, Larry P.; Crow, Mary L.

    2014-01-01

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

  16. Benefits of Improved HP Turbine Active Clearance Control

    Science.gov (United States)

    Ruiz, Rafael; Albers, Bob; Sak, Wojciech; Seitzer, Ken; Steinetz, Bruce M.

    2007-01-01

    As part of the NASA Propulsion 21 program, GE Aircraft Engines was contracted to develop an improved high pressure turbine(HPT) active clearance control (ACC) system. The system is envisioned to minimize blade tip clearances to improve HPT efficiency throughout the engine operation range simultaneously reducing fuel consumption and emissions.

  17. Bortezomib sensitizes human glioblastoma cells to induction of apoptosis by type I interferons through NOXA expression and Mcl-1 cleavage.

    Science.gov (United States)

    Wang, Ruishan; Davidoff, Andrew M; Pfeffer, Lawrence M

    2016-09-01

    Glioblastomas are highly invasive and aggressive primary brain tumors. Type I interferons have significant, pleiotropic anticancer activity. However, through various pathways many cancers become interferon-resistant, limiting interferon's clinical utility. In this study, we demonstrated that the proteasomal inhibitor bortezomib sensitized human glioblastoma cells to the antiproliferative action of interferons, which involved the induction of caspase-dependent apoptosis but not necroptosis. We found that death ligands such as TRAIL (TNF-related apoptosis-inducing ligand) were not involved in interferon/bortezomib-induced apoptosis, although interferon induced TRAIL expression. However, apoptosis was induced through an intrinsic pathway involving increased NOXA expression and Mcl-1 cleavage. Our findings may provide an important rationale for combining type I interferons with bortezomib for glioblastoma therapy. PMID:27450810

  18. Role of Nitric Oxide in Glioblastoma Therapy: Another Step to Resolve the Terrible Puzzle ?

    Science.gov (United States)

    Altieri, R; Fontanella, M; Agnoletti, A; Panciani, P P; Spena, G; Crobeddu, E; Pilloni, G; Tardivo, V; Lanotte, M; Zenga, F; Ducati, A; Garbossa, D

    2015-01-01

    Glioblastoma Multiforme, the most common and aggressive primary brain tumor, remains incurable despite of the advent of modern surgical and medical treatments. This poor prognosis depends by the recurrence after surgery and intrinsic or acquired resistance to chemotherapy and radiotherapy. Nitric oxide is a small molecule that plays a key roles in glioma pathophysiology. Many researches showing that NO is involved in induction of apoptosis, radiosensitization and chemosensitization. Therefore, NO role, if clarified, may improve the knowledge about this unsolved puzzle called GBM.

  19. Positron emission tomography-guided conformal fast neutron therapy for glioblastoma multiforme

    OpenAIRE

    Stelzer, Keith J.; Douglas, James G.; Mankoff, David A.; Silbergeld, Daniel L.; Krohn, Kenneth A.; Laramore, George E.; Spence, Alexander M.

    2008-01-01

    Glioblastoma multiforme (GBM) continues to be a difficult therapeutic challenge. Our study was conducted to determine whether improved survival and tumor control could be achieved with modern delivery of fast neutron radiation using three-dimensional treatment planning. Ten patients were enrolled. Eligibility criteria included pathologic diagnosis of GBM, age ≥ 18 years, and KPS ≥60. Patients underwent MRI and 18F-fluorodeoxyglucose PET (FDG PET) as part of initial three-dimensional treatment...

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

    Institute of Scientific and Technical Information of China (English)

    Andreas F. Hottinger; Roger Stupp; Krisztian Homicsko

    2014-01-01

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

  1. Glioblastoma extracellular vesicles: reservoirs of potential biomarkers

    Directory of Open Access Journals (Sweden)

    Redzic JS

    2014-02-01

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

  2. Cerebral Blood Flow Changes in Glioblastoma Patients Undergoing Bevacizumab Treatment Are Seen in Both Tumor and Normal Brain

    OpenAIRE

    Andre, Jalal B; Nagpal, Seema; Hippe, Daniel S; Ravanpay, Ali C.; Schmiedeskamp, Heiko; Bammer, Roland; Palagallo, Gerald J; Recht, Lawrence; Zaharchuk, Greg

    2015-01-01

    Bevacizumab (BEV) is increasingly used to treat recurrent glioblastoma (GBM) with some reported improvement in neurocognitive function despite potential neurotoxicities. We examined the effects of BEV on cerebral blood flow (CBF) within recurrent GBM tumor and in the contralateral middle cerebral artery (MCA) territory.

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

    Institute of Scientific and Technical Information of China (English)

    SHAHIDIkramullahButt; SUNHou-fang; HAMIDUllahKhanNiazi

    2005-01-01

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

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

    Science.gov (United States)

    Chan, Y C

    1993-01-01

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

  5. Glioblastoma Invoking "Killer" Rabbits of the Middle Ages.

    Science.gov (United States)

    Massoud, Tarik F; Kalnins, Aleksandrs

    2016-08-01

    We present the unusual appearance on brain magnetic resonance imaging of a glioblastoma with an uncanny shape of a rabbit. By invoking fearsome "killer" rabbits depicted in the art and literature of the Middle Ages, this image is an eerie reminder of the current lethality of this disease. There is a pressing need for more effective treatments for glioblastoma. PMID:27157288

  6. Amnesia due to bilateral hippocampal glioblastoma. MRI finding

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-11-01

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

  7. A 16-Gene Signature Distinguishes Anaplastic Astrocytoma from Glioblastoma

    OpenAIRE

    Soumya Alige Mahabala Rao; Sujaya Srinivasan; Irene Rosita Pia Patric; Alangar Sathyaranjandas Hegde; Bangalore Ashwathnarayanara Chandramouli; Arivazhagan Arimappamagan; Vani Santosh; Paturu Kondaiah; Manchanahalli R Sathyanarayana Rao; Kumaravel Somasundaram

    2014-01-01

    Anaplastic astrocytoma (AA; Grade III) and glioblastoma (GBM; Grade IV) are diffusely infiltrating tumors and are called malignant astrocytomas. The treatment regimen and prognosis are distinctly different between anaplastic astrocytoma and glioblastoma patients. Although histopathology based current grading system is well accepted and largely reproducible, intratumoral histologic variations often lead to difficulties in classification of malignant astrocytoma samples. In order to obtain a mo...

  8. Glycogen synthase kinase 3β sustains invasion of glioblastoma via the focal adhesion kinase, Rac1, and c-Jun N-terminal kinase-mediated pathway.

    Science.gov (United States)

    Chikano, Yuri; Domoto, Takahiro; Furuta, Takuya; Sabit, Hemragul; Kitano-Tamura, Ayako; Pyko, Ilya V; Takino, Takahisa; Sai, Yoshimichi; Hayashi, Yutaka; Sato, Hiroshi; Miyamoto, Ken-ichi; Nakada, Mitsutoshi; Minamoto, Toshinari

    2015-02-01

    The failure of current treatment options for glioblastoma stems from their inability to control tumor cell proliferation and invasion. Biologically targeted therapies offer great hope and one promising target is glycogen synthase kinase-3β (GSK3β), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3β compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3β also contributes to the highly invasive nature of glioblastoma. The effects of GSK3β inhibition on migration and invasion of glioblastoma cells were examined by wound-healing and Transwell assays, as well as in a mouse model of glioblastoma. We also investigated changes in cellular microarchitectures, cytoskeletal components, and proteins responsible for cell motility and invasion. Inhibition of GSK3β attenuated the migration and invasion of glioblastoma cells in vitro and that of tumor cells in a mouse model of glioblastoma. These effects were associated with suppression of the molecular axis involving focal adhesion kinase, guanine nucleotide exchange factors/Rac1 and c-Jun N-terminal kinase. Changes in cellular phenotypes responsible for cell motility and invasion were also observed, including decreased formation of lamellipodia and invadopodium-like microstructures and alterations in the subcellular localization, and activity of Rac1 and F-actin. These changes coincided with decreased expression of matrix metalloproteinases. Our results confirm the potential of GSK3β as an attractive therapeutic target against glioblastoma invasion, thus highlighting a second role in this tumor type in addition to its involvement in chemo- and radioresistance. PMID:25504636

  9. Active Listening Improve Your Ability to Listen and Lead

    CERN Document Server

    (CCL), Center for Creative Leadership

    2011-01-01

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

  10. Active filter to improve the energetic efficiency in electric installations.

    OpenAIRE

    Amarís Duarte, Hortensia; Robles Muñoz, Guillermo

    2009-01-01

    The Department of Electrical Engineering of the University Carlos III of Madrid has developed a prototype of active filter to compensate the disturbances that a nonlinear load produces. The active filters appears like the dynamic solution that best fits to the needs of compensation of electrical disturbances in industrial facilities. This active filter allows correcting the power factor of the installation. With this improvement, electrical consumes are reduced, which results in significa...

  11. 13-cis-Retinoic acid in the treatment of recurrent glioblastoma multiforme

    OpenAIRE

    See, Siew-Ju; Levin, Victor A.; Yung, W.-K. Alfred; Hess, Kenneth R.; Groves, Morris D.

    2004-01-01

    Basic science and clinical investigations have demonstrated that 13-cis-retinoic acid (cRA) has activity against malignant gliomas. To assess its effectiveness in the setting of recurrent glioblastoma multiforme (GBM), we performed a retrospective analysis of the medical records and neuroimaging results of patients with recurrent GBM who were treated with cRA. The toxicity profile of cRA, response, and effect on progression-free survival from initiation of treatment were end points of our ana...

  12. Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab

    OpenAIRE

    Prados, Michael; Cloughesy, Timothy; Samant, Meghna; Fang, Liang; Wen, Patrick Y.; Mikkelsen, Tom; Schiff, David; Abrey, Lauren E; Yung, W.K. Alfred; Paleologos, Nina; Nicholas, Martin K.; Jensen, Randy; Vredenburgh, James; Das, Asha; Friedman, Henry S.

    2010-01-01

    Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, ...

  13. The Prognostic Value of Pyrosequencing-Detected MGMT Promoter Hypermethylation in Newly Diagnosed Patients with Glioblastoma

    OpenAIRE

    Villani, Veronica; Casini, Beatrice; Pace, Andrea; Prosperini, Luca; Carapella, Carmine M.; Vidiri, Antonello; Fabi, Alessandra; Carosi, Mariantonia

    2015-01-01

    O6-methylguanine-DNA-methyltransferase (MGMT) has emerged as a relevant predictor of therapeutic response and good prognosis in patients with glioblastoma (GBM). Transcriptionally active MGMT rapidly removes the alkyl adducts, preventing the formation of cross-links and thereby causing resistance to alkylating drugs. Studies with pyrosequencing (PSQ) showed that this technique has a higher reproducibility and sensitivity than other techniques. However, the definition of a prognostically relev...

  14. Specificity Protein 1 Expression Contributes to Bcl-w-Induced Aggressiveness in Glioblastoma Multiforme

    OpenAIRE

    Lee, Woo Sang; Kwon, Junhye; Yun, Dong Ho; Lee, Young Nam; Woo, Eun Young; Park, Myung-Jin; Lee, Jae-Seon; Han, Young-Hoon; Bae, In Hwa

    2014-01-01

    We already had reported that Bcl-w promotes invasion or migration in gastric cancer cells and glioblastoma multiforme (GBM) by activating matrix metalloproteinase-2 (MMP-2) via specificity protein 1 (Sp1) or β-cateinin, respectively. High expression of Bcl-w also has been reported in GBM which is the most common malignant brain tumor and exhibits aggressive and invasive behavior. These reports propose that Bcl-w-induced signaling is strongly associated with aggressive characteristic of GBM. W...

  15. Aptamer-conjugated dendrimer-modified quantum dots for glioblastoma cells imaging

    Energy Technology Data Exchange (ETDEWEB)

    Li Zhiming; Huang Peng; He Rong; Bao Chenchen; Cui Daxiang [National Key Laboratory of Nano/Micro Fabrication Technology, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Institute of Micro-Nano Science and Technology, Shanghai Jiao Tong University, Shanghai 200240 (China); Zhang Xiaomin; Ren Qiushi [Institute for Laser Medicine and Biophotonics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240 (China)], E-mail: qsren@sjtu.edu.cn, E-mail: dxcui@sjtu.edu.cn

    2009-09-01

    Targeted quantum dots have shown potential as a platform for development of cancer imaging. Aptamers have recently been demonstrated as ideal candidates for molecular targeting applications. In present work, polyamidoamine dendrimers were used to modify surface of quantum dots and improve their solubility in water solution. Then, dendrimer-modified quantum dots were conjugated with DNA aptamer, GBI-10, can recognize the extracellular matrix protein tenascin-C on the surface of human glioblastoma cells. The dendrimer-modified quantum dots exhibit water-soluble, high quantum yield, and good biocompatibility. Aptamer-conjugated quantum dots can specifically target U251 human glioblastoma cells. High-performance aptamer-conjugated dendrimers modified quantum dot-based nanoprobes have great potential in application such as cancer imaging.

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

    Directory of Open Access Journals (Sweden)

    Yuming Jiao

    2015-06-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-04-15

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

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

    OpenAIRE

    Jorge Luiz de Brito-Gomes; Raphael José Perrier-Melo; Erik Anders Wikstrom; Manoel da Cunha Costa

    2015-01-01

    AbstractThe rate of peak workload improvement between different types of Active Video Games (AVG) in young sedentary adults was investigated. Aerobic capacity improvement after a 6-week intervention between AVG types was also compared. Twenty participants, after baseline assessments, were randomized into one of three parallel groups: structured AVG (n= 6), unstructured AVG (n= 7) and a control group (n= 7). Participants played their respective AVG 3 times a week for 6-weeks (30 minutes-sessio...

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

    Science.gov (United States)

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

    2016-01-01

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

  20. Activities and Programs That Improve Children's Executive Functions.

    Science.gov (United States)

    Diamond, Adele

    2012-10-01

    Executive functions (EFs; e.g., reasoning, working memory, and self-control) can be improved. Good news indeed, since EFs are critical for school and job success and for mental and physical health. Various activities appear to improve children's EFs. The best evidence exists for computer-based training, traditional martial arts, and two school curricula. Weaker evidence, though strong enough to pass peer review, exists for aerobics, yoga, mindfulness, and other school curricula. Here I address what can be learned from the research thus far, including that EFs need to be progressively challenged as children improve and that repeated practice is key. Children devote time and effort to activities they love; therefore, EF interventions might use children's motivation to advantage. Focusing narrowly on EFs or aerobic activity alone appears not to be as efficacious in improving EFs as also addressing children's emotional, social, and character development (as do martial arts, yoga, and curricula shown to improve EFs). Children with poorer EFs benefit more from training; hence, training might provide them an opportunity to "catch up" with their peers and not be left behind. Remaining questions include how long benefits of EF training last and who benefits most from which activities. PMID:25328287

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

    Directory of Open Access Journals (Sweden)

    Proescholdt Martin

    2009-09-01

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

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

    International Nuclear Information System (INIS)

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

  3. Is There Pseudoprogression in Secondary Glioblastomas?

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-12-01

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

  4. Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway.

    Science.gov (United States)

    Dhruv, Harshil D; Roos, Alison; Tomboc, Patrick J; Tuncali, Serdar; Chavez, Ashley; Mathews, Ian; Berens, Michael E; Loftus, Joseph C; Tran, Nhan L

    2016-02-01

    Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. Knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer's disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. Here we showed that PPF decreased GBM cell expression of TROY, inhibited glioma cell invasion, and sensitized GBM cells to TMZ. Mechanistically, PPF decreased glioma cell invasion by modulating TROY expression and downstream signaling, including AKT, NF-κB, and Rac1 activation. Thus, PPF may provide a pharmacologic approach to target TROY, inhibit cell invasion, and reduce therapeutic resistance in GBM. PMID:26559543

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

    Institute of Scientific and Technical Information of China (English)

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

    2015-01-01

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

  6. Robustness of Improving Active Maglev Motorized Spindle Equilibrium Position

    Directory of Open Access Journals (Sweden)

    Zhang Yanhong

    2013-09-01

    Full Text Available The equilibrium position of active maglev motorized spindle had great influence on the industrial processing accuracy, in order to improve the performance of active maglev motorized spindle and processing accuracy, a new control method and control device of active maglev was put forward based on H∞ mixed sensitivity. Firstly, a mathematical model was established among the electromagnetic force on the rotor, control current and position displacement of the rotor center. Secondly, the H∞ mixed sensitivity control method was used, the selection method of weighting function was discussed and H∞ robust controller was designed, the experimental results showed that for active maglev motorized spindle, the designed controller had better static and dynamic performance, position precision, so that the robustness of the motorized spindle equilibrium position was further improved, which met the requirement of high precision industrial process.  

  7. MicroRNA biomarkers in glioblastoma

    DEFF Research Database (Denmark)

    Hermansen, Simon Kjær; Kristensen, Bjarne Winther

    2013-01-01

    Recent research suggests that deregulation of microRNAs (miRNAs) is involved in initiation and progression of many cancers, including gliomas and that miRNAs hold great potential as future diagnostic and therapeutic tools in cancer. MiRNAs are a class of short non-coding RNA sequences (18...... tissues. Understanding these alterations is key to developing new biomarkers and intelligent treatment strategies. This review presents an overview of current knowledge about miRNA alterations in glioblastoma while focusing on the clinical future of miRNAs as biomarkers and discussing the strengths...

  8. Cerebellar glioblastoma multiforme in an adult

    OpenAIRE

    Mattos João Paulo; Marenco Horacio Armando; Campos José Maria; Faria Andréa Vasconcellos; Queiroz Luciano de Souza; Borges Guilherme; Oliveira Evandro de

    2006-01-01

    Cerebellar glioblastoma multiforme (GBM) is a rare tumor. This is the third case published in Brazilian literature and, the last one has been described more than 15 years ago. The aggressive behavior of GBM prompts for fast treatment, which can be hampered by the fact that the diagnosis of GBM requires a high degree of suspicion. We describe a case of GBM in a 46 years old man. In conjunction, we present a literature review including particular issues, clinical data, advances in imaging studi...

  9. Cerebellar glioblastoma multiforme in an adult

    Directory of Open Access Journals (Sweden)

    Mattos João Paulo

    2006-01-01

    Full Text Available Cerebellar glioblastoma multiforme (GBM is a rare tumor. This is the third case published in Brazilian literature and, the last one has been described more than 15 years ago. The aggressive behavior of GBM prompts for fast treatment, which can be hampered by the fact that the diagnosis of GBM requires a high degree of suspicion. We describe a case of GBM in a 46 years old man. In conjunction, we present a literature review including particular issues, clinical data, advances in imaging studies, pathological characteristics, treatment options and the behavior of such malignant tumor.

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

    Science.gov (United States)

    Montrezor, Luís H.

    2016-01-01

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

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

    DEFF Research Database (Denmark)

    Thoft-Christensen, Palle

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

  12. Active video gaming to improve balance in the elderly

    NARCIS (Netherlands)

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

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Susan M. Burden-Gulley

    2010-04-01

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

  14. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, S; Wibom, C; Andersson, U;

    2010-01-01

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

  15. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, S; Wibom, C; Andersson, U;

    2011-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    Directory of Open Access Journals (Sweden)

    Jorge Luiz de Brito-Gomes

    2015-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Ganciu Mihaela

    2015-10-01

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

  19. Integration method of 3D MR spectroscopy into treatment planning system for glioblastoma IMRT dose painting with integrated simultaneous boost

    Directory of Open Access Journals (Sweden)

    Ken Soléakhéna

    2013-01-01

    Full Text Available Abstract Background To integrate 3D MR spectroscopy imaging (MRSI in the treatment planning system (TPS for glioblastoma dose painting to guide simultaneous integrated boost (SIB in intensity-modulated radiation therapy (IMRT. Methods For sixteen glioblastoma patients, we have simulated three types of dosimetry plans, one conventional plan of 60-Gy in 3D conformational radiotherapy (3D-CRT, one 60-Gy plan in IMRT and one 72-Gy plan in SIB-IMRT. All sixteen MRSI metabolic maps were integrated into TPS, using normalization with color-space conversion and threshold-based segmentation. The fusion between the metabolic maps and the planning CT scans were assessed. Dosimetry comparisons were performed between the different plans of 60-Gy 3D-CRT, 60-Gy IMRT and 72-Gy SIB-IMRT, the last plan was targeted on MRSI abnormalities and contrast enhancement (CE. Results Fusion assessment was performed for 160 transformations. It resulted in maximum differences p  Conclusions Delivering standard doses to conventional target and higher doses to new target volumes characterized by MRSI and CE is now possible and does not increase dose to organs at risk. MRSI and CE abnormalities are now integrated for glioblastoma SIB-IMRT, concomitant with temozolomide, in an ongoing multi-institutional phase-III clinical trial. Our method of MR spectroscopy maps integration to TPS is robust and reliable; integration to neuronavigation systems with this method could also improve glioblastoma resection or guide biopsies.

  20. Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy

    International Nuclear Information System (INIS)

    Standard therapies for high grade glioma have failed to substantially improve survival and are associated with significant morbidity. At relapse, high grade gliomas, such as glioblastoma multiforme, are refractory to therapy and universally fatal. BRAF V600E-mutations have been described in a modest 6% to 7% of primary central nervous system (CNS) tumors, but with increased prevalence in the pediatric population and in certain brain tumor subtypes. The use of BRAF inhibitors have transformed melanoma therapy however their use in brain tumors remains unproven. We describe the pediatric case of a now 12 year old Caucasian male who originally presented at age 9 with a right fronto-parietal glioblastoma multiforme that recurred 2 ½ years from diagnosis. Molecular analysis of the primary tumor revealed a BRAF V600E mutation and the patient was placed on the BRAF inhibitor vemurafenib. A complete response was observed after 4 months of therapy and remains sustained at 6 months. This is the first report of a complete response of relapsed glioblastoma multiforme to targeted BRAF inhibitor therapy. While not a predominant mutation in glioblastoma multiforme, the increased prevalence of BRAF V600 mutations in pediatric CNS tumors and certain subtypes marks a population to whom this therapy could be applied. Response to this therapy suggests that BRAF inhibitors can affect primary CNS lesions when a documented and targetable mutation is present

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

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    Gaspar Reynés

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

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

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    Wang Min

    2007-05-01

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

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

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

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

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

    Science.gov (United States)

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

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

    Science.gov (United States)

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

    2015-04-01

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

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

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    Krishnan Chandramouli

    2012-08-01

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

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

    Science.gov (United States)

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

    2015-01-01

    Although active listening is an influential behavior, which can affect the social responses of others, the neural correlates underlying its perception have remained unclear. Sensing active listening in social interactions is accompanied by an improvement in the recollected impressions of relevant experiences and is thought to arouse positive feelings. We therefore hypothesized that the recognition of active listening activates the reward system, and that the emotional appraisal of experiences that had been subject to active listening would be improved. To test these hypotheses, we conducted functional magnetic resonance imaging (fMRI) on participants viewing assessments of their own personal experiences made by evaluators with or without active listening attitude. Subjects rated evaluators who showed active listening more positively. Furthermore, they rated episodes more positively when they were evaluated by individuals showing active listening. Neural activation in the ventral striatum was enhanced by perceiving active listening, suggesting that this was processed as rewarding. It also activated the right anterior insula, representing positive emotional reappraisal processes. Furthermore, the mentalizing network was activated when participants were being evaluated, irrespective of active listening behavior. Therefore, perceiving active listening appeared to result in positive emotional appraisal and to invoke mental state attribution to the active listener. PMID:25188354

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

    Science.gov (United States)

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

    2015-10-20

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

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

    Science.gov (United States)

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

    2014-10-29

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

  10. Inherited variation in immune genes and pathways and glioblastoma risk

    OpenAIRE

    Schwartzbaum, Judith A.; Xiao, Yuanyuan; Liu, Yanhong; Tsavachidis, Spyros; Berger, Mitchel S.; Bondy, Melissa L,; Chang, Jeffrey S.; Chang, Susan M.; Decker, Paul A.; Ding, Bo; Hepworth, Sarah J; Richard S. Houlston; Hosking, Fay J; Jenkins, Robert B.; Kosel, Matthew L.

    2010-01-01

    To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) an...

  11. Targeting NF-κB in glioblastoma: A therapeutic approach.

    Science.gov (United States)

    Friedmann-Morvinski, Dinorah; Narasimamurthy, Rajesh; Xia, Yifeng; Myskiw, Chad; Soda, Yasushi; Verma, Inder M

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-κB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-κB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-κB activity or targeting of inducible NF-κB genes is an attractive therapeutic approach for GBM. PMID:26824076

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

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    Soumya Alige Mahabala Rao

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2011-01-01

    The combination of active video gaming and exercise (exergaming) is suggested to improve elderly people's balance, thereby decreasing fall risk. Exergaming has been shown to increase motivation during exercise therapy, due to the enjoyable and challenging nature, which could support long-term adherence for exercising balance. However, scarce evidence is available of the direct effects of exergaming on postural control. Therefore, the aim of the study was to assess the effect of a six-week videogame-based exercise program aimed at improving balance in elderly people. Task performance and postural control were examined using an interrupted time series design. Results of multilevel analyses showed that performance on the dot task improved within the first two weeks of training. Postural control improved during the intervention. After the intervention period task performance and balance were better than before the intervention. Results of this study show that healthy elderly can benefit from a videogame-based exercise program to improve balance and that all subjects were highly motivated to exercise balance because they found gaming challenging and enjoyable. PMID:21685660

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

    Blanchard, Catlyn; Brooks, Lauren; Ebsworth-Mojica, Katherine; Didione, Louis; Wucher, Benjamin; Dewhurst, Stephen; Krysan, Damian; Dunman, Paul M; Wozniak, Rachel A F

    2016-01-01

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

  17. The somatic genomic landscape of glioblastoma.

    Science.gov (United States)

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

    2013-10-10

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

  18. Glioblastoma Multiforme Presenting as Spontaneous Intracerebral Hemorrhage

    Directory of Open Access Journals (Sweden)

    Cagatay Ozdol

    2014-06-01

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

  19. Elderly patients with glioblastoma: the treatment challenge.

    Science.gov (United States)

    Fiorentino, Alba; De Bonis, Pasquale; Chiesa, Silvia; Balducci, Mario; Fusco, Vincenzo

    2013-10-01

    The treatment for elderly patients affected by glioblastoma represents a challenge in neuro-oncology. The recent randomized trials (the NOA-8 and the NCBTSG trials) showed an advantage of temozolomide for patients with O6-methylguanine methyltransferase methylated tumors. To date, no randomized trials compared the standard treatment (radiochemotherapy) with other therapeutic approaches, due to the idea that elderly patients do not tolerate aggressive therapy. Nonetheless, with the increased lifespan and the better quality of life, the nihilism in the treatment of elderly with cancer is obsolete. Molecular (including O6-methylguanine methyltransferase) and clinical tools (including the geriatric evaluation) are needed for choosing the proper therapy for patients over 70. PMID:24117272

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2004-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Rachy Abraham

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

  2. CS-04STAT3 INVOLVEMENT IN AN EMT-LIKE PROCESS IN GLIOBLASTOMA BRAIN TUMOR INITIATING CELLS

    OpenAIRE

    Chesnelong, Charles; Luchman, Artee; Gregory Cairncross, J.; Weiss, Samuel

    2014-01-01

    Glioblastoma Multiforme (GBM) is the most aggressive subtype of brain tumour with a median survival of 15 months. Currently, GBM is managed by a combination of maximal safe resection followed by radiation and chemotherapy. However, GBM invariably recurs, highlighting the need to better delineate the basis of recurrent disease and develop novel more effective and targeted therapies. The Signal Transducer and Activator of Transcription 3 (STAT3) is abnormally active in GBM. A growing body of ev...

  3. Improving Industrial Energy Quality by an Active Current Filter

    Directory of Open Access Journals (Sweden)

    Reyes–Trujillo E

    2010-10-01

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

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

    Science.gov (United States)

    Borole, Abhijeet P.; Davison, Brian H.

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

  5. Analysis of the growth dynamics of angiogenesis dependent and independent experimental glioblastomas by multimodal small animal PET and MRI

    International Nuclear Information System (INIS)

    The hypothesis of this study was that distinct experimental glioblastoma phenotypes resembling human disease can be noninvasively distinguished at various disease stages by imaging in vivo. Cultured spheroids from 2 human glioblastomas were implanted into the brains of nude rats. Glioblastoma growth dynamics were followed by PET using 18F-FDG, 11C-methyl-L-methionine (11C-MET), and 39-deoxy- 39-18F-fluoro-thymidine (18F-FLT) and by MRI at 3-6 wk after implantation. For image validation, parameters were co-registered with immunohistochemical analysis. Two tumor phenotypes (angiogenic and infiltrative) were obtained. The angiogenic phenotype showed high uptake of 11C-MET and 18F-FLT and relatively low uptake of 18F-FDG. 11C-MET was an early indicator of vessel remodeling and tumor proliferation. 18F-FLT uptake correlated to positive Ki67 staining at 6 wk. T1- and T2-weighted MR images displayed clear tumor delineation with strong gadolinium enhancement at 6 wk. The infiltrative phenotype did not accumulate 11C-MET and 18F-FLT and impaired the 18F-FDG uptake. In contrast, the Ki67 index showed a high proliferation rate. The extent of the infiltrative tumors could be observed by MRI but with low contrast. For angiogenic glioblastomas, noninvasive assessment of tumor activity corresponds well to immunohistochemical markers, and 11C-MET was more sensitive than 18F-FLT at detecting early tumor development. In contrast, infiltrative glioblastoma growth in the absence of blood-brain barrier breakdown is difficult to noninvasively follow by existing imaging techniques, and a negative 18F-FLT PET result does not exclude the presence of proliferating glioma tissue. The angiogenic model may serve as an advanced system to study imaging-guided anti-angiogenic and antiproliferative therapies. (authors)

  6. Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme

    OpenAIRE

    Chua, Susan L.; Rosenthal, Mark A.; Wong, Shirley S.; Ashley, David M.; Woods, Anne-marie; Dowling, Anthony; Cher, Lawrence M.

    2004-01-01

    Temozolomide has established activity in the treatment of recurrent glioblastoma multiforme (GBM). Caelyx (liposomal doxorubicin) has established activity in a broad range of tumors but has not been extensively evaluated in the treatment of GBM. Phase 1 data suggest that temozolomide and Caelyx can be combined safely at full dose. In this phase 2 study, combination temozolomide (200 mg/m2 orally, days 1–5) and Caelyx (40 mg/m2 i.v., day 1) was given every 4 weeks to a cohort of 22 patients wi...

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

    Institute of Scientific and Technical Information of China (English)

    Wang Huanliang; Han Jiqing; Li Haifeng; Zheng Tieran

    2008-01-01

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

  8. Engineering titania nanostructure to tune and improve its photocatalytic activity.

    Science.gov (United States)

    Cargnello, Matteo; Montini, Tiziano; Smolin, Sergey Y; Priebe, Jacqueline B; Delgado Jaén, Juan J; Doan-Nguyen, Vicky V T; McKay, Ian S; Schwalbe, Jay A; Pohl, Marga-Martina; Gordon, Thomas R; Lu, Yupeng; Baxter, Jason B; Brückner, Angelika; Fornasiero, Paolo; Murray, Christopher B

    2016-04-12

    Photocatalytic pathways could prove crucial to the sustainable production of fuels and chemicals required for a carbon-neutral society. Electron-hole recombination is a critical problem that has, so far, limited the efficiency of the most promising photocatalytic materials. Here, we show the efficacy of anisotropy in improving charge separation and thereby boosting the activity of a titania (TiO2) photocatalytic system. Specifically, we show that H2 production in uniform, one-dimensional brookite titania nanorods is highly enhanced by engineering their length. By using complimentary characterization techniques to separately probe excited electrons and holes, we link the high observed reaction rates to the anisotropic structure, which favors efficient carrier utilization. Quantum yield values for hydrogen production from ethanol, glycerol, and glucose as high as 65%, 35%, and 6%, respectively, demonstrate the promise and generality of this approach for improving the photoactivity of semiconducting nanostructures for a wide range of reacting systems. PMID:27035977

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

    Directory of Open Access Journals (Sweden)

    Iliadis Georgios

    2012-01-01

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

  10. Cytoplasmic TRADD Confers a Worse Prognosis in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Sharmistha Chakraborty

    2013-08-01

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

  11. Repair of 3-methyladenine and abasic sites by base excision repair mediates glioblastoma resistance to temozolomide

    Directory of Open Access Journals (Sweden)

    John R Silber

    2012-11-01

    Full Text Available Alkylating agents have long played a central role in the adjuvant therapy of glioblastoma multiforme (GBM. More recently, inclusion of temozolomide (TMZ, an orally administered methylating agent with low systemic toxicity, during radiotherapy and afterward has markedly improved survival. Extensive in vitro and in vivo evidence has shown that TMZ-induced O6-methylguanine (O6-meG mediates GBM cell killing. Moreover, low or absent expression of O6-methylguanine-DNA methyltransferase (MGMT, the sole human repair protein that removes O6-meG from DNA, is frequently associated with longer survival in GBMs treated with TMZ, promoting interest in developing inhibitors of MGMT to counter resistance. However, the clinical efficacy of TMZ is unlikely to be due solely to O6-meG, as the agent produces approximately a dozen additional DNA adducts, including cytotoxic N3-methyladenine (3-meA and abasic sites. Repair of 3-meA and abasic sites, both of which are produced in greater abundance than O6-meG, is mediated by the base excision repair (BER pathway, and occurs independently of removal of O6-meG. These observations indicate that BER activities are also potential targets for strategies to potentiate TMZ cytotoxicity. Here we review the evidence that 3-meA and abasic sites mediate killing of GBM cells. We also present in vitro and in vivo evidence that alkyladenine-DNA–glycosylase, the sole repair activity that excises 3-meA from DNA, and Ape1, the major human abasic site endonuclease, mediate TMZ resistance in GBMs and represent potential anti-resistance targets.

  12. Improvement activities for the maintenance of Baffle Former Bolts

    International Nuclear Information System (INIS)

    Baffle Former Bolts (BFBs) in PWR nuclear plant have the possibility to be cracked due to Irradiation Assisted Stress Corrosion Cracking (IASCC). The maintenance guideline for BFBs had been established from Thermal and Nuclear Power Engineering Society in 2000, and BFBs have been maintained in accordance with this maintenance rules. Recently, the new edition of this guideline has been published in order to reflect latest IASCC data and more precise stress evaluation of BFB into maintenance rules. The summary of the revised contents and these improvement activities are introduced in this paper. (author)

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

    Directory of Open Access Journals (Sweden)

    Mariana Maier Gaelzer

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

  14. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    OpenAIRE

    Lee, Dae-Hee; Kim, Dong-Wook; Jung, Chang-Hwa; Lee, Yong J.; Park, Daeho

    2014-01-01

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol ...

  15. Current Trends in Targeted Therapies for Glioblastoma Multiforme

    Directory of Open Access Journals (Sweden)

    Fumiharu Ohka

    2012-01-01

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

  16. Clinical implications of microRNAs in human glioblastoma

    Directory of Open Access Journals (Sweden)

    Masahiro eMizoguchi

    2013-02-01

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

  17. Inherited variation in immune genes and pathways and glioblastoma risk.

    Science.gov (United States)

    Schwartzbaum, Judith A; Xiao, Yuanyuan; Liu, Yanhong; Tsavachidis, Spyros; Berger, Mitchel S; Bondy, Melissa L; Chang, Jeffrey S; Chang, Susan M; Decker, Paul A; Ding, Bo; Hepworth, Sarah J; Houlston, Richard S; Hosking, Fay J; Jenkins, Robert B; Kosel, Matthew L; McCoy, Lucie S; McKinney, Patricia A; Muir, Kenneth; Patoka, Joe S; Prados, Michael; Rice, Terri; Robertson, Lindsay B; Schoemaker, Minouk J; Shete, Sanjay; Swerdlow, Anthony J; Wiemels, Joe L; Wiencke, John K; Yang, Ping; Wrensch, Margaret R

    2010-10-01

    To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk. PMID:20668009

  18. Associations between polymorphisms in DNA repair genes and glioblastoma.

    Science.gov (United States)

    McKean-Cowdin, Roberta; Barnholtz-Sloan, Jill; Inskip, Peter D; Ruder, Avima M; Butler, Maryann; Rajaraman, Preetha; Razavi, Pedram; Patoka, Joe; Wiencke, John K; Bondy, Melissa L; Wrensch, Margaret

    2009-04-01

    A pooled analysis was conducted to examine the association between select variants in DNA repair genes and glioblastoma multiforme, the most common and deadliest form of adult brain tumors. Genetic data for approximately 1,000 glioblastoma multiforme cases and 2,000 controls were combined from four centers in the United States that have conducted case-control studies on adult glioblastoma multiforme, including the National Cancer Institute, the National Institute for Occupational Safety and Health, the University of Texas M. D. Anderson Cancer Center, and the University of California at San Francisco. Twelve DNA repair single-nucleotide polymorphisms were selected for investigation in the pilot collaborative project. The C allele of the PARP1 rs1136410 variant was associated with a 20% reduction in risk for glioblastoma multiforme (odds ratio(CT or CC), 0.80; 95% confidence interval, 0.67-0.95). A 44% increase in risk for glioblastoma multiforme was found for individuals homozygous for the G allele of the PRKDC rs7003908 variant (odds ratio(GG), 1.44; 95% confidence interval, 1.13-1.84); there was a statistically significant trend (P = 0.009) with increasing number of G alleles. A significant, protective effect was found when three single-nucleotide polymorphisms (ERCC2 rs13181, ERCC1 rs3212986, and GLTSCR1 rs1035938) located near each other on chromosome 19 were modeled as a haplotype. The most common haplotype (AGC) was associated with a 23% reduction in risk (P = 0.03) compared with all other haplotypes combined. Few studies have reported on the associations between variants in DNA repair genes and brain tumors, and few specifically have examined their impact on glioblastoma multiforme. Our results suggest that common variation in DNA repair genes may be associated with risk for glioblastoma multiforme. PMID:19318434

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-11-01

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

  20. Ultrasonic waste activated sludge disintegration for improving anaerobic stabilization.

    Science.gov (United States)

    Tiehm, A; Nickel, K; Zellhorn, M; Neis, U

    2001-06-01

    The pretreatment of waste activated sludge by ultrasonic disintegration was studied in order to improve the anaerobic sludge stabilization. The ultrasound frequency was varied within a range from 41 to 3217 kHz. The impact of different ultrasound intensities and treatment times was examined. Sludge disintegration was most significant at low frequencies. Low-frequency ultrasound creates large cavitation bubbles which upon collapse initiate powerful jet streams exerting strong shear forces in the liquid. The decreasing sludge disintegration efficiency observed at higher frequencies was attributed to smaller cavitation bubbles which do not allow the initiation of such strong shear forces. Short sonication times resulted in sludge floc deagglomeration without the destruction of bacteria cells. Longer sonication brought about the break-up of cell walls, the sludge solids were distintegrated and dissolved organic compounds were released. The anaerobic digestion of waste activated sludge following ultrasonic pretreatment causing microbial cell lysis was significantly improved. There was an increase in the volatile solids degradation as well as an increase in the biogas production. The increase in digestion efficiency was proportional to the degree of sludge disintegration. To a lesser degree the deagglomeration of sludge flocs also augmented the anaerobic volatile solids degradation. PMID:11337847

  1. RM-05CASE OF GLIOBLASTOMA PATIENT TREATED WITH NovoTTF THERAPY AT RECURRENCE DEGENERATING TO SARCOMA

    OpenAIRE

    Majd, Pejman; O'Connell, Daniel; Kim, Ronald; Bota, Daniela; Carrillo, Jose

    2014-01-01

    NovoTTF treatment is an FDA approved treatment strategy for recurrent Glioblastoma multiforme (GBM) management which employs alternating electric fields to the region of the malignant tumor through probes on the patient's head which is thought to improve time to disease progression of GBM via cell cycle mitosis disruption. A patient is described with recurrent GBM who had disease progression following initial standard surgical treatment and concomitant chemo-radiotherapy and was found to have...

  2. Salvage Fractionated Stereotactic Radiotherapy with or without Chemotherapy and Immunotherapy for Recurrent Glioblastoma Multiforme: A Single Institution Experience

    OpenAIRE

    Hasan, Shaakir; Chen, Eda; Lanciano, Rachelle; Yang, Jun; Hanlon, Alex; Lamond, John; Arrigo, Stephen; Ding, William; Mikhail, Michael; Ghaneie, Arezoo; Brady, Luther

    2015-01-01

    Background The current standard of care for salvage treatment of glioblastoma multiforme (GBM) is gross total resection and adjuvant chemoradiation for operable patients. Limited evidence exists to suggest that any particular treatment modality improves survival for recurrent GBM, especially if inoperable. We report our experience with fractionated stereotactic radiotherapy (fSRT) with and without chemo/immunotherapy, identifying prognostic factors associated with prolonged survival. ...

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

    Lifescience Database Archive (English)

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  4. File list: ALL.Neu.50.AllAg.Glioblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  5. File list: ALL.Neu.20.AllAg.Glioblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. File list: Oth.Neu.20.AllAg.Glioblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. File list: Oth.Neu.10.AllAg.Glioblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Neu.10.AllAg.Glioblastoma hg19 TFs and others Neural Glioblastoma SRX377963,SRX...377961,SRX377962,SRX103002,SRX377960 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Neu.10.AllAg.Glioblastoma.bed ...

  8. File list: ALL.Neu.05.AllAg.Glioblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Neu.05.AllAg.Glioblastoma hg19 All antigens Neural Glioblastoma SRX1177289,SRX1...SRX1177351,SRX1177348,SRX1177364,SRX1177320,SRX1177363,SRX1177361,SRX1177359 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Neu.05.AllAg.Glioblastoma.bed ...

  9. File list: ALL.Neu.10.AllAg.Glioblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Neu.10.AllAg.Glioblastoma hg19 All antigens Neural Glioblastoma SRX1177354,SRX1...SRX1177350,SRX1177314,SRX1177363,SRX1177364,SRX1177361,SRX1177320,SRX1177359 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Neu.10.AllAg.Glioblastoma.bed ...

  10. File list: InP.Neu.05.AllAg.Glioblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Neu.05.AllAg.Glioblastoma hg19 Input control Neural Glioblastoma SRX377964,SRX3...77966,SRX377965 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Neu.05.AllAg.Glioblastoma.bed ...

  11. File list: InP.Neu.20.AllAg.Glioblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Neu.20.AllAg.Glioblastoma hg19 Input control Neural Glioblastoma SRX377964,SRX3...77966,SRX377965 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Neu.20.AllAg.Glioblastoma.bed ...

  12. MGMT analysis at DNA, RNA and protein levels in glioblastoma tissue

    OpenAIRE

    Preusser, Matthias

    2009-01-01

    Evidence from several studies supports that the epigenetic, transcriptional and translational regulation and expression of O6-methylguaninemethyltransferase (MGMT) is relevant for prognostic and predictive considerations in glioblastoma patients. MGMT status is being used as a stratifying factor or eligibility criterion in ongoing and accruing clinical glioblastoma trials. In some cases, there is also interest in MGMT assessment of glioblastoma tissue in the dayto- ...

  13. File list: InP.Neu.10.AllAg.Glioblastoma [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Neu.10.AllAg.Glioblastoma hg19 Input control Neural Glioblastoma SRX377964,SRX3...77966,SRX377965 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Neu.10.AllAg.Glioblastoma.bed ...

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

    Lifescience Database Archive (English)

    Full Text Available InP.Neu.50.AllAg.Glioblastoma hg19 Input control Neural Glioblastoma SRX377964,SRX3...77966,SRX377965 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Neu.50.AllAg.Glioblastoma.bed ...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-03-25

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

  16. Phenotypic characterization of glioblastoma identified through shape descriptors

    Science.gov (United States)

    Chaddad, Ahmad; Desrosiers, Christian; Toews, Matthew

    2016-03-01

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

  17. Decitabine nanoconjugate sensitizes human glioblastoma cells to temozolomide.

    Science.gov (United States)

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

    2015-04-01

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

  18. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.

    Science.gov (United States)

    Berenguer-Daizé, Caroline; Astorgues-Xerri, Lucile; Odore, Elodie; Cayol, Mylène; Cvitkovic, Esteban; Noel, Kay; Bekradda, Mohamed; MacKenzie, Sarah; Rezai, Keyvan; Lokiec, François; Riveiro, Maria E; Ouafik, L'Houcine

    2016-11-01

    Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines. OTX015 displayed higher antiproliferative effects compared to its analog JQ1, with GI50 values of approximately 0.2 µM. In addition, C-MYC and CDKN1A mRNA levels increased transiently after 4 h-exposure to OTX015, while BRD2, SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK were rapidly upregulated and sustained after 24 h. Studies in three additional GBM cell lines supported the antiproliferative effects of OTX015. In U87MG cells, OTX015 showed synergistic to additive activity when administered concomitant to or before SN38, temozolomide or everolimus. Single agent oral OTX015 significantly increased survival in mice bearing orthotopic or heterotopic U87MG xenografts. OTX015 combined simultaneously with temozolomide improved mice survival over either single agent. The passage of OTX015 across the blood-brain barrier was demonstrated with OTX015 tumor levels 7 to 15-fold higher than in normal tissues, along with preferential binding of OTX015 to tumor tissue. The significant antitumor effects seen with OTX015 in GBM xenograft models highlight its therapeutic potential in GBM patients, alone or combined with conventional chemotherapies. PMID:27388964

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

    Science.gov (United States)

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

    2016-05-05

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

  20. Cardamonin induces apoptosis by suppressing STAT3 signaling pathway in glioblastoma stem cells.

    Science.gov (United States)

    Wu, Ning; Liu, Jia; Zhao, Xiangzhong; Yan, Zhiyong; Jiang, Bo; Wang, Lijun; Cao, Shousong; Shi, Dayong; Lin, Xiukun

    2015-12-01

    Glioblastoma stem cells (GSCs) are the initiating cells in glioblastoma multiforme (GBM) and contribute to the resistance of GBM to chemotherapy and radiation. In the present study, we investigated the effects of cardamonin (3,4,2,4-tetrahydroxychalcone) on the self-renewal and apoptosis of GSCs, and if its action is associated with signal transducer and activator of transcription 3 (STAT3) pathway. CD133(+) GSCs, a kind of GSCs line, was established from human glioblastoma tissues. Cardamonin inhibited the proliferation and induced apoptosis in CD133+ GSCs. The proapoptotic effects of temozolomide (TMZ) were further enhanced by cardamonin in CD133+ GSCs and U87 cells in vitro. For in vivo study, injection of 5 × 10(5) cells of CD133+ GSCs subcutaneously (s.c.) into nude mice, 100 % of large tumors were developed within 8 weeks in all mice; in contrast, only one out of five mice developed a small tumor when 5 × 10(5) cells of CD133(-) GMBs cells were injected. Cardamonin also inhibited STAT3 activation by luciferase assay and suppressed the expression of the downstream genes of STAT3, such as Bcl-XL, Bcl-2, Mcl-1, survivin, and VEGF. Furthermore, cardamonin locked nuclear translocation and dimerization of STAT3 in CD133(+) GSCs. Docking analysis confirmed that cardamonin molecule was successfully docked into the active sites of STAT3 with a highly favorable binding energy of -10.78 kcal/mol. The study provides evidence that cardamonin is a novel inhibitor of STAT3 and has the potential to be developed as a new anticancer agent targeting GSCs. This study also reveals that targeting STAT3 signal pathway is an important strategy for the treatment of human GBM. PMID:26150336

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

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

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

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

    Science.gov (United States)

    Gersh-Range, Jessica; Perrin, Marshall D.

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-05-01

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

  4. Personalized treatment strategies in glioblastoma: MGMT promoter methylation status

    Directory of Open Access Journals (Sweden)

    Thon N

    2013-09-01

    Full Text Available Niklas Thon,1 Simone Kreth,2 Friedrich-Wilhelm Kreth1 1Department of Neurosurgery, 2Department of Anaesthesiology, Hospital of the University of Munich, Campus Grosshadern, Munich, Germany Abstract: The identification of molecular genetic biomarkers considerably increased our current understanding of glioma genesis, prognostic evaluation, and treatment planning. In glioblastoma, the most malignant intrinsic brain tumor entity in adults, the promoter methylation status of the gene encoding for the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT indicates increased efficacy of current standard of care, which is concomitant and adjuvant chemoradiotherapy with the alkylating agent temozolomide. In the elderly, MGMT promoter methylation status has recently been introduced to be a predictive biomarker that can be used for stratification of treatment regimes. This review gives a short summery of epidemiological, clinical, diagnostic, and treatment aspects of patients who are currently diagnosed with glioblastoma. The most important molecular genetic markers and epigenetic alterations in glioblastoma are summarized. Special focus is given to the physiological function of DNA methylation – in particular, of the MGMT gene promoter, its clinical relevance, technical aspects of status assessment, its correlation with MGMT mRNA and protein expressions, and its place within the management cascade of glioblastoma patients. Keywords: glioblastoma, MGMT, temozolomide, personalized treatment, outcome

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

    Directory of Open Access Journals (Sweden)

    Desiree Hunt Floyd

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

  6. Cytotoxic constituents of Abutilon indicum leaves against U87MG human glioblastoma cells.

    Science.gov (United States)

    Khan, Rukaiyya Sirajuddin; Senthi, Mahibalan; Rao, Poorna Chandra; Basha, Ameer; Alvala, Mallika; Tummuri, Dinesh; Masubuti, Hironori; Fujimoto, Yoshinori; Begum, Ahil Sajeli

    2015-01-01

    The study was aimed to identify cytotoxic leads from Abutilon indicum leaves for treating glioblastoma. The petroleum ether extract, methanol extract (AIM), chloroform and ethyl acetate sub-fractions (AIM-C and AIM-E, respectively) prepared from AIM were tested for cytotoxicity on U87MG human glioblastoma cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. These extracts exhibited considerable activity (IC50 values of 42.6-64.5 μg/mL). The most active AIM-C fraction was repeatedly chromatographed to yield four known compounds, methyl trans-p-coumarate (1), methyl caffeate (2), syringic acid (3) and pinellic acid (4). Cell viability assay of 1-4 against U87MG cells indicated 2 as most active (IC50 value of 8.2 μg/mL), whereas the other three compounds were much less active. Interestingly, compounds 1-4 were non-toxic towards normal human cells (HEK-293). The content of 2 in AIM-C was estimated as 3% by HPLC. Hence, presence of some more active substances besides methyl caffeate (2) in AIM-C is anticipated. PMID:25422029

  7. Improved cosmetic activity by optimizing the Lithospermum erythrorhizon extraction process.

    Science.gov (United States)

    Kim, Ji Seon; Seo, Yong Chang; No, Ra Hwan; Lee, Hyeon Yong

    2015-01-01

    This study was conducted to expand the use of Lithospermum erythrorhizon, which is a good source of natural dye, in skin whitening and immune activation cosmetics. The goal was to provide cosmeceutical data about the extraction yield and shikonin contents of this plant by optimizing the ultrasonic extraction and high pressure extraction conditions. Under optimal extraction conditions, which consisted of 500 MPa for 60 min and 120 kHz for 90 min, 27.49 and 3.19 % (w/w) of the highest extraction yield and shikonin contents were obtained, compared to 16.32 and 1.81 % from a conventional ethanol extract (EE) control. Hyaluronidase inhibition activity was measured as 44.24 % after adding 1.0 mg/ml of ethanol extract, but it was as high as 64.19 % when using extract produced by ultrasonication with high pressure extraction (UE + HPE). The MMP-1 expression levels from skin fibroblast cells (CCD-986sk) treated with or without UV irradiation were also lowered by as much as 110.6 % after adding 1.0 mg/ml of the UE + HPE extract, relative to 126.9 % from the EE. After UVA exposure, prostaglandin E2 production from RAW 264.7 was also lower, at 110.6 %, which also indicates that the extract from the UE + HPE process enhanced skin immune activation activities. For the skin whitening activity, tyrosinase inhibitory activity was observed at 67.15 % in the HPE + UE extract, which was ca. 20 % higher than that of the EE extract (57.48 %). To reduce melanin production in Clone M-3 cells, 79.5 % of the melanin production was estimated after adding 1.0 mg/ml of the UE + HPE extract compared to that of the control (no treatment), which was similar to the 77.4 % result found in an ascorbic acid positive control. The highest shikonin secretion was conclusively obtained under the optimal conditions and resulted in a significant improvement of the cosmetic activities of L. erythrorhizon extracts. PMID:24287611

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

    Directory of Open Access Journals (Sweden)

    Abrudan C.

    2014-03-01

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

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

    Science.gov (United States)

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

    2016-04-01

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

  10. Pharmacologic inhibition of cdk4/6 arrests the growth of glioblastoma multiforme intracranial xenografts

    OpenAIRE

    Michaud, Karine; Solomon, David A.; Oermann, Eric; Kim, Jung-Sik; Zhong, Wei-Zhu; Prados, Michael D.; Ozawa, Tomoko; James, C. David; Waldman, Todd

    2010-01-01

    Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6 specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induc...

  11. Retrospective Analysis of Bevacizumab in Combination with Fotemustine in Chinese Patients with Recurrent Glioblastoma Multiforme

    OpenAIRE

    Zhiguang Liu; Guanqun Zhang; Liang Zhu; Jiangbo Wang; Dongbo Liu; Lifei Lian; Jianlin Liu; Tianbao Lai; Xiaorong Zhuang

    2015-01-01

    The aim of this study was to assess the activity and safety of bevacizumab (BEV) and fotemustine (FTM) for the treatment of recurrent glioblastoma multiforme (GBM) patients and explore the potential prognostic parameters on survival. This study retrospectively analyzed all patients with GBM who were treated with at least one cycle of BEV and FTM from July 2010 to October 2012. A total of 176 patients with recurrent GBM were enrolled. The response rate and disease control rate were 46.6% and 9...

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

    CERN Document Server

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

    1999-01-01

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

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

    International Nuclear Information System (INIS)

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

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

    KAUST Repository

    Loh, Wai Soong

    2010-08-12

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

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

    Directory of Open Access Journals (Sweden)

    Lars Donath

    2014-12-01

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

  16. Volumetry of [11C]-methionine PET uptake and MRI contrast enhancement in patients with recurrent glioblastoma multiforme

    OpenAIRE

    Galldiks, Norbert; Ullrich, Roland; Schroeter, Michael; Fink, Gereon R.; Kracht, Lutz W.

    2009-01-01

    Purpose We investigated the relationship between three-dimensional volumetric data of the metabolically active tumour volume assessed using [11C]-methionine positron emission tomography (MET-PET) and the area of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) enhancement assessed using magnetic resonance imaging (MRI) in patients with recurrent glioblastoma (GBM). Material and methods MET-PET and contrast-enhanced MRI with Gd-DTPA were performed in 12 uniformly pretreated patients wit...

  17. Accelerated hyperfractionation plus temozolomide in glioblastoma

    International Nuclear Information System (INIS)

    Hyperfractionated (HFRT) or accelerated hyperfractionated radiotherapy (AHFRT) have been discussed as a potential treatment for glioblastoma based on a hypothesized reduction of late radiation injury and prevention of repopulation. HFRT and AHFRT have been examined extensively in the pre-Temozolomide era with inconclusive results. In this study we examined the role of accelerated hyperfractionation in the Temozolomide era. Sixty-four patients who underwent AHFRT (62 of which received Temozolomide) were compared to 67 patients who underwent normofractionated radiotherapy (NFRT) (64 of which received TMZ) between 02/2009 and 10/2014. Follow-up data were analyzed until 01/2015. Median progression-free survival (PFS) was 6 months for the entire cohort. For patients treated with NFRT median PFS was 7 months, for patients treated with AHFRT median PFS was 6 months. Median overall survival (OS) was 13 months for all patients. For patients treated with NFRT median OS was 15 months, for patients treated with AHFRT median OS was 10 months. The fractionation regimen was not a predictor of PFS or OS in univariable- or multivariable analysis. There was no difference in acute toxicity profiles between the two treatment groups. Univariable and multivariable analysis did not show significant differences between NFRT and AHFRT fractionation regimens in terms of PFS or OS. The benefits are immanent: the regimen does significantly shorten hospitalization time in a patient collective with highly impaired life expectancy. We propose that the role of AHFRT + TMZ should be further examined in future prospective trials

  18. Canine Butterfly Glioblastomas: A Neuroradiological Review

    Science.gov (United States)

    Rossmeisl, John H.; Clapp, Kemba; Pancotto, Theresa E.; Emch, Samantha; Robertson, John L.; Debinski, Waldemar

    2016-01-01

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

  19. CANINE BUTTERFLY GLIOBLASTOMAS: A NEURORADIOLOGICAL REVIEW

    Directory of Open Access Journals (Sweden)

    John Henry Rossmeisl

    2016-05-01

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

  20. Imaging modalities to assess oxygen status in glioblastoma

    Directory of Open Access Journals (Sweden)

    Aurélien eCorroyer-Dulmont

    2015-08-01

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

  1. Glioblastoma and the significance of MGMT gene methylation

    Directory of Open Access Journals (Sweden)

    Payam Izadpanahi

    2014-08-01

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

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

    Science.gov (United States)

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

    2016-01-01

    Regulatory RNAs have become integral components of the synthetic biology and bioengineering toolbox for controlling gene expression. We recently expanded this toolbox by creating small transcription activating RNAs (STARs) that act by disrupting the formation of a target transcriptional terminator hairpin placed upstream of a gene. While STARs are a promising addition to the repertoire of RNA regulators, much work remains to be done to optimize the fold activation of these systems. Here we apply rational RNA engineering strategies to improve the fold activation of two STAR regulators. We demonstrate that a combination of promoter strength tuning and multiple RNA engineering strategies can improve fold activation from 5.4-fold to 13.4-fold for a STAR regulator derived from the pbuE riboswitch terminator. We then validate the generality of our approach and show that these same strategies improve fold activation from 2.1-fold to 14.6-fold for an unrelated STAR regulator, opening the door to creating a range of additional STARs to use in a broad array of biotechnologies. We also establish that the optimizations preserve the orthogonality of these STARs between themselves and a set of RNA transcriptional repressors, enabling these optimized STARs to be used in sophisticated circuits. PMID:26134708

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

    Science.gov (United States)

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

    2016-01-01

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

  4. Optimization of an Active Twist Rotor Blade Planform for Improved Active Response and Forward Flight Performance

    Science.gov (United States)

    Sekula, Martin K; Wilbur, Matthew L.

    2014-01-01

    A study was conducted to identify the optimum blade tip planform for a model-scale active twist rotor. The analysis identified blade tip design traits which simultaneously reduce rotor power of an unactuated rotor while leveraging aeromechanical couplings to tailor the active response of the blade. Optimizing the blade tip planform for minimum rotor power in forward flight provided a 5 percent improvement in performance compared to a rectangular blade tip, but reduced the vibration control authority of active twist actuation by 75 percent. Optimizing for maximum blade twist response increased the vibration control authority by 50 percent compared to the rectangular blade tip, with little effect on performance. Combined response and power optimization resulted in a blade tip design which provided similar vibration control authority to the rectangular blade tip, but with a 3.4 percent improvement in rotor performance in forward flight.

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

    Science.gov (United States)

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

    2015-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Satoru Takeuchi

    2014-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2005-01-01

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

  8. GlioLab-a space system for Glioblastoma multiforme cells on orbit behavior study

    Science.gov (United States)

    Cappelletti, Chantal; Twiggs, Robert J.

    Microgravity conditions and ionizing radiation pose significant health risks for human life in space. This is a concern for future missions and also for future space tourism flights. Nev-ertheless, at the same time it is very interesting to study the effects of these conditions in unhealthy organism like biological samples affected by cancer. It is possible that space envi-ronment increases, decreases or doesn't have any effect on cancer cells. In any case the test results give important informations about cancer treatment or space tourism flight for people affected by cancer. GlioLab is a joint project between GAUSS-Group of Astrodynamics at the "Sapienza" University of Roma and the Morehead State University (MSU) Space Science Center in Kentucky. The main goal of this project is the design and manufacturing of an autonomous space system to investigate potential effects of the space environment exposure on a human glioblastoma multiforme cell line derived from a 65-year-old male and on Normal Human Astrocytes (NHA). In particular the samples are Glioblastoma multiforme cancer cells because the radiotherapy using ionizing radiation is the only treatment after surgery that can give on ground an improvement on the survival rate for this very malignant cancer. During a mission on the ISS, GlioLab mission has to test the in orbit behavior of glioblastoma cancer cells and healthy neuronal cells, which are extremely fragile and require complex experimentation and testing. In this paper engineering solutions to design and manufacturing of an autonomous space system that can allow to keep alive these kind of cells are described. This autonomous system is characterized also by an optical device dedicated to cells behavior analysis and by microdosimeters for monitoring space radiation environment.

  9. Case comparison and literature review of glioblastoma: A tale of two tumors

    Directory of Open Access Journals (Sweden)

    Gustavo Mendez

    2014-01-01

    Full Text Available Background: Diagnosis of glioblastoma multiforme (GBM includes a heterogeneous group of tumors. We describe two cases with histopathologically and molecularly similar tumors, but very different outcomes. We attempt to illustrate the need for improved prognostic markers for GBM. Case Description: Two patients with similar molecular profiles were retrospectively identified. The following markers were assessed: O6 -methylguanine DNA methyltransferase (MGMT methylation, isocitrate dehydrogenase (IDH 1 and 2 status, epidermal growth factor receptor (EGFR amplification, phosphatase and tensin homolog (PTEN status, Ki-67, p53, and 1p/19q status. Each patient was assigned a Karnofsky performance score at presentation. Case 1 (62-year-old male was a right temporal lobe glioblastoma with a molecular profile of amplified EGFR, normal PTEN, no IDH1/2 mutation, 28.7% MGMT promoter methylation, 5-20% Ki-67, 1p deletion, and 19q intact. The patient underwent resection followed by radiation therapy and 2 years of chemotherapy, and was asymptomatic and tumor free 5 years post diagnosis. Tumor eventually recurred and the patient expired 72 months after initial diagnosis. Case 2 (63-year-old male was a right frontal white matter mass consistent with glioblastoma with a molecular profile of amplified EGFR, absent PTEN, no IDH1/2 mutation, 9.9% MGMT promoter methylation, 5-10% Ki-67, and 1p/19q status inconclusive. A radical subtotal resection was performed; however, 2 weeks later symptoms had returned. Subsequent imaging revealed a tumor larger than at diagnosis. The patient expired 3 months after initial diagnosis. Conclusion: The need for formulating more robust means to classify GBM tumor subtypes is paramount. Standard histopathologic and molecular analyses are costly and did not provide either of these patients with a realistic appraisal of their prognosis. Individualized whole genome testing similar to that being reported for medulloblastoma and other tumors

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

    Directory of Open Access Journals (Sweden)

    Xiao-Hong Shu

    2013-05-01

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

  11. Transportan 10 improves the anticancer activity of cisplatin.

    Science.gov (United States)

    Izabela, Rusiecka; Jarosław, Ruczyński; Magdalena, Alenowicz; Piotr, Rekowski; Ivan, Kocić

    2016-05-01

    The aim of this paper was to examine whether cell-penetrating peptides (CPPs) such as transportan 10 (TP10) or protein transduction domain (PTD4) may improve the anticancer activity of cisplatin (cPt). The complexes of TP10 or PTD4 with cPt were used in the experiments. They were carried out on two non-cancer (HEK293 (human embryonic kidney) and HEL299 (human embryo lung)) and two cancer (HeLa (human cervical cancer) and OS143B (human osteosarcoma 143B)) cell lines. Both complexes were tested (MTT assay) with respect to their anticancer or cytotoxic actions. TAMRA (fluorescent dye)-stained preparations were visualized in a fluorescence microscope. The long-term effect of TP10 + cPt and its components on non-cancer and cancer cell lines was observed in inverted phase contrast microscopy. In the MTT test (cell viability assay), the complex of TP10 + cPt produced a more potent effect on the cancer cell lines (HeLa, OS143B) in comparison to that observed after separate treatment with TP10 or cPt. At the same time, the action of the complex and its components was rather small on non-cancer cell lines. On the other hand, a complex of another CPP with cPt, i.e., PTD4 + cPt, was without a significant effect on the cancer cell line (OS143B). The images of the fluorescent microscopy showed TAMRA-TP10 or TAMRA-TP10 + cPt in the interior of the HeLa cells. In the case of TAMRA-PTD4 or TAMRA-PTD4 + cPt, only the first compound was found inside the cancer cell line. In contrast, none of the tested compounds gained access to the interior of the non-cancer cells (HEK293, HEL299). Long-term incubation with the TP10 + cPt (estimated by inverted phase contrast microscopy) lead to an enhanced action of the complex on cell viability (decrease in the number of cells and change in their morphology) as compared with that produced by each single agent. With regard to the tested CPPs, only TP10 improved the anticancer activity of cisplatin if both compounds were used in the form of a

  12. Disparities in receipt of modern concurrent chemoradiotherapy in glioblastoma.

    Science.gov (United States)

    Rhome, Ryan; Fisher, Rebecca; Hormigo, Adília; Parikh, Rahul R

    2016-06-01

    Temozolomide given concurrently with radiation after resection/biopsy improves survival in glioblastoma (GBM). The disparities in receipt of adjuvant single-agent chemotherapy and their association with outcome have not been well established. Observational study of a prospectively collected database, the National Cancer Database (NCDB), from 1998 to 2012 with median follow-up 12.4 months. Among the 114,979 patients in the NCDB with GBM, 44,531 patients were analyzed for disparities, and 28,279 patients were analyzed for overall survival (OS). Associations were assessed in a multivariable Cox proportional hazards regression model. Survival was estimated using the Kaplan-Meier method. Median age was 58 years. Chemotherapy use was associated with male gender, white race, younger age (≤50), higher performance status (≥70), more extensive surgery, insurance status, higher income/education, and treatment at academic centers (all p < 0.05). We found improved OS associated with type of insurance (private insurance HR 0.91, 95 % CI 0.85-0.96 and Medicare HR 1.24, 95 % CI 1.16-1.33, both p < 0.01 compared to uninsured) and treatment at academic programs (HR 0.86; p < 0.01). MGMT methylation status predicted improved OS (HR 0.54; 95 % CI 0.41-0.70, p < 0.01). 1-year OS for patients receiving chemotherapy was 55.9 % versus 35.3 % for those without (p < 0.0001). After adjustment for confounders, chemotherapy use remained associated with improved OS (HR 0.64, 95 % CI 0.63-0.66, p < 0.01). Chemotherapy utilization increased from 26.9 to 93.3 % during the study period. We have identified specific disparities in the use of chemotherapy that may be targeted to improve patient access to care. Widespread adoption of adjuvant chemoradiotherapy after resection or biopsy for GBM appears to improve OS. PMID:26970981

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

    Directory of Open Access Journals (Sweden)

    Koji eYoshimoto

    2012-12-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-11-06

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

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

    Directory of Open Access Journals (Sweden)

    Tang XJ

    2016-10-01

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

  16. Morphometic analysis of TCGA glioblastoma multiforme

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    Chang Hang

    2011-12-01

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

  17. Clinical characteristics and pathogenesis of cerebellar glioblastoma.

    Science.gov (United States)

    Takahashi, Yoshinobu; Makino, Keishi; Nakamura, Hideo; Hide, Takuichiro; Yano, Shigetoshi; Kamada, Hajime; Kuratsu, Jun-Ichi

    2014-11-01

    Cerebellar glioblastomas (GBMs) are rare, with neither their pathogenesis nor prognosis being completely understood. The present study aimed to clarify the clinical characteristics of cerebellar GBMs by comparison with supratentorial GBMs, focusing particularly on the pathogenesis. The clinical factors between cerebellar (n=10) and supratentorial (n=216) GBMs were compared. Additionally, p53 and epidermal growth factor receptor (EGFR) levels were investigated in six patients by immunostaining as well as the isocitrate dehydrogenase 1 (IDH1) status of five patients by direct sequencing. Eight males and two females participated in the present study, the mean age at diagnosis was 56.6 years and the range 37-75 years. Four patients presented with hydrocephalus and one with brainstem involvement, and two patients were diagnosed with neurofibromatosis type 1. Two patients had previously received radiotherapy, eight patients received postoperative radiotherapy and seven chemotherapy. The mean Karnofsky performance status (KPS) score was lower in patients with cerebellar GBMs compared to those with supratentorial GBM; however, the survival times did not differ between the two groups. All of the cases of six cerebellar GBMs were p53‑positive and EGFR‑negative, as detected by immunostaining, consistent with secondary GBM. However, no IDH1 mutations were detected in any of the five cases of cerebellar GBMs analyzed, indicating that these tumors were not of the secondary type. The KPS score with cerebellar GBMs may be lower due to hydrocephalus, which was ameliorated by surgery but may have impacted the survival rate. It was confirmed that cerebellar GBMs were identical to supratentorial GBMs with respect to its clinical features, with the possible exception of the KPS score. The present study's genetic analyses indicated that cerebellar GBMs may develop via a pathway different from that of either primary or secondary GBM. PMID:25199771

  18. Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase

    Institute of Scientific and Technical Information of China (English)

    Jing SHANG; Lu-lu CHEN; Eang-xi XIAO; Hui SUN; Hong-cheng DING; Hu XIAO

    2008-01-01

    Aim: To investigate whether resveratrol (RSV) can improve non-alcoholic fatty liver disease (NAFLD) and to find the possible mechanism. Methods: Rats fed a high-fat diet were treated with RSV. The liver histology was observed. Hyperinsulinemic euglycemic clamp was performed to assess insulin sensitivity. Fat accumulation was induced in HepG2 cells, and the cells were treated with RSV. AMP-activated protein kinase (AMPK) phosphorylation levels were de-termined both in the animal study and cell study. Results: Rats fed a high-fat diet developed abdominal obesity, NAFLD, and insulin resistance (IR), which were markedly improved by 10 weeks of RSV administration. RSV treatment prevented triacylglycerol (TG) accumulation in HepG2 cells that were incubated with high concentration of glucose and insulin. Both in vivo and in vitro studies showed that RSV treatment could promote the phosphorylation of AMPK, which in this study, suppressed 2 lipogenesis gene expressions, contributing to the improvement of NAFLD and IR. Conclusion: The results indicated that by re-ducing TG accumulation and improving IR, RSV could protect the liver from NAFLD. The activation of AMPK was involved in the mechanism. RSV has the therapeutic potential for preventing or treating NAFLD and IR-related metabolic disorders.

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

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    Marie Le Mercier

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

  20. Salinomycin potentiates the cytotoxic effects of TRAIL on glioblastoma cell lines.

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    Alessia Calzolari

    Full Text Available Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL has been reported to exhibit therapeutic activity in cancer. However, many tumors remain resistant to treatment with TRAIL. Therefore, small molecules that potentiate the cytotoxic effects of TRAIL could be used for combinatorial therapy. Here we found that the ionophore antibiotic salinomycin acts in synergism with TRAIL, enhancing TRAIL-induced apoptosis in glioma cells. Treatment with low doses of salinomycin in combination with TRAIL augmented the activation of caspase-3 and increased TRAIL-R2 cell surface expression. TRAIL-R2 upmodulation was required for mediating the stimulatory effect of salinomycin on TRAIL-mediated apoptosis, since it was abrogated by siRNA-mediated TRAIL-R2 knockdown. Salinomycin in synergism with TRAIL exerts a marked anti-tumor effect in nude mice xenografted with human glioblastoma cells. Our results suggest that the combination of TRAIL and salinomycin may be a useful tool to overcome TRAIL resistance in glioma cells and may represent a potential drug for treatment of these tumors. Importantly, salinomycin+TRAIL were able to induce cell death of well-defined glioblastoma stem-like lines.

  1. Radiotherapy for glioblastoma: reorganization of genome maintenance mechanisms involved in the process of inhibiting cancer

    International Nuclear Information System (INIS)

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

  2. The quantification of dynamic FET PET imaging and correlation with the clinical outcome in patients with glioblastoma

    Science.gov (United States)

    Thiele, Frank; Ehmer, Julia; Piroth, Marc D.; Eble, Michael J.; Coenen, Heinz H.; Kaiser, Hans-Juergen; Schaefer, Wolfgang M.; Buell, Ulrich; Boy, Christian

    2009-09-01

    The PET tracer O-(2-[18F]Fluoroethyl)-l-tyrosine (FET) has been shown to be valuable for different roles in the management of brain tumours. The aim of this study was to evaluate several quantitative measures of dynamic FET PET imaging in patients with resected glioblastoma. We evaluated dynamic FET PET in nine patients with histologically confirmed glioblastoma. Following FET PET, all subjects had radiation and chemotherapy. Tumour ROIs were defined by a threshold-based region-growing algorithm. We compared several standard measures of tumour uptake and uptake kinetics: SUV, SUV/background, distribution volume ratio (DVR), weighted frame differences and compartment model parameters. These measures were correlated with disease-free and overall survival, and analysed for statistical significance. We found that several measures allowed robust quantification. SUV and distribution volume did not correlate with clinical outcome. Measures that are based on a background region (SUV/BG, Logan-DVR) highly correlated with disease-free survival (r = -0.95, p survival. Some advanced measures also showed a prognostic value but no improvement over the simpler methods. We conclude that FET PET probably has a prognostic value in patients with resected glioblastoma. The ratio of SUV to background may provide a simple and valuable predictive measure of the clinical outcome. Further studies are needed to confirm these explorative results.

  3. Virtual mutagenesis of isocitrate dehydrogenase 1 involved in glioblastoma multiforme

    Institute of Scientific and Technical Information of China (English)

    WANG Ming-dong; SHI Yan-fang; WANG Hong; WANG Jia-liang; MA Wen-bin; WANG Ren-zhi

    2011-01-01

    Background Site A132Arg mutations potentially impair the affinity of isocitrate dehydrogenase 1 (IDH1) for its substrate isocitrate (ICT),consequently reducing the production of α-ketoglutarate and leading to tumor growth through the induction of the hypoxia-inducible factor-1 (HIF-1) pathway.However,given that the roles of other active sites in IDH1 substrate binding remain unclear,we aimed to investigate IDH1 mutation pattern and its influence on enzyme function.Methods Fifteen IDH1 catalytic active site candidates were selected for in silico mutagenesis and protein homology modeling.Binding free energy of the IDH1/ICT complexes with single-site mutations was compared with that of the wild type.The affinity of 10 IDH1 catalytic active sites for the ICT substrate was further calculated.Results The IDH1 active site included seven residues from chain A (A77Thr,A94Ser,A100Arg,A132Arg,A1O9Arg,A275Asp,and A279Asp) and three residues from chain B (B214Thr,B212Lys,and B252Asp) that constituted the substrate ICT-binding site.These residues were located within 0.5 nm of ICT,indicating a potential interaction with the substrate.IDH1 changes of binding free energy (△E) suggested that the A132Arg residue from chain A contributes three hydrogen bonds to the ICT α-carboxyl and β-carboxyl groups,while the other nine residues involved in ICT binding form only one or two hydrogen bonds.Amino acid substitutes at A132Arg,A109Arg,and B212Lys sites,had the greatest effect on enzyme affinity for its substrate.Conclusions Mutations at sites A132Arg,A109Arg,and B212Lys reduced IDH1 affinity for ICT,indicating these active sites may play a central role in substrate binding.Mutations at sites A77Thr,A94Ser,and A275Asp increased the affinity of IDH1 for ICT,which may enhance IDN1 catalytic activity.Mutant IDH1 proteins with higher catalytic activity than the wild-type IDH1 could potentially be used as a novel gene therapy for glioblastoma multiforme.

  4. Integration method of 3D MR spectroscopy into treatment planning system for glioblastoma IMRT dose painting with integrated simultaneous boost

    International Nuclear Information System (INIS)

    To integrate 3D MR spectroscopy imaging (MRSI) in the treatment planning system (TPS) for glioblastoma dose painting to guide simultaneous integrated boost (SIB) in intensity-modulated radiation therapy (IMRT). For sixteen glioblastoma patients, we have simulated three types of dosimetry plans, one conventional plan of 60-Gy in 3D conformational radiotherapy (3D-CRT), one 60-Gy plan in IMRT and one 72-Gy plan in SIB-IMRT. All sixteen MRSI metabolic maps were integrated into TPS, using normalization with color-space conversion and threshold-based segmentation. The fusion between the metabolic maps and the planning CT scans were assessed. Dosimetry comparisons were performed between the different plans of 60-Gy 3D-CRT, 60-Gy IMRT and 72-Gy SIB-IMRT, the last plan was targeted on MRSI abnormalities and contrast enhancement (CE). Fusion assessment was performed for 160 transformations. It resulted in maximum differences <1.00 mm for translation parameters and ≤1.15° for rotation. Dosimetry plans of 72-Gy SIB-IMRT and 60-Gy IMRT showed a significantly decreased maximum dose to the brainstem (44.00 and 44.30 vs. 57.01 Gy) and decreased high dose-volumes to normal brain (19 and 20 vs. 23% and 7 and 7 vs. 12%) compared to 60-Gy 3D-CRT (p < 0.05). Delivering standard doses to conventional target and higher doses to new target volumes characterized by MRSI and CE is now possible and does not increase dose to organs at risk. MRSI and CE abnormalities are now integrated for glioblastoma SIB-IMRT, concomitant with temozolomide, in an ongoing multi-institutional phase-III clinical trial. Our method of MR spectroscopy maps integration to TPS is robust and reliable; integration to neuronavigation systems with this method could also improve glioblastoma resection or guide biopsies

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

    Science.gov (United States)

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

    2012-01-01

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

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

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    Maria Zeniou

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

  7. Glioblastoma stem-like cells give rise to tumour endothelium

    NARCIS (Netherlands)

    R. Wang; K. Chadalavada; J. Wilshire; U. Kowalik; K.E. Hovinga; A. Geber; B. Fligelman; M. Leversha; C. Brennan; V. Tabar

    2010-01-01

    Glioblastoma (GBM) is among the most aggressive of human cancers(1). A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia(2). Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poo

  8. Personalized treatment strategies in glioblastoma: MGMT promoter methylation status

    Science.gov (United States)

    Thon, Niklas; Kreth, Simone; Kreth, Friedrich-Wilhelm

    2013-01-01

    The identification of molecular genetic biomarkers considerably increased our current understanding of glioma genesis, prognostic evaluation, and treatment planning. In glioblastoma, the most malignant intrinsic brain tumor entity in adults, the promoter methylation status of the gene encoding for the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) indicates increased efficacy of current standard of care, which is concomitant and adjuvant chemoradiotherapy with the alkylating agent temozolomide. In the elderly, MGMT promoter methylation status has recently been introduced to be a predictive biomarker that can be used for stratification of treatment regimes. This review gives a short summery of epidemiological, clinical, diagnostic, and treatment aspects of patients who are currently diagnosed with glioblastoma. The most important molecular genetic markers and epigenetic alterations in glioblastoma are summarized. Special focus is given to the physiological function of DNA methylation–in particular, of the MGMT gene promoter, its clinical relevance, technical aspects of status assessment, its correlation with MGMT mRNA and protein expressions, and its place within the management cascade of glioblastoma patients. PMID:24109190

  9. Cerebellar glioblastoma multiforme presenting as a cerebellopontine angle mass

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    Anupam Jindal

    2006-01-01

    Full Text Available Cerebellar glioblastoma multiforme (GBM is a highly malignant brain tumour, which is exceedingly rare and such tumour presenting as cerebellopontine angle (CPA mass is even rarer. We here discuss the case of a 15-year-old girl who had cerebellar GBM presenting as CPA mass that resembled meningioma on CT scan and was managed successfully with minimal problems.

  10. MGMT gene silencing and benefit from temozolomide in glioblastoma

    NARCIS (Netherlands)

    Hegi, ME; Diserens, A; Gorlia, T; Hamou, M; de Tribolet, N; Weller, M; Kros, JM; Hainfellner, JA; Mason, W; Mariani, L; Bromberg, JEC; Hau, P; Mirimanoff, RO; Cairncross, JG; Janzer, RC; Stupp, R

    2005-01-01

    BACKGROUND: Epigenetic silencing of the MGMT (O(sup 6)-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship bet

  11. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    Science.gov (United States)

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

    2014-01-01

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

  12. PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma.

    Directory of Open Access Journals (Sweden)

    Georg Karpel-Massler

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

  13. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

    International Nuclear Information System (INIS)

    Purpose: Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials: Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV46 and CTV60, respectively). MTVCho and MTVNAA were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results: The MRSI coverage of the brain was between 70% and 76%. The MTVNAA were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTVCho was outside of the edema (median, 33%) and for some patients it was also outside of the CTV46 and CTV60. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTVCho for these patients were outside of CTV60. Conclusions: This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on metabolic information

  14. Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis.

    Science.gov (United States)

    Lamborn, Kathleen R; Chang, Susan M; Prados, Michael D

    2004-07-01

    Survival for patients with glioblastoma multiforme is short, and current treatments provide limited benefit. Therefore, there is interest in conducting phase 2 trials of experimental treatments in newly diagnosed patients. However, this requires historical data with which to compare the experimental therapies. Knowledge of prognostic markers would also allow stratification into risk groups for phase 3 randomized trials. In this retrospective study of 832 glioblastoma multiforme patients enrolled into prospective clinical trials at the time of initial diagnosis, we evaluated several potential prognostic markers for survival to establish risk groups. Analyses were done using both Cox proportional hazards modeling and recursive partitioning analyses. Initially, patients from 8 clinical trials, 6 of which included adjuvant chemotherapy, were included. Subsequent analyses excluded trials with interstitial brachytherapy, and finally included only nonbrachytherapy trials with planned adjuvant chemotherapy. The initial analysis defined 4 risk groups. The 2 lower risk groups included patients under the age of 40, the lowest risk group being young patients with tumor in the frontal lobe only. An intermediate-risk group included patients with Karnofsky performance status (KPS) >70, subtotal or total resection, and age between 40 and 65. The highest risk group included all patients over 65 and patients between 40 and 65 with either KPS<80 or biopsy only. Subgroup analyses indicated that inclusion of adjuvant chemotherapy provides an increase in survival, although that improvement tends to be minimal for patients over age 65, for patients over age 40 with KPS less than 80, and for those treated with brachytherapy.

  15. Effects of ionizing radiation in combination with Erufosine on T98G glioblastoma xenograft tumours: a study in NMRI nu/nu mice

    International Nuclear Information System (INIS)

    Erufosine is a promising anticancer drug that increases the efficacy of radiotherapy in glioblastoma cell lines in vitro. Moreover, treatment of nude mice with repeated intraperitoneal or subcutaneous injections of Erufosine is well tolerated and yields drug concentrations in the brain tissue that are higher than the concentrations required for cytotoxic drug effects on glioblastoma cell lines in vitro. In the present study we aimed to evaluate the effects of a combined treatment with radiotherapy and Erufosine on growth and local control of T98G subcutaneous glioblastoma xenograft-tumours in NMRI nu/nu mice. We show that repeated intraperitoneal injections of Erufosine resulted in a significant drug accumulation in T98G xenograft tumours on NMRI nu/nu mice. Moreover, short-term treatment with 5 intraperitoneal Erufosine injections caused a transient decrease in the growth of T98G tumours without radiotherapy. Furthermore, an increased radiation-induced growth delay of T98G xenograft tumours was observed when fractionated irradiation was combined with short-term Erufosine-treatment. However, no beneficial drug effects on fractionated radiotherapy in terms of local tumour control were observed. We conclude that short-term treatment with Erufosine is not sufficient to significantly improve local control in combination with radiotherapy in T98G glioblastoma xenograft tumours. Further studies are needed to evaluate efficacy of extended drug treatment schedules

  16. MiR-21 up-regulation mediates glioblastoma cancer stem cells apoptosis and proliferation by targeting FASLG.

    Science.gov (United States)

    Shang, Chao; Guo, Yan; Hong, Yang; Liu, Yun-hui; Xue, Yi-xue

    2015-03-01

    To investigate whether miR-21 can affect the apoptosis and proliferation of glioblastoma cancer stem cells (GSCs) from down-regulating FASLG. The expression of miRNA-21 was detected by quantitative real-time PCR in normal brain tissue and glioblastoma samples, and the changes of miRNA-21 expression between GSCs and non-GSCs were also detected. The apoptosis and proliferation ability of miR-21 in GSCs were analyzed by MTT and flow cytometry assay after anti-miR-21 transfection. For the regulation mechanism analysis of miR-21, TargetScan, PicTar and microRNA were selected to predict some potential target genes of miR-21. The predicted gene was identified to be the direct and specific target gene of miR-21 by luciferase activities assay and western blot. RNA interference technology was used to confirm the apoptosis and proliferation effects of miR-21 were directly induced by FASLG. The expression of miR-21 increased significantly in glioblastoma contrast to normal brain tissue, and miR-21 up-regulated in GSCs remarkably. The proliferation of GSCs cell could be inhibited with high-expression of miR-21 and this effect could be restored by miR-21 knocked down. Mechanism analysis revealed that FASLG was a specific and direct target gene of miR-21. The advanced effects of anti-miR-21 on GSCs apoptosis and proliferation were mediated by expression of silenced FASLG. In summary, aberrantly expressed miR-21 regulates GSCs apoptosis and proliferation partly through directly down-regulating FASLG protein expression in GSCs and this might offer a new potential therapeutic stratagem for glioblastoma. PMID:25394756

  17. Active learning - a condition for continuous improvement of Macedonian institutions

    OpenAIRE

    Mitreva, Elizabeta; Prodanovska, Vesna

    2010-01-01

    Each institution ought to give a maximal effort for its own self-maintenance and constant improvement. This continuous improvement comes when the organizational performances are maximizing, managing and broadening the competences within the organization with a new attitude which is based on the continuous learning, innovation and improvement. New management system of the TQM (Total Quality Management) strategy demands lot less finance and timing, and might have same or even stronger effec...

  18. Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown

    International Nuclear Information System (INIS)

    Studies of the role of the cytokine macrophage-migration-inhibitory-factor (MIF) in malignant tumors have revealed its stimulating influence on cell-cycle progression, angiogenesis and anti-apoptosis. Here we show that in vitro targeting MIF in cultures of human malignant glioblastoma cells by either antisense plasmid introduction or anti-MIF antibody treatment reduced the growth rates of tumor cells. Of note is the marked decrease of proliferation under confluent and over-confluent conditions, implying a role of MIF in overcoming contact inhibition. Several proteins involved in contact inhibition including p27, p21, p53 and CEBPalpha are upregulated in the MIF antisense clones indicating a restoration of contact inhibition in the tumor cells. Correspondingly, we observed a marked increase in MIF mRNA and protein content under higher cell densities in LN18 cells. Furthermore, we showed the relevance of the enzymatic active site of MIF for the proliferation of glioblastoma cells by using the MIF-tautomerase inhibitor ISO-1. Our study adds another puzzle stone to the role of MIF in tumor growth and progression by showing the importance of MIF for overcoming contact inhibition

  19. Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown

    Directory of Open Access Journals (Sweden)

    Meyer Bernhard

    2009-12-01

    Full Text Available Abstract Background Studies of the role of the cytokine macrophage-migration-inhibitory-factor (MIF in malignant tumors have revealed its stimulating influence on cell-cycle progression, angiogenesis and anti-apoptosis. Results Here we show that in vitro targeting MIF in cultures of human malignant glioblastoma cells by either antisense plasmid introduction or anti-MIF antibody treatment reduced the growth rates of tumor cells. Of note is the marked decrease of proliferation under confluent and over-confluent conditions, implying a role of MIF in overcoming contact inhibition. Several proteins involved in contact inhibition including p27, p21, p53 and CEBPalpha are upregulated in the MIF antisense clones indicating a restoration of contact inhibition in the tumor cells. Correspondingly, we observed a marked increase in MIF mRNA and protein content under higher cell densities in LN18 cells. Furthermore, we showed the relevance of the enzymatic active site of MIF for the proliferation of glioblastoma cells by using the MIF-tautomerase inhibitor ISO-1. Conclusion Our study adds another puzzle stone to the role of MIF in tumor growth and progression by showing the importance of MIF for overcoming contact inhibition.

  20. The impact of bevacizumab treatment on survival and quality of life in newly diagnosed glioblastoma patients

    DEFF Research Database (Denmark)

    Poulsen, Hans Skovgaard; Urup, Thomas; Michaelsen, Signe Regner;

    2014-01-01

    Glioblastoma multiforme (GBM) remains one of the most devastating tumors, and patients have a median survival of 15 months despite aggressive local and systemic therapy, including maximal surgical resection, radiation therapy, and concomitant and adjuvant temozolomide. The purpose of antineoplastic...... treatment is therefore to prolong life, with a maintenance or improvement of quality of life. GBM is a highly vascular tumor and overexpresses the vascular endothelial growth factor A, which promotes angiogenesis. Preclinical data have suggested that anti-angiogenic treatment efficiently inhibits tumor...... growth. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A, and treatment has shown impressive response rates in recurrent GBM. In addition, it has been shown that response is correlated to prolonged survival and improved quality of life. Several investigations...

  1. Comparing predictive models of glioblastoma multiforme built using multi-institutional and local data sources.

    Science.gov (United States)

    Singleton, Kyle W; Hsu, William; Bui, Alex A T

    2012-01-01

    The growing amount of electronic data collected from patient care and clinical trials is motivating the creation of national repositories where multiple institutions share data about their patient cohorts. Such efforts aim to provide sufficient sample sizes for data mining and predictive modeling, ultimately improving treatment recommendations and patient outcome prediction. While these repositories offer the potential to improve our understanding of a disease, potential issues need to be addressed to ensure that multi-site data and resultant predictive models are useful to non-contributing institutions. In this paper we examine the challenges of utilizing National Cancer Institute datasets for modeling glioblastoma multiforme. We created several types of prognostic models and compared their results against models generated using data solely from our institution. While overall model performance between the data sources was similar, different variables were selected during model generation, suggesting that mapping data resources between models is not a straightforward issue.

  2. Bifidobacterium activation in technologies of health-improving mayonnaise

    OpenAIRE

    Маковська, Тетяна Валентинівна; Ткаченко, Наталія Андріївна

    2015-01-01

    One of the key areas of oil and fat industry today is to develop a range of fat emulsion products that provide good health. Emulsion fat mayonnaise type products deserve special attention among the products of oil and fat industry with the health-improving properties.Guidelines for the production of health-improving mayonnaise enriched with bifidobacteria, in the scientific literature aren’t available. Mayonnaise is an unfavorable environment for the development and preservation of bacteria o...

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

    OpenAIRE

    Favreau-Peigne, Angélique; Fromhage, Lutz; McNamara, John M.; Meah, Lianne F.S.; Houston, Alasdair I.

    2015-01-01

    We consider a behavioural model of an animal choosing between two activities, based on positive feedback, and examine the effect of introducing cross inhibition between the motivations for the two activities. While cross-inhibition has previously been included in models of decision making, the question of what benefit it may provide to an animal's activity selection behaviour has not previously been studied. In neuroscience and in collective behaviour cross-inhibition, and other equivalent me...

  4. Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression.

    Science.gov (United States)

    Lan, Fengming; Yang, Yang; Han, Jing; Wu, Qiaoli; Yu, Huiming; Yue, Xiao

    2016-02-01

    The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC50) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN. PMID:26648123

  5. The improved physical activity index for measuring physical activity in EPIC Germany.

    Directory of Open Access Journals (Sweden)

    Angelika Wientzek

    Full Text Available In the European Investigation into Cancer and Nutrition study (EPIC, physical activity (PA has been indexed as a cross-tabulation between PA at work and recreational activity. As the proportion of non-working participants increases, other categorization strategies are needed. Therefore, our aim was to develop a valid PA index for this population, which will also be able to express PA continuously. In the German EPIC centers Potsdam and Heidelberg, a clustered sample of 3,766 participants was re-invited to the study center. 1,615 participants agreed to participate and 1,344 participants were finally included in this study. PA was measured by questionnaires on defined activities and a 7-day combined heart rate and acceleration sensor. In a training sample of 433 participants, the Improved Physical Activity Index (IPAI was developed. Its performance was evaluated in a validation sample of 911 participants and compared with the Cambridge Index and the Total PA Index. The IPAI consists of items covering five areas including PA at work, sport, cycling, television viewing, and computer use. The correlations of the IPAI with accelerometer counts in the training and validation sample ranged r = 0.40-0.43 and with physical activity energy expenditure (PAEE r = 0.33-0.40 and were higher than for the Cambridge Index and the Total PA Index previously applied in EPIC. In non-working participants the IPAI showed higher correlations than the Cambridge Index and the Total PA Index, with r = 0.34 for accelerometer counts and r = 0.29 for PAEE. In conclusion, we developed a valid physical activity index which is able to express PA continuously as well as to categorize participants according to their PA level. In populations with increasing rates of non-working people the performance of the IPAI is better than the established indices used in EPIC.

  6. Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth

    Institute of Scientific and Technical Information of China (English)

    Qi QI; Xia LIU; Shiyong LI; Harish C JOSHI; Keqiang YE

    2013-01-01

    Aim:Noscapine (NOS) is a non-narcotic opium alkaloid with anti-tumor activity.The aim of this study was to investigate the effects of the combination of NOS with conventional chemotherapeutics temozolamide (TMZ),bis-chloroethylnitrosourea (BCNU),or cisplatin (ClS)on human glioblastoma cells.Methods:U87MG human glioblastoma cells were examined.Cell proliferation was quantified using MTT assay.Western blotting and flow cytometry were used to examine apoptosis and the expression of active caspase-3 and cleaved PARP.Mouse tumor xenograft model bearing U87MG cells was treated with TMZ (2 mg·kg1~-1,ip) or ClS (2 mg/kg,ip 3 times a week) alone or in combination with NOS (200 mg·kg-l·d-1,ig) for 3 weeks.Immunohistochemistry was used to investigate the expression of active caspase-3 and Ki67 following treatment in vivo.The safety of the combined treatments was evaluated based on the body weight and histological studies of the animal's organs.Results:NOS (10 or 20 mol/L) markedly increased the anti-proliferation effects of TMZ,BCNU,and ClS on U87MG cells in vitro.The calculated combination index (Cl) values of NOS-ClS,NOS-TMZ,and NOS-BCNU (20 μmoVL) were 0.45,0.51,and 0.57,respectively,demonstrating synergistic inhibition of the drug combinations.In tumor xenograft models,combined treatment with NOS robustly augmented the anti-cancer actions of TMZ and ClS,and showed no detectable toxicity.The combined treatments significantly enhanced the apoptosis,the activated caspase-3 and PARP levels in U87MG cells in vitro,and reduced Ki67 staining and increased the activated caspase-3 level in the shrinking xenografts in vivo.Conclusion:NOS synergistically potentiated the efficacy of FDA-approved anti-cancer drugs against human glioblastoma cells,thereby allowing them to be used at lower doses and hence minimizing their toxic side effects.

  7. Somatic mutations in glioblastoma are associated with methylguanine-DNA methyltransferase methylation

    OpenAIRE

    McDonald, Kerrie L.; Tabone, Tania; Nowak, Anna K; Erber, Wendy N.

    2015-01-01

    The high level of methylguanine-DNA methyltransferase (MGMT) in glioblastoma is responsible for resistance to alkylating agents, such as temozolomide (TMZ). In glioblastomas with a methylated MGMT promoter, MGMT deficiency is presumed, resulting in an enhanced effect of TMZ. The aim of the present study was to investigate whether genomic alterations work synergistically with MGMT methylation status and contribute to the response to treatment and overall prognosis in glioblastoma. The current ...

  8. Contrast-enhancing tumor growth dynamics of preoperative, treatment-naive human glioblastoma.

    OpenAIRE

    Ellingson, BM; Nguyen, HN; Lai, A.(Sezione INFN di Cagliari, Cagliari, Italy); Nechifor, RE; Zaw, O; Pope, WB; Yong, WH; Nghiemphu, PL; Liau, LM; Cloughesy, TF

    2016-01-01

    Little is known about the natural growth characteristics of untreated glioblastoma before surgical or therapeutic intervention, because patients are rapidly treated after preliminary radiographic diagnosis. Understanding the growth characteristics of uninhibited human glioblastoma may be useful for characterizing changes in response to therapy. Thus, the objective of the current study was to explore tumor growth dynamics in a cohort of patients with untreated glioblastoma before surgical or t...

  9. Improving Adherence Physical Activity with a Smartphone Application Based on Adults with Intellectual Disabilities (APPCOID)

    OpenAIRE

    Pérez-Cruzado, David; Cuesta-Vargas, Antonio I.

    2013-01-01

    Background People with intellectual disabilities (ID) have lower levels of physical activity and quality of life and they have a lot of barriers to face when taking part in physical activity. Other problems are the poor adherence to physical activity such people have so this study is designed to improve adherence to physical activity for people with intellectual disabilities with the assistance of an application for smartphones. The aim of the study will be to improve physical activity and ph...

  10. Quality Improvement and Infrastructure Activity Costs in Software Development: A Longitudinal Analysis

    OpenAIRE

    Donald E. Harter; Slaughter, Sandra A.

    2003-01-01

    This study draws upon theories of task interdependence and organizational inertia to analyze the effect of quality improvement on infrastructure activity costs in software development. Although increasing evidence indicates that quality improvement reduces software development costs, the impact on infrastructure activities is not known. Infrastructure activities include services like computer operations, data integration, and configuration management that support software development. Because...

  11. Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment

    NARCIS (Netherlands)

    Angevaren, Maaike; Aufdemkampe, Geert; Verhaar, H. J. J.; Aleman, A.; Vanhees, Luc

    2008-01-01

    Background Physical activity is beneficial for healthy ageing. It may also help maintain good cognitive function in older age. Aerobic activity improves cardiovascular fitness, but it is not known whether this sort of fitness is necessary for improved cognitive function. Studies in which activity, f

  12. Improving health through policies that promote active travel

    DEFF Research Database (Denmark)

    de Nazelle, Audrey; Nieuwenhuijsen, Mark J; Antó, Josep M;

    2011-01-01

    Substantial policy changes to control obesity, limit chronic disease, and reduce air pollution emissions, including greenhouse gasses, have been recommended. Transportation and planning policies that promote active travel by walking and cycling can contribute to these goals, potentially yielding...

  13. FASB Proposes Improved Disclosures for Derivatives and Hedging Activities

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ The Financial Accounting Standards Board (FASB) today issued a proposal that would provide investors and others with better information about the effects of derivative and hedging activities on a company's financial statements.

  14. Silica–enzyme–ionic liquid composites for improved enzymatic activity

    OpenAIRE

    Katsuya Kato; Yuki Kawachi; Hitomi Nakamura

    2014-01-01

    Trypsin and pepsin enzyme-catalyzed precipitation of silica, synthesized by sol–gel chemistry in an ionic liquid, produces a composite material that demonstrates high enzymatic activity. This study investigates the structural properties of this silica–enzyme–ionic liquid composite material that allows for the retention of enzyme hydrolysis and condensation activity. The composite was prepared from a mixture of organo-functionalized triethoxysilane and tetraethoxysilane in an ionic liquid via ...

  15. Performance improvement clarification for refrigeration system using active system monitoring

    DEFF Research Database (Denmark)

    Green, Torben; Niemann, Hans Henrik; Izadi-Zamanabadi, Roozbeh

    2011-01-01

    This paper addresses the problem of determining whether a refrigeration plant has the possibility of delivering a better performance of the operation. The controllers are wellknown but detailed knowledge about the underlying dynamics of the refrigeration plant is not available. Thus, the question...... is if it is possible to achieve a better performance by changing the controller parameter. An approach to active system monitoring, based on active fault diagnosis techniques, is employed in order to evaluate changes in the system performance under operation....

  16. Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Carrasco-Garcia, Estefania; Saceda, Miguel [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad de Investigacion, Hospital General Universitario de Elche, 03203 Elche (Alicante) (Spain); Grasso, Silvina; Rocamora-Reverte, Lourdes; Conde, Mariano; Gomez-Martinez, Angeles [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Garcia-Morales, Pilar [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad de Investigacion, Hospital General Universitario de Elche, 03203 Elche (Alicante) (Spain); Ferragut, Jose A. [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Martinez-Lacaci, Isabel, E-mail: imlacaci@umh.es [Instituto de Biologia Molecular y Celular, Universidad Miguel Hernandez, 03202 Elche (Alicante) (Spain); Unidad AECC de Investigacion Traslacional en Cancer, Hospital Universitario Virgen de la Arrixaca, 30120 Murcia (Spain)

    2011-06-10

    Signaling through the epidermal growth factor receptor (EGFR) is relevant in glioblastoma. We have determined the effects of the EGFR inhibitor AG1478 in glioblastoma cell lines and found that U87 and LN-229 cells were very sensitive to this drug, since their proliferation diminished and underwent a marked G{sub 1} arrest. T98 cells were a little more refractory to growth inhibition and A172 cells did not undergo a G{sub 1} arrest. This G{sub 1} arrest was associated with up-regulation of p27{sup kip1}, whose protein turnover was stabilized. EGFR autophosphorylation was blocked with AG1478 to the same extent in all the cell lines. Other small-molecule EGFR tyrosine kinase inhibitors employed in the clinic, such as gefitinib, erlotinib and lapatinib, were able to abrogate proliferation of glioblastoma cell lines, which underwent a G{sub 1} arrest. However, the EGFR monoclonal antibody, cetuximab had no effect on cell proliferation and consistently, had no effect on cell cycle either. Similarly, cetuximab did not inhibit proliferation of U87 {Delta}EGFR cells or primary glioblastoma cell cultures, whereas small-molecule EGFR inhibitors did. Activity of downstream signaling molecules of EGFR such as Akt and especially ERK1/2 was interrupted with EGFR tyrosine kinase inhibitors, whereas cetuximab treatment could not sustain this blockade over time. Small-molecule EGFR inhibitors were able to prevent phosphorylation of erbB3 and erbB4, whereas cetuximab only hindered EGFR phosphorylation, suggesting that EGFR tyrosine kinase inhibitors may mediate their anti-proliferative effects through other erbB family members. We can conclude that small-molecule EGFR inhibitors may be a therapeutic approach for the treatment of glioblastoma patients.

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

    Science.gov (United States)

    Kang, Bo; Zhou, Yanwen; Zheng, Min; Wang, Ying-Jie

    2015-09-01

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

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

    Science.gov (United States)

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

    2015-10-01

    Glioblastoma multiforme (GBM) is the most common and malignant form of the glial tumors. Advanced and treated GBM is rarely associated with pregnancy for many reasons. Glioblastoma multiforme presenting during pregnancy carries unique challenges to the patient, baby, family, and health care providers. We describe an unusual case of advanced GBM that was treated with maximum doses of chemotherapy and radiations, and she became pregnant and presented at eighteenth weeks of gestation. Her medical management was associated with a significant ethical dilemma. We managed to deliver the baby safely through cesarean section at week 28 despite the critical condition of the mother. Unfortunately, the mother died 2 weeks post delivery. We concluded that although recurrent and treated GBM is rarely associated with pregnancy and carries dismal prognosis, but if it occurs, it can still be carried, and a multidisciplinary team work is the key for successful outcome. PMID:26492122

  19. Activation Cross Sections Improvements needed for IFE Power Reactors Designs

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez, A; Cabellos, O; Sanz, J; FalQuina, R; Latkowski, J; Reyes, S

    2003-10-02

    Uncertainties in the prediction of the neutron induced long-lived activity in the natural elements from H to Bi due to activation cross section uncertainties are estimated assuming as neutron environment those of the HYLIFE-II and Sombrero vessel structures. The latest available activation cross section data are employed. The random variables used in the uncertainty analysis have been the concentration limits (CL's) corresponding to hands-on recycling, remote recycling and shallow land burial, quantities typically considered in ranking elements under waste management considerations. The CL standard value (CL{sub nom}), i.e. without uncertainties, is compared with the 95th percentile CL value (CL95). The results of the analysis are very helpful in assessing the quality of the current activation data for IFE applications, providing a rational basis for programmatic priority assignments for new cross sections measurements or evaluations. The HYLIFE-II results shown that a significant error is estimated in predicting the activation of several elements. The estimated errors in the Sombrero case are much less important.

  20. Prognostic factors in glioblastoma multiforme. 10 years experience of a single institution

    International Nuclear Information System (INIS)

    Background: To analyze prognostic factors in patients with a glioblastoma multiforme treated in an academic institute over the last 10 years. Patients and method: From 1988 to 1998, 198 patients with pathologically confirmed glioblastoma multiforme were analyzed. Five radiation schedules were used mainly based on pretreatment selection criteria: 1. 60 Gy in 30 fractions followed by an interstitial iridium-192 (Ir-192) boost for selected patients with a good performance and a small circumscribed tumor, 2. 66 Gy in 33 fractions for good performance patients, 3. 40 Gy in eight fractions or 4. 28 Gy in four fractions for poor prognostic patients and 5. no irradiation. Results: Median survival was 16 months, 7 months, 5.6 months, 6.6 months and 1.8 months for the groups treated with Ir-192, 66 Gy, 40 Gy, 28 Gy and the group without treatment, respectively. No significant improvement in survival was encountered over the last 10 years. At multivariate analysis patients treated with a hypofractionated scheme showed a similar survival probability and duration of palliative effect compared to the conventionally fractionated group. The poor prognostic groups receiving radiotherapy had a highly significant better survival compared to the no-treatment group. Patients treated with an Ir-192 boost had a better median survival compared to a historical group matched on selection criteria but without boost treatment (16 vs 9.7 months, n.s.). However, survival at 2 years was similar. Analysis on pretreatment characteristics at multivariate analysis revealed age, neurological performance, addition of radiotherapy, total resection, tumor size post surgery and deterioration before start of radiotherapy (borderline) as significant prognostic factors for survival. Conclusion: Despite technical developments in surgery and radiotherapy over the last 10 years, survival of patients with a glioblastoma multiforme has not improved in our institution. The analysis of prognostic factors

  1. Prioritising Investments in Marketing Activities to Improve Business Performance

    DEFF Research Database (Denmark)

    Martensen, Anne; Mouritsen, Jan

    2014-01-01

    The purpose of this study is to prioritise investments in marketing activities based on their effect on business performance (BP). On the basis of the European Foundation for Quality Management (EFQM) model adapted to a marketing context, four generic marketing activities are structured in two...... and retain competent employees and the second, to collect, disseminate and act upon market insight in the form of measurement of effectiveness and production of intelligence. These provide resources for the development of a customer-oriented marketing strategy that in turn helps innovation and cross...

  2. Radiotherapy with and without temozolomide in elderly patients with glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Niyazi, M.; Schwarz, S.B.; Belka, C. [Ludwig-Maximilian-Univ. Munich, Muenchen (Germany). Dept. of Radiation Oncology; Suchorska, B. [Ludwig-Maximilian-Univ. Munich, Muenchen (Germany). Dept. of Neurosurgery

    2012-02-15

    The optimal treatment for elderly patients (age {>=} 70 years) with glioblastoma (GBM) remains controversial. We conducted a retrospective analysis in 43 consecutive elderly patients with glioblastoma who either underwent radiotherapy (RT) or radiotherapy plus concomitant temozolomide (TMZ). A total of 43 patients ({>=} 70 years of age, median age 75.8 years) with newly diagnosed glioblastoma and a Karnofsky performance status (KPS) {>=} 70 were treated with RT alone (median 60 Gy in 2 Gy single fractions) or RT plus TMZ at a dose of 75 mg/m{sup 2} per day. The two groups were well-balanced; univariate (log-rank test) and multivariate Cox proportional hazards analysis were used to identify relevant prognostic factors. The median overall survival (mOS) of the entire patient cohort was 264 days (8.8 months) and the median progression-free survival (PFS) was 192 days (6.4 months). The factors age, sex, previous surgery, KPS, and concomitant use of TMZ had no significant influence on OS/PFS; multivariate analysis was performed to obtain adjusted hazard ratios. TMZ use resulted in a trend toward poorer overall survival when applied concomitantly (314 days compared to 192 days within the TMZ group, p = 0.106). The subgroup analysis revealed that TMZ use resulted in significantly worse survival rates in patients with KPS70 (p = 0.027), but for patients with KPS80 this difference was not detectable. TMZ should only be used carefully in elderly patients with unfavorable KPS. In this patient cohort, radiotherapy alone is a reasonable option. Standard RT plus concomitant TMZ may be an advantageous treatment option for elderly patients with newly diagnosed glioblastoma who present with good prognostic factors. (orig.)

  3. Personalized treatment strategies in glioblastoma: MGMT promoter methylation status

    OpenAIRE

    Thon N; Kreth S; Kreth FW

    2013-01-01

    Niklas Thon,1 Simone Kreth,2 Friedrich-Wilhelm Kreth1 1Department of Neurosurgery, 2Department of Anaesthesiology, Hospital of the University of Munich, Campus Grosshadern, Munich, Germany Abstract: The identification of molecular genetic biomarkers considerably increased our current understanding of glioma genesis, prognostic evaluation, and treatment planning. In glioblastoma, the most malignant intrinsic brain tumor entity in adults, the promoter methylation status of the gene encoding fo...

  4. Role of bevacizumab therapy in the management of glioblastoma

    OpenAIRE

    Levin, Victor

    2010-01-01

    Scott J Peak, Victor A LevinNeuro-Oncology Program, Department of Neurosurgery and Neuroscience, Kaiser Permanente, Redwood City, CA, USAAbstract: Glioblastoma is one of the most common primary brain tumors and one of the most difficult to treat. In population-based studies only 30% of patients will survive 1 year and in the most efficacious surgery, irradiation, and chemotherapy clinical trials approximately 20% will live 2 years. Bevacizumab is a recombinant, antivascular epidermal growth f...

  5. Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

    OpenAIRE

    Sun, Tao; Nicole M Warrington; Luo, Jingqin; Brooks, Michael D.; Dahiya, Sonika; Snyder, Steven C.; Sengupta, Rajarshi; Rubin, Joshua B.

    2014-01-01

    The prevalence of brain tumors in males is common but unexplained. While sex differences in disease are typically mediated through acute sex hormone actions, sex-specific differences in brain tumor rates are comparable at all ages, suggesting that factors other than sex hormones underlie this discrepancy. We found that mesenchymal glioblastoma (Mes-GBM) affects more males as the result of cell-intrinsic sexual dimorphism in astrocyte transformation. We used astrocytes from neurofibromin-defic...

  6. Glioblastoma and intracranial aneurysms: Case report and review of literature

    OpenAIRE

    Rushna Ali; Aqueel Pabaney; Adam Robin; Horia Marin; Mark Rosenblum

    2015-01-01

    Background: There is a paucity of data on the association of glioblastoma multiforme (GBM) with intracranial aneurysms. It is an important clinical entity for physicians to be aware of and its presence illustrates several critical features of the pathophysiology of malignant glioma. In this article we present a case of a middle cerebral artery (MCA) pseudoaneurysm that occurred in a patient with recurrent GBM as well discuss the current literature relating to this unique combination of pathol...

  7. Efficacy and safety of bevacizumab for the treatment of glioblastoma

    OpenAIRE

    YU, ZHIYUN; Zhao, Gang; Zhang, Zhonghua; Li, Yunqian; Chen, Yong; Wang, Nan; Zhao, Zhongying; XIE, GUIFANG

    2015-01-01

    Glioblastoma (GBM) is the most common and devastating primary malignant intracranial tumor in adults. The current first-line treatment for patients with newly diagnosed GBM is surgical resection followed by radiotherapy plus concomitant and adjuvant temozolomide. This treatment protocol may prolong the survival period of the patient, however it is not curative and more effective therapeutic strategies are required. GBM is a type of highly vascularized tumor with increased expression levels of...

  8. Antivascular Endothelial Growth Factor Antibody for Treatment of Glioblastoma Multiforme

    OpenAIRE

    Hanson, Joseph A.; Hsu, Frank P K; Jacob, Arun T; Bota, Daniela A.; Alexandru, Daniela

    2013-01-01

    Despite aggressive investigation, glioblastoma multiforme (GBM) remains one of the deadliest cancers, with low progression-free survival and high one-year mortality. Current first-line therapy includes surgery with adjuvant radiation therapy and cytotoxic chemotherapy, but virtually all tumors recur. Given the highly vascular nature of GBM and its high expression of vascular endothelial growth factor and other angiogenic factors, recent investigation has turned to bevacizumab, an antivascular...

  9. An integrative characterization of recurrent molecular aberrations in glioblastoma genomes

    OpenAIRE

    Sintupisut, Nardnisa; Liu, Pei-Ling; Yeang, Chen-Hsiang

    2013-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Decades of investigations and the recent effort of the Cancer Genome Atlas (TCGA) project have mapped many molecular alterations in GBM cells. Alterations on DNAs may dysregulate gene expressions and drive malignancy of tumors. It is thus important to uncover causal and statistical dependency between ‘effector’ molecular aberrations and ‘target’ gene expressions in GBMs. A rich collection of prior st...

  10. NT-38MerTK AS A TARGET IN GLIOBLASTOMA

    OpenAIRE

    Wu, Jing; Huey, Lauren; Bash, Ryan E.; Cohen, Stephanie M.; Matthew G Ewend; Wang, Xiaodong; Graham, Douglas K.; Frye, Stephen V.; Earp, H. Shelton; Miller, C Ryan

    2014-01-01

    Glioma-associated macrophages and microglia (GIM) are infiltrating immune cells that modulate the glioblastoma (GBM) micro-environment. Pharmacological targeting of GIM represents a promising therapeutic strategy. MerTK receptor tyrosine kinase triggers macrophage ingestion of apoptotic material and polarizes macrophages to an M2-like, immunosuppressive phenotype that promotes tumor growth. In addition, aberrant MerTK expression in GBM tumor cells can provide pro-survival, pro-invasion and ch...

  11. Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma

    OpenAIRE

    Larson, Erik W.; Peterson, Halloran E.; Lamoreaux, Wayne T.; Mackay, Alexander R.; Fairbanks, Robert K; Call, Jason A.; Carlson, Jonathan D.; Ling, Benjamin C; Demakas, John J.; Cooke, Barton S; Lee, Christopher M

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with a survival prognosis of 14-16 mo for the highest functioning patients. Despite aggressive, multimodal upfront therapies, the majority of GBMs will recur in approximately six months. Salvage therapy options for recurrent GBM (rGBM) are an area of intense research. This study compares recent survival and quality of life outcomes following Gamma Knife radiosurgery (GKRS) salvage therapy. Following a PubMed search...

  12. Recurrent Glioblastoma Multiforme: Implication of Nonenhancing Lesions on Bevacizumab Treatment

    OpenAIRE

    Daniela Alexandru; Hung-Wen Kao; Mark Linskey; Ronald Kim; Hasso, Anton N; Daniela Bota

    2013-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumors, accounting for 15-20% of all intracranial tumors. It is one of the most lethal tumors of the central nervous system with a median survival from diagnosis on the order of 6 to 18 months. Despite aggressive resection and chemoradiation, the tumor always recurs. Magnetic Resonance (MR) imaging is an essential component in the diagnosis, treatment planning, and following response. However, the imaging features of recurrent GBM...

  13. ASSOCIATIONS BETWEEN POLYMORPHISMS IN DNA REPAIR GENES AND GLIOBLASTOMA

    OpenAIRE

    McKean-Cowdin, Roberta; Barnholtz-Sloan, Jill; Inskip, Peter; Ruder, Avima; Butler, MaryAnn; Rajaraman, Preetha; Razavi, Pedram; Patoka, Joe; Wiencke, John; Bondy, Melissa; Wrensch, Margaret

    2009-01-01

    A pooled analysis was conducted to examine the association between select variants in DNA repair genes and glioblastoma multiforme (GBM), the most common and deadliest form of adult brain tumors. Genetic data for approximately 1,000 GBM cases and 2,000 controls were combined from four centers in the United States that have conducted case-control studies of adult GBM including the National Cancer Institute, the National Institute for Occupational Safety and Health, the University of Texas M.D....

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

    OpenAIRE

    Iliadis Georgios; Kotoula Vassiliki; Chatzisotiriou Athanasios; Televantou Despina; Eleftheraki Anastasia G; Lambaki Sofia; Misailidou Despina; Selviaridis Panagiotis; Fountzilas George

    2012-01-01

    Abstract Background In this study several tumor-related volumes were assessed by means of a computer-based application and a survival analysis was conducted to evaluate the prognostic significance of pre- and postoperative volumetric data in patients harboring glioblastomas. In addition, MGMT (O6-methylguanine methyltransferase) related parameters were compared with those of volumetry in order to observe possible relevance of this molecule in tumor development. Methods We prospectively analyz...

  15. MGMT Methylation Status: The Advent of Stratified Therapy in Glioblastoma?

    OpenAIRE

    Peter Hau; Roger Stupp; Hegi, Monika E.

    2007-01-01

    Glioblastomas are the most malignant gliomas with median survival times of only 15 months despite modern therapies. All standard treatments are palliative. Pathogenetic factors are diverse, hence, stratified treatment plans are warranted considering the molecular heterogeneity among these tumors. However, most patients are treated with "one fits all" standard therapies, many of them with minor response and major toxicities. The integration of clinical and molecular information, now becoming a...

  16. Glioblastoma and the significance of MGMT gene methylation

    OpenAIRE

    Payam Izadpanahi; Kazem Anvari; Mitra Fazl Ersi

    2014-01-01

    In this research Glioblastoma has been studied as one of the most common brain tumors and a short review of the available therapeutic methods have presented including surgery, radiotherapy, chemotherapy and particularly adjuvant chemotherapy with temozolomide, as the most effective developed treatment. Moreover, MGMT gene promoter methylation has been introduced as an important predictive factor of treatment response to temozolamide. The different mechanisms of methylation and the availableli...

  17. BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors

    Directory of Open Access Journals (Sweden)

    Pinsker Marcus O

    2010-02-01

    Full Text Available Abstract Background The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU, one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare. Methods We performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m2 BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS, tumor burden, pretreatment with temozolomide (TMZ, type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model. Results The median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15, median overall survival 22 weeks (95% CI: 18-27. The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression. No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off. Conclusion In summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are

  18. New Molecular Targets in the Angiogenic Vessels of Glioblastoma Tumors

    OpenAIRE

    Anderson, Joshua C.; McFarland, Braden C.; Gladson, Candece L.

    2008-01-01

    Anti-angiogenesis approaches have the potential to be particularly effective in the treatment of glioblastoma (GBM) tumors. These tumors exhibit extremely high levels of neovascularization, which may contribute to their extremely aggressive behavior not only by providing oxygenation and nutrition, but also by establishing a leaky vasculature that lacks a blood-brain barrier. This leaky vasculature enables migration of tumor cells as well as the build up of fluid that exacerbates tissue damage...

  19. Current Trends in Targeted Therapies for Glioblastoma Multiforme

    OpenAIRE

    Fumiharu Ohka; Atsushi Natsume; Toshihiko Wakabayashi

    2012-01-01

    Glioblastoma multiforme (GBM) is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas. Despite aggressive treatment including surgery, adjuvant TMZ-based chemotherapy, and radiotherapy, GBM still has a dismal prognosis: the median survival is 14.6 months from diagnosis. To date, many studies report several determinants of resistance to this aggressive therapy: (1) O6-methylguanine-DNA methyltransferase (MGMT), (2) the complexity ...

  20. Synthetic analogs of anoplin show improved antimicrobial activities

    DEFF Research Database (Denmark)

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

    2013-01-01

    700221) (VRE), and Candida albicans (ATCC 200955). The anoplin analogs contain substitutions in amino acid positions 2, 3, 5, 6, 8, 9, and 10. We use these peptides to study the effect of altering the charge and hydrophobicity of anoplin on activity against red blood cells and microorganisms. We find...

  1. Glioblastoma multiforme of the pineal region: case report

    Directory of Open Access Journals (Sweden)

    Gasparetto Emerson Leandro

    2003-01-01

    Full Text Available PURPOSE: pineal region tumors are uncommon, and comprise more frequently three categories: germ cell, parenchymal cell and glial tumors. Most pineal gliomas are low-grade astrocytomas. Glioblastoma multiforme, the most aggressive and common brain tumor, is extremely rare at this location with only few cases reported. CASE DESCRIPTION: a 29-year-old woman with a two month history of headache, nuchal pain, fever, nausea and seizures and physical examination showing nuchal rigidity, generalized hypotony, hypotrophy and hyper-reflexia, Babinski sign and left VI cranial par palsy. CT scan examination revealed a ill-defined hypodense lesion at the pineal region with heterogeneous contrast enhancement. MRI showed a lesion at the pineal region infiltrating the right thalamic region. The patient underwent a right craniotomy with partial resection of the mass. The histological examination of paraffin-embedded material defined the diagnosis of glioblastoma multiforme. Post-operative radiotherapy was indicated but the patient refused the treatment and died two months afterwards. CONCLUSION: in spite of its rarity at this location, glioblastoma multiforme should be considered in the differential diagnosis of aggressive lesions at the pineal region.

  2. MiRNA expression patterns predict survival in glioblastoma

    International Nuclear Information System (INIS)

    In order to define new prognostic subgroups in patients with glioblastoma a miRNA screen (> 1000 miRNAs) from paraffin tissues followed by a bio-mathematical analysis was performed. 35 glioblastoma patients treated between 7/2005 - 8/2008 at a single institution with surgery and postoperative radio(chemo)therapy were included in this retrospective analysis. For microarray analysis the febit biochip 'Geniom® Biochip MPEA homo-sapiens' was used. Total RNA was isolated from FFPE tissue sections and 1100 different miRNAs were analyzed. It was possible to define a distinct miRNA expression pattern allowing for a separation of distinct prognostic subgroups. The defined miRNA pattern was significantly associated with early death versus long-term survival (split at 450 days) (p = 0.01). The pattern and the prognostic power were both independent of the MGMT status. At present, this is the first dataset defining a prognostic role of miRNA expression patterns in patients with glioblastoma. Having defined such a pattern, a prospective validation of this observation is required

  3. Arrested neural and advanced mesenchymal differentiation of glioblastoma cells-comparative study with neural progenitors

    Directory of Open Access Journals (Sweden)

    Biernat Wojciech

    2009-02-01

    Full Text Available Abstract Background Although features of variable differentiation in glioblastoma cell cultures have been reported, a comparative analysis of differentiation properties of normal neural GFAP positive progenitors, and those shown by glioblastoma cells, has not been performed. Methods Following methods were used to compare glioblastoma cells and GFAP+NNP (NHA: exposure to neural differentiation medium, exposure to adipogenic and osteogenic medium, western blot analysis, immunocytochemistry, single cell assay, BrdU incorporation assay. To characterize glioblastoma cells EGFR amplification analysis, LOH/MSI analysis, and P53 nucleotide sequence analysis were performed. Results In vitro differentiation of cancer cells derived from eight glioblastomas was compared with GFAP-positive normal neural progenitors (GFAP+NNP. Prior to exposure to differentiation medium, both types of cells showed similar multilineage phenotype (CD44+/MAP2+/GFAP+/Vimentin+/Beta III-tubulin+/Fibronectin+ and were positive for SOX-2 and Nestin. In contrast to GFAP+NNP, an efficient differentiation arrest was observed in all cell lines isolated from glioblastomas. Nevertheless, a subpopulation of cells isolated from four glioblastomas differentiated after serum-starvation with varying efficiency into derivatives indistinguishable from the neural derivatives of GFAP+NNP. Moreover, the cells derived from a majority of glioblastomas (7 out of 8, as well as GFAP+NNP, showed features of mesenchymal differentiation when exposed to medium with serum. Conclusion Our results showed that stable co-expression of multilineage markers by glioblastoma cells resulted from differentiation arrest. According to our data up to 95% of glioblastoma cells can present in vitro multilineage phenotype. The mesenchymal differentiation of glioblastoma cells is advanced and similar to mesenchymal differentiation of normal neural progenitors GFAP+NNP.

  4. 5-aminolevulinic acid guidance during awake craniotomy to maximise extent of safe resection of glioblastoma multiforme.

    Science.gov (United States)

    Corns, Robert; Mukherjee, Soumya; Johansen, Anja; Sivakumar, Gnanamurthy

    2015-01-01

    Overall survival for patients with glioblastoma multiforme (GBM) has been consistently shown to improve when the surgeon achieves a gross total resection of the tumour. It has also been demonstrated that surgical adjuncts such as 5-aminolevulinic acid (5-ALA) fluorescence--which delineates malignant tumour tissue--normal brain tissue margin seen using violet-blue excitation under an operating microscope--helps achieve this. We describe the case of a patient with recurrent left frontal GBM encroaching on Broca's area (eloquent brain). Gross total resection of the tumour was achieved by combining two techniques, awake resection to prevent damage to eloquent brain and 5-ALA fluorescence guidance to maximise the extent of tumour resection.This technique led to gross total resection of all T1-enhancing tumour with the avoidance of neurological deficit. The authors recommend this technique in patients when awake surgery can be tolerated and gross total resection is the aim of surgery. PMID:26177997

  5. External beam re-irradiation, combination chemoradiotherapy, and particle therapy for the treatment of recurrent glioblastoma

    Science.gov (United States)

    Taunk, Neil K.; Moraes, Fabio Y.; Escorcia, Freddy E.; Mendez, Lucas Castro; Beal, Kathryn; Marta, Gustavo N.

    2016-01-01

    SUMMARY Glioblastoma is a common aggressive primary malignant brain tumor, and is nearly universal in progression and mortality after initial treatment. Re-irradiation presents a promising treatment option for progressive disease, both palliating symptoms and potentially extending survival. Highly conformal radiation techniques such as stereotactic radiosurgery and hypofractionated radiosurgery are effective short courses of treatment that allow delivery of high doses of therapeutic radiation with steep dose gradients to protect normal tissue. Patients with higher performance status, younger age, and longer interval between primary treatment and progression represent the best candidates for re-irradiation. Multiple studies are also underway involving combinations of radiation and systemic therapy to bend the survival curve and improve the therapeutic index. In the multimodal treatment of recurrent high-grade glioma, the use of surgery, radiation, and systemic therapy should be highly individualized. Here we comprehensively review radiation therapy and techniques, along with discussion of combination treatment and novel strategies. PMID:26781426

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

    Directory of Open Access Journals (Sweden)

    Fei Ye

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

  7. Using an Improved Clustering Method to Detect Anomaly Activities

    Institute of Scientific and Technical Information of China (English)

    LI Han; ZHANG Nan; BAO Lihui

    2006-01-01

    In this paper, an improved k-means based clustering method (IKCM) is proposed. By refining the initial cluster centers and adjusting the number of clusters by splitting and merging procedures, it can avoid the algorithm resulting in the situation of locally optimal solution and reduce the number of clusters dependency. The IKCM has been implemented and tested. We perform experiments on KDD-99 data set. The comparison experiments with H-means+also have been conducted. The results obtained in this study are very encouraging.

  8. Ontology-based improvement to human activity recognition

    Science.gov (United States)

    Tahmoush, David; Bonial, Claire

    2016-05-01

    Human activity recognition has often prioritized low-level features extracted from imagery or video over higher-level class attributes and ontologies because they have traditionally been more effective on small datasets. However, by including knowledge-driven associations between actions and attributes while recognizing the lower-level attributes with their temporal relationships, we can attempt a hybrid approach that is more easily extensible to much larger datasets. We demonstrate a combination of hard and soft features with a comparison factor that prioritizes one approach over the other with a relative weight. We then exhaustively search over the comparison factor to evaluate the performance of a hybrid human activity recognition approach in comparison to the base hard approach at 84% accuracy and the current state-of-the-art.

  9. Improvement of enterprise activities based on process management

    OpenAIRE

    Łuczak, Ja.

    2015-01-01

    Process management has been increasingly popular for several years now, yet most frequently it is limited to fragmentary actions, at times even to declarative activity. Few organizations have brought their management systems in conformity with the idea of process management; more frequently some particular actions within the range of process approach may be observed. Specialization allows efficient realizations of tasks; however, it separates individual organizational unities and amount...

  10. Supercritical fractionation of rosemary extracts to improve the antioxidant activity

    OpenAIRE

    Vicente, G. de; García-Risco, Mónica R.; Fornari, Tiziana; Reglero, Guillermo

    2012-01-01

    A supercritical CO 2 pilot plant was employed to extract rosemary (Rosmarinus officinalis L.) leaves and to thoroughly study the effect of time on the yield, composition and antioxidant activity of the different fractions produced. Six extraction assays were carried out, varying the fractionation procedure using a two-stage depressurization system coupled to the extractor vessel. The concentration of the main antioxidant compound in rosemary, i.e. carnosic acid, and the DPPH test were employe...

  11. Improving teacher awareness through activity, badge and content visualizations

    OpenAIRE

    Charleer, Sven; Santos Odriozola, Jose Luis; Klerkx, Joris; Duval, Erik

    2014-01-01

    This paper introduces LARAe (Learning Analytics Reflection & Awareness environment), a teacher-oriented dashboard that visualizes learning traces from students, badges and course content. We also present an evaluation of the dashboard in a course on Human-Computer Interaction. The LARAe teacher dashboard provides a detailed overview of group and individual activities, achievements and course outcomes. To help visualize the abundance of traces, badges are used to abstract essential aspects of ...

  12. Variable Patterned Pudendal Nerve Stimuli Improves Reflex Bladder Activation

    OpenAIRE

    Bruns, Tim M.; Bhadra, Narendra; Gustafson, Kenneth J.

    2008-01-01

    We evaluated variable patterns of pudendal nerve (PN) stimuli for reflex bladder excitation. Reflex activation of the bladder has been demonstrated previously with 20–33 Hz continuous stimulation of PN afferents. Neuronal circuits accessed by afferent mediated pathways may respond better to physiological patterned stimuli than continuous stimulation. Unilateral PN nerve cuffs were placed in neurologically intact male cats. PN stimulation (0.5–100 Hz) was performed under isovolumetric conditio...

  13. An Improved Virial Estimate of Solar Active Region Energy

    OpenAIRE

    Wheatland, M. S.; Metcalf, T. R.

    2005-01-01

    The MHD virial theorem may be used to estimate the magnetic energy of active regions based on vector magnetic fields measured at the photosphere or chromosphere. However, the virial estimate depends on the measured vector magnetic field being force-free. Departure from force-freeness leads to an unknown systematic error in the virial energy estimate, and an origin dependence of the result. We present a method for estimating the systematic error by assuming that magnetic forces are confined to...

  14. On the road to improved scheduling - fitting activities to capacity

    DEFF Research Database (Denmark)

    Lindhard, Søren Munch; Wandahl, Søren

    2012-01-01

    Last Planner System has through the sounding process increased the reliability of the schedule. The sound activities are moved to a buffer and afterwards selected to the Weekly Work Plans to match capacity. Therefore, in order to maximise productivity it is essential to ensure that the sounding...... solutions to the problem are suggested and discussed. It is proposed to simplify the production by decreasing the number of trades and tasks completed at site. This can be achieved by increasing...

  15. EG-11DYSREGULATION OF MGMT IN GLIOBLASTOMA: FRIEND OR FOE?

    Science.gov (United States)

    Rapkins, Robert W.; Hitchins, Megan P.; McDonald, Kerrie L.

    2014-01-01

    Glioblastoma (GBM) is the most common and lethal form of brain cancer (median survival <15 months). The DNA alkylating agent, temozolomide, is used as the standard chemotherapeutic agent, resulting in mispairing of guanine with thymidine that leads to cellular arrest. However, in GBM patients the O6-methylguanine-DNA methyltransferase (MGMT) protein protects DNA from damage induced by temozolomide. Nevertheless, loss of MGMT expression is a frequent event in human malignancies and typically the result of MGMT promoter methylation. MGMT methylation has been strongly associated with the T-allele of the rs16906252 SNP (C/T) in colorectal carcinoma, pleural mesothelioma, and lung cancers. We therefore examined the T-allele and MGMT methylation in temozolmide-treated GBM patients. In 255 temozolomide-treated GBM patients, we found that the T-allele was significantly more frequent in patients with a methylated MGMT promoter. The unadjusted hazard ratio for death in carriers of the T-allele compared to wild-type, irrespective of methylation status, was 0.39 (95%CI:0.21-0.73; p = 0.003), indicating a 61% relative reduction in the risk for death of T-allele carriers. Surprisingly, GBM patients harboring the T-allele in the absence of MGMT methylation showed a survival benefit comparable to those with MGMT methylation (median survival: 15.5 months) and significantly better than the median survival of wild-type, unmethylated patients (median survival: 10.3 months). This suggests that the T-allele may reduce MGMT activity by mechanisms independent of methylation. Genotyping of 451 healthy controls indicated the frequency of carriage of the T-allele was 13% (MAF 0.065). In contrast, carriage of the T-allele in 160 GBM patients was 17%. Significantly, elevated risks were associated with carriage of the T-allele and development of GBM (odds ratio of 2.62 [95%CI:1.7-4.2]). We report that the T-allele (rs16906252) has predictive (response to temozolomide) and prognostic value (MGMT

  16. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

    Energy Technology Data Exchange (ETDEWEB)

    Parra, N. Andres [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Maudsley, Andrew A. [Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida (United States); Gupta, Rakesh K. [Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, Haryana (India); Ishkanian, Fazilat; Huang, Kris [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Walker, Gail R. [Biostatistics and Bioinformatics Core Resource, Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (United States); Padgett, Kyle [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida (United States); Roy, Bhaswati [Department of Radiology and Imaging, Fortis Memorial Research Institute, Gurgaon, Haryana (India); Panoff, Joseph; Markoe, Arnold [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Stoyanova, Radka, E-mail: RStoyanova@med.miami.edu [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States)

    2014-10-01

    Purpose: Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials: Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV{sub 46} and CTV{sub 60}, respectively). MTV{sub Cho} and MTV{sub NAA} were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results: The MRSI coverage of the brain was between 70% and 76%. The MTV{sub NAA} were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTV{sub Cho} was outside of the edema (median, 33%) and for some patients it was also outside of the CTV{sub 46} and CTV{sub 60}. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTV{sub Cho} for these patients were outside of CTV{sub 60}. Conclusions: This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on

  17. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.

    NARCIS (Netherlands)

    Stupp, R.; Hegi, M.E.; Mason, W.P.; Bent, M.J. van den; Taphoorn, M.J.B.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; Hau, P.; Brandes, A.A.; Gijtenbeek, J.M.M.; Marosi, C.; Vecht, C.J.; Mokhtari, K.; Wesseling, P.; Villa, S.; Eisenhauer, E.; Gorlia, T.; Weller, M.; Lacombe, D.; Cairncross, J.G.; Mirimanoff, R.O.

    2009-01-01

    BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and ad

  18. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study : 5-year analysis of the EORTC-NCIC trial

    NARCIS (Netherlands)

    Stupp, Roger; Hegi, Monika E.; Mason, Warren P.; van den Bent, Martin J.; Taphoorn, Martin J. B.; Janzer, Robert C.; Ludwin, Samuel K.; Allgeier, Anouk; Fisher, Barbara; Belanger, Karl; Hau, Peter; Brandes, Alba A.; Gijtenbeek, Johanna; Marosi, Christine; Vecht, Charles J.; Mokhtari, Karima; Wesseling, Pieter; Villa, Salvador; Eisenhauer, Elizabeth; Gorlia, Thierry; Weller, Michael; Lacombe, Denis; Cairncross, J. Gregory; Mirimanoff, Rene-Olivier

    2009-01-01

    Background In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adj

  19. Initiation and characterization of a glioblastoma multiforme derived cell line.

    Directory of Open Access Journals (Sweden)

    Carmen Lucía Roa

    2009-11-01

    Full Text Available Introducción: Las líneas celulares y los cultivos primarios son una excelente herramienta para el estudio de la biología, desarrollo y respuesta a la terapia en tumores cerebrales. Objetivo: Establecer y caracterizar una línea celular derivada de un glioblastoma multiforme como un modelo de estudio in vitro para la extrapolación y aplicación futura en terapia génica. Material y métodos: Se obtuvo una muestra de un paciente con diagnóstico clínico e histopatológico de glioblastoma multiforme, se caracterizó mediante inmunohistoquímica en cortes de tejido y por inmunocitoquímica sobre células cultivadas a partir del tumor desde el inicio del cultivo y durante los seis primeros pases, con dos tipos de marcadores específicos para glía: GFAP (glial fibrillary acidic protein y S-100 (proteína de unión a calcio. Además, se evaluó la expresión de p53 y Bcl-2, como moduladores de apoptosis. Por último se hizo la caracterización citogenética. Resultados: Histopatológicamente, se confirmó el diagnóstico de glioblastoma multiforme. En los cultivos primarios se encontraron características citomorfológicas propias de un glioblastoma: células fibroblastoides planas, células con escaso citoplasma con 3 ó más procesos y por último bipolares o unipolares. Se encontró una expresión diferencial con los cuatro marcadores, con un patrón de marcaciones a nivel citoplasmático y nuclear a través de los pases estudiados. La línea celular se caracterizó por ser en su mayoría aneuploide con un número modal cromosómico entre 43 y 45, con un gran número de poliploidías (55-102 , XXYY y endo-reduplicaciones (end 45, X, -Y. Conclusión: Se estableció una línea celular derivada de un glioblastoma multiforme con un fenotipo estable, con un notable mantenimiento del perfil glial y citogenético.

  20. Improving Decision-Making Activities for Meningitis and Malaria

    Science.gov (United States)

    Ceccato, Pietro; Trzaska, Sylwia; Garcia-Pando, Carlos Perez; Kalashnikova, Olga; del Corral, John; Cousin, Remi; Blumenthal, M. Benno; Bell, Michael; Connor, Stephen J.; Thomson, Madeleine C.

    2013-01-01

    Public health professionals are increasingly concerned about the potential impact that climate variability and change can have on infectious disease. The International Research Institute for Climate and Society (IRI) is developing new products to increase the public health community's capacity to understand, use and demand the appropriate climate data and climate information to mitigate the public health impacts of climate on infectious disease, in particular meningitis and malaria. In this paper, we present the new and improved products that have been developed for: (i) estimating dust aerosol for forecasting risks of meningitis and (ii) for monitoring temperature and rainfall and integrating them into a vectorial capacity model for forecasting risks of malaria epidemics. We also present how the products have been integrated into a knowledge system (IRI Data Library Map Room, SERVIR) to support the use of climate and environmental information in climate-sensitive health decision-making.

  1. Information systems as a tool to improve legal metrology activities

    Science.gov (United States)

    Rodrigues Filho, B. A.; Soratto, A. N. R.; Gonçalves, R. F.

    2016-07-01

    This study explores the importance of information systems applied to legal metrology as a tool to improve the control of measuring instruments used in trade. The information system implanted in Brazil has also helped to understand and appraise the control of the measurements due to the behavior of the errors and deviations of instruments used in trade, allowing the allocation of resources wisely, leading to a more effective planning and control on the legal metrology field. A study case analyzing the fuel sector is carried out in order to show the conformity of fuel dispersers according to maximum permissible errors. The statistics of measurement errors of 167,310 fuel dispensers of gasoline, ethanol and diesel used in the field were analyzed demonstrating the accordance of the fuel market in Brazil to the legal requirements.

  2. Improving Decision-Making Activities for Meningitis and Malaria

    Science.gov (United States)

    Ceccato, P.; Trzaska, S.; Perez, C.; Kalashnikova, O. V.; del Corral, J.; Cousin, R.; Blumenthal, M. B.; Connor, S.; Thomson, M. C.

    2012-12-01

    Public health professionals are increasingly concerned about the potential impact that climate variability and change can have on infectious disease. The International Research Institute for Climate and Society (IRI) is developing new products to increase the public health community's capacity to understand, use, and demand the appropriate climate data and climate information to mitigate the public health impacts of climate on infectious disease, in particular Meningitis and Malaria. In this paper we present the new and improved products that have been developed for monitoring dust, temperature, rainfall and vectorial capacity model for monitoring and forecasting risks of Meningitis and Malaria epidemics. We also present how the products have been integrated into a knowledge system (IRI Data Library Map room, SERVIR) to support the use of climate and environmental information in climate-sensitive health decision-making.

  3. Fenton peroxidation improves the drying performance of waste activated sludge.

    Science.gov (United States)

    Dewil, Raf; Baeyens, Jan; Neyens, Elisabeth

    2005-01-31

    Advanced sludge treatment processes (AST) reduce the amount of sludge produced and improve the dewaterability, thus probably also affecting the heat transfer properties and the drying characteristics of the sludge. This paper studies the influence of the Fenton peroxidation on the thermal conductivity of the sludge. Results demonstrate that the Fenton's peroxidation positively influences the sludge cake consistency and hence enhances the mechanical dewaterability and the drying characteristics of the dewatered sludge. For the two sludges used in this study, i.e. obtained from the wastewater treatment plants (WWTP) of Tienen and Sint-Niklaas--the dry solids content of the mechanically dewatered sludge increased from 22.5% to 40.3% and from 18.7% to 35.2%, respectively. The effective thermal conductivity k(e) of the untreated and the peroxidized sludges is measured and used to determine the heat transfer coefficient h(s). An average improvement for k(e) of 16.7% (Tienen) and 5.8% (Sint-Niklaas) was observed. Consequently the value of h(s) increased with 15.6% (Tienen) and 5.0% (Sint-Niklaas). This increased heat transfer coefficient in combination with the increased dewaterability has direct implications on the design of sludge dryers. A plate-to-plate calculation of a multiple hearth dryer illustrates that the number of plates required to dry the peroxidized sludge to 90% DS is less than half the number of plates needed to dry untreated sludge. This results in reduced dryer dimensions or a higher capacity for an existing dryer of given dimensions. PMID:15629575

  4. A designer bleomycin with significantly improved DNA cleavage activity.

    Science.gov (United States)

    Huang, Sheng-Xiong; Feng, Zhiyang; Wang, Liyan; Galm, Ute; Wendt-Pienkowski, Evelyn; Yang, Dong; Tao, Meifeng; Coughlin, Jane M; Duan, Yanwen; Shen, Ben

    2012-08-15

    The bleomycins (BLMs) are used clinically in combination with a number of other agents for the treatment of several types of tumors, and the BLM, etoposide, and cisplatin treatment regimen cures 90-95% of metastatic testicular cancer patients. BLM-induced pneumonitis is the most feared, dose-limiting side effect of BLM in chemotherapy, which can progress into lung fibrosis and affect up to 46% of the total patient population. There have been continued efforts to develop new BLM analogues in the search for anticancer drugs with better clinical efficacy and lower lung toxicity. We have previously cloned and characterized the biosynthetic gene clusters for BLMs from Streptomyces verticillus ATCC15003, tallysomycins from Streptoalloteichus hindustanus E465-94 ATCC31158, and zorbamycin (ZBM) from Streptomyces flavoviridis SB9001. Comparative analysis of the three biosynthetic machineries provided the molecular basis for the formulation of hypotheses to engineer novel analogues. We now report engineered production of three new analogues, 6'-hydroxy-ZBM, BLM Z, and 6'-deoxy-BLM Z and the evaluation of their DNA cleavage activities as a measurement for their potential anticancer activity. Our findings unveiled: (i) the disaccharide moiety plays an important role in the DNA cleavage activity of BLMs and ZBMs, (ii) the ZBM disaccharide significantly enhances the potency of BLM, and (iii) 6'-deoxy-BLM Z represents the most potent BLM analogue known to date. The fact that 6'-deoxy-BLM Z can be produced in reasonable quantities by microbial fermentation should greatly facilitate follow-up mechanistic and preclinical studies to potentially advance this analogue into a clinical drug.

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

    OpenAIRE

    Lars Donath; Katharina Imhof; Ralf Roth; Lukas Zahner

    2014-01-01

    Strategies to early develop and implement motor skill promotion in preschoolers are lacking. Thus, we examined the effects of a card-based exercise promotion program in a kindergarten setting. 214 preschool children (5.5 ± 0.6 y, range 4.2–6.7 y) were examined in the present intervention study. Body mass index (BMI) and waist circumference were measured. Children were randomly assigned to the KIDZ-Box® physical activity intervention program (INT: n = 107) or the control group (CON: n = 107). ...

  6. Mining bipartite graphs to improve semantic pedophile activity detection

    OpenAIRE

    Fournier, Raphaël; Danisch, Maximilien

    2014-01-01

    International audience Peer-to-peer (P2P) networks are popular to exchange large volumes of data through the Internet. Paedophile activity is a very important topic for our society and some works have recently attempted to gauge the extent of paedophile exchanges on P2P networks. A key issue is to obtain an efficient detection tool, which may decide if a sequence of keywords is related to the topic or not. We propose to use social network analysis in a large dataset from a P2P network to i...

  7. Application Of Active Screen Method For Ion Nitriding Efficiency Improvement

    Directory of Open Access Journals (Sweden)

    Ogórek M.

    2015-06-01

    Full Text Available Paper presents the research of austenitic steel AISI 304 after ion nitriding at 400°C and at t =4h, for the two different variants of samples distribution in the working plasma reactive chamber tube. In order to assess the effectiveness of ion nitriding variants emission spectroscopy – GDOES, surface hardness tests, microstructure research (LM of nitrided layers were made. It has been found that the use of active screens increases the surface layer thickness and depth of nitrogen diffusion into austenitic steel 304.

  8. Improved cosmetic activity by optimizing the Lithospermum erythrorhizon extraction process

    OpenAIRE

    Kim, Ji Seon; Seo, Yong Chang; No, Ra Hwan; Lee, Hyeon Yong

    2013-01-01

    This study was conducted to expand the use of Lithospermum erythrorhizon, which is a good source of natural dye, in skin whitening and immune activation cosmetics. The goal was to provide cosmeceutical data about the extraction yield and shikonin contents of this plant by optimizing the ultrasonic extraction and high pressure extraction conditions. Under optimal extraction conditions, which consisted of 500 MPa for 60 min and 120 kHz for 90 min, 27.49 and 3.19 % (w/w) of the highest extractio...

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

    Directory of Open Access Journals (Sweden)

    Lu Lizhi

    2006-12-01

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

  10. MRI texture features as biomarkers to predict MGMT methylation status in glioblastomas

    OpenAIRE

    Korfiatis, Panagiotis; Kline, Timothy L.; Coufalova, Lucie; Lachance, Daniel H.; Parney, Ian F.; Carter, Rickey E.; Buckner, Jan C.; Erickson, Bradley J

    2016-01-01

    Purpose: Imaging biomarker research focuses on discovering relationships between radiological features and histological findings. In glioblastoma patients, methylation of the O6-methylguanine methyltransferase (MGMT) gene promoter is positively correlated with an increased effectiveness of current standard of care. In this paper, the authors investigate texture features as potential imaging biomarkers for capturing the MGMT methylation status of glioblastoma multiforme (GBM) tumors when combi...

  11. Glioblastomas with Oligodendroglial Component – Common Origin of the Different Histological Parts and Genetic Subclassification

    Directory of Open Access Journals (Sweden)

    Barbara Klink

    2010-01-01

    Full Text Available Background: Glioblastomas are the most common and most malignant brain tumors in adults. A small subgroup of glioblastomas contains areas with histological features of oligodendroglial differentiation (GBMO. Our objective was to genetically characterize the oligodendroglial and the astrocytic parts of GBMOs and correlate morphologic and genetic features with clinical data.

  12. Necrosis de médula espinal, edema cerebral y glioblastoma

    OpenAIRE

    Iglesias Rozas, José Rafael, 1942-

    1987-01-01

    Cinco imágenes de una necrosis de la médula espinal, un edema cerebral y un glioblastoma en una paciente de 76 años. Five pictures of a spinal cord necrosis, a cerebral edema and a glioblastoma in a 76-year-old female patient.

  13. Using NLP meta, Milton, metaphor models, for improving the activity of the organization

    Directory of Open Access Journals (Sweden)

    Cornel Marian IOSIF

    2010-12-01

    Full Text Available The objective of this paper is the improving of the three methods from the neuro- linguistic programming – metaphor, Milton model and the meta-model, so by using this in daily activities by an organization to improve the activities witch, are performed and to have a more efficient allocation of the available resources.

  14. GROWTH OF MANAGERIAL PERFORMANCE BY IMPROVING AUDITING ACTIVITY

    Directory of Open Access Journals (Sweden)

    Daniel DĂNECI-PĂTRĂU

    2014-04-01

    Full Text Available To reflect the place and role of internal audit in the economic entity and its function as assistant manager in this paper we followed the presentation of the preliminary assumptions of a model for measuring the quality of internal audit. Also, we presented a possible model of research regarding managerial effectiveness. Questions that sought answer in this research are: How can we streamline internal audit? What is meant by effective internal audit? What is the relationship between internal audit efficiency and performance management? Recording a high level of performance of internal audit provide a high level of performance of the whole economic entity. Of course, responsible for the implementation of recommendations made by the Internal Auditor is the manager, but in our opinion, as long as the internal audit department conducts activities / tasks with maximum seriousness, conscientiousness and professionalism, the manager will be to some extent forced to implement the recommendations, having a high confidence in those.

  15. Using robust statistics to improve neutron activation analysis results

    Energy Technology Data Exchange (ETDEWEB)

    Zahn, Guilherme S.; Genezini, Frederico A.; Ticianelli, Regina B.; Figueiredo, Ana Maria G., E-mail: gzahn@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Centro do Reator de Pesquisas

    2011-07-01

    Neutron activation analysis (NAA) is an analytical technique where an unknown sample is submitted to a neutron flux in a nuclear reactor, and its elemental composition is calculated by measuring the induced activity produced. By using the relative NAA method, one or more well-characterized samples (usually certified reference materials - CRMs) are irradiated together with the unknown ones, and the concentration of each element is then calculated by comparing the areas of the gamma ray peaks related to that element. When two or more CRMs are used as reference, the concentration of each element can be determined by several different ways, either using more than one gamma ray peak for that element (when available), or using the results obtained in the comparison with each CRM. Therefore, determining the best estimate for the concentration of each element in the sample can be a delicate issue. In this work, samples from three CRMs were irradiated together and the elemental concentration in one of them was calculated using the other two as reference. Two sets of peaks were analyzed for each element: a smaller set containing only the literature-recommended gamma-ray peaks and a larger one containing all peaks related to that element that could be quantified in the gamma-ray spectra; the most recommended transition was also used as a benchmark. The resulting data for each element was then reduced using up to five different statistical approaches: the usual (and not robust) unweighted and weighted means, together with three robust means: the Limitation of Relative Statistical Weight, Normalized Residuals and Rajeval. The resulting concentration values were then compared to the certified value for each element, allowing for discussion on both the performance of each statistical tool and on the best choice of peaks for each element. (author)

  16. TENDENCY OF IMPROVEMENT ANALYSIS OF VENTURE ACTIVITY FOR MANAGEMENT DECISIONS

    Directory of Open Access Journals (Sweden)

    G.Yu. Iakovetс

    2015-03-01

    Full Text Available The questions concerning the definition of current trends and prospects of venture financing new innovative enterprises as one of the most effective and alternative, but with a high degree of risk financing sources of the entity. The features of venture financing that is different from other sources of business financing, as well as income from investments of venture capital can greatly exceed the volume of investments, but at the same time such financing risks are significant, so it all makes it necessary to build an effective system of venture capital investments in the workplace. In the course of the study also revealed problems of analysis and minimization of risks in the performance of venture financing of innovative enterprises. Defining characteristics analysis and risk assessment of venture financing helps to find ways to minimize and systematization, avoidance and prevention of risks in the performance of venture capital. The study also identified the major areas of improvement analysis of venture capital for management decisions.

  17. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy†

    Science.gov (United States)

    Raizer, Jeffrey J.; Abrey, Lauren E.; Lassman, Andrew B.; Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Yung, W.K. Alfred; Gilbert, Mark R.; Aldape, Kenneth A.; Wen, Patrick Y.; Fine, Howard A.; Mehta, Minesh; DeAngelis, Lisa M.; Lieberman, Frank; Cloughesy, Timothy F.; Robins, H. Ian; Dancey, Janet; Prados, Michael D.

    2010-01-01

    Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was not allowed. Patients received 150 mg/day erlotinib. Patients requiring surgery were treated 7 days prior to tumor removal for PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) and intracellular signaling pathways. Ninety-six patients were evaluable (53 recurrent MG and 43 NP GBM); 5 patients were not evaluable for response. PFS-6 in recurrent GBM was 3% with a median PFS of 2 months; PFS-6 in recurrent AG was 27% with a median PFS of 2 months. Twelve-month survival was 57% in NP GBMs post-RT. Primary toxicity was dermatologic. The tissue-to-plasma ratio normalized to nanograms per gram dry weight for erlotinib and OSI-420 ranged from 25% to 44% and 30% to 59%, respectively, for pretreated surgical patients. No effect on EGFR or intratumoral signaling was seen. Patients with NP GBM post-RT who developed rash in cycle 1 had improved survival (P < .001). Single-agent activity of erlotinib is minimal for recurrent MGs and marginally beneficial following RT for NP GBM patients. Development of rash in cycle 1 correlates with survival in patients with NP GBM after RT. PMID:20150372

  18. Activities of CEZ Inc. and improvement of the environment

    Energy Technology Data Exchange (ETDEWEB)

    Kindl, I.V. [Czech Power Co. (CEZ), Prague (Czechoslovakia)

    1995-12-01

    All highly developed nations round the world have gradually assumed the responsibility for the quality of the environment at their respective territories by creating the preconditions (by setting forth concepts, and the legislative, economic and institutional framework as well as the educational information and resources systems) stimulating both individuals and corporate bodies to take care of the environment. Damaging the environment is punished. The approach has been successful in most of the countries. Companies and individuals have begun to recognize the correlations existing between their production and consumption activities and the environment and their direct responsibility for the environmental conditions, realizing that to remove a source of environmental damage or to minimis the damage caused by it in both necessary and more beneficial than being penalized (up to ban of operation) both economically and in broader social terms for failing to comply with the relevant laws. Since 1990 a number of the so-called {open_quotes}ecological{close_quotes} laws, formerly sorely lacking, have been enacted, such as the Environment Act, the Environmental Effects Assessment Act, and the Wastes Act, and the Clean Air Act has been fundamentally amended so that to meet again the requirements of effective protection of the atmosphere from pollutants. In the area of economic tools, the duty of the waste producer to pay for the waste produced was introduced, the fines for air pollution were raised significantly and the polluted waste water discharge fines were amended to keep pace with the devaluation of the local currency.

  19. Mesoporous Metal-Containing Carbon Nitrides for Improved Photocatalytic Activities

    Directory of Open Access Journals (Sweden)

    Jie Luo

    2013-01-01

    Full Text Available Graphitic carbon nitrides (g-C3N4 have attracted increasing interest due to their unusual properties and promising applications in water splitting, heterogeneous catalysis, and organic contaminant degradation. In this study, a new method was developed for the synthesis of mesoporous Fe contained g-C3N4 (m-Fe-C3N4 photocatalyst by using SiO2 nanoparticles as hard template and dicyandiamide as precursor. The physicochemical properties of m-Fe-C3N4 were thoroughly investigated. The XRD and XPS results indicated that Fe was strongly coordinated with the g-C3N4 matrix and that the doping and mesoporous structure partially deteriorated its crystalline structure. The UV-visible absorption spectra revealed that m-Fe-C3N4 with a unique electronic structure displays an increased band gap in combination with a slightly reduced absorbance, implying that mesoporous structure modified the electronic properties of g-Fe-C3N4. The photocatalytic activity of m-Fe-C3N4 for photodegradation of Rhodamine B (RhB was much higher than that of g-Fe-C3N4, clearly demonstrating porous structure positive effect.

  20. Bevacizumab impairs oxidative energy metabolism and shows antitumoral effects in recurrent glioblastomas: a 31P/1H MRSI and quantitative magnetic resonance imaging study

    OpenAIRE

    HATTINGEN, ELKE; Jurcoane, Alina; Bähr, Oliver; Rieger, Johannes; Magerkurth, Jörg; Anti, Sandra; Steinbach, Joachim P.; Pilatus, Ulrich

    2011-01-01

    Bevacizumab shows unprecedented rates of response in recurrent glioblastomas (GBM), but the detailed mechanisms are still unclear. We employed in vivo magnetic resonance spectroscopic imaging (MRSI) and quantitative magnetic resonance imaging to investigate whether bevacizumab alters oxygen and energy metabolism and whether this effect has antitumoral activity in recurrent GBM. 31P and 1H MRSI, apparent diffusion coefficient (ADC), and high-resolution T2 and T2′ mapping (indirect marker of ox...

  1. Improved Chemical Structure-Activity Modeling Through Data Augmentation.

    Science.gov (United States)

    Cortes-Ciriano, Isidro; Bender, Andreas

    2015-12-28

    Extending the original training data with simulated unobserved data points has proven powerful to increase both the generalization ability of predictive models and their robustness against changes in the structure of data (e.g., systematic drifts in the response variable) in diverse areas such as the analysis of spectroscopic data or the detection of conserved domains in protein sequences. In this contribution, we explore the effect of data augmentation in the predictive power of QSAR models, quantified by the RMSE values on the test set. We collected 8 diverse data sets from the literature and ChEMBL version 19 reporting compound activity as pIC50 values. The original training data were replicated (i.e., augmented) N times (N ∈ 0, 1, 2, 4, 6, 8, 10), and these replications were perturbed with Gaussian noise (μ = 0, σ = σnoise) on either (i) the pIC50 values, (ii) the compound descriptors, (iii) both the compound descriptors and the pIC50 values, or (iv) none of them. The effect of data augmentation was evaluated across three different algorithms (RF, GBM, and SVM radial) and two descriptor types (Morgan fingerprints and physicochemical-property-based descriptors). The influence of all factor levels was analyzed with a balanced fixed-effect full-factorial experiment. Overall, data augmentation constantly led to increased predictive power on the test set by 10-15%. Injecting noise on (i) compound descriptors or on (ii) both compound descriptors and pIC50 values led to the highest drop of RMSEtest values (from 0.67-0.72 to 0.60-0.63 pIC50 units). The maximum increase in predictive power provided by data augmentation is reached when the training data is replicated one time. Therefore, extending the original training data with one perturbed repetition thereof represents a reasonable trade-off between the increased performance of the models and the computational cost of data augmentation, namely increase of (i) model complexity due to the need for optimizing

  2. Dioscin, a natural steroid saponin, induces apoptosis and DNA damage through reactive oxygen species: a potential new drug for treatment of glioblastoma multiforme.

    Science.gov (United States)

    Lv, Linlin; Zheng, Lingli; Dong, Deshi; Xu, Lina; Yin, Lianhong; Xu, Youwei; Qi, Yan; Han, Xu; Peng, Jinyong

    2013-09-01

    Dioscin, a natural product obtained from medicinal plants shows lipid-lowering, anti-cancer and hepatoprotective effects. However, the effect of it on glioblastoma is unclear. In this study, dioscin significantly inhibited proliferation of C6 glioma cells and caused reactive oxygen species (ROS) generation and Ca²⁺ release. ROS accumulation affected levels of malondialdehyde, nitric oxide, glutathione disulfide and glutathione, and caused cell apoptosis. In addition, ROS generation caused mitochondrial damage including structural changes, increased mitochondrial permeability transition and decreased mitochondria membrane potential, which led to the release of cytochrome C, nuclear translation of programmed cell death-5 and increased activities of caspase-3,9. Simultaneously, dioscin down-regulated protein expression of Bcl-2, Bcl-xl, up-regulated expression of Bak, Bax, Bid and cleaved poly (ADP-ribose) polymerase. Also, oxygen stress induced S-phase arrest of cancer cells by way of regulating expression of DNA Topo I, p53, CDK2 and Cyclin A and caused DNA damage. In a rat allograft model, dioscin significantly inhibited tumor size and extended the life cycle of the rats. In conclusion, dioscin shows noteworthy anti-cancer activity on glioblastoma cells by promoting ROS accumulation, inducing DNA damage and activating mitochondrial signal pathways. Ultimately, we believe dioscin has promise as a new therapy for the treatment of glioblastoma. PMID:23871826

  3. Trimodal Glioblastoma Treatment Consisting of Concurrent Radiotherapy, Temozolomide, and the Novel TGF-β Receptor I Kinase Inhibitor LY2109761

    Directory of Open Access Journals (Sweden)

    Mengxian Zhang

    2011-06-01

    Full Text Available Here we investigate the effects of the novel transforming growth factor-β receptor I (TGF-βRI serine/threonine kinase inhibitor LY2109761 on glioblastoma when combined with the present clinical standard combination regimen radiotherapy and temozolomide (TMZ. Human GBM U87 (methylated MGMT promoter, T98 (unmethylated MGMT promoter, and endothelial cells (HUVECs were treated with combinations of LY2109761, TMZ, and radiation. We found that LY2109761 reduced clonogenic survival of U87 and T98 cells and further enhanced the radiation-induced anticlonogenicity. In addition, LY2109761 had antimigratory and antiangiogenic effects in Matrigel migration and tube formation assays. In vivo, in human xenograft tumors growing subcutaneously on BALB/c nu/nu mice, LY2109761 delayed tumor growth alone and in combination with fractionated radiation and TMZ. Interestingly, as expected, the methylated U87 model was more sensitive to TMZ than the unmethylated T98 model in all experiments, whereas the opposite was found for LY2109761. Moreover, with respect to tumor angiogenesis, while LY2109761 decreased the glioblastoma proliferation index (Ki-67 and the microvessel density (CD31 count, the relative pericyte coverage (α-SMA/CD31 ratio increased in particular after triple therapy, suggesting a vascular normalization effect induced by LY2109761. This normalization could be attributed in part to a decrease in the Ang-2/Ang-1 messenger RNA ratio. LY2109761 also reduced tumor blood perfusion as quantified by noninvasive dynamic contrast-enhanced magnetic resonance imaging. Together, the data indicate that the addition of a TGF-βRI kinase inhibitor to the present clinical standard (radiation plus TMZ has the potential to improve clinical outcome in human glioblastoma, especially in patients with unmethylated MGMT promoter status.

  4. Improved activity and thermostability of Bacillus pumilus lipase by directed evolution

    NARCIS (Netherlands)

    Akbulut, Nagihan; Ozturk, Merve Tuzlakoglu; Pijning, Tjaard; Ozturk, Saliha Issever; Gumusel, Fusun

    2013-01-01

    To improve enzymatic activity of Bacillus pumilus lipases, DNA shuffling was applied to two lipase genes from local B. pumilus isolates. Using a high-throughput activity assay, the mutant with highest activity was selected. This chimeric mutant (L3-3), carrying two crossover positions and three poin

  5. Physical Activity: A Tool for Improving Health (Part 3--Recommended Amounts of Physical Activity for Optimal Health)

    Science.gov (United States)

    Gallaway, Patrick J.; Hongu, Nobuko

    2016-01-01

    By promoting physical activities and incorporating them into their community-based programs, Extension professionals are improving the health of individuals, particularly those with limited resources. This article is the third in a three-part series describing the benefits of physical activity for human health: (1) biological health benefits of…

  6. Canadian recommendations for the treatment of glioblastoma multiforme.

    Science.gov (United States)

    Mason, W P; Maestro, R Del; Eisenstat, D; Forsyth, P; Fulton, D; Laperrière, N; Macdonald, D; Perry, J; Thiessen, B

    2007-06-01

    RECOMMENDATION 1: Management of patients with glioblastoma multiforme (GBM) should be highly individualized and should take a multidisciplinary approach involving neuro-oncology, neurosurgery, radiation oncology, and pathology, to optimize treatment outcomes. Patients and caregivers should be kept informed of the progress of treatment at every stage. RECOMMENDATION 2: Sufficient tissue should be obtained during surgery for cytogenetic analysis and, whenever feasible, for tumour banking. RECOMMENDATION 3: Surgery is an integral part of the treatment plan, to establish a histopathologic diagnosis and to achieve safe, maximal, and feasible tumour resection, which may improve clinical signs and symptoms. RECOMMENDATION 4: The preoperative imaging modality of choice is magnetic resonance imaging (MRI) with gadolinium as the contrast agent. Other imaging modalities, such as positron emission tomography with [(18)F]-fluoro-deoxy-d-glucose, may also be considered in selected cases. Postoperative imaging (mri or computed tomography) is recommended within 72 hours of surgery to evaluate the extent of resection. RECOMMENDATION 5: Postoperative external-beam radiotherapy is recommended as standard therapy for patients with gbm. The recommended dose is 60 Gy in 2-Gy fractions. The recommended clinical target volume should be identified with gadolinium-enhanced T1-weighted mri, with a margin in the order of 2-3 cm. Target volumes should be determined based on a postsurgical planning MRI. A shorter course of radiation may be considered for older patients with poor performance status. RECOMMENDATION 6: During RT, temozolomide 75 mg/m(2) should be administered concurrently for the full duration of radio-therapy, typically 42 days. Temozolomide should be given approximately 1 hour before radiation therapy, and at the same time on the days that no radiotherapy is scheduled. RECOMMENDATION 7: Adjuvant temozolomide 150 mg/m(2), in a 5/28-day schedule, is recommended for cycle 1

  7. How do Australian Small and Medium Enterprises Communicate their Environmental Improvement Activities Online?

    Directory of Open Access Journals (Sweden)

    Craig Parker

    2011-03-01

    Full Text Available There have been calls in the IS/eBusiness literature for research on "green" IS/IT in a Small and Medium Enterprises (SMEs context. The Corporate Social Responsibility (CSR literature has neglected the issue of how SMEs can use websites to communicate their environmental improvement activities. This paper links these two previously separate disciplines by reporting on a content analysis of 443 Australian SME websites from four industry sectors to identify if and how they use websites to communicate their environmental improvement activities. The study found that 47 websites were communicating such activities in some form. A detailed analysis was undertaken of these 47 websites to identify emergent themes relating to how these SMEs were communicating their environmental improvement activities. These themes resulted in a reconceptualisation of the traditional "4 Ps" of marketing for online communication of environmental improvement activities by SMEs: profile; product; process and prominence.

  8. Tumor regrowth between surgery and initiation of adjuvant therapy in patients with newly diagnosed glioblastoma

    Science.gov (United States)

    Pirzkall, Andrea; McGue, Colleen; Saraswathy, Suja; Cha, Soonmee; Liu, Raymond; Vandenberg, Scott; Lamborn, Kathleen R.; Berger, Mitchel S.; Chang, Susan M.; Nelson, Sarah J.

    2009-01-01

    To assess incidence and degree of regrowth in glioblastoma between surgery and radiation therapy (RT) and to correlate regrowth with presurgical imaging and survival, we examined images of 32 patients with newly diagnosed glioblastoma who underwent MR spectroscopic imaging (MRSI), perfusion-weighted imaging (PWI), and diffusion-weighted imaging (DWI) prior to surgery, after surgery, and prior to RT/temozolomide. Contrast enhancement (CE) in the pre-RT MR image was compared with postsurgical DWI to differentiate tumor growth from postsurgical infarct. MRSI and PWI parameters were analyzed prior to surgery and pre-RT. Postsurgical MRI indicated that 18 patients had gross total and 14 subtotal resections. Twenty-one patients showed reduced diffusion, and 25 patients showed new or increased CE. In eight patients (25%), the new CE was confined to areas of postsurgical reduced diffusion. In the other 17 patients (53%), new CE was found to be indicative of tumor growth or a combination of tumor growth and surgical injury. Higher perfusion and creatine within nonenhancing tumor in the presurgery MR were associated with subsequent tumor growth. High levels of choline and reduced diffusion in pre-RT CE suggested active metabolism and tumor cell proliferation. Median survival was 14.6 months in patients with interim tumor growth and 24 months in patients with no growth. Increased volume or new onset of CE between surgery and RT was attributed to tumor growth in 53% of patients and was associated with shorter survival. This suggests that reducing the time between surgery and adjuvant therapy may be important. The acquisition of metabolic and physiologic imaging data prior to adjuvant therapy may also be valuable in assessing regions of new CE and nonenhancing tumor. PMID:19229057

  9. Glioblastoma research 2006-2010: pattern of citation and systematic review of highly cited articles.

    Science.gov (United States)

    Nieder, Carsten; Astner, Sabrina T; Grosu, Anca L

    2012-11-01

    High and continuously increasing research activity related to different aspects of pathogenesis, epidemiology, diagnosis and treatment of glioblastoma has been performed between 2006 and 2010. Different measures of impact, visibility and quality of published research are available, each with its own pros and cons. For this review, article citation rate was chosen. Articles were identified through systematic search of the abstract database PubMed followed by analyses of total number of citations and proportion of highly cited articles, arbitrarily defined as those with ≥100, 50-99, and 25-49 citations, respectively (citation database Scopus). Overall 5831 scientific articles on the subject were published during this time period. 1.5% of all articles accumulated at least 100 citations, 3.2% were cited between 50 and 99 times, and 7.5% were cited between 25 and 49 times. Among the 10 most cited articles, 7 reported on genomic analyses, molecular subclasses of glioblastoma and/or stem cells. Overall, 18 randomized clinical trials were published between 2006 and 2010, including those with phase II design. Thirty-nine percent of them accumulated at least 50 citations and 72% were cited at least 25 times. In general, annual citation rate appeared to gradually increase during the first 2-3 years after publication before reaching high levels. A large variety of preclinical and clinical topics achieved at least 25 citations. However, areas such as quality of life, side effects, and end-of-life care were underrepresented. Efforts to increase their visibility might be warranted. PMID:22516416

  10. The involvement of mitochondrial apoptotic pathway in eugenol-induced cell death in human glioblastoma cells.

    Science.gov (United States)

    Liang, Wei-Zhe; Chou, Chiang-Ting; Hsu, Shu-Shong; Liao, Wei-Chuan; Shieh, Pochuen; Kuo, Daih-Huang; Tseng, Hui-Wen; Kuo, Chun-Chi; Jan, Chung-Ren

    2015-01-01

    Eugenol, a natural phenolic constituent of clove oil, has a wide range of applications in medicine as a local antiseptic and anesthetic. However, the effect of eugenol on human glioblastoma is unclear. This study examined whether eugenol elevated intracellular free Ca(2+) levels ([Ca(2+)]i) and induced apoptosis in DBTRG-05MG human glioblastoma cells. Eugenol evoked [Ca(2+)]i rises which were reduced by removing extracellular Ca(2+). Eugenol-induced [Ca(2+)]i rises were not altered by store-operated Ca(2+) channel blockers but were inhibited by the PKC inhibitor GF109203X and the transient receptor potential channel melastatin 8 (TRPM8) antagonist capsazepine. In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) or 2,5-di-tert-butylhydroquinone (BHQ) abolished eugenol-induced [Ca(2+)]i rises. The phospholipase C (PLC) inhibitor U73122 significantly inhibited eugenol-induced [Ca(2+)]i rises. Eugenol killed cells which were not reversed by prechelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). Eugenol induced apoptosis through increasing reactive oxygen species (ROS) production, decreasing mitochondrial membrane potential, releasing cytochrome c and activating caspase-9/caspase-3. Together, in DBTRG-05MG cells, eugenol evoked [Ca(2+)]i rises by inducing PLC-dependent release of Ca(2+) from the endoplasmic reticulum and caused Ca(2+) influx possibly through TRPM8 or PKC-sensitive channels. Furthermore, eugenol induced the mitochondrial apoptotic pathway. PMID:25455450

  11. Glioblastoma research 2006-2010: pattern of citation and systematic review of highly cited articles.

    Science.gov (United States)

    Nieder, Carsten; Astner, Sabrina T; Grosu, Anca L

    2012-11-01

    High and continuously increasing research activity related to different aspects of pathogenesis, epidemiology, diagnosis and treatment of glioblastoma has been performed between 2006 and 2010. Different measures of impact, visibility and quality of published research are available, each with its own pros and cons. For this review, article citation rate was chosen. Articles were identified through systematic search of the abstract database PubMed followed by analyses of total number of citations and proportion of highly cited articles, arbitrarily defined as those with ≥100, 50-99, and 25-49 citations, respectively (citation database Scopus). Overall 5831 scientific articles on the subject were published during this time period. 1.5% of all articles accumulated at least 100 citations, 3.2% were cited between 50 and 99 times, and 7.5% were cited between 25 and 49 times. Among the 10 most cited articles, 7 reported on genomic analyses, molecular subclasses of glioblastoma and/or stem cells. Overall, 18 randomized clinical trials were published between 2006 and 2010, including those with phase II design. Thirty-nine percent of them accumulated at least 50 citations and 72% were cited at least 25 times. In general, annual citation rate appeared to gradually increase during the first 2-3 years after publication before reaching high levels. A large variety of preclinical and clinical topics achieved at least 25 citations. However, areas such as quality of life, side effects, and end-of-life care were underrepresented. Efforts to increase their visibility might be warranted.

  12. Can online activities improve attitude to homework and improve academic performance in science with fifth year students at second level

    OpenAIRE

    O'Dea, Michael

    2013-01-01

    non-peer-reviewed The purpose of this investigation was to determine if online activities could improve attitude and academic achievement in Science with a group of students at secondary level education. The problems with homework are experienced by educators worldwide and with the use of online multimedia and technology, this investigation sought to determine if this could bring about a change. A group of sixteen students were involved in the investigation; these students were studying...

  13. Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future direction

    Directory of Open Access Journals (Sweden)

    Supriya Mallick

    2015-01-01

    Full Text Available Glioblastoma multiforme (GBM is the most aggressive form of primary brain tumor. Maximal safe surgical resection followed by adjuvant partial brain radiation with concurrent and adjuvant temozolomide (TMZ (oral alkylating agent is the standard of care. Five years survival in TMZ treated patient reaches 9.8%. We aimed to summarize the changes in the management of GBM beyond conventional temozolomide based adjuvant treatment. We searched the PUBMED with the following key words: Glioblastoma, phase III trial, Phase II trial, adjuvant treatment in GBM. Clinical research has found a wide range of molecular aberrations in GBM and attempts are being made to further improve survival with the addition of different classes of drugs. Angiogenesis inhibitors, oncolytic vaccines, dose dense TMZ, and anti-epidermal growth factor receptor monoclonal antibody in phase III trials have failed to improve survival. Recent studies have also shown that the management strategies might be different and needs to be customized as per the age of patients such as pediatric and elderly patients. In addition, treatments should be personalized depending on the molecular aberrations. We reviewed all published phase III trials for newly diagnosed GBM as well as also looked into possible future directions in this review. Limited progress has happed beyond conventional TMZ in the adjuvant treatment of GBM. Newer insights are emerging about treatment intensification and introduction of newer molecular targeted drugs with more information about molecular aberrations.

  14. The radiosensitizing effect of a N(4)-tolyl-2-acetylpyridine derived thiosemicarbazone and its metallic complex against a glioblastoma cell line

    Energy Technology Data Exchange (ETDEWEB)

    Vilas Boas, Fabricio A.S.; Hudson, Luiza O.; Santos, Raquel G. dos [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil). Lab. de Radiobiologia], e-mail: fasvb@cdtn.br, e-mail: luluhud@yahoo.com.br, e-mail: santosr@cdtn.br; Mendes, Isolda C.; Beraldo, Heloisa O. [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Quimica], e-mail: Isolda.mendes@terra.com.br, e-mail: hberaldo@pq.cnpq.br

    2009-07-01

    Cancer is one of the most prevalent and difficult diseases to be treated. Despite the efforts at improving diagnose and treatment, the success is still very limited. One of the factors implicated in such limitation is the inherent radioresistance of most tumors, specially the cerebral ones. They are poorly vascularized due to the rapid growth of cells and disorganized angiogenesis that leads to hypoxic tissue that increases radioresistance. Also another issue is the side effects of exposition to high levels of radiation and chemicals. Combined approaches using both chemo and radiotherapy are one of the most effective strategies applied to maximize the results and decrease the side effects of the treatment to the patient. One of the drugs that are commonly used is cisplatin that has some, yet limited result. Given this context, our group has been testing several synthetic compounds of the thiosemicarbazone class. These chemicals have broad pharmacologic profile including antitumoral effect. We have shown in previous works the effective reduction of cell viability and proliferation using very low concentrations of thiosemicarbazones both in free form and complexed with metals like copper. In this work we present another application of this compound that can also be used as a radiosensitization agent in glioblastoma multiform cell line RT-2 present that the combined approach increases de effect of gamma radiation. Also, that the coordination to copper apparently does not increase this activity. (author)

  15. The radiosensitizing effect of a N(4)-tolyl-2-acetylpyridine derived thiosemicarbazone and its metallic complex against a glioblastoma cell line

    International Nuclear Information System (INIS)

    Cancer is one of the most prevalent and difficult diseases to be treated. Despite the efforts at improving diagnose and treatment, the success is still very limited. One of the factors implicated in such limitation is the inherent radioresistance of most tumors, specially the cerebral ones. They are poorly vascularized due to the rapid growth of cells and disorganized angiogenesis that leads to hypoxic tissue that increases radioresistance. Also another issue is the side effects of exposition to high levels of radiation and chemicals. Combined approaches using both chemo and radiotherapy are one of the most effective strategies applied to maximize the results and decrease the side effects of the treatment to the patient. One of the drugs that are commonly used is cisplatin that has some, yet limited result. Given this context, our group has been testing several synthetic compounds of the thiosemicarbazone class. These chemicals have broad pharmacologic profile including antitumoral effect. We have shown in previous works the effective reduction of cell viability and proliferation using very low concentrations of thiosemicarbazones both in free form and complexed with metals like copper. In this work we present another application of this compound that can also be used as a radiosensitization agent in glioblastoma multiform cell line RT-2 present that the combined approach increases de effect of gamma radiation. Also, that the coordination to copper apparently does not increase this activity. (author)

  16. mTOR Promotes Survival and Astrocytic Characteristics Induced by Pten/Akt Signaling in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Xiaoyi Hu

    2005-04-01

    Full Text Available Combined activation of Ras and Akt leads to the formation of astrocytic glioblastoma multiforme (GBM in mice. In human GBMs, AKT is not mutated but is activated in approximately 70% of these tumors, in association with loss of PTEN and/or activation of receptor tyrosine kinases. Mechanistic justification for the therapeutic blockade of targets downstream of AKT, such as mTOR, in these cancers requires demonstration that the oncogenic effect of PTEN loss is through elevated AKT activity. We demonstrate here that loss of Pten is similar to Akt activation in the context of glioma formation in mice. We further delineate the role of mTOR activity downstream of Akt in the maintenance of Akt+KRas-induced GBMs. Blockade of mTOR results in regional apoptosis in these tumors and conversion in the character of surviving tumor cells from astrocytoma to oligodendroglioma. These data suggest that mTOR activity is required for the survival of some cells within these GBMs, and mTOR appears required for the maintenance of astrocytic character in the surviving cells. Furthermore, our study provides the first example of conversion between two distinct tumor types usually thought of as belonging to specific lineages, and provides evidence for signal transduction-mediated transdifferentiation between glioma subtypes.

  17. MGMT-independent temozolomide resistance in pediatric glioblastoma cells associated with a PI3-kinase-mediated HOX/stem cell gene signature

    DEFF Research Database (Denmark)

    Gaspar, Nathalie; Marshall, Lynley; Perryman, Lara;

    2010-01-01

    Sensitivity to temozolomide is restricted to a subset of glioblastoma patients, with the major determinant of resistance being a lack of promoter methylation of the gene encoding the repair protein DNA methyltransferase MGMT, although other mechanisms are thought to be active. There are, however......, limited preclinical data in model systems derived from pediatric glioma patients. We screened a series of cell lines for temozolomide efficacy in vitro, and investigated the differential mechanisms of resistance involved. In the majority of cell lines, a lack of MGMT promoter methylation and subsequent...... protein overexpression were linked to temozolomide resistance. An exception was the pediatric glioblastoma line KNS42. Expression profiling data revealed a coordinated upregulation of HOX gene expression in resistant lines, especially KNS42, which was reversed by phosphoinositide 3-kinase pathway...

  18. Methotrexate-loaded biodegradable nanoparticles: preparation, characterization and evaluation of its cytotoxic potential against U-343 MGa human neuronal glioblastoma cells

    Indian Academy of Sciences (India)

    Kranti P Musmade; Praful B Deshpande; Prashant B Musmade; M Naseer Maliyakkal; A Ranjith Kumar; M Sreenivasa Reddy; N Udupa

    2014-06-01

    Nanoparticles represent one of the attractive alternatives in the effective treatment of cancer chemotherapy. In the present work, formulation and development of a novel methotrexate (MTX)-loaded biodegradable nanoparticles using poly(D,L-lactide-co-glycolide) (PLGA) was carried out. The prepared nanoparticles were evaluated for physicochemical properties such as particle size, zeta potential, release studies, etc and also evaluated for its in vitro cytotoxic potential against U-343 MGa human neuronal glioblastoma cells. Particle size of optimized formulation was < 200 nm. There was a considerable decrease in cell viability and enhancement in cytotoxic activity of MTX-loaded nanoparticles compared to MTX alone when tested against U-343 MGa human neuronal glioblastoma cells.

  19. Applicable advances in the molecular pathology of glioblastoma.

    Science.gov (United States)

    Ranjit, Melissa; Motomura, Kazuya; Ohka, Fumiharu; Wakabayashi, Toshihiko; Natsume, Atsushi

    2015-07-01

    Comprising more than 80% of malignant brain tumors, glioma has proven to be a daunting cause of mortality in a vast majority of the human population. Progressive and extensive research on malignant glioma has substantially enhanced our understanding of glioma cell biology and molecular pathology. Subtypes of glioma such as astrocytoma and oligodendroglioma are currently grouped together into one pathological class, where they show many differences in histology and molecular etiology. This indicates that it may be beneficial to consider a new and radical subclassification. Thus, we summarize recent developments in glioblastoma multiforme (GBM) subtypes, immunohistochemical analyses useful for diagnoses and the biological evaluation and therapeutic implications of gliomas in this review.

  20. Primary spinal cord glioblastoma multiforme presenting with transverse myelitis

    Directory of Open Access Journals (Sweden)

    Melikhan Cerci

    2014-06-01

    Full Text Available Primary spinal cord tumors are rarely encountered in childhood period. Ependymomas and pilocytic astrocytomas comprise the majority of spinal cord tumors in children. Spinal glioblastoma multiforme (GM (grade IV astrocytoma is a rare clinical entity accounting for only 1-3% of all pediatric intramedullary tumors. We report a 3- year-8- month-old male with primary spinal cord GM who presented with back pain, paraparesis, gait disturbance and loss of sphincter control and initially diagnosed as transverse myelitis. [Cukurova Med J 2014; 39(3.000: 606-610

  1. Glioblastoma, gadolinium (III) and NCT. An in vitro study

    International Nuclear Information System (INIS)

    We treated cultured human glioblastoma cells with gadolinium (III) [gadopentetic acid] and we found that: a) cells do internalise this element; b) gadolinium can be localised in the cells nuclei; c) exposure of the cultures to a neutron beam produced a significant and immediate cell death. Although cell survival was also influenced in the irradiated controls it was further reduced (about 50%) in cells pre-exposed to 10 mg/ml gadopentetic acid. We also found that Gd uptake, as measured by ICP-AES, was concentration dependent. (author)

  2. Oncogene addiction and non-oncogene addiction in glioblastoma therapy

    Institute of Scientific and Technical Information of China (English)

    Kimberly Ng; Clark C.Chen

    2011-01-01

    @@ INTRODUCTION Glioblastoma is the most common form of primary brain tumor.The incidence of this tumor is fairly low,with 2-3 cases per 100 000 people in Europe and North America.1It is one of the most aggressive forms of cancer.2 Without treatment,the median survival is approximately 3 months.3 The current standard of treatment involves maximal surgical resection followed by concurrent radiation therapy and chemotherapy with the DNA alkylating agent,temozolomide.4,5 With this regimen,the median survival is approximately 14 months.For nearly all affected,the treatments available remain palliative.

  3. MGMT Methylation Status: The Advent of Stratified Therapy in Glioblastoma?

    Directory of Open Access Journals (Sweden)

    Peter Hau

    2007-01-01

    Full Text Available Glioblastomas are the most malignant gliomas with median survival times of only 15 months despite modern therapies. All standard treatments are palliative. Pathogenetic factors are diverse, hence, stratified treatment plans are warranted considering the molecular heterogeneity among these tumors. However, most patients are treated with "one fits all" standard therapies, many of them with minor response and major toxicities. The integration of clinical and molecular information, now becoming available using new tools such as gene arrays, proteomics, and molecular imaging, will take us to an era where more targeted and effective treatments may be implemented.

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

    International Nuclear Information System (INIS)

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

  5. Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, Arnulf; Vaupel, Peter; Stockinger, Marcus; Schmidberger, Heinz [University Medical Center, Department of Radiooncology and Radiotherapy, Mainz (Germany); Struss, Hans-Garlich [University Medical Center, Department of Laboratory Medicine, Mainz (Germany); Giese, Alf [University Medical Center, Department of Neurosurgery, Mainz (Germany)

    2014-10-15

    In comparison to normal brain tissue, glioblastomas exhibit significantly increased glucose uptake. Brain edema is a common complication during adjuvant chemoradiotherapy, leading to a requirement for glucocorticoid treatment. Glucocorticoid treatment frequently causes considerable deregulation of blood glucose levels. Therefore, episodes of hyperglycemia may contribute to radio- and/or chemoresistance. This study comprises a retrospective analysis of the influence of hyperglycemic episodes (HEs) during adjuvant therapy on the overall survival of 106 glioblastoma multiforme patients. The occurrence of one or more deregulated blood glucose value(s) > 10 mM is associated with a reduction in median overall survival from 16.7 to 8.8 months. A significantly poorer overall survival of patients with hyperglycemia could also be detected in subgroup analyses of patients with complete tumor resection and complete treatment according to the EORTC 22891/26891 trial protocol, as well as in a multivariate Cox proportional hazards analysis. A history of diabetes mellitus had no influence on prognosis. Our data suggest that the observed negative impact of elevated blood glucose levels on overall survival may not solely be explained by the patients' poorer general condition; the elevated blood glucose concentration itself may play a pathogenetic role. This could be due to increased activity of antioxidant systems, elevated expression of DNA damage response proteins and protection of hypoxic tumor cells against apoptosis combined with hypoxia-mediated radioresistance. A possible prognostic impact of elevated blood glucose levels during the period of adjuvant (chemo-) radiotherapy of glioblastoma should be evaluated in a prospective clinical trial. (orig.) [German] Glioblastome zeigen im Vergleich mit normalem Gehirngewebe eine deutlich vermehrte Glukoseaufnahme. Im Rahmen der adjuvanten Radio(chemo)therapie von Glioblastomen treten vielfach Hirnoedeme auf, die eine

  6. STAT6 expression in glioblastoma promotes invasive growth

    Directory of Open Access Journals (Sweden)

    Silva Corinne M

    2011-05-01

    Full Text Available Abstract Background Glioblastoma (GBM is a highly aggressive malignant primary brain tumor, characterized by rapid growth, diffuse infiltration of cells into both adjacent and remote brain regions, and a generalized resistance to currently available treatment modalities. Recent reports in the literature suggest that Signal Transducers and Activators of Transcription (STATs play important roles in the regulation of GBM pathophysiology. Methods STAT6 protein expression was analyzed by Western blotting in GBM cell lines and by immunohistochemistry in a tissue microarray (TMA of glioma patient tissues. We utilized shRNA against STAT6 to investigate the effects of prolonged STAT6 depletion on the growth and invasion of two STAT6-positive GBM cell lines. Cell proliferation was assessed by measuring 3H-Thymidine uptake over time. Invasion was measured using an in vitro transwell assay in which cells invade through a type IV collagen matrix toward a chemoattractant (Fetal Bovine Serum. Cells were then stained and counted. Kaplan-Meyer survival curves were generated to show the correlation between STAT6 gene expression and patient survival in 343 glioma patients and in a subset of patients with only GBM. Gene expression microarray and clinical data were acquired from the Rembrandt 1 public data depository (https://caintegrator.nci.nih.gov/rembrandt/. Lastly, a genome-wide expression microarray analysis was performed to compare gene expression in wild-type GBM cells to expression in stable STAT6 knockdown clones. Results STAT6 was expressed in 2 GBM cell lines, U-1242MG and U-87MG, and in normal astrocytes (NHA but not in the U-251MG GBM cell line. In our TMA study, STAT6 immunostaining was visible in the majority of astrocytomas of all grades (I-IV but not in normal brain tissue. In positive cells, STAT6 was localized exclusively in the nuclei over 95% of the time. STAT6-deficient GBM cells showed a reduction in 3H-Thymidine uptake compared to the wild

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-05-01

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

  9. PACAP and VIP inhibit the invasiveness of glioblastoma cells exposed to hypoxia through the regulation of HIFs and EGFR expression

    Directory of Open Access Journals (Sweden)

    Grazia eMaugeri

    2016-05-01

    Full Text Available Pituitary adenylate cyclase-activating polypeptide (PACAP and vasoactive intestinal peptide (VIP through the binding of vasoactive intestinal peptide receptors (VIPRs, perform a wide variety of effects in human cancers, including glioblastoma multiforme (GBM. This tumor is characterized by extensive areas of hypoxia, which triggers the expression of hypoxia-inducible factors (HIFs. HIFs not only mediate angiogenesis but also tumor cell migration and invasion. Furthermore, HIFs activation is linked to epidermal growth factor receptor (EGFR overexpression. Previous studies have shown that VIP interferes with the invasive nature of gliomas by regulating cell migration. However, the role of VIP family members in GBM infiltration under low oxygen tension has not been clarified yet. Therefore, in the present study we have investigated, for the first time, the molecular mechanisms involved in the anti-invasive effect of PACAP or VIP in U87MG glioblastoma cells exposed to hypoxia induced by treatment with desferrioxamine (DFX. The results suggest that either PACAP or VIP exert an anti-infiltrative effect under low oxygen tension by modulating HIFs and EGFR expression, key elements involved in cell migration and angiogenesis. These peptides act through the inhibition of PI3K/Akt and MAPK/ERK signaling pathways, which are known to have a crucial role in HIFs regulation. In conclusion, the modulation of hypoxic event and the anti-invasive effect exerted by some VIP family members might open new insights in the therapeutic approach to GBM.

  10. PACAP and VIP Inhibit the Invasiveness of Glioblastoma Cells Exposed to Hypoxia through the Regulation of HIFs and EGFR Expression.

    Science.gov (United States)

    Maugeri, Grazia; Grazia D'Amico, Agata; Reitano, Rita; Magro, Gaetano; Cavallaro, Sebastiano; Salomone, Salvatore; D'Agata, Velia

    2016-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) through the binding of vasoactive intestinal peptide receptors (VIPRs), perform a wide variety of effects in human cancers, including glioblastoma multiforme (GBM). This tumor is characterized by extensive areas of hypoxia, which triggers the expression of hypoxia-inducible factors (HIFs). HIFs not only mediate angiogenesis but also tumor cell migration and invasion. Furthermore, HIFs activation is linked to epidermal growth factor receptor (EGFR) overexpression. Previous studies have shown that VIP interferes with the invasive nature of gliomas by regulating cell migration. However, the role of VIP family members in GBM infiltration under low oxygen tension has not been clarified yet. Therefore, in the present study we have investigated, for the first time, the molecular mechanisms involved in the anti-invasive effect of PACAP or VIP in U87MG glioblastoma cells exposed to hypoxia induced by treatment with desferrioxamine (DFX). The results suggest that either PACAP or VIP exert an anti-infiltrative effect under low oxygen tension by modulating HIFs and EGFR expression, key elements involved in cell migration and angiogenesis. These peptides act through the inhibition of PI3K/Akt and MAPK/ERK signaling pathways, which are known to have a crucial role in HIFs regulation. PMID:27303300

  11. Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[{sup 18}F]fluoroethyl)-l-tyrosine PET

    Energy Technology Data Exchange (ETDEWEB)

    Galldiks, Norbert [University of Cologne, Department of Neurology, Cologne (Germany); Forschungszentrum Juelich, Institute of Neuroscience and Medicine, Juelich (Germany); University of Cologne, Center of Integrated Oncology (CIO), Cologne (Germany); Dunkl, Veronika; Fink, Gereon R. [University of Cologne, Department of Neurology, Cologne (Germany); Forschungszentrum Juelich, Institute of Neuroscience and Medicine, Juelich (Germany); Stoffels, Gabriele [Forschungszentrum Juelich, Institute of Neuroscience and Medicine, Juelich (Germany); Hutterer, Markus; Hau, Peter [University of Regensburg, Department of Neurology and Wilhelm Sander-NeuroOncology Unit, Regensburg (Germany); Rapp, Marion; Sabel, Michael [Heinrich Heine University Duesseldorf, Department of Neurosurgery, Duesseldorf (Germany); Reifenberger, Guido [Heinrich Heine University Duesseldorf, Department of Neuropathology, Duesseldorf (Germany); Kebir, Sied [University of Bonn, Department of Neurology, Bonn (Germany); Dorn, Franziska [University of Cologne, Department of Neuroradiology, Cologne (Germany); Blau, Tobias [University of Cologne, Department of Neuropathology, Cologne (Germany); Herrlinger, Ulrich [University of Cologne, Center of Integrated Oncology (CIO), Cologne (Germany); University of Bonn, Department of Neurology, Bonn (Germany); Ruge, Maximilian I. [University of Cologne, Center of Integrated Oncology (CIO), Cologne (Germany); University of Cologne, Department of Stereotaxy and Functional Neurosurgery, Cologne (Germany); Kocher, Martin [University of Cologne, Center of Integrated Oncology (CIO), Cologne (Germany); University of Cologne, Department of Radiation Oncology, Cologne (Germany); Goldbrunner, Roland [University of Cologne, Center of Integrated Oncology (CIO), Cologne (Germany); University of Cologne, Department of Neurosurgery, Cologne (Germany); Drzezga, Alexander; Schmidt, Matthias [University of Cologne, Department of Nuclear Medicine, Cologne (Germany); Langen, Karl-Josef [Forschungszentrum Juelich, Institute of Neuroscience and Medicine, Juelich (Germany); University of Aachen, Department of Nuclear Medicine, Aachen (Germany)

    2015-04-01

    The follow-up of glioblastoma patients after radiochemotherapy with conventional MRI can be difficult since reactive alterations to the blood-brain barrier with contrast enhancement may mimic tumour progression (i.e. pseudoprogression, PsP). The aim of this study was to assess the clinical value of O-(2-{sup 18}F-fluoroethyl)-l-tyrosine ({sup 18}F-FET) PET in the differentiation of PsP and early tumour progression (EP) after radiochemotherapy of glioblastoma. A group of 22 glioblastoma patients with new contrast-enhancing lesions or lesions showing increased enhancement (>25 %) on standard MRI within the first 12 weeks after completion of radiochemotherapy with concomitant temozolomide (median 7 weeks) were additionally examined using amino acid PET with {sup 18}F-FET. Maximum and mean tumour-to-brain ratios (TBR{sub max}, TBR{sub mean}) were determined. {sup 18}F-FET uptake kinetic parameters (i.e. patterns of time-activity curves, TAC) were also evaluated. Classification as PsP or EP was based on the clinical course (no treatment change at least for 6 months), follow-up MR imaging and/or histopathological findings. Imaging results were also related to overall survival (OS). PsP was confirmed in 11 of the 22 patients. In patients with PsP, {sup 18}F-FET uptake was significantly lower than in patients with EP (TBR{sub max} 1.9 ± 0.4 vs. 2.8 ± 0.5, TBR{sub mean} 1.8 ± 0.2 vs. 2.3 ± 0.3; both P < 0.001) and presence of MGMT promoter methylation was significantly more frequent (P = 0.05). Furthermore, a TAC type II or III was more frequently present in patients with EP (P = 0.04). Receiver operating characteristic analysis showed that the optimal {sup 18}F-FET TBR{sub max} cut-off value for identifying PsP was 2.3 (sensitivity 100 %, specificity 91 %, accuracy 96 %, AUC 0.94 ± 0.06; P < 0.001). Univariate survival analysis showed that a TBR{sub max} <2.3 predicted a significantly longer OS (median OS 23 vs. 12 months; P = 0.046). {sup 18}F-FET PET may facilitate

  12. Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-l-tyrosine PET

    International Nuclear Information System (INIS)

    The follow-up of glioblastoma patients after radiochemotherapy with conventional MRI can be difficult since reactive alterations to the blood-brain barrier with contrast enhancement may mimic tumour progression (i.e. pseudoprogression, PsP). The aim of this study was to assess the clinical value of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET in the differentiation of PsP and early tumour progression (EP) after radiochemotherapy of glioblastoma. A group of 22 glioblastoma patients with new contrast-enhancing lesions or lesions showing increased enhancement (>25 %) on standard MRI within the first 12 weeks after completion of radiochemotherapy with concomitant temozolomide (median 7 weeks) were additionally examined using amino acid PET with 18F-FET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) were determined. 18F-FET uptake kinetic parameters (i.e. patterns of time-activity curves, TAC) were also evaluated. Classification as PsP or EP was based on the clinical course (no treatment change at least for 6 months), follow-up MR imaging and/or histopathological findings. Imaging results were also related to overall survival (OS). PsP was confirmed in 11 of the 22 patients. In patients with PsP, 18F-FET uptake was significantly lower than in patients with EP (TBRmax 1.9 ± 0.4 vs. 2.8 ± 0.5, TBRmean 1.8 ± 0.2 vs. 2.3 ± 0.3; both P < 0.001) and presence of MGMT promoter methylation was significantly more frequent (P = 0.05). Furthermore, a TAC type II or III was more frequently present in patients with EP (P = 0.04). Receiver operating characteristic analysis showed that the optimal 18F-FET TBRmax cut-off value for identifying PsP was 2.3 (sensitivity 100 %, specificity 91 %, accuracy 96 %, AUC 0.94 ± 0.06; P < 0.001). Univariate survival analysis showed that a TBRmax <2.3 predicted a significantly longer OS (median OS 23 vs. 12 months; P = 0.046). 18F-FET PET may facilitate the diagnosis of PsP following radiochemotherapy of glioblastoma. (orig.)

  13. The effect of AZD2171- or sTRAIL/Apo2L-loaded polylactic-co-glycolic acid microspheres on a subcutaneous glioblastoma model.

    Science.gov (United States)

    Shivinsky, Anna; Bronshtein, Tomer; Haber, Tom; Machluf, Marcelle

    2015-08-01

    Studies with AZD2171-a new anti-angiogenic inhibitor of tyrosine kinases associated with VEGF signaling-have shown great promise for treating glioblastoma. Unfortunately, AZD2171 success is limited by low permeability through the blood-brain barrier. Due to AZD2171's short half-life and high toxicity, its local administration will require multiple intracranial procedures, making this approach clinically unfeasible. In this study, we investigated the potential of the highly hydrophobic AZD2171, released from modified polylactic-co-glycolic acid microspheres (PLGA-MS), to treat glioblastoma. To further demonstrate the versatile loading capacity of this system, the same PLGA formulation, which was found optimal for the loading and release of AZD2171, was tested with sTRAIL/Apo2L-a biologic drug that is very different than AZD2171 in its molecular weight, solubility, and charge. AZD2171 released from PLGA-MS was at least effective as the free drug in inhibiting endothelial growth and proliferation (in vitro), and, surprisingly, had a profound cytotoxic effect also towards in vitro cultured glioblastoma cell-lines (U87 and A172). Complete tumor inhibition was achieved following a single treatment with AZD2171-loaded PLGA-MS (6 (mg)/kg) administered locally adjacent to human U87 glioma tumors inoculated subcutaneously in nude mice. This improved effect, compared to other therapeutic approaches involving AZD2171, was shown to affect both tumor vasculature and the glioma cells. sTRAIL-loaded microspheres, administered at very low doses (0.3 (mg)/kg), led to 35 % inhibition of tumor growth in 2 weeks. Collectively, our results provide pre-clinical evidence for the potential of PLGA formulations of AZD2171 and sTRAIL to serve as an effective treatment for glioblastoma.

  14. Doxycycline Improves Filarial Lymphedema Independent of Active Filarial Infection: A Randomized Controlled Trial

    OpenAIRE

    Mand, S; DEBRAH, A Y; Klarmann, U; Batsa, L.; Marfo-Debrekyei, Y.; Kwarteng, A; S. SPECHT; Belda-Domene, A.; Fimmers, R; Taylor, M; Adjei, O.; Hoerauf, A.

    2012-01-01

    Treatment with doxycycline leads to improvement of filarial lymphedema independent of active infection (ie, patients positive or negative for circulating filarial antigen). Therefore, doxycycline (200 mg/d for 6 weeks) should be considered for patients with stage 1–3 lymphedema to improve morbidity management.

  15. Performance Improvement of Shunt Active Power Filter With Dual Parallel Topology

    DEFF Research Database (Denmark)

    Asiminoaei, Lucian; Lascu, Cristian; Blaabjerg, Frede;

    2007-01-01

    loop and the other is in a feedforward loop for harmonic compensation. Thus, both active power filters bring their own characteristic advantages, i.e., the feedback filter improves the steady-state performance of the harmonic mitigation and the feedforward filter improves the dynamic response. Another...

  16. Improving Enzyme Activity and Broadening Selectivity for Biological Desulfurization and Upgrading of Petroleum Feedstocks

    Energy Technology Data Exchange (ETDEWEB)

    Abhijeet P. Borole; Choo Y. Hamilton; Karen Miller; Brian Davison; Matthew Grossman; Robert Shong

    2003-05-12

    The objective of this project was to develop improved biocatalysts for desulfurization and upgrading of petroleum feedstocks. The goal was to improve the activity and broaden the selectivity of desulfurization enzymes using directed evolution as a tool as well as to explore the impact of ring-opening on biological desulfurization

  17. A Study on the Improvement of Student’s Reading Ability Through Active-Reading

    Institute of Scientific and Technical Information of China (English)

    胡伟

    2012-01-01

    The present study presents a detailed report of a project aims at improving my students’reading skills are poor.And this essay argues that the active-reading method has the characteristics of go-aheadism and effectiveness,and it is a good way to help students improve their reading skills.

  18. Improving Settling Dynamics of Activated Sludge by Adding Fine Talc Powder

    DEFF Research Database (Denmark)

    Rasmussen, Michael R.; Larsen, Torben; Clauss, F.

    1996-01-01

    . The settling velocity was measured with a recirculated settling column under different concentrations and turbulence levels. Numerical simulation of a secondary settling tank indicates that adding fine powder will improve the overall performance considerably.......The effect of adding varying mixtures of talc and chlorite powder to activated sludge in order to improve the settling characteristic has been studied. The powder is found to improve the settling velocity of the sludge, strictly by increasing the average density of the sludge floc aggregate...

  19. Primary glioblastoma of the trigeminal nerve root entry zone: case report.

    Science.gov (United States)

    Breshears, Jonathan D; Ivan, Michael E; Cotter, Jennifer A; Bollen, Andrew W; Theodosopoulos, Phillip V; Berger, Mitchel S

    2015-01-01

    Gliomas of the cranial nerve root entry zone are rare clinical entities. There have been 11 reported cases in the literature, including only 2 glioblastomas. The authors report the case of a 67-year-old man who presented with isolated facial numbness and was found to have a glioblastoma involving the trigeminal nerve root entry zone. After biopsy the patient completed treatment with conformal radiation and concomitant temozolomide, and at 23 weeks after surgery he demonstrated symptom progression despite the treatment described. This is the first reported case of a glioblastoma of the trigeminal nerve root entry zone. PMID:25380115

  20. Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells

    DEFF Research Database (Denmark)

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

    2015-01-01

    Glioblastomas display hierarchies with self-renewing cancer stem-like cells (CSCs). RNA sequencing and enhancer mapping revealed regulatory programs unique to CSCs causing upregulation of the iron transporter transferrin, the top differentially expressed gene compared with tissue-specific progeni......Glioblastomas display hierarchies with self-renewing cancer stem-like cells (CSCs). RNA sequencing and enhancer mapping revealed regulatory programs unique to CSCs causing upregulation of the iron transporter transferrin, the top differentially expressed gene compared with tissue......-specific progenitors. Direct interrogation of iron uptake demonstrated that CSCs potently extract iron from the microenvironment more effectively than other tumor cells. Systematic interrogation of iron flux determined that CSCs preferentially require transferrin receptor and ferritin, two core iron regulators......, to propagate and form tumors in vivo. Depleting ferritin disrupted CSC mitotic progression, through the STAT3-FoxM1 regulatory axis, revealing an iron-regulated CSC pathway. Iron is a unique, primordial metal fundamental for earliest life forms, on which CSCs have an epigenetically programmed, targetable...

  1. Stem Cell Niches in Glioblastoma: A Neuropathological View

    Directory of Open Access Journals (Sweden)

    Davide Schiffer

    2014-01-01

    Full Text Available Glioblastoma (GBM stem cells (GSCs, responsible for tumor growth, recurrence, and resistance to therapies, are considered the real therapeutic target, if they had no molecular mechanisms of resistance, in comparison with the mass of more differentiated cells which are insensitive to therapies just because of being differentiated and nonproliferating. GSCs occur in tumor niches where both stemness status and angiogenesis are conditioned by the microenvironment. In both perivascular and perinecrotic niches, hypoxia plays a fundamental role. Fifteen glioblastomas have been studied by immunohistochemistry and immunofluorescence for stemness and differentiation antigens. It has been found that circumscribed necroses develop inside hyperproliferating areas that are characterized by high expression of stemness antigens. Necrosis developed inside them because of the imbalance between the proliferation of tumor cells and endothelial cells; it reduces the number of GSCs to a thin ring around the former hyperproliferating area. The perinecrotic GSCs are nothing else that the survivors remnants of those populating hyperproliferating areas. In the tumor, GSCs coincide with malignant areas so that the need to detect where they are located is not so urgent.

  2. Improved activity of immobilized horseradish peroxidase on gold nanoparticles in the presence of bovine serum albumin

    International Nuclear Information System (INIS)

    The using of macromolecular additives is known to be a simple and effective way to improve the activity of immobilized enzymes on solid support, yet the mechanism has not been well understood. Taking horseradish peroxidase (HRP) as an example, only 30 % of its catalytic activity was kept after being immobilized on the surface of 25-nm Au nanoparticles, mainly attributed to the conformational change of the heme-containing active site. The catalytic activity of HRP was significantly improved to 80 % when a certain amount of bovine serum albumin (BSA) was added at the initial stage of the immobilization. Systematic spectral investigation indicated that the addition of BSA inhibited the tertiary structure change around the active site, which was a prerequisite for improved activity of the immobilized HRP. Steady-state kinetic analyses revealed that the introduction of BSA could effectively improve the turnover rate of substrate to product in spite of slight reduced affinity to substrates, which also contributed to the improved catalytic activity

  3. Improved activity of immobilized horseradish peroxidase on gold nanoparticles in the presence of bovine serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Ni, Yuyang; Li, Jun; Huang, Zhenzhen; He, Ke; Zhuang, Jiaqi; Yang, Wensheng, E-mail: wsyang@jlu.edu.cn [Jilin University, State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry (China)

    2013-11-15

    The using of macromolecular additives is known to be a simple and effective way to improve the activity of immobilized enzymes on solid support, yet the mechanism has not been well understood. Taking horseradish peroxidase (HRP) as an example, only 30 % of its catalytic activity was kept after being immobilized on the surface of 25-nm Au nanoparticles, mainly attributed to the conformational change of the heme-containing active site. The catalytic activity of HRP was significantly improved to 80 % when a certain amount of bovine serum albumin (BSA) was added at the initial stage of the immobilization. Systematic spectral investigation indicated that the addition of BSA inhibited the tertiary structure change around the active site, which was a prerequisite for improved activity of the immobilized HRP. Steady-state kinetic analyses revealed that the introduction of BSA could effectively improve the turnover rate of substrate to product in spite of slight reduced affinity to substrates, which also contributed to the improved catalytic activity.

  4. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma.

    Science.gov (United States)

    Scholz, Alexander; Harter, Patrick N; Cremer, Sebastian; Yalcin, Burak H; Gurnik, Stefanie; Yamaji, Maiko; Di Tacchio, Mariangela; Sommer, Kathleen; Baumgarten, Peter; Bähr, Oliver; Steinbach, Joachim P; Trojan, Jörg; Glas, Martin; Herrlinger, Ulrich; Krex, Dietmar; Meinhardt, Matthias; Weyerbrock, Astrid; Timmer, Marco; Goldbrunner, Roland; Deckert, Martina; Braun, Christian; Schittenhelm, Jens; Frueh, Jochen T; Ullrich, Evelyn; Mittelbronn, Michel; Plate, Karl H; Reiss, Yvonne

    2016-01-01

    Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti-angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin-2 (Ang-2) as a potential target in both naive and bevacizumab-treated glioblastoma. Ang-2 expression was absent in normal human brain endothelium, while the highest Ang-2 levels were observed in bevacizumab-treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang-2, whereas the combined inhibition of VEGF and Ang-2 leads to extended survival, decreased vascular permeability, depletion of tumor-associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206(+) (M2-like) macrophages were identified as potential novel targets following anti-angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang-2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang-2 may potentially overcome resistance to bevacizumab therapy. PMID:26666269

  5. Mutations Closer to the Active Site Improve the Promiscuous Aldolase Activity of 4-Oxalocrotonate Tautomerase More Effectively than Distant Mutations.

    Science.gov (United States)

    Rahimi, Mehran; van der Meer, Jan-Ytzen; Geertsema, Edzard M; Poddar, Harshwardhan; Baas, Bert-Jan; Poelarends, Gerrit J

    2016-07-01

    The enzyme 4-oxalocrotonate tautomerase (4-OT), which catalyzes enol-keto tautomerization as part of a degradative pathway for aromatic hydrocarbons, promiscuously catalyzes various carbon-carbon bond-forming reactions. These include the aldol condensation of acetaldehyde with benzaldehyde to yield cinnamaldehyde. Here, we demonstrate that 4-OT can be engineered into a more efficient aldolase for this condensation reaction, with a >5000-fold improvement in catalytic efficiency (kcat /Km ) and a >10(7) -fold change in reaction specificity, by exploring small libraries in which only "hotspots" are varied. The hotspots were identified by systematic mutagenesis (covering each residue), followed by a screen for single mutations that give a strong improvement in the desired aldolase activity. All beneficial mutations were near the active site of 4-OT, thus underpinning the notion that new catalytic activities of a promiscuous enzyme are more effectively enhanced by mutations close to the active site. PMID:27238293

  6. Statin use and survival following glioblastoma multiforme

    DEFF Research Database (Denmark)

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

    2014-01-01

    AIM: While some studies indicate a potential chemopreventive effect of statin use on the risk of glioma, the effect of statins on the prognosis of brain tumours has not yet been examined. We thus conducted a cohort study evaluating the influence of statin use on survival in patients with glioblas......AIM: While some studies indicate a potential chemopreventive effect of statin use on the risk of glioma, the effect of statins on the prognosis of brain tumours has not yet been examined. We thus conducted a cohort study evaluating the influence of statin use on survival in patients...... redeemed prescriptions) was matched to two statin non-users (models were used to compute hazard ratios (HRs) and 95% confidence intervals (CI) for all......: 0.63-1.01). CONCLUSION: Long-term prediagnostic statin use may improve survival following GBM....

  7. Targeting complement activation in brain-dead donors improves renal function after transplantation

    NARCIS (Netherlands)

    Damman, Jeffrey; Hoeger, Simone; Boneschansker, Leo; Theruvath, Ashok; Waldherr, Ruediger; Leuvenink, Henri G.; Ploeg, Rutger J.; Yard, Benito A.; Seelen, Marc A.

    2011-01-01

    Kidneys recovered from brain-dead donors have inferior outcomes after transplantation compared to kidneys from living donors. Since complement activation plays an important role in renal transplant related injury, targeting complement activation in brain-dead donors might improve renal function afte

  8. The improvement of methodical aspects of assessing the effectiveness of activity of joint stock companies

    OpenAIRE

    Проволоцька, Олена Миколаївна; Чаусов, Олександр Васильович

    2015-01-01

    In work improved theoretical and methodological aspects of assessing the effectiveness of activity of the company. There are proposed to analyse the effectiveness of activity in two main directions: from the company's position as a business entity and a shareholder's vision as a depositor funds. Proposed instruments tested in conditions of PJSC «AMKR».

  9. Physical Activity: A Tool for Improving Health (Part 2-Mental Health Benefits)

    Science.gov (United States)

    Gallaway, Patrick J.; Hongu, Nobuko

    2016-01-01

    By promoting physical activities and incorporating them into their community-based programs, Extension professionals are improving the health of individuals, particularly those with limited resources. This article is the second in a three-part series describing the benefits of physical activity for human health: (1) biological health benefits of…

  10. 45 CFR 98.51 - Activities to improve the quality of child care.

    Science.gov (United States)

    2010-10-01

    ... health and safety, nutrition, first aid, the recognition of communicable diseases, child abuse detection... 45 Public Welfare 1 2010-10-01 2010-10-01 false Activities to improve the quality of child care... CHILD CARE AND DEVELOPMENT FUND Use of Child Care and Development Funds § 98.51 Activities to...

  11. Physical Activity: A Tool for Improving Health (Part 1--Biological Health Benefits)

    Science.gov (United States)

    Gallaway, Patrick J.; Hongu, Nobuko

    2015-01-01

    Extension educators have been promoting and incorporating physical activities into their community-based programs and improving the health of individuals, particularly those with limited resources. This article is the first of a three-part series describing the benefits of physical activity for human health: 1) biological health benefits of…

  12. Improved Insulin Resistance and Lipid Metabolism by Cinnamon Extract through Activation of Peroxisome Proliferator-Activated Receptors

    OpenAIRE

    Xiaoyan Sheng; Yuebo Zhang; Zhenwei Gong; Cheng Huang; Ying Qin Zang

    2008-01-01

    Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors involved in the regulation of insulin resistance and adipogenesis. Cinnamon, a widely used spice in food preparation and traditional antidiabetic remedy, is found to activate PPARγ and α, resulting in improved insulin resistance, reduced fasted glucose, FFA, LDL-c, and AST levels in high-caloric diet-induced obesity (DIO) and db/db mice in its water extract form. In vitro studies demonstrate that cinnamon increase...

  13. The role of basic fibroblast growth factor in glioblastoma multiforme and glioblastoma stem cells and in their in vitro culture.

    Science.gov (United States)

    Haley, Elizabeth M; Kim, Yonghyun

    2014-04-28

    Glioblastoma multiforme (GBM) is the most malignant form of central nervous system tumor, and current therapies are largely ineffective at treating the cancer. Developing a more complete understanding of the mechanisms controlling the tumor is important in order to explore new possible treatment options. It is speculated that the presence of glioblastoma stem or stem-like cells (GSCs), a rare type of pluripotent cancer cell that possesses the ability to self-renew and generate tumors, could be an important factor contributing to the resistance to treatment and deadliness of the cancer. A comprehensive knowledge of the mechanisms controlling the expression and properties of GSCs is currently lacking, and one promising area for further exploration is in the influence of basic fibroblast growth factor (FGF-2) on GSCs. Recent studies reveal that FGF-2 plays a significant part in regulating GBM, and the growth factor is commonly included as a supplement in media used to culture GSCs in vitro. However, the particular role that FGF-2 plays in GSCs has not been as extensively explored. Therefore, understanding how FGF-2 is involved in GSCs and in GBMs could be an important step towards a more complete comprehension of the managing the disease. In this review, we look at the structure, signaling pathways, and specific role of FGF-2 in GBM and GSCs. In addition, we explore the use of FGF-2 in cell culture and using its synthetic analogs as a potential alternative to the growth factor in culture medium.

  14. Does a physical activity referral scheme improve the physical activity among routine primary health care patients?

    OpenAIRE

    Leijon, Matti E; Bendtsen, Preben; Nilsen, Per; Festin, Karin; Ståhle, A

    2009-01-01

    Physical activity referral (PAR) schemes or concepts occur in varying forms. Because few physical activity intervention studies have been carried out in routine health care settings, it is difficult to translate research findings into daily practice. The aim of this study was to analyze the effectiveness of a PAR scheme implemented in routine primary health care. The study did not include a control group and was based on the ordinary staff's work efforts and follow-up measures. During a 2-yea...

  15. Using activity-based costing and theory of constraints to guide continuous improvement in managed care.

    Science.gov (United States)

    Roybal, H; Baxendale, S J; Gupta, M

    1999-01-01

    Activity-based costing and the theory of constraints have been applied successfully in many manufacturing organizations. Recently, those concepts have been applied in service organizations. This article describes the application of activity-based costing and the theory of constraints in a managed care mental health and substance abuse organization. One of the unique aspects of this particular application was the integration of activity-based costing and the theory of constraints to guide process improvement efforts. This article describes the activity-based costing model and the application of the theory of constraint's focusing steps with an emphasis on unused capacities of activities in the organization.

  16. Using activity-based costing and theory of constraints to guide continuous improvement in managed care.

    Science.gov (United States)

    Roybal, H; Baxendale, S J; Gupta, M

    1999-01-01

    Activity-based costing and the theory of constraints have been applied successfully in many manufacturing organizations. Recently, those concepts have been applied in service organizations. This article describes the application of activity-based costing and the theory of constraints in a managed care mental health and substance abuse organization. One of the unique aspects of this particular application was the integration of activity-based costing and the theory of constraints to guide process improvement efforts. This article describes the activity-based costing model and the application of the theory of constraint's focusing steps with an emphasis on unused capacities of activities in the organization. PMID:10350791

  17. Using Speed Reading and Extensive Reading Activities to Improve Students’ Reading Fluency

    OpenAIRE

    Sri Wardani

    2015-01-01

    Abstract: This study examines the implementation of Speed Reading and Extensive Reading activities to improve students’ reading fluency of students. Using a Classroom Action Research, Speed Reading and Extensive Reading activities was applied in 2 cycles with 2 x 45 minutes per week. Speed Reading and Extensive Reading activities were taught using three phase techniques: Pre-Reading, Whilst-Reading, and Post-Reading. Speed Reading was implemented through some techniques including scanning, sk...

  18. An LPV Control Approach for Comfort and Suspension Travel Improvements of Semi-Active Suspension Systems

    OpenAIRE

    Do, Anh Lam; Spelta, Cristiano; Savaresi, Sergio,; Sename, Olivier; Dugard, Luc; Delvecchio, Diego

    2010-01-01

    International audience In this paper, we present a new H¥=LPV control method to improve the trade-off between comfort and suspension travel. Firstly, a semi-active automotive suspension uipped with a nonlinear static semi-active damper is presented. Secondly, the semi-active suspension system is reformulated in the LPV framework which can be handled in a polytopic way. Finally, in numerical analysis, to emphasize the performance of the proposed controller, the end-stop event is introduced....

  19. P17.70CAN ELDERLY PATIENTS WITH GLIOBLASTOMA BENEFIT FROM CONVENTIONAL CHEMO-RADIOTHERAPY TREATMENT?

    Science.gov (United States)

    Pineda, E.; Valduvieco, I.; Pujol, T.; Oleaga, L.; Ribalta, T.; Caral, L.; Gonzalez, J.; Boget, T.; Graus, F.; Verger, E.

    2014-01-01

    BACKGROUND: Glioblastoma (GBM) is the most life-threatening primary brain tumor, especially in elderly. Despite aggressive treatment, median survival among all GBM patients is only 12-15 months and is worse in elderly (6-9 months). The standard of care for elderly remains controversial. The purpose of this study is to assess the benefit of conventional treatment (Stupp regimen) in elderly patients. METHOD: We retrospectively reviewed a prospective database of 209 patients who were diagnosed with GBM at a single center from January 2005 to March 2013. All patients were divided into younger and elderly groups based on the cut-off age of 65 years. RESULTS: Of 209 patients diagnosed with GBM, 122 (58%) patients were younger than 65 years, and 87 (42%) patients were 65 years old or older. No differences were found in basal patient characteristics and neither in grade of resection between age subgroups. However elderly received less active treatment, radio-chemotherapy was less frequent in elderly (51% vs 73%) but radiotherapy alone (18% vs 8%) and non-oncological treatment after surgery was more frequent in elderly (31% vs 18%) (p = 0.002). No differences in median survival were found in elderly patients who received the same approach treatment than young patients. Median OS was 10.8 months in all GBM patients, 8.7 months in older and 13.6 months in younger patients (p = 0.019). Of all, 106 (51%) patients received Stupp regimen, 41 (47%) elderly and 65 (53%) young. Median OS in patients treated with conventional treatment was 18 months, without differences by age, 15.3 months in older and 18 months in younger (p = 0.228), neither differences were found in PFS (global of 8.2 months, 9.7 and 8.2 months, p = 0.307). MGMT status information was available only for 45.5% of patients that received Stupp regimen, 23 MGMT methylated, 25 MGMT unmethylated and 58 patients with MGMT not evaluable or not done. Surprisingly, no differences in OS were found between groups by MGMT

  20. Does Improving Exercise Capacity and Daily Activity Represent the Holistic Perspective of a New COPD Approach?

    Science.gov (United States)

    Di Marco, Fabiano; Santus, Pierachille; Sotgiu, Giovanni; Blasi, Francesco; Centanni, Stefano

    2015-01-01

    In COPD patients a reduced daily activity has been well documented, resulting from both respiratory and non-respiratory manifestations of the disease. An evaluation by multisensory armband has confirmed that daily physical activity is mainly associated with dynamic hyperinflation, regardless of COPD severity. This aspect is crucial, since exercise capacity is closely correlated to life expectancy. Notwithstanding the causal key role of lung impairment in the patient's symptoms, some authors have suggested that other factors, such as systemic inflammation and co-morbidities, have an important role, particularly as mortality risk factors. Many studies suggest the efficacy of bronchodilators and rehabilitation in improving exercise capacity, and, speaking in terms of daily life, in increasing the number of days in which patients are able to perform their usual activities. On this evidence, the first aim in the management of COPD should be to improve exercise capacity and daily activity since these outcomes have direct effects on patients' quality of life, co-morbidities (heart and metabolic diseases), and prognosis. Thus, improving physical activity represents a modern approach aimed at dealing with both pulmonary and systemic manifestations of the disease. It is however worth of notice to remember that in patients affected by COPD the relationship between the improvement of "potential" exercise capacity and daily physical activity has been found to be only moderate to weak. Obtaining a significant behavior modification with regard to daily physical activity, together with the optimization of therapy thus represents currently the true challenge. PMID:26457460