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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

    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

    ... 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. Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

    Martyn A. Sharpe

    2015-09-01

    Full Text Available The last major advance in the treatment of glioblastoma multiforme (GBM was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P+-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

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

    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, ...

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

    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...

  6. Invasive Glioblastoma Cells Acquire Stemness and Increased Akt Activation

    Jennifer R. Molina

    2010-06-01

    Full Text Available Glioblastoma multiforme (GBM is the most frequent and most aggressive brain tumor in adults. The dismal prognosis is due to postsurgery recurrences arising from escaped invasive tumor cells. The signaling pathways activated in invasive cells are under investigation, and models are currently designed in search for therapeutic targets. We developed here an in vivo model of human invasive GBM in mouse brain from a GBM cell line with moderate tumorigenicity that allowed simultaneous primary tumor growth and dispersal of tumor cells in the brain parenchyma. This strategy allowed for the first time the isolation and characterization of matched sets of tumor mass (Core and invasive (Inv cells. Both cell populations, but more markedly Inv cells, acquired stem cell markers, neurosphere renewal ability, and resistance to rapamycin-induced apoptosis relative to parental cells. The comparative phenotypic analysis between Inv and Core cells showed significantly increased tumorigenicity in vivo and increased invasion with decreased proliferation in vitro for Inv cells. Examination of a large array of signaling pathways revealed extracellular signal-regulated kinase (Erk down-modulation and Akt activation in Inv cells and an opposite profile in Core cells. Akt activation correlated with the increased tumorigenicity, stemness, and invasiveness, whereas Erk activation correlated with the proliferation of the cells. These results underscore complementary roles of the Erk and Akt pathways for GBM proliferation and dispersal and raise important implications for a concurrent inhibitory therapy.

  7. Antisense epidermal growth factor receptor RNA transfection in human glioblastoma cells down-regulates telomerase activity and telomere length

    Tian, X-X; Pang, JC-S; J. Zheng; Chen, J; To, S S T; Ng, H-K

    2002-01-01

    Epidermal growth factor receptor is overexpressed and/or amplified in up to 50% of glioblastomas, suggesting an important role of this gene in glial tumorigenesis and progression. In the present study we demonstrated that epidermal growth factor receptor is involved in regulation of telomerase activity in glioblastoma. Antisense-epidermal growth factor receptor approach was used to inhibit epidermal growth factor receptor expression of glioblastoma U87MG cells. Telomerase activity in antisens...

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

    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.

  9. Evaluation Of Lenalidomide Activity On Glioblastoma Cell Lines In Vitro

    Mut, Melike; Gregory POLAR; Carpenter, Joan E.; Gerard REDPATH; Larner, James; Schiff, David; Shaffrey, Mark E.

    2007-01-01

    Purpose: Thalidomide analog, Lenalidomide (Revlimid®) is a chemotherapeutic agent. In this study, lenalidomide was used in human glioblastoma multiforme (GBM) cell lines to determine its pro-apoptotic, anti-proliferative and radiosensitizing properties. Methods: The GBM cells were treated with lenalidomide [0, 1, 5, 30, 60 µM] before ultravioletB (UVB) [0, 50, 100 mj] or γ -irradiation [0, 5, 20 Gy], and kept in drug for 5 days. Viable cell numbers were determined by trypan blue exclusion. Th...

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

    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.

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

    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...

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

    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

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

    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

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

    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

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

    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

  16. STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications

    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.

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

    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.

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

    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

  19. Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

    Chakrabarti, Mrinmay; Ray, Swapan K

    2016-03-01

    Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo. PMID:26573275

  20. Valproic Acid Use During Radiation Therapy for Glioblastoma Associated With Improved Survival

    Purpose: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS). Methods and Materials: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS. Results: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, −0.09 to 1.17), independently of RTOG RPA class and seizure history. Conclusions: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted

  1. Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

    Since most glioblastomas express both wild-type EGFR and EGFRvIII as well as HER2/neu, they are excellent targets for activated T cells (ATC) armed with bispecific antibodies (BiAbs) that target EGFR and HER2. ATC were generated from PBMC activated for 14 days with anti-CD3 monoclonal antibody in the presence of interleukin-2 and armed with chemically heteroconjugated anti-CD3×anti-HER2/neu (HER2Bi) and/or anti-CD3×anti-EGFR (EGFRBi). HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and 51Cr-release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines. EGFRBi-armed ATC killed up to 85% of U87, U118, and U251 targets at effector:target ratios (E:T) ranging from 1:1 to 25:1. Engagement of tumor by EGFRBi-armed ATC induced Th1 and Th2 cytokine secretion by armed ATC. HER2Bi-armed ATC exhibited comparable cytotoxicity against U118 and U251, but did not kill HER2-negative U87 cells. HER2Bi- or EGFRBi-armed ATC exhibited 50—80% cytotoxicity against four primary glioblastoma lines as well as a temozolomide (TMZ)-resistant variant of U251. Both CD133– and CD133+ subpopulations were killed by armed ATC. Targeting both HER2Bi and EGFRBi simultaneously showed enhanced efficacy than arming with a single BiAb. Armed ATC maintained effectiveness after irradiation and in the presence of TMZ at a therapeutic concentration and were capable of killing multiple targets. High-grade gliomas are suitable for specific targeting by armed ATC. These data, together with additional animal studies, may provide the preclinical support for the use of armed ATC as a valuable addition to current treatment regimens

  2. Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells

    Ionizing radiation (IR) therapy is a primary treatment for glioblastoma multiforme (GBM), a common and devastating brain tumor in humans. IR has been shown to induce PI3K-Akt activation in many cell types, and activation of the PI3K-Akt signaling pathway has been correlated with radioresistance. Initially, the effects of IR on Akt activation were assessed in multiple human GBM cell lines. Next, to evaluate a potential causative role of IR-induced Akt activation on radiosensitivity, Akt activation was inhibited during IR with several complementary genetic and pharmacological approaches, and radiosensitivity measured using clonogenic survival assays. Three of the eight cell lines tested demonstrated IR-induced Akt activation. Further studies revealed that IR-induced Akt activation was dependent upon the presence of a serum factor, and could be inhibited by the EGFR inhibitor AG1478. Inhibition of PI3K activation with LY294002, or with inducible wild-type PTEN, inhibition of EGFR, as well as direct inhibition of Akt with two Akt inhibitors during irradiation increased the radiosensitivity of U87MG cells. These results suggest that Akt may be a central player in a feedback loop whereby activation of Akt induced by IR increases radioresistance of GBM cells. Targeting the Akt signaling pathway may have important therapeutic implications when used in combination with IR in the treatment of a subset of brain tumor patients

  3. CDBG Public Improvements Activity

    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,...

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

    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...

  5. BCL-2 activation by ionizing radiation in a glioblastoma cell line

    Purpose: p53 is known to be involved in the cellular response to DNA damage. Alterations of the p53 gene also represent the most common changes found in cancer cells. In order to investigate specific gene expression changes following ionizing radiation of p53-deficient cells we have used as a model system a highly radioresistant glioblastoma cell line with inducible p53 Materials and Methods: Human glioblastoma T98G cells growing either exponentially or after release from G0/G1 synchrony were irradiated and the expression level of Bcl-2 and related cell survival factors were evaluated after different doses of ionizing radiation. A derivative of the T98G cell line, harboring a dexamethasone-inducible wild-type p53 was also used to investigate the role of p53 in Bcl-2 induction. Western analyses were mainly used to analyze expression levels of Bcl-2, Mcl-1, Bcl-X, and cyclins. In our search for differentially-induced genes which might mediate activation of Bcl-2 we have used the RNA arbitrarily primed polymerase chain reaction (RAP-PCR). Differentially expressed gene products were gel-purified, cloned, sequenced and their expression tested by Northern analyses. Results: We have found an increase in Bcl-2, Mcl-1, and Bcl-x protein levels after irradiation of T98G cells. The induction was maximal in synchronized cells, when irradiation was done 16 hrs following exit from Go/G1. A 3-fold Bcl-2 induction and 4-fold Mcl-1 increase was observed starting 4 hr after 4 Gy irradiation. This increase was maintained for at least 24 hrs for both proteins, although the peak of Mcl-1 induction was reached after 8 hrs. The induction coincided with cyclin A accumulation, suggesting that the cells were irradiated in G1 and the increase of Bcl-2 protein levels happened when the cells reached S-phase. GM47.23 cells showed a similar induction in the absence, but not presence of Dex, the inducer used to activate wild-type p53. Cells treated with Dex produced wild-type p53 protein, which

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

    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

  7. Tectal glioblastoma Glioblastoma tetal

    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.

  8. Cervical metastatic glioblastoma multiforme

    Glioblastoma multiforme (GBM) is the most common and most malignant primary brain tumour in adults. In spite of the hostile nature of glioblastoma multiforme (GBM), extracranial spread is not a common event. With improving management choices and survival times, reports of extracranial occurrence of GBM have increased. Most commonly these metastases are to the lungs, lymph nodes, neck, skull, scalp, liver, and bones; may be evident on routine follow-up images of the original lesion. Head and neck metastasis of GBM can be debilitating. We present a case of cervical metastasis of GBM and discuss possible mechanisms of extraneural spread of this tumour. (author)

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

    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.

  10. Menthol increases human glioblastoma intracellular Ca2+, BK channel activity and cell migration

    Bartley Jeremy W

    2009-09-01

    Full Text Available Abstract This study examined the effect of menthol, an agonist for transient receptor potential melastatin 8 (TRPM8 ion channels, to increase intracellular Ca2+ concentration, [Ca2+]i, in human glioblastoma cells (DBTRG cells, which resulted in activation of the large-conductance Ca2+-activated K+ membrane ion channels (BK channels. Voltage ramps applied over 300 ms from -100 to 100 mV resulted in membrane currents with marked inwardly- and outwardly-rectifying components. Paxilline (2 μM abolished the outwardly-rectifying current. Outwardly-rectifying on-cell patch currents were increased markedly by menthol (100 μM added to the bath. The estimated on-cell conductance of these channels was 253 pS. Kinetic analysis showed that added menthol increased channel open probability and mean open frequency after 5 min. In a similar time course menthol increased [Ca2+]i, and this increase was abolished either by added paxilline, tetraethylammonium ion or by Ca2+-free external solution. Finally, menthol stimulated the rate of DBTRG cell migration into scratch wounds made in confluent cells, and this also was inhibited by paxilline or by tetraethylammonium ion. We conclude that menthol, a TRPM8 agonist, increases DBTRG cell [Ca2+]i that in turn activates membrane BK ion channels. Inhibition of BK channels by paxilline reverses menthol-stimulated increase of [Ca2+]i and of cell migration. Thus, BK channels function to maintain elevations in [Ca2+]i needed to sustain increases in DBTRG cell migration.

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

    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

  12. Mutations in glioblastoma oncosuppressive pathways pave the way for oncomodulatory activity of cytomegalovirus

    Hollon, Todd C; Price, Richard L.; Kwon, Chang-Hyuk; Chiocca, E. Antonio

    2013-01-01

    Over the last decade, cytomegalovirus (CMV) has been suggested to promote the development of glioblastoma multiforme (GBM). Recent evidence demonstrates that CMV contributes to the progression of GBM in the context of oncosuppressor gene mutations. This finding provides further insights into the mechanisms whereby CMV exacerbates the malignancy of GBM.

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

    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...

  14. Level of Notch activation determines the effect on growth and stem cell-like features in glioblastoma multiforme neurosphere cultures

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

    2013-01-01

    Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in glioblastoma multiforme (GBM) and they are assigned a central role in tumor initiation, progression and relapse. The Notch pathway is important for maintenance and cell fate decisions in the...... normal NSC population. Notch signaling is often deregulated in GBM and recent results suggest that this pathway plays a significant role in bCSC as well. We therefore wished to further elucidate the role of Notch activation in GBM-derived bCSC....

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

    NamPhongNguyen

    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.

  16. 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

    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...

  17. NG2 expression in glioblastoma identifies an actively proliferating population with an aggressive molecular signature

    Al-Mayhani, M. Talal F.; Grenfell, Richard; Narita, Masashi; Piccirillo, Sara; Kenney-Herbert, Emma; Fawcett, James W.; Collins, V. Peter; Ichimura, Koichi; Watts, Colin

    2011-01-01

    Glioblastoma multiforme (GBM) is the most common type of primary brain tumor and a highly malignant and heterogeneous cancer. Current conventional therapies fail to eradicate or curb GBM cell growth. Hence, exploring the cellular and molecular basis of GBM cell growth is vital to develop novel therapeutic approaches. Neuroglia (NG)-2 is a transmembrane proteoglycan expressed by NG2+ progenitors and is strongly linked to cell proliferation in the normal brain. By using NG2 as a biomarker we id...

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

    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...

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

    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...

  20. Does adding FDG-PET to MRI improve the differentiation between primary cerebral lymphoma and glioblastoma? Observer performance study

    It is sometimes difficult to distinguish between primary central nervous system lymphomas (PCNSL) and glioblastoma multiforme (GBM). The aim of this study was to investigate whether the addition of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography ([18F]FDG-PET) and apparent diffusion coefficients (ADC) to conventional MRI improves diagnostic accuracy for distinguishing between PCNSL and GBM with similar MRI findings. We used conventional- and diffusion-weighted MRI and FDG-PET scans of 21 patients with histologically confirmed brain tumors exhibiting similar MRI findings (PCNSL, n=14, GBM, n=7) in our observer performance study that consisted of 3 interpretation sessions. ADC and maximum standard uptake values (SUVmax) of the tumors were calculated. Three radiologists first interpreted conventional MRI (1st session), then they read images to which the ADC value had been added (2nd session), and finally they interpreted images supplemented with SUVmax (3rd session). Observer performance was evaluated using κ statistic and receiver operating characteristics analyses. The addition of ADC values to conventional MRI failed to improve the differentiation between PCNSL and GBM. The addition of SUVmax at the third session improved the diagnostic accuracy of all 3 readers and resulted in higher interobserver agreement; mean accuracy was 95% (range 93-100%). In one observer the accuracy of tumor differentiation was significantly improved at the third compared to the second session (p=0.017). In a selected group of PCNSL and GBM with similar MRI findings, the addition of quantitative FDG-PET to MRI may improve their differentiation. ADC measurement did not allow further discrimination. (author)

  1. Glioblastoma familiar

    Walter O. Arruda

    1995-06-01

    Full Text Available The authors describe a family with three members affected by glioblastoma. The proband patient, a 7 year-old girl, developed a rare complication, a pulmonary metastasis. Chromosomal analysis of her peripheral blood lymphocytes showed a normal karyotype (46, XX, without structural abnormalities. Cytogenetic study of the tumor cells disclosed several abnormalities: 46, XX, 7q - / 46, XX, -2, 4p-, 7p-, +15/ 46, XX. Some aspects about genetics of glial neoplasms are discussed.

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

    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

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

    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

  4. AT-12PHASE 1/2 STUDY OF TH-302, INVESTIGATIONAL HYPOXIA-ACTIVATED PRODRUG, AND BEVACIZUMAB IN PATIENTS WITH BEVACIZUMAB-REFRACTORY RECURRENT GLIOBLASTOMA

    Brenner, Andrew; Floyd, John (S.I.), 1572-1649; Eng, Clarence; Kroll, Stew; Fichtel, Lisa; Gruslova, Aleksandra; Lodi, Alessia; Tiziani, Stefano

    2014-01-01

    BACKGROUND: Hypoxia is implicated in the pathogenesis of glioblastoma multiforme (GBM), and greater hypoxic burden is associated with poorer outcomes in GBM. Treatment with bevacizumab (BEV) may increase intratumoral hypoxia. An ongoing phase 1/2 study (NCT01403610) investigates safety and activity of TH-302, an investigational hypoxia-activated prodrug, combined with BEV in patients with BEV-refractory GBM. METHODS: Single center, dose-escalation, prospective study with 2:1 randomization to ...

  5. Mesenchymal Migration as a Therapeutic Target in Glioblastoma

    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.

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

    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 ...

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

    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...

  8. Metabolic modulation of glioblastoma with dichloroacetate.

    Michelakis, E D; Sutendra, G; Dromparis, P; Webster, L; Haromy, A; Niven, E; Maguire, C; Gammer, T-L; Mackey, J R; Fulton, D; Abdulkarim, B; McMurtry, M S; Petruk, K C

    2010-05-12

    Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma. PMID:20463368

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

    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

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

    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

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

    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.

  12. Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition

    Paul A. Clark

    2012-05-01

    Full Text Available Epidermal growth factor receptor (EGFR signaling is strongly implicated in glioblastoma (GBM tumorigenesis. However, molecular agents targeting EGFR have demonstrated minimal efficacy in clinical trials, suggesting the existence of GBM resistance mechanisms. GBM cells with stem-like properties (CSCs are highly efficient at tumor initiation and exhibit therapeutic resistance. In this study, GBMCSC lines showed sphere-forming and tumor initiation capacity after EGF withdrawal from cell culture media, compared with normal neural stem cells that rapidly perished after EGF withdrawal. Compensatory activation of related ERBB family receptors (ERBB2 and ERBB3 was observed in GBM CSCs deprived of EGFR signal (EGF deprivation or cetuximab inhibition, suggesting an intrinsic GBM resistance mechanism for EGFR-targeted therapy. Dual inhibition of EGFR and ERBB2 with lapatinib significantly reduced GBM proliferation in colony formation assays compared to cetuximab-mediated EGFR-specific inhibition. Phosphorylation of downstream ERBB signaling components (AKT, ERK1/2 and GBM CSC proliferation were inhibited by lapatinib. Collectively, these findings show that GBM therapeutic resistance to EGFR inhibitors may be explained by compensatory activation of EGFR-related family members (ERBB2, ERBB3 enabling GBM CSC proliferation, and therefore simultaneous blockade of multiple ERBB family members may be required for more efficacious GBM therapy.

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

    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. 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. 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 < 0.05) when compared with the rats injected only with gliomas or with gliomas plus inactivated apyrase. According to the pathological analysis, the malignant gliomas induced by C6 injection and co-injected with apyrase presented a significant reduction in the mitotic index and other histological characteristics that indicate a less invasive/proliferative tumor. Reduction of proliferation induced by apyrase co-injection was confirmed by counting the percentage of Ki67 positive glioma cell nuclei. According to counts with CD31, vessel density and neoformation was higher in the C6 group 20 days after implantation. Confirming this observation, rats treated with apyrase presented less VEGF staining in comparison to the control group. These results

  14. Bevacizumab for the Treatment of Recurrent Glioblastoma

    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...

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

    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.

  16. Morphine modulates doxorubicin uptake and improves efficacy of chemotherapy in an intracranial xenograft model of human glioblastoma

    da Ros, Martina; Iorio, Anna Lisa; Consolante, Dario; Cardile, Francesco; Muratori, Monica; Fantappiè, Ornella; Lucchesi, Maurizio; Guidi, Milena; Pisano, Claudio; Sardi, Iacopo

    2016-01-01

    Morphine may alter the permeability of Blood-Brain Barrier (BBB), enhancing the access of molecules normally unable to cross it, as Doxorubicin (Dox). In addition, morphine seems to mediate the uptake of Dox into the brain by its reduced efflux mediated by P-glycoprotein (P-gp). We evaluated the antitumor efficacy of Dox plus morphine treatment by an orthotopic glioblastoma xenograft model. Foxn1 mice were injected with U87MG-luc cells in the left lobe of the brain and treated with Dox (5 mg/kg and 2.5 mg/kg, weekly) with or without morphine pretreatment (10 mg/kg, weekly). Bioluminescence imaging (BLI) was used to monitoring tumor growth and response to therapy. Additionally, we investigated the role of morphine on the uptake of Dox by MDCKII cells transfected with human MDR1 gene encoding for P-gp. The data demonstrate that only Dox 5 mg/kg determined a significant tumor regression while the lower dose (2.5 mg/kg) was not effective. However, if combined with morphine, the group treated with Dox 2.5 mg/kg showed a decreasing tumor growth. The average BLI for Dox 2.5 mg/kg plus morphine was 5 fold lower than Dox 2.5 mg/kg alone (P=0.0053) and 8 fold lower than vehicle (P=0.0004). Additionally, Dox increased in MDCKII-P-gp transfected cells only in the presence of morphine with a significantly higher level comparing control group (3.84) vs Dox plus morphine group (12.29, P<0.05). Our results indicate that Dox alone and in combination with morphine appear to be effective in controlling the growth of glioblastoma in a xenograft mouse model. PMID:27152241

  17. Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy.

    Masayuki Nitta

    Full Text Available Despite the critical role of Epidermal Growth Factor Receptor (EGFR in glioblastoma pathogenesis, EGFR targeted therapies have achieved limited clinical efficacy. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII, an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER genes required for the repair of Reactive Oxygen Species (ROS-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1. Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.

  18. Involvement of Akt/NF-κB pathway in antitumor effects of parthenolide on glioblastoma cells in vitro and in vivo

    Glioblastoma is the most common and most aggressive form of malignant glioma and is very difficult to treat. Controlling tumour cell invasion and angiogenesis is essential to improve the prognosis of glioblastoma patients. Since constitutive activation of nuclear factor-κB (NF-κB) is necessary for tumour progression, NF-κB may be an important pharmacological target for this disease. Our study aimed to evaluate the antitumour effects of parthenolide, a NF-κB inhibitor, in two human glioblastoma cell lines (U87MG and U373) and in glioblastoma xenografts. Furthermore, we aimed to investigate the molecular mechanisms underlying these effects. The anti-invasive and anti-angiogenic effects of parthenolide were analysed using in vitro invasion and angiogenesis assays. Parthenolide-induced growth inhibition of glioblastoma cells in vitro was determined using the MTT (methyl thiazolyl tetrazolium) assay. In addition, the effect of parthenolide on orthotropic implantation in vivo was evaluated using an intracerebral human glioblastoma xenograft model. We found that parthenolide suppresses proliferation, invasion, and tumour- induced angiogenesis of glioblastoma cells. Molecular studies demonstrated that parthenolide suppresses gene and protein expression of angiogenic factors. Furthermore, parthenolide reduced Akt phosphorylation and activated mitochondrial signalling, suggesting that the antitumour function of parthenolide may be mediated not only by the inhibition of NF-κB but also by the inhibition of Akt signalling and the activation of apoptotic proteins. Parthenolide suppressed neovascularity and tumour growth in glioblastoma xenografts. The present study identified parthenolide as a new therapeutic agent for glioblastomas

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

    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

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

    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.

  1. 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

    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.

  2. Activation of Multiple ERBB Family Receptors Mediates Glioblastoma Cancer Stem-like Cell Resistance to EGFR-Targeted Inhibition12

    Clark, Paul A.; Iida, Mari; Daniel M. Treisman; Kalluri, Haviryaji; Ezhilan, Sathyapriya; Zorniak, Michael; Deric L. Wheeler; Kuo, John S.

    2012-01-01

    Epidermal growth factor receptor (EGFR) signaling is strongly implicated in glioblastoma (GBM) tumorigenesis. However, molecular agents targeting EGFR have demonstrated minimal efficacy in clinical trials, suggesting the existence of GBM resistance mechanisms. GBM cells with stem-like properties (CSCs) are highly efficient at tumor initiation and exhibit therapeutic resistance. In this study, GBMCSC lines showed sphere-forming and tumor initiation capacity after EGF withdrawal from cell cultu...

  3. Planned activities to improve safety

    This document presents the fulfilling of the Brazilian obligations under the Convention on Nuclear Safety. The Chapter 6 of the document contains some details about the planed activities to safety improvements

  4. Multiple extraneural metastasis of glioblastoma multiforme

    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.

  5. Stereotactic Radiosurgery for Glioblastoma.

    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

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

    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. PMID:21813511

  7. Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma

    Recent studies have shown a survival benefit for patients with recurrent glioblastomas treated with stereotactic brachytherapy. On the basis of these encouraging results, we began a prospective study in 1987 to evaluate the use of brachytherapy in patients with newly diagnosed glioblastoma. Patients were considered eligible for this study if they met the following criteria: Karnofsky performance status 70% or greater; tumor size not greater than 5 cm in any dimension; a radiographically well delineated, supratentorial lesion not involving the ependymal surfaces; and pathologically confirmed glioblastoma. We treated 35 such patients between 1987 and 1990 with stereotactic brachytherapy as part of their initial therapy. The treatment protocol involved surgery, partial brain external-beam radiotherapy, and stereotactic brachytherapy with temporary high-activity iodine 125 sources giving an additional 50 Gy to the tumor bed. Chemotherapy was not used in the initial management of these 35 patients. To compare our results with those obtained in a matched control group, we identified 40 patients with glioblastoma treated with surgery and external radiotherapy, with or without chemotherapy, between 1977 and 1986 at our institution. These patients had clinical and radiographic characteristics that would have made them eligible for the brachytherapy protocol. Survival rates at 1 and 2 years after diagnosis were 87% and 57%, respectively, for patients receiving brachytherapy versus 40% and 12.5%, respectively, for the controls (P less than .001). We conclude that stereotactic brachytherapy improves the survival of patients with glioblastoma when it can be incorporated into the initial treatment approach. Unfortunately, only about one in four patients with glioblastoma are suitable candidates for brachytherapy at the time of initial presentation

  8. Improved Active Vibration Isolation Systems

    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.

  9. Direct effect of bevacizumab on glioblastoma cell lines in vitro.

    Simon, Thomas; Coquerel, Bérénice; Petit, Alexandre; Kassim, Yusra; Demange, Elise; Le Cerf, Didier; Perrot, Valérie; Vannier, Jean-Pierre

    2014-12-01

    Bevacizumab is a humanized monoclonal antibody directed against the pro-angiogenic factor vascular and endothelial growth factor-A (VEGF-A) used in the treatment of glioblastomas. Although most patients respond initially to this treatment, studies have shown that glioblastomas eventually recur. Several non-mutually exclusive theories based on the anti-angiogenic effect of bevacizumab have been proposed to explain these mechanisms of resistance. In this report, we studied whether bevacizumab can act directly on malignant glioblastoma cells. We observe changes in the expression profiles of components of the VEGF/VEGF-R pathway and in the response to a VEGF-A stimulus following bevacizumab treatment. In addition, we show that bevacizumab itself acts on glioblastoma cells by activating the Akt and Erks survival signaling pathways. Bevacizumab also enhances proliferation and invasiveness of glioblastoma cells in hyaluronic acid hydrogel. We propose that the paradoxical effect of bevacizumab on glioblastoma cells could be due to changes in the VEGF-A-dependent autocrine loop as well as in the intracellular survival pathways, leading to the enhancement of tumor aggressiveness. Investigation of how bevacizumab interacts with glioblastoma cells and the resulting downstream signaling pathways will help targeting populations of resistant glioblastoma cells. PMID:25113866

  10. Cytomegalovirus and glioblastoma; controversies and opportunities.

    Lawler, Sean E

    2015-07-01

    One of the more polarized ongoing debates in the brain tumor field over recent years has centered on the association of cytomegalovirus (CMV) with glioblastoma. Several laboratories have reported the presence of CMV antigens in glioblastoma patient specimens, whereas others have failed to detect them. CMV genomic DNA and mRNAs have been detected by PCR, but not in next-generation sequencing studies. CMV promotes high grade glioma progression in a mouse genetic model, and many CMV proteins promote cancer hallmarks in vitro, but actively replicating virus has not been isolated from tumor samples. A consensus is gradually emerging in which the presence of CMV antigens in glioblastoma is increasingly accepted. However, it remains challenging to understand this mechanistically due to the low levels of CMV nucleic acids and the absence of viral replication observed in tumors thus far. Nonetheless, these observations have inspired the development of novel therapeutic approaches based on anti-viral drugs and immunotherapy. The potential benefit of valganciclovir in glioblastoma has generated great interest, but efficacy remains to be established in a randomized trial. Also, early stage immunotherapy trials targeting CMV have shown promise. In the near future we will know more answers to these questions, and although areas of controversy may remain, and the mechanisms and roles of CMV in tumor growth are yet to be clearly defined, this widespread virus may have created important new therapeutic concepts and opportunities for the treatment of glioblastoma. PMID:25682092

  11. Emerging Biomarkers in Glioblastoma

    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.

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

    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.

  13. Why Is There a Lack of Consensus on Molecular Subgroups of Glioblastoma? Understanding the Nature of Biological and Statistical Variability in Glioblastoma Expression Data

    Nicholas F. Marko; Quackenbush, John; Weil, Robert J.

    2011-01-01

    Introduction Gene expression patterns characterizing clinically-relevant molecular subgroups of glioblastoma are difficult to reproduce. We suspect a combination of biological and analytic factors confounds interpretation of glioblastoma expression data. We seek to clarify the nature and relative contributions of these factors, to focus additional investigations, and to improve the accuracy and consistency of translational glioblastoma analyses. Methods We analyzed gene expression and clinica...

  14. Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells

    Tahmasebi Mirgani M

    2014-01-01

    Full Text Available Maryam Tahmasebi Mirgani,1 Benedetta Isacchi,2 Majid Sadeghizadeh,1,* Fabio Marra,3 Anna Rita Bilia,2,* Seyed Javad Mowla,1 Farhood Najafi,4 Esmael Babaei51Department of Genetics, Tarbiat Modares University, Tehran, Iran; 2Department of Chemistry, University of Florence, Sesto Fiorentino, Italy; 3Department of Experimental and Clinical Medicine, University of Florence, Italy; 4Department of Resin and Additives, Institute for Color Science and Technology, Tehran, Iran; 5Department of Biology, University of Tabriz, Tabriz, Iran*These authors contributed equally to this workAbstract: Glioblastoma is an invasive tumor of the central nervous system. Tumor recurrence resulting from ineffective current treatments, mainly due to the blood–brain barrier, highlights the need for innovative therapeutic alternatives. The recent availability of nanotechnology represents a novel targeted strategy in cancer therapy. Natural products have received considerable attention for cancer therapy because of general lower side effects. Curcumin is a new candidate for anticancer treatment, but its low bioavailability and water solubility represent the main disadvantages of its use. Here, curcumin was efficiently encapsulated in a nontoxic nanocarrier, termed dendrosome, to overcome these problems. Dendrosomal curcumin was prepared as 142 nm spherical structures with constant physical and chemical stability. The inhibitory role of dendrosomal curcumin on the proliferation of U87MG cells, a cellular model of glioblastoma, was evaluated by considering master genes of pluripotency and regulatory miRNA (microribonucleic acid. Methylthiazol tetrazolium assay and flow cytometry were used to detect the antiproliferative effects of dendrosomal curcumin. Annexin-V-FLUOS and caspase assay were used to quantify apoptosis. Real-time polymerase chain reaction was used to analyze the expression of OCT4 (octamer binding protein 4 gene variants (OCT4A, OCT4B, and OCT4B1, SOX-2 (SRY

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

    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

  16. Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells.

    Tahmasebi Mirgani, Maryam; Isacchi, Benedetta; Sadeghizadeh, Majid; Marra, Fabio; Bilia, Anna Rita; Mowla, Seyed Javad; Najafi, Farhood; Babaei, Esmael

    2014-01-01

    Glioblastoma is an invasive tumor of the central nervous system. Tumor recurrence resulting from ineffective current treatments, mainly due to the blood-brain barrier, highlights the need for innovative therapeutic alternatives. The recent availability of nanotechnology represents a novel targeted strategy in cancer therapy. Natural products have received considerable attention for cancer therapy because of general lower side effects. Curcumin is a new candidate for anticancer treatment, but its low bioavailability and water solubility represent the main disadvantages of its use. Here, curcumin was efficiently encapsulated in a nontoxic nanocarrier, termed dendrosome, to overcome these problems. Dendrosomal curcumin was prepared as 142 nm spherical structures with constant physical and chemical stability. The inhibitory role of dendrosomal curcumin on the proliferation of U87MG cells, a cellular model of glioblastoma, was evaluated by considering master genes of pluripotency and regulatory miRNA (microribonucleic acid). Methylthiazol tetrazolium assay and flow cytometry were used to detect the antiproliferative effects of dendrosomal curcumin. Annexin-V-FLUOS and caspase assay were used to quantify apoptosis. Real-time polymerase chain reaction was used to analyze the expression of OCT4 (octamer binding protein 4) gene variants (OCT4A, OCT4B, and OCT4B1), SOX-2 (SRY [sex determining region Y]-box 2), Nanog, and miR-145. Dendrosomal curcumin efficiently suppresses U87MG cells growth with no cytotoxicity related to dendrosome. Additionally, the accumulation of cells in the SubG1 phase was observed in a time- and dose-dependent manner as well as higher rates of apoptosis after dendrosomal curcumin treatment. Conversely, nonneoplastic cells were not affected by this formulation. Dendrosomal curcumin significantly decreased the relative expression of OCT4A, OCT4B1, SOX-2, and Nanog along with noticeable overexpression of miR-145 as the upstream regulator. This suggests

  17. Coordination of glioblastoma cell motility by PKCι

    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

  18. Irinotecan and Bevacizumab in Glioblastoma-A Review

    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.

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

    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...

  20. 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.

    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...

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

    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

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

    CHEN, CHIEN-MIN; SYU, JHIH-PU; WAY, TZONG-DER; HUANG, LI-JIAU; KUO, SHENG-CHU; LIN, CHUNG-TIEN; LIN, CHIH-LI

    2015-01-01

    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. PMID:26329365

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

    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...

  4. Immunological Evasion in Glioblastoma

    Magaña-Maldonado, Roxana; Chávez-Cortez, Elda Georgina; Olascoaga-Arellano, Nora Karen; López-Mejía, Mariana; Maldonado-Leal, Fernando Manuel; Sotelo, Julio

    2016-01-01

    Glioblastoma is the most aggressive tumor in Central Nervous System in adults. Among its features, modulation of immune system stands out. Although immune system is capable of detecting and eliminating tumor cells mainly by cytotoxic T and NK cells, tumor microenvironment suppresses an effective response through recruitment of modulator cells such as regulatory T cells, monocyte-derived suppressor cells, M2 macrophages, and microglia as well as secretion of immunomodulators including IL-6, IL-10, CSF-1, TGF-β, and CCL2. Other mechanisms that induce immunosuppression include enzymes as indolamine 2,3-dioxygenase. For this reason it is important to develop new therapies that avoid this immune evasion to promote an effective response against glioblastoma. PMID:27294132

  5. Immunological Evasion in Glioblastoma

    Roxana Magaña-Maldonado

    2016-01-01

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

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

    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.

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

    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

  8. Motor Activity Improves Temporal Expectancy

    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 hypothe- sis, 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 consis...

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

    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.

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

    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

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

    Surgical resection followed by radiotherapy and temozolomide in newly diagnosed glioblastoma can prolong survival, but it is not curative. For patients with disease progression after frontline therapy, there is no standard of care, although further surgery, chemotherapy, and radiotherapy may be used. Antiangiogenic therapies may be appropriate for treating glioblastomas because angiogenesis is critical to tumor growth. In a large, noncomparative phase II trial, bevacizumab was evaluated alone and with irinotecan in patients with recurrent glioblastoma; combination treatment was associated with an estimated 6-month progression-free survival (PFS) rate of 50.3%, a median overall survival of 8.9 months, and a response rate of 37.8%. Single-agent bevacizumab also exceeded the predetermined threshold of activity for salvage chemotherapy (6-month PFS rate, 15%), achieving a 6-month PFS rate of 42.6% (p < 0.0001). On the basis of these results and those from another phase II trial, the US Food and Drug Administration granted accelerated approval of single-agent bevacizumab for the treatment of glioblastoma that has progressed following prior therapy. Potential antiangiogenic agents-such as cilengitide and XL184-also show evidence of single-agent activity in recurrent glioblastoma. Moreover, the use of antiangiogenic agents with radiation at disease progression may improve the therapeutic ratio of single-modality approaches. Overall, these agents appear to be well tolerated, with adverse event profiles similar to those reported in studies of other solid tumors. Further research is needed to determine the role of antiangiogenic therapy in frontline treatment and to identify the optimal schedule and partnering agents for use in combination therapy

  12. IMPROVING CAUSE DETECTION SYSTEMS WITH ACTIVE LEARNING

    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. How I treat glioblastoma in older patients.

    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

  14. Dopamine signaling: target in glioblastoma

    Bartek, Jiří; Hodný, Zdeněk

    2014-01-01

    Roč. 5, č. 5 (2014), 1116-1117. ISSN 1949-2553 Institutional support: RVO:68378050 Keywords : Dopamine signaling * glioblastoma * MAPK Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.359, year: 2014

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

    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...

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

    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...

  17. DD-02PHARMACODYNAMIC BIOMARKER ASSESSMENTS IN A PHASE I/II TRIAL OF THE HYPOXIA-ACTIVATED PRODRUG TH-302 AND BEVACIZUMAB IN BEVACIZUMAB-REFRACTORY RECURRENT GLIOBLASTOMA

    Cavazos, David; Gruslova, Aleksandra; Sun, J.; Floyd, John R.; Fichtel, Lisa; Tadi, Surendar; Lodi, Alessia; Tiziani, Stefano; van der Hart, C.P.; Eng, Clarence; Brenner, Andrew

    2014-01-01

    BACKGROUND: Glioblastoma (GBM) remains an incurable malignancy with rapid progression and poor survival. GBM exhibits a hypoxic nature, and treatment with bevacizumab (BEV) may increase intratumoral hypoxia. TH-302 is an investigational prodrug that selectively releases the DNA cross-linker (Br-IPM) under hypoxic conditions. A phase I/II trial (NCT01403610) is evaluating the safety and efficacy of combined TH-302 and BEV treatment in patients with BEV-refractory GBM and investigating pharmaco...

  18. Lactate levels with glioblastoma multiforme.

    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

  19. Recurrent Glioblastoma: Where we stand

    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...

  20. Neural Stem Cells and Glioblastoma

    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...

  1. Lactate levels with glioblastoma multiforme

    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 ...

  2. Physical Activity Improves Quality of Life

    ... 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 ...

  3. 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?

    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

  4. 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?

    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

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

    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

  6. Supratentorial glioblastoma multiforme with spinal metastases

    Abhidha Shah

    2010-01-01

    Full Text Available Glioblastoma multiforme is the most common malignant brain tumor in adults. Metastasis of intracranial glioblastoma via the cerebrospinal fluid to the spine is a rare occurrence. We present two cases of glioblastoma multiforme with spinal leptomeningeal spread who presented with back pain and paraparesis.

  7. Software Engineering Improvement Activities/Plan

    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.

  8. Glioblastoma with spinal seeding

    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.)

  9. Glioblastoma with spinal seeding

    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.)

  10. 5-ALA based photodynamic management of glioblastoma

    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.

  11. Titanocene Difluorides with Improved Cytotoxic Activity

    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.

  12. Activities toward PSA quality improvement in Japan

    PSA of adequate quality is indispensable for expanding the field of risk-informed plant management. Activities to construct framework of improving PSA quality in Japan, such as arrangement of PSA standard, adopting parameters based on operational experience of Japanese NPPs, and implementation of PSA peer review, are in progress. (author)

  13. Chimeric enzymes with improved cellulase activities

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

    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.

  15. Combination treatment with fasudil and clioquinol produces synergistic anti-tumor effects in U87 glioblastoma cells by activating apoptosis and autophagy.

    He, Mingliang; Luo, Ming; Liu, Qingyu; Chen, Jingkao; Li, Kaishu; Zheng, Meiguang; Weng, Yinlun; Ouyang, Leping; Liu, Anmin

    2016-04-01

    Survival of patients with glioblastoma (GBM) remains poor, and novel treatment methods are urgently needed. In this study, we tested the effects of a combination of fasudil, a ROCK inhibitor, and clioquinol, an 8-hydroxyquinoline derivative with antimicrobial properties, on human GBM U87 cells. Combination treatment synergistically inhibited the viability of glioma cells but not mouse normal neuron HT22 cells and significantly induced mitochondria-mediated apoptosis. Moreover, the combination was also found to trigger macro-autophagy (henceforth referred to as autophagy) by increasing the expression levels of several proteins involved in the induction of autophagy. Further studies showed that 3-methyladenine (3-MA) or chloroquine (CQ), two autophagy inhibitors, abrogated the cytotoxic effects of the combination treatment as well as the autophagy. Overall, we demonstrated that fasudil and clioquinol show synergistic anti-cancer effects, providing evidence for the further development of combination therapy for GBM. PMID:26725099

  16. Corticosteroids compromise survival in glioblastoma.

    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

  17. A paired comparison between glioblastoma "stem cells" and differentiated cells.

    Schneider, Matthias; Ströbele, Stephanie; Nonnenmacher, Lisa; Siegelin, Markus D; Tepper, Melanie; Stroh, Sebastien; Hasslacher, Sebastian; Enzenmüller, Stefanie; Strauss, Gudrun; Baumann, Bernd; Karpel-Massler, Georg; Westhoff, Mike-Andrew; Debatin, Klaus-Michael; Halatsch, Marc-Eric

    2016-04-01

    Cancer stem cells (CSC) have been postulated to be responsible for the key features of a malignancy and its maintenances, as well as therapy resistance, while differentiated cells are believed to make up the rapidly growing tumour bulk. It is therefore important to understand the characteristics of those two distinct cell populations in order to devise treatment strategies which effectively target both cohorts, in particular with respect to cancers, such as glioblastoma. Glioblastoma is the most common primary brain tumour in adults, with a mean patient survival of 12-15 months. Importantly, therapeutic improvements have not been forthcoming in the last decade. In this study we compare key features of three pairs of glioblastoma cell populations, each pair consisting of stem cell-like and differentiated cells derived from an individual patient. Our data suggest that while growth rates and expression of key survival- and apoptosis-mediating proteins are more similar according to differentiation status than genetic similarity, we found no intrinsic differences in response to standard therapeutic interventions, namely exposure to radiation or the alkylating agent temozolomide. Interestingly, we could demonstrate that both stem cell-like and differentiated cells possess the ability to form stem cell-containing tumours in immunocompromised mice and that differentiated cells could potentially be dedifferentiated to potential stem cells. Taken together our data suggest that the differences between tumour stem cell and differentiated cell are particular fluent in glioblastoma. PMID:26519239

  18. Role of bevacizumab therapy in the management of glioblastoma

    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

  19. Effectiveness of Radiotherapy for Elderly Patients With Glioblastoma

    Purpose: Radiotherapy plays a central role in the definitive treatment of glioblastoma. However, the optimal management of elderly patients with glioblastoma remains controversial, as the relative benefit in this patient population is unclear. To better understand the role that radiation plays in the treatment of glioblastoma in the elderly, we analyzed factors influencing patient survival using a large population-based registry. Methods and Materials: A total of 2,836 patients more than 70 years of age diagnosed with glioblastoma between 1993 and 2005 were identified from the Surveillance, Epidemiology, and End Results (SEER) registry. Demographic and clinical variables used in the analysis included gender, ethnicity, tumor size, age at diagnosis, surgery, and radiotherapy. Cancer-specific survival and overall survival were evaluated using the Kaplan-Meier method. Univariate and multivariate analysis were performed using Cox regression. Results: Radiotherapy was administered in 64% of these patients, and surgery was performed in 68%. Among 2,836 patients, 46% received surgery and radiotherapy, 22% underwent surgery only, 18% underwent radiotherapy only, and 14% did not undergo either treatment. The median survival for patients who underwent surgery and radiotherapy was 8 months. The median survival for patients who underwent radiotherapy only was 4 months, and for patients who underwent surgery only was 3 months. Those who received neither surgery nor radiotherapy had a median survival of 2 months (p < 0.001). Multivariate analysis showed that radiotherapy significantly improved cancer-specific survival (hazard ratio [HR], 0.43, 95% confidence interval [CI] 0.38-0.49) after adjusting for surgery, tumor size, gender, ethnicity, and age at diagnosis. Other factors associated with Cancer-specific survival included surgery, tumor size, age at diagnosis, and ethnicity. Analysis using overall survival as the endpoint yielded very similar results. Conclusions: Elderly

  20. Activized Learning: Transforming Passive to Active with Improved Label Complexity

    Hanneke, Steve

    2011-01-01

    We study the theoretical advantages of active learning over passive learning. Specifically, we prove that, in noise-free classifier learning for VC classes, any passive learning algorithm can be transformed into an active learning algorithm with asymptotically strictly superior label complexity for all nontrivial target functions and distributions. We further provide a general characterization of the magnitudes of these improvements in terms of a novel generalization of the disagreement coeff...

  1. Ecological Factors Improving Efficiency of Business Activities

    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...

  2. Irinotecan and bevacizumab in recurrent glioblastoma multiforme

    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...

  3. Sorafenib induces growth arrest and apoptosis of human glioblastoma cells via dephosphorylation of STAT3

    Yang, Fan; Brown, Christine; Buettner, Ralf; HEDVAT, MICHAEL; Starr, Renate; Scuto, Anna; Schroeder, Anne; Jensen, Michael; Jove, Richard

    2010-01-01

    Glioblastoma is the most common type of primary brain tumor and is rapidly progressive with few treatment options. Here, we report that sorafenib (≤ 10 μM) inhibited cell proliferation and induced apoptosis in two established cell lines (U87, U251) and two primary cultures (PBT015, PBT022) from human glioblastomas. Effects of sorafenib on these tumor cells were associated with inhibiting phosphorylated STAT3 (Tyr705). Expression of a constitutively activated STAT3 mutant partially blocked the...

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

    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. Label-free microscopic assessment of glioblastoma biopsy specimens prior to biobanking [corrected].

    Georges, Joseph; Zehri, Aqib; Carlson, Elizabeth; Nichols, Joshua; Mooney, Michael A; Martirosyan, Nikolay L; Ghaffari, Layla; Kalani, M Yashar S; Eschbacher, Jennifer; Feuerstein, Burt; Anderson, Trent; Preul, Mark C; Van Keuren-Jensen, Kendall; Nakaji, Peter

    2014-02-01

    Glioblastoma is the most common primary brain tumor with a median 12- to 15-month patient survival. Improving patient survival involves better understanding the biological mechanisms of glioblastoma tumorigenesis and seeking targeted molecular therapies. Central to furthering these advances is the collection and storage of surgical biopsies (biobanking) for research. This paper addresses an imaging modality, confocal reflectance microscopy (CRM), for safely screening glioblastoma biopsy samples prior to biobanking to increase the quality of tissue provided for research and clinical trials. These data indicate that CRM can immediately identify cellularity of tissue biopsies from animal models of glioblastoma. When screening fresh human biopsy samples, CRM can differentiate a cellular glioblastoma biopsy from a necrotic biopsy without altering DNA, RNA, or protein expression of sampled tissue. These data illustrate CRM's potential for rapidly and safely screening clinical biopsy samples prior to biobanking, which demonstrates its potential as an effective screening technique that can improve the quality of tissue biobanked for patients with glioblastoma. PMID:24484261

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

    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. Ecological Factors Improving Efficiency of Business Activities

    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.

  8. The Study of Glioblastoma Differentiation Possibility

    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.

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

    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

    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.

    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. Epigenetic pathways and glioblastoma treatment

    Clarke, Jennifer; Penas, Clara; Pastori, Chiara; Komotar, Ricardo J.; Bregy, Amade; Shah, Ashish H; Wahlestedt, Claes; Ayad, Nagi G.

    2013-01-01

    Glioblastoma multiforme (GBM) is the most common malignant adult brain tumor. Standard GBM treatment includes maximal safe surgical resection with combination radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. Alarmingly, patient survival at five-years is below 10%. This is in part due to the invasive behavior of the tumor and the resulting inability to resect greater than 98% of some tumors. In fact, recurrence after such treatment may be inevitable, even in cases where gross total r...

  13. Statin use and survival following glioblastoma multiforme

    Gaist, David; Hallas, Jesper; Friis, Søren; Hansen, Steinbjørn; Sørensen, Henrik Toft

    2014-01-01

    glioblastoma multiforme (GBM). METHODS: We identified 1562 patients diagnosed with GBM during 2000-2009 from the Danish Cancer Registry and linked this cohort to Danish nationwide demographic and health registries. Within the GBM cohort, each patient recorded as using statins prior to diagnosis (defined as ≥2......-cause death associated with prediagnostic statin use. RESULTS: A total of 339 GBM patients were included in the analyses. Of these, 325 died during median follow-up of 6.9 months (interquartile range: 3.8-13.4 months). Prediagnostic statin use was associated with a reduced HR of death (0.79; 95% CI: 0......% CI: 0.63-1.01). CONCLUSION: Long-term prediagnostic statin use may improve survival following GBM....

  14. Spatiotemporal Evolution of the Primary Glioblastoma Genome.

    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

  15. Cases of glioblastoma multiforme metastasizing to spinal cord

    Karaca Metehan

    2006-01-01

    Full Text Available Cases of glioblastoma multiforme (GBM metastasizing to the leptomeninx or the intramedullary spine are quite rare and prognoses are relatively poor. We present three cases of GBM with spinal metastasis, one of which also had leptomeningeal dissemination. Three patients with GBM were admitted to our clinic for postoperative radiotherapy after surgery. Leptomeningeal metastasis and dissemination were diagnosed with magnetic resonance imaging. Radiotherapy provided only temporary relief from pain with small improvement in neurological deficit but no survival advantage.

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

    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...

  17. Clonal evolution of glioblastoma under therapy.

    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

  18. Amnesia due to bilateral hippocampal glioblastoma

    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.)

  19. Glioblastoma Multiforme: Relationship to Subventricular Zone and Recurrence

    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...

  20. Network Modeling Identifies Patient-specific Pathways in Glioblastoma

    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

  1. Current concepts in glioblastoma imaging

    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.

  2. Evolving Molecular Genetics of Glioblastoma

    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...

  3. TSPO Imaging in Glioblastoma Multiforme

    Jensen, Per; Feng, Ling; Law, Ian; Svarer, Claus; Knudsen, Gitte M; Mikkelsen, Jens D; de Nijs, Robin; Larsen, Vibeke A; Dyssegaard, Agnete; Thomsen, Gerda; Fischer, Walter; Guilloteau, Denis; Pinborg, Lars H

    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...

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

    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...

  5. Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma.

    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

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

    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

  7. MicroRNA involvement in glioblastoma pathogenesis

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

  8. Saponin 1 Induces Apoptosis and Suppresses NF-κB-Mediated Survival Signaling in Glioblastoma Multiforme (GBM)

    Li, Juan; Tang, Haifeng; Zhang, Yun; Tang, Chi; Li, Bo; Wang, Yuangang; Gao, Zhenhui; Luo, Peng; Yin, Anan; Wang, Xiaoyang; Cheng, Guang; Fei, Zhou

    2013-01-01

    Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells) and human hepatocellular carcinoma (Hep-G2 cells). Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM) U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhi...

  9. Strategies in Gene Therapy for Glioblastoma

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

    2013-10-22

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

  10. Strategies in Gene Therapy for Glioblastoma

    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

  11. Advanced case of glioblastoma multiforme and pregnancy

    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...

  12. Current data and strategy in glioblastoma multiforme

    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...

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

    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

  14. Developing a Novel Embryo-Larval Zebrafish Xenograft Assay to Prioritize Human Glioblastoma Therapeutics.

    Wehmas, Leah Christine; Tanguay, Robert L; Punnoose, Alex; Greenwood, Juliet A

    2016-08-01

    Glioblastoma is an aggressive brain cancer requiring improved treatments. Existing methods of drug discovery and development require years before new therapeutics become available to patients. Zebrafish xenograft models hold promise for prioritizing drug development. We have developed an embryo-larval zebrafish xenograft assay in which cancer cells are implanted in a brain microenvironment to discover and prioritize compounds that impact glioblastoma proliferation, migration, and invasion. We illustrate the utility of our assay by evaluating the well-studied, phosphatidylinositide 3-kinase inhibitor LY294002 and zinc oxide nanoparticles (ZnO NPs), which demonstrate selective cancer cytotoxicity in cell culture, but the in vivo effectiveness has not been established. Exposures of 3.125-6.25 μM LY294002 significantly decreased proliferation up to 34% with concentration-dependent trends. Exposure to 6.25 μM LY294002 significantly inhibited migration/invasion by ∼27% within the glioblastoma cell mass (0-80 μm) and by ∼32% in the next distance region (81-160 μm). Unexpectedly, ZnO enhanced glioblastoma proliferation by ∼19% and migration/invasion by ∼35% at the periphery of the cell mass (161+ μm); however, dissolution of these NPs make it difficult to discern whether this was a nano or ionic effect. These results demonstrate that we have a short, relevant, and sensitive zebrafish-based assay to aid glioblastoma therapeutic development. PMID:27158859

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

    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.

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

    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 ...

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

    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.

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

    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.

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

    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

  20. Cyclin G2 Promotes Hypoxia- Driven Local Invasion of Glioblastoma by Orchestrating Cytoskeletal Dynamics

    Atsushi Fujimura

    2013-11-01

    Full Text Available Microenvironmental conditions such as hypoxia potentiate the local invasion of malignant tumors including glioblastomas by modulating signal transduction and protein modification, yet the mechanism by which hypoxia controls cytoskeletal dynamics to promote the local invasion is not well defined. Here, we show that cyclin G2 plays pivotal roles in the cytoskeletal dynamics in hypoxia-driven invasion by glioblastoma cells. Cyclin G2 is a hypoxia-induced and cytoskeleton-associated protein and is required for glioblastoma expansion. Mechanistically, cyclin G2 recruits cortactin to the juxtamembrane through its SH3 domain-binding motif and consequently promotes the restricted tyrosine phosphorylation of cortactin in concert with src. Moreover, cyclin G2 interacts with filamentous actin to facilitate the formation of membrane ruffles. In primary glioblastoma, cyclin G2 is abundantly expressed in severely hypoxic regions such as pseudopalisades, which consist of actively migrating glioma cells. Furthermore, we show the effectiveness of dasatinib against hypoxia-driven, cyclin G2-involved invasion in vitro and in vivo. Our findings elucidate the mechanism of cytoskeletal regulation by which severe hypoxia promotes the local invasion and may provide a therapeutic target in glioblastoma.

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

    Michaelsen, Signe Regner; Christensen, Ib Jarle; Grunnet, Kirsten; Stockhausen, Marie-Thérése; Broholm, Helle; Kosteljanetz, Michael; Poulsen, Hans Skovgaard

    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...

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

    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.

  3. Research reactor management. Safety improvement activities in HANARO

    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)

  4. Epithelioid/rhabdoid glioblastoma: a highly aggressive subtype of glioblastoma.

    Sugimoto, Kazutaka; Ideguchi, Makoto; Kimura, Tokuhiro; Kajiwara, Koji; Imoto, Hirochika; Sadahiro, Hirokazu; Ishii, Aya; Kawano, Hiroo; Ikeda, Eiji; Suzuki, Michiyasu

    2016-04-01

    Epithelioid glioblastoma (GBM) and rhabdoid GBM are rare variants that are morphologically similar, but there is no consensus on the characteristics of each disease. These tumors have aggressive features of early recurrence and leptomeningeal dissemination and tend to develop in younger patients compared to typical GBM. The prognosis is normally worse than typical GBM, even with intensive chemoradiotherapy after surgical resection. Thus, accurate diagnosis and effective therapy for epithelioid/rhabdoid GBM are required. Four consecutive patients aged 16-48 years were diagnosed with epithelioid/rhabdoid GBM by pathological and immunohistochemical analysis at Yamaguchi University Hospital from 2006 to 2012. Two of these patients had relatively long-term survival (19 and 23 months after diagnosis). Two cases had a BRAF V600E mutation, whereas no ATRX mutation was present in any cases. All patients suffered leptomeningeal and/or spinal dissemination that worsened their prognosis. These results illustrate the need for a new therapeutic approach, such as molecular targeted drug therapy like BRAF inhibition, in addition to standard chemoradiotherapy for typical GBM. PMID:26667174

  5. Current activities on safety improvement at Ukrainian NPPs

    This report describes general development status of the national programs on safety improvement of the Ukrainian NPPs, basic approaches adopted for planning and implementation of safety improvement works, and state of implementation of principal technical activities aimed at safety improvement of Ukrainian NPPs. (author)

  6. Cisgenic Barley with Improved Phytase Activity

    Holme, Inger; Dionisio, Giuseppe; Brinch-Pedersen, Henrik;

    2010-01-01

    based on the cisgenesis concept. In contrast to transgenesis, cisgenesis implies that the plant is transformed only with its own or very closely related genetic material. Furthermore, all “helper” genes and gene sequences of foreign nature are removed from the transformed plant lines. Cisgenic crops are......-DNA borders in order to promote integration of the two genes at unlinked places in the plant genome. Transformed T0 plants show increases in the phytase activity of mature seeds from 1,400 in wild type to 8,950 FTU/kg in T0 plants. T1 plants of each transformant are currently screened with PCR for extra...... copies of the genomic phytase gene and the selection gene to identify segregation between the two genes. Presently, we have identified two cisgenic T1 plants without vector backbone and selection gene but with an extra copy of the genomic phytase gene....

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

    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.

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

    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...

  9. Synthetic analogs of anoplin show improved antimicrobial activities

    Munk, Jens; Uggerhøj, Lars Erik; Poulsen, Tanja Juul;

    2013-01-01

    We present the antimicrobial and hemolytic activities of the decapeptide anoplin and 19 analogs thereof tested against methicillin-resistant Staphylococcus aureus ATCC 33591 (MRSA), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), vancomycin-resistant Enterococcus faecium (ATCC...... that increasing the charge and/or hydrophobicity improves antimicrobial activity and increases hemolytic activity. For each strain tested, we identify at least six anoplin analogs with an improved therapeutic index compared with anoplin, the only exception being Enterococcus faecium, against which only...

  10. Extraneural Glioblastoma Multiforme Vertebral Metastasis

    Goodwin, C. Rory; Liang, Lydia; Abu-Bonsrah, Nancy; Hdeib, Alia; Elder, Benjamin D.; Kosztowski, Thomas; Bettegowda, Chetan; Laterra, John; Burger, Peter; Sciubba, Daniel M.

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor; however, extraneural metastasis is uncommon. Of those that metastasize extraneurally, metastases to the vertebral bodies represent a significant proportion. We present a review of 28 cases from the published literature of GBM metastasis to the vertebra. The mean age at presentation was 38.4 years with an average overall survival of 26 months. Patients were either asymptomatic with metastasis discovered at autopsy or presented with varying degrees of pain, weakness of the extremities, or other neurologic deficits. Of the cases that included the time to spinal metastasis, the average time was 26.4 months with a reported survival of 10 months after diagnosis of vertebral metastasis. A significant number of patients had no treatments for their spinal metastasis, although the intracranial lesions were treated extensively with surgery and/or adjuvant therapy. With increasing incremental gains in the survival of patients with GBM, clinicians will encounter patients with extracranial metastasis. As such, this review presents timely information concerning the presentation and outcomes of patients with vertebral metastasis. PMID:26704201

  11. Evolving Molecular Genetics of Glioblastoma

    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.

  12. Management of glioblastoma multiforme in pregnancy.

    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

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

    Salacz ME

    2016-04-01

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

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

    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.

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

    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.

  16. Benefits of Improved HP Turbine Active Clearance Control

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

    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…

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

    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.

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

    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

  20. Glioblastoma multiforme in the very elderly.

    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

  1. Immunological targeting of cytomegalovirus for glioblastoma therapy

    Nair, Smita K.; Sampson, John H.; Mitchell, Duane A.

    2014-01-01

    Human cytomegalovirus (CMV) is purportedly present in glioblastoma (GBM) while absent from the normal brain, making CMV antigens potentially ideal immunological anti-GBM targets. We recently demonstrated that patient-derived CMV pp65-specific T cells are capable of recognizing and killing autologous GBM tumor cells. This data supports CMV antigen-directed immunotherapies against GBM.

  2. Current Studies of Immunotherapy on Glioblastoma.

    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

  3. Stereotactic radiosurgery for glioblastoma: retrospective analysis

    This retrospective study was done to better understand the conditions for which stereotactic radiosurgery (SRS) for glioblastoma may be efficacious. Between 2000 and 2007, 33 patients with a pathological diagnosis of glioblastoma received SRS with the Novalis® Shaped Beam Radiosurgery system. Eighteen patients (54%) underwent salvage SRS for recurrence while 15 (45%) patients received upfront SRS following standard fractionated RT for newly diagnosed glioblastoma. There were no RTOG grade >2 acute side effects. The median survival after SRS was 6.7 months (range 1.4 – 74.7). There was no significant difference in overall survival (from the time of initial diagnosis) with respect to the timing of SRS (p = 0.2). There was significantly better progression free survival in patients treated with SRS as consolidation versus at the time of recurrence (p = 0.04). The majority of patients failed within or at the margin of the SRS treatment volume (21/26 evaluable for recurrence). SRS is well tolerated in the treatment of glioblastoma. As there was no difference in survival whether SRS is delivered upfront or at recurrence, the treatment for each patient should be individualized. Future studies are needed to identify patients most likely to respond to SRS

  4. Small cell glioblastoma or small cell carcinoma

    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...

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

    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...

  6. Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration

    Michaud-Levesque, Jonathan; Bousquet-Gagnon, Nathalie; Beliveau, Richard, E-mail: oncomol@nobel.si.uqam.ca

    2012-05-01

    Evidence has suggested that STAT3 functions as an oncogene in gliomagenesis. As a consequence, changes in the inflammatory microenvironment are thought to promote tumor development. Regardless of its origin, cancer-related inflammation has many tumor-promoting effects, such as the promotion of cell cycle progression, cell proliferation, cell migration and cell survival. Given that IL-6, a major cancer-related inflammatory cytokine, regulates STAT3 activation and is upregulated in glioblastoma, we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by IL-6, and to determine the underlying mechanisms of action. In this study, we show that quercetin is a potent inhibitor of the IL-6-induced STAT3 signaling pathway in T98G and U87 glioblastoma cells. Exposure to quercetin resulted in the reduction of GP130, JAK1 and STAT3 activation by IL-6, as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6. Interestingly, quercetin also modulated the expression of two target genes regulated by STAT3, i.e. cyclin D1 and matrix metalloproteinase-2 (MMP-2). Moreover, quercetin reduced the recruitment of STAT3 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of IL-6. Overall, these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6, with a potential role in the prevention and treatment of glioblastoma.

  7. Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration

    Evidence has suggested that STAT3 functions as an oncogene in gliomagenesis. As a consequence, changes in the inflammatory microenvironment are thought to promote tumor development. Regardless of its origin, cancer-related inflammation has many tumor-promoting effects, such as the promotion of cell cycle progression, cell proliferation, cell migration and cell survival. Given that IL-6, a major cancer-related inflammatory cytokine, regulates STAT3 activation and is upregulated in glioblastoma, we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by IL-6, and to determine the underlying mechanisms of action. In this study, we show that quercetin is a potent inhibitor of the IL-6-induced STAT3 signaling pathway in T98G and U87 glioblastoma cells. Exposure to quercetin resulted in the reduction of GP130, JAK1 and STAT3 activation by IL-6, as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6. Interestingly, quercetin also modulated the expression of two target genes regulated by STAT3, i.e. cyclin D1 and matrix metalloproteinase-2 (MMP-2). Moreover, quercetin reduced the recruitment of STAT3 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of IL-6. Overall, these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6, with a potential role in the prevention and treatment of glioblastoma.

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

    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...

  9. Active Listening Improve Your Ability to Listen and Lead

    (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. Wogonoside induces autophagy-related apoptosis in human glioblastoma cells.

    Zhang, Li; Wang, Handong; Cong, Zixiang; Xu, Jianguo; Zhu, Jianhong; Ji, Xiangjun; Ding, Ke

    2014-09-01

    Wogonoside, a bioactive flavonoid extracted from the root of Scutellaria baicalensis Georgi, has shown preclinical anticancer efficacy in various cancer models. However, the effects of wogonoside on glioblastoma cells remain unclear. In the present study, we found that wogonoside exhibited a cytotoxic effect on human glioblastoma cells. The suppression of cell viability was due to the induction of mitochondrial apoptosis. Furthermore, the presence of autophagic hallmarks, including an increase in punctate microtubule associated protein 1 light chain 3 (LC3) dots, changes in cellular morphology and increased levels of autophagy-related proteins were observed in the wogonoside-treated cells. Wogonoside treatment also enhanced autophagic flux as reflected by the increased acidic vesicular organelle (AVO) formation, p62 degradation and LC3 turnover. Notably, blockade of autophagy by a chemical inhibitor or RNA interference decreased the anticancer effect of wogonoside. In addition, the p38 mitogen-activated protein kinase (MAPK) signaling pathway, the phosphatidylinositide 3-kinase/protein kinase B/mammalian target of rapamycin/p70S6 kinase (PI3K/AKT/mTOR/p70S6K) signaling pathway and reactive oxygen species (ROS) participated in wogonoside-induced autophagy and apoptosis. These findings support the initiation of further studies of wogonoside as a candidate for the treatment of human malignant glioma. PMID:24970553

  11. Customized cooking method improves total antioxidant activity in selected vegetables.

    Ng, Zhi-Xiang; Chai, Jen-Wai; Kuppusamy, Umah Rani

    2011-03-01

    The present study compares water-soluble phenolic content (WPC) and antioxidant activities in Chinese long bean (Vigna unguiculata), bitter gourd (Momordica charantia), water convolvulus (Ipomoea aquatica) and broccoli (Brassica olearacea) prior to and after subjecting to boiling, microwaving and pressure cooking. The total antioxidant activity was increased in cooked water convolvulus, broccoli and bitter gourd, estimated based on the ferric reducing antioxidant power, the Trolox equivalent antioxidant capacity and 2,2-diphenyl-1-picryl-hydrazyl radical scavenging activity. Pressure cooking did not cause any significant decline in the antioxidant property. Boiling generally improved the overall antioxidant activity in all the vegetables. Correlation analysis suggests that WPC contributed to significant antioxidant activities in these vegetables. Thus, prudence in selecting an appropriate cooking method for different vegetables may improve or preserve their nutritional value. PMID:21250903

  12. Saponins: the potential chemotherapeutic agents in pursuing new anti-glioblastoma drugs.

    Tian, Xiangrong; Tang, Haifeng; Lin, Houwen; Cheng, Guang; Wang, Siwang; Zhang, Xing

    2013-10-01

    Saponins are natural glycosides consisting of a triterpene or steroid aglycone with a range of pharmacological properties such as significant anti-tumor activity. In this article, we review our recent progress in the studies of the saponins possessing anticancer effects, especially anti-glioblastoma effects from twelve species of marine organisms and terrestrial plants. The anti-glioblastoma active saponins discovered by other researchers in recent decades are also reviewed and compared. Systematic extraction, isolation and structural elucidation on the saponin constituents from three species of starfishes, five species of sea cucumbers and four species of medicinal plants led to the identification of more than 129 saponins, among which 76 saponins are new compounds. Most of the new compounds were found to possess relatively rare structural features showing in vitro cytotoxicity against tumor cells, especially glioblastoma cells. Several saponins exhibited significant anti-glioblastoma effects in vivo by in situ administration (interstitial chemotherapy) and their haemolytic side effects were avoided in the tests. Multiple mechanisms of action, such as interfering with cell cycle progression, inducing apoptosis, promoting stabilization of microtubule, as well as several signal transduction pathways, were involved in their anticancer effects. The review provided valuable leads for pursuing new anti-glioblastoma drugs, and established a new viewpoint for further development of these marine and terrestrial organisms. The successful approach to administrate saponins in situ conquered the bottleneck in the development of saponins as new drugs- haemolytic effects. It means that saponins may be developed as potential chemotherapeutic agents in pursuing new antiglioblastoma drugs. PMID:24032516

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

    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

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

    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...

  15. The tumor suppressive role of WIF1 in glioblastoma

    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...

  16. Does glioblastoma cyst fluid promote sciatic nerve regeneration?

    Rafet Özay; Abit Aktas; Mevlüt Özgür Taskapilioglu; Bora Gürer; Bülent Erdogan; Yusuf Sükrü Çaglar

    2015-01-01

    Glioblastoma cyst fluid contains growth factors and extracellular matrix proteins which are known as neurotrophic and neurite-promoting agents. Therefore, we hypothesized that glioblastoma cyst fluid can promote the regeneration of injured peripheral nerves. To validate this hypothesis, we transected rat sciatic nerve, performed epineural anastomosis, and wrapped the injured sciatic nerve with glioblastoma cyst fluid- or saline-soaked gelatin sponges. Neurological function and histomorphologi...

  17. Detection of MGMT promoter methylation in glioblastoma using pyrosequencing

    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

    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. Cross inhibition improves activity selection when switching incurs time costs

    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].

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

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

    Bernhart, Eva; Damm, Sabine; Wintersperger, Andrea [Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz (Austria); DeVaney, Trevor [Institute of Biophysics, Medical University of Graz (Austria); Zimmer, Andreas [Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, Karl-Franzens University, Graz (Austria); Raynham, Tony; Ireson, Christopher [Cancer Research Technology Ltd, London (United Kingdom); Sattler, Wolfgang, E-mail: wolfgang.sattler@medunigraz.at [Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz (Austria)

    2013-08-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which, despite combined modality treatment, reoccurs and is invariably fatal for affected patients. Recently, a member of the serine/threonine protein kinase D (PRKD) family, PRKD2, was shown to be a potent mediator of glioblastoma growth. Here we studied the role of PRKD2 in U87MG glioblastoma cell migration and invasion in response to sphingosine-1-phosphate (S1P), an activator of PRKD2 and a GBM mitogen. Time-lapse microscopy demonstrated that random cell migration was significantly diminished in response to PRKD2 silencing. The pharmacological PRKD family inhibitor CRT0066101 decreased chemotactic migration and invasion across uncoated or matrigel-coated Transwell inserts. Silencing of PRKD2 attenuated migration and invasion of U87MG cells even more effectively. In terms of downstream signaling, CRT0066101 prevented PRKD2 autophosphorylation and inhibited p44/42 MAPK and to a smaller extent p54/46 JNK and p38 MAPK activation. PRKD2 silencing impaired activation of p44/42 MAPK and p54/46 JNK, downregulated nuclear c-Jun protein levels and decreased c-Jun{sup S73} phosphorylation without affecting the NFκB pathway. Finally, qPCR array analyses revealed that silencing of PRKD2 downregulates mRNA levels of integrin alpha-2 and -4 (ITGA2 and -4), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and matrix metallopeptidase 1 (MMP1). Findings of the present study identify PRKD2 as a potential target to interfere with glioblastoma cell migration and invasion, two major determinants contributing to recurrence of glioblastoma after multimodality treatment. Highlights: • Sphingosine-1-phosphate induces glioma cell migration and invasion. • Part of the effects is mediated by protein kinase D2 (PRKD2) activation. • Inactivation of PRKD2 attenuates glioblastoma cell migration and invasion. • Both, RNAi and pharmacological inhibition of PRKD2 inhibits MAPK

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

    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...

  3. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme.

    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

  4. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme

    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.

  5. p53-Dependent G1 arrest and p53-independent apoptosis influence the radio biologic response of glioblastoma

    Purpose: Loss of the p53 tumor suppressor gene has been associated with tumor progression, disease relapse, poor response to antineoplastic therapy, and poor prognosis in many malignancies. We have investigated the contribution of p53-mediated radiation-induced apoptosis and G1 arrest to the well described radiation resistance of glioblastoma multiforme (GM) cells. Methods and Materials: Radiation survival in vitro was quantitated using linear quadratic and repair-saturation mathematical models. Isogenic derivatives of glioblastoma cells differing only in their p53 status were generated using a retroviral vector expressing a dominant negative mutant of p53. Radiation-induced apoptosis was assayed by Flourescence-activated cell sorter (FACS) analysis, terminal deoxynucleotide transferase labeling technique, and chromatin morphology. Cells were synchronized in early G1 phase and mitotic and labeling indices were measured. Results: Radiation-induced apoptosis of GM cells was independent of functional wild-type p53 (wt p53). Decreased susceptibility to radiation-induced apoptosis was associated with lower α values characterizing the shoulder of the clonogenic radiation survival curve. Using isogenic GM cells differing only in their p53 activity, we found that a p53-mediated function, radiation-induced G1 arrest, could also influence the value of α and clonogenic radiation resistance. Inactivation of wt p53 function by a dominant negative mutant of p53 resulted in a significantly diminished α value with no alteration in cellular susceptibility to radiation-induced apoptosis. The clonal derivative U87-LUX.8 expressing a functional wt p53 had an α (Gy-1) value of 0.609, whereas the isogenic clonal derivative U87-175.4 lacking wt p53 function had an α (Gy-1) value of 0.175. Conclusion: We conclude that two distinct cellular responses to radiation, p53-independent apoptosis and p53-dependent G1-arrest, influence radiobiological parameters that characterize the

  6. Active video gaming to improve balance in the elderly

    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

  7. Cancer Stem Cell Hierarchy in Glioblastoma Multiforme

    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 ...

  8. Detection of primary cilia in human glioblastoma

    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...

  9. Bevacizumab for the Treatment of Glioblastoma

    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...

  10. The challenges associated with molecular targeted therapies for glioblastoma.

    Jue, Toni Rose; McDonald, Kerrie L

    2016-05-01

    Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults. Improvements in the treatment of GBM have remained static since the advent of the standard therapy which includes radiation with concurrent and adjuvant temozolomide treatment. Developing treatment and diagnostic or companion biomarker combinations is transforming the way we treat numerous cancers. However, can this emerging paradigm be also effective for GBM? Can GBM be treated the same way as other cancers? Here we review the challenges for a personalized molecular targeted therapeutic approach in GBM. The specific challenges for establishing a personalized molecular targeted medicine program for GBM patients include overcoming the blood brain barrier, unravelling the intra- and inter-heterogeneity that exists and the importance of developing more relevant animal models that recapitulate a patient's GBM tumor. PMID:26900075

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

    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

  12. Development of targeted therapies in treatment of glioblastoma

    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.

  13. Aplastic anemia with concurrent temozolomide treatment in a patient with glioblastoma multiforme

    J. Oh; Kutas, G.J.; Davey, P.; Morrison, M; Perry, J R

    2010-01-01

    Temozolomide (tmz) is an oral alkylating agent used during concurrent and adjuvant chemotherapy for newly diagnosed glioblastoma multiforme. Temozolomide is generally well tolerated and improves survival; however, severe adverse events have occasionally been reported. Here, we report the case of a patient who developed aplastic anemia with related complications in the setting of concurrent tmz treatment with radiotherapy. This case illustrates that aplastic anemia is a rare side effect of tmz...

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

    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...

  15. Reirradiation for recurrent glioblastoma by cyberknife

    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)

  16. Orphan drugs in glioblastoma multiforme: a review

    Lassen U

    2014-11-01

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

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

    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.

  18. Current activities of safety improvements at Ukrainian NPPs

    The basic idea leading the program of safety improvements at Ukrainian NPPs is further development of nuclear power required to ensure at least 40% of country's energy supply. Activities concerning safety improvements of Ukrainian NPPs involved four reactor types: WWER-1000 (V-5) large series, WWER-1000 (V-302, V-338) small series, WWER-400 (V-213) and RBMK (second generation). Most significant safety improvements covered reactor core integrity, reactor components and cooling systems integrity, instrumentation and control system, power supply, internal hazards. Additional measures related to WWER-440 were concerned with feedwater supply, instrumentation and control systems, and containment. Improvements related to Chernobylsk NPP unit 3 involved supervision, control and protection systems; safety assessment and supporting systems; fire safety. The role of quality assurance and training is emphasised when operational safety is concerned. Planned safety upgrading measures are mentioned

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

    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

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

    Gutin Philip H

    2011-01-01

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

  1. Survivin inhibition and DNA double-strand break repair: A molecular mechanism to overcome radioresistance in glioblastoma

    Background and purpose: Gliomas display prime examples of ionizing radiation (IR) resistant tumors. The IAP Survivin is reported to be critically involved in radiation resistance by anti-apoptotic and by caspase-independent mechanisms. The present study aimed to elucidate an interrelationship between Survivin’s cellular localization and DNA damage repair in glioma cells. Material and methods: Cellular distribution and nuclear complex formation were assayed by immunoblotting, immunofluorescence staining and co-immunoprecipitation of Survivin bound proteins in LN229 glioblastoma cells. Apoptosis induction, survival and DNA repair following IR were assayed by means of caspase3/7 activity, clonogenic assay, γ-H2AX/53BP1 foci formation, single cell gel electrophoresis assay, and DNA-PKcs kinase assay in the presence of Survivin siRNA or over expression of Survivin-GFP. Results: Following irradiation, we observed a nuclear accumulation and a direct interrelationship between Survivin, MDC1, γ-H2AX, 53BP1 and DNA-PKcs, which was confirmed by immunofluorescence co-localization. Survivin downregulation by siRNA resulted in an increased apoptotic fraction, decreased clonogenic survival and increased DNA-damage, as demonstrated by higher amount of DNA breaks and an increased amount of γ-H2AX/53BP1 foci post irradiation. Furthermore, we detected in Survivin-depleted LN229 cells a hampered S2056 (auto)phosphorylation and a significantly decreased DNA-PKcs kinase activity. Conclusion: Nuclear accumulation of Survivin and interaction with components of the DNA-double-strand break (DSB) repair machinery indicates Survivin to regulate DSB damage repair that leads to a significant improvement of survival of LN229 glioblastoma cells.

  2. Glioblastoma extracellular vesicles: reservoirs of potential biomarkers

    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

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

    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.

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

    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.

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

    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.

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

    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

  7. Amnesia due to bilateral hippocampal glioblastoma. MRI finding

    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.).

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

    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...

  9. Structure-activity relationship and properties optimization of a series of quinazoline-2,4-diones as inhibitors of the canonical Wnt pathway.

    Nencini, Arianna; Pratelli, Carmela; Quinn, Joanna M; Salerno, Massimiliano; Tunici, Patrizia; De Robertis, Alessandra; Valensin, Silvia; Mennillo, Federica; Rossi, Marco; Bakker, Annette; Benicchi, Tiziana; Cappelli, Federico; Turlizzi, Elisa; Nibbio, Martina; Caradonna, Nicola P; Zanelli, Ugo; Andreini, Matteo; Magnani, Matteo; Varrone, Maurizio

    2015-05-01

    Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors. PMID:25847770

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

    Pedro M Paz-Alonso

    2009-09-01

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

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

    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.

  12. Inhibition of Notch Signaling Blocks Growth of Glioblastoma Cell Lines and Tumor Neurospheres

    Chen, Jie; Kesari, Santosh; Rooney, Christine; Strack, Peter R.; Chen, Jihua; Shen, Huangxuan; Wu, Lizi; Griffin, James D.

    2010-01-01

    Glioblastoma (GBM) is the most common malignant brain tumor that is characterized by high proliferative rate and invasiveness. Since dysregulation of Notch signaling is implicated in the pathogenesis of many human cancers, here we investigated the role of Notch signaling in GBM. We found that there is aberrant activation of Notch signaling in GBM cell lines and human GBM-derived neurospheres. Inhibition of Notch signaling via the expression of a dominant negative form of the Notch coactivator...

  13. Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs

    Jiang, Pengfei; Mukthavavam, Rajesh; Chao, Ying; Bharati, Ila Sri; Fogal, Valentina; Pastorino, Sandra; Cong, Xiuli; Nomura, Natsuko; Gallagher, Matt; Abbasi, Taher; Vali, Shireen; Pingle, Sandeep C; Makale, Milan; Kesari, Santosh

    2014-01-01

    Background Glioblastoma (GBM) is a therapeutic challenge, associated with high mortality. More effective GBM therapeutic options are urgently needed. Hence, we screened a large multi-class drug panel comprising the NIH clinical collection (NCC) that includes 446 FDA-approved drugs, with the goal of identifying new GBM therapeutics for rapid entry into clinical trials for GBM. Methods Screens using human GBM cell lines revealed 22 drugs with potent anti-GBM activity, including serotonergic blo...

  14. Characterization and immunotherapeutic potential of γδ T-cells in patients with glioblastoma

    Bryant, Nichole L.; Suarez-Cuervo, Catalina; Gillespie, G. Yancey; Markert, James M.; Nabors, L. Burt; Meleth, Sreelatha; Lopez, Richard D.; Lamb, Lawrence S.

    2009-01-01

    Classical immunotherapeutic approaches to glioblastoma multiforme (GBM) have shown mixed results, and therapies focused on innate lymphocyte activity against GBM have not been rigorously evaluated. We examined peripheral blood lymphocyte phenotype, γδ T-cell number, mitogenic response, and cytotoxicity against GBM cell lines and primary tumor explants from GBM patients at selected time points prior to and during GBM therapy. Healthy volunteers served as controls and were grouped by age. T-cel...

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

    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...

  16. Identification and characterization of a small molecule inhibitor of WNT signaling in glioblastoma cells

    De Robertis, Alessandra; Valensin, Silvia; Rossi, Marco; Tunici, Patrizia; Verani, Margherita; De Rosa, Antonella; Giordano, Cinzia; Varrone, Maurizio; Nencini, Arianna; Pratelli, Carmela; Benicchi, Tiziana; Bakker, Annette; Hill, Jeffrey; Sangthongpitag, Kanda; Pendharkar, Vishal

    2013-01-01

    Glioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive and highly invasive phenotype of these tumors makes them among the most anatomically damaging human cancers with a median survival of less than one year. Although canonical WNT pathway activation in cancers has been historically linked to the presence of mutations involving key components of the pathway (APC, β-CATENIN or AXIN proteins), an increasing number of studies suggest t...

  17. 13-cis-Retinoic acid in the treatment of recurrent glioblastoma multiforme

    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...

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

    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, ...

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

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

    2013-01-01

    Bevacizumab combined with chemotherapy has recently shown promising efficacy in recurrent high-grade glioma. Phosphatase and tensin homolog (PTEN) mutation in glioblastoma multiforme (GBM) patients causes abnormally high activity of the pathways of Phosphatidylinositide 3-kinases (PI3K), Protein...... been investigated, but with the hypothesis that temsirolimus might provide complimentary therapeutic benefit in combination with bevacizumab, we included patients with progressive GBM after bevacizumab in an open phase II study....

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

    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...

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

    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

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

    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 to...... the direction of the wind and occur when the bridge is exposed to wind velocity above critical value called the flutter wind velocity Ucr....

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

    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.

  4. Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging

    Umanskaya, Alisa; Santulli, Gaetano; Xie, Wenjun; Andersson, Daniel C; Reiken, Steven R.; Marks, Andrew R.

    2014-01-01

    Age-related muscle weakness has major adverse consequences on quality of life, increasing the risk of falls, fractures, and movement impairments. Albeit an increased oxidative state has been shown to contribute to age-dependent reduction in skeletal muscle function, little is known about the mechanisms connecting oxidation and muscle weakness. We show here that genetically enhancing mitochondrial antioxidant activity causes improved skeletal muscle function and voluntary exercise in aged mice...

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

    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.

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

    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.)

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

    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.)

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

    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

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

    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.

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

    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

  11. Selective Estrogen Receptor β Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma.

    Sareddy, Gangadhara R; Li, Xiaonan; Liu, Jinyou; Viswanadhapalli, Suryavathi; Garcia, Lauren; Gruslova, Aleksandra; Cavazos, David; Garcia, Mike; Strom, Anders M; Gustafsson, Jan-Ake; Tekmal, Rajeshwar Rao; Brenner, Andrew; Vadlamudi, Ratna K

    2016-01-01

    Glioblastomas (GBM), deadly brain tumors, have greater incidence in males than females. Epidemiological evidence supports a tumor suppressive role of estrogen; however, estrogen as a potential therapy for GBM is limited due to safety concerns. Since GBM express ERβ, a second receptor for estrogen, targeting ERβ with a selective agonist may be a potential novel GBM therapy. In the present study, we examined the therapeutic effect of the selective synthetic ERβ agonist LY500307 using in vitro and in vivo GBM models. Treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes in vitro. ERβ agonists promoted apoptosis of GBM cells, and mechanistic studies using RNA sequencing revealed that LY500307 modulated several pathways related to apoptosis, cell cycle, and DNA damage response. Further, LY500307 sensitized GBM cells to several FDA-approved chemotherapeutic drugs including cisplatin, lomustine and temozolomide. LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of GBM tumors in an orthotopic model and improved the overall survival of tumor-bearing mice in the GL26 syngeneic glioma model. Our results demonstrate that LY500307 has potential as a therapeutic agent for GBM. PMID:27126081

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

    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

  13. Prioritising Investments in Marketing Activities to Improve Business Performance

    Martensen, Anne; Mouritsen, Jan

    2014-01-01

    dimensions: (1) Small m: marketing strategy and marketing implementation and (2) big M: cross-functional coordination and innovation. Big M and small m interact and influence BP similarly. When considering investing in marketing activities to improve financial performance, the first priority is to recruit......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...

  14. Is There Pseudoprogression in Secondary Glioblastomas?

    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.

  15. Improved catalytic activity of laser generated bimetallic and trimetallic nanoparticles.

    Singh, Rina; Soni, R K

    2014-09-01

    We report synthesis of silver nanoparticles, bimetallic (Al2O3@Ag) nanoparticles and trimetallic (Al2O3@AgAu) nanoparticles by nanosecond pulse laser ablation (PLA) in deionized water. Two-step laser ablation methodologies were adopted for the synthesis of bi- and tri-metallic nanoparticles. In this method a silver or gold target was ablated in colloidal solution of γ-alumina nanoparticles prepared by PLA. The TEM image analysis of bimetallic and trimetallic particles reveals deposition of fine silver particles and Ag-Au alloy particles, respectively, on large alumina particles. The laser generated nanoparticles were tested for catalytic reduction of 4-nitrophenol to 4-aminophenol and showed excellent catalytic behaviour. The catalytic rate was greatly improved by incorporation of additional metal in silver nanoparticles. The catalytic efficiency of trimetallic Al2O3@AgAu for reduction of 4-nitrophenol to 4-aminophenol was remarkably enhanced and the catalytic reaction was completed in just 5 sec. Even at very low concentration, both Al2O3@Ag nanoparticles and Al2O3@AgAu nanoparticles showed improved rate of catalytic reduction than monometallic silver nanoparticles. Our results demonstrate that alumina particles in the solution not only provide the active sites for particle dispersion but also improve the catalytic activity. PMID:25924343

  16. Improvement of active filter for HIMAC power sources

    For the power sources of the synchrotron electromagnets for the heavy particle beam cancer therapy apparatus HIMAC in National Institute of Radiological Science, in order to stabilize the taken-out beam, the ripple property as low as below 1 x 10-6 is required. As for this electromagnet power sources, various devices were applied to lower ripples, and the required specifications have been satisfied. Also the beam spill is stable, but slight variation has been observed, therefore, by improving the performance of the active filter, the ripples were improved. The specifications of the electromagnet power sources and the whole constitution of the power source system are shown. In the HIMAC power sources, the means for having realized the low ripple performance so far are explained. Those are the absorption of the ineffective power generated from the power sources, the control of the ripples of common made due to the transducer thyristor, and the sure compensation of ripples by the control circuit for the power sources. By adding the band pass filters to the active filter, its characteristics were improved. As the result, 1200 Hz ripple component was reduced by 41 db, thus the sufficient effect was obtained. Hereafter, by the high sensitivity measurement of the current of electromagnets and the evaluation of magnetic fields, the validity will be evaluated. (K.I.)

  17. Targeting and treatment of glioblastomas with human mesenchymal stem cells carrying ferrociphenol lipid nanocapsules

    Clavreul A

    2015-02-01

    Full Text Available Anne Clavreul,1 Angélique Montagu,2 Anne-Laure Lainé,2 Clément Tétaud,2 Nolwenn Lautram,2 Florence Franconi,3 Catherine Passirani,2 Anne Vessières,4 Claudia N Montero-Menei,2 Philippe Menei1 1Département de Neurochirurgie, Centre Hospitalier Universitaire, Angers, France; 2INSERM UMR-S 1066, Université d’Angers, LUNAM Université, Angers, France; 3CIFAB-PRIMEX, Université d’Angers, LUNAM Université, Angers, France; 4CNRS-UMR 7223, ENSCP, Paris, France Abstract: Recently developed drug delivery nanosystems, such as lipid nanocapsules (LNCs, hold great promise for the treatment of glioblastomas (GBs. In this study, we used a subpopulation of human mesenchymal stem cells, “marrow-isolated adult multilineage inducible” (MIAMI cells, which have endogenous tumor-homing activity, to deliver LNCs containing an organometallic complex (ferrociphenol or Fc-diOH, in the orthotopic U87MG GB model. We determined the optimal dose of Fc-diOH-LNCs that can be carried by MIAMI cells and compared the efficacy of Fc-diOH-LNC-loaded MIAMI cells with that of the free-standing Fc-diOH-LNC system. We showed that MIAMI cells entrapped an optimal dose of about 20 pg Fc-diOH per cell, with no effect on cell viability or migration capacity. The survival of U87MG-bearing mice was longer after the intratumoral injection of Fc-diOH-LNC-loaded MIAMI cells than after the injection of Fc-diOH-LNCs alone. The greater effect of the Fc-diOH-LNC-loaded MIAMI cells may be accounted for by their peritumoral distribution and a longer residence time of the drug within the tumor. These results confirm the potential of combinations of stem cell therapy and nanotechnology to improve the local tissue distribution of anticancer drugs in GB.Keywords: glioblastoma, mesenchymal stem cells, nanoparticle, drug delivery, targeting 

  18. Cerebellar glioblastoma multiforme in an adult

    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...

  19. Cerebellar glioblastoma multiforme in an adult

    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.

  20. Improving Industrial Energy Quality by an Active Current Filter

    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.

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

    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.

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

    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

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

    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.

  4. Improvement activities for the maintenance of Baffle Former Bolts

    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)

  5. A cost-minimising analysis of standard radiotherapy and two experimental therapies in glioblastoma

    Background and purpose: Accelerated radiotherapy (ART) and intracavity brachytherapy (ICBT) have been introduced in the primary treatment of glioblastoma. Our objective was to determine total treatment costs, hospitalisation time, and treatment outcome in these two experimental therapies compared to standard treatment. Materials and methods: In the time period 1985 to 1st May 1999, a total of 174 patients with histologically confirmed glioblastoma multiforme were given postoperative radiotherapy according to three different treatment schedules at three different time intervals. A conventional regime of external radiotherapy (54 Gy/30 fractions) was given to 58 patients (group I), 75 patients were treated with ART (48 Gy/twice daily 30 fractions) (group II), and 41 patients were given ICBT (60 Gy/ten fractions) (group III). Treatment costs including surgery, hospital stay, hospital hotel stay, and radiotherapy were calculated. Results: The total mean costs employing the three treatment alternatives were calculated to $25,618 (group I), $23,442 (group II), and $14,534 (group III). Total mean stay in hospital for the whole primary treatment was 48.8, 41.6, and 19 days for groups I, II, and III respectively. Median survival figures were 16, 14, and 13 months for groups I, II, and III, respectively. Conclusions: The total cost of postoperative radiotherapy in glioblastoma is comparable to other health care services. ART did not improve the total treatment cost or influence the need for hospitalisation compared to standard treatment. ICBT seemed to have economic benefits with less need for hospitalisation

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

    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.

  7. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    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...

  8. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    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...

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

    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

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

    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

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

    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.

  12. Gene analysis and dynamics of tumor stem cell in human glioblastoma cells after radiation

    Because glioblastoma is the most malignant central nervous system (CNS) tumor, it is very difficult to cure despite surgery and adjuvant therapy. At present, surgery, radiotherapy, and chemotherapy are combined in the treatment of each patient. However, glioblastoma have radiotherapy and chemotherapy resistance, and this is not a radical treatment. We suspect that the tumor stem cell affects the recurrence, radiotherapy resistance and chemotherapy resistance of the tumor. Many studies suggest that tumor stem cells play an important role in tumorgenesis and tumor progression. Using human glioblastoma cell lines (T98G, A172), irradiated (0 Gy, 30 Gy, 60 Gy) glioblastoma cells were prepared under the same conditions as clinical therapy. We performed the analysis of cell proliferation rate, side population analysis by fluorescence-activated cell sorter (FACS), isolation of CD133+ cells and genetic analysis (human stem cell), using these cells. In the results of this study, the stem cell-related genes were highly expressed in the CD133+ cells compared with the CD133- cells. Therefore, it suggested that the CD133+ cells may contain tumor stem cells. In T98G, when compared to unirradiated cells and 60 Gy-irradiated cells, the cell proliferation rate for 30 Gy-irradiated cells tended to be higher, and stem cell-related genes were highly expressed in 30 Gy-irradiated CD133+ cells. In other words, in T98G, from the viewpoint of antitumor effects, the results suggest that chemotherapy may show more effect in 30 Gy-irradiated. In this genetic analysis, we suggest that CD133+ cells strongly affect tumor proliferation. In addition, CD133+ cells affect the resistance and the effect of treatments because some kind of changes occur in CD133+ cells after radiation. (author)

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

    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.

  14. Improvements in the Precise Measurement of Gamma Activity

    The precise measurement of the gamma radioactivity of sources in solid or liquid form has been significantly improved by two developments described in this paper. In one case the total gamma radiation from a highly active solid source, containing as much as 10mCi of a radioactive substance, is measured with a relative standard deviation of 0.03%. This is done by integrating the current from 4π scintillation detector during a 10-second measurement interval, thus generating a voltage which is recorded to five significant digits. The difficulties usually encountered with pulse-counting techniques of intensely active sources are eliminated, and the advantage is gained of having the precision related to the detection of a signal from 1010 events. Two prototype instruments have been constructed, each consisting of a detector, operational amplifier, digital voltmeter and crystal-controlled timer. They are capable of measuring the gamma activity of specimens slightly more than 1 m in length and nearly 4 cm in diameter. This significant improvement in the precise measurement of large quantities of radioactivity should find wide application in many fields. In the second case, the precise measurement of gamma activity is applied to liquid samples. Essential to the success of the method is the use of ageometry which is absolutely constant, and which eliminates the need for a measurement of the source volume. These aims are achieved by inserting a tall, cylindrical, flat-bottomed container into a well-type detector, and filling it with the radioactive solution until the top of the liquid is effectively at an 'infinite' distance from the detector. Additional amounts of the radioactive solution do not change the observed count rate. Other factors necessary for the attainment of high precision are the use of precise counting standards, self-absorption corrections for the radioactive element, and the specification of other solute concentrations in the solution. This technique

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

    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.

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

    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

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

    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.

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

    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.

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

    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...

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

    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

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

    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

  2. Comparison of solitary cerebral metastasis and glioblastoma multiform

    The purpose of this study is to evaluate the MR images of solitary cerebral metastasis and glioblastoma multiform to determine the differential findings. Ten cases of solitary cerebral metastasis and 14 cases of glioblastoma multiform were retrospectively reviewed, all of which were proved by pathologically. The MR findings were compared in regard to tumor size and location, degree of edema, enhancement pattern, and shape of rime enhancement. Mean maximum diameter or solitary cerebral metastasis was 3.85 cm(s.d. 1.47). Metastatic lesions were located in corticomedullary junction(70%) with cerebellum in 2 cases. The locations of glioblastoma multiform were white matter(64%) without cerebellar involvement and the mean maximum diameter was 5.43 cm(s.d. 0.99). In solitary cerebral metastasis, the size of edema was larger than the tumor diameter in 50%, but glioblastoma multiform did not show severe degree of edema. Rim enhancement seen in 7 cases of solitary cerebral metastasis showed unilocular shape and complete rim in 6 cases, and even thickness and smooth inner margine in 5 cases. However, rim enhancement seen in 11 cases of glioblastoma multiform showed multilocular appearance with septa in all cases, incomplete rim in 5 cases, and uneven thickness and irregular inner margin in 10 cases. Tumor location, degree of edema, and rim enhancement pattern on Gd-enhanced MR may be useful in differentiation between solitary cerebral metastasis and glioblastoma multiform

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

    Soumya Alige Mahabala Rao

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

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

    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. Attitudes to Improving Speaking Skills by Guided Individual Activities

    Galina Kavaliauskienė

    2014-06-01

    Full Text Available Students’ perceptions of difficulties in speaking on professional issues are in the focus of the present article. It is generally assumed that the skill of speaking a foreign language is very difficult to master, while speaking on professional topics involves such difficulties as the usage of specific vocabulary and ability to deal with listeners’ oncoming arguments. The aims of the current research are to investigate learners’ attitudes to the level of difficulty in speaking activi - ties on a subject matter at university and apply an innovative approach to improving their speaking skills. The methodology applied was focused on guided individual learning (GIL, with gradually increasing amount of spontaneity in public talks on the subject matter, starting with prepared short talks on an ESP issue leading to group discussions; moving on to Power Point presentations, involving spontaneous deviations from the subject and followed by question time; further, adding some complex subject matter, such as a discussion on a problematic professional subject suggested by learning materials; and, eventually, speaking impromptu on an issue, with a high level of control of one’s speaking skills. The research method of the learners’ attitudes employed the survey on learner attitudes to four different speaking activities in the classroom, which included short talks, Power Point Presentations, discussions and speaking impromptu. The questionnaire was administered to students of two different specializations by the end of the semester. The respondents were students who studied Psychology and Social Work at the Faculty of Social Policy, at Mykolas Romeris University in Vilnius, Lithuania. The respondents were asked to indicate the degree of difficulty they had with the various speaking activities on the Likert’s scale ranging from “very difficult” (1 to “very easy” (5. The results indicated that perceptions of difficulties to developing speaking

  6. Elderly patients with glioblastoma: the treatment challenge.

    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

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

    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...

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

    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...

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

    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.

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

    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)

  11. Cytoplasmic TRADD Confers a Worse Prognosis in Glioblastoma

    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.

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

    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. 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. 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). Our findings implicate that volumetric parameters may have a significant role in the prognosis of GBM patients. Furthermore, volumetry

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

    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

  14. Transportan 10 improves the anticancer activity of cisplatin.

    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

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

    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).

  16. Bioaugmentation to improve nitrification in activated sludge treatment.

    Leu, Shao-Yuan; Stenstrom, Michael K

    2010-06-01

    Bioaugmentation is a proposed technique to improve nutrient removal in municipal wastewater treatment. Compared with commonly used nitrification/denitrification (NDN) processes, bioaugmentation may be able to reduce tankage or land requirements. Many approaches for bioaugmentation have been developed, but few studies have compared the benefits among different approaches. This paper quantifies the effectiveness of bioaugmentation processes and investigates three major "onsite" bioaugmentation alternatives: 1) the parallel-plants approach, which uses acclimated biomass grown in a nitrifying "long-SRT" (sludge retention time) plant to augment a low-SRT treatment plant; 2) the enricher-reactor approach, which uses an offline reactor to produce the augmentation cultures; and 3) the enricher-reactor/return activated sludge (ER-RAS) approach, which grows enrichment culture in a reaeration reactor that receives a portion of the recycle activated sludge. Kinetic models were developed to simulate each approach, and the benefits of various approaches are presented on the same basis with controllable parameters, such as bioaugmentation levels, aeration tank volume, and temperatures. Examples were given to illustrate the potential benefits of bioaugmentation by upgrading a "carbon-only" wastewater treatment plant to nitrification. Simulation results suggested that all bioaugmentation approaches can decrease the minimum SRT for nitrification. The parallel-plants approach creates the highest concentration of biomass but may fail at too low temperature. The ER-RAS approach likely would be more useful at lower temperature and required less reactor volume; enricher-reactor approach would likely be more advantageous in the presence of inhibitory compound(s). PMID:20572460

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

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

    2016-06-01

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

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

    HONG, JING-FANG; SONG, YING-FANG; LIU, ZHENG; ZHENG, ZHAO-CONG; CHEN, HONG-JIE; WANG, SHOU-SEN

    2016-01-01

    The aim of the present study was to investigate the in vitro and in vivo anticancer and apoptotic effects of taraxerol acetate in U87 human glioblastoma cells. The effects on cell cycle phase distribution, cell cycle-associated proteins, autophagy, DNA fragmentation and cell migration were assessed. Cell viability was determined using the MTT assay, and phase contrast and fluorescence microscopy was utilized to determine the viability and apoptotic morphological features of the U87 cells. Flow cytometry using propidium iodide and Annexin V-fluorescein isothiocyanate demonstrated the effect of taraxerol acetate on the cell cycle phase distribution and apoptosis induction. Western blot analysis was performed to investigate the effect of the taraxerol acetate on cell cycle-associated proteins and autophagy-linked LC3B-II proteins. The results demonstrated that taraxerol acetate induced dose- and time-dependent cytotoxic effects in the U87 cells. Apoptotic induction following taraxerol acetate treatment was observed and the percentage of apoptotic cells increased from 7.3% in the control cells, to 16.1, 44.1 and 76.7% in the 10, 50 and 150 µM taraxerol acetate-treated cells, respectively. Furthermore, taraxerol acetate treatment led to sub-G1 cell cycle arrest with a corresponding decrease in the number of S-phase cells. DNA fragments were observed as a result of the gel electrophoresis experiment following taraxerol acetate treatment. To investigate the inhibitory effects of taraxerol acetate on the migration of U87 cell, a wound healing assay was conducted. The number of cells that migrated to the scratched area decreased significantly following treatment with taraxerol acetate. In addition, taraxerol acetate inhibited tumor growth in a mouse xenograft model. Administration of 0.25 and 0.75 µg/g taraxerol acetate reduced the tumor weight from 1.2 g in the phosphate-buffered saline (PBS)-treated group (control) to 0.81 and 0.42 g, respectively. Similarly, 0.25 and 0

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

    Gaelzer, Mariana Maier; Coelho, Bárbara Paranhos; de Quadros, Alice Hoffmann; Hoppe, Juliana Bender; Terra, Silvia Resende; Guerra, Maria Cristina Barea; Usach, Vanina; Guma, Fátima Costa Rodrigues; Gonçalves, Carlos Alberto Saraiva; Setton-Avruj, Patrícia; Battastini, Ana Maria Oliveira; Salbego, Christianne Gazzana

    2016-01-01

    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. PMID:27123999

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

    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 exists. We analysed a cohort of patients with recurrent GBM treated with frame-less hypofractionated stereotactic radiation therapy with a total dose of 25 Gy in 5 fractions. Of 91 consecutive patients with newly diagnosed GBM treated between 2007 and 2012 with conventional adjuvant chemo-radiation therapy, 15 underwent salvage RT at recurrence. The median time interval between primary RT and salvage RT was 10.8 months (range, 6–54 months). Overall, patients undergoing salvage RT showed a longer survival, with a median survival of 33 vs. 9.9 months (p= 0.00149). Median overall survival (OS) from salvage RT was 9.5 months. No patients demonstrated clinically significant acute morbidity, and all patients were able to complete the prescribed radiation therapy without interruption. Our results suggest that hypofractionated stereotactic radiation therapy is effective and safe in recurrent GBM. However, until prospective randomized trials will confirm these results, the decision for salvage treatment should remain individual and based on a multidisciplinary evaluation of each patient

  1. Clinical implications of microRNAs in human glioblastoma

    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.

  2. Current Trends in Targeted Therapies for Glioblastoma Multiforme

    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.

  3. Lipidomic Analysis of Glioblastoma Multiforme Using Mass Spectrometry

    Ha, Soo Jung; Showalter, Gordon; Cai, Shanbao; Wang, Haiyan; Liu, Wei Michael; Cohen-Gadol, Aaron A.; Sarkaria, Jann N.; Rickus, Jenna; Springer, John; Adamec, Jiri; Pollok, Karen E.; Clase, Kari L.

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant form of primary brain tumors. It is highly invasive and current treatment options have not improved the survival rate over the past twenty years. Novel approaches and technologies from systems biology have the potential to identify biomarkers that could serve as new therapeutic targets for GBM. This study employed lipid profiling technology to investigate lipid biomarkers in ectopic and orthotopic human GBM xenograft models. Primary patient cell lines, GBM10 and GBM43, were injected into the flank and the right cerebral hemisphere of NOD/SCID mice. Tumors were harvested from the brain and flank and proteins, metabolites, and lipids extracted from each sample. Reverse phase based high performance liquid chromatography coupled with Fourier transform ion cyclotron resonance mass spectrometry (LC-FTMS) was used to analyze the lipid profiles of tumor samples. Statistical and clustering analyses were performed to detect differences. Over 500 lipids were identified in each tumor model and lipids with the greatest fold effect in the comparison of ectopic versus orthotopic tumor models fell predominantly into four main classes of lipids: glycosphingolipids, glycerophoshpoethanolamines, triradylglycerols, and glycerophosphoserines. Lipidomic analysis revealed differences in glycosphingolipid and triglyceride profiles when the same tumor was propagated in the flank versus the brain. These results underscore the importance of the surrounding physiological environment on tumor development and are consistent with the hypothesis that specific classes of lipids are critical for GBM tumor growth in different anatomical sites. PMID:17929901

  4. Safety Culture Improvement Activities of YGN 3 and 4

    In nuclear power industry all over the world, we can never overemphasize the importance of nuclear safety. After the Chernobyl accident occurred in 1986, Korean nuclear energy industry had made every effort to enhance nuclear safety culture further. And, as a result of the efforts, Korean government declared the five principles for the nuclear energy safety regulation, which were included in the Nuclear Energy Safety Policy Statement published in 1994. In 2001, through the announcement of Nuclear Safety Charter for the peaceful use of nuclear energy, the Ministry of Science and Technology proclaimed at home and abroad that the protection of citizens and environment by securing nuclear safety should be the highest priority in nuclear energy industry. Occupying almost 40% share of domestic electricity generation, Korea Hydro and Nuclear Power Co. decided 'Safety Top Priority Management' as president's management policy, and clearly presented the safety goal to the personnel. By this, the management can effectively place stress on securing safety, which is our highest priority and the only way to win public confidence toward nuclear energy industry. This is prepared to shortly introduce the activities for improving safety culture in Yonggwang Nuclear Power unit 3 and 4 (YGN 3 and 4)

  5. Some improvements in low-activity gamma spectrometry

    In this study the authors have analysed some problems encountered in their experiments. The choice of an optimum geometry is particularly important in the case of low-activity measurements for which the counting rate needs to be maximized; the variations in the radius/height ratio in a Marinelli-type geometry for different detector dimensions are examined, and significant improvements in the counting rate are noted. In addition, two methods of secondary standard preparation are compared: the first, involving a single mixed source (containing a mixture of standards prepared by a primary laboratory), can only cause a shift in the calibration curve; the second, involving several individual (primary) sources, can in addition change the shape of the curve; the consequences of these different deformations were studied with a view to choosing the best method of preparing secondary standards. The measurements apply to various samples: water, milk, crushed vegetable matter, animal tissues, organic sediments, and sand; the gamma absorption in samples of different compositions was compared in order to establish the minimum number of secondary sources to be prepared. (author)

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

    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 ...

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

    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...

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

    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. ...

  9. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival

    Kloepper, Jonas; Riedemann, Lars; Amoozgar, Zohreh; Seano, Giorgio; Susek, Katharina; Yu, Veronica; Dalvie, Nisha; Amelung, Robin L.; Datta, Meenal; Song, Jonathan W.; Askoxylakis, Vasileios; Taylor, Jennie W.; Lu-Emerson, Christine; Batista, Ana; Kirkpatrick, Nathaniel D.

    2016-01-01

    Improving survival of patients with glioblastoma (GBM) using antiangiogenic therapy remains a challenge. In this study we show that dual blockade of angiopoietin-2 and vascular endothelial growth factor delays tumor growth and enhances survival benefits through reprogramming of tumor-associated macrophages toward an antitumor phenotype as well as by pruning immature tumor vessels. The antitumor immunomodulatory potential of this dual blockade supports clinical testing of this approach for GBM...

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

    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.

  11. 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

    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)

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

    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

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

    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

  14. 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.

    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

  15. MGMT-independent temozolomide resistance in pediatric glioblastoma cells associated with a PI3-kinase-mediated HOX/stem cell gene signature

    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....../HOXA10 expression, and a drug-resistant, progenitor cell phenotype in MGMT-independent pediatric glioblastoma....

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

    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- ...

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

    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 ...

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

    Full Text Available ALL.Neu.50.AllAg.Glioblastoma hg19 All antigens Neural Glioblastoma SRX377963,SRX37...SRX1177363,SRX1177362,SRX1177292,SRX1177288,SRX1177290,SRX1177306,SRX1177305 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Neu.50.AllAg.Glioblastoma.bed ...

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

    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 ...

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

    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 ...

  1. Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost ± hyperthermia for glioblastoma multiforme

    Purpose: To determine if adjuvant interstitial hyperthermia (HT) significantly improves survival of patients with glioblastoma undergoing brain brachytherapy boost after conventional radiotherapy. Materials and Methods: Adults with newly-diagnosed, unifocal, circumscribed, supratentorial glioblastoma ≤ 5 cm in diameter were registered postoperatively on a Phase II/III prospective randomized trial (BTRC 6G-90-2) and treated with partial brain radiotherapy at 1.8 Gy per daily fraction to 59.4 Gy with oral hydroxyurea. If the tumor was still deemed to be implantable on the post-teletherapy imaging study, the patient was randomized to brachytherapy boost alone or brachytherapy boost + HT (high-activity iodine-125 temporary implants giving 60 Gy at 0.40-0.60 Gy/h ± helical coil microwave antenna interstitial HT for 30 min immediately before and after brachytherapy). Survival from diagnosis was estimated using the Kaplan-Meier method. Survival curves were compared with the log rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards method. Results: >From August 1990 through August 1995, a total of 118 patients were entered on the trial, of which 111 were eligible. Patient age ranged from 21-75 years (median, 55 years) and KPS ranged from 70-100 (median, 90). Forty patients were randomized to brachytherapy (arm A) and 40 to brachytherapy + HT (arm B). Chiefly due to tumor progression, 31 patients never reached randomization. Thirty-three of 40 arm A patients and 35 of 40 arm B patients were evaluable and actually underwent brachytherapy boost and 31 evaluable arm B patients actually received HT. The median steady-state T90 was 42.1 deg. C and the median T90 thermal dose was about 12 CEM 43 deg. T90. Survival analyzed by intent to treat was significantly longer for arm B than for arm A (median survival 89 vs. 76 weeks; p = 0.055 by the log rank test). Analyzing only implanted patients, the median survival was 91 weeks for 35 arm

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

    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

  3. Synchronous multicentric glioblastoma with PNET and O subtypes: Possible pathogenesis

    Kai Rui Wan

    2014-01-01

    Full Text Available Background: Glioblastomas (GBM are highly infiltrative, cellular and mitotically active tumors with large histologic variations within and between tumours. Several subtypes have been described including the GBM with oligodendroglial differentiation (GBM-O and primitive neuroectodermal tumour components (GBM-PNET. We report the first described case of a patient with synchronous multi-centric GBM-O and GBM-PNET components. Case Description: A patient, who presented with a short history of progressive headache and difficulty with memory recall, was found on MRI imaging to have two intracranial lesions. These showed heterogeneous enhancement and were found in the left frontal and left temporal regions. The patient underwent gross total resection of these two lesions which were found to show GBM-O and GBM-PNET differentiations. Conclusion: Although tumour cell migration in the context of GBM is a well-recognized phenomenon, the traditional hypothesis is not able to satisfactorily explain this case of multicentric GBM whereby the two lesions demonstrate different cell origins. More current understanding of the migratory pathways from the subventricular zone provide an alternate and plausible pathway that fits our patient′s unusual diagnosis.

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

    Grodzik M

    2011-11-01

    Full Text Available Marta Grodzik1, Ewa Sawosz1, Mateusz Wierzbicki1, Piotr Orlowski1, Anna Hotowy2, Tomasz Niemiec1, Maciej Szmidt3, Katarzyna Mitura4, André Chwalibog21Division of Biotechnology and Biochemistry of Nutrition, Warsaw University of Life Sciences, Warsaw, Poland; 2Department of Basic Animal and Veterinary Science, University of Copenhagen, Copenhagen, Denmark; 3Division of Histology and Embryology, Warsaw University of Life Sciences, Warsaw, Poland; 4Department of Biomedical Engineering, Koszalin University of Technology, Koszalin, PolandAbstract: 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 chorioallantoic 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, and vessel area. Quantitative real-time polymerase chain reaction analysis showed downregulated fibroblast growth factor-2 and vascular endothelial growth factor expression at the messenger ribonucleic acid level. The present results demonstrate antiangiogenic activity of carbon nanoparticles, making them potential factors for anticancer therapy.Keywords: cancer, nanoparticle, embryo, angiogenesis, FGF-2, VEGF

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

    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.

  6. Nanocarriers for the treatment of glioblastoma multiforme: Current state-of-the-art.

    Karim, Reatul; Palazzo, Claudio; Evrard, Brigitte; Piel, Geraldine

    2016-04-10

    Glioblastoma multiforme, a grade IV glioma, is the most frequently occurring and invasive primary tumor of the central nervous system, which causes about 4% of cancer-associated-deaths, making it one of the most fatal cancers. With present treatments, using state-of-the-art technologies, the median survival is about 14months and 2year survival rate is merely 3-5%. Hence, novel therapeutic approaches are urgently necessary. However, most drug molecules are not able to cross the blood-brain barrier, which is one of the major difficulties in glioblastoma treatment. This review describes the features of blood-brain barrier, and its anatomical changes with different stages of tumor growth. Moreover, various strategies to improve brain drug delivery i.e. tight junction opening, chemical modification of the drug, efflux transporter inhibition, convection-enhanced delivery, craniotomy-based drug delivery and drug delivery nanosystems are discussed. Nanocarriers are one of the highly potential drug transport systems that have gained huge research focus over the last few decades for site specific drug delivery, including drug delivery to the brain. Properly designed nanocolloids are capable to cross the blood-brain barrier and specifically deliver the drug in the brain tumor tissue. They can carry both hydrophilic and hydrophobic drugs, protect them from degradation, release the drug for sustained period, significantly improve the plasma circulation half-life and reduce toxic effects. Among various nanocarriers, liposomes, polymeric nanoparticles and lipid nanocapsules are the most widely studied, and are discussed in this review. For each type of nanocarrier, a general discussion describing their composition, characteristics, types and various uses is followed by their specific application to glioblastoma treatment. Moreover, some of the main challenges regarding toxicity and standardized evaluation techniques are narrated in brief. PMID:26892752

  7. Can schoolyard improvements increase physical activity for the least active students, or just provide better opportunities for the most active?

    Breum, Lars; Toftager, M.; Troelsen, J.

    Introduction School physical activity interventions can improve the physical environment and organizational environment of schools to increase the opportunities for physical activity (PA) in recess. The purpose of this study was to evaluate if improvements to the outdoor physical environment at the...... of PA during recess and in leisure time. The multicomponent intervention comprised 11 components, and included a combination of changes to the physical environment and organizational changes. Results At baseline, 73% of the students reported to engage in sport outside school and were characterized as...... “the most active”. At the intervention schools the proportion of student who reported good possibilities for outdoor PA increased (71% to 75%), while the proportion decreased at the comparison schools (87% to 68%). The proportion of students reporting to be active daily during recess decreased for all...

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

    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

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

    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

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

    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

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

    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

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

    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. PMID:27048878

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

    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...

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

    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...

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

    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...

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

    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

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

    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.

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

    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...

  19. Accelerated hyperfractionation plus temozolomide in glioblastoma

    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

  20. CANINE BUTTERFLY GLIOBLASTOMAS: A NEURORADIOLOGICAL REVIEW

    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.

  1. Canine Butterfly Glioblastomas: A Neuroradiological Review

    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.

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

    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.

  3. Glioblastoma and the significance of MGMT gene methylation

    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.

  4. Coincidence of an anterior cerebral artery aneurysm and a glioblastoma: case report and review of literature

    Nguyen HS

    2015-11-01

    Full Text Available Ha Son Nguyen,1 Ninh Doan,1 Michael Gelsomino,1 Saman Shabani,1 Wade Mueller,1 Osama O Zaidat2 1Department of Neurosurgery, 2Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA Background: The association between glioblastoma and intracranial aneurysm is rare. Treatment guidelines do not exist, and operative mortality and morbidity are significantly high. To our knowledge, no prior cases have employed endovascular therapy for the treatment of these intratumor intracranial aneurysms followed by tumor resection. Case presentation: A 74-year-old male, history of a left A2 aneurysm, presented after a motor vehicle accident at low speeds. Imaging was concerning for a possible traumatic brain contusion, an aneurysmal hemorrhage given history of left A2 aneurysm, or a hemorrhage from an underlying tumor given profound edema. The patient was discussed at the brain tumor board, where the plan was to address the aneurysm followed by resection of the mass versus close monitoring with subsequent imaging. The high risk of rehemorrhage, given the real possibility of an aneurysmal hemorrhage, motivated prompt treatment of the aneurysm. The patient was taken to the angiography suite; an anterosuperiorly projecting azygous A2 aneurysm, measuring 4.5 mm × 5.5 mm with a neck width at 3.5 mm and a small daughter sac, was completely obliterated with primary coiling. The following day, he underwent a left craniotomy along a forehead skin crease for mass excision. Final pathology revealed glioblastoma. The patient recovered well from both procedures, with a baseline neurological exam. The patient subsequently underwent hypofractionated radiation and temodar. Conclusion: To our knowledge, no prior cases have employed endovascular therapy for the treatment of these intracranial aneurysms. We emphasize that efforts to introduce less invasive elements may improve the overall outcomes in this rare patient population. Keywords: intracranial aneurysm

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

    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

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

    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.

  7. Psychological self-improvement mechanisms in sports activities

    Svetlana V. Kochetkova

    2011-07-01

    Full Text Available Experimental justification of ‘sandwich’ model self-regulation structure and possibilities of finger gymnastics and mental training combination use to improve psychological readiness to work (target shooting case study.

  8. Assessment of epidermal growth factor receptor status in glioblastomas

    Hui-Jun Zhu

    2013-10-01

    Full Text Available Introduction: Our previous study showed that a newly designed tracer radioiodinated 6-(3-morpholinopropoxy-7-ethoxy-4-(3'-iodophenoxyquinazoline ([125I]PYK is promising for the evaluation of the epidermal growth factor receptor (EGFR status and prediction of gefitinib treatment of non-small cell lung cancer. EGFR is over-expressed and mutated also in glioblastoma. In the present study, the expressions and mutation of EGFR were tested with [125I] PYK in glioblastoma in vitro and in vivo to determine whether this could be used to predict the sensitivity of glioblastoma to gefitinib treatment. Materials and Methods: Glioblastoma cell lines with different expression of EGFR were tested. Growth inhibition of cell lines by gefitinib was assessed by the 3-(4, 5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide (MTT colorimetric assay. Uptake levels of [125I]PYK were evaluated in cell lines in vitro. Tumor targeting of [125I]PYK was examined by a biodistribution study and imaging by single photon emission computed tomography (SPECT. Results: High concentrations of gefitinib were needed to suppress EGFR-mediated proliferation. The uptake of [125I] PYK in cell lines in vitro was low, and showed no correlation with EGFR expression or mutation status. Biodistribution study and SPECT imaging with [125I]PYK for xenografts showed no [125I]PYK uptake. Conclusion: The results showed prediction of gefitinib effectiveness was difficult in glioblastoma by [125I]PYK, which might be due to the complicated expression of EGFR status in glioblastoma. Thus, new tracers for sites downstream of the mutant EGFR should be investigated in further studies.

  9. Bifidobacterium activation in technologies of health-improving mayonnaise

    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...

  10. The improved physical activity index for measuring physical activity in EPIC Germany.

    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.

  11. Tumor-penetrating peptide functionalization enhances the anti-glioblastoma effect of doxorubicin liposomes

    The targeted therapeutic effect of nano drug delivery system for glioblastoma has been hampered by the weak enhanced permeability and retention (EPR) effect of glioblastoma and the low delivering efficiency of NDDS in glioblastoma tissue. In this study, a tumor-penetrating peptide (RGERPPR), the specific ligand of neuropilin-1 overexpressed on glioblastoma and endothelial cells, was used as a targeting moiety to enhance the anti-glioblastoma effect of doxorubicin liposomes. Firstly, RGERPPR-PEG-DSPE was synthesized and used to prepare the RGERPPR peptide-functionalized liposomes (RGE-LS), which showed vesicle sizes of around 90 nm and narrow size distributions. The cellular uptake and in vivo near-infrared fluorescence imaging test displayed that RGE-LS exhibited increased uptake by glioblastoma cells and intracranial glioblastoma tissues. The cytotoxicity assay and anti-glioblastoma study proved that RGERPPR functionalization significantly enhanced the in vitro inhibitory effect of doxorubicin liposomes on glioblastoma cells and prolonged the median survival time of nude mice bearing intracranial glioblastoma. Finally, the immunofluorescence analysis evidenced that RGE-LS were able to penetrate through tumor vessels and stroma and deep into the whole tumor tissue. The results indicated that tumor-penetrating peptide functionalization is an effective strategy for enhancing the anti-glioblastoma effect of doxorubicin liposomes. (paper)

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

    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...

  13. Memory Suppression is an Active Process that Improves Over Childhood

    Paz-Alonso, Pedro M.; Ghetti, Simona; Bryan J Matlen; Anderson, Michael C.; Bunge, Silvia A.

    2009-01-01

    We all have memories that we prefer not to think about. The ability to suppress retrieval of unwanted memories has been documented in behavioral and neuroimaging research using the Think/No-Think (TNT) paradigm with adults. Attempts to stop memory retrieval are associated with increased activation of lateral prefrontal cortex (PFC) and concomitant reduced activation in medial temporal lobe (MTL) structures. However, the extent to which children have the ability to actively suppress their memo...

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

    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

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

    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

  16. Analysis of p53 and miRNA expressions after irradiation in glioblastoma cell lines

    Glioblastoma is a malignant brain tumor which is difficult to completely cure by surgical treatment and consequently in attempt for cure it is treated with a combination of radiotherapy and chemotherapy following surgery. Unfortunately however, these procedures are not curative for this type of tumor due to the development of resistance to anticancer drugs and radiation during treatment. P53 is a radiation-resistant factor. It plays an important role in apoptosis regulation. When cells are irradiated DNA is injured; P53 is then activated and it regulates the transcription of the target genes related to apoptosis. However, the p53 gene is defective or mutated in 50% of glioblastoma cases, thereby impairing the transcription activation capability, and thus the P53 apoptosis induction pathway does not function and apoptosis is not induced. Accordingly, the cells are less radiosensitive and show marked resistance to radiation. Apoptosis induction is an important cancer-suppressive function and it determines the sensitivity to treatments, such as chemotherapy and radiotherapy. miRNA which regulates this gene transcription has recently been reported. miRNAs are small RNAs comprised of 21-23 base-pairs. They bind to several proteins to form complexes, and bind to the N-terminal of the target mRNA for the post-transcriptional inhibition of gene expression. In this study, we analyzed the protein expression of P53, Bcl-2, Bax, and Caspase9 and miRNA expression-regulating genes involved in the P53 apoptosis pathway using a P53 mutant, T98G glioblastoma cells, and P53 wild-type A172 glioblastoma cells. Regarding miRNA, the involvement of P53-regulating mi-125b, mi-34a, mi-504, mi-380-5P, mi-885-5P, mi-145, Bax-regulating mi-21, mi-222, and mi-34a, and mi-21-regulating Bcl-2 and Caspase9 was suggested. In particular, P53 and mi-34a expressions in P53 wild-type A172 cells and Bcl-2 and mi-21 expressions in the P53 mutant type were closely involved in the P53 apoptosis induction

  17. Improving Adherence Physical Activity with a Smartphone Application Based on Adults with Intellectual Disabilities (APPCOID)

    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...

  18. Quality Improvement and Infrastructure Activity Costs in Software Development: A Longitudinal Analysis

    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...

  19. Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment

    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

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

    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.

  1. FASB Proposes Improved Disclosures for Derivatives and Hedging Activities

    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.

  2. Improving health through policies that promote active travel

    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...

  3. Silica–enzyme–ionic liquid composites for improved enzymatic activity

    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 ...

  4. Morphometic analysis of TCGA glioblastoma multiforme

    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

  5. SP-05VENOUS THROMBOEMBOLISM AND GLIOBLASTOMA

    Yust-Katz, Shlomit; Mandel, Jacob; Ying, Yuan; Wu, Jimin; Courtney, C.; Ladha, Harshad; Pawar, Tushar; Gilbert, Mark; Armstrong, Terri

    2014-01-01

    The risk of venous thromboembolism (VTE) is very high for patients with brain tumors; Glioblastoma (GB) specifically is one of the most at risk cancers. The aim of this study is to estimate the frequency and identify potential risk factors of GB patients developing VTE during adjuvant chemotherapy and to test if the Khorana scale accurately predicts the risk of VTE among this patient population. We retrospectively reviewed patients with GB treated at MD Anderson during the years 2005-2011. The target population of our study was patients who developed VTE after starting adjuvant chemotherapy. Patients were excluded if they did not start treatment with the established standard of care, had less than 6 months follow up or if they developed VTE before starting adjuvant treatment. The study sample included 440 patients. 64 (14.5%) of them developed VTE. The median time to develop VTE was 6.5 months. On multivariate analysis male sex, BMI≥ 35, KPS ≤80, history of VTE and steroid therapy were significantly associated with the development of VTE. We also found that in this patient sample, the Khorana scale was not a valid predictive model in GB patients due to very poor specificity. Of the 64 patients who developed a VTE, 36 were treated with anticoagulation, 2 with an IVC filter, and 21 with both. Complications secondary to anticoagulation were reported in 16% (n = 10) of patients. The complications included intracranial hemorrhage, bleeding to other organs and thrombocytopenia. VTE is very common in patients with GB. Currently, we are lacking a scale that accurately predicts the risk of VTE among GB patients. Predictive scales used for other cancers do not seem valid for GB due to the unique nature of the disease. Future studies are needed to create an accurate predictive model for VTE in GB patients.

  6. PARP-1 protein expression in glioblastoma multiforme

    A. Galia

    2012-02-01

    Full Text Available One of the most common type of primary brain tumors in adults is the glioblastoma multiforme (GBM (World Health Organization grade IV astrocytoma. It is the most common malignant and aggressive form of glioma and it is among the most lethal ones. Poly (ADP-ribose polymerase 1 (PARP-1 gene, located to 1q42, plays an important role for the efficient maintenance of genome integrity. PARP-1 protein is required for the apoptosis-inducing factor (AIF translocation from the mitochondria to the nucleus. PARP-1 is proteolytically cleaved at the onset of apoptosis by caspase-3. Microarray analysis of PARP-1 gene expression in more than 8,000 samples revealed that PARP-1 is more highly expressed in several types of cancer compared with the equivalent normal tissues. Overall, the most differences in PARP-1 gene expression have been observed in breast, ovarian, endometrial, lung, and skin cancers, and non-Hodgkin’s lymphoma. We evaluated the expression of PARP-1 protein in normal brain tissues and primary GBM by immunohistochemistry. Positive nuclear PARP-1 staining was found in all samples with GBM, but not in normal neurons from controls (n=4 and GBM patients (n=27. No cytoplasmic staining was observed in any sample. In conclusion, PARP-1 gene is expressed in GBM. This finding may be envisioned as an attempt to trigger apoptosis in this tumor, as well as in many other malignancies. The presence of the protein exclusively at the nucleus further support the function played by this gene in genome integrity maintenance and apoptosis. Finally, PARP-1 staining may be used as GBM cell marker.

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

    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.

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

    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.

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

    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)

  10. Activation Cross Sections Improvements needed for IFE Power Reactors Designs

    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.

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

    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. PMID:21739168

  12. 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.

    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.

  13. Knockdown of checkpoint kinase 1 is associated with the increased radiosensitivity of glioblastoma stem-like cells

    Glioblastoma multiforme is an aggressive brain tumor with a poor prognosis. The glioblastoma stem-like cells (GSCs) represent a rare fraction of human glioblastoma cells with the capacity for multi-lineage differentiation, self-renewal and exact recapitulation of the original tumor. Interestingly, GSCs are more radioresistant compared with other tumor cells. In addition, the remarkable radioresistance of GSCs has been known to promote radiotherapy failure and therefore is associated with a significantly higher risk of a local tumor recurrence. Moreover, the hyperactive cell cycle checkpoint kinase (Chk) 1 and 2 play a pivotal role in the DNA damage response including radiation and chemical therapy. Based on aforementioned, we hypothesized that knockdown of Chk1 or Chk2 might confer radiosensitivity on GSCs and thereby increases the efficiency of radiotherapy. In this study, we knocked down the expression of Chk1 or Chk2 in human GSCs using lentivirus-delivered short hairpin RNA (shRNA) to examine its effect on the radiosensitivity. After radiation, the apoptosis rate and the cell cycle of GSCs were measured with Flow Cytometry. Compared with control GSCs (apoptosis, 7.82±0.38%; G2/M arrest, 60.20±1.28%), Chk1 knockdown in GSCs increased the apoptosis rate (37.87±0.32%) and decreased the degree of the G2/M arrest (22.37±2.01%). In contrast, the radiosensitivity was not enhanced by Chk2 knockdown in GSCs. These results suggest that depletion of Chk1 may improve the radio-sensitivity of GSCs via inducing cell apoptosis. In summary, the therapy targeting Chk1 gene in the GSCs may be a novel way to treat glioblastoma. (author)

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

    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

  15. Nestin expression in the cell lines derived from glioblastoma multiforme

    Nestin is a protein belonging to class VI of intermediate filaments that is produced in stem/progenitor cells in the mammalian CNS during development and is consecutively replaced by other intermediate filament proteins (neurofilaments, GFAP). Down-regulated nestin may be re-expressed in the adult organism under certain pathological conditions (brain injury, ischemia, inflammation, neoplastic transformation). Our work focused on a detailed study of the nestin cytoskeleton in cell lines derived from glioblastoma multiforme, because re-expression of nestin together with down-regulation of GFAP has been previously reported in this type of brain tumor. Two cell lines were derived from the tumor tissue of patients treated for glioblastoma multiforme. Nestin and other cytoskeletal proteins were visualized using imunocytochemical methods: indirect immunofluorescence and immunogold-labelling. Using epifluorescence and confocal microscopy, we described the morphology of nestin-positive intermediate filaments in glioblastoma cells of both primary cultures and the derived cell lines, as well as the reorganization of nestin during mitosis. Our most important result came through transmission electron microscopy and provided clear evidence that nestin is present in the cell nucleus. Detailed information concerning the pattern of the nestin cytoskeleton in glioblastoma cell lines and especially the demonstration of nestin in the nucleus represent an important background for further studies of nestin re-expression in relationship to tumor malignancy and invasive potential

  16. The Role of Protein Kinase CK2 in Glioblastoma Development

    Ji, Haitao; Lu, Zhimin

    2013-01-01

    Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor in adults, and its response to current therapies is limited. Protein kinase CK2 is overexpressed in GBM and regulates GBM cell survival, proliferation, and migration and brain tumorigenesis. Targeting CK2 for GBM treatment may benefit GBM patients.

  17. Reduction of nitroxides and radioprotective ability in glioblastoma cells

    Electron spin resonance (ESR) analyses were performed to clarify whether glioblastoma cells scavenge hydroxyl radicals (·OH) generated by x-ray irradiation. The rate of bioreduction of nitroxides by three human glioblastoma cells was also evaluated by the same technique and compared with their x-ray sensitivity. Aerated culture media containing 200 mM of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) with or without U87MG cells were irradiated with x-rays at a dose of 20 Gy. ESR was measured immediately after each irradiation. Continuous changes of the ESR spectra of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) were analyzed in cell suspensions of TK1, U87MG, and A172 at a concentration of 1.0 x 107 cells/ml containing 5 μM Tempol. As a result, the signal of DMPO-OH in the U87MG cell suspension decayed faster than that in the control culture media without cells, and the rate of bioreduction of Tempol in each glioblastoma cell suspension was correlated with the x-ray sensitivity defined from the colony-forming assay in those cell lines. It was indicated that the resistance of glioblastoma cells to ionizing radiation could be closely related to their ability to scavenge radical species generated by ionizing radiation. (author)

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

    Grodzik, Marta; Sawosz, Ewa; Wierzbicki, Mateusz; Orlowski, Piotr; Hotowy, Anna Malgorzata; Niemiec, Tomasz; Szmidt, Maciej; Mitura, Katarzyna; Chwalibog, André

    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...

  19. Cerebellar glioblastoma multiforme presenting as a cerebellopontine angle mass

    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.

  20. Prognostic significance of neutrophil-to-lymphocyte ratio in glioblastoma

    George A Alexiou

    2014-12-01

    Full Text Available Aim: The neutrophil-to-lymphocyte ratio (NLR has prognostic value in patients with a variety of cancers. The purpose of this study was to investigate the prognostic value of NLR in patients with glioblastoma. Methods: A prospective study was conducted on patients receiving surgery for glioblastoma. Preoperative NLR was recorded and correlated with other prognostic factors and survival. Results: Fifty-one patients were included in the study. The mean NLR ratio was 6.7 ± 4.6. Using receiver operating characteristic curve analysis, an NLR cut-off value of 4.7 was determined to best predict survival. Patients with NLR ratios exceeding 4.7 differed significantly from those with NLR ratios ≤ 4.7 and were associated with reduced survival. Patients with gross total tumor excision had a median survival of 18 months, whereas the median survival time was 11 months in patients with subtotal tumor excision. No significant difference in survival was observed with respect to patient age, gender, Karnofsky performance status, or tumor location. Using multivariate analysis, NLR and extent of tumor resection were identified as factors with independent prognostic power. Conclusion: Neutrophil-to-lymphocyte ratio is an inexpensive, widely available biomarker of glioblastoma aggressiveness and should be used alongside current glioblastoma prognostic factors.

  1. Emerging insights into the molecular and cellular basis of glioblastoma

    Dunn, Gavin P.; Rinne, Mikael L.; Wykosky, Jill; Genovese, Giannicola; Quayle, Steven N.; Dunn, Ian F.; Agarwalla, Pankaj K.; Chheda, Milan G.; Campos, Benito; Wang, Alan; Brennan, Cameron; Ligon, Keith L.; Furnari, Frank; Cavenee, Webster K.; Depinho, Ronald A.; Chin, Lynda; Hahn, William C.

    2012-01-01

    Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that “glioblastoma” represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions. PMID:22508724

  2. The Dynamics of Interactions Among Immune and Glioblastoma Cells.

    Eder, Katalin; Kalman, Bernadette

    2015-12-01

    Glioblastoma is the most common intracranial malignancy that constitutes about 50 % of all gliomas. Despite aggressive, multimodal therapy consisting of surgery, radiation, and chemotherapy, the outcome of patients with glioblastoma remains poor with 5-year survival rates of <10 %. Resistance to conventional therapies is most likely caused by several factors. Alterations in the functions of local immune mediators may represent a critical contributor to this resistance. The tumor microenvironment contains innate and adaptive immune cells in addition to the cancer cells and their surrounding stroma. These various cells communicate with each other by means of direct cell-cell contact or by soluble factors including cytokines and chemokines, and act in autocrine and paracrine manners to modulate tumor growth. There are dynamic interactions among the local immune elements and the tumor cells, where primarily the protective immune cells attempt to overcome the malignant cells. However, by developing somatic mutations and epigenetic modifications, the glioblastoma tumor cells acquire the capability of counteracting the local immune responses, and even exploit the immune cells and products for their own growth benefits. In this review, we survey those immune mechanisms that likely contribute to glioblastoma pathogenesis and may serve as a basis for novel treatment strategies. PMID:26224516

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

    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

  4. On the road to improved scheduling - fitting activities to capacity

    Lindhard, Søren Munch; Wandahl, Søren

    Last Planner System has through the sounding process increased the reliability of the schedule. The sound activities are moved to a buffer and afterwards selected to the Weekly Work Plans to match capacity. Therefore, in order to maximise productivity it is essential to ensure that the sounding p...

  5. Improving Reading Comprehension by Using Media Literacy Activities.

    Hobbs, Renee

    2001-01-01

    Argues that media literacy activities in the English language arts classroom can promote the strategies of reflective thinking, self-monitoring, close observation, and visualization. Shows how one seventh-grade teacher develops students' understanding of character development by using a film excerpt, a graphic organizer for developing…

  6. Prognostic factors for survival of patients with glioblastoma: Recursive partitioning analysis1

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

    2004-01-01

    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. PMID:15279715

  7. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    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

  8. PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma.

    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.

  9. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

    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

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

    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

  11. Ontology-based improvement to human activity recognition

    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.

  12. Improving Regulatory Bodies’ Activities in Africa Through Regional Cooperation

    The Forum of Nuclear Regulatory Bodies in Africa (FNRBA) is presented as a good regional platform that plays key role in assisting the establishment of regulatory bodies and in enhancing and sustaining their activities. The FNRBA is founded on the aspirations of its members and the lessons learned from other similar regulatory networks. To achieve its objectives, the FNRBA needs more partners to learn and enhance its activities effectively, and particularly in the domain of radioactive sources control. The FNRBA is open to all nuclear regulatory bodies in the region and is voluntary. This cooperation makes use of the triangular cooperation mechanism that involves advanced and less advanced countries working together with assistance from the IAEA and other partners in development. (author)

  13. Improvement of enterprise activities based on process management

    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...

  14. IMPROVEMENT OF TAROM ACTIVITY BY THE REVENUE MANAGEMENT SYSTEM

    CÃTÃLIN PETRUª; CRISTINA STATE

    2012-01-01

    The aim of our research is to highlight ways of efficiency of activity of TAROM through implementation of the Revenue Management System. Revenue Management System is an approach adopted by companies that want to optimize their revenue stream. This is achieved through a thorough understanding of the market, and involves plotting the direction to follow in order to have the best economic results in the same conditions of cost and space. One of the effects that Revenue Management System and Yiel...

  15. Variable Patterned Pudendal Nerve Stimuli Improves Reflex Bladder Activation

    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...

  16. Application Of Active Screen Method For Ion Nitriding Efficiency Improvement

    Ogórek M.; Frączek T.; Skuza Z.

    2015-01-01

    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 i...

  17. Supercritical fractionation of rosemary extracts to improve the antioxidant activity

    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...

  18. Improving teacher awareness through activity, badge and content visualizations

    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 ...

  19. High-energy radiation improves flotation activity of kerosene

    The radiation-chemical effect of high-energy radiation on the flotation properties of kerosene was studied. For flotation of a molybdenum-quartz mixture it is shown that the use of irradiated kerosene increases molybdenum extraction by 8%. The increased flotation properties of kerosene upon irradiation persist for a long time. Irradiated kerosene shows no induced activity. Its utilization does not require any protective measures

  20. Lenalidomide normalizes tumor vessels in colorectal cancer improving chemotherapy activity

    Leuci, V.; Maione, F.; Rotolo, R.; Giraudo, E; Sassi, F.; Migliardi, G.; Todorovic, M.; Gammaitoni, L.; Mesiano, G.; Giraudo, L.; Luraghi, P.; Leone, F.; Bussolino, F.; Grignani, G.; Aglietta, M.

    2016-01-01

    Background Angiogenesis inhibition is a promising approach for treating metastatic colorectal cancer (mCRC). Recent evidences support the seemingly counterintuitive ability of certain antiangiogenic drugs to promote normalization of residual tumor vessels with important clinical implications. Lenalidomide is an oral drug with immune-modulatory and anti-angiogenic activity against selected hematologic malignancies but as yet little is known regarding its effectiveness for solid tumors. The aim...

  1. An Improved Virial Estimate of Solar Active Region Energy

    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...

  2. Improved methane storage capacities by sorption on wet active carbons

    Perrin, A.; Celzard, A.; Marache, J.F.; Furdin, G. [Universite Henri Poincare, Nancy (France). Laboratoire de Chimie du Solide Mineral

    2004-07-01

    The possibility of storing large amounts of natural gas within wet active carbons is examined. The sorption isotherms of methane at 2{sup o}C and up to 8 MPa are built for four carbonaceous materials. Three of them originate from the same precursor (coconut shell), are physically activated at various burn-offs and are mainly microporous. The fourth material is a highly mesoporous chemically activated pinewood carbon. These adsorbents are wetted with a constant weight ratio water/carbon close to 1. The resulting isotherms all exhibit a marked step occurring near the expected formation pressure of methane hydrates, thus supporting their occurrence within the porous materials. The amount of gas stored at the highest pressures investigated then ranges from 6 to 17 mol/kg of wet adsorbent (i.e., corresponding to 10-36 mol/kg of dry carbon), depending on the material. The results are discussed on the basis of the known pore texture of each adsorbent, and stoichiometries of the formed hydrates are calculated. Considerations about adsorption/desorption kinetics and metastability are also developed. (author)

  3. Information systems as a tool to improve legal metrology activities

    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.

  4. Improving Decision-Making Activities for Meningitis and Malaria

    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.

  5. Improving Decision-Making Activities for Meningitis and Malaria

    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.

  6. Fenton peroxidation improves the drying performance of waste activated sludge.

    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

  7. Mining bipartite graphs to improve semantic pedophile activity detection

    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...

  8. Highly active vitrification plant remote handling operational experience and improvements

    Operational experience and technological innovation in the area of remote handling is described for the Sellafield Waste Vitrification Plant (WVP). This plant turns Highly Active Liquid Wastes (HALW) into radioactively immobile, solid forms. The technology needed for remote handling of HALWs, such as ejectors and power fluidics is described as is the mechanical handling needed after the vitrification process. Key features of WVP are described, such as the in-cell cranes, master-slave manipulators and swabbing robots. The severity of the in-cell environment has highlighted the need for innovation in the remote handling equipment and these changes are also described. (UK)

  9. Improved modelling of a parallel plate active magnetic regenerator

    Engelbrecht, Kurt; Tušek, J.; Nielsen, Kaspar Kirstein;

    2013-01-01

    Much of the active magnetic regenerator (AMR) modelling presented in the literature considers only the solid and fluid domains of the regenerator and ignores other physical effects that have been shown to be important, such as demagnetizing fields in the regenerator, parasitic heat losses and fluid...... flow maldistribution in the regenerator. This paper studies the effects of these loss mechanisms and compares theoretical results with experimental results obtained on an experimental AMR device. Three parallel plate regenerators were tested, each having different demagnetizing field characteristics...

  10. Application Of Active Screen Method For Ion Nitriding Efficiency Improvement

    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.

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

    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...

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

    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

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

    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.

  14. Caffeine suppresses the progression of human glioblastoma via cathepsin B and MAPK signaling pathway.

    Cheng, Yu-Chen; Ding, You-Ming; Hueng, Dueng-Yuan; Chen, Jang-Yi; Chen, Ying

    2016-07-01

    Glioblastoma has aggressive proliferative and invasive properties. We investigated the effect of caffeine on the invasion and the anti-cancer effect in human glioblastomas. Caffeine reduced the invasion in U-87MG, GBM8401 and LN229 cells. Caffeine decreased mRNA, protein expression, and activity of cathepsin B. Besides, mRNA and protein expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) was upregulated by caffeine treatment, whereas matrix metalloproteinase-2 (MMP-2) was downregulated. The expression of Ki67, p-p38, phospforylated extracellular regulated protein kinases (p-ERK), and membranous integrin β1 and β3 was decreased by caffeine. The Rho-associated protein kinase (ROCK) inhibitor, Y27632, blocked the caffeine-mediated reduction of cathepsin B, phosphorylated focal adhesion kinase (p-FAK), and p-ERK, and invasion. Moreover, caffeine decreased the tumor size, cathepsin B and Ki67 expression in animal model. Caffeine reduced the invasion of glioma cells through ROCK-cathepsin B/FAK/ERK signaling pathway and tumor growth in orthotopic xenograft animal model, supporting the anti-cancer potential in glioma therapy. PMID:27260469

  15. Using NLP meta, Milton, metaphor models, for improving the activity of the organization

    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.

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

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

    2014-01-01

    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 in......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...

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

    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. PMID:23304418

  18. miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways.

    Liu, Zhenlin; Jiang, Zhongmin; Huang, Jianyong; Huang, Shuqiang; Li, Yanxia; Yu, Simiao; Yu, Shizhu; Liu, Xiaozhi

    2014-05-01

    Epidermal growth factor receptor (EGFR) signaling regulates glioblastoma cell proliferation, survival, migration and invasion and plays a key role in tumor progression. We show that microRNA-7 (miR-7) is a common regulator of the phosphoinositide-3-kinase (PI3K)/ATK and Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, both of which are launched by EGFR through its two direct targets, the transcription factors PI3K and Raf-1, respectively. Enforced expression of miR-7 markedly decreased expression of PI3K, phosphorylated Akt, Raf-1, phosphorylated MEK 1/2, and cyclin D1, as well as slightly reduced expression of EGFR. Forced expression of PI3K or Raf-1 transcripts lacking the 3'-untranslated region (3'-UTR) partially reversed the effects of miR-7 on cell growth inhibition and cell cycle arrest in glioma cells. Additionally, transient expression of miR-7 in glioblastoma cells strongly inhibited in vivo glioblastoma xenograft growth. We conclude that miR-7 is a potential tumor suppressor in glioblastoma that acts by targeting multiple oncogenes related to the downstream pathway of EGFR and may serve as a novel therapeutic target for malignant gliomas. PMID:24603851

  19. Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression.

    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

  20. GROWTH OF MANAGERIAL PERFORMANCE BY IMPROVING AUDITING ACTIVITY

    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.

  1. TENDENCY OF IMPROVEMENT ANALYSIS OF VENTURE ACTIVITY FOR MANAGEMENT DECISIONS

    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.

  2. Using robust statistics to improve neutron activation analysis results

    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)

  3. Using robust statistics to improve neutron activation analysis results

    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)

  4. Mesoporous Metal-Containing Carbon Nitrides for Improved Photocatalytic Activities

    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.

  5. Activities of CEZ Inc. and improvement of the environment

    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.

  6. Contrast-enhancing tumor growth dynamics of preoperative, treatment-naive human glioblastoma.

    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...

  7. Somatic mutations in glioblastoma are associated with methylguanine-DNA methyltransferase methylation

    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. Improved activity and thermostability of Bacillus pumilus lipase by directed evolution

    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

  9. Physical Activity: A Tool for Improving Health (Part 3--Recommended Amounts of Physical Activity for Optimal Health)

    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…

  10. In vivo radiation sensitivity of glioblastoma multiforme

    Purpose: Human glioblastoma (GBM) is one of the most resistant tumors to radiation. In previous reports, we have demonstrated a wide range of radiation sensitivity of GBM in vitro; that is, SF2 values of 0.2 to 0.8. The great sensitivity of some of the cell lines is not in accord with the almost invariably fatal clinical outcome of patients with GBM. The sensitivity of cells in vitro pertains to cells cultured in optimal nutritional conditions. The TCD50 (the radiation dose necessary to control 50% of the tumors locally) determined in lab animals is analogous to the use of radiation with curative intent in clinical radiation oncology. The aim of the present study was (a) to evaluate the sensitivity of GBM in vivo relative to that of other tumor types and (b) assess the relationship between the single dose TCD50 of the xenografts and the sensitivity of the corresponding cell lines in vitro. Methods and Materials: The TCD50 assay was used to study twelve human tumor lines. Four previously published values were added. A total of 10 GBM, 4 squamous cell carcinoma (SCC), 1 soft tissue sarcoma (STS), and 1 cancer colon (CC) are included in the analysis. For further suppression of the residual immune system, all the animals received 6 Gy whole-body irradiation 1 day before transplantation. Local tumor irradiations were given as a single dose, under conditions of clamp hypoxia using a Cs irradiator. Results: The TCD50 values for the 10 GBM xenografts varied between 32.5 and 75.2 Gy, with an average of 47.2 ± 13.1 Gy. The TCD50 values for the SCC were similar to those of the GBM and ranged from 40.7 and 54.4 Gy, with a mean of 46.8 ± 6.4. The difference between the average TCD50 of GBM and SCC was not significant. The STS and CC xenografts had TCD50 values of 46.0 and 49.2 Gy, respectively. No correlation was found between the TCD50 in vivo and the SF2 or D0 in vitro. Conclusions: Our data on GBM xenografts showed a wide range of sensitivities to single dose irradiation

  11. How do Australian Small and Medium Enterprises Communicate their Environmental Improvement Activities Online?

    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.

  12. Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines

    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.

  13. Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines

    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 G1 arrest. T98 cells were a little more refractory to growth inhibition and A172 cells did not undergo a G1 arrest. This G1 arrest was associated with up-regulation of p27kip1, 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 G1 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 ΔEGFR 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.

  14. Can online activities improve attitude to homework and improve academic performance in science with fifth year students at second level

    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...

  15. Prognostic factors in glioblastoma multiforme. 10 years experience of a single institution

    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

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

    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

  17. Short-term effects of radiation in glioblastoma spheroids

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

    2016-01-01

    investigate the short-term effects of radiation of spheroids containing tumor-initiating stem-like cells. We used a patient-derived glioblastoma stem cell enriched culture (T76) and the standard glioblastoma cell line U87. Primary spheroids were irradiated with doses between 2 and 50 Gy and assessed after two...... capacity. Gene expression analysis of nine stem cell- and two hypoxia-related genes did not reveal any upregulation after radiation. In conclusion, this study suggests that a major short-term effect of radiation is pronounced reduction of tumor cell proliferation. We found no upregulation of stem cell......-related genes. This may suggest a limited effect of targeting these genes within the first days after radiation therapy....

  18. Cellule Staminali di Glioblastoma: Terapia Oncolitica con Vettori Erpetici Ingegnerizzati

    Sgubin, Donatella

    2014-01-01

    Il Glioblastoma (GBM), nonostante i migliori standard terapeutici, rimane una patologia a prognosi infausta. L’ipotesi delle Glioma Stem-like Cells (GSCs) prevede che, nella massa tumorale, sia presente una popolazione di cellule resistenti alla chemio e radioterapia e che tali cellule siano quindi le possibili responsabili della recidiva di malattia. Le GSCs, che possiedono caratteristiche comuni alle cellule staminali fisiologicamente presenti nel cervello adulto, sono cellule a lenta cresc...

  19. Genetic Characteristics of Glioblastoma: Clinical Implications of Heterogeneity

    Qian Li

    2015-01-01

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

  20. Radiotherapy with and without temozolomide in elderly patients with glioblastoma

    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/m2 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.)

  1. Molecular Characteristics in MRI-Classified Group 1 Glioblastoma Multiforme

    Chin-HsingAnnieLin; RebeccaAIhrie; ArturoAlvarez-Buylla; RobertNEisenman

    2013-01-01

    Glioblastoma multiforme (GBM) is a clinically and pathologically heterogeneous brain tumor. Previous studies of transcriptional profiling have revealed biologically relevant GBM subtypes associated with specific mutations and dysregulated pathways. Here, we applied a modified proteome to uncover abnormal protein expression profile in a MRI-classified group I GBM (GBM1), which has a spatial relationship with one of the adult neural stem cell niches, subventricular zone (SVZ). Most importantly,...

  2. Master Regulators, Regulatory Networks, and Pathways of Glioblastoma Subtypes

    Serdar Bozdag; Aiguo Li; Mehmet Baysan; Fine, Howard A.

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor. GBM samples are classified into subtypes based on their transcriptomic and epigenetic profiles. Despite numerous studies to better characterize GBM biology, a comprehensive study to identify GBM subtype- specific master regulators, gene regulatory networks, and pathways is missing. Here, we used FastMEDUSA to compute master regulators and gene regulatory networks for each GBM subtype. We also ran Gene Set Enrichment Analy...

  3. The proteomic response in glioblastoma in young patients

    Deighton, Ruth F.; Le Bihan, Thierry; Martin, Sarah F; Barrios-Llerena, Martin E.; Gerth, Alice M. J.; Kerr, Lorraine E.; McCulloch, James; Whittle, Ian R

    2014-01-01

    Increasing age is an important prognostic variable in glioblastoma (GBM). We have defined the proteomic response in GBM samples from 7 young patients (mean age 36 years) compared to peritumoural-control samples from 10 young patients (mean age 32 years). 2-Dimensional-gel-electrophoresis, image analysis, and protein identification (LC/MS) were performed. 68 proteins were significantly altered in young GBM samples with 29 proteins upregulated and 39 proteins downregulated. Over 50 proteins are...

  4. Genetic investigation of multicentric glioblastoma multiforme: case report.

    Schroeder, Brett; Shah, Nameeta; Rostad, Steve; McCullough, Brendan; Aguedan, Brian; Foltz, Greg; Cobbs, Charles

    2016-05-01

    The authors report a case of multicentric glioblastoma multiforme (GBM) in which all 4 tumor foci were resected and evaluated using both comparative genomic hybridization array and RNA sequencing. Genetic analysis showed that the tumors shared a common origin, although each had its own unique set of genetic aberrations. The authors note that the genetic heterogeneity of multicentric GBM likely contributes to the failures of current treatments. The case underscores the necessity of increased genetic investigation. PMID:26473785

  5. Current Trends in Targeted Therapies for Glioblastoma Multiforme

    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 ...

  6. Role of bevacizumab therapy in the management of glioblastoma

    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...

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

    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...

  8. New Molecular Targets in the Angiogenic Vessels of Glioblastoma Tumors

    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...

  9. BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors

    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

  10. Glioblastoma and intracranial aneurysms: Case report and review of literature

    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...

  11. Efficacy and safety of bevacizumab for the treatment of glioblastoma

    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...

  12. Antivascular Endothelial Growth Factor Antibody for Treatment of Glioblastoma Multiforme

    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...

  13. An integrative characterization of recurrent molecular aberrations in glioblastoma genomes

    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...

  14. NT-38MerTK AS A TARGET IN GLIOBLASTOMA

    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...

  15. Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma

    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...

  16. Recurrent Glioblastoma Multiforme: Implication of Nonenhancing Lesions on Bevacizumab Treatment

    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...

  17. ASSOCIATIONS BETWEEN POLYMORPHISMS IN DNA REPAIR GENES AND GLIOBLASTOMA

    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....

  18. The identification of mitochondrial DNA variants in glioblastoma multiforme

    Yeung, Ka Yu; Dickinson, Adam; Donoghue, Jacqueline F.; Polekhina, Galina; Stefan J. White; Grammatopoulos, Dimitris K; McKenzie, Matthew; Johns, Terrance G; John, Justin C St

    2014-01-01

    Background Mitochondrial DNA (mtDNA) encodes key proteins of the electron transfer chain (ETC), which produces ATP through oxidative phosphorylation (OXPHOS) and is essential for cells to perform specialised functions. Tumor-initiating cells use aerobic glycolysis, a combination of glycolysis and low levels of OXPHOS, to promote rapid cell proliferation and tumor growth. Glioblastoma multiforme (GBM) is an aggressively malignant brain tumor and mitochondria have been proposed to play a vital ...

  19. Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

    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...

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

    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...

  1. MGMT Methylation Status: The Advent of Stratified Therapy in Glioblastoma?

    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...

  2. Glioblastoma and the significance of MGMT gene methylation

    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...

  3. Current Challenges in Glioblastoma: Intratumour Heterogeneity, Residual Disease, and Models to Predict Disease Recurrence.

    Ellis, Hayley P; Greenslade, Mark; Powell, Ben; Spiteri, Inmaculada; Sottoriva, Andrea; Kurian, Kathreena M

    2015-01-01

    Glioblastoma (GB) is the most common primary malignant brain tumor, and despite the availability of chemotherapy and radiotherapy to combat the disease, overall survival remains low with a high incidence of tumor recurrence. Technological advances are continually improving our understanding of the disease, and in particular, our knowledge of clonal evolution, intratumor heterogeneity, and possible reservoirs of residual disease. These may inform how we approach clinical treatment and recurrence in GB. Mathematical modeling (including neural networks) and strategies such as multiple sampling during tumor resection and genetic analysis of circulating cancer cells, may be of great future benefit to help predict the nature of residual disease and resistance to standard and molecular therapies in GB. PMID:26636033

  4. 5-aminolevulinic acid guidance during awake craniotomy to maximise extent of safe resection of glioblastoma multiforme.

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

    Telmo A.B. Belsuzarri

    2015-03-01

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

  6. Pharmacokinetics and tolerance of nicotinamide combined with radiation therapy in patients with glioblastoma multiforme

    The pharmacokinetic properties of nicotinamide and its tolerance were studied in seven patients affected by glioblastoma multiforme and treated with two fractions per day of radiation therapy. Nicotinamide was given orally at two daily doses of 4 g and then 2 g separated by a 6-h-interval. The treatment was well tolerated in almost all patients and had no effect on blood pressure, cardiac rhythm or body temperature. Pharmacokinetic analysis showed peak plasma levels (Cmax) above 100 mg/l 45 minutes after the administration of both doses. This was followed by a biexponential decay of plasma concentrations with a thermal half life of 9.4 h. Tumours were irradiated 1 hour after each drug dose to match with drug Cmax in plasma, and although it is too early to evaluate the tumour response, the drug levels achieved should be sufficient to improve radiation therapy. (orig.)

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

    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

  8. MiRNA expression patterns predict survival in glioblastoma

    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

  9. Glioblastoma multiforme of the pineal region: case report

    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.

  10. 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.

    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

  11. 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

    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

  12. Arrested neural and advanced mesenchymal differentiation of glioblastoma cells-comparative study with neural progenitors

    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.

  13. Program to improve the effectiveness of education and professional activities of college students

    I.V. Vlaskina

    2013-01-01

    We describe a training program on “Psychology of effective professional activity”, realized on the basis of the Ural College of the Beauty Industry. The purpose of this discipline is to improve the effectiveness of education and professional activities of college students acquiring professions of “Human-Human” type. To improve effectiveness of education and professional activities, this program provides formation of professionally important qualities of students. The results of the program ca...

  14. Volumetric Spectroscopic Imaging of Glioblastoma Multiforme Radiation Treatment Volumes

    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

  15. EG-11DYSREGULATION OF MGMT IN GLIOBLASTOMA: FRIEND OR FOE?

    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. Improving Settling Dynamics of Activated Sludge by Adding Fine Talc Powder

    Rasmussen, Michael R.; Larsen, Torben; Clauss, F.

    1996-01-01

    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. 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....

  17. A Study on the Improvement of Student’s Reading Ability Through Active-Reading

    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. Performance Improvement of Shunt Active Power Filter With Dual Parallel Topology

    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...

  19. Improving Enzyme Activity and Broadening Selectivity for Biological Desulfurization and Upgrading of Petroleum Feedstocks

    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

  20. Doxycycline Improves Filarial Lymphedema Independent of Active Filarial Infection: A Randomized Controlled Trial

    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.

  1. The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model

    Garcia, Celina; Dubois, Luiz Gustavo; Xavier, Anna Lenice; Geraldo, Luiz Henrique; da Fonseca, Anna Carolina Carvalho; Correia, Ana Helena; Meirelles, Fernanda; Ventura, Grasiella; Romão, Luciana; Canedo, Nathalie Henriques Silva; de Souza, Jorge Marcondes; de Menezes, João Ricardo Lacerda; Moura-Neto, Vivaldo; Tovar-Moll, Fernanda; Lima, Flavia Regina Souza

    2014-01-01

    Background Glioblastoma (GBM) is the most common primary brain tumor and the most aggressive glial tumor. This tumor is highly heterogeneous, angiogenic, and insensitive to radio- and chemotherapy. Here we have investigated the progression of GBM produced by the injection of human GBM cells into the brain parenchyma of immunocompetent mice. Methods Xenotransplanted animals were submitted to magnetic resonance imaging (MRI) and histopathological analyses. Results Our data show that two weeks a...

  2. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain

    Lee, Se Jeong; Kang, Won Young; Yoon, Yeup; Jin, Ju Youn; Song, Hye Jin; Her, Jung Hyun; Kang, Sang Mi; Hwang, Yu Kyeong; Kang, Kyeong Jin; Joo, Kyeung Min; Nam, Do-Hyun

    2015-01-01

    Background Glioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Molecular mechanisms inhibiting systemic metastasis of GBM would be a novel therapeutic candidate for GBM in the brain. Methods Patient-derived GBM cells were primarily cultured from surgical samples of GBM patients and were inoculated into the brains of immune deficient BALB/c-nude or NOD-SCID IL2Rgammanull (NSG) mice. Human NK cells were...

  3. Glioblastoma patients in Slovenia from 1997 to 2008

    Glioblastoma is the most common primary brain tumour. It has a poor prognosis despite some advances in treatment that have been achieved over the last ten years. In Slovenia, 50 to 60 glioblastoma patients are diagnosed each year. In order to establish whether the current treatment options have any influence on the survival of the Slovenian glioblastoma patients, their data in the period from the beginning of the year 1997 to the end of the year 2008 have been analysed. All patients treated at the Institute of Oncology Ljubljana from 1997 to 2008 were included in the retrospective study. Demographics, treatment details, and survival time after the diagnosis were collected and statistically analysed for the group as a whole and for subgroups. From 1997 to 2008, 527 adult patients were diagnosed with glioblastoma and referred to the Institute of Oncology for further treatment. Their median age was 59 years (from 20 to 85) and all but one had the diagnosis confirmed by a pathologist. Gross total resection was reported by surgeons in 261 (49.5%) patients; good functional status (WHO 0 or 1) after surgery was observed in 336 (63.7%) patients, radiotherapy was performed in 422 (80.1%) patients, in 317 (75.1%) of them with radical intent, and 198 (62.5 %) of those received some form of systemic treatment (usually temozolomide). The median survival of all patients amounted to 9.7 months. There was no difference in median survival of all patients or of all treated patients before or after the chemo-radiotherapy era. However, the overall survival of patients treated with radical intent was significantly better (11.4 months; p < 0.05). A better survival was also noticed in radically treated patients who received additional temozolomide therapy (11.4 vs. 13.1 months; p = 0.014). The longer survival was associated with a younger age and a good performance status as well as with a more extensive tumour resection. In patients treated with radical intent, having a good performance

  4. Initiation and characterization of a glioblastoma multiforme derived cell line.

    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.

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

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

    2016-08-01

    Glioblastoma (GBM) is the most aggressive brain tumor in adults. It is strongly infiltrated by microglia and peripheral monocytes that support tumor growth. In the present study we used RNA sequencing to compare the expression profile of CD11b(+) human glioblastoma-associated microglia/monocytes (hGAMs) to CD11b(+) microglia isolated from non-tumor samples. Hierarchical clustering and principal component analysis showed a clear separation of the two sample groups and we identified 334 significantly regulated genes in hGAMs. In comparison to human control microglia hGAMs upregulated genes associated with mitotic cell cycle, cell migration, cell adhesion, and extracellular matrix organization. We validated the expression of several genes associated with extracellular matrix organization in samples of human control microglia, hGAMs, and the hGAMs-depleted fraction via qPCR. The comparison to murine GAMs (mGAMs) showed that both cell populations share a significant fraction of upregulated transcripts compared with their respective controls. These genes were mostly related to mitotic cell cycle. However, in contrast to murine cells, human GAMs did not upregulate genes associated to immune activation. Comparison of human and murine GAMs expression data to several data sets of in vitro-activated human macrophages and murine microglia showed that, in contrast to mGAMs, hGAMs share a smaller overlap to these data sets in general and in particular to cells activated by proinflammatory stimulation with LPS + INFγ or TNFα. Our findings provide new insights into the biology of human glioblastoma-associated microglia/monocytes and give detailed information about the validity of murine experimental models. GLIA 2016 GLIA 2016;64:1416-1436. PMID:27312099

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

    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

  7. Improved activity of immobilized horseradish peroxidase on gold nanoparticles in the presence of bovine serum albumin

    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

  8. Improved activity of immobilized horseradish peroxidase on gold nanoparticles in the presence of bovine serum albumin

    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.

  9. Transcription factor 3 controls cell proliferation and migration in glioblastoma multiforme cell lines.

    Li, Ruiting; Li, Yinghui; Hu, Xin; Lian, Haiwei; Wang, Lei; Fu, Hui

    2016-06-01

    Transcription factor 3 (TCF3) is a member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family. Recent studies have demonstrated its potential carcinogenic properties. Here we show that TCF3 was upregulated in glioma tissues compared with normal brain tissues. This upregulation of the TCF3 gene probably has functional significance in brain-tumor progression. Our studies on glioblastoma multiforme (GBM) cell lines show that knock-down of TCF3 induced apoptosis and inhibited cell migration. Further analysis revealed that down-regulation of TCF3 gene expression inhibits Akt and Erk1/2 activation, suggesting that the carcinogenic properties of TCF3 in GBM are partially mediated by the phosphatidylinositol 3-kinase-Akt and MAPK-Erk signaling pathways. Considered together, the results of this study demonstrate that high levels of TCF3 in gliomas potentially promote glioma development through the Akt and Erk pathways. PMID:27105323

  10. MTR-18 Predictive Biomarkers Of Bevacizumab Response In Recurrent Glioblastoma Patients

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

    2015-01-01

    Bevacizumab (BEV) plus chemotherapy has shown activity in recurrent glioblastoma (GBM). However, the prognosis varies and only one third of patients have a durable clinical response to BEV combination therapy. Recent findings from a randomized phase-3 study (AVAglio) indicate that patients with the...... evaluate the predictive and prognostic value of GBM subtypes in recurrent GBM patients treated with BEV therapy. The secondary objective was to identify biomarkers able to predict response to BEV therapy in recurrent GBM patients. METHODS: A total of 90 recurrent GBM patients treated with BEV combination...... proneural GBM subtype have a survival benefit when treated with BEV in combination with standard treatment. However, no validated biomarkers able to predict BEV response have been identified and the biology reflecting a clinical BEV response is poorly understood. The primary objective of this study was to...

  11. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy†

    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

  12. A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy.

    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

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

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

    1998-05-01

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

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

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

  15. MRI texture features as biomarkers to predict MGMT methylation status in glioblastomas

    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...

  16. Glioblastomas with Oligodendroglial Component – Common Origin of the Different Histological Parts and Genetic Subclassification

    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.

  17. Necrosis de médula espinal, edema cerebral y glioblastoma

    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.

  18. Mutations Closer to the Active Site Improve the Promiscuous Aldolase Activity of 4-Oxalocrotonate Tautomerase More Effectively than Distant Mutations.

    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

  19. Physical Activity: A Tool for Improving Health (Part 1--Biological Health Benefits)

    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…

  20. The improvement of methodical aspects of assessing the effectiveness of activity of joint stock companies

    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».