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GBM
Terms modified by GBM Selected AbstractsEffects of aminoguanidine and tolrestat on the development of ocular and renal structural changes in experimental diabetic ratsDIABETES OBESITY & METABOLISM, Issue 1 2002Ö. Azal Studies that researched the role of aminoguanidine and tolestat in the prevention of diabetic retinopathy and nephropathy resulted in conflicting data. We investigated the effects of these agents in the prevention of ocular and renal changes in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by intravenous injection of STZ in 30 rats. Ten rats that were not given STZ served as non-diabetic control (Group 1). Ten STZ-diabetic rats that were not given any treatment served as diabetic control (Group 2). Groups 3 and 4 were composed of STZ-induced diabetic rats (10 each) that were given tolrestat and aminoguanidine respectively. Eyes and kidneys were examined at the 24th week under electronmicroscopy. Cataract was observed in all six of the surviving rats in Groups 2 and 4, and in one of 6 surviving rats in group 3. Cataract development was lower in Group 3 than Groups 2 and 4. All retinal samples obtained from group 2 demonstrated a number of structural abnormalities, whereas there were no significant ultrastructural changes in groups 3 and 4. Groups 2 and 3 demonstrated mesangial proliferation and expansion, diffuse glomerular basement membrane (GBM) thickening, and focal GBM thickening in the bulb form. Group 4 demonstrated a normally appearing mesangial space, minimal diffuse but no focal GBM thickening. The urinary albumin excretion (UAE) was lower in Group 4 than the other groups. In conclusion, our results suggest that aminoguanidine may be an important agent for the prevention of renal changes, whereas tolrestat may be effective for the prevention of ocular changes in diabetes mellitus. [source] Targeting the p53 tumor suppressor gene function in glioblastomas using small chemical moleculesDRUG DEVELOPMENT RESEARCH, Issue 10 2006Roberta Magrini Abstract Glioblastoma multiforme (GBM) is recognized as the most frequent and malignant glioma of which two genetically different subtypes can be distinguished. Primary, de novo glioblastomas show a p53 wild type (wt) status and in 10% of the cases hdm2 overexpression/amplifications occur. In these tumors, the inactivation of the tumor suppressor p53 is elicited by enhanced hdm2-mediated degradation of p53. Secondary glioblastomas, on the other hand, show inactivating p53 mutations (mut) in 40% of the cases. Based on these observations, reactivating the function of p53 might hold promise for treatment of GBM. In wt p53 tumors showing increased hdm2 levels, the therapeutic strategy might be to inhibit the activity of hdm2 by treatment with small molecules like nutlin-3. For mut p53 glioblastomas, p53 function might be restored using small chemical entities such as PRIMA-1. Drug Dev. Res. 67:790,800, 2006. © 2007 Wiley-Liss, Inc. [source] Role of mast cells in experimental anti-glomerular basement membrane glomerulonephritisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2005Kathrin Hochegger Abstract Recently, divergent reports on the role of mast cells (MC) in different glomerular diseases have brought our attention to their role in an accelerated model of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Genetically MC-deficient KitW/KitW - v mice, MC-reconstituted KitW/KitW - v mice and Kit+/+ control mice were subjected to anti-GBM GN. Kit+/+ mice developed moderate proteinuria and glomerular damage following the induction of anti-GBM nephritis. In contrast, proteinuria and glomerular damage were dramatically increased in MC-deficient KitW/KitW - v mice. MC-reconstituted KitW/KitW - v mice showed proteinuria and glomerular damage comparable to Kit+/+ mice. A significant increase in infiltrating T cells and macrophages was detected in MC-deficient KitW/KitW - v mice as compared to Kit+/+ control mice and MC-reconstituted KitW/KitW - v mice. Accordingly, we observed an increase of TGF-,1 mRNA in kidneys from KitW/KitW - v mice. Interestingly, we did not detect MC in the kidney using either Giemsa staining or RT-real-time PCR, but MC were found in the regional lymph nodes. Finally, mortality of KitW/KitW - v mice was significantly increased after the induction of anti-GBM GN due to uremia. Our report provides the first direct evidence that MC are protective in anti-GBM GN, possibly by modulating the influx of effector T cells and macrophages to inflammatory sites in the kidney. [source] Glioblastoma cells incorporate into tumor vasculature and contribute to vascular radioresistanceINTERNATIONAL JOURNAL OF CANCER, Issue 9 2010Candice A. Shaifer Abstract Glioblastoma multiforme (GBM) remains the most devastating neoplasm of the central nervous system and has a dismal prognosis. Ionizing radiation represents an effective therapy for GBM, but radiotherapy remains only palliative because of radioresistance. In this study, we demonstrate that glioma cells participate in tumor vascularization and contribute to vascular radioresistance. Using a 3-dimensional coculture system, we observed an intimate interaction of glioma cells with endothelial cells whereby endothelial cells form vascular structures, followed by the recruitment and vascular patterning of glioma cells. In addition, tumor cells stabilize the vascular structures and render them radioresistant. Blocking initial endothelial vascular formation with endothelial-specific inhibitors prevented tumor cells from forming any structures. However, these inhibitors exhibited minimum effects on vascular structures formed by tumor cells, due to the absence of the targeted receptors on tumor cells. Consistent with the in vitro findings, we show that glioma cells form perfused blood vessels in xenograft tumor models. Together, these data suggest that glioma cells mimic endothelial cells and incorporate into tumor vasculature, which may contribute to radioresistance observed in GBM. Therefore, interventions aimed at the glioma vasculature should take into consideration the chimeric nature of the tumor vasculature. [source] MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcomeINTERNATIONAL JOURNAL OF CANCER, Issue 4 2009Ulrika Andersson Abstract The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan,Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56,3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81,2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41,3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations. © 2009 UICC [source] Inhibition of telomerase in the endothelial cells disrupts tumor angiogenesis in glioblastoma xenograftsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2008Maria Laura Falchetti Abstract Tumor angiogenesis is a complex process that involves a series of interactions between tumor cells and endothelial cells (ECs). In vitro, glioblastoma multiforme (GBM) cells are known to induce an increase in proliferation, migration and tube formation by the ECs. We have previously shown that in human GBM specimens the proliferating ECs of the tumor vasculature express the catalytic component of telomerase, hTERT, and that telomerase can be upregulated in human ECs by exposing these cells to GBM in vitro. Here, we developed a controlled in vivo assay of tumor angiogenesis in which primary human umbilical vascular endothelial cells (HUVECs) were subcutaneously grafted with or without human GBM cells in immunocompromised mice as Matrigel implants. We found that primary HUVECs did not survive in Matrigel implants, and that telomerase upregulation had little effect on HUVEC survival. In the presence of GBM cells, however, the grafted HUVECs not only survived in Matrigel implants but developed tubule structures that integrated with murine microvessels. Telomerase upregulation in HUVECs enhanced such effect. More importantly, inhibition of telomerase in HUVECs completely abolished tubule formation and greatly reduced survival of these cells in the tumor xenografts. Our data demonstrate that telomerase upregulation by the ECs is a key requisite for GBM tumor angiogenesis. © 2007 Wiley-Liss, Inc. [source] Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomasINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008Suely K.N. Marie Abstract We have performed cDNA microarray analyses to identify gene expression differences between highly invasive glioblastoma multiforme (GBM) and typically benign pilocytic astrocytomas (PA). Despite the significant clinical and pathological differences between the 2 tumor types, only 63 genes were found to exhibit 2-fold or greater overexpression in GBM as compared to PA. Forty percent of these genes are related to the regulation of the cell cycle and mitosis. QT-PCR validation of 6 overexpressed genes: MELK, AUKB, ASPM, PRC1, IL13RA2 and KIAA0101 confirmed at least a 5-fold increase in the average expression levels in GBM. Maternal embryonic leucine zipper kinase (MELK) exhibited the most statistically significant difference. A more detailed investigation of MELK expression was undertaken to study its oncogenic relevance. In the examination of more than 100 tumors of the central nervous system, we found progressively higher expression of MELK with astrocytoma grade and a noteworthy uniformity of high level expression in GBM. Similar level of overexpression was also observed in medulloblastoma. We found neither gene promoter hypomethylation nor amplification to be a factor in MELK expression, but were able to demonstrate that MELK knockdown in malignant astrocytoma cell lines caused a reduction in proliferation and anchorage-independent growth in in vitro assays. Our results indicate that GBM and PA differ by the expression of surprisingly few genes. Among them, MELK correlated with malignancy grade in astrocytomas and represents a therapeutic target for the management of the most frequent brain tumors in adult and children. © 2007 Wiley-Liss, Inc. [source] Telomerase inhibition by stable RNA interference impairs tumor growth and angiogenesis in glioblastoma xenograftsINTERNATIONAL JOURNAL OF CANCER, Issue 9 2006Roberto Pallini Abstract Telomerase is highly expressed in advanced stages of most cancers where it allows the clonal expansion of transformed cells by counteracting telomere erosion. Telomerase may also contribute to tumor progression through still undefined cell growth-promoting functions. Here, we inhibited telomerase activity in 2 human glioblastoma (GBM) cell lines, TB10 and U87MG, by targeting the catalytic subunit, hTERT, via stable RNA interference (RNAi). Although the reduction in telomerase activity had no effect on GBM cell growth in vitro, the development of tumors in subcutaneously and intracranially grafted nude mice was significantly inhibited by antitelomerase RNAi. The in vivo effect was observed within a relatively small number of population doublings, suggesting that telomerase inhibition may hinder cancer cell growth in vivo prior to a substantial shortening of telomere length. Tumor xenografts that arose from telomerase-inhibited GBM cells also showed a less-malignant phenotype due both to the absence of massive necrosis and to reduced angiogenesis. © 2005 Wiley-Liss, Inc. [source] Hydro-meteorological variability in the greater Ganges,Brahmaputra,Meghna basinsINTERNATIONAL JOURNAL OF CLIMATOLOGY, Issue 12 2004MD. Rashed Chowdhury Abstract The flows of the Ganges, Brahmaputra and Meghna (GBM) are highly seasonal, and heavily influenced by monsoon rainfall. As a result, these rivers swell to their banks and often overflow during the monsoon months. This is most pronounced in the downstream regions, particularly in Bangladesh, which is the lowest riparian country. The objective of this paper is to study this hydro-meteorological variability in the greater GBM regions, including the headwater regions in India and their role in streamflows in Bangladesh, and explore the large-scale oceanic factors affecting this hydro-meteorological variability. Global precipitation data, Bangladesh rainfall and streamflow records have been analysed and related to large-scale climate patterns, including upstream rainfall, regional atmospheric circulation and patterns of sea-surface temperature. The findings have quantified how the streamflows of these rivers in Bangladesh are highly correlated with the rainfall in the upper catchments with typically a lag of about 1 month. Therefore, streamflows in Bangladesh could be reasonably estimated for 1 to 3 months in advance (especially for the Ganges and Brahmaputra rivers) by employing simple correlation, if rainfall data from countries further up are available on a real-time and continuous basis. In the absence of rainfall data, streamflow forecasts are still possible from unusually warm or cold sea-surface temperatures in the tropics. The study concludes that hydro-meteorological information flow between Bangladesh and other neighbouring countries is essential for developing a knowledge base for evaluating the potential implications of seasonal streamflow forecast in the GBM basins in Bangladesh. Copyright © 2004 Royal Meteorological Society [source] A role for the transcription factor HEY1 in glioblastomaJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2009Esther Hulleman Abstract Glioblastoma multiforme (GBM), the highest-grade glioma, is the most frequent tumour of the brain with a very poor prognosis and limited therapeutic options. Although little is known about the molecular mechanisms that underlie glioblastoma formation, a number of signal transduction routes, such as the Notch and Ras signalling pathways, seem to play an important role in the formation of GBM. In the present study, we show by in situ hybridization on primary tumour material that the transcription factor HEY1, a target of the Notch signalling pathway, is specifically up-regulated in glioma and that expression of HEY1 in GBM correlates with tumour-grade and survival. In addition, we show by chromatin immunoprecipitations, luciferase assays and Northern blot experiments that HEY1 is a bona fide target of the E2F family of transcription factors, connecting the Ras and Notch signalling pathways. Finally, we show that ectopic expression of HEY1 induces cell proliferation in neural stem cells, while depletion of HEY1 by RNA interference reduces proliferation of glioblastoma cells in tissue culture. Together, these data imply a role for HEY1 in the progression of GBM, and therefore we propose that HEY1 may be a therapeutic target for glioblastoma patients. Moreover, HEY1 may represent a molecular marker to distinguish GBM patients with a longer survival prognosis from those at high risk. [source] Non-patient related variables affecting levels of vascular endothelial growth factor in urine biospecimensJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 4 2008M. J. Kirk Abstract Vascular endothelial growth factor (VEGF) is an angiogenic protein proposed to be an important biomarker for the prediction of tumour growth and disease progression. Recent studies suggest that VEGF measurements in biospecimens, including urine, may have predictive value across a range of cancers. However, the reproducibility and reliability of urinary VEGF measurements have not been determined. We collected urine samples from patients receiving radiation treatment for glioblastoma multiforme (GBM) and examined the effects of five variables on measured VEGF levels using an ELISA assay. To quantify the factors affecting the precision of the assay, two variables were examined: the variation between ELISA kits with different lot numbers and the variation between different technicians. Three variables were tested for their effects on measured VEGF concentration: the time the specimen spent at room temperature prior to assay, the addition of protease inhibitors prior to specimen storage and the alteration of urinary pH. This study found that VEGF levels were consistent across three different ELISA kit lot numbers. However, significant variation was observed between results obtained by different technicians. VEGF concentrations were dependent on time at room temperature before measurement, with higher values observed 3,7 hrs after removal from the freezer. No significant difference was observed in VEGF levels with the addition of protease inhibitors, and alteration of urinary pH did not significantly affect VEGF measurements. In conclusion, this determination of the conditions necessary to reliably measure urinary VEGF levels will be useful for future studies related to protein biomarkers and disease progression. [source] Intimate partner violence relationship dissolution among couples with children: the counterintuitive role of "Law and Order" neighborhoodsJOURNAL OF COMMUNITY PSYCHOLOGY, Issue 4 2010Clifton R. Emery This study examined the relationship between intimate partner violence (IPV) relationship dissolution and neighborhood concentrated disadvantage, ethnic heterogeneity, residential instability, collective efficacy, and legal cynicism. Data from the Project on Human Development in Chicago Neighborhoods (PHDCN) Longitudinal survey were used to identify 658 cases of IPV in Wave 1. A generalized boosting model (GBM) was used to determine the best proximal predictors of relationship dissolution from the longitudinal data. Controlling for these predictors, logistic regression of neighborhood characteristics from the PHDCN community survey was used to predict IPV relationship dissolution in Wave 2. Counterintuitively, the authors find that neighborhoods high in legal cynicism have a greater likelihood of IPV relationship dissolution, controlling for other variables in the logistic regression model. However, analyses did not find that IPV relationship dissolution was related to neighborhood concentrated disadvantage, ethnic heterogeneity, residential instability, and collective efficacy. © 2010 Wiley Periodicals, Inc. [source] Causes and consequences of proteinuria: the kidney filtration barrier and progressive renal failureJOURNAL OF INTERNAL MEDICINE, Issue 3 2003K. Tryggvason Abstract., Tryggvason K, Pettersson E (Karolinska Institute, Stockholm, Sweden). Causes and consequences of proteinuria: the kidney filtration barrier and progressive renal failure (Review). J Intern Med 2003; 254: 216,224. The past few years have witnessed a major breakthrough in the understanding of the molecular mechanisms and ultrastructural changes behind the development of proteinuria. The discovery of several proteins in the glomerular podocyte and slit diaphragm, where mutations lead to disease, has revealed the importance of this cell with its diaphragm as the major filtration barrier as opposed to the glomerular basement membrane (GBM) previously ascribed this function. Furthermore, accumulating clinical as well as experimental evidence points to the harmful effects of proteinuria, irrespective of the original damage. The purpose of this review is to shed light on what we know today about the two sides of this ,coin', the causes and the consequences of proteinuria. [source] The natural compound n -butylidenephthalide derived from Angelica sinensis inhibits malignant brain tumor growth in vitro and in vivo3JOURNAL OF NEUROCHEMISTRY, Issue 4 2006Nu-Man Tsai Abstract The naturally-occurring compound, n -butylidenephthalide (BP), which is isolated from the chloroform extract of Angelica sinensis (AS-C), has been investigated with respect to the treatment of angina. In this study, we have examined the anti-tumor effects of n -butylidenephthalide on glioblastoma multiforme (GBM) brain tumors both in vitro and in vivo. In vitro, GBM cells were treated with BP, and the effects of proliferation, cell cycle and apoptosis were determined. In vivo, DBTRG-05MG, the human GBM tumor, and RG2, the rat GBM tumor, were injected subcutaneously or intracerebrally with BP. The effects on tumor growth were determined by tumor volumes, magnetic resonance imaging and survival rate. Here, we report on the potency of BP in suppressing growth of malignant brain tumor cells without simultaneous fibroblast cytotocixity. BP up-regulated the expression of Cyclin Kinase Inhibitor (CKI), including p21 and p27, to decrease phosphorylation of Rb proteins, and down-regulated the cell-cycle regulators, resulting in cell arrest at the G0/G1 phase for DBTRG-05MG and RG2 cells, respectively. The apoptosis-associated proteins were dramatically increased and activated by BP in DBTRG-05MG cells and RG2 cells, but RG2 cells did not express p53 protein. In vitro results showed that BP triggered both p53-dependent and independent pathways for apoptosis. In vivo, BP not only suppressed growth of subcutaneous rat and human brain tumors but also, reduced the volume of GBM tumors in situ, significantly prolonging survival rate. These in vitro and in vivo anti-cancer effects indicate that BP could serve as a new anti-brain tumor drug. [source] Combined Use of F-18 Fluorocholine Positron Emission Tomography and Magnetic Resonance Spectroscopy for Brain Tumor EvaluationJOURNAL OF NEUROIMAGING, Issue 3 2004Sandi A. Kwee MD ABSTRACT Background. Choline metabolism is often abnormal in malignant brain tumors.Methods. Brain positron emission tomography (PET) imaging with F-18 fluorocholine (FCH) was performed on 2 patients with intracranial lesions suspected to be high-grade malignant gliomas on the basis of magnetic resonance (MR) imaging and multivoxel 1H-MR spectroscopic imaging (MRSI) findings. Standardized uptake value (SUV) measurements on PET were compared with measurements of choline/creatine metabolite ratio on MRSI in corresponding regions. Brain biopsy revealed glioblastoma multiforme (GBM) in one case and demyelinating disease in the other.Results. In the case of GBM, the tumor demonstrated increased FCH uptake on PET. The mean and maximum SUV in areas of the tumor correlated with regional choline/ creatine ratio measurements (r= 0.76,P < .001;r= 0.83,P < .001, respectively). In the case of tumefactive demyelinating lesions, the lesion demonstrated low FCH uptake, which did not correlate with choline/ creatine ratio measurements.Conclusions. Assessments of choline metabolism may aid in evaluating intracranial mass lesions. [source] Intraoperative magnetic resonance imaging in the surgical treatment of cerebral metastasesJOURNAL OF SURGICAL ONCOLOGY, Issue 5 2010Christian Senft MD Abstract Background and Objectives To report on the value of intraoperative magnetic resonance imaging (iMRI) in the neurosurgical treatment of cerebral metastases (CM). Methods We performed a total of 204 surgical procedures with the use of a mobile ultra-low-field iMRI-unit. Of these, there were 12 craniotomies and 2 minimal-invasive procedures for CM, and 63 craniotomies for glioblastoma (GBM). Results On intraoperative imaging, all tumors could be localized and targeted with the help of the integrated neuronavigation system. Intraoperative imaging resulted in continued tumor resection due to unexpected residual tumor tissue in 13 patients harboring GBM (20.6%), but no patient with a CM (0%). In two patients with cystic CM, iMRI helped to achieve complete collapse of cysts by means of stereotactic aspiration, relieving mass effect and allowing for adjuvant radiotherapy. All patients subsequently received adjuvant treatment according to clinical protocols. Conclusion Surgical resection represents one of several treatment modalities in metastatic brain disease. iMRI is useful for neuronavigation and resection control and as an adjunct in minimal-invasive procedures in patients with CM; however, its exact value is yet to be determined by prospective randomized trials. J. Surg. Oncol. 2010; 101:436,441. © 2010 Wiley-Liss, Inc. [source] Water Resources Modeling of the Ganges-Brahmaputra-Meghna River Basins Using Satellite Remote Sensing Data,JOURNAL OF THE AMERICAN WATER RESOURCES ASSOCIATION, Issue 6 2009Bushra Nishat Nishat, Bushra and S.M. Mahbubur Rahman, 2009. Water Resources Modeling of the Ganges-Brahmaputra-Meghna River Basins Using Satellite Remote Sensing Data. Journal of the American Water Resources Association (JAWRA) 45(6):1313-1327. Abstract:, Large-scale water resources modeling can provide useful insights on future water availability scenarios for downstream nations in anticipation of proposed upstream water resources projects in large international river basins (IRBs). However, model set up can be challenging due to the large amounts of data requirement on both static states (soils, vegetation, topography, drainage network, etc.) and dynamic variables (rainfall, streamflow, soil moisture, evapotranspiration, etc.) over the basin from multiple nations and data collection agencies. Under such circumstances, satellite remote sensing provides a more pragmatic and convenient alternative because of the vantage of space and easy availability from a single data platform. In this paper, we demonstrate a modeling effort to set up a water resources management model, MIKE BASIN, over the Ganges, Brahmaputra, and Meghna (GBM) river basins. The model is set up with the objective of providing Bangladesh, the lowermost riparian nation in the GBM basins, a framework for assessing proposed water diversion scenarios in the upstream transboundary regions of India and deriving quantitative impacts on water availability. Using an array of satellite remote sensing data on topography, vegetation, and rainfall from the transboundary regions, we demonstrate that it is possible to calibrate MIKE BASIN to a satisfactory level and predict streamflow in the Ganges and Brahmaputra rivers at the entry points of Bangladesh at relevant scales of water resources management. Simulated runoff for the Ganges and Brahmaputra rivers follow the trends in the rated discharge for the calibration period. However, monthly flow volume differs from the actual rated flow by (,) 8% to (+) 20% in the Ganges basin, by (,) 15 to (+) 12% in the Brahmaputra basin, and by (,) 15 to (+) 19% in the Meghna basin. Our large-scale modeling initiative is generic enough for other downstream nations in IRBs to adopt for their own modeling needs. [source] Genetic modification of mesenchymal stem cells to express a single-chain antibody against EGFRvIII on the cell surfaceJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 4 2010Irina V. Balyasnikova Abstract Human adult mesenchymal stem cells (hMSCs) are under active investigation as cellular carriers for gene therapy. hMSCs possess natural tropism toward tumours; however, the targeting of hMSCs to specific cell populations within tumours is unexplored. In the case of glioblastoma multiforme (GBM), at least half of the tumours express EGFRvIII on the cell surface, an ideal target for antibody-mediated gene/drug delivery. In this study, we investigated the feasibility of genetically modifying hMSCs to express a single-chain antibody (scFv) to EGFRvIII on their surfaces. Nucleofection was used to transfect hMSCs with cDNA encoding scFv EGFRvIII fused with PDGFR or human B7-1 transmembrane domains. The expression of scFv EGFRvIII on the cell surface was assessed by FACS. A stable population of scFv EGFRvIII-expressing hMSCs was selected, based on antibiotic resistance, and enriched using FACS. We found that nucleofection allows the efficient expression of scFv EGFRvIII on the cell surface of hMSCs. hMSCs transfected with the construct encoding scFv EGFRvIII as a fusion with PDGFRtm showed scFv EGFRvIII expression in up to 86% of cells. Most importantly, human MSCs expressing scFv against EGFRvIII demonstrated enhanced binding to U87-EGFRvIII cells in vitro and significantly increased retention in human U87-EGFRvIII-expressing tumours in vivo. In summary, we provide the first conclusive evidence of genetic modification of hMSCs with a single-chain antibody against an antigen expressed on the surface of tumour cells, thereby opening up a new venue for enhanced delivery of gene therapy applications in the context of malignant brain cancer. Copyright © 2009 John Wiley & Sons, Ltd. [source] Optical touch pointer for fluorescence guided glioblastoma resection using 5-aminolevulinic acid,LASERS IN SURGERY AND MEDICINE, Issue 1 2010Neda Haj-Hosseini MS Abstract Background and Objective Total tumor resection in patients with glioblastoma multiforme (GBM) is difficult to achieve due to the tumor's infiltrative way of growing and morphological similarity to the surrounding functioning brain tissue. The diagnosis is usually subjectively performed using a surgical microscope. The objective of this study was to develop and evaluate a hand-held optical touch pointer using a fluorescence spectroscopy system to quantitatively distinguish healthy from malignant brain tissue intraoperatively. Study Design/Materials and Methods A fluorescence spectroscopy system with pulsed modulation was designed considering optimum energy delivery to the tissue, minimal photobleaching of PpIX and omission of the ambient light background in the operating room (OR). 5-Aminolevulinic acid (5-ALA) of 5,mg/kg body weight was given to the patients with a presumed GBM prior to surgery. During the surgery a laser pulse at 405,nm was delivered to the tissue. PpIX in glioblastoma tumor cells assigned with peaks at 635 and 704,nm was detected using a fiber optical probe. Results/Conclusion By using the pulsed fluorescence spectroscopy, PpIX fluorescence is quantitatively detected in the GBM. An effective suppression of low power lamp background from the recorded spectra in addition to a significant reduction of high power surgical lights is achieved. Lasers Surg. Med. 42:9,14, 2010. © 2010 Wiley-Liss, Inc. [source] Monoclonal antibody against rat podocyte-derived macrophagic cells reacts with crescent-forming cells in an experimental modelNEPHROLOGY, Issue 5 2003MICHIAKI ORIKASA SUMMARY: The origin of crescent-forming cells in crescentic glomerulonephritis has not been clarified in spite of the application of monoclonal antibodies (mAbs) against glomerular epithelial cells or monocytes/macrophages. This study was undertaken to characterize the cellular composition of crescents using a new marker, mAb OS-3, produced against macrophagic cells derived from podocytes in normal rat glomerular culture. Monoclonal antibody OS-3 was confirmed to be reactive with some normal epithelial cells of Bowman's capsule. Female Wistar Kyoto rats were injected with rabbit antiglomerular basement membrane (GBM) serum and killed at 2 h, 1, 3, 7, 14 days and 2 months, respectively. The mAb OS-3-positive cells were segmentally observed in glomeruli at 3 days, increased at 14 days, but decreased at 2 months. These cells lacked reactivity with antipodocalyxin in double immunofluorescence (IF) staining. In immunoelectron microscopy of a glomerulus on day 3 and 7, however, reaction products were observed within cells located on the outer surface of the GBM, which were considered to be podocyte in terms of its localization. In conclusion, we have shown a possibility that damaged podocytes partly constitute crescent-forming cells with phenotypic changes, visualized by positive staining with mAb OS-3. We propose a novel concept of crescent formation, suggesting that crescents may be partly composed of phenotypically changed cells, which could not be detected by typical markers for glomerular epithelial cells or monocytes/macrophages. [source] Inflammatory cytokines in glomerulonephritisNEPHROLOGY, Issue 2002RC ATKINS SUMMARY: The importance of various inflammatory cytokines in mediating renal disease is now recognized, and the potential for the use of cytokine blockade as a therapeutic intervention is under active investigation. Studies in rat anti-glomerular basement membrane (GBM) disease model showed that antagonism of the proinflammatory cytokine IL-1 inhibited induction of glomerulonephritis, and prevented progression of established disease. A second cytokine Tumour Necrosis Factor-alpha (TNF-,) had similar proinflammatory effects to IL-1 in this model. Blocking the actions of both cytokines together, however, had no added benefit. Another cytokine Macrophage Migration Inhibitory Factor (MIF) has been shown to override the anti-inflammatory effects of corticosteriods. Renal MIF is markedly up-regulated in rat anti-GBM disease and blocking studies have demonstrated MIF plays a pathological role in mediating renal injury in this model. the importance of MIF in glomerulonephritis has been demonstrated by the fact that MIF is produced locally within the kidney, that it reflects the severity of the cellular immune response, and can be measured in the urine. Macrophage Migration Inhibitory Factor is up-regulated in human glomerular disease and correlates with loss of renal function and is thus a potential target for therapy for human glomerulonephritis. Thus, the inflammatory cytokines, IL 1, TNF-, and MIF each play a role in the immune/inflammatory process in glomerulonephritis. Blocking their action reduces disease and cytokine blocking agents have therapeutic potential. [source] Review: On TRAIL for malignant glioma therapy?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2010J. M. A. Kuijlen J. M. A. Kuijlen, E. Bremer, J. J. A. Mooij, W. F. A. den Dunnen and W. Helfrich (2010) Neuropathology and Applied Neurobiology36, 168,182 On TRAIL for malignant glioma therapy? Glioblastoma (GBM) is a devastating cancer with a median survival of around 15 months. Significant advances in treatment have not been achieved yet, even with a host of new therapeutics under investigation. Therefore, the quest for a cure for GBM remains as intense as ever. Of particular interest for GBM therapy is the selective induction of apoptosis using the pro-apoptotic tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL signals apoptosis via its two agonistic receptors TRAIL-R1 and TRAIL-R2. TRAIL is normally present as homotrimeric transmembrane protein, but can also be processed into a soluble trimeric form (sTRAIL). Recombinant sTRAIL has strong tumouricidal activity towards GBM cells, with no or minimal toxicity towards normal human cells. Unfortunately, GBM is a very heterogeneous tumour, with multiple genetically aberrant clones within one tumour. Consequently, any single agent therapy is likely to be not effective enough. However, the anti-GBM activity of TRAIL can be synergistically enhanced by a variety of conventional and novel targeted therapies, making TRAIL an ideal candidate for combinatorial strategies. Here we will, after briefly detailing the biology of TRAIL/TRAIL receptor signalling, focus on the promises and pitfalls of recombinant TRAIL as a therapeutic agent alone and in combinatorial therapeutic approaches for GBM. [source] Identification of MRI and 1H MRSI parameters that may predict survival for patients with malignant gliomasNMR IN BIOMEDICINE, Issue 1 2004Xiaojuan Li Abstract Although MR imaging (MRI) and MR spectroscopic imaging (MRSI) have been applied in the diagnosis and treatment planning for brain tumors, their prognostic significance has not yet been determined. The goal of this study was to identify pre-treatment MRI and MRSI parameters for patients with malignant glioma that may be useful in predicting survival. Two populations of patients with newly-diagnosed malignant glioma were examined with MRI and three-dimensional proton (1H) MRSI. Thirty-nine patients (22 grade 3 and 17 glioblastoma multiforme, GBM) were studied prior to surgery, and 33 GBM patients were studied after surgery but prior to treatment with radiation and chemotherapy. Signal intensities of choline (Cho), creatine (Cr), N -acetyl aspartate (NAA), and lactate/lipid (LL) were estimated from the spectra. Recursive partitioning methods were applied to parameters that included age, histological grade, MRI and MRSI variables to generate survival trees. Patients were grouped into high and low risk categories and the corresponding Kaplan,Meier curves were plotted for comparison between groups. The parameters that were selected by recursive partitioning as being predictive of poor outcome were older age, larger contrast enhancement, higher Cho-to-Cr, higher Cho-to-NAA, higher LL and lower Cr-to-NAA abnormalities. The survival functions were significantly different between the sub-groups of patients obtained from the survival tree for both pre-surgery and post-surgery data. The results of this study suggest that pre-treatment MRI and three-dimensional 1H-MRSI provide information that predicts outcome for patients with malignant gliomas and have drawn attention to variables that should be examined prospectively in future studies using these techniques. Copyright © 2004 John Wiley & Sons, Ltd. [source] Renal corpuscle of the sturgeon kidney: An ultrastructural, chemical dissection, and lectin-binding studyTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 2 2003José L. Ojeda Abstract The sturgeon is an ancient species of fish that thrives in a wide range of ecological environments, from freshwater to seawater. Basic in this process of adaptation is the ability of the kidney to control fluid filtration and urine formation. However, the morphological basis of this process is mostly unknown. The aim of the present study was to use microdissection techniques (scanning electron microscopy (SEM), transmission electron microscopy (TEM), and lectin-binding histochemistry) to examine the structure of the renal corpuscle of the sturgeon Acipenser nacarii in order to reveal morphologic features that could be related to function, phylogeny, and habitat. The renal corpuscles are aligned along the intrarrenal arteries. The urinary pole shows a siphon-like neck segment (NS) in 92% of the nephrons, whose structural characteristics are different from those of other fish. The podocytes have cuboidal cellular bodies, intercellular contacts, and poorly developed cell processes. The podocyte glycocalyx contains N-acetylglucosamine and lacks sialic acid. The structural and lectin-binding patterns are similar to those found in the immature mammalian kidney. The glomerular basement membrane (GBM) is very thick and consists of three layers: a lamina rara externa, a lamina densa, and a thick subendothelial lamina. The latter contains tubular microfibrils, collagen fibers, and long mesangial cell processes. Frequently, the podocyte bodies attach directly to the GBM, and the area occupied by the filtration slits is very small. Furthermore, the GBM shows a glycosylation pattern different from that observed in most vertebrates. Contrary to what would be expected in sturgeons living in freshwater, the A. nacarii renal corpuscle morphology suggests a low glomerular filtration rate. Anat Rec Part A 272A: 563,573, 2003. © 2003 Wiley-Liss, Inc. [source] Lessons from studies on focal segmental glomerulosclerosis: an important role for parietal epithelial cells?THE JOURNAL OF PATHOLOGY, Issue 3 2006B Smeets Abstract Glomerular diseases are caused by multiple mechanisms. Progressive glomerular injury is characterized by the development of segmental or global glomerulosclerosis independent of the nature of the underlying renal disease. Most studies on glomerular disease focus on the constituents of the filtration barrier (podocytes, glomerular basement membrane (GBM), endothelial cells) or the mesangial cells. Little attention is given to the epithelial cells lining Bowman's capsule, the so called parietal epithelial cells (PECs). This ,lack of attention' is partly explained by the presumed ,passive' function of PECs, which are large, flattened cells that cover Bowman's capsule in a single cell layer and form a barrier between the ultrafiltrate and the periglomerular interstitium, in normal glomerular physiology. A more important reason has been the lack of an established primary role for the parietal epithelium in glomerular diseases. However, in recent years, several studies have demonstrated that PECs are involved in extracapillary proliferation. In addition, PECs can become highly active, proliferating cells, expressing many growth factors, chemokines, cytokines, and their receptors. It was recently demonstrated that PECs also play a part in the development of focal segmental glomerulosclerosis (FSGS). This review summarises current knowledge of the PEC, with emphasis on the role of PECs in the development of FSGS. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Increase of Integrin-Linked Kinase Activity in Cultured Podocytes upon Stimulation with Plasma from Patients with Recurrent FSGSAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2008M. Hattori Recurrent focal segmental glomerulosclerosis (FSGS) is a major challenge in the field of transplantation. Integrin-linked kinase (ILK) has emerged as a key mediator of podocyte,glomerular basement membrane (GBM) interactions. To clarify the involvement of plasma factors in FSGS recurrence, we examined the effects of plasma from FSGS patients with or without posttransplant recurrence on cultured podocytes, focusing particularly on ILK activity. Podocytes from a conditionally immortalized mouse podocyte cell line were treated with plasma from 11 FSGS patients, and ILK activity was determined using an immune complex kinase assay. Treatment with plasma from three patients with recurrence induced an increase in ILK activity. In contrast, no increase in ILK activity was observed in cultured podocytes treated with plasma from the remaining three patients with recurrence and five patients without recurrence. Cultured podocytes treated with plasma that induced ILK activity showed alterations of focal contact and detachment from the laminin matrix. In conclusion, this preliminary study provides experimental evidence suggesting the possible presence of circulating toxic factors in the plasma of some patients with recurrent FSGS, which induce an increase in podocyte ILK activity that may lead to the detachment of podocytes from the GBM. [source] Residual tumor cells are unique cellular targets in glioblastoma,ANNALS OF NEUROLOGY, Issue 2 2010Martin Glas MD Residual tumor cells remain beyond the margins of every glioblastoma (GBM) resection. Their resistance to postsurgical therapy is considered a major driving force of mortality, but their biology remains largely uncharacterized. In this study, residual tumor cells were derived via experimental biopsy of the resection margin after standard neurosurgery for direct comparison with samples from the routinely resected tumor tissue. In vitro analysis of proliferation, invasion, stem cell qualities, GBM-typical antigens, genotypes, and in vitro drug and irradiation challenge studies revealed these cells as unique entities. Our findings suggest a need for characterization of residual tumor cells to optimize diagnosis and treatment of GBM. ANN NEUROL 2010;68:264,269 [source] Patterns of care in elderly glioblastoma patients,ANNALS OF NEUROLOGY, Issue 6 2008Fabio M. Iwamoto MD Objective To evaluate the patterns of care in elderly glioblastoma (GBM) patients from a large population-based registry. Methods We identified a cohort of GBM patients 65 years or older from Surveillance, Epidemiology, and End Results cancer registry data linked with Medicare claims between 1994 and 2002. We assessed the impact of demographic characteristics and comorbidities on the probability of undergoing surgical resection, radiotherapy (RT), and chemotherapy within 3 months of diagnosis using multivariate logistic regression. Results A total of 4,137 patients with GBM were included, with a median overall survival of 4 months. Sixty-one percent of patients underwent resection at diagnosis; 65% received RT and 10% received chemotherapy within 3 months of diagnosis. In a multivariate regression analysis, age was the most significant predictor of resection, RT, or chemotherapy. Black race (odds ratio [OR], 0.64; p = 0.008) was associated with lower rates of surgical resection. Factors associated with decreased likelihood of receiving RT included unmarried marital status (OR, 0.64; p < 0.0001) and more comorbidities (OR, 0.55; p < 0.0001). Factors associated with decreased likelihood of receiving chemotherapy included unmarried marital status (OR, 0.59; p = 0.0002) and more comorbidities (OR, 0.56; p = 0.02). Interpretation Survival of elderly GBM patients was poor in this population-based study. Age, marital status, and comorbidities influenced the probability of receiving RT or chemotherapy in this cohort. Ann Neurol 2008;64:628,634 [source] Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecanAPMIS, Issue 8 2010Benedikte Hasselbalch Hasselbalch B, Eriksen JG, Broholm H, Christensen IJ, Grunnet K, Horsman MR, Poulsen HS, Stockhausen M-T, Lassen U. Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan. APMIS 2010; 118: 585,94. Several recent studies have demonstrated a beneficial effect of anti-angiogenic treatment with the vascular endothelial growth factor-neutralizing antibody bevacizumab in recurrent high-grade glioma. In the current study, immunohistochemical evaluation of biomarkers involved in angiogenesis, hypoxia and mediators of the epidermal growth factor receptor (EGFR) pathway were investigated. Tumor tissue was obtained from a previous phase II study, treating recurrent primary glioblastoma multiforme (GBM) patients with the EGFR inhibitor cetuximab in combination with bevacizumab and irinotecan. Of the 37 patients with available tumor tissue, 29 were evaluable for response. We concurrently performed immunohistochemical stainings on tumor tissue from 21 GBM patients treated with bevacizumab and irinotecan. We found a tendency of correlation between the hypoxia-related markers, indicating that they share the same regulatory mechanisms. None of the EGFR-related biomarkers showed any significant correlations with each other. None of the biomarkers tested alone or in combination could identify a patient population likely to benefit from bevacizumab and irinotecan, with or without the addition of cetuximab. There is still an urgent need for one or more reliable and reproducible biomarkers able to predict the efficacy of anti-angiogenic therapy. [source] A2B5 Cells from Human Glioblastoma have Cancer Stem Cell PropertiesBRAIN PATHOLOGY, Issue 1 2010Aurélie Tchoghandjian Abstract Glioblastomas, like other cancers, harbor small cell populations with the capability of sustaining tumor formation. These cells are referred to as cancer stem cells. We isolated cells expressing the surface marker A2B5 from three human glioblastomas (GBM) and showed that after grafting into nude mice, they generated dense and highly infiltrative tumors. Then, we extensively studied A2B5+ cells isolated from 11 human GBM. These cells display neurosphere-like, self-renewal, asymmetrical cell division properties and have multipotency capability. Stereotactic xenografts of dissociated A2B5+ -derived secondary spheres revealed that as few as 1000 cells produced a tumor. Moreover, flow cytometry characterization of A2B5+ -derived spheres revealed three distinct populations of cells: A2B5+/CD133+, A2B5+/CD133 - and A2B5 - /CD133 - , with striking proportion differences among GBM. Both A2B5+/CD133+ and A2B5+/CD133 - cell fractions displayed a high proliferative index, the potential to generate spheres and produced tumors in nude mice. Finally, we generated two green fluorescent protein-cell lines that display,after serum induction,distinct proliferative and migratory properties, and differ in their CD133 level of expression. Taken together, our results suggest that transformed A2B5+ cells are crucial for the initiation and maintenance of GBM, although CD133 expression is more involved in determining the tumor's behavior. [source] | |||||||||||||||||||||||||||||||||||||