Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Proceed order?

Export
  • 1
  • 2
  • 3
    Keywords: EXPRESSION ; CELL ; Germany ; KINASE ; GENE ; GENES ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; transcription ; DRUG ; TUMORS ; PATIENT ; treatment ; ALPHA ; culture ; AMPLIFICATION ; COPY NUMBER ; NUMBER ; REGION ; FUTURE ; gene amplification ; OVEREXPRESSION ; ASTROCYTOMAS ; GLIOMAS ; targeting ; ONCOLOGY ; SUBSET ; GLIOMA ; GRADE ; TRANSLATION ; FACTOR VEGF ; LEVEL ; SIZE ; KINASES ; oligodendroglioma ; glioblastoma multiforme ; GLIOBLASTOMA-MULTIFORME ; KIT ; USA ; DRUGS ; GENE AMPLIFICATIONS ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; SET ; KDR ; AUTOCRINE LOOP ; HUMAN-MALIGNANT GLIOMAS ; PDGFRA
    Abstract: A subset of glioblastomas (GBMs) carry gene amplifications on chromosomal segment 4q12. To characterize this amplicon in detail, we analyzed a set of 100 samples consisting of 65 GBMs, 10 WHO grade III astrocytomas, 12 oligodendrogliomas, and 13 glioma cell cultures. We applied multiplex ligation-dependent probe amplification to determine the gene dosage of PDGFRA, KIT, and KDR and the flanking genes USP46, RASL11B, LNX1, CHIC2, SEC3L1, and IGFBP7. The amplicon was highly variable in size and copy number and extended over a region of up to 5 Mb. Amplifications on 4q12 were observed in 15% of GBMs and 23% of GBM cell cultures but not in 22 other gliomas. We analyzed transcription and translation of some genes within this amplicon. Gene amplification generally correlated with high transcript levels but did not necessarily result in increased protein levels. However, we detected frequent expression of proteins encoded by PDGFRA, KIT, and KDR in GBMs and GBM cell cultures independent of the amplification status. Future treatment of GBM patients may include drugs targeting multiple kinases that are encoded by genes on chromosomal segment 4q12
    Type of Publication: Journal article published
    PubMed ID: 17504929
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; THERAPY ; TYROSINE KINASE ; GENE ; GENES ; HYBRIDIZATION ; PROTEIN ; DRUG ; TUMORS ; LINES ; PATIENT ; LIGAND ; prognosis ; REDUCTION ; CONTRAST ; CELL-LINES ; GROWTH-FACTOR RECEPTOR ; PHOSPHORYLATION ; chromosome ; TARGET ; NO ; IN-SITU ; LESIONS ; AMPLIFICATION ; MUTATION ; METASTASIS ; PROSTATE-CANCER ; CELL-LINE ; LINE ; MUTATIONS ; HOMOLOG ; US ; LIGANDS ; TARGETS ; FLUORESCENCE ; POOR-PROGNOSIS ; SARCOMA ; fluorescence in situ hybridization ; PTEN ; TP53 ; EPIDERMAL-GROWTH-FACTOR ; ONCOLOGY ; TUMOR-SUPPRESSOR ; THERAPIES ; INCREASE ; EGFR ; cell proliferation ; LEVEL ; analysis ; SUPPRESSOR ; tumor suppressor gene ; NERVE ; USA ; DRUGS ; KINASE INHIBITOR ; epidermal growth factor receptor ; GROWTH-FACTOR-RECEPTOR ; receptor tyrosine kinase ; SOMATIC MUTATIONS ; comparison ; ErbB2 ; neurofibromatosis ; TARGETED THERAPY ; tumor suppressor ; EGF ; TRASTUZUMAB ; FACTOR-RECEPTOR ; growth factor ; MPNST ; NEU PROTOONCOGENE ; SCHWANN-CELLS
    Abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n=37). Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analysis revealed increased EGFR dosage in 28% of MPNSTs. ERBB2 and three tumor suppressor genes (PTEN [phosphatase and tensin homolog deleted on chromosome 10], CDKN2A [cyclin-dependent kinase inhibitor 2A], and TP53 [tumor protein p53]) were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNSTs revealed an increase in genetic lesions in MPNSTs. No somatic mutations were found within tyrosine-kinase-encoding exons of EGFR and ERBB2. However, at the protein level, expression of EGFR and erbB2 was frequently detected in MPNSTs. EGFR expression was significantly associated with increased EGFR gene dosage. The EGFR ligands transforming growth factor a and EGF were more strongly expressed in MPNSTs than in neurofibromas. The effects of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, were determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients. Neuro-Oncology 10, 946-957, 2008 (Posted to Neuro-Oncology [serial online], Doc. D07-00250, July 23, 2008. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2008-053)
    Type of Publication: Journal article published
    PubMed ID: 18650488
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Keywords: TOOL ; MRI ; PATTERNS ; RECURRENCE ; PATTERN ; GLIOBLASTOMA
    Abstract: At least 10% of glioblastoma relapses occur at distant and even contralateral locations. This disseminated growth limits surgical intervention and contributes to neurological morbidity. Preclinical data pointed toward a role for temozolomide (TMZ) in reducing radiotherapy-induced glioma cell invasiveness. Our objective was to develop and validate a new analysis tool of MRI data to examine the clinical recurrence pattern of glioblastomas. MRIcro software was used to map the location and extent of initial preoperative and recurrent tumors on MRI of 63 patients in the European Organisation for Research and Treatment of Cancer (EORTC) 26981/22981/National Cancer Institute of Canada (NCIC) CE.3 study into the same stereotaxic space. This allowed us to examine changes of site and distance between the initial and the recurrent tumor on the group level. Thirty of the 63 patients were treated using radiotherapy, while the other patients completed a radiotherapy-plus-TMZ treatment. Baseline characteristics (median age, KPS) and outcome data (progression-free survival, overall survival) of the patients included in this analysis resemble those of the general study cohort. The patient groups did not differ in the promoter methylation status of methyl guanine methyltransferase (MGMT). Overall frequency of distant recurrences was 20%. Analysis of recurrence patterns revealed no difference between the groups in the size of the recurrent tumor or in the differential effect on the distance of the recurrences from the preoperative tumor location. The data show the feasibility of groupwise recurrence pattern analysis. An effect of TMZ treatment on the recurrence pattern in the EORTC 26981/22981/NCIC CE.3 study could not be demonstrated.
    Type of Publication: Journal article published
    PubMed ID: 18676355
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Keywords: CELLS ; CELL ; Germany ; EXPOSURE ; PROTEIN ; DRUG ; DNA ; MECHANISM ; DNA-REPAIR ; PERIPHERAL-BLOOD ; DNA repair ; review ; brain tumor ; METHYLTRANSFERASE ; GLIOMA ; MALIGNANT GLIOMA ; MGMT ; BASE EXCISION-REPAIR ; PROMOTER HYPERMETHYLATION ; PHASE-I TRIAL ; ADJUVANT TEMOZOLOMIDE ; temozolomide ; HIGH-GRADE GLIOMAS ; DIAGNOSED GLIOBLASTOMA-MULTIFORME ; METHYLATING AGENTS ; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY ; O-6-methylguanine DNA methyltransferase
    Abstract: One barrier to successful treatment of malignant glioma is resistance to alkylating agents such as temozolomide. The cytotoxic activity of temozolomide and other alkylating agents is believed to manifest largely by the formation of O-6-methylguanine DNA adducts. Consequently, the primary mechanism of resistance to temozolomide is a function of the activity of the DNA repair enzyme O-6-methylguanine DNA methyltransferase (MGMT). Fortuitously, MGMT is inactivated after each reaction (i.e., suicide enzyme). Therefore, if the rate of DNA alkylation were to outpace the rate of MGMT protein synthesis, the enzyme could, in theory, be depleted. Several studies have shown that prolonged exposure to temozolomide can deplete MGMT activity in blood cells, a process that could potentially increase the antitumor activity of the drug. To date, however, there are limited data demonstrating the depletion of MGMT activity in tumor tissue exposed to temozolomide. A variety of dosing schedules that increase the duration of exposure and the cumulative dose of temozolomide are currently being investigated for the treatment of glioma, with the goal of improving antitumor activity and overcoming resistance. These alternative dosing regimens have been shown to deplete MGMT activity in peripheral blood mononuclear cells, but the regimen that provides the best balance between enhanced antitumor activity and acceptable hematologic toxicity has yet to be determined. Neuro-Oncology 11, 69-79, 2009 ( Posted to Neuro-Oncology [serial online], Doc. D08-00030, September 4, 2008. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2008-078)
    Type of Publication: Journal article published
    PubMed ID: 18772354
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Keywords: COMPLEX, COMPLEXES, GENOMIC ABERRATIONS, GLIOBLASTOMA
    Abstract: Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.
    Type of Publication: Journal article published
    PubMed ID: 19304958
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Abstract: Previous findings suggest an angiogenesis-regulating function of the p53 tumor suppressor protein in various malignancies. With several antiangiogenic agents entering the clinic, we assessed the value of the TP53 status in predicting angiogenesis in glioblastoma in vivo and examined underlying angiogenic-signaling pathways in vitro. We identified 26 TP53 wild-type and 9 TP53 mutated treatment-naive, primary, isocitrate dehydrogenase 1 (IDH1) wild-type glioblastoma specimens by sequence analysis and quantified vascularization. P53 responsiveness of the angiogenesis-related target genes, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), thrombospondin 1 (TSP-1), brain-specific angiogenesis inhibitor 1 (BAI1), and collagen prolyl-4-hydroxylase alpha 2 (P4HA2), was evaluated by (i) overexpression of wild-type p53 in homozygously TP53-deleted LN-308 cells; (ii) shRNA-mediated p53 knockdown in the TP53 wild-type LNT-229 cells; and (iii) chemical induction of wild-type p53 expression in LNT-229 cells by camptothecin. Irrespective of the TP53 status, vascularization did not differ significantly between the two groups of glioblastoma specimens. Of all target genes, only P4HA2 mRNA was upregulated through wild-type p53. As opposed to several nonglial tumors, in glioblastoma cells, p53-mediated transcriptional induction of P4HA2 mRNA neither resulted in increased levels of P4HA2 protein or antiangiogenic endostatin nor did it influence endothelial cell sprouting, viability, or transmigration in vitro. Moreover, p53-uncoupled stable overexpression of P4HA2 in LN-308 cells did not affect endothelial cell viability. These data challenge the view of p53 as an angiogenesis-regulator in glioblastoma in that relevant signaling pathways are silenced, potentially contributing to the angiogenic switch during malignant progression
    Type of Publication: Journal article published
    PubMed ID: 20504876
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Abstract: Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p 〈 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.
    Type of Publication: Journal article published
    PubMed ID: 21292686
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Keywords: INHIBITOR ; IN-VIVO ; THERAPY ; MALIGNANT GLIOMA ; TGF-BETA ; HIGH-GRADE GLIOMA ; CRITERIA ; INVASIVENESS ; GLIOBLASTOMA
    Type of Publication: Journal article published
    PubMed ID: 21558079
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...