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  • 1
    ISSN: 1420-9071
    Keywords: Key words. Angiotensin II; angiotensin IV; enalapril; losartan; cell proliferation; rat endometrium.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Oestrogens are known to enhance angiotensin biosynthesis by increasing the elaboration of its precursor, angiotensinogen. On the other hand, we found that inhibition of angiotensin-converting enzyme (ACE) suppressed the proliferative response of the rat anterior pituitary gland to oestrogens. To answer the question whether the angiotensin system is involved in the control of the cell proliferation of the uterine epithelium, the effects of an ACE inhibitor, enalapril maleate, and of angiotensins II and IV, alone or together with losartan, an antagonist of angiotensin receptor type 1 (AT1), on endometrial epithelial cell proliferation have been studied. The experiments were performed on ovariectomized female Wistar rats. In the first experiment the animals were injected with a single dose of oestradiol benzoate or received an injection of solvent only. Half of the oestrogen-treated rats were injected additionally with enalapril maleate (EN, twice daily). The incorporation of bromodeoxyuridine (BrDU) into endometrial cell nuclei was used as an index of cell proliferation. It was found that oestradiol alone dramatically increased the BrDU labelling index (LI) of endometrial cell nuclei, and this effect was partially blocked by the simultaneous treatment with EN. In the second experiment, the animals were injected intraperitoneally with angiotensin II (AII), angiotensin IV (AIV) or saline, alone or together with losartan. It was found that AIV induced an increase in the LI in uterine epithelium, and this effect was not blocked by the simultaneous treatment with losartan. The increase in LI in uterine epithelium was also observed in the rats treated with AII and with losartan. These findings suggest an involvement of angiotensin IV in the control of uterine epithelium cell proliferation.
    Type of Medium: Electronic Resource
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  82. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20110601-20110605; Freiburg i. Br.; DOC11hnod094 /20110419/
    Publication Date: 2011-04-19
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
    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
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  • 4
    Keywords: CANCER ; EXPRESSION ; GENE ; DIFFERENTIATION ; VARIANTS ; DISCOVERY ; ALPHA ; ALIGNMENT ; ESTROGEN
    Abstract: Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.
    Type of Publication: Journal article published
    PubMed ID: 23404370
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  • 5
    Keywords: GENE ; TYPE-1 ; DELETION ; MUTATIONS ; GERMLINE ; SUPPRESSOR ; SPECTRUM ; soft-tissue sarcoma ; NF1 ; MEK INHIBITION
    Abstract: Malignant peripheral nerve sheath tumors (MPNST) derive from the Schwann cell or perineurial cell lineage and occur either sporadically or in association with the tumor syndrome neurofibromatosis type 1 (NF1). MPNST often pose a diagnostic challenge due to their frequent lack of pathognomonic morphological or immunohistochemical features. Mutations in the NF1 tumor suppressor gene are found in all NF1-associated and many sporadic MPNST. The presence of NF1 mutation may have the potential to differentiate MPNST from several morphologically similar neoplasms; however, mutation detection is hampered by the size of the gene and the lack of mutational hot spots. Here we describe a newly developed monoclonal antibody binding to the C-terminus of neurofibromin (clone NFC) which was selected for optimal performance in routinely processed formalin-fixed and paraffin-embedded tissue. NFC immunohistochemistry revealed loss of neurofibromin in 22/25 (88 %) of NF1-associated and 26/61 (43 %) of sporadic MPNST. There was a strong association of neurofibromin loss with deletions affecting the NF1 gene (P 〈 0.01). In a series of 256 soft tissue tumors of different histotypes NFC staining showed loss of neurofibromin in 2/8 myxofibrosarcomas, 2/12 (16 %) pleomorphic liposarcomas, 1/16 (6 %) leiomyosarcomas, and 4/28 (14 %) unclassified undifferentiated pleomorphic sarcomas. However, loss of neurofibromin was not observed in 22 synovial sarcomas, 27 schwannomas, 23 solitary fibrous tumors, 14 low-grade fibromyxoid sarcomas, 50 dedifferentiated liposarcomas, 27 myxoid liposarcomas, 13 angiosarcomas, 9 extraskeletal myxoid chondrosarcomas, and 7 epitheloid sarcomas. Immunohistochemistry using antibody NFC may substantially facilitate sarcoma research and diagnostics.
    Type of Publication: Journal article published
    PubMed ID: 24464231
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; Germany ; GENE-EXPRESSION ; PROTEIN ; TUMORS ; PATIENT ; MARKER ; prognosis ; CONTRAST ; treatment ; TYPE-1 ; ASSOCIATION ; polymorphism ; TARGET ; MUTANT ; NO ; IDENTIFICATION ; NEOPLASIA ; PROGRESSION ; MUTATION ; TUMOR PROGRESSION ; METASTASIS ; p53 ; MUTATIONS ; SOFT-TISSUE SARCOMAS ; CARCINOMAS ; RECURRENT ; POOR-PROGNOSIS ; TP53 ; MMP ; WILD-TYPE P53 ; MATRIX ; ONCOLOGY ; GRADE ; MALIGNANT PROGRESSION ; LEVEL ; NEUROFIBROMATOSIS TYPE-1 ; USA ; matrix metalloproteinase ; METALLOPROTEINASE ; MATRIX-METALLOPROTEINASE ; malignant peripheral nerve sheath tumor ; neurofibromatosis type 1 ; HUMAN COLLAGENASE-3 MMP-13 ; matrix metalloproteinase 13 ; POLYMORPHIC VARIANTS ; TP53 MUTATIONS
    Abstract: Malignant peripheral nerve sheath tumors ( MPNST) are sarcomas with poor prognosis and limited treatment options. Factors contributing to tumor progression are largely unknown. We therefore examined MPNST from 22 neurofibromatosis type 1 (NF1) patients, 14 non-NF1 patients, and 14 neurofibroma patients for matrix metalloproteinase 13 (MMP-13) expression. Because wild-type and mutant p53 were shown to differentially regulate MMP-13 expression, TP53 status and protein levels were also determined. MMP-13 expression was detected in 58% of MPNST and was significantly associated with recurrent MPNST (P =.019). p53 was observed in 78% of MPNST and was found to be strongly associated with MMP- 13 expression ( P =.005). In contrast, 14 neurofibromas lacked MMP- 13 and p53 expressions. TP53 mutations were found in only 11% of MPNST and were associated with high tumor grades (P=.029). No significant association between mutant TP53 and MMP- 13 was observed, indicating that other factors drive MMP- 13 expression in MPNST. The presence of metastasis was linked to p53Pro(72) polymorphism (P=.041) and shorter survival. In summary, our data suggest that MMP-13 expression in nerve sheath tumors is coupled with malignant progression. Therefore, MMP- 13 may serve as a marker for progression and as a therapeutic target
    Type of Publication: Journal article published
    PubMed ID: 17786186
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  • 7
  • 8
    Keywords: pathology ; THERAPIES ; FAMILIES ; MEMBER ; NEW-YORK ; FAMILY ; EXPRESSION ; THERAPY ; EGFR ; GENETIC ALTERATION ; USA
    Type of Publication: Meeting abstract published
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  • 9
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  58. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC); 20070426-20070429; Leipzig; DOCSO.04.03 /20070411/
    Publication Date: 2007-04-04
    Keywords: astrocytoma ; ependymoma ; spine ; Astrozytom ; Ependymom ; Wirbelsäule ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 10
    Keywords: EXPRESSION ; IN-VIVO ; PATHWAY ; CANCER-CELLS ; KAPPA-B ; C-MYC ; Ras ; APOPTOSIS-INDUCING LIGAND ; DRUG-INDUCED APOPTOSIS ; COLON CELLS ; DEATH RECEPTOR-4 ; OXYGEN SPECIES ROS
    Abstract: Malignant peripheral nerve sheath tumor (MPNST) is a rare aggressive form of sarcoma often associated with the tumor syndrome neurofibromatosis type 1 (NF1). We investigated the effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) on NF1 associated MPNST and determinants of TRAIL sensitivity. MPNST cell lines with complete neurofibromin deficiency were sensitive to apoptotic cell death induced by TRAIL whereas MPNST cells with retained neurofibromin expression or normal human Schwann cells were resistant. Increased sensitivity to TRAIL was associated with overexpression of death receptors, especially DR5. Re-expression of the GAP related domain of neurofibromin (NF1-GRD) suppressed DR5 expression and decreased sensitivity to TRAIL. We show that death receptor expression and TRAIL sensitivity critically depend on c-MYC and that c-MYC amounts are increased by MEK/ERK and PI3K/AKT signalling pathways which are suppressed by neurofibromin. Furthermore PI3K/AKT signalling strongly suppresses the MYC-antagonist MAD1 which significantly contributes to TRAIL sensitivity. Re-expression of the NF1-GRD decreased c-MYC and increased MAD1 amounts suggesting that neurofibromin influences TRAIL sensitivity at least in part by modulating the MYC/MAX/MAD network. The phytochemical curcumin further increased the sensitivity of neurofibromin deficient MPNST cells to TRAIL. This was presumably mediated by ROS, as it correlated with increased ROS production, was blocked by N-acetylcysteine and mimicked by exogenous ROS.
    Type of Publication: Journal article published
    PubMed ID: 23437333
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