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  • 1
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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.; DOC11hnod423 /20110419/
    Publication Date: 2011-04-19
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
    Abstract: BACKGROUND: A major hallmark of malignant progression in human astrocytomas is the formation of new blood vessels. Antiangiogenic therapy using the anti-vascular endothelial growth factor (VEGF)-antibody bevacizumab leads to increased progression-free survival in glioblastoma patients but does not influence their overall survival. To date, it is unclear why antiangiogenic therapy fails in many glioblastoma patients, while a small subpopulation profits considerably from this treatment. METHODS: The aim of our study was to determine the expression of VEGF-A and its (co-) receptors by immunohistochemistry and to test the association with patient survival in 350 glioma patients. Additionally, VEGF-A expression was analyzed by in-situ hybridization. In 18 patients, the protein expression was compared with the bevacizumab response according to extended and modified RANO criteria. RESULTS: We found a heterogeneous expression pattern of VEGF and its receptors in glioblastoma patients with significantly lower levels in WHO grade II and III tumors and normal-appearing brain tissue (P 〈 .001). Pilocytic astrocytomas (WHO grade I) showed significantly higher VEGFR-1, -2 and neuropilin-1 levels as compared to WHO grade II and III astrocytomas (P 〈 .01) but at lower levels than glioblastomas. The expression of neuropilin-2 was low in all tumors. There was neither a significant correlation between protein expression and patient survival nor between protein levels and bevacizumab response after modified RANO criteria. CONCLUSION: Since our data indicate that beneficial response to bevacizumab treatment is independent of the expression of VEGF-A and its (co-) receptors, further investigation is needed to decipher the underlying mechanisms of antiangiogenic treatment response.
    Type of Publication: Journal article published
    PubMed ID: 26627848
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  • 3
    Abstract: BACKGROUND: Glioblastoma (GBM) is the most common and malignant intracranial tumor in adults and currently incurable. To specifically target natural killer (NK) cell activity to GBM, we employed NK-92/5.28.z cells that are continuously expanding human NK cells expressing an ErbB2-specific chimeric antigen receptor (CAR). METHODS: ErbB2 expression in 56 primary tumors, four primary cell cultures, and seven established cell lines was assessed by immunohistochemistry and flow cytometry. Cell killing activity of NK-92/5.28.z cells was analyzed in in vitro cytotoxicity assays. In vivo antitumor activity was evaluated in NOD-SCID IL2Rgamma(null) (NSG) mice carrying orthotopic human GBM xenografts (6 to 11 mice per group) and C57BL/6 mice carrying subcutaneous and orthotopic ErbB2-expressing murine GBM tumors (5 to 8 mice per group). Statistical tests were two-sided. RESULTS: We found elevated ErbB2 protein expression in 41% of primary GBM samples and in the majority of GBM cell lines investigated. In in vitro assays, NK-92/5.28.z in contrast to untargeted NK-92 cells lysed all ErbB2-positive established and primary GBM cells analyzed. Potent in vivo antitumor activity of NK-92/5.28.z was observed in orthotopic GBM xenograft models in NSG mice, leading to a marked extension of symptom-free survival upon repeated stereotactic injection of CAR NK cells into the tumor area (median survival of 200.5 days upon treatment with NK-92/5.28.z vs 73 days upon treatment with parental NK-92 cells, P 〈 .001). In immunocompetent mice, local therapy with NK-92/5.28.z cells resulted in cures of transplanted syngeneic GBM in four of five mice carrying subcutaneous tumors and five of eight mice carrying intracranial tumors, induction of endogenous antitumor immunity, and long-term protection against tumor rechallenge at distant sites. CONCLUSIONS: Our data demonstrate the potential of ErbB2-specific NK-92/5.28.z cells for adoptive immunotherapy of glioblastoma, justifying evaluation of this approach for the treatment of ErbB2-positive GBM in clinical studies.
    Type of Publication: Journal article published
    PubMed ID: 26640245
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  • 4
    Keywords: CANCER ; EXPRESSION ; THERAPY ; T-LYMPHOCYTES ; ANTITUMOR IMMUNITY ; FIBRILLARY ACIDIC PROTEIN ; INDUCED CELL-DEATH ; CD137 ; 4-1BB ; ANTI-CD137
    Abstract: AIMS: The prognosis of patients with malignant gliomas is still dismal despite maximum treatment. Novel therapeutic alternatives targeting tumorigenic pathways are, therefore, demanded. In murine glioma models, targeting of tumor necrosis factor receptor superfamily (TNFRSF) 9 led to complete tumor eradication. Thus, TNFRSF9 might also constitute a promising target in human diffuse gliomas. Since there is a lack of data, we aimed to define the expression pattern and cellular source of TNFRSF9 in human gliomas. METHODS: We investigated TNFRSF9 expression in normal human CNS tissue and glioma specimens using immunohistochemistry, immunofluorescence and western blotting techniques. RESULTS: Our results show that TNFRSF9 is considerably upregulated in human gliomas when compared to normal brain tissue. In addition, our data provides evidence for an immune cell-independent de novo expression pattern of TNFRSF9 in mainly non-neoplastic reactive astrocytes and excludes classic immunological cell types, namely lymphocytes and microglia as the source of TNFRSF9. Moreover, TNFRSF9 is predominantly expressed in a perivascular and peri-tumoral distribution with significantly higher expression in IDH1 mutant gliomas. CONCLUSIONS: Our findings provide a novel, TNFRSF9-positive, reactive astrocytic phenotype and challenge the therapeutic suitability of TNFRSF9 as a promising target for human gliomas.
    Type of Publication: Journal article published
    PubMed ID: 24606203
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  • 5
    Keywords: RECEPTOR ; ANGIOGENESIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VIVO ; THERAPY ; T-CELLS ; BINDING ; UP-REGULATION ; NK cells ; NKG2D ; CELL-MIGRATION ; RAT-BRAIN ; INHIBITORS ; GLIOMA ; immunology ; GLIOBLASTOMA ; NK-CELLS ; MIF
    Abstract: Macrophage migration inhibitory factor (MIF), which inhibits apoptosis and promotes angiogenesis, is expressed in cancers suppressing immune surveillance. Its biological role in human glioblastoma is, however, only poorly understood. We examined in-vivo expression of MIF in 166 gliomas and 23 normal control brains by immunohistochemistry. MIF immunoreactivity was enhanced in neoplastic astrocytes in WHO grade II glioma and increased significantly in higher tumour grades (III-IV). MIF expression was further assessed in 12 glioma cell lines in vitro. Quantitative RT-PCR showed that MIF mRNA expression was elevated up to 800-fold in malignant glioma cells compared with normal brain. This translated into high protein levels as assessed by immunoblotting of total cell lysates and by ELISA-based measurement of secreted MIF. Wild-type p53-retaining glioma cell lines expressed higher levels of MIF, which may be connected with the previously described role of MIF as a negative regulator of wild-type p53 signalling in tumour cells. Stable knockdown of MIF by shRNA in glioma cells significantly increased tumour cell susceptibility towards NK cell-mediated cytotoxicity. Furthermore, supernatant from mock-transfected cells, but not from MIF knockdown cells, induced downregulation of the activating immune receptor NKG2D on NK and CD8(+) T cells. We thus propose that human glioma cell-derived MIF contributes to the immune escape of malignant gliomas by counteracting NK and cytotoxic T-cell-mediated tumour immune surveillance. Considering its further cell-intrinsic and extrinsic tumour-promoting effects and the availability of small molecule inhibitors, MIF seems to be a promising candidate for future glioma therapy
    Type of Publication: Journal article published
    PubMed ID: 21773885
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  • 6
    Electronic Resource
    Electronic Resource
    College Park, Md. : American Institute of Physics (AIP)
    Journal of Mathematical Physics 39 (1998), S. 2437-2454 
    ISSN: 1089-7658
    Source: AIP Digital Archive
    Topics: Mathematics , Physics
    Notes: We discuss Bloch and Wannier functions composed of Gaussian orbitals. The fact that the Bloch functions may be expressed in terms of θ-functions is used to discuss them in detail. We study not only their analyticity properties, but also features of expectation values of some specifically chosen Hamiltonians. We also investigate the localization properties of various choices of Wannier functions and compare them with the original Gauss functions. Likewise, we discuss in a more general context the relationship between the analyticity properties of Bloch functions and the localization properties of corresponding Wannier functions. © 1998 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    [S.l.] : International Union of Crystallography (IUCr)
    Acta crystallographica 53 (1997), S. 456-466 
    ISSN: 1600-5724
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Notes: Left- and double-coset decompositions of space groups are systematically analysed by putting the emphasis on the introduction of special auxiliary groups. An algorithm is tailored to exploit the specific structure of space groups. The new results are, amongst others, an efficient alternative method to determine for space groups minimal sets of double-coset representatives and a general formula that gives the structure and number of left cosets that are contained in double cosets. Left-coset and double-coset decompositions of space groups are exploited in domain structure analysis.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    College Park, Md. : American Institute of Physics (AIP)
    Journal of Mathematical Physics 40 (1999), S. 2757-2781 
    ISSN: 1089-7658
    Source: AIP Digital Archive
    Topics: Mathematics , Physics
    Notes: We discuss Bloch and Wannier functions related to oscillator eigenfunctions. In particular, we construct complete sets of mutually orthogonal Bloch and Wannier functions. We show that they can be expressed in several ways in terms of theta functions and their derivatives. We also analyze their localization properties and discuss expectation values for specifically chosen Hamiltonians. © 1999 American Institute of Physics.
    Type of Medium: Electronic Resource
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