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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 January 2014, Vol.111(1), pp.409-14
    Description: A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
    Keywords: Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents, Alkylating -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Cell Cycle Proteins -- Metabolism ; Glioblastoma -- Drug Therapy ; Glioma -- Drug Therapy ; Intracellular Signaling Peptides and Proteins -- Metabolism ; O(6)-Methylguanine-DNA Methyltransferase -- Pharmacology ; Tor Serine-Threonine Kinases -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Journal of Clinical Oncology, 05/20/2016, Vol.34(15_suppl), pp.11587-11587
    ISSN: 0732-183X
    E-ISSN: 1527-7755
    Source: CrossRef
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  • 3
    Language: English
    In: Oncotarget, 13 October 2015, Vol.6(31), pp.31050-68
    Description: Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.
    Keywords: Angiogenesis ; Glioblastoma ; Invasion ; Phosphatase and Tensin Homolog Deleted on Chromosome 10 (Pten) ; Vascular Endothelial Growth Factor Receptor (Vegfr)-2 ; Drug Resistance, Neoplasm ; Neovascularization, Pathologic ; Angiogenesis Inhibitors -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Glioma -- Drug Therapy ; Pten Phosphohydrolase -- Deficiency ; Vascular Endothelial Growth Factor Receptor-2 -- Metabolism
    E-ISSN: 1949-2553
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  • 4
    Language: English
    In: Molecular cancer research : MCR, May 2018, Vol.16(5), pp.767-776
    Description: CD95 (Fas/APO-1), a death receptor family member, activity has been linked to tumorigenicity in multiple cancers, including glioblastoma multiforme (GBM). A phase II clinical trial on relapsed glioblastoma patients demonstrated that targeted inhibition of CD95 signaling via the CD95 ligand (CD95L) binding and neutralizing Fc-fusion protein APG101 (asunercept) prolonged patient survival. Although CD95 signaling may be relevant for multiple aspects of tumor growth, the mechanism of action of APG101 in glioblastoma is not clear. APG101 action was examined by proliferation, apoptosis, and invasion assays with human and murine glioma and human microglial cells, as well as therapy studies with orthotopic gliomas and clinical data. APG101 inhibits CD95L-mediated invasion of glioma cells. APG101 treatment was effective in glioma-bearing mice, independently of the presence or absence of CD4 and CD8 T lymphocytes, which should be sensitive to CD95L. Combined with radiotherapy, APG101 demonstrated a reduction of tumor growth, fewer tumor satellites, reduced activity of matrix metalloproteinases (MMP) as well as prolonged survival of tumor-bearing mice compared with radiotherapy alone. Inhibiting rather than inducing CD95 activity is a break-of-paradigm therapeutic approach for malignant gliomas. Evidence, both and , is provided that CD95L-binding fusion protein treatment enhanced the efficacy of radiotherapy and reduced unwanted proinfiltrative effects by reducing metalloproteinase activity by directly affecting the tumor cells. APG101 (asunercept) successfully used in a controlled phase II glioblastoma trial (NCT01071837) acts anti-invasively by inhibiting matrix metalloproteinase signaling, resulting in additive effects together with radiotherapy and helping to further develop a treatment for this devastating disease. .
    Keywords: Fas Ligand Protein -- Antagonists & Inhibitors ; Glioblastoma -- Radiotherapy ; Immunoglobulin G -- Therapeutic Use ; Recombinant Fusion Proteins -- Therapeutic Use ; Fas Receptor -- Therapeutic Use
    ISSN: 15417786
    E-ISSN: 1557-3125
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  • 5
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 January 2019, Vol.25(1), pp.253-265
    Description: Resistance is an obstacle of glioma therapy. Despite targeted interventions, tumors harbor primary resistance or become resistant over short course of treatment. This study examined the mouse double minute 2 (MDM2) inhibitor RG7388 together with radiotherapy and analyzed strategies to overcome acquired MDM2 inhibitor resistance in glioblastoma. Effects of RG7388 and radiotherapy were analyzed in p53 wild-type glioblastoma cell lines and glioma-initiating cells. RG7388 resistant cells were generated by increasing RG7388 doses over 3 months. Regulated pathways were investigated by microarray, qRT-PCR, and immunoblot analysis and specifically inhibited to evaluate rational salvage therapies at RG7388 resistance. Effects of RG7388 and trametinib treatment were challenged in an orthotopical mouse model with RG7388 resistant U87MG glioblastoma cells. MDM2 inhibition required functional p53 and showed synergistic activity with radiotherapy in first-line treatment. Long-term exposure to RG7388 induced resistance by activation of the extracellular signal-regulated kinases 1/2 (ERK1/2)-insulin growth factor binding protein 1 (IGFBP1) signaling cascade, which was specifically overcome by ERK1/2 pathway inhibition with trametinib and knockdown of IGFBP1. Combining trametinib with continued RG7388 treatment enhanced antitumor effects at RG7388 resistance and . These data provide a rationale for combining RG7388 and radiotherapy as first-line therapy with a specific relevance for tumors insensitive to alkylating standard chemotherapy and for the addition of trametinib to continued RG7388 treatment as salvage therapy after acquired resistance against RG7388 for clinical practice.
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 6
    Language: English
    In: ALTEX, 1998, Vol.15(5), pp.43-45
    Description: In the study in vitro alternatives to a non-validated and harmful animal test for the absence of extraneous virus in live vaccines were investigated. For evaluation of a suitable in vitro method the porcine herpesvirus (Aujeszkyvirus, Pseudorabiesvirus) was used as a model virus. In artificially contaminated live vaccines the aujeszkyvirus could be detected by moleculargenetical and cellular methods. Regarding the threshold values of virus detection in vitro tests showed to be more efficacious than animal testing. Meanwhile the European Pharmacopoeia Commission deleted the animal test for extraneous virus from two monographs. The discussion, if respective animal testing can be cancelled for the other live vaccines as well, is still ongoing. The study was supported by the German Ministry of Education, Science, Research and Technology.
    ISSN: 1868-596X
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 7
    Language: English
    In: ALTEX, 1994, Vol.11(5), pp.62-67
    Description: Pasteurella multocida toxoid is the most important antigen in vaccines against progressive atrophic rhinitis in pigs. Testing antibodies against Pasteurella multocida toxin in a cell culture neutralisation assay on embryonic bovine lung cells and a modified, commercially available enzyme-linked immunosorbent assay (DAKO, Denmark) is sensitive and gives good reproducible results. Determination of antitoxin antibodies in swine and guinea pigs simultaneously in both methods resulted in good coefficients of correlation (r = 0.88 and 0.93). Induction of antibodies to Pasteurella multocida toxin by thirty batches of ten toxoid containing vaccines was tested by subcutaneous application of one fifth pigdose (0.4-1 ml) twice in intervals of three weeks. The animals showed neither signs if illness nor significant local or systemic reactions. Three weeks after the second immunisation 25 batches induced titres being at least 2 log2 dilutions higher than a parallel titrated reference serum (mean titre of reference serum was 1:23.26〈/superior). Five batches belonging to one vaccine induced no detectable antibodies to the toxin. Additional testing of two negative and one positive batch of this vaccine in the target species by immunising them twice according to the manufacturers scheme, gave identical results. Therefore it is concluded that immunisation of guinea pigs and determination of humoural immune response in vitro, is a potent and ethical justifiable method to judge the quality of the Pasteurella multocida toxoid component of vaccines against progressive atrophic rhinitis in pigs.
    ISSN: 1868-596X
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 8
    Language: English
    In: ALTEX, 1998, Vol.15(5), pp.46-49
    Description: At present, the complete inactivation of rabies virus in rabies vaccines ad us. vet. is proven by an animal experiment which causes severe suffering, the intracerebral injection of mice. This animal experiment yet is not validated. We have quantified the sensitivity of the mouse test and examined whether the animal experiment may be replaced by the immunofluorescence assay (IFT) as an in vitro method. Detection limits of both assays were determined depending on the examined product, i.e. prior to and after the addition of adjuvans and preservative, respectively. Furthermore, symptoms of the rabies desease were recorded and their severity was classified on a range of 1-5. Symptoms of rabies-infected mice were clear and highly specific. Symptoms classified as 〉/= 2 in context with a loss of 〉/= 15% of the initial weight were defined as humane endpoints of the desease. The quantitative detection of active virus was not inhibited in the presence of even high concentrations of inactivated virus. The detection limit of the mouse test was 10 viruses ml-1 independent of the examined product. The detection limit of the IFT prior to the addition of adjuvans and preservative was 10 viruses ml-1 as well. After the addition of these substances the detection limit rose to 103 viruses ml-1. Advantages and disadvantages of the mouse test and IFT are discussed.
    ISSN: 1868-596X
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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