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Berlin Brandenburg

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  • 2012  (7)
  • Cinatl, J.
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  • 2012  (7)
  • 1
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e36506
    Description: Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.
    Keywords: Research Article ; Biology ; Medicine ; Virology ; Infectious Diseases ; Molecular Biology ; Oncology ; Dermatology
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: Medical Microbiology and Immunology, 2012, Vol.201(3), pp.403-405
    Description: Erratum to: Med Microbiol Immunol (2011) 200:193–202 DOI 10.1007/s00430-011-0191-4 The authors would like to correct the errors in the original publication of the article. The errors include details under the sub-headings “Sequence evolution of selected VZV genes in resistant Mutants”, Discussion, and in Figs. 3 and 4 and Table 3. The corrected sentences, figures and table are given below for your reading. Fig. 3 Amino acid substitutions found within the vDNA pol encoded by ORF28. Black boxes indicate highly conserved regions. Mutations found in our resistant isolates are indicated in red
    Keywords: Public Health;
    ISSN: 0300-8584
    E-ISSN: 1432-1831
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  • 3
    In: Acta Ophthalmologica, March 2012, Vol.90(2), pp.e98-e103
    Description: To compare cytokines in undiluted vitreous of treatment‐naïve patients with macular oedema without vitreomacular traction secondary to branch (BRVO), central (CRVO) and hemi‐central (H‐CRVO) retinal vein occlusion. Ninety‐four patients (median age 72 years, 42 men) underwent an intravitreal combination therapy, including a single‐site 23‐gauge core vitrectomy and the application of bevacizumab and dexamethasone due to vision‐decreasing macular oedema. Among these were 43 patients with BRVO, 35 with CRVO and 16 patients with hemi‐CRVO, which were distributed in a fresh or old retinal vein occlusion type (seven or more months after onset). Undiluted vitreous samples were analysed for interleukin 6 (IL‐6), monocyte chemoattractant protein‐1 (MCP‐1) and vascular endothelial growth factor (VEGF‐A) with cytometric BEAD assay. Vitreous samples from patients with idiopathic epiretinal membrane served as controls ( = 14). The mean cytokine values were highest in the CRVO group with IL‐6 = 64.7 pg/ml (SD ± 115.8), MCP‐1 = 1015.8 pg/ml (±970.1) and VEGF‐A = 278.4 pg/ml (±512.8), followed by the H‐CRVO group with IL‐6 = 59.9 pg/ml (SD ± 97.5), MCP‐1 = 938.8 pg/ml (±561.1) and VEGF‐A = 211.5 pg/ml (±232.4). The BRVO group had IL‐6 = 23.2 pg/ml (SD ± 48.8), MCP‐1 = 602.6 pg/ml (±490.3) and VEGF‐A = 161.8 pg/ml (±314.4). The values of MCP‐1 and VEGF‐A were significantly different for CRVO or H‐CRVO versus BRVO. All values were significantly higher than in the control samples, which had 6.2 ± 3.4 pg/ml (IL‐6), 253 ± 74 pg/ml (MCP‐1) and 7 ± 4.9 pg/ml (VEGF‐A). Within the old RVO type, only MCP‐1 was significantly different for CRVO or H‐CRVO versus BRVO. Both inflammatory markers and VEGF‐A were higher in CRVO and H‐CRVO than in BRVO undiluted vitreous samples. It seems that monocyte recruitment to the vessel wall, which might underlie the importance of eosinophils in tissue remodelling after RVO, is of special interest owing to the significant difference in MCP‐1 in the older RVO types.
    Keywords: Cytometric Bead Array ; Interleukin 6 ; Monocyte Chemoattractant Protein ; Retinal Vein Occlusion ; Vascular Endothelial Growth Factor ; Vitreous Samples
    ISSN: 1755-375X
    E-ISSN: 1755-3768
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  • 4
    Language: English
    In: The American Journal of Pathology, April 2012, Vol.180(4), pp.1370-1377
    Description: The influences of cytotoxic drugs on endothelial cells remain incompletely understood. Herein, we examined the effects of chemotherapeutic agents in experimental angiogenesis models and analyzed vessel densities in clinical neuroblastoma tumor samples. Cisplatin (20 to 500 ng/mL), doxorubicin (4 to 100 ng/mL), and vincristine (0.5 to 4 ng/mL), drugs commonly involved in neuroblastoma therapy protocols, induced pro-angiogenic effects in different angiogenesis models. They enhanced endothelial cell tube formation, endothelial cell sprouting from spheroids, formation of tip cells in the sprouting assay, expression of αvβ3 integrin, and vitronectin binding. All three drugs increased global cellular kinase phosphorylation levels, including the angiogenesis-relevant molecules protein kinase Cβ and Akt. Pharmacological inhibition of protein kinase Cβ or Akt upstream of phosphatidylinositol 3-kinase reduced chemotherapy-induced endothelial cell tube formation. Moreover, the investigated chemotherapeutics dose dependently induced vessel formation in the chick chorioallantoic membrane assay. Tumor samples from seven high-risk patients with neuroblastoma were analyzed for vessel density by IHC. Results revealed that neuroblastoma samples taken after chemotherapy consistently showed an enhanced microvessel density compared with the corresponding samples taken before chemotherapy. In conclusion, our data show that chemotherapy can activate endothelial cells by inducing multiple pro-angiogenic signaling pathways and exert pro-angiogenic effects and . Moreover, we report a previously unrecognized clinical phenomenon that might, in part, be explained by our experimental observations: chemotherapy-associated enhanced vessel formation in tumors from patients with neuroblastoma.
    Keywords: Medicine
    ISSN: 0002-9440
    E-ISSN: 1525-2191
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  • 5
    Language: English
    In: Letters in Drug Design & Discovery, 2012, Vol.9(9), p.815-822
    Description: The anticancer drug candidate (1-methyl-3-(p-cyanobenzyl)benzimidazole-2-ylidene)silver(I)acetate (SBC1) was tested in vitro against human neuroblastoma cells, UKF-NB-3 and UKF-NB-6, delivering IC50 values of 29 +/- 5 and 29 +/- 4 μM, while further testing against cisplatin-, carboplatin- and oxaliplatin-resistant UKF-NB-3/6 sub-lines showed no cross-resistance with respect to SBC1. A similar trend was found for SBC1 against the human colon carcinoma cell line HCT8 with an IC50 value of 3.1 +/- 0.9 μM; SBC1 was again able to break cisplatin- and carboplatin-resistance in the corresponding sub-lines. SBC1 was also tested against the prostate cancer cell line PC-3 and its paclitaxel-resistant sub-line, which gave IC50 values of 14.1 +/- 0.9 and 14.5 +/- 0.8 μM, which indicated no cross-resistance with paclitaxel. In order to test the possible transport of SBC1 via albumin the binding of SBC1 against this transport protein was measured using a fluorescence titration, which gave an ΔG value of 28 +/- 3 kJ/mol. In circular dichroism and DNA denaturation assays SBC1 proved to be a strongly DNA-binding drug candidate. SBC1 was then given at 25 and 50 mg/kg/d, in four injections to two cohorts of eight CAKI-1 tumor-bearing NMRI:nu/nu mice, while a further cohort was treated with solvent only. At these two dosages SBC1 showed a borderline toxicity leading to mortality and body weight loss, while no significant tumor growth reduction or influence on blood parameter with respect to the solvent-treated control group was observed. Further in vivo testing against zebrafish larvae revealed significant toxicity of SBC1 at micromolar concentrations; no useable anti-angiogenic dosage was observed.
    Keywords: Anticancer Drug ; Anti-Angiogenic Drug ; Carbene-Silver Complex ; Renal Cell Cancer ; Albumin-Binding Assay ; Dnabinding Assay ; Xenograft Mouse Model ; Zebrafish Intersegmental Vessel Assay
    ISSN: 1570-1808
    E-ISSN: 1875-628X
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  • 6
    Language: English
    In: Biochemical Pharmacology, 2012, Vol.83(2), pp.228-240
    Description: 5-Lipoxygenase (5-LO) is a crucial enzyme of the arachidonic acid (AA) cascade and catalyzes the formation of bioactive leukotrienes (LTs) which are involved in inflammatory diseases and allergic reactions. The pathophysiological effects of LTs are considered to be prevented by 5-LO inhibitors. In this study we present cyclohexyl-[6-methyl-2-(4-morpholin-4-yl-phenyl)-imidazo[1,2- ]pyridin-3-yl]-amine ( ), a novel imidazo[1,2- ]pyridine based compound and its characterization in several assays. suppresses 5-LO activity in intact polymorphonuclear leukocytes with an IC value of 0.16 μM and exhibits full inhibitory potency in cell free assays (IC value of 0.05 μM for purified 5-LO). The efficacy of was not affected by the redox tone or the concentration of exogenous AA, characteristic drawbacks known for the class of nonredox-type 5-LO inhibitors. Furthermore, suppressed 5-LO activity independently of the cell stimulus or the activation pathway of 5-LO contrary to what is known for some nonredox-type inhibitors. Using molecular modeling and site-directed mutagenesis studies, we were able to derive a feasible binding region within the C2-like domain of 5-LO that can serve as a new starting point for optimization and development of new 5-LO inhibitors targeting this site. has promising effects on cell viability of tumor cells without mutagenic activity. Hence the drug may possess potential for intervention with inflammatory and allergic diseases and certain types of cancer including leukemia.
    Keywords: 5-Lipoxygenase ; Inflammation ; Inhibitor ; Leukotrienes ; Molecular Modeling ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0006-2952
    E-ISSN: 1873-2968
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  • 7
    Language: English
    In: Materials Today, September 2012, Vol.15(9), pp.394-404
    Description: The demand to develop convergent technology platforms, such as bio-functionalized medical devices, is rapidly increasing. However, the loss of biological function of the effector molecules during sterilization represents a significant and general problem. Therefore, we have developed and characterized a nano-coating (NC) formulation capable of maintaining the functionality of proteins on biological-device combination products. As a proof of concept, the NC preserved the structural and functional integrity of an otherwise highly fragile antibody immobilized on polyurethane during deleterious sterilizing irradiation (≥ 25 kGy). The NC procedure enables straight-forward terminal sterilization of bio-functionalized materials while preserving optimal conditioning of the bioactive surface.
    Keywords: Engineering
    ISSN: 1369-7021
    E-ISSN: 1873-4103
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