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Berlin Brandenburg

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  • 1
    Language: English
    In: Vaccine, 16 December 2013, Vol.31(52), pp.6194-6200
    Description: The non-structural protein NS1 of the influenza virus counteracts the interferon-mediated immune response of the host. We investigated the safety and immunogenicity of a trivalent formulation containing influenza H1N1, H3N2 and B strains lacking NS1 (delNS1-trivalent). Healthy adult study participants who were seronegative for at least one strain present in the vaccine formulation were randomized to receive a single intranasal dose of delNS1-trivalent vaccine at 7.0 log10 TCID50/subject ( = 39) or placebo ( = 41). Intranasal vaccination with the live replication-deficient delNS1-trivalent vaccine was well tolerated with no treatment-related serious adverse events. The most common adverse events identified, i.e. headache, oropharyngeal pain and rhinitis-like symptoms, were mainly mild and transient and distributed similarly in the treatment and placebo groups. Significant vaccine-specific immune responses were induced. Pre-existing low antibody titers or seronegativity for the corresponding vaccine strain yielded better response rates. We show that vaccination with a replication-deficient trivalent influenza vaccine containing H1N1, H3N2 and B strains lacking NS1 is safe and induces significant levels of antibodies (ClinicalTrials.gov identifier ).
    Keywords: Influenza ; Ns1 ; Intranasal ; Trivalent ; Live-Attenuated ; Reverse Genetics ; Medicine ; Biology ; Veterinary Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0264-410X
    E-ISSN: 1873-2518
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  • 2
    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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  • 3
    Language: English
    In: The Journal of infectious diseases, 01 February 2010, Vol.201(3), pp.354-62
    Description: BACKGROUND. The nonstructural protein NS1 of influenza virus counteracts the interferon-mediated immune response of the host. By deleting the open reading frame of NS1, we have generated a novel type of influenza vaccine. We studied the safety and immunogenicity of an influenza strain lacking the NS1 gene (DeltaNS1-H1N1) in healthy volunteers. METHODS. Healthy seronegative adult volunteers were randomized to receive either a single intranasal dose of the DeltaNS1-H1N1 A/New Caledonia vaccine at 1 of 5 dose levels (6.4, 6.7, 7.0, 7.4, and 7.7 log(10) median tissue culture infective dose) (n = 36 recipients) or placebo (n = 12 recipients). RESULTS. Intranasal vaccination with the replication-deficient DeltaNS1-H1N1 vaccine was well tolerated. Rhinitis-like symptoms and headache were the most common adverse events identified during the 28-day observation period. Adverse events were similarly distributed between the treatment and placebo groups. Vaccine-specific local and serum antibodies were induced in a dose-dependent manner. In the highest dose group, vaccine-specific antibodies were detected in 10 of 12 volunteers. Importantly, the vaccine also induced neutralizing antibodies against heterologous drift variants. CONCLUSIONS. We show that vaccination with an influenza virus strain lacking the viral interferon antagonist NS1 induces statistically significant levels of strain-specific and cross-neutralizing antibodies despite the highly attenuated replication-deficient phenotype. Further studies are warranted to determine whether these results translate into protection from influenza virus infection. TRIAL REGISTRATION. ClinicalTrials.gov identifier: NCT00724997 .
    Keywords: Influenza A Virus, H1n1 Subtype -- Immunology ; Influenza Vaccines -- Immunology ; Influenza, Human -- Prevention & Control ; Vaccines, Attenuated -- Immunology ; Viral Nonstructural Proteins -- Genetics
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 4
    Language: English
    In: Omics : a journal of integrative biology, December 2010, Vol.14(6), pp.651-63
    Description: Pyrrolidine dithiocarbamate (PDTC), a known inhibitor of NFκB activation, has antioxidative as well as antiviral activities. PDTC is effective against several virus families, indicating that its antiviral mechanism targets host rather than viral functions. To investigate its mode of action, we used baker's yeast as a simple eukaryotic model system and two types of genome-wide analysis. First, expression profiling using whole-genome DNA microarrays identifies more than 200 genes differentially regulated upon PDTC exposure. Interestingly, the Aft1-dependent iron regulon is a main target of PDTC, indicating a lack of iron availability. Moreover, the PDTC-caused zinc influx triggers a strong regulatory effect on zinc transporters due to the cytoplasmic zinc excess. Second, phenotypic screening the EUROSCARF collection for PDTC hypersensitivity identifies numerous mutants implicated in vacuolar maintenance, acidification as well as in transport, mitochondrial organization, and translation. Notably, the screening data indicate significant overlaps of PDTC-sensitive genes and those mediating zinc tolerance. Hence, we show that PDTC induces cytoplasmic zinc excess, eliciting vacuolar detoxification, which in turn, disturbs iron homeostasis and activates the iron-dependent regulator Aft1. Our work reveals a complex crosstalk in yeast ion homeostasis and the underlying regulatory networks.
    Keywords: Genomics ; Homeostasis -- Drug Effects ; Iron -- Metabolism ; Pyrrolidines -- Pharmacology ; Regulon -- Drug Effects ; Saccharomyces Cerevisiae -- Metabolism ; Thiocarbamates -- Pharmacology ; Zinc -- Metabolism
    ISSN: 15362310
    E-ISSN: 1557-8100
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  • 5
    In: The Journal of Virology, 2002, Vol. 76(12), p.6004
    ISSN: 0022-538X
    ISSN: 0022538X
    Source: American Society of Microbiology
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  • 6
    Language: English
    In: FEBS Letters, 2004, Vol.560(1), pp.51-55
    Description: Peptide-based fluoromethyl ketones have been considered for many years to be highly specific caspase inhibitors distinctly blocking the progress of apoptosis in a variety of systems. Here we demonstrate that these compounds can significantly reduce rhinovirus multiplication in cell culture. In their methylated forms they block eIF4GI cleavage in vivo and in vitro and inhibit the activity of picornaviral 2A proteinases.
    Keywords: Rhinovirus ; Picornavirus ; 2a Proteinase ; Eif4gi Cleavage ; Caspase Inhibitor ; Apoptosis ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0014-5793
    E-ISSN: 1873-3468
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  • 7
    Language: English
    In: Analytica Chimica Acta, 2004, Vol.516(1), pp.119-124
    Description: A new, fully automated pre-column derivatization reaction was developed for the quantitative determination of dithiocarbamates in plasma samples. For complexation, an aliquot of the sample was mixed with an aliquot of a 5 mM Co(II) solution on the autosampler tray. Optimum conditions for the reaction were achieved at a tray temperature of 20 degree C and a reaction time of 11 min. Liquid chromatography (LC) separation was performed on a C18 ODS column using a binary gradient consisting of phosphate buffer and methanol. The colored complex of dithiocarbamate and Co(III) was quantified by UV detection at 330 nm. The assay was applied for the determination of pyrrolidine dithiocarbamate, a potent antiviral compound for the inhibition of human rhinoviruses and influenza viruses, in plasma samples. Limits of quantification were 1.4-2.9 mu g ml super(-1).
    Keywords: Pre-Column Derivatization Reaction ; Pyrrolidine Dithiocarbamate ; Hplc Uv-Detection ; Co(II) Complex ; Chemistry
    ISSN: 0003-2670
    E-ISSN: 1873-4324
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  • 8
    Language: English
    In: FEBS Letters, 2002, Vol.523(1), pp.53-57
    Description: Infection of mammalian cells with picornaviruses like entero-, rhino-, and aphthoviruses leads to an inhibition of cap-dependent cellular protein synthesis by the cleavage of both translation initiation factors, eIF4GI and eIF4GII. In entero- and rhinovirus infection this cleavage process is mediated by the viral 2A proteinase (2A super(pro)). In order to discriminate between a direct mode of eIF4G cleavage and an indirect cleavage via activation of a cellular proteinase, a thermosensitive 2A super(pro) mutant (ts-2A super(pro)) of human rhinovirus 2 was employed. Temperature shift experiments of cytoplasmic HeLa cell extracts incubated with ts-2A super(pro) strongly support a direct mode of cleavage of eIF4GI and eIF4GII by the viral 2A super(pro).
    Keywords: Human Rhinovirus ; Host Cell Shut-Off ; Viral Proteinase ; Eif4g Cleavage ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0014-5793
    E-ISSN: 1873-3468
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  • 9
    Language: English
    In: Journal of Biological Chemistry, 06/30/2000, Vol.275(26), pp.20084-20089
    Description: Rhino- and enteroviruses encode two proteinases, 2A and 3C, which are responsible for the processing of the viral polyprotein and for cleavage of several cellular proteins. To identify further targets of the 2A proteinase of human rhinovirus serotype 2 (HRV2), an in vitro cleavage assay followed by two-dimensional electrophoresis was employed. Cytokeratin 8, a member of the intermediate filament group of proteins, was found to be proteolytically cleaved in vitro by the 2A proteinase of HRV2 and of coxsackievirus B4 and in vivo during HRV2 infection of HeLa cells. The cleavage results in removal of 14 amino acids from the N-terminal head domain of cytokeratin 8. However, other intermediate filament proteins (cytokeratins 7 and 18 and vimentin) were not cleaved in the course of the HRV2 infection. Compared with the processing of the eucaryotic translation initiation factors 4GI and 4GII, cleavage of cytokeratin 8 occurs late in the infection cycle at the time of the onset of the cytopathic effect.
    Keywords: Viral Proteins ; Cysteine Endopeptidases -- Metabolism ; Keratins -- Metabolism ; Rhinovirus -- Enzymology;
    ISSN: 0021-9258
    E-ISSN: 1083-351X
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  • 10
    Language: English
    In: European Journal of Immunology, February 2010, Vol.40(2), pp.321-329
    Description: IL‐35 is a heterodimer of EBV‐induced gene 3 and of the p35 subunit of IL‐12, and recently identified as an inhibitory cytokine produced by natural Treg in mice, but not in humans. Here we demonstrate that DC activated by human rhinoviruses (R‐DC) induce IL‐35 production and release, as well as a suppressor function in CD4 and CD8 T cells derived from human peripheral blood but not in naïve T cells from cord blood. The induction of IL‐35‐producing T cells by R‐DC was FOXP3‐independent, but blocking of B7‐H1 (CD274) and sialoadhesin (CD169) on R‐DC with mAb against both receptors prevented the induction of IL‐35. Thus, the combinatorial signal delivered by R‐DC to T cells B7‐H1 and sialoadhesin is crucial for the induction of human IL‐35 Treg. These results demonstrate a novel pathway and its components for the induction of immune‐inhibitory T cells.
    Keywords: Human Rhinovirus ; Il‐35 ; Treg
    ISSN: 0014-2980
    E-ISSN: 1521-4141
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