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  1. Artikel ; Online: Baseline interpatient hepatitis B viral diversity differentiates HBsAg outcomes in patients treated with tenofovir disoproxil fumarate.

    Charuworn, Prista / Hengen, Paul N / Aguilar Schall, Raul / Dinh, Phillip / Ge, Dongliang / Corsa, Amoreena / Reesink, Hendrik W / Zoulim, Fabien / Kitrinos, Kathryn M

    Journal of hepatology

    2015  Band 62, Heft 5, Seite(n) 1033–1039

    Abstract: Background and aims: HBsAg loss is a desired, but rare, treatment-induced clinical endpoint in chronic hepatitis B (CHB). Few studies have evaluated viral factors contributing to HBsAg loss.: Methods: This study evaluated baseline interpatient ... ...

    Abstract Background and aims: HBsAg loss is a desired, but rare, treatment-induced clinical endpoint in chronic hepatitis B (CHB). Few studies have evaluated viral factors contributing to HBsAg loss.
    Methods: This study evaluated baseline interpatient sequence diversity across the HBV genome in tenofovir disoproxil fumarate-treated patients who lost HBsAg and compared it to that of control patients with high HBsAg levels throughout therapy. Twenty-one HBeAg+ patients (14 genotype (GT) A and 7 GT D) who achieved HBsAg loss and 27 controls (17 GT A and 10 GT D), were analyzed. Population sequencing was performed on baseline samples and pairwise genetic distances were calculated for 17 overlapping regions across the HBV genome as a measure of interpatient viral diversity.
    Results: Overall, viral diversity was up to 10-fold higher across GT D patients compared to GT A patients throughout the HBV genome. Within the pol/RT and HBs genes, interpatient viral diversity was significantly lower among HBsAg loss patients for both GT A and D, with the difference driven largely by a reduction in diversity in the small S gene. Conversely, interpatient viral diversity was generally higher in HBsAg loss patients across the HBx gene regulatory elements and precore region.
    Conclusion: In HBsAg loss patients, less interpatient viral diversity was observed within structural-coding regions while specific regions across the HBx and precore genes encoding nonstructural regulatory elements generally displayed higher interpatient viral diversity. These distinct patterns may reflect different responses to adaptive pressure for HBV genomic structural and nonstructural elements.
    Mesh-Begriff(e) Adult ; Antiviral Agents/pharmacology ; DNA, Viral/genetics ; Disease Transmission, Infectious ; Female ; Genetic Variation/drug effects ; Hepatitis B Surface Antigens/genetics ; Hepatitis B e Antigens/genetics ; Hepatitis B virus/drug effects ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/drug therapy ; Hepatitis B, Chronic/immunology ; Hepatitis B, Chronic/transmission ; Hepatitis B, Chronic/virology ; Humans ; Male ; Tenofovir/pharmacology
    Chemische Substanzen Antiviral Agents ; DNA, Viral ; Hepatitis B Surface Antigens ; Hepatitis B e Antigens ; Tenofovir (99YXE507IL)
    Sprache Englisch
    Erscheinungsdatum 2015-05
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 605953-3
    ISSN 1600-0641 ; 0168-8278
    ISSN (online) 1600-0641
    ISSN 0168-8278
    DOI 10.1016/j.jhep.2014.12.008
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Molecular flip-flops formed by overlapping Fis sites.

    Hengen, Paul N / Lyakhov, Ilya G / Stewart, Lisa E / Schneider, Thomas D

    Nucleic acids research

    2003  Band 31, Heft 22, Seite(n) 6663–6673

    Abstract: The DNA-binding protein Fis frequently uses pairs of sites 7 or 11 base pairs (bp) apart. Two overlapping Fis sites separated by 11 bp are found in the Escherichia coli origin of chromosomal replication. Only one of these sites is bound by Fis at a time, ...

    Abstract The DNA-binding protein Fis frequently uses pairs of sites 7 or 11 base pairs (bp) apart. Two overlapping Fis sites separated by 11 bp are found in the Escherichia coli origin of chromosomal replication. Only one of these sites is bound by Fis at a time, so the structure is a molecular flip-flop that could direct alternative firing of replication complexes in opposite directions. Alternatively, the flip-flop could represent part of an on-off switch for replication. Because they can be used to create precise switched states, molecular flip-flops could be used as the basis of a novel molecular computer.
    Mesh-Begriff(e) Bacterial Proteins/metabolism ; Base Sequence ; Binding Sites/genetics ; Binding, Competitive ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/metabolism ; Dimerization ; Electrophoretic Mobility Shift Assay ; Escherichia coli/genetics ; Factor For Inversion Stimulation Protein/chemistry ; Factor For Inversion Stimulation Protein/metabolism ; Models, Genetic ; Models, Molecular ; Molecular Sequence Data ; Oligonucleotides/chemistry ; Oligonucleotides/genetics ; Oligonucleotides/metabolism ; Protein Binding ; Replication Origin/genetics ; Sequence Homology, Nucleic Acid
    Chemische Substanzen Bacterial Proteins ; DNA-Binding Proteins ; DnaA protein, Bacteria ; Factor For Inversion Stimulation Protein ; Oligonucleotides
    Sprache Englisch
    Erscheinungsdatum 2003-10-01
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkg877
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor.

    Nelson, David / Yoshida, Eric M / Paulson, Matthew S / Hengen, Paul N / Ge, Dongliang / Kanwar, Bittoo / McNally, John / Pang, Phillip S / Subramanian, G Mani / McHutchison, John G / Urbanek, Petr / Lawitz, Eric / Urban, Thomas J

    Antiviral therapy

    2014  Band 19, Heft 7, Seite(n) 679–686

    Abstract: Background: Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype ...

    Abstract Background: Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype 1 HCV who received combination therapy that included GS-9256, a novel potent inhibitor of HCV NS3 serine protease, as part of a Phase IIb trial.
    Methods: Of the 200 patients sampled, 176 had confirmed European ancestry and were included in the analysis. Infinium HumanOmni5BeadChip (Illumina, Inc., San Diego, CA, USA) was used for genotyping. A categorical analysis of low (grade 0-1) versus high (grade 2-4) bilirubin toxicity grade and a quantitative trait locus mapping of peak bilirubin concentrations was performed.
    Results: A total of 4,466,809 genetic markers were analysed. No single variant showed a statistically significant association with observed bilirubin elevations in this patient population. In a targeted analysis of single nucleotide polymorphisms in genes known to be involved in bilirubin transport, no significant differences in allele frequency between high and low bilirubin toxicity grade were observed.
    Conclusions: These results indicate that risk for bilirubin elevation in patients receiving GS-9256 is unlikely to be strongly influenced by common genetic variants with large effects. The current study cannot rule out a role for common variants of weak effect, or a more complex model, including multiple contributing factors, such as rare variants and as yet unidentified environmental influences.
    Mesh-Begriff(e) Adult ; Aged ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Bilirubin/blood ; Computational Biology ; Female ; Genome-Wide Association Study ; Genotype ; Hepacivirus/drug effects ; Hepacivirus/metabolism ; Hepatitis C/blood ; Hepatitis C/drug therapy ; Hepatitis C/genetics ; Humans ; Male ; Microbial Sensitivity Tests ; Middle Aged ; Organic Anion Transporters/genetics ; Organic Anion Transporters, Sodium-Independent/genetics ; Peptides, Cyclic/pharmacology ; Peptides, Cyclic/therapeutic use ; Pharmacogenetics ; Phenotype ; Phosphinic Acids/pharmacology ; Phosphinic Acids/therapeutic use ; Polymorphism, Single Nucleotide ; Solute Carrier Organic Anion Transporter Family Member 1B3 ; Solute Carrier Organic Anion Transporter Family Member 1b1 ; Viral Nonstructural Proteins/antagonists & inhibitors ; Young Adult
    Chemische Substanzen Antiviral Agents ; GS-9256 ; NS3 protein, hepatitis C virus ; Organic Anion Transporters ; Organic Anion Transporters, Sodium-Independent ; Peptides, Cyclic ; Phosphinic Acids ; SLCO1B1 protein, human ; SLCO1B3 protein, human ; Solute Carrier Organic Anion Transporter Family Member 1B3 ; Solute Carrier Organic Anion Transporter Family Member 1b1 ; Viral Nonstructural Proteins ; Bilirubin (RFM9X3LJ49)
    Sprache Englisch
    Erscheinungsdatum 2014
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1339842-8
    ISSN 2040-2058 ; 1359-6535
    ISSN (online) 2040-2058
    ISSN 1359-6535
    DOI 10.3851/IMP2747
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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