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  • Springer (CrossRef)  (5)
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  • 1
    Language: English
    In: Cellular and Molecular Life Sciences, 2011, Vol.68(6), pp.1079-1090
    Description: Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated for the first time that Raf activation is involved in HCMV IEA expression.
    Keywords: Human cytomegalovirus ; Sorafenib ; Kinase inhibitor ; Raf ; Immediate early antigen ; Cancer chemotherapy ; Oncomodulation ; Antiviral therapy
    ISSN: 1420-682X
    E-ISSN: 1420-9071
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  • 2
    Language: English
    In: Medical microbiology and immunology, June 2015, Vol.204(3), pp.285-93
    Description: The morphogenesis of human cytomegalovirus (HCMV) particles is incompletely understood. Analysis of the protein composition of HCMV virions and subviral dense bodies (DBs) by mass spectrometry provides valuable information to increase our knowledge about viral morphogenesis. Here we addressed the viral proteome of virions and DBs from two fibroblast-passaged isolates and the widely used endotheliotropic TB4-BAC40 strain of HCMV. The results show a striking concordance of the particle proteomes of different strains. One surprising finding was that only low levels of gpUL128-131A were found in TB40-BAC4 virions. These three proteins, together with gH and gL, form a protein complex that is critical for the endothelial cell tropism of that strain. This indicates that either few molecules of that complex per virion or a small fraction of pentamer-positive virions suffice to retain the tropism. Furthermore, using a pp65-deficient variant of TB40-BAC4, we confirm our previous finding that the major tegument protein serves as a scaffold to support the upload of a fraction of the outer tegument proteins into particles. The results demonstrate that HCMV particle morphogenesis is an orchestrated process that leads to the formation of particles with a largely strain-independent protein composition.
    Keywords: Proteome ; Proteomics ; Virion ; Cytomegalovirus -- Classification ; Viral Proteins -- Metabolism
    ISSN: 03008584
    E-ISSN: 1432-1831
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  • 3
    Language: English
    In: Clinical Rheumatology, 2012, Vol.31(8), pp.1163-1168
    Description: Recent data suggest that atherosclerotic disease is increased in patients with idiopathic inflammatory myositis (IIM) and that dyslipidemia is a significant risk factor for cardiovascular events. Lipid-lowering agents may be associated with myopathic side effects. The current work evaluates the use of lipid-lowering therapy in patients with IIM treated by IIM specialists belonging to the International Myositis Assessment and Clinical Studies (IMACS) Group. The IMACS Group is a multidisciplinary coalition of experts with significant interest and experience in IIM. IMACS members were asked to complete an 18-item online survey detailing their clinical practice on monitoring and treating hypercholesterolemia in IIM patients. Specific questions regarding the types of lipid-lowering therapies used in IIM patients and any side effects associated with treatment were asked. Sixty-three IMACS members representing 23 countries and a minimum of 1,641 IIM patients participated in the online survey. Seventy-six percent of these specialists treating adult IIM patients use lipid-lowering therapies in their patients. HMG co-enzymeA reductase inhibitors (statins) were the most commonly used agents (93 %). Thirty-six cases of worsening myositis associated with statin use were reported in over 300 patients using lipid-lowering therapies. Seven of eight responders who reported worsening in myositis with lipid-lowering therapies reported cases in which the myositis improved after holding therapy. This survey suggests that statins are commonly used by physicians specializing in the treatment of patients with IIM and that some myositis patients worsen with statin use and may improve on dechallenge. More research regarding the safety of lipid-lowering agents in patients with IIM is warranted.
    Keywords: Dermatomyositis ; Dyslipidemia ; Idiopathic inflammatory myositis ; Inclusion body myositis ; Myositis ; Polymyositis ; Statins
    ISSN: 0770-3198
    E-ISSN: 1434-9949
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  • 4
    Language: English
    In: Rheumatology International, 2012, Vol.32(9), pp.2725-2729
    Description: Patient overall satisfaction with health (PSH) was measured by a subset of questions from the Arthritis Impact Measurement Scales II. Based on longitudinal observations for 267 early rheumatoid arthritis (RA) patients of the United States Western Consortium (WC) cohort receiving first non-biologic DMARD treatment, we estimated the 1-year change in PSH ( $$\Updelta$$ PSH). Logistic regression analysis was used to estimate the association of improvement in $$\Updelta$$ PSH with the core set of clinical and patient-reported components of disease activity scores (DAS). Most patients were more satisfied with health after 1 year of treatment (80%); few achieved DAS28-ESR minimal disease activity (27%) or remission (7%). Laboratory and joint count measures were not associated with improved 12-month PSH. Patients with greater HAQ-DI ( P = 0.0473) and self-reported stiffness ( P = 0.0669) were more likely to have a perceived overall health benefit from treatment. Regardless of objective disease status, patients are generally satisfied with first-line treatment, which could present a challenge to implementing DAS-guided treatment change. Patients with greater self-reported functional limitations might have lower expectations for treatment benefit and be less willing to modify their current therapy; subjective assessments of function and stiffness could be particularly useful in identifying these patients.
    Keywords: Disease activity score ; Disease-modifying antirheumatic drugs ; Remission ; Rheumatoid arthritis ; Patient-reported outcome ; Patient satisfaction ; Stiffness
    ISSN: 0172-8172
    E-ISSN: 1437-160X
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  • 5
    Language: English
    In: Conservation Genetics, 2010, Vol.11(1), pp.195-211
    Description: The population status of the harbour porpoise ( Phocoena phocoena ) in the Baltic area has been a continuous matter of debate. Here we present the by far most comprehensive genetic population structure assessment to date for this region, both with regard to geographic coverage and sample size: 497 porpoise samples from North Sea, Skagerrak, Kattegat, Belt Sea, and Inner Baltic Sea were sequenced at the mitochondrial Control Region and 305 of these specimens were typed at 15 polymorphic microsatellite loci. Samples were stratified according to sample type (stranding vs. by-caught), sex, and season (breeding vs. non-breeding season). Our data provide ample evidence for a population split between the Skagerrak and the Belt Sea, with a transition zone in the Kattegat area. Among other measures, this was particularly visible in significant frequency shifts of the most abundant mitochondrial haplotypes. A particular haplotype almost absent in the North Sea was the most abundant in Belt Sea and Inner Baltic Sea. Microsatellites yielded a similar pattern (i.e., turnover in occurrence of clusters identified by STRUCTURE). Moreover, a highly significant association between microsatellite assignment and unlinked mitochondrial haplotypes further indicates a split between North Sea and Baltic porpoises. For the Inner Baltic Sea, we consistently recovered a small, but significant separation from the Belt Sea population. Despite recent arguments that separation should exceed a predefined threshold before populations shall be managed separately, we argue in favour of precautionary acknowledging the Inner Baltic porpoises as a separate management unit, which should receive particular attention, as it is threatened by various factors, in particular local fishery measures.
    Keywords: Demographic independence ; Management unit ; Mitochondrial DNA ; Microsatellites ; Phocoena phocoena ; Population
    ISSN: 1566-0621
    E-ISSN: 1572-9737
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