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951.
952.
Eliford Ngaimisi Abiy Habtewold Omary Minzi Eyasu Makonnen Sabina Mugusi Wondwossen Amogne Getnet Yimer Klaus-Dieter Riedel Mohammed Janabi Getachew Aderaye Ferdinand Mugusi Leif Bertilsson Eleni Aklillu Juergen Burhenne 《PloS one》2013,8(7)
Objectives
We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations.Methods
ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done.Result
Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART.Conclusion
We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations. 相似文献953.
Sen Mui Tan Markus Kapp Christin Flechsig Kerstin Kapp Johannes E. Rachor Matthias Eyrich Juergen Loeffler Hermann Einsele Goetz U. Grigoleit 《Cytotherapy》2013,15(4):492-506
Background aimsDendritic cells (DC) have been vigorously investigated as an immunological basis for therapeutic vaccination against cancer and infections, even among patients after allogeneic stem cell transplantation.MethodsEffective induction of cell-mediated immunity strongly depends on the ability of DC to (i) migrate to the draining lymphoid organs mediated by chemokine receptors, (ii) prime T cells through high expression of costimulatory molecules and major histocompatibility complexes and (iii) secret Th1-polarizing cytokines such as Interleukin-12 (IL-12). However, there is no protocol to generate fully matured and functional DC according to methodical requirements of current good manufacturing practice (CGMP) guidelines.ResultsWe established a protocol conforming to CGMP standards that permits the generation of fully matured and functional DC on the basis of cell culture in adherence bags with the use of serum-free media with a maturation cocktail, containing tumor necrosis factor-alpha/Interferon-alpha/polyinosinic:polycytidylic acid. Our DC superiorly display three critical features for an effective induction of cell-mediated immunity without evidence of exhaustion, along with its ability to prime infectious or tumor-specific T cells in a short-term cell culture.ConclusionsOur newly developed protocol offers an attractive method to produce fully matured Th1-polarizing DC with proven migratory and stimulatory capacity for any clinical application according to CGMP standards. 相似文献
954.
955.
Katrin H?gner Thorsten Wolff Stephan Pleschka Stephanie Plog Achim D. Gruber Ulrich Kalinke Hans-Dieter Walmrath Johannes Bodner Stefan Gattenl?hner Peter Lewe-Schlosser Mikhail Matrosovich Werner Seeger Juergen Lohmeyer Susanne Herold 《PLoS pathogens》2013,9(2)
Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis-inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB-dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury. 相似文献
956.
Neurons in the mammalian neocortex arise from asymmetric divisions of progenitors residing in the ventricular zone. While in most progenitor divisions, the mitotic spindle is parallel to the ventricular surface, some progenitors reorient the spindle and divide in oblique orientations. Here, we use conditional deletion and overexpression of mouse Inscuteable (mInsc) to analyze the relevance of spindle reorientation in cortical progenitors. Mutating mInsc almost abolishes oblique and vertical mitotic spindles, while mInsc overexpression has the opposite effect. Our data suggest that oblique divisions are essential for generating the correct numbers of neurons in all cortical layers. Using clonal analysis, we demonstrate that spindle orientation affects the rate of indirect neurogenesis, a process where progenitors give rise to basal progenitors, which in turn divide symmetrically into two differentiating neurons. Our results indicate that the orientation of progenitor cell divisions is important for correct lineage specification in the developing mammalian brain. 相似文献
957.
Hopkins D Gomathinayagam S Rittenhour AM Du M Hoyt E Karaveg K Mitchell T Nett JH Sharkey NJ Stadheim TA Li H Hamilton SR 《Glycobiology》2011,21(12):1616-1626
The methylotrophic yeast, Pichia pastoris, is an important organism used for the production of therapeutic proteins. However, the presence of fungal-like glycans, such as those containing β-mannose (Man) linkages, can elicit an immune response or bind to Man receptors, thus reducing their efficacy. Recent studies have confirmed that P. pastoris has four genes from the β-mannosyl transferase (BMT) family and that Bmt2p is responsible for the majority of β-Man linkages on glycans. While expressing recombinant human erythropoietin (rhEPO) in a developmental glycoengineered strain devoid of BMT2 gene expression, cross-reactivity was observed with an antibody raised against host cell antigens. Treatment of the rhEPO with protein N-glycosidase F eliminated cross-reactivity, indicating that the antigen was associated with the glycan. Thorough analysis of the glycan profile of rhEPO demonstrated the presence of low amounts of α-1,2-mannosidase resistant high-Man glycoforms. In an attempt to eliminate the α-mannosidase resistant glycoforms, we used a systemic approach to genetically knock-out the remaining members of the BMT family culminating in a quadruple bmt2,4,1,3 knock-out strain. Data presented here conclude that the additive elimination of Bmt2p, Bmt3p and Bmt1p activities are required for total abolition of β-Man-associated glycans and their related antigenicity. Taken together, the elimination of β-Man containing glycoforms represents an important step forward for the Pichia production platform as a suitable system for the production of therapeutic glycoproteins. 相似文献
958.
van Eis MJ Evenou JP Floersheim P Gaul C Cowan-Jacob SW Monovich L Rummel G Schuler W Stark W Strauss A von Matt A Vangrevelinghe E Wagner J Soldermann N 《Bioorganic & medicinal chemistry letters》2011,21(24):7367-7372
The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes δ, ε, η, θ (in particular PKCε/η, and display a 10–100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCθ-dependent pathways in vitro and in vivo. In vitro, a-CD3/a-CD28-induced lymphocyte proliferation could be effectively blocked in 10% rat whole blood. In mice, 11 dose-dependently inhibited Staphylococcus aureus enterotoxin B-triggered IL-2 serum levels after oral dosing. 相似文献
959.
Tye H Mueller SG Prestle J Scheuerer S Schindler M Nosse B Prevost N Brown CJ Heifetz A Moeller C Pedret-Dunn A Whittaker M 《Bioorganic & medicinal chemistry letters》2011,21(1):34-37
The discovery of a novel series of 5-HT2C agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT2A and 5-HT2B receptors were identified. One of the analogues (7g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity. 相似文献
960.
Claus Neurohr Anna L Hoffmann Patrick Huppmann Vivian A Herrera Franziska Ihle Stefan Leuschner Werner von Wulffen Tobias Meis Carlos Baezner Hanno Leuchte Rainer Baumgartner Gregor Zimmermann Juergen Behr 《Respiratory research》2011,12(1):66