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achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.

Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL-based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.Anti-citrullinated protein/peptide antibodies (ACPA) play important roles in the pathogenesis of rheumatoid arthritis (RA). ACPA-positive (ACPA+ ) and ACPA-negative (ACPA- ) RA were suggested to be different disease subsets, with distinct differences in genetic variation and clinical outcomes. The aims of the present study were to compare gene expression profiles in ACPA+ and ACPA- RA, and to identify novel candidate gene signatures that might serve as therapeutic targets. Comprehensive transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from ACPA+ and ACPA- RA patients and healthy controls was performed via RNA sequencing. A validation cohort was used to further investigate differentially expressed genes via polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Spearman's correlation test was used to evaluate the correlation of differentially expressed genes and the clinical and laboratory data of the patients. The role of differentially expressed genes in osteoclastogenesis was further investigated. Expression of C-X-C motif chemokine ligand 2 (CXCL2) was significantly increased in ACPA+ RA than in ACPA- RA, which was validated in PBMCs and serum. CXCL2 promoted the migration of CD14+ monocytes and increased osteoclastogenesis in RA patients. RAW264.7 macrophages were used to investigate specific mechanisms, and the results suggested that CXCL2 stimulated osteoclastogenesis via extracellular receptor kinase (ERK) mitogen-activated protein kinase (MAPK) and nuclear factor kappa B pathways. In conclusion, CXCL2 was highly expressed in ACPA+ RA than in ACPA- RA. CXCL2 promoted osteoclastogenesis and was related to bone erosion in RA, which suggests that the blockade of CXCL2 might be a novel strategy for the treatment of RA.Immunogenicity risk assessment is a critical element in protein drug development. Currently, the risk assessment is most often performed using MHC-associated peptide proteomics (MAPPs) and/or T-cell activation assays. However, this is a highly costly procedure that encompasses limited sensitivity imposed by sample sizes, the MHC repertoire of the tested donor cohort and the experimental procedures applied. Recent work has suggested that these techniques could be complemented by accurate, high-throughput and cost-effective prediction of in silico models. However, this work covered a very limited set of therapeutic proteins and eluted ligand (EL) data. Here, we resolved these limitations by showcasing, in a broader setting, the versatility of in silico models for assessment of protein drug immunogenicity. selleck chemical A method for prediction of MHC class II antigen presentation was developed on the hereto largest available mass spectrometry (MS) HLA-DR EL data set. Using independent test sets, the performance of the method for prediction of HLA-DR antigen presentation hotspots was benchmarked. In particular, the method was showcased on a set of protein sequences including four therapeutic proteins and demonstrated to accurately predict the experimental MS hotspot regions at a significantly lower false-positive rate compared with other methods. This gain in performance was particularly pronounced when compared to the NetMHCIIpan-3.2 method trained on binding affinity data. These results suggest that in silico methods trained on MS HLA EL data can effectively and accurately be used to complement MAPPs assays for the risk assessment of protein drugs.

Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key drivers of type 2 inflammation. In phase 2b (NCT01854047) and phase 3 LIBERTY ASTHMA QUEST (NCT02414854), add-on dupilumab 200/300mg every 2weeks (q2w) reduced severe exacerbations, improved prebronchodilator (pre-BD) forced expiratory volume in 1second (FEV

) and quality of life measures, and it was generally well tolerated in patients with uncontrolled, persistent (phase 2b), or moderate-to-severe (phase 3) asthma.

In patients on high-dose inhaled corticosteroids (ICS) with type 2-high asthma (subgroups including baseline blood eosinophils ≥150/300cells/µL and/or fractional exhaled nitric oxide [FeNO] ≥25ppb), annualized severe exacerbation rates over the treatment period, changes from baseline in pre-BD FEV

and asthma control (5-item asthma control questionnaire [ACQ-5]) were analyzed.

In high-dose ICS type 2-high subgroups, dupilumab 200/300mg q2w vs placebo in the phase 2b (24weeks) and phase 3 (52weeks) studies significantly reduced severe exacerbations by 55%-69%/57%-60% (all P<.05) and 53%-69%/48%-66% (all P<.001), respectively, except in patients with≥300 eosinophils/µL in phase 2b study (24%/50% (P=.52/0.15). Across subgroups, pre-BD FEV

improved by 0.18-0.22L/0.19-0.24L (all P<.05) and 0.23-0.36L/0.15-0.25L (all P<.01) and ACQ-5 scores were reduced by 0.46-0.55/0.47-0.85 (all P<.05) and 0.38-0.50/0.24-0.30 (all P<.05), respectively, except dupilumab 200mg q2w in phase 2b in patients with FeNO≥25ppb (0.41; P=.09). Dupilumab was also effective in patients taking medium-dose ICS.

Dupilumab significantly reduced severe exacerbations and improved lung function and asthma control in patients with type 2-high asthma on high-dose ICS at baseline.

Dupilumab significantly reduced severe exacerbations and improved lung function and asthma control in patients with type 2-high asthma on high-dose ICS at baseline.In latitudinal avian migrants, increasing photoperiods induce fat deposition and body mass increase, and subsequent night-time migratory restlessness in captive birds, but the underlying mechanisms remain poorly understood. We hypothesized that an enhanced hypothalamic neuronal plasticity was associated with the photostimulated spring migration phenotype. We tested this idea in adult migratory red-headed buntings (Emberiza bruniceps), as compared with resident Indian weaverbirds (Ploceus philippinus). Birds were exposed to a stimulatory long photoperiod (14L10D, LP), while controls were kept on a short photoperiod (10L14D, SP). Under both photoperiods, one half of birds also received a high calorie, protein- and fat-rich diet (SP-R, LP-R) while the other half stayed on the normal diet (SP-N, LP-N). Thirty days later, as expected, the LP had induced multiple changes in the behaviour and physiology in migratory buntings. Photostimulated buntings also developed a preference for the rich food diet. Most interestingly, the LP and the rich diet, both separately and in association, increased neurogenesis in the mediobasal hypothalamus (MBH), as measured by an increased number of cells immunoreactive for doublecortin (DCX), a marker of recently born neurons, in buntings, but not weaverbirds.