5′UTR Variants of Ribosomal Protein S19 Transcript Determine Translational Efficiency: Implications for Diamond-Blackfan Anemia and Tissue Variability

Background: Diamond-Blackfan anemia (DBA) is a lineage specific and congenital erythroblastopenia. The disease is associated with mutations in genes encoding ribosomal proteins resulting in perturbed ribosomal subunit biosynthesis. The RPS19 gene is mutated in approximately 25 % of DBA patients and a variety of coding mutations have been described, all presumably leading to haploinsufficiency. A subset of patients carries rare polymorphic sequence variants within the 59untranslated region (59UTR) of RPS19. The functional significance of these variants remains unclear. Methodology/Principal Findings: We analyzed the distribution of transcriptional start sites (TSS) for RPS19 mRNAs in testis and K562 cells. Twenty-nine novel RPS19 transcripts were identified with different 59UTR length. Quantification of expressed w.t. 59UTR variants revealed that a short 59UTR correlates with high levels of RPS19. The total levels of RPS19 transcripts showed a broad variation between tissues. We also expressed three polymorphic RPS19 59UTR variants identified in DBA patients. The sequence variants include two insertions (c.-147_-146insGCCA and c.-147_-146insAGCC) and one deletion (c.-144_-141delTTTC). The three 59UTR polymorphisms are associated with a 20–30 % reduction in RPS19 protein levels when compared to the wild-type (w.t.) 59UTR of corresponding length. Conclusions: The RPS19 gene uses a broad range of TSS and a short 59UTR is associated with increased levels of RPS19. Comparisons between tissues showed a broad variation in the total amount of RPS19 mRNA and in the distribution of TS

The impact of biologics and tofacitinib on cardiovascular risk factors and outcomes in patients with rheumatic disease: a systematic literature review

Introduction Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients. Methods A systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events. Results Of the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated. Conclusions Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients