High-throughput RNA-sequencing reveals novel targets of tofacitinib in the treatment of rheumatoid arthritis.

OBJECTIVES: Although tofacitinib has been confirmed to have good efficacy and safety in the treatment of rheumatoid arthritis (RA), the relevant mechanism at the whole transcriptome level has not yet been revealed. In this study, peripheral blood mononuclear cells (PBMCs) from patients with active RA before and after tofacitinib treatment were analysed using whole transcriptome sequencing technology. METHODS: Fourteen patients with active RA were selected to detect the alterations of mRNAs, lncRNAs, circRNAs, and miRNAs in PBMCs before and after tofacitinib treatment using whole transcriptome sequencing. Through bioinformatics analysis, differentially expressed RNAs and their functions were identified. Then the competitive endogenous RNA (ceRNA) network and the protein interaction network were constructed. And qRT-PCR validation was performed for RNAs in the ceRNA network. RESULTS: Based on 69 DEmRNAs, 1743 DElncRNAs, 41 DEcircRNAs, and 4 DEmiRNAs obtained from whole transcriptome sequencing, an RNA interaction network including mRNA DEPDC1, lncRNA ENSG00000272574, circRNA hsa_circ_0034415, miR-190a-5p, and miR-1298-5p was constructed according to ceRNA theory. The qRT-PCR validation results of DEPDC1, hsa_circ_0034415 and miR-1298-5p involved in the network were consistent with the sequencing results, which provided important research evidence for further study of these RNAs. CONCLUSIONS: The new discovered circRNA/lncRNA-miRNA-mRNA network in RA patients relevant to tofacitinib therapy will provide new enlightenment for the role of tofacitinib in the treatment of RA and shed light on a new direction for further exploring the deep-seated mechanism of this drug.

Re-evaluation of dipeptidyl peptidase-4 inhibitors in patients with heart failure and diabetes mellitus.

OBJECTIVES: The question of whether dipeptidyl peptidase-4 inhibitors (DPP-4i) should be preferred as new glucose-lowering agents in heart failure is controversial. This studyaimed to evaluate the effects of DPP-4i treatment on all-cause mortality and cardiovascular outcomes in patients with heart failure. METHODS: We searched for available studies of DPP-4i therapy in heart failure and performed a pooled analysis. Outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), acute coronary syndrome, and acute myocardial infarction. RESULTS: Treatment with DPP-4i did not reduce the risk of all-cause death, cardiovascular death, or hospitalization for heart failure. Subgroup analyses showed that DPP-4i significantly reduced all-cause mortality in trials with > 40% female patients (OR 0.30, 95% CI [0.16, 0.58], P = 0.0003) and in trials with > 20% patients with heart failure with preserved ejection fraction (HFpEF) (OR 0.34, 95% CI [0.19, 0.60], P = 0.0003). Changes in LVEF and LVEDV showed no statistical differences between the 2 groups. Accordingly, DPP-4i did not alter the risk of acute coronary syndrome and acute myocardial infarction. CONCLUSIONS: DPP-4i may reduce all-cause mortality in heart failure patients in subgroups of women and HFpEF and has a high coronary safety profile.

Computational modeling of the cephalic arch with jugulocephalic vein variant predicts hemodynamic profiles in patients with brachiocephalic fistula.

BACKGROUND: The cephalic vein is often used in for arteriovenous fistula creation; however, the cephalic vein variation is common. This study will propose new theoretical explanations for a new discovered variation of cephalic vein draining into external jugular vein with "T-junction" shape by means of 3D computational hemodynamic modeling, which may provide reference for clinical practice. METHODS: The precise measurements were conducted for the variant right cephalic vein draining into external jugular vein and for a normal right cephalic vein as a control. After processing the anatomical data, 3D geometrical model was reconstructed. Then, the influent field inside the variant jugulocephalic vein was mathematically modeled to get a detailed description of hemodynamic environment. RESULTS: The anatomical parameters of the "T-junction" jugulocephalic vein variant were much more different from the normal right cephalic vein. The wall shear stress of variant cephalic vein at the corresponding position was higher and changed more rapidly than that of normal cephalic vein. The shear rate contour lines are disordered in several areas of the variant cephalic vein, indicating that the hemodynamic parameters in these areas are unstable. The hemodynamic characteristics at the confluence of the variant cephalic vein are more complex, with more areas where hemodynamic parameters are disrupted. CONCLUSIONS: The variation of cephalic arch in a "T-junction" with external jugular vein largely altered the fluid dynamics, especially in hemodialysis patients with brachiocephalic fistula in terms of the simulating flow in 3D computational model. This computational model provides hemodynamic profiles for stabilizing or modulating fluid dynamics in patients with jugulocephalic vein variant after brachiocephalic fistula.