This prospective, double-blinded, randomized controlled study aimed to investigate the efficacy and safety of oral tadalafil in patients receiving background ambrisentan therapy. Current treatments for pulmonary arterial hypertension (PAH) remain insufficient, resulting in high mortality rates. The addition of oral tadalafil, a phosphodiesterase-5 inhibitor, to background ambrisentan may provide a safe and effective therapeutic strategy. A total of 124 patients who had been treated with ambrisentan for at least 4 months and had a stable 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC) for at least 1 month were randomized to either the oral tadalafil or placebo group. Treatment differences in 6MWD, changes in FC, clinical worsening (CW) and adverse events were analyzed after 16 weeks of treatment. At week 16, the tadalafil group showed a significantly improved exercise capacity as assessed by the 6MWD (P<0.05). In addition, 5 (8.3%) patients receiving tadalafil add-on therapy had CW vs. 15 (23.4%) with placebo (P<0.05). No significant differences were found in adverse events or changes in hemodynamic parameters between the placebo and tadalafil groups. Tadalafil 40 mg was well-tolerated as add-on therapy to background ambrisentan. However, the data from this study are insufficient to prove the additional therapeutic benefits of tadalafil add-on therapy.

Cellular junctions play a critical role in structural connection and signal communication between cells in various tissues. Although there are structural and functional varieties, cellular junctions include tight junctions, adherens junctions, focal adhesion junctions, and tissue specific junctions such as PECAM-1 junctions in endothelial cells (EC), desmosomes in epithelial cells, and hemidesmosomes in EC. Cellular junction dysfunction and deterioration are indicative of clinical diseases. MicroRNAs (miRNA) are ~20 nucleotide, noncoding RNAs that play an important role in posttranscriptional regulation for almost all genes. Unsurprisingly, miRNAs regulate junction protein gene expression and control junction structure integrity. In contrast, abnormal miRNA regulation of junction protein gene expression results in abnormal junction structure, causing related diseases. The major components of tight junctions include zonula occluden-1 (ZO-1), claudin-1, claudin-5, and occludin. The miRNA regulation of ZO-1 has been intensively investigated. ZO-1 and other tight junction proteins such as claudin-5 and occludin were positively regulated by miR-126, miR-107, and miR21 in different models. In contrast, ZO-1, claudin-5, and occludin were negatively regulated by miR-181a, miR-98, and miR150. Abnormal tight junction miRNA regulation accompanies cerebral middle artery ischemia, brain trauma, glioma metastasis, and so forth. The major components of adherens junctions include VE-cadherin, β-catenin, plakoglobin, P120, and vinculin. VE-cadherin and β-catenin were regulated by miR-9, miR-99b, miR-181a, and so forth. These regulations directly affect VE-cadherin-β-catenin complex stability and further affect embryo and tumor angiogenesis, vascular development, and so forth. miR-155 and miR-126 have been shown to regulate PECAM-1 and affect neutrophil rolling and EC junction integrity. In focal adhesion junctions, the major components are integrin β4, paxillin, and focal adhesion kinase (FAK). Integrin β4 has been regulated by miR-184, miR-205, and miR-9. Paxillin has been regulated by miR-137, miR-145, and miR-218 in different models. FAK has been regulated by miR-7, miR-138, and miR-135. Deregulation of miRNAs is caused by viral infections, tumorigenesis, and so forth. By regulation of posttranscription, miRNAs manipulate junction protein expression in all cellular processes and further determine cellular fate and development. Elucidation of these regulatory mechanisms will become a new alternative therapy for many diseases, such as cancers and inflammatory diseases.

Sepsis, an under-recognized health problem, is a major cause of death.  More than 750,000 individuals develop sepsis annually, of whom 215,000 die of the disease. Clinical and experimental evidence indicates that patients with sepsis present with rapid impairment of immune function; biomarkers are therefore needed to enable early detection of this condition. Reduced monocyte human leukocyte antigen-DR (HLA-DR) expression, which is measured by flow cytometry, is currently the most popular biomarker for sepsis detection. In addition, the determination of HLA-DR expression provides valuable information in terms of predicting mortality and risk of secondary infections. HLA-DR levels have been shown to be inversely correlated with the severity of sepsis and immune dysfunction. In this review, we provide an overview of the association between sepsis and HLA-DR expression in terms of the predictive value of the latter in sepsis.