Regulation of ADAM10 and ADAM17 by Sorafenib Inhibits Epithelial-to-Mesenchymal Transition in Epstein-Barr Virus-Infected Retinal Pigment Epithelial Cells

PURPOSE. The a-disintegrin-and-metalloprotease (ADAM) family proteins are widely expressed in the different layers of the retina throughout development. The effect of ADAM proteins on the epithelial-to-mesenchymal transition (EMT) in proliferative vitreoretinopathy (PVR) or AMD is yet to be elucidated. In this study we used Epstein-Barr virus (EBV)-transformed adult retinal pigment epithelial (ARPE) cells to investigate how sorafenib, a multikinase inhibitor, modulates ADAM proteins to control EMT. METHODS. Epithelial to mesenchymal transition and related mechanisms in EBV-infected ARPE cells were determined by RT-PCR, Western blot, invasion assay, ELISA assay, and gene silencing with siRNA. RESULTS. Mesenchymal-like ARPE/EBV cells exhibited considerably increased cellular migration and invasion compared with ARPE cells and produced EMT-related cytokines. Sorafenib significantly inhibited production of TGF-b1, VEGF, IL-6, IL-8, MCP-1, and TNF-a and blocked the activation of migration-related signaling molecules, such as HIF-1a, p-STAT3, MMP2, and Ang-1. The expression of mature ADAM10, ADAM17, and cleaved Notch 1 proteins in ARPE/EBV cells was downregulated after treatment with sorafenib through the regulatory activity of nardilysin (NRD-1). Gene silencing of NRD-1 in ARPE/EBV cells attenuated secretion of EMT-related cytokines and expression of ADAM10 and 17 and upregulated epithelial markers. CONCLUSIONS. Sorafenib controls the mesenchymal characteristics of EBV-infected ARPE cells. Nardilysin and ADAM family proteins might be new targets for the prevention or control of EMT in retinal diseases

The mediating role of the left ventricular mass index on the relationship between the fluid balance and left ventricular diastolic function in patients with chronic kidney disease

Background The pathophysiological mechanism of cardiovascular disease in patients with chronic kidney disease (CKD) is complicated. Mediation analysis is an important statistical tool for gaining insight into the complex mechanisms of exposure-outcome effects. We investigated the potential mediating role of the left ventricular mass index (LVMI) on the association between fluid balance (overhydration/extracellular water, OH/ECW) and left ventricular diastolic function (E/e´ ratio) in patients with CKD not yet on dialysis. Methods Bioimpedance spectroscopy, echocardiography, and laboratory evaluations were performed on 425 consecutive patients on the same day. The patients were classified into two groups according to the estimated glomerular filtration rate corresponding to CKD stages 3 and 5. Mediation analysis was performed using the PROCESS macro and bootstrapping methods. Results OH/ECW and LVMI were positively correlated with the E/e´ ratio in both the CKD stages 3 and five groups. In CKD stage 5, there was a statistically significant association between OH/ECW and LVMI, whereas no correlation was observed in CKD stage 3. In the mediation analysis, LVMI positively mediated the relationship between OH/ECW and E/e´ ratio when controlling for confounders in patients with CKD stage 5 (B = 2.602; Boot 95% confidence interval, 1.313–4.076). Conclusion In our analysis, the indirect effect of mediators was significant in patients with advanced CKD. Therefore, our study suggests that further research on several other risk factors may be needed to determine the underlying mechanisms of association between the associated factors in all CKD stages

Pseudocoarctation of the Aorta Associated with the Anomalous Origin of the Left Vertebral Artery: a Case Report

Pseudocoarctation of the aorta is a rare congenital anomaly of the aortic arch, and it has been described as an elongation of the aortic arch with "kinking" at the level of the ligamentum arteriosum without a pressure gradient across the lesion. The treatment for this condition is controversial. We report here on an unusual case of pseudocoarctation of the aorta associated with the anomalous origin of the left vertebral artery and we include a review of the medical literature

Angiomyofibroblastoma-Like Tumor of the Scrotum

Various tumors can occur in the scrotum. Of them, angiomyofibroblastoma-like tumors are very rare mesenchymal tumors. Angiomyofibroblastoma-like tumors cannot be easily differentially diagnosed from other malignant tumors invading the male genital tract on the basis of clinical characteristics and imaging study. Therefore, surgical removal and a histopathologic diagnosis must also be performed

Contrast enhancement behavior of hydrogen silsesquioxane in a salty developer

The authors investigated a contrast enhancement behavior of hydrogen silsesquioxane (HSQ) in a salty development system (NaOH/NaCl). Time-resolved analysis of contrast curves and line-grating patterns were carried out to investigate the unique properties of a salty development process. In NaOH developer without salt, the development process was saturated beyond a certain development time. On the other hand, the addition of salt enabled a continuous development, which was not observed in the pure NaOH development. The continuous thinning process enhances the contrast of HSQ in the salty developer, which allows a fast collapsing behavior in HSQ line-grating patterns. During development process, salt seems to have the role of modifying HSQ by breaking network bonds preferentially, leading to a continuous development rate