Glucocorticoids Hijack Runx2 to Stimulate Wif1 for Suppression of Osteoblast Growth and Differentiation.

Inhibition of Runx2 is one of many mechanisms that suppress bone formation in glucocorticoid (GC)-induced osteoporosis (GIO). We profiled mRNA expression in ST2/Rx2(dox) cells after treatment with doxycycline (dox; to induce Runx2) and/or the synthetic GC dexamethasone (dex). As expected, dex typically antagonized Runx2-driven transcription. Select genes, however, were synergistic stimulated and this was confirmed by RT-qPCR. Among the genes synergistically stimulated by GCs and Runx2 was Wnt inhibitory Factor 1 (Wif1), and Wif1 protein was readily detectable in medium conditioned by cultures co-treated with dox and dex, but neither alone. Cooperation between Runx2 and GCs in stimulating Wif1 was also observed in primary preosteoblast cultures. GCs strongly inhibited dox-driven alkaline phosphatase (ALP) activity in control ST2/Rx2(dox) cells, but not in cells in which Wif1 was silenced. Unlike its anti-mitogenic activity in committed osteoblasts, induction of Runx2 transiently increased the percentage of cells in S-phase and accelerated proliferation in the ST2 mesenchymal pluripotent cell culture model. Furthermore, like the inhibition of Runx2-driven ALP activity, dex antagonized the transient mitogenic effect of Runx2 in ST2/Rx2(dox) cultures, and this inhibition eased upon Wif1 silencing. Plausibly, homeostatic feedback loops that rely on Runx2 activation to compensate for bone loss in GIO are thwarted, exacerbating disease progression through stimulation of Wif1. J. Cell. Physiol. 232: 145-153, 2017. © 2016 Wiley Periodicals, Inc.

Comparison of Sofosbuvir Plus Ribavirin Treatment with Pegylated Interferon Plus Ribavirin Treatment for Chronic Hepatitis C Genotype 2.

BACKGROUND: Sofosbuvir plus ribavirin (RBV) therapy showed higher sustained virological response at 12 weeks after treatment (SVR12) than pegylated interferon (peg-IFN) plus RBV; however, liver function, fibrosis, and hepatocellular carcinoma markers have not been assessed so far. SUMMARY: Patients (n = 21) receiving Sofosbuvir plus RBV and those (n = 24) receiving peg-IFN plus RBV were enrolled in this study. Changes in alanine aminotransferase (ALT) and α-fetoprotein (AFP) levels, platelet (PLT) counts, FIB-4, and aspartate aminotransferase-to-platelet ratio index (APRI) in both groups were assessed in patients achieving SVR12. Also, fibrosis regression was assessed using pathophysiological biomarkers, such as hyaluronic acid, bone morphogenetic protein 7 (BMP-7), and connective tissue growth factor (CTGF) in the Sofosbuvir plus RBV group. In both groups, while the reduction in ALT levels was significant that of AFP was not. Compared with the baseline, although serum PLT count at the end of treatment (EOT) was significantly higher in the Sofosbuvir plus RBV group, it was significantly lower in the peg-IFN plus RBV group. Although a significant decline in fibrosis markers such as FIB-4 and APRI was observed between the baseline and at EOT in the Sofosbuvir plus RBV group, no significant change of these markers was observed in the peg-IFN plus RBV group. Moreover, BMP-7 and CTGF were significantly lower at EOT than the baseline in the Sofosbuvir plus RBV group. Key Message: The treatment with Sofosbuvir plus RBV results in not only a higher SVR, but also improves the liver function and the degree of fibrosis.

Efficacy and Safety of Sofosbuvir Plus Ribavirin Treatment for Patients with Chronic Hepatitis C Genotype 2.

OBJECTIVES: The efficacy of sofosbuvir plus ribavirin (RBV) treatment for hepatitis C virus (HCV) genotype 2 focusing on virological response was compared with that of pegylated interferon (peg-IFN) plus RBV treatment. Safety of the former focusing on the decline in hemoglobin levels was compared with that of the latter and assessed in terms of age and inosine triphosphatase (ITPA). METHODS: Patients (n = 17) receiving sofosbuvir plus RBV and those (n = 24) receiving peg-IFN plus RBV diagnosed with chronic HCV genotype 2 were enrolled in this study, and the efficacy and safety of both treatments were assessed. RESULTS: Rapid virological response was attained with sofosbuvir plus RBV treatment compared with peg-IFN plus RBV treatment. All patients under sofosbuvir plus RBV treatment achieved end-of-treatment response compared with 70% who sustained viral response under the peg-IFN plus RBV treatment, with the former demonstrating greater virological response. The decline in hemoglobin levels under the former treatment was greater than that under the latter and in patients over 65 years of age with ITPA gene major. CONCLUSION: Efficacy and safety of sofosbuvir plus RBV treatment were clearly demonstrated compared with those of peg-IFN plus RBV treatment. The decline in hemoglobin levels was not related to the discontinuation of the former treatment, irrespective of age or the effect of the ITPA gene.

[Prevention of spinal hypotension associated with cesarean section by aortocaval compression--left 15 degree table tilt vs. uterine displacement by hand].

Women undergoing elective cesarean delivery were randomly assigned to receive a spinal anesthesia in either the semi-lateral (group SL) position or the supine position with uterine displacement (group UD). After spinal injection, group SL patients were turned to a 15 degrees left lateral supine position, and group UD patients had uterine displacement by hand. Ephedrine 4 mg i.v. was administered in case of nausea/vomiting and/or hypotension, defined as a systolic blood pressure below 100 mmHg. Arm systolic arterial pressure and leg systolic arterial pressure were similar in both groups, but the lowest leg systolic arterial pressure until delivery was significantly lower in the UD group (P < 0.05). Mean ephedrine requirement was significantly less in the SL group (P < 0.05). Apgar scores did not differ, but umbilical artery pH values were significantly higher in patients of the group SL (P < 0.01).

Fusion with heat-resistant obscure (Hero) proteins have the potential to improve the molecular property of recombinant proteins.

Although recombinant proteins are widely used in biotechnology and pharmaceutical industries, improving their solubility and stability is often a challenging issue. We recently discovered a class of highly unstructured heat-resistant obscure (Hero) proteins, which function to protect other "client" proteins in trans from various stresses in vitro and in vivo. Here, we show that fusion of Hero proteins in cis can enhance the molecular property of recombinant proteins. Fusion with Hero11 improved the otherwise challenging production of TAR DNA-binding protein of 43 kDa (TDP-43) in Escherichia coli. Moreover, fusing with Hero9 strongly protected the activity of firefly luciferase bearing destabilizing mutations against heat and other stress conditions. These data suggest that Hero proteins have the potential to be used as versatile stabilization tags for recombinant protein production.