Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study of ustekinumab in Japanese patients with active polymyositis and dermatomyositis who have not adequately responded to one or more standard-of-care treatments.

OBJECTIVES: To evaluate the efficacy and safety of ustekinumab (UST) in a multicentre, randomised, double-blind, placebo-controlled trial in adult Japanese patients with active polymyositis (PM) and dermatomyositis (DM). METHODS: Fifty-one Japanese adults diagnosed with active PM/DM who did not respond adequately to one or more standard-of-care treatments were randomised 1:1 to receive UST (n=25) or placebo (n=26). Participants received body weight-range based intravenous administration of UST (6 mg/kg) or placebo at week 0 followed by 90 mg subcutaneous (SC) administration of UST or placebo every 8 weeks from week 8 to week 24. At week 24, placebo group crossed over to receive body weight-range based intravenous administration of UST, and thereafter, all participants received/were to receive SC administration of UST 90 mg every 8 weeks (week 32 through to week 72). The primary efficacy endpoint was the proportion of participants who achieved minimal improvement (≥20) in the International Myositis Assessment and Clinical Studies Total Improvement Score (IMACS TIS) at week 24. RESULTS: No statistically significant difference was seen in the proportion of participants who achieved minimal improvement (≥20) in IMACS TIS at week 24 between the treatment groups (UST 64.0% vs placebo 61.5%, p=0.94) based on the primary estimand of the primary endpoint analysis. CONCLUSIONS: UST was safe and well tolerated but did not meet the primary efficacy endpoint in adult Japanese participants with active PM/DM based on the primary analysis at week 24 in the study. TRIAL REGISTRATION NUMBER: NCT03981744.

Designation of enzyme activity of glycine-N-acyltransferase family genes and depression of glycine-N-acyltransferase in human hepatocellular carcinoma.

The human glycine-N-acyltransferase (hGLYAT) gene and two related-genes (GLYATL1 and GLYATL2) were isolated. Human GLYAT, GLYATL1, and GLYATL2 cDNAs were isolated and shown to encode polypeptides of 295, 302, and 294 amino acids, respectively. GLYAT catalyzes glycine-N-acyltransfer reaction with benzoyl-CoA acting as a typical aralkyl transferase, while GLYATL1 catalyzed glutamine-N-acyltransfer reaction with phenylacetyl-CoA as an arylacetyl transferase. GLYAT was shown to be expressed specifically in the liver and kidney, and the cellular localization of GLYAT protein was restricted to the mitochondria. Interestingly, labeling using highly affinity purified anti-GLYAT antibody revealed that GLYAT expression was suppressed in all hepatocellular carcinomas, but not in other liver diseases. hGLYAT repression in cancerous cells in the liver was controlled at the transcriptional level. hGLYAT is a good candidate as a novel marker of hepatocellular carcinoma and may be a key molecule in the transition between differentiation and carcinogenesis of liver cells.

Importance of transient receptor potential vanilloid 4 (TRPV4) in epidermal barrier function in human skin keratinocytes.

The state of the skin changes drastically depending on the ambient temperature. Skin epidermal keratinocytes express thermosensitive transient receptor potential vanilloid (TRPV) cation channels, TRPV3 and TRPV4. These multimodal receptors are activated by various kinds of chemical and physical stimuli, including warm temperatures (>30°C). It has been suggested that TRPV4 is involved in cell-cell junction maturation; however, the effect of temperature fluctuations on TRPV4-dependent barrier homeostasis is unclear. In the present study, we demonstrated that activation of TRPV4 was crucial for barrier formation and recovery, both of which were critical for the prevention of excess dehydration of human skin keratinocytes. TRPV4 activation by physiological skin temperature (33°C), GSK1016790A or 4α-PDD allowed influx of Ca(2+) from extracellular spaces which promoted cell-cell junction development. These changes resulted in augmentation of intercellular barrier integrity in vitro and ex vivo. TRPV4 disruption reduced the increase in trans-epidermal resistance and increased intercellular permeation after a Ca(2+) switch. Furthermore, barrier recovery after the disruption of the stratum corneum was accelerated by the activation of TRPV4 either by warm temperature or a chemical activator. Our results suggest that physiological skin temperatures play important roles in cell-cell junction and skin barrier homeostasis through TRPV4 activation.