A new regulatory switch in a JAK protein kinase.

Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over-stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhibitors of a JAK kinase has led to our characterization of a previously unknown kinase conformation arising from presentation of Tyr962 of TYK2 to an inhibitory small molecule via an H-bonding interaction. A small minority of protein kinase domains has a Tyrosine residue in this position within the αC-ß4 loop, and it is the only amino acid commonly seen here with H-bonding potential. These discoveries will aid design of inhibitors that discriminate among the JAK family and more widely among protein kinases.

Reduced esophageal cancer incidence in statin users, particularly with cyclo-oxygenase inhibition.

AIM: To examine the association between statin use and the development of esophageal cancer METHODS: We performed a systematic review and meta-analysis. Multiple databases (Pubmed, EMBASE, Cochrane Library, Web of Science, Wiley Interscience and Google Scholar) were systematically searched for studies reporting the association of statin use and the development of esophageal cancer. Literature searching and data abstraction were performed independently by two separate researchers. The quality of studies reviewed was evaluated using the Newcastle-Ottawa Quality assessment scale. Meta-analysis on the relationship between statin use and cancer incidence was performed. The effect of the combination of statin plus a cyclo-oxygenase inhibitor was also examined. RESULTS: Eleven studies met eligibility criteria, 9 high and 2 medium quality. All were observational studies. Studies examining adenocarcinoma development in Barrett's esophagus included 317 cancers and 1999 controls, population-based studies examining all esophageal cancers included 371203 cancers and 6083150 controls. In the Barrett's population the use of statins (OR = 0.57; 95%CI: 0.43-0.75) and cyclo-oxygenase inhibitors (OR = 0.59; 95%CI: 0.45-0.77) were independently associated with a reduced incidence of adenocarcinoma. Combined use of a statin plus cyclo-oxygenase inhibitor was associated with an even lower adenocarcinoma incidence (OR = 0.26; 95%CI: 0.1-0.68). There was more heterogeneity in the population-based studies but pooled adjusted data showed that statin use was associated with a lower incidence of all combined esophageal cancers (OR = 0.81; 95%CI: 0.75-0.88). CONCLUSION: Statin use in patients with Barrett's oesophagus is associated with a significantly lower incidence of adenocarcinoma. The chemopreventive actions of statins, especially combined with cyclo-oxygenase inhibitors deserve further exploration.