Hsp90 inhibition suppresses NF-κB transcriptional activation via Sirt-2 in human lung microvascular endothelial cells.

The ability of anti-heat shock protein 90 (Hsp90) drugs to attenuate NF-κB-mediated transcription is the major basis for their anti-inflammatory properties. While the molecular mechanisms underlying this effect are not clear, they appear to be distinct in human endothelial cells. We now show for the first time that type 2 sirtuin (Sirt-2) histone deacetylase binds human NF-κB target gene promoter and prevents the recruitment of NF-κB proteins and subsequent assembly of RNA polymerase II complex in human lung microvascular endothelial cells. Hsp90 inhibitors stabilize the Sirt-2/promoter interaction and impose a "transcriptional block," which is reversed by either inhibition or downregulation of Sirt-2 protein expression. Furthermore, this process is independent of NF-κB (p65) Lysine 310 deacetylation, suggesting that it is distinct from known Sirt-2-dependent mechanisms. We demonstrate that Sirt-2 is recruited to NF-κB target gene promoter via interaction with core histones. Upon inflammatory challenge, chromatin remodeling and core histone H3 displacement from the promoter region removes Sirt-2 and allows NF-κB/coactivator recruitment essential for RNA Pol II-dependent mRNA induction. This novel mechanism may have important implications in pulmonary inflammation.

Addressing the process improvement science knowledge and skills of program directors and associate program directors.

BACKGROUND: Process improvement (PI) science is relatively new to healthcare and has only recently been introduced to medical education. Most residency faculty lack training or experience in PI science activities. We assessed the impact of PI science education on the knowledge and attitudes of a group of residency and fellowship program directors and associate program directors using their respective Accreditation Council for Graduate Medical Education annual program evaluations (APEs) as an experiential object. METHODS: For this pre/post study, 16 program directors and 7 associate program directors were surveyed before and after 4 didactic modules. The APEs for the 2 years prior to the intervention and in the fall after the intervention were analyzed. Mentoring in the use of these skills in the preparation of the APEs was provided. RESULTS: The participants demonstrated improved knowledge in some areas and increased awareness of deficits in other areas. APE quality did not show consistent improvement following the intervention. CONCLUSION: The PI science knowledge and skill gaps of program directors and associate program directors are likely to impact the content and success of residency curricula. The designed PI science curriculum was slightly effective. Using the APE as the experiential object was convenient, but the APE was not the best project for a PI exercise. New, effective strategies and interventions to develop expertise in PI science are important as programs grapple with meeting new requirements, ensuring quality programs, and preparing residents and fellows for practice.