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

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice

IMPORTANCE: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. OBJECTIVE: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. EXPOSURES: Genetic test results. MAIN OUTCOMES AND MEASURES: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. RESULTS: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). CONCLUSIONS AND RELEVANCE: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes

Annual Report to the Nation on the Status of Cancer, 1975-2008, Featuring Cancers Associated With Excess Weight and Lack of Sufficient Physical Activity

BACKGROUND: Annual updates on cancer occurrence and trends in the United States are provided through collaboration between the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR). This year’s report highlights the increased cancer risk associated with excess weight (overweight or obesity) and lack of sufficient physical activity (\u3c150 minutes of physical activity per week). METHODS: Data on cancer incidence were obtained from the CDC, NCI, and NAACCR; data on cancer deaths were obtained from the CDC’s National Center for Health Statistics. Annual percent changes in incidence and death rates (age-standardized to the 2000 US population) for all cancers combined and for the leading cancers among men and among women were estimated by joinpoint analysis of long-term trends (incidence for 1992-2008 and mortality for 1975-2008) and short-term trends (1999-2008). Information was obtained from national surveys about the proportion of US children, adolescents, and adults who are overweight, obese, insufficiently physically active, or physically inactive. RESULTS: Death rates from all cancers combined decreased from 1999 to 2008, continuing a decline that began in the early 1990s, among men and among women in most racial and ethnic groups. Death rates decreased from 1999 to 2008 for most cancer sites, including the 4 most common cancers (lung, colorectum, breast, and prostate). The incidence of prostate and colorectal cancers also decreased from 1999 to 2008. Lung cancer incidence declined from 1999 to 2008 among men and from 2004 to 2008 among women. Breast cancer incidence decreased from 1999 to 2004 but was stable from 2004 to 2008. Incidence increased for several cancers, including pancreas, kidney, and adenocarcinoma of the esophagus, which are associated with excess weight. CONCLUSIONS: Although improvements are reported in the US cancer burden, excess weight and lack of sufficient physical activity contribute to the increased incidence of many cancers, adversely affect quality of life for cancer survivors, and may worsen prognosis for several cancers. The current report highlights the importance of efforts to promote healthy weight and sufficient physical activity in reducing the cancer burden in the United States