Changes in environmental tobacco smoke (ETS) exposure over a 20-year period: cross-sectional and longitudinal analyses

AIMS:  To examine long‐term changes in environmental tobacco smoke (ETS) exposure in British men between 1978 and 2000, using serum cotinine. DESIGN:  Prospective cohort: British Regional Heart Study. SETTING:  General practices in 24 towns in England, Wales and Scotland. PARTICIPANTS:  Non‐smoking men: 2125 studied at baseline [questionnaire (Q1): 1978–80, aged 40–59 years], 3046 studied 20 years later (Q20: 1998–2000, aged 60–79 years) and 1208 studied at both times. Non‐smokers were men reporting no current smoking with cotinine < 15 ng/ml at Q1 and/or Q20. MEASUREMENTS: Serum cotinine to assess ETS exposure. FINDINGS:  In cross‐sectional analysis, geometric mean cotinine level declined from 1.36 ng/ml [95% confidence interval (CI): 1.31, 1.42] at Q1 to 0.19 ng/ml (95% CI: 0.18, 0.19) at Q20. The prevalence of cotinine levels ≤ 0.7 ng/ml [associated with low coronary heart disease (CHD) risk] rose from 27.1% at Q1 to 83.3% at Q20. Manual social class and northern region of residence were associated with higher mean cotinine levels both at Q1 and Q20; older age was associated with lower cotinine level at Q20 only. Among 1208 persistent non‐smokers, cotinine fell by 1.47 ng/ml (95% CI: 1.37, 1.57), 86% decline. Absolute falls in cotinine were greater in manual occupational groups, in the Midlands and Scotland compared to southern England, although percentage decline was very similar across groups. CONCLUSIONS:  A marked decline in ETS exposure occurred in Britain between 1978 and 2000, which is likely to have reduced ETS‐related disease risks appreciably before the introduction of legislation banning smoking in public places

Elevated NCOR1 disrupts PPARalpha/gamma signaling in prostate cancer and forms a targetable epigenetic lesion

The loss of anti-proliferative responsiveness in prostate cancer cell lines toward ligands for vitamin D receptor, retinoic acid receptors/retinoid X receptors and peroxisome proliferator activated receptor (PPAR)alpha/gamma may entail underlying epigenetic events, as ligand insensitivity reflects significantly altered messenger RNA expression of corepressors and histone-modifying enzymes. Expression patterns were dependent on phases of the cell cycle and associated with repressed basal gene expression of vitamin D receptor and PPARalpha/gamma target genes, for example CDKN1A [encodes p21((waf1/cip1))]. Elevated nuclear corepressor 1 (NCOR1) and nuclear corepressor 2/silencing mediator of retinoic acid and thyroid hormone receptor protein levels were detected in prostate cancer cell lines compared with non-malignant counterparts. Knockdown of the corepressor NCOR1 significantly elevated basal expression of a cohort of target genes, including CDKN1A. Both chemical [histone deacetylases inhibitor (HDACi)] and NCOR1 knockdown targeting enhanced anti-proliferative sensitivity toward PPARalpha/gamma ligands in prostate cancer cell lines. Pursuing PPARalpha/gamma signaling, microarray approaches were undertaken to identify pathways and genes regulated uniquely by a combination of PPARalpha/gamma activation and HDAC inhibition. Again, HDACi and knockdown approaches demonstrated that elevated NCOR1 expression and activity distorted PPARalpha/gamma gene targets centered on, for example cell cycle control, including CDKN1A and TGFBRAP1. Quantitative real time polymerase chain reaction validation and chromatin immunoprecipitation assays both confirmed that elevated NCOR1 disrupted the ability of PPARalpha/gamma to regulate key target genes (CDKN1A and TGFBRAP1). Interrogation of these relationships in prostate cancer samples using principal component and partial correlation analyses established significant interdependent relationships between NCOR1-PPARalpha/gamma and representative target genes, independently of androgen receptor expression. Therefore, we conclude that elevated NCOR1 distorts the actions of PPARalpha/gamma selectively and generates a potential epigenetic lesion with diagnostic and prognostic significance

Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL)

Purpose: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety. Methods: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition. Results: Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0–24] and 14 [0–24], number of days alive and discharged from the ICU through day 28 were 15 [0–22] and 10 [0–22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group. Conclusion: Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified