Resveratrol, a naturally occurring stilbene, induced apoptosis in human breast cancer MCF-7 cells. The mechanism of this effect was dependent on mitogen-activated protein kinase (MAPK, ERK1/2) activation and was associated with serine phosphorylation and acetylation of p53. Treatment of MCF-7 cells with resveratrol in the presence of 17β-oestradiol (E2) further enhanced MAPK activation, but E2 blocked resveratrol-induced apoptosis, as measured by nucleosome ELISA and DNA fragmentation assays. E2 inhibited resveratrol-stimulated phosphorylation of serines 15, 20 and 392 of p53 and acetylation of p53 in a concentration- and time-dependent manner. These effects of E2 on resveratrol action were blocked by ICI 182,780 (ICI), an inhibitor of the nuclear oestrogen receptor-α (ER). ICI 182,780 did not block the actions of resveratrol, alone. Electrophoretic mobility studies of p53 binding to DNA and of p21 expression indicated that E2 inhibited resveratrol-induced, p53-directed transcriptional activity. These results suggest that E2 inhibits p53-dependent apoptosis in MCF-7 cells by interfering with post-translational modifications of p53 which are essential for p53-dependent DNA binding and consequent stimulation of apoptotic pathways. These studies provide insight into the complex pathways by which apoptosis is induced by resveratrol in E2-depleted and -repleted environments.

Importance: There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more or less supplemental oxygen. Objective: To compare the effects of different pulse oximeter oxygen saturation (SpO2) target ranges on death or major morbidity.Design, Setting, and Participants: Prospectively planned, individual participant data meta-analysis of five randomized clinical trials (conducted 2005-2014), enrolling infants born at less than 28 weeks' gestation.Exposure: Targeting a lower (85-89%) versus higher (91-95%) SpO2 range. Main Outcomes and Measures:The primary outcome was a composite of death or major disability by 18-24 months' corrected age (bilateral blindness, deafness, cerebral palsy with the Gross Motor Function Classification System (GMFCS) level 2 or higher, or Bayley-III cognitive or language score less than 85). There were 16 secondary outcomes including death, major disability, retinopathy of prematurity (ROP) requiring treatment, blindness, severe necrotizing enterocolitis (NEC).