Sleep restriction and circadian clock disruption are associated with metabolic disorders such as obesity, insulin resistance, and diabetes. The metabolic pathways involved in human sleep, however, have yet to be investigated with the use of a metabolomics approach. Here we have used untargeted and targeted liquid chromatography (LC)/MS metabolomics to examine the effect of acute sleep deprivation on plasma metabolite rhythms. Twelve healthy young male subjects remained in controlled laboratory conditions with respect to environmental light, sleep, meals, and posture during a 24-h wake/ sleep cycle, followed by 24 h of wakefulness. Two-hourly plasma samples collected over the 48 h period were analyzed by LC/MS. Principal component analysis revealed a clear time of day variation with a significant cosine fit during the wake/sleep cycle and during 24 h of wakefulness in untargeted and targeted analysis. Of 171 metabolites quantified, daily rhythms were observed in the majority (n = 109), with 78 of these maintaining their rhythmicity during 24 h of wakefulness, most with reduced amplitude (n = 66). During sleep deprivation, 27 metabolites (tryptophan, serotonin, taurine, 8 acylcarnitines, 13 glycerophospholipids, and 3 sphingolipids) exhibited significantly increased levels compared with during sleep. The increased levels of serotonin, tryptophan, and taurine may explain the antidepressive effect of acute sleep deprivation and deserve further study. This report, to our knowledge the first of metabolic profiling during sleep and sleep deprivation and characterization of 24 h rhythms under these conditions, offers a novel view of human sleep/wake regulation.circadian rhythms | total sleep deprivation | melatonin | depression | biomarker C ircadian clocks control the timing of most daily biological processes, including cyclic changes in metabolism and the sleep/wake cycle (1). There is a clear link between the circadian timing system and metabolism (2-4), with disrupted circadian rhythms, sleep restriction, and sleep deprivation associated with metabolic disorders (obesity, insulin resistance, diabetes) and cardiovascular disease (5-8). The underlying mechanisms linking metabolic disease, circadian clock misalignment, and sleep restriction are the subject of current research, elucidation of which will require a global "systems" approach (9). Transcriptomic studies have shown that rhythmic gene expression may be affected by sleep restriction, sleep deprivation, and mistimed sleep (10-12), but, as yet, no studies have directly investigated the effect that sleep and sleep deprivation may have on the metabolic profile. Metabolic profiling, or "metabolomics," is the profiling of small-molecule metabolites and offers the potential to characterize specific metabolic phenotypes associated with disrupted circadian timing and sleep loss. Metabolomics has an advantage over other "omics" techniques, in that it directly samples the metabolic changes in an organism and integrates information from changes at the gene, transcript, an...

The efficacy of olaparib was consistent with previous studies. However, the efficacy of PLD was greater than expected. Olaparib 400 mg twice per day is a suitable dose to explore in further studies in this patient population.

Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), doselimiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18 F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.Results: Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 hÁmmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18 F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinumrefractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.Conclusion: Pictilisib was safely administered with a doseproportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels !100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.