FTY720 and SEW2871 reverse the inhibitory effect of S1P on natural killer cell mediated lysis of K562 tumor cells and dendritic cells but not on cytokine release

The aims of this study are to examine the effect of sphingosine 1-phosphate (S1P) on IL-2-activated natural killer (NK) cell lysis of K562 tumor cells and immature dendritic cells (iDCs), and to investigate the mechanisms involved in S1P activity. Our results show that S1P protected K562 cells or iDCs from NK cell lysis, which was reversed by FTY720 and SEW2871, the antagonists of S1P₁. S1P did not modulate the expression of NKG2D, NKp30, NKp44 or CD158 on the surface of NK cells, and neither affected the expression of CD80, CD83, or CD86 on the surface of DCs. In contrast, it increased the expression of HLA-I and HLA-E on DCs, an activity that was inhibited by FTY720 or SEW2871. Similarly, the inhibitory effect of S1P for NK cell lysis of K562 cells was directed toward S1P₁ expressed on the tumor cells but not on NK cells. Further analysis indicates that NK cells secreted various cytokines and chemokines with various intensities: (1) low (IL-4, IL-6, IL-12, TNF-α and MCP-1); (2) intermediate (IL-1β, IL-10, TGF-β1, and IL-17A); (3) high (IFN-γ, and MIP-1α); and (4) very high (MIP-1β). S1P significantly reduced the release of IL-17A and IFN-γ from NK cells, but this inhibition was S1P₁-independent. These results indicate that S1P is an anti-inflammatory molecule, and that S1P₁ is important for the interaction among NK cells and tumor cells or DCs leading to up-regulation of HLA-I and HLA-E on the surface of DCs, but not in S1P inhibition of the release of inflammatory cytokines from NK cells. Further, the results suggest that FTY720 and SEW2871 may potentially be used as prophylactic and/or therapeutic drugs to treat cancer patients.     

Trajectories of sleepiness and insomnia symptoms in Norwegian nurses with and without night work and rotational work

Numerous cross-sectional studies report high prevalence rates of sleepiness and insomnia in shift workers, but few longitudinal studies exist. We investigated trajectories of sleepiness and insomnia symptoms in a sample of Norwegian nurses across four measurements, spanning a total of four years (sleepiness) and five years (insomnia). The participants completed the Epworth Sleepiness Scale and the Bergen Insomnia Scale at each measurement instance. Latent growth curve models were used to analyse the data. Separate models examined night work (night work, entering and leaving night work) and rotational work (rotational work, entering and leaving rotational work) as predictors for trajectories of sleepiness and insomnia symptoms, respectively. Baseline values of sleepiness and insomnia were higher among rotational shift workers than among workers with fixed shifts (day or night). The results showed that night work throughout the period and entering night work during the period were not associated with different trajectories of sleepiness or insomnia symptoms, compared to not having night work. The same results were found for rotational work and entering rotational work, compared to not having rotational work. Leaving night work and leaving rotational work were associated with a decrease in sleepiness and insomnia symptoms, compared to staying in such work.     

The effect of synthetic gestagens on progesterone formation in vitro in human placenta of early pregnancy.

Villous tissue from 26 placentae of 7-17 weeks was incubated with radioactive pregnenolone alone and with pregnenolone in the presence of progesterone and 9 synthetic gestagenic steroids and the progesterone formation was measured after 30 min. When progesterone was present in a concentration of 31 or 310 mumol/1 the conversion rate of labelled pregnenolone to progesterone was reduced to 88.6 and 82.2% of that of the respective control incubations. Dydrogesterone, allyloestrenol, lynoestrenol and norethynodrel under similar conditions did not inhibit the formation of progesterone. The inhibitory effects of megoestrol acetate, medroxyprogesterone acetate and norgestrel were close to that of progesterone. Norethisterone and methyloestrenolone were the most effective inhibitors of progesterone formation: when incubated in an equimolar concentration (35 mumol/1) with pregnenolone (50 microgram) the progesterone formation was reduced to 60.0-62.7% and 29.1-34.0% respectively of that of the respective control experiments.