Variations in sleep associated with different types of hormonal contraceptives.

Progesterone and some of its metabolites are neuroactive steroids that affect sleep by increasing melatonin secretion and stimulating GABA-A receptors. The effect of progestogens in hormonal contraceptives on sleep has not been thoroughly investigated. This observational study assessed possible associations in sleep changes induced by estrogen-progestogens in contraceptives in 108 women between the ages of 20 and 50 years. We assessed mean nightly sleep time with a 31-day sleep diary, and subjective sleep quality with the five subjective subscores of the Pittsburgh Sleep Quality Index (PSQI). Included women were of childbearing age, healthy, sexually active and had been using a hormonal contraceptive method (pill, intrauterine system (IUS), subcutaneous implant, vaginal ring) for at least six months. Results were compared to a matched control group that did not use hormonal contraceptives. The longest mean nightly sleep time, compared to control (450 min), occurred in women who used progestogen-only oral contraception (510 min), followed by IUS delivery of levonorgestrel 13.5 mg (480 min) and oral ethinylestradiol 0.02/0.03 mg plus gestodene 0.075 mg (475 min). Global subjective sleep quality was influenced most by the administration of etonorgestrel 0.120 mg/ethinylestradiol 0.015 mg via the vaginal route. Our results show that low-doses of progestins affect various aspects of sleep, and that this is influenced by the route of administration.

Plasmacytoid dendritic cells play a key role in tumor progression in lipopolysaccharide-stimulated lung tumor-bearing mice.

The antitumor activity of LPS was first described by Dr. William Coley. However, its role in lung cancer remains unclear. The aim of our study was to elucidate the dose-dependent effects of LPS (0.1-10 µg/mouse) in a mouse model of B16-F10-induced metastatic lung cancer. Lung tumor growth increased at 3 and 7 d after the administration of low-dose LPS (0.1 µg/mouse) compared with control mice. This was associated with an influx of plasmacytoid dendritic cells (pDCs), regulatory T cells, myeloid-derived suppressor cells, and CD8(+) regulatory T cells. In contrast, high-dose LPS (10 µg/mouse) reduced lung tumor burden and was associated with a greater influx of pDCs, as well as a stronger Th1 and Th17 polarization. Depletion of pDCs during low-dose LPS administration resulted in a decreased lung tumor burden. Depletion of pDCs during high-dose LPS treatment resulted in an increased tumor burden. The dichotomy in LPS effects was due to the phenotype of pDCs, which were immunosuppressive after the low-dose LPS, and Th1- and T cytotoxic-polarizing cells after the high-dose LPS. Adoptive transfer of T cells into nude mice demonstrated that CD8(+) T cells were responsible for pDC recruitment following low-dose LPS administration, whereas CD4(+) T cells were required for pDC influx after the high-dose LPS. In conclusion, our data suggest differential effects of low-dose versus high-dose LPS on pDC phenotype and tumor progression or regression in the lungs of mice.

Polyinosinic-polycytidylic acid limits tumor outgrowth in a mouse model of metastatic lung cancer.

Polyinosinic-polycytidylic acid (poly I:C), a TLR3 ligand, is currently being tested in human clinical trials as an adjuvant to anti-cancer vaccines and in combination with other therapies. However, little is known about its activity in established pulmonary metastasis. The aim of our study was to elucidate the effect of poly I:C (1, 10, or 100 µg/mouse) in a mouse model of B16-F10-induced metastatic lung cancer. Lung tumor growth was arrested after a single administration of poly I:C. This was associated with higher influx of mature dendritic cells (DCs), which drove toward a Th1-like, Th17-like, and cytotoxic immune environment. The interference with IFN type I receptor signaling by means of a specific mAb reversed poly I:C-mediated tumor regression due to lower presence of myeloid DCs, cytotoxic DCs (CD11c(+)CD8(+)), NKT cells, CD8(+) T cells, and Th1-like cytokines. Moreover, the adoptive transfer of poly I:C-activated bone marrow-derived DCs into tumor-bearing mice resulted in activities similar to those of the systemic administration of poly I:C on lung tumor burden. In conclusion, our data prove that poly I:C has potential anti-tumor activity in a mouse model of established pulmonary metastasis. The activation of DCs and the production of IFN type I are responsible for an effective T cytotoxic immune response against metastatic lung cancer progression after poly I:C treatment.

Plasmacytoid dendritic cells and their therapeutic activity in cancer.

In the last decade several studies provided evidence that plasmacytoid dendritic cells (pDCs) infiltrate human neoplasms with poor prognosis. However, the role of tumor-associated pDCs remains controversial. Various studies indicate that pDCs play an immuno-suppressive role and facilitate tumor progression in both animal models and humans. In contrast, others found that the presence of activated tumor-associated pDCs results in tumor regression in mice. Given these findings, understanding pDC function in tumor biology is an important necessity and may pave the way for novel therapeutic strategies to fight malignancies.