RESUMEN
Modern urban human activities are largely restricted to the indoors, deprived of direct sunlight containing visible and near-infrared (NIR) wavelengths at high irradiance levels. Therapeutic exposure to doses of red and NIR, known as photobiomodulation (PBM), has been effective for a broad range of conditions. In a double-blind, randomized, placebo-controlled study, we aimed to assess the effects of a PBM home set-up on various aspects of well-being, health, sleep, and circadian rhythms in healthy human subjects with mild sleep complaints. The effects of three NIR light (850 nm) doses (1, 4, or 6.5 J·cm-2) were examined against the placebo. Exposure was presented five days per week between 9:30 am and 12:30 pm for four consecutive weeks. The study was conducted in both summer and winter to include seasonal variation. The results showed PBM treatment only at 6.5 J·cm-2 to have consistent positive benefits on well-being and health, specifically improving mood, reducing drowsiness, reducing IFN-γ, and resting heart rate. This was only observed in winter. No significant effects on sleep or circadian rhythms were noted. This study provides further evidence that adequate exposure to NIR, especially during low sunlight conditions, such as in the winter, can be beneficial for human health and wellness.
RESUMEN
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far. Aims of this study were to explore how representative HGSOC PDXs are of their corresponding patient tumor methylome and to evaluate the effect of epigenetic therapy and cisplatin on putative epigenetically regulated genes and their related pathways in PDXs. METHODS: Genome-wide analysis of the DNA methylome of HGSOC patients with their corresponding PDXs, from different generations, was performed using Infinium 450 K methylation arrays. Furthermore, we analyzed global methylome changes after treatment of HGSOC PDXs with the FDA approved demethylating agent decitabine and cisplatin. Findings were validated by bisulfite pyrosequencing with subsequent pathway analysis. Publicly available datasets comprising HGSOC patients were used to analyze the prognostic value of the identified genes. RESULTS: Only 0.6-1.0 % of all analyzed CpGs (388,696 CpGs) changed significantly (p < 0.01) during propagation, showing that HGSOC PDXs were epigenetically stable. Treatment of F3 PDXs with decitabine caused a significant reduction in methylation in 10.6 % of CpG sites in comparison to untreated PDXs (p < 0.01, false discovery rate <10 %). Cisplatin treatment had a marginal effect on the PDX methylome. Pathway analysis of decitabine-treated PDX tumors revealed several putative epigenetically regulated pathways (e.g., the Src family kinase pathway). In particular, the C-terminal Src kinase (CSK) gene was successfully validated for epigenetic regulation in different PDX models and ovarian cancer cell lines. Low CSK methylation and high CSK expression were both significantly associated (p < 0.05) with improved progression-free survival and overall survival in HGSOC patients. CONCLUSIONS: HGSOC PDXs resemble the global epigenome of patients over many generations and can be modulated by epigenetic drugs. Novel epigenetically regulated genes such as CSK and related pathways were identified in HGSOC. Our observations encourage future application of PDXs for cancer epigenome studies.
