Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line K562, on active (histone H3 lysine 9 acetylation, H3K9ac and histone H3 lysine 4 tri-methylation, H3K4me3) and repressive (histone H3 lysine 9 tri-methylation, H3K9me3) histone marks by Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). Both selenite and MSA had major effects on histone marks but the effects of MSA were more pronounced. Gene ontology analysis revealed that selenite affected genes involved in response to oxygen and hypoxia, whereas MSA affected distinct gene sets associated with cell adhesion and glucocorticoid receptors, also apparent by global gene expression analysis using RNA sequencing. The correlation to adhesion was functionally confirmed by a significantly weakened ability of MSA treated cells to attach to fibronectin and linked to decreased expression of integrin beta 1. A striking loss of cellular adhesion was also confirmed in primary patient AML cells. Recent strategies to enhance the cytotoxicity of chemotherapeutic drugs by disrupting the interaction between leukemic and stromal cells in the bone marrow are of increasing interest; and organic selenium compounds like MSA might be promising candidates. In conclusion, these results provide new insight on the mechanism of action of selenium compounds, and will be of value for the understanding, usage, and development of new selenium compounds as anticancer agents.

Background As longevity and retirement ages are increasing, knowledge is needed on factors hindering extended working lives. The aim of this study was to explore how sickness absence (SA) and disability pension (DP) due to mental and/or somatic diagnoses before age 65 were associated with being in paid work when aged 66-71. Methods A 6-year prospective population-based cohort study of all 98,551 people (48% women) in Sweden who turned 65 years in 2010 (baseline year) and had been in paid work at any point when aged 60-64. Microdata from nationwide registers were used. Exposure variables were SA (spells >14 days) and/or DP in 2005-2009, and the outcome variable was paid work at any point in 2011-2016. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for associations between exposures and outcome, controlling for sociodemographic factors in 2010, stratified by sex. Results Most women (56.0%) and men (66.3%) had no SA or DP when aged 60-64. Of the women, 42.7% and of the men 53.3% were in paid work after the age of 65. Those with SA due to mental diagnoses had lower OR of being in paid work (women 0.76; 95% CI: 0.69-0.84; men 0.74; 0.65-0.84). This association was weaker for SA due to somatic diagnoses (women 0.87; 0.84-0.91; men 0.92; 0.89-0.96). Having had SA due to both mental and somatic diagnoses was associated with lower OR for men (0.77; 0.65-0.91) but not women (0.98; 0.88-1.09). Full- or part-time DP had the strongest association with not being in paid work regardless of diagnosis group and sex (e.g., women mental DP 0.39; 0.34-0.45; women somatic DP 0.38; 0.35-0.41; men mental DP 0.36; 0.29-0.43; men somatic DP 0.35; 0.32-0.38). Conclusions SA due to mental diagnoses had a stronger association with not being in paid work after age 65 than SA due to somatic diagnoses. The results highlight the importance of identifying factors that hinder older workers with mental disorders to extend their working lives. Key messages