Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards CXCL12

Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies

Potential cellular and biochemical mechanisms of exercise and physical activity on the ageing process

Exercise in young adults has been consistently shown to improve various aspects of physiological and psychological health but we are now realising the potential benefits of exercise with advancing age. Specifically, exercise improves cardiovascular, musculoskeletal, and metabolic health through reductions in oxidative stress, chronic low-grade inflammation and modulating cellular processes within a variety of tissues. In this this chapter we will discuss the effects of acute and chronic exercise on these processes and conditions in an ageing population, and how physical activity affects our vasculature, skeletal muscle function, our immune system, and cardiometabolic risk in older adults

Green synthesis of oxazolidinones via heterogeneous catalysis.

internationa

Association of Serum 25-Hydroxyvitamin D Deficiency with Risk of Incidence of Disability in Basic Activities of Daily Living in Adults >50 Years of Age

BACKGROUND: Vitamin D deficiency compromises muscle function and is related to the etiology of several clinical conditions that can contribute to the development of disability. However, there are few epidemiological studies investigating the association between vitamin D deficiency and the incidence of disability. OBJECTIVES: We aimed to assess whether vitamin D deficiency is associated with the incidence of disability in basic activities of daily living (BADL) and to verify whether there are sex differences in this association. METHODS: A 4-y follow-up study was conducted involving individuals aged 50 y or older who participated in ELSA (English Longitudinal Study of Ageing). The sample consisted of 4814 participants free of disability at baseline according to the modified Katz Index. Vitamin D was assessed by serum 25-hydroxyvitamin D [25(OH)D] concentrations and the participants were classified as sufficient (>50 nmol/L), insufficient (>30 to ≤50 nmol/L), or deficient (≤30 nmol/L). Sociodemographic, behavioral, and clinical characteristics were also investigated. BADL were re-evaluated after 2 and 4 y of follow-up. The report of any difficulty to perform ≥1 BADL was considered as an incident case of disability. Poisson models stratified by sex and controlled for sociodemographic, behavioral, and clinical characteristics were carried out. RESULTS: After 4-y follow-up, deficient serum 25(OH)D was a risk factor for the incidence of BADL disability in both women (IRR: 1.53; 95% CI: 1.16, 2.03) and men (IRR: 1.44; 95% CI: 1.02, 2.02). However, insufficient serum 25(OH)D was not a risk factor for the incidence of BADL disability in either men or women. CONCLUSIONS: Independently of sex, deficient serum 25(OH)D concentrations were associated with increased risk of incidence of BADL disability in adults >50 y old and should be an additional target of clinical strategies to prevent disability in these populations