Principal limitation of cell therapy is cell loss after transplantation because of the interplay between ischemia, inflammation, and apoptosis. We investigated the mechanism of preconditioning of mesenchymal stem cells (MSCs) with oxytocin (OT), which has been proposed as a novel strategy for enhancing therapeutic potential of these cells in ischemic heart. In this study, we demonstrate that rat MSCs express binding sites for OT receptor and OT receptor transcript and protein as detected by RT-PCR and immunofluorescence, respectively. In response to OT (10(-10) to 10(-6) M) treatment, MSCs respond with rapid calcium mobilization and up-regulation of the protective protein kinase B (PKB or Akt) and phospho-ERK1/2 proteins. In OT-stimulated cells, phospho-Akt accumulates intracellularly close to the mitochondrial marker cytochrome c oxidase subunit 4. Functional analyses reveal the involvement of Akt/ERK1/2 pathways in cell proliferation, migration, and protection against the cytotoxic and apoptotic effects of hypoxia and serum deprivation. In addition, OT preconditioning increases MSC glucose uptake. Genes with angiogenic, antiapoptotic, and cardiac antiremodeling properties, such as heat shock proteins (hsps) HSP27, HSP32, HSP70, vascular endothelial growth factor, thrombospondin, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, TIMP-3, and matrix metalloproteinase-2, were also up-regulated upon OT exposure. Moreover, coculture with OT-preconditioned MSC reduces apoptosis, as measured using terminal transferase dUTP nick end labeling assay in newborn rat cardiomyocytes exposed to hypoxia and reoxygenation. In conclusion, these results indicate that OT treatment evokes MSC protection through both intrinsic pathways and secretion of cytoprotective factors. Ex vivo cellular treatment with OT represents an attractive strategy aimed to maximize the biological and functional properties of effector cells.

Background. People with metastatic cancers experience poor quality of life (QoL), fatigue, and decreased physical function. Exercise improves these symptoms in the curative setting, but the efficacy and safety of exercise in the metastatic setting is uncertain.Methods. Prospective, randomized trials of moderate/high-intensity aerobic exercise or resistance training vs. control in patients with advanced/metastatic solid cancers were identified from prior reviews and updated using a search of PubMed. The mean and SD for validated outcome measures (QoL, physical function, and fatigue) were extracted for intervention and control groups at baseline and postintervention. The Mann-Whitney test was used to evaluate the effect of exercise on the pooled change between baseline and postintervention. Safety was evaluated qualitatively.Results. Sixteen trials were analyzed. Among patients with scores at the mean or 2SD above, exercise was not associated with significant or clinical difference in QoL or fatigue. In patients with baseline scores 2SD below mean, exercise was associated with nonsignificant difference meeting minimal clinical important difference in QoL (À2.8 vs. 4.6, P ¼ 0.28). For function, patients at the mean had nonstatistically significant, but clinically meaningful difference in the six-minute walk test (6-MWT) (14.7 vs. 29.0 m, P ¼ 0.44). In patients 2 SD below the mean, there was a clinically meaningful difference in two patient-reported functional subscales (0.1 vs. 5.3, P ¼ 0.076 and 0.44 vs. 8.5, P ¼ 0.465) and a clinically meaningful improvement in the 6-MWT (À7.5 vs. 27.0 m, P ¼ 0.34), although none of these associations met statistical significance. There were no differences in falls, fractures, or pain.Discussion. Exercise is associated with clinically meaningful improvements in QoL, function, and 6-MWT in some patients with metastatic cancer. Despite poor reporting of safety, there was no signal of increased harm from exercise in this setting.

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