Objective: We investigated associations of walking and other leisure-time physical activity (LTPA) with environmental characteristics and transportation modes in older Japanese adults. Methods:This cross-sectional study in 2010-2011 used data from 421 community-dwelling older adults aged 65-85 years living in Kasama City, rural Japan. We used the Physical Activity Scale for the Elderly to assess walking and other LTPAs, and the International Physical Activity Questionnaire Environment Module for neighborhood environments. Results:After adjusting for confounders, we found that good traffic safety and aesthetics were positively associated with high levels of walking (ORs=1.64-2.12); whereas, good access to public transportation was negatively associated with walking (OR=0.64, 95% CI=0.42-0.98). Good access to recreational facilities, presence of sidewalks, absence of hills, seeing people exercise, and aesthetically pleasing surroundings were positively associated with high levels of LTPA except walking (ORs=1.61-2.13). Individuals who rode bicycles more than once per week were more likely to engage in a LTPA except walking (1-3 days:OR=1.72, 95% CI=1.03-2.87; ≥ 4 days: OR=2.90, 95% CI=1.71-4.93). Conclusion:This study adds information on correlates of physical activity among older Japanese adults; the positive association between LTPA except walking and the frequency of bicycle travel is an especially new and intriguing finding.

Varieties of transforming growth factor-β (TGF-β) antagonists have been developed to intervene with excessive TGF-β signalling activity in cancer. Activin receptor-like kinase5 (ALK5) inhibitors antagonize TGF-β signalling by blocking TGF-β receptor-activated Smad (R-Smad) phosphorylation. Here we report the novel mechanisms how ALK5 inhibitors exert a therapeutic effect on a mouse B16 melanoma model. Oral treatment with a novel ALK5 inhibitor, EW-7197 (2.5 mg/kg daily) or a representative ALK5 inhibitor, LY-2157299 (75 mg/kg bid) suppressed the progression of melanoma with enhanced cytotoxic T-lymphocyte (CTL) responses. Notably, ALK5 inhibitors not only blocked R-Smad phosphorylation, but also induced ubiquitin-mediated degradation of the common Smad, Smad4 mainly in CD8+ T cells in melanoma-bearing mice. Accordingly, T-cell-specific deletion of Smad4 was sufficient to suppress the progression of melanoma. We further identified eomesodermin (Eomes), the T-box transcription factor regulating CTL functions, as a specific target repressed by TGF-β via Smad4 and Smad3 in CD8+ T cells. Thus, ALK5 inhibition enhances anti-melanoma CTL responses through ubiquitin-mediated degradation of Smad4 in addition to the direct inhibitory effect on R-Smad phosphorylation.