BackgroundAs the population ages, cognitive decline and dementia have become major health concerns in the UK. Loneliness has been linked to cognitive decline, but the reverse causality of this association remains unclear. This study aims to examine whether there is a bidirectional relationship between loneliness and cognitive function in older English adults (age 50 years and over) over a 10-year follow-up.MethodsData came from a nationally representative sample of 5885 participants in the English Longitudinal Study of Ageing (ELSA), free of stroke or dementia and followed every 2 years up to wave 7 (2014–15). At each wave, cognitive function was measured with word recall and verbal fluency tests, and loneliness was measured with the abridged version of the revised UCLA Loneliness Scale. Bivariate dual change score models were used to assess the multivariate associations between loneliness and cognitive function, used interchangeably as exposures and outcomes.ResultsGreater loneliness at baseline was associated with poorer memory [β intercept = −0.03, standard error (SE) = 0.01, P  =  0.016] and verbal fluency (β intercept = −0.01, SE  =  001, P =  0.027) at baseline, and with a stronger linear rate of decline in both memory (β linear slope = −0.07, SE  =  001, P  ≤ 0.001) and verbal fluency (β linear slope = −0.09, SE  =  0.03, P =  0.003) over a 10-year follow-up period, although the performance on verbal fluency did not change substantially on average over this period. We also found that higher baseline memory, but not verbal fluency, predicted a slower change in loneliness (β linear slope = −0.01, SE  =  001, P =  0.004) and that a linear decline in memory was associated with an acceleration in loneliness (β quadratic slope = −0.02, SE  =  001, P  ≤ 0.001) during follow-up.ConclusionsHigher loneliness is associated with poorer cognitive function at baseline and contributes to a worsening in memory and verbal fluency over a decade. These factors seem, however, to be partially intertwined, since baseline memory and its rate of decline also contribute to an increase in loneliness over time.

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The pan-Src family kinase inhibitor dasatinib has been approved for chronic myeloid leukemia treatment but displays limited activity in lung cancer patients. In this study, we used a deuterium substitution strategy to develop a class of novel chemicals based on dasatinib and found that these compounds maintain inhibition on c-Src activity and display anti-non-small cell lung cancer activity in vitro and in vivo. BRP800, one of these compounds, was chosen for further studies. BRP800 mainly displayed antiproliferative but not proapoptotic activity. Molecularly, BRP800 did not show significant effects on the expression of antiapoptotic genes, such as Bcl-2 and Mcl1, or on the activation of apoptotic enzymes, such as caspase-3, -8 or 9. However, BRP800 decreased expression of cell cycle promoting genes such as cyclins D1, D3, E, A and CDK4 and 6, and increased the expression of cell cycle negative regulators including p21, p27 and p53. Consistent with these findings, BRP800 arrested cells at the G0/G1 phase in a concentration-dependent manner, and the G0/G1 fraction was increased from 64% in control to 85% in BRP800-treated cells. We also evaluated the effects of BRP800 on NSCLC xenografts using H460 as a model in nude mice. Compared with the known NSCLC drug docetaxel, BRP800 displayed potent and similar antitumor activity but with less toxicity. These findings suggest that the deuterated analog of dasatinib is antiproliferative by inhibiting c-Src and disrupting cell cycle progression, and could be further developed as a novel drug for non-small lung cancer treatment.