BackgroundAccumulating evidence has shown that tumor-associated macrophages (TAMs) play a critical role in tumor progression. Targeting TAMs is a potential strategy for tumor immunotherapy. However, the mechanism underlying the TAM phenotype and function needs to be resolved. Our previous studies have demonstrated that miR-125a can reverse the TAM phenotype toward antitumor. Meanwhile, we have found that miR-125a and miR-99b cluster in the first intron of the same host gene, and are transcribed simultaneously in bone marrow-derived macrophages (BMDMs) following LPS+IFNγ stimulation. However, it remains unclear whether miR-99b by itself can exert an antitumor effect by regulating macrophage phenotype.MethodsmiR-99b and/or miR-125a were delivered into TAMs of orthotopic hepatocellular carcinoma (HCC) or subcutaneous Lewis lung cancer (LLC) mice. The effect of treatment was evaluated by live imaging, TUNEL staining and survival tests. The phenotype of the immune cells was determined by qRT-PCR, ELISA, western blot and FACS. The capability of miR-99b-mediated macrophage phagocytosis and antigen presentation was detected by FACS and immunofluorescence staining. The underlying molecular mechanism was examined by qRT-PCR, reporter assay and western blot, and further verified in the tumor model. The expression of miR-99b and its target genes was determined in TAMs sorted from tumor and adjacent tissues in patients with liver cancer.ResultsTargeted delivery of miR-99b and/or miR-125a into TAMs significantly impeded the growth of HCC and LLC, especially after miR-99b delivery. More importantly, the delivery of miR-99b re-educated TAM toward antitumor phenotype with enhanced immune surveillance. Further investigation of mechanisms showed that macrophage-specific overexpression of miR-99b promoted M1 while suppressing M2 macrophage polarization by targeting κB-Ras2 and/or mTOR, respectively. miR-99b-overexpressed M1 macrophage was characterized by stronger capability of phagocytosis and antigen presentation. Additionally, delivery of simTOR or siκB-Ras2 into TAMs inhibited miR-99b antagomir-triggered tumor growth. Finally, miR-99b expression was lower in TAMs of patients with liver cancer than that in adjacent tissues, while the expression of κB-Ras2 and mTOR was reversed.ConclusionsOur results reveal the mechanism of miR-99b-mediated TAM phenotype, indicating that TAM-targeted delivery of miR-99b is a potential strategy for cancer immunotherapy.

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ObjectiveNight shifts have adverse cognitive outcomes that might be attenuated by daytime napping. The neurovisceral integration model suggests that resting vagally mediated heart rate variability (vmHRV) is linked with cognitive function. This study investigated the relationship between resting vmHRV and cognitive function after different nap durations in interns after shift work.MethodsA total of 105 interns were randomly allocated to one of three groups (non-nap, n = 35; 15-min nap, n = 35; 45-min nap, n = 35) to perform cognitive tests and resting vmHRV at 12:00, 15:00 and 18:00. Information processing (digit symbol substitution test; DSST), motor speed (finger tapping test; FTT), response selection (choice reaction time; CRT), and attention shifts (shifting attention test; SAT) were assessed. Resting vmHRV was assessed at baseline and during each cognitive task across groups.ResultsCompared with the non-nap control, the 15-min and 45-min naps improved all outcome measures (including subjective sleepiness and cognitive performance) at 15:00, with some benefits maintained at 18:00. The 15-min nap produced significantly greater benefits on the FTT at 15:00 after napping than did the 45-min nap. Resting vmHRV was significantly correlated with DSST and SAT performance. In addition, FTT performance was the only significant predictor of DSST performance across different nap durations.ConclusionOur results demonstrate links between daytime napping (in particular, a 15-min nap) and improved cognitive control in relation to autonomic activity after shift work in interns. These results indicated that autonomic activity when awake plays a crucial role in DSST and SAT performance and facilitated the understanding of differences in neurocognitive mechanisms underlying information processing after different nap durations.

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