M1 macrophage-related gene model for NSCLC immunotherapy response prediction.

Patients diagnosed with non-small cell lung cancer (NSCLC) have a limited lifespan and exhibit poor immunotherapy outcomes. M1 macrophages have been found to be essential for antitumor immunity. This study aims to develop an immunotherapy response evaluation model for NSCLC patients based on transcription. RNA sequencing profiles of 254 advanced-stage NSCLC patients treated with immunotherapy are downloaded from the POPLAR and OAK projects. Immune cell infiltration in NSCLC patients is examined, and thereafter, different coexpressed genes are identified. Next, the impact of M1 macrophage-related genes on the prognosis of NSCLC patients is investigated. Six M1 macrophage coexpressed genes, namely, NKX2-1, CD8A , SFTA3, IL2RB, IDO1, and CXCL9, exhibit a strong association with the prognosis of NSCLC and serve as effective predictors for immunotherapy response. A response model is constructed using a Cox regression model and Lasso Cox regression analysis. The M1 genes are validated in our TD-FOREKNOW NSCLC clinical trial by RT-qPCR. The response model shows excellent immunotherapy response prediction and prognosis evaluation value in advanced-stage NSCLC. This model can effectively predict advanced NSCLC prognosis and aid in identifying patients who could benefit from customized immunotherapy as well as sensitive drugs.

PIEZO1 Promotes the Migration of Endothelial Cells via Enhancing CXCR4 Expression under Simulated Microgravity.

Exposure to microgravity during spaceflight induces the alterations in endothelial cell function associated with post-flight cardiovascular deconditioning. PIEZO1 is a major mechanosensitive ion channel that regulates endothelial cell function. In this study, we used a two-dimensional clinostat to investigate the expression of PIEZO1 and its regulatory mechanism on human umbilical vein endothelial cells (HUVECs) under simulated microgravity. Utilizing quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis, we observed that PIEZO1 expression was significantly increased in response to simulated microgravity. Moreover, we found microgravity promoted endothelial cells migration by increasing expression of PIEZO1. Proteomics analysis highlighted the importance of C-X-C chemokine receptor type 4(CXCR4) as a main target molecule of PIEZO1 in HUVECs. CXCR4 protein level was increased with simulated microgravity and decreased with PIEZO1 knock down. The mechanistic study showed that PIEZO1 enhances CXCR4 expression via Ca2+ influx. In addition, CXCR4 could promote endothelial cell migration under simulated microgravity. Taken together, these results suggest that the upregulation of PIEZO1 in response to simulated microgravity regulates endothelial cell migration due to enhancing CXCR4 expression via Ca2+ influx.

Hypoxic acclimatization training improves the resistance to motion sickness.

Objective: Vestibular provocation is one of the main causes of flight illusions, and its occurrence is closely related to the susceptibility of motion sickness (MS). However, existing training programs have limited effect in improving the resistance to motion sickness. In this study, we investigated the effects of hypoxia acclimatization training (HAT) on the resistance to motion sickness. Methods: Healthy military college students were identified as subjects according to the criteria. MS model was induced by a rotary chair. Experimental groups included control, HAT, 3D roller training (3DRT), and combined training. Results: The Graybiel scores were decreased in the HAT group and the 3DRT group and further decreased in the combined training group in MS induced by the rotary chair. Participants had a significant increase in blood pressure after the rotary chair test and a significant increase in the heart rate during the rotary chair test, but these changes disappeared in all three training groups. Additionally, LFn was increased, HFn was decreased, and LF/HF was increased accordingly during the rotary chair test in the control group, but the changes of these three parameters were completely opposite in the three training groups during the rotary chair test. Compared with the control group, the decreasing changes in pupillary contraction velocity (PCV) and pupillary minimum diameter (PMD) of the three training groups were smaller. In particular, the binocular PCV changes were further attenuated in the combined training group. Conclusion: Our research provides a possible candidate solution for training military pilots in the resistance to motion sickness.

Notch signaling regulates vessel structure and function via Hspg2.

The abnormal structure of tumor blood vessels is an important reason for the low efficacy of anti-tumor drugs. Notch signaling is an evolutionarily highly conserved signaling pathway that plays an important role in vessel development. However, the role and mechanism of Notch signaling in the formation of vascular structure is not fully understood. In this study, we demonstrated that blocking Notch signaling in endothelial cells (ECs) leads to obstructed tumor blood vessel basement membrane formation and the reduction of blood perfusion, as well as blood-retinal barrier (BRB) and blood-brain barrier (BBB) destruction in healthy mice. Endothelial Notch overactivation exacerbates the increases in tumor blood vessel basement membrane and blood perfusion ratio, and promotes recruitment of retinal vascular smooth muscle cells in neonatal mice. Notch signaling also regulates the formation of adhesion junctions (AJs) in ECs. In addition, we confirmed that Notch signaling regulates the AJs of ECs by regulating the expression of downstream gene Hspg2. This research is of great theoretical and practical significance for understanding the mechanism of tumor vascular structure formation as well as the search for new targets for vascular-targeted therapy.

Night shifts in interns: Effects of daytime napping on autonomic activity and cognitive function.

Objective: Night 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. Methods: A 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. Results: Compared 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. Conclusion: Our 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.

Targeted delivery of miR-99b reprograms tumor-associated macrophage phenotype leading to tumor regression.

BACKGROUND: Accumulating 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. METHODS: miR-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. RESULTS: Targeted 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. CONCLUSIONS: Our 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.