RESUMEN
BACKGROUND: The molecular biology mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear, resulting in a lack of specific therapeutic targets and limited clinical treatment options. The NLRP3 pyroptotic pathway, induced by neuroinflammation, is known to promote the development of POCD. Research has shown that lncRNA MEG3 exacerbates cell pyroptosis in various neurological injuries, though the precise mechanism remains to be investigated. METHODS: In vitro and in vivo models of POCD were established through treatment with sevoflurane. Gene and protein expression were investigated using qRT-PCR, Western blot analysis, ELISA, and histological staining. Additionally, cell viability and injury were assessed through CCK-8 and LDH assays. Hippocampal-dependent memory and cognitive abilities were evaluated using the Morris Water Maze (MWM) test. Furthermore, the interactions between MEG3 and EZH2/YTHDC1 were validated through RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP). RESULTS: Our findings reveal that sevoflurane significantly reduced MEG3 and pyroptosis-related proteins in mice. The overexpression of MEG3 protected mice against sevoflurane-induced cognitive dysfunction and reversed sevoflurane-induced pyroptosis in hippocampal neurons. MEG3 induced the downregulation of NLRP3 expression and reduced mRNA stability through its interaction with EZH2/YTHDC1. CONCLUSION: In conclusion, our study elucidates that MEG3 inhibits the NLRP3 inflammasome and hippocampal neuron pyroptosis through the recruitment of EZH2/YTHDC1. These findings shed light on the underlying mechanism of MEG3 in the regulation of POCD and suggest that MEG3 could serve as a potential therapeutic target for the treatment of POCD.
RESUMEN
OBJECTIVE: Survival and treatment of patients with microinvasive breast cancer (MIBC) remain controversial. In this paper, we evaluated whether adjuvant chemotherapy is necessary for patients with MIBC to identify risk factors influencing its prognosis and decide the indication for adjuvant chemotherapy. METHODS: In this retrospective study, 108 patients with MIBC were recruited according to seventh edition of the staging manual of the American Joint Committee on Cancer (AJCC). The subjects were divided into chemotherapy and non-chemotherapy groups. We compared the 5-year disease-free survival (DFS) and overall survival (OS) rates between groups. Furthermore, we analyzed the factors related to prognosis for patients with MIBC using univariate and multivariate analyses. We also evaluated the impact of adjuvant chemotherapy on the prognostic factors by subgroup analysis after median follow-up time of 33 months (13-104 months). RESULTS: The 5-year DFS and OS rates for the chemotherapy group were 93.7% and 97.5%, whereas those for the non-chemotherapy group were 89.7% and 100%. RESULTS indicate that 5-year DFS was superior, but OS was inferior, in the former group compared with the latter group. However, no statistical significance was observed in the 5-year DFS (P=0.223) or OS (P=0.530) rate of the two groups. Most relevant poor-prognostic factors were Ki-67 overexpression and negative hormonal receptors. Cumulative survival was 98.2% vs. 86.5% between low Ki-67 (≤20%) and high Ki-67 (>20%). The hazard ratio of patients with high Ki-67 was 16.585 [95% confidence interval (CI), 1.969-139.724; P=0.010]. Meanwhile, ER(-)/PR(-) patients with MIBC had cumulative survival of 79.3% compared with 97.5% for ER(+) or PR(+) patients with MIBC. The hazard ratio for ER(-)/PR(-) patients with MIBC was 19.149 (95% CI, 3.702-99.057; P<0.001). Subgroup analysis showed that chemotherapy could improve the outcomes of ER(-)/PR(-) patients (P=0.014), but not those who overexpress Ki-67 (P=0.105). CONCLUSIONS: Patients with MIBC who overexpress Ki-67 and with negative hormonal receptors have relatively substantial risk of relapse within the first five years after surgery. However, adjuvant chemotherapy can only improve the outcomes of ER(-)/PR(-) patients, but not those who overexpress Ki-67. Further studies with prolonged follow-up of large cohorts are recommended to assess the prognostic significance and treatment of this lesion.