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Developmental sevoflurane exposure leads to widespread neuronal cell death known as sevoflurane-induced neurotoxicity (SIN). Receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL)-driven necroptosis plays an important role in cell fate. Previous research has shown that inhibition of RIPK1 activity alone did not attenuate SIN. Since RIPK3/MLKL signaling could also be activated by Z-DNA/RNA binding protein 1 (ZBP1), the present study was designed to investigate whether ZBP1-mediated and RIPK3/MLKL-driven necroptosis is involved in SIN through in vitro and in vivo experiments. We found that sevoflurane priming triggers neuronal cell death and LDH release in a time-dependent manner. The expression levels of RIPK1, RIPK3, ZBP1 and membrane phosphorylated MLKL were also dramatically enhanced in SIN. Intriguingly, knockdown of RIPK3, but not RIPK1, abolished MLKL-mediated neuronal necroptosis in SIN. Additionally, inhibition of RIPK3-mediated necroptosis with GSK'872, rather than inhibition of apoptosis with zVAD, significantly ameliorated SIN. Further investigation showed that sevoflurane treatment causes mitochondrial DNA (mtDNA) release into the cytosol. Accordingly, ZBP1 senses cytosolic mtDNA and consequently activates RIPK3/MLKL signaling. This conclusion was reinforced by the evidence that knockdown of ZBP1 or depleting mtDNA with ethidium bromide remarkably improved SIN. Finally, the administration of the RIPK3 inhibitor GSK'872 relieved sevoflurane-induced spatial and emotional disorders without influence on locomotor activity. Altogether, these results illustrate that ZBP1 senses cytosolic mtDNA to induce RIPK3/MLKL-driven necroptosis in SIN. Elucidating the role of necroptosis in SIN will provide new insights into understanding the mechanism of anesthetic exposure in the developing brain.

OBJECTIVES: To investigate the prediction value of a radiomics model based on apparent diffusion coefficient (ADC) maps for pelvic lymph node metastasis (PLNM) in patients with stage IB–IIA cervical squamous cell carcinoma (CSCC). METHODS: A total of 153 stage IB–IIA CSCC patients who underwent preoperative MRI including DWI from January 2015 to October 2017 were retrospectively studied and divided into a training cohort ( n = 102) and a validation cohort ( n = 51). Radiomics features were extracted from the ADC maps. The one-way ANOVA method, Mann-Whitney U test and Pearson’s correlation analysis were used for selecting radiomics features. Logistic regression analyses were used to develop the model. ROC analyses were used to evaluate the prediction performance of the model. RESULTS: Clinical stage, tumor diameter, and MR-reported lymph node (LN) status were significantly associated with LN status ( p < 0.05 for both the training and validation cohorts). The radiomics model, which incorporated clinical stage, MR-reported LN status, and grey-level non-uniformity, showed good predictive performance in the training group (AUC 0.864; 95% CI, 0.782 – 0.924) and the validation group (AUC 0.870; 95% CI, 0.747 – 0.948). The performance of the radiomics model was significantly better than that of each predictive factor alone. CONCLUSION: The presented radiomics model, a non-invasive preoperative prediction tool, has the potential to have more predictive efficacy than clinical and radiological factors for differentiating between metastatic and non-metastatic lymph nodes. ADVANCES IN KNOWLEDGE: A radiomics model derived from the ADC maps of primary lesions demonstrated good performance for predicting PLNM in stage IB-IIA CSCC patients and may help to improve clinical decision-making.