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ABSTRACTMolecular mechanisms behind potentially inferior prognosis of old cholangiocarcinoma (CCA) patients are unclear. Prevalence of interventional targets and the difference between young and old CCA patients are valuable for promising precision medicine. A total of 188 CCA patients with baseline tumor tissue samples were subgrouped into the young (≤45 years) and old (>45 years) sub-cohorts. Somatic and germline mutation profiles, differentially enriched genetic alterations, and actionable genetic alterations were compared. An external dataset was used for the validation of molecular features and the comparison of overall survival (OS). Compared to young patients, KRASalterations were more common in old patients (P = .04), while FGFR2fusions were less frequent (P = .05). TERTpromoter mutations were exclusively detected in old patients. The external dataset (N = 392) revealed no significant difference in OS between young and old patients; however, old patient-enriched KRAS(hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.37–2.80) and TERTalterations (HR: 2.03, 95% CI: 1.22–3.38) were associated with inferior OS. Approximately 38.3% of patients were identified of actionable oncogenic mutations indicative of a potential response to targeted therapy or immunotherapy. Actionable FGFR2fusions (P = .01) and BRAFV600E(P = .04) mutations were more frequent in young females than old patients. The enrichment of KRAS/TERTalterations in CCA patients over 45 years resulted in inferior OS. Approximately one-third of CCA patients were eligible for targeted therapy or immunotherapy given the actionable mutations carried, especially young females.

The mortality risk related to anaesthesia in China remains poorly characterized. The objective of this study was to evaluate the anaesthesia-related mortality in terms of its incidence, changes, causes and preventability in Hubei, China, between 2017 and 2021 using a series of annual surveys.

Neuronal network reconstruction is a pivotal determinant for functional recovery after spinal cord injury (SCI), the process of which includes synaptogenesis. Slit2 protein has been identified as a key regulator of axon regeneration and synapse formation in the vertebrate. Meanwhile, RhoA is the converging cascade of inhibitory molecules that interrupt synaptic plasticity in SCI. In the present study, we investigated the interaction among Slit2, Robo1, and RhoA and the potential roles of Slit2 in the pathological process of SCI. We showed that Slit2 was decreased, whereas Robo1 and RhoA were increased in the same surviving neurons in the spinal cord following SCI. We also found that inhibition of Slit2 led to upregulation of the expression of Robo1 and RhoA. However, the severe dysfunctions of the locomotor performance induced by SCI were reversed by treatments of Slit2-N, the active portion of Slit2, knockdown of Robo1 by the RNAi lentivirus, or inhibition of RhoA by the C3 exoenzyme, respectively. Further results suggested that downregulation of Slit2 and therefore upregulation of Robo1 and RhoA inhibited the activity of growth cone and hindered the formation of new synapses of surviving neurons near the injury sites of the spinal cord following SCI. Our study indicated a new mechanism of deficiency of synaptogenesis during the development of SCI and provided a potential strategy for the treatment of SCI.