Depression is a debilitating mental disease that inflicts significant harm upon individuals and society, yet effective treatment options remain elusive. At present, the pathogenesis of multiple depression is not fully clear, but its occurrence can be related to biological or environmental pathways, among which Brain-derived neurotrophic factor (BDNF) can unequivocally act on two downstream receptors, tyrosine kinase receptor (TrkB) and the p75 neurotrophin receptor (p75NTR), then affect the related signal pathways, affecting the occurrence and development of depression. Accumulating studies have revealed that BDNF-related pathways are critical in the pathophysiology of depression, and their interaction can further influence the efficacy of depression treatment. In this review, we mainly summarized the signaling pathways associated with BDNF and classified them according to different receptors and related molecules, providing promising insights and future directions in the treatment of depression.

The platelet-to-lymphocyte ratio (PLR) is a novel indicator of inflammation, but research on the links and mechanisms between the PLR and long-term health conditions is lacking. This study aimed to evaluate the relationship between phenotypic age (PhenoAge) mediated PLR and mortality among US adults. A total of 37,182 participants from the National Health and Nutrition Examination Survey (NHANES) database (1999–2018) were included to evaluate the PLR's relevance to survival by Cox regression models. The associations between the PLR and mortality were apparent using restricted cubic spline regression. Mediation analyses were conducted to investigate the mediated effects of PhenoAge on the associations of PLR with mortality. Compared to the PLR in Quintile 1 participants, the multivariable-adjusted Cox model showed the PLR in Quintile 5 was linked with greater risks of death from all-cause (HR, 1.14; 95 % CI: 1.04–1.25), cardiovascular disease (CVD) (HR, 1.26; 95 % CI: 1.01–1.57) and respiratory disease (HR, 1.98; 95 % CI: 1.35–2.90). The risk of death from cancer was approximately 28 % lower for participants with the PLR in the fourth quintile. Restricted cubic splines showed the U-shaped relationships between PLR and all-cause and cancer mortality, and the positively linear relationships between PLR and cardiovascular disease (CVD) and respiratory mortality. Moreover, mediation analysis revealed that PhenoAge partially mediated 45.33 %, 44.26 %, and 15.35 % of the associations of PLR with all-cause, CVD, and respiratory disease mortality, respectively. The PLR, a valuable index that should be recommended for use, was independently linked with all-cause and cause-specific mortality, with PhenoAge playing a partial mediating role in the relationships.

Advanced intrahepatic cholangiocarcinoma (ICC) may be liver-confined or liver-dominant after curative resection is no longer feasible. This distribution supports a role for locoregional therapy (LRT), whereas occult or established extrahepatic disease still requires systemic control. This narrative review integrates the most recent clinical and mechanistic evidence for combining LRT with chemotherapy, immune checkpoint inhibition, molecularly targeted treatment, and cellular therapy. Randomized phase III biliary tract cancer trials support gemcitabine-cisplatin plus durvalumab or pembrolizumab as first-line systemic therapy, but the primary analyses improved median overall survival by only 1.3 and 1.8 months. Evidence for adding LRT is less mature and heterogeneous. Prospective single-arm studies of yttrium-90 radioembolization, hepatic arterial infusion, radiotherapy, and cryoablation-based combinations report activity in selected ICC populations, but most lack a contemporary control and cannot isolate the contribution of LRT. No biomarker has validated the incremental benefit of a specific LRT. Clinical development should therefore specify the LRT modality and exposure, disease distribution, systemic backbone, treatment intent, and safety boundary. Routine adoption requires reproducible protocols, comparative survival and safety endpoints, and paired biomarker collection.