Laryngeal transplantation offers a promising avenue for functional restoration following total laryngectomy, yet concerns regarding cancer recurrence and perioperative challenges persist. This pilot study evaluates the preliminary outcomes of a refined surgical technique and postoperative follow-up protocol specifically for cancer patients. Between 2023 and 2024, four patients underwent laryngeal transplantation at West China Hospital, with immunosuppressive therapy, microbial prophylaxis, and postoperative rehabilitation. Over a follow-up period ranging from 10 to 26 months, outcomes were heterogeneous. Two recipients (T4 laryngeal squamous cell carcinoma) achieved excellent functional recovery in swallowing and phonation with sustained rejection-free survival for 20 and 23 months and disease-free survival for 20 and 26 months, respectively, though both remained tracheostoma dependent. One of these survivors is currently undergoing treatment for graft rejection after unilateral cessation of immunosuppressants. The remaining two patients succumbed to severe pneumonia with sepsis and tumor recurrence at 10 and 11 months posttransplant. Functional assessments in surviving cases indicated progressive nerve regeneration, with optimal voice and swallowing outcomes achieved approximately 6-8 months postsurgery. Ultimately, these findings demonstrate the technical feasibility of laryngeal transplantation in a pilot cohort of cancer patients, providing critical data for future protocol refinement.

The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has significantly improved the survival in EGFR-mutant lung cancer patients. Our team developed limertinib (ASK120067), a novel third-generation EGFR inhibitor with remarkable antitumor effects, which has been launched in China. Despite initial therapeutic responses, EGFR TKIs-treated patients ultimately experience fatal metastatic recurrence and disease progression. However, the underlying mechanism of driving metastasis remains poorly understood. Here, we aim to investigate the pro-metastatic mechanism following treatment with third-generation EGFR TKIs. Transcriptomics analyses of EGFR TKI-resistant tumor models revealed an aberrant upregulation of S1PR3, which conferred enhanced metastatic potential to lung cancer. S1PR3 inhibition dramatically reduced metastasis in resistant cells, while its overexpression potentiated metastatic abilities in parental cells. Notably, S1PR3 was highly enriched in clinical samples with AZD9291 resistance and correlates with poor prognosis. Mechanistically, we found that S1PR3 upregulated RAC1-GTP expression to activate PAK1, thereby promoting epithelial-mesenchymal transition (EMT) and enhancing metastatic capacity of resistant cells. Further studies identified that the overexpression of fibroblast growth factor receptor 1 (FGFR1) increased S1PR3 expression through signal transducer and activator of transcription 4 (STAT4) to promote the emergence of metastatic-resistant cells. Importantly, targeting S1PR3 or FGFR1 blocks metastasis in EGFR TKI-resistant models.

ABSTRACTThe immune microenvironment of invasive mucinous adenocarcinoma of the lung (IMA), a rare and heterogeneous subtype, remains poorly characterized, limiting insights into its potential response to immunotherapy. In this multicenter study, we systematically evaluated programmed cell death ligand 1 (PD‐L1) expression (using tumor proportion score, TPS, and combined positive score, CPS) and cluster of differentiation 8‐positive (CD8+) tumor‐infiltrating lymphocyte (TIL) infiltration in the largest cohort to date of pathologically confirmed pure IMAs (n = 312), supported by single‑cell transcriptomic analysis. PD‐L1 positivity was low (TPS≥1%: 9.0%; CPS≥1: 28.5%). While PD‐L1 alone showed no prognostic significance, high CD8+ TIL percentage and density were independent, favorable prognostic factors for relapse‐free survival, particularly in patients not receiving adjuvant therapy. By integrating TPS and CD8+ TIL percentage, we established a novel four‐category immune phenotype classification that identified a distinct subgroup (Type IV: PD‐L1+/CD8+) with significantly better outcomes. Preliminary analysis of 20 patients who received immune checkpoint inhibitors suggested that Type IV patients may derive greater clinical benefit. Single‐cell RNA sequencing analyses revealed a paucity of effector CD8+ T cells in IMA. This work defines the unique immune landscape of IMA, introduces a clinically relevant immune phenotyping framework with prognostic and predictive potential, and provides a rationale for future immunotherapeutic strategies in this rare malignancy.

ABSTRACTAutoimmune diseases (AIDs) arise from complex immune dysregulations involving multiple immune cell types, cytokines, and molecular mediators. Among these, microRNAs (miRNAs) have recently emerged as key regulators of leukocyte processes and are frequently dysregulated in AIDs. However, their role in disease pathophysiology remains poorly understood. In this study, we performed a comprehensive analysis of miRNA expression in three immune populations, namely, CD14+ monocytes, neutrophils, and CD8+ T cells, in multiple sclerosis (MS) and type 1 diabetes (T1D), two prototypical AIDs. Our results reveal distinct patterns of miRNA dysregulation in each cell type, with monocytes from T1D patients showing enhanced M1 polarization and supporting inflammatory vascular damage. On the other hand, CD8+ T cells from MS patients show profound alterations related to CD8+ T cell‐fate commitment, apoptosis regulation, and migratory capacity. Notably, we identified miRNAs that regulate key transcription factors such as FOXP3, IRF4, and RORγt, potentially shaping T cell differentiation programs. Our results suggest that miRNA networks play a central role in orchestrating disease‐specific dysregulation in AIDs. By elucidating these intricate regulatory mechanisms, our study provides a foundation for future therapeutic strategies targeting miRNAs in autoimmunity.

We aimed to evaluate associations of chronotype, genetic risk, and lifestyle with depression and anxiety. A total of 242,391 participants without anxiety and depression at baseline in UK Biobank were included. During a total of 3,393,260.1 and 1,371,872.8 person-years follow-up, we found 11,824 (4.88%) incident depression and 10,051 (4.15%) incident anxiety cases, respectively. Compared with definite morning group, individuals with intermediate (HR = 1.09, 95% CI = 1.04‒1.13) and definite evening chronotype (HR = 1.45, 95% CI = 1.36‒1.55) have higher risks of depression, and individuals with definite evening chronotype (HR = 1.27, 95% CI = 1.18‒1.37) have a higher risk of anxiety. We found joint association between chronotype and genetic risk, those with high genetic risk and definite evening chronotype had the highest risk of depression (HR = 2.01, 95% CI = 1.81‒2.23) and anxiety (HR = 1.40, 95% CI = 1.24‒1.58). We also found joint association between chronotype and lifestyle, those with least healthy lifestyle and definite evening chronotype had the highest risk of depression (HR = 1.99, 95% CI = 1.65‒2.40) and anxiety (HR = 1.69, 95% CI = 1.36‒2.10). Individuals with evening chronotype are associated with higher risks of depression and anxiety.

ABSTRACTPulmonary fibrosis is a chronic and progressive interstitial lung disease with limited treatment options aside from lung transplantation. Bleomycin (BLM)‐induced lung injury is the most commonly used experimental model to mimic the key pathological features of human pulmonary fibrosis, which include an early inflammatory phase and a later fibrotic phase. Neutrophil infiltration and M2 macrophage activation are key events in these stages, respectively. However, the molecular mechanisms by which BLM triggers pulmonary inflammation and fibrosis remain incompletely understood. In this study, we found that BLM treatment induced ROS‐mediated oxidative damage in the lungs, leading to an inflammatory microenvironment and the release of oxidized mitochondrial DNA (oxid‐mtDNA). Oxid‐mtDNA was shown to contribute to the early inflammatory response by promoting neutrophil recruitment and enhancing macrophage polarization, which subsequently drove tissue remodeling and fibrosis. Notably, direct injection of oxid‐mtDNA into the lungs recapitulated the fibrotic features observed in the BLM model. Furthermore, studies using STING‐ and NLRP3‐deficient mice demonstrated that loss of either pathway significantly attenuated BLM‐induced inflammation and fibrosis, implicating their involvement downstream of oxid‐mtDNA signaling. Collectively, our findings identify oxid‐mtDNA as a critical mediator linking oxidative injury to immune activation and fibrotic remodeling in the lung, offering new insights into pulmonary fibrosis pathogenesis and potential therapeutic targets.

Epilepsy is a prevalent and often severe neurological disorder with significant economic and societal impacts. Despite adequate trials with two or more antiseizure medications (ASMs), approximately one-third of patients continue to experience drug-resistant epilepsy. Surgery remains the most effective treatment for patients with drug-resistant focal epilepsy, yet it may be underutilized. Given the unsatisfactory clinical outcomes, it is imperative to investigate the molecular pathogenesis of epilepsy and to develop novel therapeutic strategies. This review systematically outlines the advances in understanding the etiology and molecular pathogenesis of epilepsy. These advances have identified diverse therapeutic targets, stimulating the development of emerging therapies, including novel ASM, minimally invasive surgery, neurostimulation, focused ultrasound, nanomedicine, gamma-aminobutyric acid (GABA)ergic cell therapy, and gene therapy. Additionally, the review comprehensively evaluates emerging therapies for epilepsy from different perspectives by integrating findings from both preclinical and clinical studies. These innovative approaches offer the potential for long-term seizure control. A great deal of future research is still needed to overcome current shortcomings. This work provides a cohesive framework that bridges molecular mechanisms with therapeutic applications. Such efforts may provide novel ideas and optimizing approaches in the field, ultimately advancing the precision and effectiveness of epilepsy treatments in the future.