Zhujiang Hospital

Asthma is a chronic inflammatory airway disease characterized by airway remodeling and hyperresponsiveness, driven in part by TGF-β1-induced epithelial-mesenchymal transition (EMT). The natural compound 1,8-cineol, derived from Eucalyptus globulus, has shown anti-inflammatory potential. This study aimed to investigate its protective effects against EMT and airway inflammation via the NF-κB/COX-2 pathway. In vivo, ovalbumin-sensitized BALB/c mice were treated with 1,8-cineol (50 mg/kg) to evaluate airway resistance, lung compliance, and inflammatory markers (IgE, IL-4, IL-13, IL-17). Histopathological changes were assessed via H&E and PAS staining. In vitro, TGF-β1-stimulated BEAS-2B cells were treated with 1,8-cineol to analyze EMT markers (α-SMA, E-cadherin, N-cadherin), migration capacity, and NF-κB/COX-2 signaling using RT-qPCR, Western blotting, and transwell assays. 1,8-cineol significantly attenuated airway hyperresponsiveness and reduced EMT markers (α-SMA, N-cadherin) in OVA-sensitized mice, while improving lung compliance. In BEAS-2B cells, it suppressed TGF-β1-induced EMT and migration without cytotoxicity. Mechanistically, 1,8-cineol downregulated NF-κB phosphorylation and COX-2 expression. OVA challenge elevated serum IgE and BALF cytokines (IL-4, IL-13, IL-17), which were mitigated by 1,8-cineol. 1,8-cineol inhibits TGF-β1-driven EMT and airway inflammation by modulating the NF-κB/COX-2 pathway, highlighting its therapeutic potential for asthma.

Dysregulation of the CARD11-BCL10-MALT1 (CBM) complex is associated with a group of inborn errors of immunity termed “CBM-opathies,” which encompass a spectrum of clinical manifestations including combined immunodeficiency, autoimmune inflammation, atopic disorders, and lymphoproliferation. In this study, we identified novel compound heterozygous variants in the CBM complex in a patient with a family history of immune dysfunction. The patient inherited the variants CARD11 p.K215N and MALT1 p.K543R/p.M732T from asymptomatic carrier parents. Phenotypically, the patient exhibited a developmental arrest of B lymphocytes at the transitional/naïve B cell stage, accompanied by activation of virus-response pathways. Impaired development of T follicular helper cells was linked to defective germinal center formation and agammaglobulinemia. Furthermore, the patient showed expansion of T peripheral helper cells and a deficiency in regulatory T cells, both associated with autoimmunity and colitis. In vitro studies confirmed an imbalance in Tph/Tfh cell differentiation. Single-cell RNA sequencing further revealed a deficiency in B cell development and an enriched population of pro-inflammatory CD3dimCD4−CD8−CD247+ T cells, functionally enriched in the MAPK signaling pathway. Mechanistically, the MALT1 K543R and M732T variants attenuated MALT1’s enzymatic activity and compromised its protein stability, while the CARD11K215N variant disrupted CARD11-mediated promotion of BCL10 filament formation. We demonstrated that these three variants act synergistically to impair NF-κB activation. Specifically, CARD11K215N cooperates with the co-pathogenic MALT1M732T and the modifier variant MALT1K543R to destabilize the functional integrity of the CBM complex, thereby driving the patient’s phenotype. In summary, our study provides new insights into the pathogenesis of autoimmune inflammatory disorders within the spectrum of CBM-opathies and reveals a potential role for the CBM complex in regulating the balance between T peripheral helper and T follicular helper cells. Identified three novel variants in the CBM complex in a patient with a family history of immune dysfunction. CARD11K215N/MALT1K543R/M732T variants impaired B cell development and CD4+T cell differentiation, especially T peripheral helper and T follicular helper cells, by destabilizing the functional integrity of CBM complex.

The optimal sequencing of radiotherapy (RT) combined with immunotherapy (iRT) and the value of chemotherapy remain undefined for advanced non-small cell lung cancer (NSCLC), where randomized data are limited. To compare real-world overall survival (OS) between sequential and concurrent iRT in newly diagnosed advanced NSCLC, assess the effect of immune checkpoint inhibitor (ICI) maintenance after RT in refractory disease, and evaluate the association of chemotherapy with survival. This is a territory-wide study (OCEANUS) based on the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System (more than 90% population coverage). Patients with NSCLC diagnosed from January 1, 2010, to December 31, 2021, who subsequently received iRT for advanced or refractory disease were included. Overlap weighting was the primary propensity score-weighted method, with inverse probability of treatment weighting used for sensitivity analysis. Data were analyzed from December 2024 to April 2025. Sequential vs concurrent iRT for newly diagnosed advanced NSCLC; RT with vs without ICI maintenance for refractory NSCLC; receipt of chemotherapy. The primary outcome was real-world OS after landmark, estimated with weighted Kaplan-Meier and Cox models. When proportional hazards were violated (per Schoenfeld residuals), treatment effects were summarized using restricted mean survival time. Of 3522 patients who received ICIs, 335 received RT, including 155 with newly diagnosed advanced and 180 with refractory NSCLC. Of these, 247 (73.7%) were male, and the median (range) age was 64 (34-90) years. In newly diagnosed NSCLC, patients treated with sequential iRT had significant longer real-world OS than those treated with concurrent iRT (median, 20.3 months [95% CI, 13.3 to not reached] vs 16.0 months [95% CI, 8.3-30.0]; adjusted hazard ratio, 0.68; 95% CI, 0.47-0.99; P = .045). Chemotherapy was also associated with longer survival in patients with newly diagnosed advanced NSCLC. In refractory NSCLC, RT with ICI maintenance was associated with a numerically longer median real-world OS (11.2 months [95% CI, 7.9-20.6] vs 6.7 months [95% CI, 4.4-17.4]; P = .20). Addition of chemotherapy was not significant for real-world OS. Inverse probability of treatment weighting analyses produced similar estimates. In this cohort study, sequential iRT was associated with longer survival than concurrent iRT in patients with newly diagnosed advanced NSCLC, and chemotherapy was associated with longer survival. In patients with refractory NSCLC who survived at least 90 days, RT with ICI maintenance resulted in nonsignificantly longer survival and an unclear association with chemotherapy. These findings are hypothesis generating and support prospective randomized studies to define optimal sequencing of iRT and use of systemic treatment partners.

Considerable efforts have been dedicated to developing effective treatments for post-stroke executive impairment (PSEI), among which repetitive transcranial magnetic stimulation (rTMS) has shown great potential. This study aimed to investigate the therapeutic effects of high-frequency rTMS on working memory (WM) and response inhibition (RI) of executive functions in PSEI patients and the potential neural mechanisms. In a randomized, double-blind trial, 10 Hz rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) in 32 PSEI patients for 10 days, who were divided into real and sham rTMS groups. The Stroop color-word test (SCWT), digit span test (DST), and functional near-infrared spectroscopy (fNIRS) were used for assessment before and after the intervention. Resting-state functional connectivity (rsFC) and graph theory methods were used to analyze changes in brain function. Compared to the sham rTMS group, the real rTMS group showed significant reductions in SCWT response time (F = 4.223, p = 0.049) and improvements in DST forward scores (F = 4.739, p = 0.037) after the intervention. Moreover, the real rTMS group demonstrated significant enhancements in rsFC from left DLPFC to the right DLPFC (F = 8.538, p = 0.007) and the right posterior parietal cortex (F = 9.905, p = 0.004), as well as in the Degree Centrality of the left DLPFC (F = 7.144, p = 0.012), which were respectively significantly correlated with reduced SCWT response time and increased DST forward scores. High-frequency rTMS effectively improves WM and RI performance in patients with PSEI, which may be attributed to the remodeling of specific connectivity patterns and enhancement of local communication efficiency within the frontoparietal network.

BackgroundPreservation of normal-quality infrapatellar fat pads (IPFP) during total knee arthroplasty (TKA) has been proposed, and IPFP of abnormal quality are recommended for resection.MethodsIn this trial, patients with knee osteoarthritis (OA) undergoing TKA were stratified by IPFP status on magnetic resonance imaging (Group 1 with normal IPFP [signal intensity score ≤1; ranging from 0 to 3]; Group 2 with abnormal IPFP [signal intensity score ≥2]) and randomly assigned in a 1:1 ratio to IPFP preservation or IPFP resection. The primary outcome was 12-month change in the mean of five Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales (KOOS5), which range from 0 (worst) to 100 (best).ResultsIn Group 1, 179 participants were randomly allocated to IPFP preservation (n=90) and IPFP resection (n=89), and 198 participants were randomly assigned to IPFP preservation (n=101) and IPFP resection (n=97) in Group 2. The increases in KOOS5 score were 38.1 and 36.1 in Group 1 and were 39.2 and 37.5 in Group 2 in IPFP preservation and IPFP resection groups, respectively, resulting in between-group differences of 1.9 (95% confidence interval [CI], −1.7 to 5.6) in Group 1 and 1.6 (95% CI, −1.3 to 4.6) in Group 2. Adverse events were predominantly nonserious musculoskeletal or skin-related events (three vs. two in Group 1 and eight vs. two in Group 2).ConclusionsResection of abnormal IPFP and preservation of normal IPFP did not improve postoperative outcomes 12 months after TKA. (Funded by National Key Research & Development Program of China, Clinical Research Startup Program of Southern Medical University, and National Natural Science Foundation of China; ClinicalTrials.gov number, NCT03763448.)

Abstract Although our previous study implied that kinesin family member 20A (KIF20A) is frequently up-regulated in prostate cancer (PCa) and links to poor survival, the roles and mechanism remain largely poor understood. In this study, we further reported that KIF20A overexpressed in PCa and docetaxel resistance cells, and predicted unfavorable prognosis. Moreover, KIF20A accelerated the PCa cells proliferation and conferred resistance to docetaxel in vitro and in vivo. A mechanistic study revealed that KIF20A promotes PCa progression by activating β-catenin pathway. Furthermore, KIF20A physically interacted with USP15, a crucial deubiquitinating enzyme to catalyze K-63 linked deubiquitination of K393 and K495 lysine resident of G3BP1, thus up-regulated G3BP1 activated β-catenin subsequently. Altogether, our study revealed the clinical significance of KIF20A in PCa, and implied that targeting KIF20A might be a promising strategy to delay the PCa proliferation and overcome docetaxel resistance.