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BackgroundTumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma (ICC) remain unclear.MethodsWe explored the distributions of TANs and TAMs in patient-derived ICC samples by multiplex immunofluorescent staining and tested their separate and combined effects on ICC in vitro and in vivo. We then investigated the mechanistic basis of the effects using PCR array, western blot analysis and ELISA experiments. Finally, we validated our results in a tissue microarray composed of primary tumor tissues from 359 patients with ICC.ResultsThe spatial distributions of TANs and TAMs were correlated with each other in patient-derived ICC samples. Interaction between TANs and TAMs enhanced the proliferation and invasion abilities of ICC cells in vitro and tumor progression in a mouse xenograft model of ICC. TANs and TAMs produced higher levels of oncostatin M and interleukin-11, respectively, in co-culture than in monoculture. Both of those cytokines activated STAT3 signaling in ICC cells. Knockdown of STAT3 abolished the protumor effect of TANs and TAMs on ICC. In tumor samples from patients with ICC, increased TAN and TAM levels were correlated with elevated p-STAT3 expression. All three of those factors were independent predictors of patient outcomes.ConclusionsTANs and TAMs interact to promote ICC progression by activating STAT3.

Reprogramming oncogenic signaling pathways to generate anti-tumor effects is a promising strategy for targeted cancer intervention, without significant off-target effects. Although reprogramming multi-oncoprotein interactions in a single signaling pathway axis has been shown to achieve sustained efficacy, there are several challenges that limit its clinical application. Herein, we transformed the mouse double minute 2 homolog (MDM2)-heat shock cognate protein 70 (HSC70) axis, a tumor-promoting pathway, into an activator of anti-tumor immunity using the Path-editor, an artificial selenoprotein. Once it enters the cell, Path-editor decomposes into PMI and PPI peptides: PMI inhibits MDM2-mediated p53 degradation and promotes HSC70 expression, while PPI binds to HSC70, enabling its ability to selectively degrade the programmed cell death ligand 1 (PD-L1). As a proof of concept, we tested its performance in microsatellite-stable (MSS) colorectal cancer, which typically displays limited responsiveness to immunotherapy. The results indicated that Path-editor effectively attenuated PD-L1 expression and reversed immune evasion in both CT26 allografts and humanized patient-derived tumor xenograft (PDX) models, thereby inhibiting tumor progression with high biosafety. Therefore, this paper introduces Path-editor as a paradigm for reprogramming oncogenic multi-protein pathways, utilizing selenium-assisted approach to achieve the rapid design of tumor-specific pathway editors. This strategy is expected to reverse immune escape in MSS colorectal cancer and treat difficult malignancies. [Display omitted] •Reprogram MDM2-HSC70 axis triggers antitumor immunity via selenoprotein Path-editor.•Dual-peptide Path-editor degrades PD-L1 and boosts p53 for overcoming immune evasion.•Selenium-driven pathway editing inhibits tumor growth with high biosafety in vivo.

Background and purpose As mental health issues receive increasing global attention, particularly the prevalence of depression and anxiety symptoms among college students, exploring effective intervention measures becomes crucial. This study aims to investigate the impact of physical activity on depression and anxiety among college students and to delve into the mediating role of self-esteem in these impacts. Methods A structured questionnaire was used to survey 326 undergraduates from three universities in Hainan Province. The questionnaire assessed their self-reported responses to physical activity, depression, anxiety, and self-esteem. Partial Least Squares Structural Equation Modeling (PLS-SEM) was employed to analyze the data collected in this study. Results The results indicate that physical activity significantly negatively affects students’ depression ( β = -0.262, t  = 4.268, p  < 0.001) and anxiety ( β = -0.170, t  = 2.849, p  < 0.01). Furthermore, self-esteem partially mediates the relationship between physical activity and both depression ( β = -0.081, t  = 3.158, p  < 0.01) and anxiety ( β = -0.063, t  = 2.806, p  < 0.01). Discussion In conclusion, the findings provide a theoretical basis for developing physical activity programs aimed at enhancing college students’ mental health, suggesting that future interventions should focus on increasing participation in physical activities and enhancing self-esteem to alleviate depression and anxiety, thus comprehensively improving students’ psychological well-being.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the formation of amyloid plaques, neurofibrillary tangles and progressive cognitive decline. Amyloid-beta peptide (Aβ) monoclonal antibody therapeutic clinical trials have nearly failed, raising significant concerns about other etiological hypotheses about AD. Recent evidence suggests that AD patients also exhibit persistent neuronal loss and neuronal death accompanied by brain iron deposition or overload-related oxidative stress. Ferroptosis is a type of cell death that depends on iron, unlike autophagy and apoptosis. Inhibiting neuronal ferroptosis function is effective in improving cognitive impairment in AD. Notably, new research shows that ferroptosis in AD is crucially dependent on glial cell activation. This review examines the relationship between the imbalance of iron metabolism, the regulation of iron homeostasis in glial cells and neuronal death in AD pathology. Finally, the review summarizes some current drug research in AD targeting iron homeostasis, many novel iron-chelating compounds and natural compounds showing potential AD-modifying properties that may provide therapeutic targets for treating AD.

The high prevalence of pre-existing neutralizing antibodies (NAbs) against adeno-associated virus (AAV) poses a major obstacle to in vivo gene therapy. Current immunosuppressive (IS) strategies, such as corticosteroids, are limited by toxicity and adverse effects. To explore safer alternatives, we evaluated dihydroartemisinin (DHA), a synthetic derivative of artemisinin inspired by traditional Chinese medicine (TCM), as a potential IS agent. In vivo experiments were conducted by administering DHA at either 30 or 210 days post-injection (PI) of rAAVDJ vectors. Anti-AAV NAb levels, transgene expression, and vector genome biodistribution were assessed. Flow cytometry was used to quantify CD20 B cells, germinal center B cells, and plasma cells in the spleen. Splenic gene expression profiling, liver histology, and serum biochemical analyses were performed to evaluate immunological and safety responses. In vitro, the impact of DHA and its serum metabolites on rAAV infection efficiency was tested in HEK293 cells. DHA administration significantly reduced anti-AAV NAb levels without compromising transgene expression or vector genome distribution. DHA treatment resulted in a reduction of splenic CD20 B cells, germinal center B cells, and plasma cells, alongside changes in splenic gene expression profiles. Liver histology and serum markers confirmed that DHA at 125 mg/kg/day did not induce hepatotoxicity. In vitro assays demonstrated that DHA and its blood metabolites did not interfere with rAAV infection of HEK293 cells across multiple serotypes. These findings suggest that DHA is a safe and effective agent for modulating humoral immune responses to AAV vectors. Our results provide proof-of-concept evidence supporting the use of TCM-derived compounds to address immunological barriers in gene therapy.

Background Epithelial-mesenchymal transition (EMT) plays a crucial role in the migration and invasion capabilities of glioblastoma (GBM) cells. Several studies have established tubulin as a significant regulator of the EMT process. Tubulin beta 2B class IIb (TUBB2B), a critical component of microtubules, has been linked to the prognosis of various tumors. However, the specific biological function and mechanism of TUBB2B in GBM remain unclear. Methods In vitro experiments demonstrated that TUBB2B knockdown inhibited the migration and invasion of GBM cells, while its overexpression enhanced these capabilities. Western blot, immunofluorescence (IF) and co-immunoprecipitation (Co-IP) assays revealed that TUBB2B interacts with Vimentin. Molecular docking and residue mutation scanning indicated that TUBB2B interacts with Vimentin at the R391/K392/A393/F394 sites. In vivo experiments using nude mice confirmed that TUBB2B knockdown inhibited GBM cell invasion and migration. Results TUBB2B was upregulated in GBM tissue samples compared with normal tissues. The sites of TUBB2B(R391/K392/A393/F394) physically interacts with Vimentin to induce EMT, which promotes migration and invasion. Conclusion TUBB2B may regulate EMT and promote the migration and invasion of GBM cells through its interaction with Vimentin, highlighting TUBB2B as a potential therapeutic target for GBM.

The parameters of gravity dams and foundation materials objectively exhibit spatial variability due to environmental and load influences, which significantly affect the safety status of dam structures. Therefore, a safety risk analysis method for a gravity dam–foundation system based on random field theory is proposed in this paper. Spatial variabilities in materials are particularly considered by using the finite element method. Then, composite response surface equations for the performance function (PF) of strength and stability failure are established, and then, the system failure risk is obtained using the Monte Carlo method. The proposed method solves the problem wherein the effect of spatial variability on failure risk cannot be reflected accurately by the performance function of multi-element sliding paths, and the difficulties in solving the failure risk of the series–parallel system due to multiple failure paths and their complex correlations. The application of a gravity dam shows that the developed method overcomes the disadvantages of the traditional method, such as the homogenization of the spatially random characteristics of parameters and the overestimation of failure risk in the system due to large variance estimation.

Slope stability is a major safety concern of rockfill embankments. Since rockfills are incohesive materials, only friction angle is considered as a shear strength parameter in the slope stability analysis of rockfill embankments. Recently, it was found that confining pressure can significantly affect the mean value and variance of the friction angle of rockfills. Since the confining pressure spatially varies within a rockfill embankment, the effect of stress-dependent spatial variability in the friction angle of rockfills should be investigated for slope stability evaluation of rockfill embankments. In the framework of the Limit Equilibrium Method (LEM), an approach is proposed for the slope stability analysis of rockfill embankments considering the stress-dependent spatial variability in the friction angle. The safety factors of slope stability are computed with variable values of the friction angle at the bases of slices which are determined by the stress-dependent mean value and variance of the friction angle of rockfills. The slope stability of a homogeneous rockfill embankment is analyzed to illustrate the proposed approach, and a parametric analysis is carried out to explore the effect of variation in the parameters of the variance function of friction angle on slope stability. The illustrative example demonstrates that the stress-dependent spatial variability of friction angle along the slip surface is obvious and is affected by the location of the slip surface and the loading condition. The effects of the stress-dependent spatial variability of the friction angle on the slope stability of high rockfill embankments should be considered.

Objectives. Factors prognostic of survival in liver transplant (LT) recipients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) remain unclear. This study evaluated risk factors for survival in LT recipients with HBV-ACLF and determined the scoring system optimal for assessing patient prognosis. Methods. This retrospective study included 323 HBV-ACLF related patients undergoing LT, including 112, 146, and 65 patients with HBV-ACLF grades 1, 2, and 3, respectively. Overall survival (OS) was estimated by the Kaplan–Meier method, and factors associated with survival were analysed by multivariate Cox proportional hazards models. Pretransplant prognostic scoring systems were compared by receiver operating characteristic (ROC) curve analysis. Results. The one-year survival rate was significantly lower in HBV-ACLF grade 3 (80.0%) than in grades 1 (93.8%) and 2 (91.8%) recipients (p=0.0063). Cox multivariate analysis showed that age >53 years (hazard ratio (HR) 3.731; 95% confidence interval (CI) 1.640–8.407), WBC count >8.6 × 109/L (HR 4.544; 95% CI 1.140–18.107), HBV-ACLF 3 (HR 2.729; 95% CI 1.050–7.096), and cold ischaemia time >8.5 hours (HR 2.867; 95% CI, 1.38–5.921) were independently prognostic of 1-year survival. Comparisons of pretransplant scoring systems showed that chronic liver failure-consortium ACLF score (CLIF-C ACLFs) was superior to COSSH-ACLF, MELD-Na, and MELD scores in predicting 1-year OS in these patients. Conclusions. Age >53 years, WBC counts >8.6 × 109/L, HBV-ACLF grade 3, and cold ischaemia time >8.5 hours are independently prognostic of OS in LT recipients with HBV-ACLF. CLIF-C ACLFs is superior to other scoring methods in predicting 1-year OS in these patients.

Almost all high-grade gliomas, particularly glioblastoma (GBM), are highly migratory and aggressive. Migrasomes are organelles produced by highly migratory cells capable of mediating intercellular communication. Thus, GBM cells may produce migrasomes during migration. However, it remains unclear whether migrasomes can influence GBM migration and invasion. In this study, we observed the presence and formation of migrasomes in GBM cells. We found that expression levels of key migrasome formation factor, tetraspanin 4 ( TSPAN4 ), correlated positively with pathological grade and poor prognosis of GBM based on the databases and clinical samples analysis. Subsequently, we knocked down TSPAN4 and found that GBM cell migration and invasion were significantly inhibited due to the reduced formation of migrasomes. We further confirmed that migrasomes are enriched in extracellular matrix (ECM)-related proteins such as p21-activating kinase 4 (PAK4) and laminin alpha 4 (LAMA4). Our experimental results suggest that migrasomes promote GBM cells migration by releasing such proteins into the extracellular space. Overall, we identified migrasomes in GBM and the molecular mechanisms by which they regulate them, providing potential targets for treating GBM. Observation of migrasomes in glioblastoma (GBM) and analysis of migrasome-enriched proteins revealed that migrasomes promote GBM migration and invasion by releasing the extracellular matrix-associated proteins PAK4 and LAMA4.