OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is characterized by complex pathogenesis and poor prognosis. In recent years, epithelial-mesenchymal transition (EMT) in tumor initiation and progression has attracted increasing attention. Enhancer of zeste homolog 2 (EZH2), which is aberrantly expressed in various tumors, may be closely related to the EMT process. This study aims to examine the expression and correlation of EZH2 and EMT markers in ESCC cells and tissues, evaluate the effects of EZH2 knockdown on ESCC cell proliferation, invasion, and migration, and explore how EZH2 contributes to the malignant biological behavior of ESCC. METHODS: Bioinformatics analyses were used to assess EZH2 expression levels in ESCC. Small interfering RNA was used to knock down EZH2 in ESCC cell lines EC109 and EC9706. Cell proliferation, invasion, and migration were evaluated using cell counting kit-8 (CCK-8), wound healing, and Transwell assays. Protein and mRNA expression levels of EZH2, E-cadherin (E-cad), and vimentin (Vim) were detected by Western blotting and real time fluorogenic quantitative PCR (RT-qPCR), respectively. Immunohistochemical (IHC) staining was performed on 70 ESCC tissue samples and 40 paired adjacent normal tissues collected from the First Affiliated Hospital of Shihezi University between 2010 and 2016 to assess the expression of EZH2, E-cad, and Vim, and to analyze their associations with clinicopathological feature and patient prognosis. RESULTS: Bioinformatics analysis showed that EZH2 was highly expressed in ESCC (P<0.001), and high EZH2 expression was associated with worse prognosis (P<0.001). CCK-8, wound healing, and Transwell assays demonstrated that EZH2 knockdown significantly suppressed the proliferation, invasion, and migration of ESCC cells (P<0.001). In addition, Vim expression was significantly reduced, while E-cad expression was significantly increased at both protein and mRNA levels in EZH2-silenced cells (all P<0.05). IHC staining analysis revealed higher expression of EZH2 and Vim and lower expression of E-cad in ESCC tissues compared to adjacent normal tissues. Kaplan-Meier survival analysis showed that low expression of EZH2 and Vim and high expression of E-cad were associated with longer survival (all P<0.05). CONCLUSIONS EZH2 promotes malignant biological behavior in ESCC by mediating EMT. Elevated EZH2 expression is associated with poor prognosis in ESCC patients.
Humans ; Enhancer of Zeste Homolog 2 Protein/physiology* ; Esophageal Squamous Cell Carcinoma/pathology* ; Epithelial-Mesenchymal Transition/genetics* ; Esophageal Neoplasms/metabolism* ; Cell Proliferation ; Cell Line, Tumor ; Cell Movement ; Cadherins/genetics* ; Vimentin/genetics* ; Male ; Female ; Middle Aged ; Neoplasm Invasiveness ; Prognosis ; RNA, Small Interfering/genetics* ; Gene Expression Regulation, Neoplastic

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with few effective treatments currently available. The multifactorial nature of AD, shaped by genetic, environmental, and biological factors, complicates both research and clinical management. Recent advances in artificial intelligence (AI) and multi-omics technologies provide new opportunities to elucidate the molecular mechanisms of AD and identify early biomarkers for diagnosis and prognosis. AI-driven approaches such as machine learning, deep learning, and network-based models have enabled the integration of large-scale genomic, transcriptomic, proteomic, metabolomic, and microbiomic datasets. These efforts have facilitated the discovery of novel molecular signatures and therapeutic targets. Methods including deep belief networks and joint deep semi-non-negative matrix factorization have contributed to improvements in disease classification and patient stratification. However, ongoing challenges remain. These include data heterogeneity, limited interpretability of complex models, a lack of large and diverse datasets, and insufficient clinical validation. The absence of standardized multi-omics data processing methods further restricts progress. This review systematically summarizes recent advances in AI-driven multi-omics research in AD, highlighting achievements in early diagnosis and biomarker discovery while discussing limitations and future directions needed to advance these approaches toward clinical application.

The prefrontal cortex (PFC) plays a pivotal role in orchestrating higher-order emotional and cognitive processes, a function that depends on the precise modulation of synaptic activity. Although pharmacological studies have demonstrated that dopamine signaling through dopamine D1 receptor (DRD1) in the PFC is essential for these functions, the cell-type-specific and molecular mechanisms underlying the neuromodulatory effects remain elusive. Using cell-type-specific knockout mice and patch-clamp recordings, we investigated the regulatory role of DRD1 on neurons and astrocytes in synaptic transmission and plasticity. Furthermore, we explored the mechanisms by which DRD1 on astrocytes regulate synaptic transmission and plasticity at the cellular level, as well as emotional and cognitive functions at the behavioral level, through two-photon imaging, microdialysis, high-performance liquid chromatography, transcriptome sequencing, and behavioral testing. We found that conditional knockout of the Drd1 in astrocytes (CKO^AST) increased glutamatergic synaptic transmission and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC), whereas Drd1 deletion in pyramidal neurons did not affect synaptic transmission. The elevated level of d-serine in the mPFC of CKO^AST mice increased glutamatergic transmission and LTP through NMDA receptors. In addition, CKO^AST mice exhibited abnormal emotional and cognitive function. Notably, these behavioral changes in CKO^AST mice could be reversed through the administration of d-serine degrease to the mPFC. These results highlight the critical role of the astrocytic DRD1 in modulating mPFC synaptic transmission and plasticity, as well as higher brain functions through d-serine, and may shed light on the treatment of mental disorders.

Objective:To develop and validate a deep learning-based multimodal model integrating clinical and radiomic features for predicting acute kidney injury（AKI）risk after partial nephrectomy.Methods:A retrospective analysis was conducted on 416 patients who underwent partial nephrectomy at Zhongshan Hospital，Fudan University from January 2023 to January 2025. The cohort included 100 AKI patients［defined by a ≥ 25% reduction in postoperative evaluated glomerular filtration rate（eGFR）within 48 hours sustained for >24 hours］and 316 non-AKI patients（1∶3 ratio，randomly matched with 16 additional cases for redundancy）. Clinical and radiomic features were extracted from preoperative contrast-enhanced CT scans using PyRadiomics. Demographics included 259 males and 158 females，with a median age of 57（49，65）years，body mass index of（24.1 ± 3.3）kg/m2，preoperative eGFR of（88.5 ± 18.3）ml/（min·1.73 m2），postoperative eGFR（48-hour）of（76.0 ± 21.9）ml/（min·1.73 m2），Zhongshan Score（ZSscore）of 7.34 ± 2.01，and R.E.N.A.L. score of 7.50 ± 1.71. All tumors were T 1a stage. Patients were divided into training（n = 312）and test（n = 104）sets（3∶1 ratio）. A clinical model was constructed via multivariate logistic regression，while radiomic and combined（clinical + radiomic）models utilized an artificial neural network（ANN）with 1 input layer，5 hidden layers，1 output layer，and 10 5 training epochs. Model performance was evaluated by using receiver operating characteristic（ROC）curves and area under the curve（AUC），and was compared to the Martini model. Feature contributions were interpreted via SHapley Additive exPlanations（SHAP）. Results:In the test set，the results of multivariate logistic regression showed that patient’s weight，preoperative eGFR，R.E.N.A.L. score，surgical approach，and operation time were risk factors for AKI（ P < 0.05）. The AUC of the clinical feature prediction model constructed based on the above factors was 0.852（95% CI 0.775?0.929）. In the test set，the AUC of the Martini model was 0.725（95% CI 0.565?0.791）. The radiomic model，trained on 1 315 imaging features，achieved an AUC of 0.898（95% CI 0.804?0.993）with 94.2%（98/104）accuracy. The combined clinical and radiomic model，integrating 1 315 radiomic features and clinical features，demonstrated superior performance with an AUC of 0.946（95% CI 0.887?1.000）and 96.2%（100/104）accuracy，outperforming both the clinical model（ P = 0.03）and the Martini model（ P < 0.01）. SHAP analysis identified the top five predictors in the combined model：ZSscore（SHAP value：0.78），long-run low gray-level emphasis（SHAP value：0.61），run-length non-uniformity（SHAP value：0.58），size-zone non-uniformity（SHAP value：0.46），and gray-level co-occurrence matrix joint energy（SHAP value：0.36）. Conclusions:The deep learning-based multimodal model integrating clinical and radiomic features accurately predicts AKI risk after partial nephrectomy，offering a novel strategy for preoperative risk stratification and personalized intervention.

Objective:To investigate the spatial distribution patterns of local tumor progression（LTP）after microwave ablation（MWA）for colorectal liver metastases（CRLMs）and identify high-risk progression zones.Methods:A total of 471 CRLM lesions from 246 patients treated with MWA at the Chinese PLA General Hospital between September 2009 and March 2022 were retrospectively analyzed. Three-dimensional visualized MRI image fusion technology was employed to evaluate the spatial relationship between ablation margins（AM）and LTP. The liver was partitioned into nine specific anatomical regions. Machine learning（Boruta algorithm）was used to assess the importance of these regions on LTP risk. Multivariate analysis of LTP was performed at the tumor level and at the patient level using the Cox mixed effects model and the Cox regression model，respectively.Results:LTP occurred in 115 lesions，with an LTP rate of 40.0%（80/200）in ablated lesions which were located in the high-risk progression area，and 12.9%（35/271）in low-risk progression area. Multivariate analysis identified AM < 5 mm，tumor size ≥3 cm and location in high-risk zones as independent risk factors for LTP. Notably，LTP in high-risk zones predominantly clustered around the ablation needle tip.Conclusions:Post-MWA LTP in CRLMs exhibits distinct spatial clustering，particularly at the needle tip within high-risk progression zones. These findings provide critical insights for optimizing ablation strategies and improving clinical outcomes.

Liver transplantation is the preferred treatment for cirrhosis, end-stage liver failure, and hepatocellular carcinoma, and is also the only effective curative method. Liver ischemia-reperfusion injury (IRI) is one of the main adverse reactions of liver transplantation. During the operation, ischemia mediates the occurrence of liver IRI, promoting the cascade activation of reactive oxygen species and pro-inflammatory signals in Kupffer cells. With continued hepatocellular death during ischemia, damage-associated molecular patterns (DAMPs) accumulate and are released into systemic circulation, triggering a cytokine and chemokine storm, resulting in poor prognosis, postoperative liver failure, systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS). In liver transplantation-related IRI, PANoptosis—including apoptosis, pyroptosis, necroptosis, ferroptosis, and autophagy—participates in the process, but a comprehensive review is lacking. This article systematically elaborates on the roles of different types of cell death in liver IRI and the crosstalk among these pathways. It also discusses the protective effects of inhibiting different forms of cell death, aiming to provide direction for future basic research and offer new ideas and strategies for the clinical treatment of liver IRI.

AIM:To investigate the immunosuppressive effects of M2-like tumor-associated macrophages(M2-TAMs)on CD8+T cells within the tumor microenvironment of esophageal cancer.METHODS:Multiplex fluores-cence immunohistochemistry was used to analyze the distribution of immune cells in esophageal cancer tissues.An in vitro co-culture system was established,and flow cytometry along with Calcein-AM/PI staining was employed to assess the im-pact of M2-TAMs on CD8+T cell function.The GEPIA database was utilized to evaluate the prognostic significance of PDCD1 expression in esophageal cancer patients and to analyze the correlations between gene expressions.Immunohisto-chemistry(IHC)was performed to detect the expression of TGF-β1 in esophageal cancer tissues.Flow cytometry and en-zyme-linked immunosorbent assay(ELISA)were used to measure PD-1,IFN-γ and TNF-α expression in CD8+T cells fol-lowing treatment with a TGF-β1 inhibitor.RESULTS:Compared with early-stage(stage I)esophageal cancer patients,the patients with advanced disease(stages Ⅱ to Ⅳ)exhibited dynamic changes in the infiltration of CD4+T cells,CD8+T cells,Tregs,and M2-TAMs within tumor tissues,with significant correlations observed among these cell populations(P<0.05).The distribution of M2-TAMs and Tregs was positively correlated with poor prognosis(P<0.05),while that of CD8+T cells was negatively correlated(P<0.05).In contrast,CD4+T cell infiltration showed no significant association with clinical outcomes(P>0.05).Co-culture of CD8+T cells with M2-TAMs resulted in significant downregulation of CD107a,granzyme B,IFN-γ and TNF-α expression(P<0.01).Additionally,M2-TAM-treated CD8+T cells co-cultured with esophageal cancer cells led to reduced apoptosis of cancer cells.High expression of PDCD1 was significantly associated with poor prognosis(P<0.05),and significant correlations were observed between CD8A and PDCD1 expression,as well as between TGF-β1 and CD274 gene expression(P<0.01).TGF-β1 was also significantly associated with CD163+macro-phage infiltration and the progression of esophageal cancer(P<0.05).Treatment with a TGF-β1 inhibitor in the M2-TAM and CD8+T cell co-culture system significantly down-regulated PD-1 expression and increased the secretion of IFN-γ and TNF-α(P<0.01).CONCLUSION:The TGF-β1 derived from M2-TAMs inhibits the antitumor activity of CD8+T cells in the esophageal cancer microenvironment,suggesting potential therapeutic targets for overcoming immunosuppression in esophageal cancer.

Dendrobium is the largest genus of the Orchidaceae family.The fresh and dried stems of many species of this genus have been used as Shihu(Dendrobii Caulis)in traditional Chinese medicine,it is known as the foremost of the"Nine Great Herbs of China".Ancient texts highlight its uses for"strengthening yin,enhancing essence,nourishing the five viscera,alleviating fatigue,and dispelling skin heat and prickly heat".Modern research confirms that the polysaccharides and alkaloids it contains have antiviral ef-fects,it can apply in treating immunodeficiency caused by viral infections clinically.While studies are gradually uncovering the antivi-ral mechanisms and material basis of Dendrobium,the lack of systematic analysis and organization has hindered its resource develop-ment.The paper employed CiteSpace software for bibliometric analysis of Chinese and English literature on Dendrobium.It reviewed the herbalism,material basis,and mechanisms of its antiviral properties building upon the systematic review of ancient materia medica and modern literature.Results indicate that Dendrobium can boost vital energy and resist pathogens,showing great potential in antiviral drug development.

AIM:To investigate the immunosuppressive effects of M2-like tumor-associated macrophages(M2-TAMs)on CD8+T cells within the tumor microenvironment of esophageal cancer.METHODS:Multiplex fluores-cence immunohistochemistry was used to analyze the distribution of immune cells in esophageal cancer tissues.An in vitro co-culture system was established,and flow cytometry along with Calcein-AM/PI staining was employed to assess the im-pact of M2-TAMs on CD8+T cell function.The GEPIA database was utilized to evaluate the prognostic significance of PDCD1 expression in esophageal cancer patients and to analyze the correlations between gene expressions.Immunohisto-chemistry(IHC)was performed to detect the expression of TGF-β1 in esophageal cancer tissues.Flow cytometry and en-zyme-linked immunosorbent assay(ELISA)were used to measure PD-1,IFN-γ and TNF-α expression in CD8+T cells fol-lowing treatment with a TGF-β1 inhibitor.RESULTS:Compared with early-stage(stage I)esophageal cancer patients,the patients with advanced disease(stages Ⅱ to Ⅳ)exhibited dynamic changes in the infiltration of CD4+T cells,CD8+T cells,Tregs,and M2-TAMs within tumor tissues,with significant correlations observed among these cell populations(P<0.05).The distribution of M2-TAMs and Tregs was positively correlated with poor prognosis(P<0.05),while that of CD8+T cells was negatively correlated(P<0.05).In contrast,CD4+T cell infiltration showed no significant association with clinical outcomes(P>0.05).Co-culture of CD8+T cells with M2-TAMs resulted in significant downregulation of CD107a,granzyme B,IFN-γ and TNF-α expression(P<0.01).Additionally,M2-TAM-treated CD8+T cells co-cultured with esophageal cancer cells led to reduced apoptosis of cancer cells.High expression of PDCD1 was significantly associated with poor prognosis(P<0.05),and significant correlations were observed between CD8A and PDCD1 expression,as well as between TGF-β1 and CD274 gene expression(P<0.01).TGF-β1 was also significantly associated with CD163+macro-phage infiltration and the progression of esophageal cancer(P<0.05).Treatment with a TGF-β1 inhibitor in the M2-TAM and CD8+T cell co-culture system significantly down-regulated PD-1 expression and increased the secretion of IFN-γ and TNF-α(P<0.01).CONCLUSION:The TGF-β1 derived from M2-TAMs inhibits the antitumor activity of CD8+T cells in the esophageal cancer microenvironment,suggesting potential therapeutic targets for overcoming immunosuppression in esophageal cancer.