It is proposed that cold qi-induced accumulation encapsulates the core pathogenesis of the inflammation-cancer transformation in inflammatory bowel disease （IBD）. Cold pathogens may serve as the initiating factor. When first invading the intestines， cold pathogens obstruct the flow of qi； over time， the lingering cold impairs the middle jiao （焦）， eventually leading to the accumulation of cold-phlegm and blood stasis. Based on the progressive nature of this transformation， the process can be divided into three stages， active stage， remission stage， and carcinogenic stage. In the active stage， the main pathogenesis involves stagnation of cold qi and accumulation of damp-heat in the intestines； in the remission stage， cold qi impairs the spleen， disrupting its transport and transformation functions； and in the carcinogenic stage， the mechanisms include cold-induced accumulation， phlegm accumulation from cold， and stagnation of cold and blood stasis. Accordingly， the treatment strategies are proposed.In the active stage， regulating qi， relieving stagnation， and harmonizing cold and heat； in the remission stage， warming yang， dispersing cold， tonifying qi， and strengthening the spleen； and in the carcinogenic stage， promoting qi circulation， dispersing cold， resolving phlegm， activating yang， and eliminating stasis to remove accumulation. These approaches aim to interrupt the transformation of IBD into colorectal cancer.

Sennoside A (SA), a typical prodrug, exerts its laxative effect only after its transformation into rheinanthrone catalyzed by gut microbial hydrolases and reductases. Hydrolases have been identified, but reductases remain unknown. By linking a photoreactive group to the SA scaffold, we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling (ABPP). From lysates of an active strain, Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), 397 proteins were enriched and subsequently identified using mass spectrometry (MS). Among these proteins, chromate reductase/nicotinamide adenine dinucleotide (NADH) phosphate (NADPH)-dependent flavin mononucleotide (FMN) reductase/oxygen-insensitive NADPH nitroreductase (nfrA) was identified as a potent SA reductase through further bioinformatic analysis and The Universal Protein Resource (UniProt) database screening. We also determined that recombinant nfrA could reduce SA. Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.

Myocardial infarction (MI) is the leading cause of cardiovascular disease-related death worldwide. Nonetheless, existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and suboptimal patient adherence. Caffeic acid (CA) is a bioactive polyphenolic compound with important anti-inflammatory, anti-bacterial and anti-oxidant functions. Still, its specific role and mechanism in treating cardiovascular disease remain to be further studied. In recent years, a large number of studies have shown that the kelch-like ECH-associated protein 1/nuclear factor erythroid 2 related factor 2 (Keap1/Nrf2) pathway is a key factor in the occurrence and development of cardiovascular diseases. In this study, H₂O₂-induced oxidative stress model of H9c2 cells and left anterior descending branch (LAD) conjunctival induced acute myocardial infarction reperfusion (AMI/R) model were used to evaluate the protective effect of CA on the heart. The interaction between CA and Keap1 was analyzed by CA-labeled fluorescence probe, target fishing, isothermal titration calorimetry (ITC), protein crystallography and surface plasmon resonance (SPR). Our results suggested that CA binds Keap1 and degrades Keap1 in a p62-dependent manner, further promoting nuclear transcription of Nrf2 and thus effectively reducing oxidative stress. In addition, based on the three-dimensional eutectic structure, it was confirmed that CA directly targets Keap1 protein by interacting with residues M550 and N532, inducing conformation changes in Keap1 protein. We also found that the CA analog chlorogenic acid (GCA) can bind Keap1. In conclusion, this study elucidates a novel molecular mechanism and structural basis for the protective effects of CA against oxidative damage via the Keap1-Nrf2 pathway.

Objective:This multicenter retrospective study aimed to analyze the clinicopathological features of duodenal adenocarcinoma (DA) and identify prognostic factors for postoperative survival.Methods:Demographic characteristics, clinicopathological features, treatment outcomes and survival of DA patients undergoing surgical treatment at 18 Chinese medical centers from January 2012 to December 2023 were retrospectively analyzed.Results:Among the 2 056 DA patients included, 46.8% (963) had extra-ampullary DA (EA-DA), and 53.2% (1 093) had peri-ampullary DA (PA-DA). The 1-, 3-, and 5-year overall survival (OS) rates for patients who underwent radical surgery were 93.2%, 71.0%, and 57.2%, respectively. The median overall survival was 76 months, and the median progression-free survival (PFS) was 65 months. No differences in survival were observed between the laparotomy group and minimally invasive surgery (MIS) group either before or after propensity score matching (OS: 76 vs. 75 months before PSM, P=0.986; OS: 75 vs. 75 months after PSM, P=0.602). Furthermore, there were no significant differences between-group in operation time and postoperative complications ( P＞0.05). The MIS group experienced less intraoperative blood loss and shorter hospital stays. The multivariate Cox regression analysis revealed that advanced age ( HR=1.43,95% CI:1.18-1.73), elevated carbohydrate antigen 19-9 levels ( HR=1.24,95% CI:1.02-1.51), perineural invasion ( HR=1.44,95% CI:1.14-1.81), vascular invasion ( HR=1.35,95% CI:1.07-1.71), advanced T stage (T3-4 vs. T1-2: HR=1.86,95% CI:1.49-2.31), regional lymph node metastasis ( HR=1.93,95% CI:1.58-2.36), preoperative biliary drainage ( HR=1.26,95% CI:1.04-1.53), intraoperative blood loss ( HR=1.34,95% CI:1.11-1.62), clinically significant postoperative pancreatic fistulas ( HR=1.53,95% CI:1.12-2.09), and postoperative hemorrhage ( HR=1.62,95% CI:1.14-2.29) were independent risk factors for poor prognosis after surgery (all P＜0.05). Conclusions:Radical surgery is associated with favorable overall survival among DA patients, and no difference in survival is observed between EA-DA and PA-DA patients. MIS is a reliable alternative for DA treatment.

Objective To analyze the expression levels of TIPE2 and Ki67 in endometrial carcinoma(EC)and their relationship with clinicopathological parameters and prognosis.Methods Tissue samples and clinical data of 96 patients with EC who underwent surgical resection,120 patients who underwent total hysterec-tomy due to uterine fibroids and 120 patients who underwent total hysterectomy or curettage admitted to our hospital from February 2020 to February 2022 were retrospectively collected as the research objects,which were divided into the EC group,the normal endometrial group and the atypical hyperplasia endometrial group,respectively.All 3 groups were followed up until March 28,2023.Immunohistochemistry was used to detect the expression levels of TIPE2 and Ki67 in tissue samples of the three groups,and to analyze the relationship between the levels of TIPE2 and Ki67 and clinicopathological parameters and prognosis.Receiver operating characteristic curve(ROC)was used to analyze its diagnostic value for poor prognosis.Results The expression levels of TIPE2 and Ki67 in cancer tissues of the EC group were higher than those of the normal endometrial group and the atypical hyperplasia endometrial group,and those of the atypical hyperplasia endometrial group were higher than those of the normal endometrial group(P<0.05).The expression levels of TIPE2 and Ki67 in EC tissues were higher in patients with FIGO stage Ⅲ,lymph node metastasis,postmenopausal status,and ER and PR negative than patients with stageⅡ,no lymph node metastasis,premenopausal status,and ER and PR positive(P<0.05).Moreover,the expres-sion level of Ki67 in EC tissues was higher in p53 positive patients than in p53 negative patients(P<0.05),and there was a positive correlation between the both expression levels of TIPE2 and Ki67 in EC tissues(r=0.569,P<0.05).Compared with the poor prognosis group,the expression levels of TIPE2 and Ki67 in EC tissues in the good prognosis group were downregulated(P<0.05),and the AUC value of the combined detection of TIPE2 and Ki67 expression levels was 0.905,which was significantly higher than that of the single detection(P<0.05),sensitivity was 86.67%and specificity was 87.88%,and the predictive value was higher.Conclusion TIPE2 and Ki67 were highly expressed in EC tissues,and there was a positive correlation between the two,and their high expressions were related to clinicopathological features,and their combined detection had high predictive value for poor prognosis of EC.

Objective:To develop and validate machine learning models for predicting the cumulative live birth rate (CLBR) following in vitro fertilization (IVF) and to analyze key predictive features using SHAP values. Methods:This retrospective study included data from patients who underwent IVF-embryo transfer at the Department of Reproductive Medicine, Baoding Maternal and Child Health Hospital, between January 2017 and December 2022. Patients were categorized into two groups based on live birth outcome: the live birth group ( n=1 036) and the non-live birth group ( n=756). The dataset was randomly divided into a training set and a validation set in a ratio of 7∶3. Five algorithms were utilized for model development: logistic regression, random forest, extreme gradient boosting (XGBoost), support vector machine, and neural networks. Model performance was assessed using the area under the receiver operating characteristic (AUC) curve, F1 score, and calibration curves. Clinical decision curve analysis (DCA) was employed to evaluate the clinical utility of the models. SHAP values were used to interpret feature importance in the XGBoost model and enhance its explainability. Results:The XGBoost model demonstrated the best performance in predicting CLBR,with accuracy of 72.44%, AUC of 0.775, and F1 score of 0.654, accuracy and F1 score outperforming logistic regression (accuracy was 70.02%, F1 score was 0.585), random forest (accuracy was 71.69%, F1 score was 0.606), support vector machine (accuracy was 70.20%, F1 score was 0.607), and neural network (accuracy was 68.72%, F1 score was 0.560). The calibration curve of XGBoost closely aligned with the diagonal line, indicating that the predicted probabilities were very close to the actual outcomes, demonstrating good calibration. DCA indicated that the XGBoost model provided higher net benefits across a wide range of clinical decision thresholds. SHAP value analysis identified number of previous IVF failures, antral follicle count, anti-Müllerian hormone level, percentage of normal sperm morphology, and sperm DNA fragmentation index as key predictors of CLBR.Conclusion:The XGBoost model exhibits excellent predictive performance and calibration for CLBR, with SHAP values providing important insights into feature importance. This model has the potential to support the development of personalized treatment strategies in clinical practice. However, its generalizability needs to be validated using external datasets to ensure its applicability to diverse populations.

Objective To investigate the predictive value of pre-transfer serum fibroblast growth factor 21(FGF-21),anti-Müllerian hormone(AMH),and neuropilin-1(NRP-1)for early pregnancy loss at 6 weeks following in vitro fertilization-embryo transfer(IVF-ET),and to establish an early predictive model based on serum biochemical markers.Methods This prospective study consecutively enrolled 322 women who achieved clinical pregnancy after IVF-ET at our center between September 2022 and September 2024.Participants were randomly divided into a modeling cohort(n=225)and a validation cohort(n=97)at a 7:3 ratio.According to ultrasound findings at 6 weeks of gestation,patients in the modeling cohort were classified into an early pregnancy loss group(n=59)and an ongoing pregnancy group(n=166).Baseline clinical characteristics and pre-transfer serum levels of FGF-21,AMH,and NRP-1 were collected.Multivariate logistic regression was applied to identify inde-pendent risk factors for early pregnancy loss and to construct a predictive model.Model discrimination,calibra-tion,and stability were evaluated using receiver operating characteristic(ROC)curves,the Hosmer-Lemeshow goodness-of-fit test,and bootstrap resampling in both cohorts.Results Univariate analysis revealed that the FSH/LH ratio,antral follicle count,and number of retrieved oocytes were significantly associated with early pregnancy loss(P<0.001).Compared with the ongoing pregnancy group,women with early loss showed significantly elevated pre-transfer serum FGF-21 levels,whereas AMH and NRP-1 levels were markedly reduced(P<0.001).Multivariate logistic regression demonstrated that an FSH/LH ratio<1.8(OR=1.629,P=0.002)and higher FGF-21 levels(OR=1.338,P=0.002)were independent risk factors,while higher AMH(OR=0.741,P=0.010)and NRP-1 levels(OR=0.874,P=0.007)were protective.Stratified analysis indicated that among patients with FSH/LH≥1.8,FGF-21 levels were significantly higher and AMH and NRP-1 levels significantly lower(all P<0.001).Interaction analysis further suggested that the FSH/LH ratio significantly modified the associations between these biomarkers and pregnancy loss risk(P for interaction<0.05).Specifically,in the higher FSH/LH subgroup,the risk effect of FGF-21 was amplified,while the protective effects of AMH and NRP-1 were more pronounced.The combined predictive model achieved C-indices of 0.869(95%CI:0.826～0.926)in the modeling cohort and 0.835(95%CI:0.811～0.907)in the validation cohort.Its AUC for predicting early pregnancy loss was 0.934 in the modeling co-hort and 0.909 in the validation cohort,both significantly outperforming individual markers(AUCs:FGF-21=0.867,AMH=0.881,NRP-1=0.853;Z=2.024,1.831;P<0.001).Decision curve analysis showed that the model provided consistent net clinical benefit across threshold probabilities of 0.1～0.4,underscoring its clinical utility.Conclusions Elevated pre-transfer serum FGF-21 and reduced AMH and NRP-1 levels are strongly associ-ated with early pregnancy loss at 6 weeks after IVF-ET.The predictive model developed in this study demonstrates robust accuracy and stability,offering substantial clinical application value for early risk stratification.

Objective To characterize the expression patterns of serum microRNA-497(miR-497)in patients with colorectal cancer(CRC)and to investigate its associations with clinicopathological characteristics,diagnostic performance,and long-term prognostic outcomes.Methods This study retrospectively analyzed data from 122 patients with CRC admitted to the hospital between March 2020 and March 2022(CRC group),and enrolled 100 healthy individuals undergoing routine physical examinations(healthy control group)for comparison.Serum samples were collected from all participants prior to any surgical intervention,and the expression levels of miR-497 in serum were quantified using real-time quantitative polymerase chain reaction(qRT-PCR).Simulta-neously,the levels of carcinoembryonic antigen(CEA)and carbohydrate antigen 199(CA199)were measured.To investigate the association between miR-497 expression and clinicopathological characteristics,we evaluated its diagnostic performance using receiver operating characteristic(ROC)curve analysis.Furthermore,Kaplan-Meier survival analysis and Cox proportional hazards regression models were employed to assess its impact on patient prognosis.Results Compared to healthy individuals,CRC patients exhibited significantly lower serum miR-497 expression levels(P<0.001).Notably,miR-497 expression was strongly correlated with TNM stage progression and lymph node metastasis(P<0.001),but showed no significant association with tumor location,patient sex,or age.Diagnostic evaluation using ROC curves demonstrated that miR-497 achieved an AUC of 0.845 for CRC detection,outperforming CEA(AUC=0.748)and CA19-9(AUC=0.702),with DeLong's test confirming the statistically significant differences(P<0.05).Kaplan-Meier survival analysis revealed a significantly higher 3-year DFS rate among patients with high miR-497 expression(84.06%)compared to those with low expression(64.58%),with median DFS not reached in the high-expression group versus 36 months in the low-expression group(P=0.015).Multivariate Cox regression analysis confirmed that reduced miR-497 expression(HR=1.923,95%CI:1.184～3.125),advanced TNM stage(HR=2.511,95%CI:1.421～4.437),and lymph node metastasis(HR=1.753,95%CI:1.151～2.664)were independently associated with poorer disease-free survival outcomes.Conclusions Serum miR-497 is downregulated in patients with CRC and is significantly associated with tumor progression and poor prognosis.It demonstrates high diagnostic accuracy and strong potential for prognostic evalua-tion,highlighting its promise as a biomarker for auxiliary diagnosis and outcome prediction in CRC.

Objective:To investigate the clinical efficacy and factors influencing treatment of pediatric noninfectious uveitis with Adalimumab (ADA).Methods:A retrospective clinical study. A total of 86 pediatric patients with non-infectious uveitis, diagnosed and treated with ADA at Department of Uveitis Specialist of Xi'an People's Hospital (Xi' an Fourth Hospital) from January 1, 2021 to December 31, 2023, were included in this study. The age of all patients was ≤16 years. Among them, 55 (63.95%, 55/86) patients received ADA combined with one immunosuppressive agent, 28 (32.56%, 28/86) patients received ADA combined with ≥2 immunosuppressive agents, and 3 (3.49%, 3/86) patients received ADA alone without any immunosuppressive agents. All patients underwent best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) examinations. The thickness of the retinal nerve fiber layer (RNFL) in the macular region was measured using an OCT device. The cumulative treatment effectiveness rate at 12 months post-treatment was evaluated using the Kaplan-Meier survival analysis. Multivariate analysis was performed using the Cox proportional hazards regression model, and the optimal predictive model was selected based on the Bayesian information criterion. The association between different treatment regimens and various clinical outcomes was assessed.Results:Among the 86 pediatric patients, 42 were male and 44 were female, with a mean age of (10.47±3.23) years. The distribution of uveitis types was as follows: anterior uveitis in 37 cases, intermediate uveitis in 15 cases, posterior uveitis in 10 cases, and panuveitis in 24 cases. Anterior chamber cells (ACC), keratic precipitates, and synechiae were present in 66, 55, and 38 cases, respectively. The cumulative treatment effectiveness at 12 months was 85.1% [95% confidence interval ( CI) 71.9-92.2], with a median time to treatment effectiveness of 3 months. Compared with baseline, after 6 months of treatment, the BCVA, RNFL thickness ( Z=?6.323, ?8.017), and the grading of ACC and vitreous haze ( χ2= ?6.917, ?5.027) showed significant improvement, with statistically significant differences ( P<0.05). Multivariate analysis revealed that ACC (hazard ratio=22.31, 95% CI 2.43-204.68) and anterior uveitis (hazard ratio=3.88, 95% CI 2.03-7.42) were significantly associated with treatment effectiveness ( P<0.05). Patients with ACC had a median time to treatment effectiveness of 2 months, with a 12-month cumulative treatment effectiveness of 95.5% (95% CI 86.3-98.5). Patients with anterior uveitis had a median time to treatment effectiveness of 2 months, with a 12-month cumulative treatment effectiveness of 97.3% (95% CI 81.3-99.6). Patients without anterior uveitis had a median time to treatment effectiveness of 5 months, with a 12-month cumulative treatment effectiveness of 76.7% (95% CI 54.1-88.2). The cumulative recurrence risk at 12 months was 15.6% (95% CI 6.2-24.1). Conclusion:ADA is safe and effective in treating pediatric non-infectious uveitis, and ACC and anterior uveitis are associated with response rate.

The aim of this study is to explore the immunogenicity of African swine fever virus p37 recombinant protein in mice.C57BL/6J mice were immunized subcutaneously in the abdomen using p37 recombinant protein as antigen.The second immunization was performed 21 d after the first immunization.Serum-specific antibody levels were detected by ELISA;serum cytokine levels were detected using a multifactor assay technique;mice splenic lymphocytes were isolated 7 d after sec-ondary immunization,and the number of splenic lymphocytes secreting IFN-γ after recombinant protein stimulation was detected by ELISpot;and the ratio of CD4+T cells to CD8+T cells was detected by flow cytometry.The results of indirect ELISA showed that p37 recombinant protein could stimulate mice to produce high levels of specific antibodies;ELISpot showed that p37 recom-binant protein could significantly stimulate splenic lymphocytes to produce IFN-γ(P＜0.001)and activate cellular immune responses;the results of flow cytometry showed that it could signifi-cantly stimulate the differentiation of T-lymphocytes to CD4+T-lymphocytes(P＜0.001).In ad-dition,serum levels of IL-2,IL-4,IFN-γ,and TNF-α immune-related cytokines were significantly higher after the second immunization.Immunization of mice with p37 recombinant protein induced strong humoral and cellular immune responses with good immunogenicity,providing reference for the subsequent epitope identification and functional study of p37 protein and the antigen screening of ASF mRNA vaccine.