OBJECTIVE: To investigate the effects of sodium valproate (VPA) in inhibiting Erastin-induced ferroptosis in bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanisms. METHODS: BMSCs were isolated from bone marrow of 8-week-old Spragur Dawley rats and identified [cell surface antigens CD90, CD44, and CD45 were analyzed by flow cytometry, and osteogenic and adipogenic differentiation abilities were assessed by alizarin red S (ARS) and oil red O staining, respectively]. Cells of passage 3 were used for the Erastin-induced ferroptosis model, with different concentrations of VPA for intervention. The optimal drug concentration was determined using the cell counting kit 8 assay. The experiment was divided into 4 groups: group A, cells were cultured in osteogenic induction medium for 24 hours; group B, cells were cultured in osteogenic induction medium containing optimal concentration Erastin for 24 hours; group C, cells were cultured in osteogenic induction medium containing optimal concentration Erastin and VPA for 24 hours; group D, cells were cultured in osteogenic induction medium containing optimal concentration Erastin and VPA, and 8 μmol/L EX527 for 24 hours. The mitochondrial state of the cells was evaluated, including the levels of malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS). Osteogenic capacity was assessed by alkaline phosphatase (ALP) activity and ARS staining. Western blot analysis was performed to detect the expressions of osteogenic-related proteins [Runt-related transcription factor 2 (RUNX2) and osteopontin (OPN)], ferroptosis-related proteins [glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11)], and pathway-related proteins [adenosine monophosphate-activated protein kinase (AMPK) and Sirtuin 1 (SIRT1)]. RESULTS: The cultured cells were identified as BMSCs. VPA inhibited Erastin-induced ferroptosis and the decline of osteogenic ability in BMSCs, acting through the activation of the AMPK/SIRT1 pathway. VPA significantly reduced the levels of ROS and MDA in Erastin-treated BMSCs and significantly increased GSH levels. Additionally, the expression levels of ferroptosis-related proteins (GPX4, FTH1, and SLC7A11) significantly decreased. VPA also upregulated the expressions of osteogenic-related proteins (RUNX2 and OPN), enhanced mineralization and osteogenic differentiation, and increased the expressions of pathway-related proteins (AMPK and SIRT1). These effects could be reversed by the SIRT1 inhibitor EX527. CONCLUSION VPA inhibits ferroptosis in BMSCs through the AMPK/SIRT1 axis and promotes osteogenesis.
Mesenchymal Stem Cells/metabolism* ; Ferroptosis/drug effects* ; Animals ; Valproic Acid/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Sirtuin 1/metabolism* ; Cell Differentiation/drug effects* ; Cells, Cultured ; AMP-Activated Protein Kinases/metabolism* ; Osteogenesis/drug effects* ; Piperazines/pharmacology* ; Bone Marrow Cells/cytology* ; Reactive Oxygen Species/metabolism* ; Signal Transduction/drug effects*

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

To achieve the goal of"eliminating viral hepatitis as a public health hazard by 2030",extensive screening,active prevention,and antiviral therapy are currently recommended for chronic hepatitis B virus(HBV)infection;however,no consensus has been reached on whether to initiate antiviral therapy for patients in the immune-tolerant phase of chronic HBV infection.Some experts believe that patients in the immune-tolerant phase tend to have a stable liver immune microenvironment,with a low risk of disease progression and poor response to treatment,and thus it is not recommended to initiate antiviral therapy.However,various other studies have shown that patients in the immune-tolerant phase still have inflammatory damage in the liver,with a risk of disease progression and a high level of cost effectiveness,and therefore,some experts suggest that antiviral therapy should be actively initiated for patients in the immune-tolerant phase.This article performs a literature review of the definition of patients in the immune-tolerant phase of chronic HBV infection and the advantages and disadvantages of antiviral therapy and conducts a preliminary analysis based on previous studies,in order to accumulate the evidence for whether to initiate antiviral therapy in the immune-tolerant phase of chronic HBV infection and lay a foundation for standardized clinical diagnosis and treatment of patients in the immune-tolerant phase.

Objective To determine the scores of patients with a confirmed diagnosis of drug-induced liver injury(DILI)using Roussel Uclaf Causality Assessment Method(RUCAM),Maria&Victorino assessment scale,and Revised Electronic Causality Assessment Method(RECAM),to compare the accuracy of the three scales in diagnosis,and to investigate their clinical significance in the diagnosis of DILI.Methods A total of 98 patients with a confirmed diagnosis of DILI who were hospitalized in Peking University First Hospital from January 2011 to December 2022 were enrolled,with liver biopsy results supporting DILI and a clear history of medication.Clinical data were collected from all subjects,and the above causality assessment scales were used for scoring.The chi-square test was used to analyze the diagnostic accuracy of the causality assessment scales,and the weighted kappa coefficient was used to analyze the consistency between the three scales.Results For all patients with DILI enrolled,RECAM had the highest accuracy,with a significant difference compared with RUCAM(χ2=5.667,P=0.017).RUCAM and RECAM had moderate consistency in diagnosis(κw=0.469),while RECAM and Maria&Victorino scale had poor consistency(κw=0.156).For the patients with acute DILI,RECAM,RUCAM,and Maria&Victorino scales had a diagnostic inconsistency rate of 3.7%,11.1%,and 42.6%,respectively;for the patients with hepatocellular type DILI,the three scales of a diagnostic inconsistency rate of 8.9%,21.4%,and 62.5%,respectively;for the patients with cholestasis type or mixed type DILI,the three scales of a diagnostic inconsistency rate of 10.0%,22.5%,and 47.5%,respectively.Conclusion The use of RECAM and RUCAM scales in acute DILI can improve diagnostic rate,and for hepatocellular type DILI and DILI with the clinical manifestation of cholestasis(cholestasis type DILI and mixed type DILI),the use of RECAM and RUCAM scales can also improve diagnostic rate.The selection of causality assessment scales with a relatively high accuracy based on the course and clinical classification of the disease may help to further improve clinical diagnostic rate.

With the continuous advancement of technology and the increasing understanding of metastatic renal cell carcinoma(mRCC),the treatment paradigm of mRCC has undergone significant transformation.Currently,in addition to surgery,mRCC is mainly treated with targeted therapy and immunotherapy,which have shown significant efficacy but also face challenges such as drug resistance and non-responsiveness persist.To address these issues,ongoing research and development of new technologies and drugs are under way.This article presents a comprehensive review of targeted therapy,immunotherapy,exploratory therapeutic options and treatment trends of mRCC.By summarizing the differences in technological principles and patient populations,it is argued that combination therapy and precision medicine will become the primary directions for future developments.Subsequent research will focus on optimizing the synergistic integration of diverse therapeutic techniques and achieving more precise patient stratification to realize more effective treatment.

Objective:To explore the influence of social exclusion on the relapse tendency of female drug re-hab patients,and the mediating role of self-esteem and the moderating role of positive psychological capital.Method:A total of 288 female drug rehabilitation patients were selected,and the Social Exclusion Question-naire(SEQ)was used to assess the degree of social exclusion experienced by the patients.The Relapse Tendency Questionnaire(RPQ)was used to evaluate the current tendency of drug relapse.The Rosenberg Self-Esteem Scale(RSES)was used to evaluate the self-esteem level of the patients,and the Positive Psychological Capital Question-naire(PPCQ)was used to evaluate their level of positive psychological capital.Results:The SEQ scores of female drug rehab patients were positively correlated with the RPQ scores(β=0.41,P＜0.001),The RSES scores had a mediating effect between the scores of SEQ and RPQ,with a mediation effect size of 0.09(95％CI:0.04-0.15,accounting for 20.6％of the total effect).The PPCQ scores had a moderating effect between the scores of RSES and RPQ(β=-0.08,P＜0.05)and between the scores of SEQ and RPQ(β=0.10,P＜0.05).Conclusion:So-cial exclusion could not only directly affect but also indirectly affect the relapse tendency through self-esteem of fe-male drug rehab patients.Positive psychological capital could moderate the relationship between social exclusion,self-esteem,and relapse tendency.

Objective:To investigate the characteristics of spatiotemporal heterogeneity in pathological grading during the latent and invas-ive growth phases of non-metastatic renal cell carcinoma(RCC)and its correlation with clinical outcomes.Methods:A retrospective analysis was conducted on the case data of 316 RCC patients with local recurrence(LR)and 429 RCC patients with venous tumor thrombus(VTT)who underwent surgical treatment at 13 medical centers in China from January 2003 to December 2023.Pathological grade differences between primary tumor(PT)and LR,and between PT and VTT were selected as scenarios for the application of spatiotemporal heterogen-eity in the dynamic progression of RCC.Pathological grading changes were defined according to a new four-tier scheme(upgrading,down-grading,stable low-grade,and stable high-grade).Stable low-or high-grade was defined as low-grade(WHO/ISUP grade Ⅰ or Ⅱ)or high-grade(WHO/ISUP grade Ⅲ or Ⅳ)in both PT and LR/VTT.Upgrading was defined as low-grade in the PT and high-grade in the LR/VTT;con-versely,downgrading was defined as high-grade in the PT and low-grade in the LR/VTT.The potential influencing factors of pathological grading changes and their impact on patient prognosis were analyzed.Results:The median cancer-specific survival(CSS)for RCC patients with VTT and RCC patients with LR was 83 months and 76 months,respectively.The 5-year CSS rates were 65.6%and 60.6%,respectively.Pathological grading changes were observed in 38.0%of patients with PT and VTT and in 43.6%of patients with PT and LR.Lasso-Logistic re-gression analysis revealed a close correlation between primary tumor necrosis and pathological grading changes.Kaplan-Meier survival curves indicated a significant correlation between pathological grading changes and prognosis.Replacing the pathological grading in Leibovich,UISS,and GRANT scores with pathological grading changes significantly improved the predictive performance of the models(P<0.05).Conclusions:Spatiotemporal heterogeneity in pathological grading exists during the dynamic progression of non-metastatic RCC.Compared to the pathological grading of isolated events,the spatiotemporal variation in pathological grading serves as a more accurate in-dependent prognostic factor for RCC patients with VTT and RCC patients with LR.Incorporating pathological grading changes can signific-antly improve the predictive performance of existing prognostic models.

Objective:To compare the therapeutic effects of partial nephrectomy (PN) and cryoablation (CA) in patients with stage cT 1N 0M 0 renal cell carcinoma (RCC). Methods:A retrospective analysis was conducted on clinical data of patients with stage cT 1N 0M 0 RCC who underwent CA and PN treatment at The First Affiliated Hospital of Naval Medical University and Shanghai Ninth People's Hospital between March 2011 and December 2019. There were 50 cases in the CA group (36 from The First Affiliated Hospital of Naval Medical University and 14 from the Shanghai Ninth People's Hospital), and 1 323 cases in the PN group (all from The First Affiliated Hospital of Naval Medical University). PN included open surgery, laparoscopic surgery, or robotic surgery performed under general anesthesia through the abdominal or retroperitoneal approach. CA included laparoscopic surgery under general anesthesia and percutaneous treatment guided by CT or ultrasound under local anesthesia. Propensity score matching was performed based on baseline data of the patients to obtain balanced samples between the two groups using a 1∶2 nearest-neighbor matching method. After matching, comparisons were made between the two groups in terms of perioperative conditions, overall survival (OS), and recurrence-free survival (RFS). Results:After PSM, patient distributions were closely balanced in baseline data such as gender (male/female: 28/19 cases in CA group and 58/36 cases in PN group), age [66.0(53.0, 75.0) years vs. 59.5(50.0, 69.3) years], body mass index[ (24.1 ± 6.4) kg/m 2 vs. (24.1 ± 3.1) kg/m 2], Charlson comorbidity index [1(0, 2) vs. 1(0, 2)], history of malignant tumors [19.1% (9/47) vs. 17.0% (16/94)], preoperative estimated glomerular filtration rate (eGFR) [85.2(65.5, 97.1) ml/(min·1.73m 2) vs. 87.0(73.4, 100.4) ml/(min·1.73m 2)], and R. E.N.A.L. score [6(5, 7) vs. 7(6, 8)] between CA(n=47) and PN(n=94) group. There were significant differences in operative time [97.5(81.2, 117.5) min vs. 145.0(110.2, 185.0) min, P<0.001], estimated blood loss [85.0(50.0, 100.0) ml vs. 100.0(75.0, 200.0)ml, P=0.021], length of hospital stay [3.0(2.0, 4.0) days vs. 7.6(5.0, 9.0) days, P<0.001] between the CA and the PN group. No significant differences were observed in the incidence of postoperative complications [4.3% (2/47) vs. 5.3% (5/94), P=0.784], the eGFR within one week after surgery [83.7(65.6, 106.6) ml/(min·1.73m 2) vs. 83.2(66.7, 97.7) ml/(min·1.73m 2), P=0.645], the median follow-up time [ 93 (67, 126) months vs. 85 (68, 139) months, P=0.955], the RFS rate[81.8% vs. 96.8%, P=0.074], or the OS rate [85.7% vs. 97.8%, P=0.190] between the CA and the PN group. Conclusions:For patients with cT 1N 0M 0 stage RCC, CA and PN demonstrate comparable oncologic treatment efficacy, while CA offering the advantages of shorter surgical time, shorter hospital stay, and less blood loss.

Focal therapy for renal cell carcinoma is a precision treatment technique that directly targets and destroys cancerous lesions while preserving the maximum amount of surrounding healthy kidney tissue through localized intervention. It is primarily indicated for early-stage renal cell carcinoma in patients with tumors ≤4 cm in diameter (T 1a), particularly for those at higher surgical risk. Compared to traditional radical nephrectomy and partial nephrectomy, focal therapy offers several advantages, including lower physical demands on the patient, minimally invasive nature, reduced risk of complications, and faster recovery. The focal therapy techniques currently utilized in clinical practice include cryoablation, radiofrequency ablation, microwave ablation, irreversible electroporation, high-intensity focused ultrasound, and stereotactic body radiotherapy. This article reviews the principles of various focal therapy techniques, patient selection, and the oncological outcomes, complications, and renal function preservation associated with these focal therapies.

Objective To analyze the characteristics of time in range(TIR)and its relationship with oxidative stress(OS)and insulin resistance status(HOMA-IR)in patients with type 2 diabetes mellitus(T2DM)and sleep apnea-hypopnea syndrome(OSAHS).Methods According to apnea-hypopnea index(AHI),165 T2DM in patients were divided into simple T2DM group(AHI<5 times/h,n=43),T2DM combine OSAHS mild group(OSAHS-G,5≤AHI<15 times/h,n=51),T2DM combined OSAHS moderate group(OSAHS-M,15≤AHI≤30 times/h,n=40)and T2DM combine OSAHS severe group(OSAHS-S,AHI>30 times/h,n=31).TIR was calculated by dynamic blood glucose monitoring.Superoxide dismutase(SOD),glutathione peroxidase(GSH-Px)and other indexes were detected and analyzed.Results Compared with simple T2DM group,the levels of HOMA-IR,8-iso-PGF2a and Ox-LDL were higher in T2DM combined OSAHS-G,OSAHS-M or OSAHS-S group,while the levels of TIR,SOD and GSH-Px were lower(P<0.05).Pearson correlation analysis showed that TIR was positively correlated with the levels of SOD and GSH-Px(P<0.05 or P<0.01),and negatively correlated with the levels of 8-iso-PGF2a,Ox-LDL,HbA1c,HOMA-IR and the severity of OSAHS(P<0.01).Logistic regression analysis showed that TIR,SOD and GSH-Px were protective factors for severe OSAHS in T2DM patients,while 8-iso-PGE2a and Ox-LDL were the risk factors for severe OSAHS.Conclusions The glucose level fluctuates greatly in patients with T2DM and OSAHS.Insulin resistance and oxidative stress are factors that affect the normalization of TIR.