BackgroundNegative symptoms of schizophrenia impose a substantial burden on society， and the current antipsychotic drugs have limited efficacy in treating these symptoms. Intermittent theta burst stimulation （iTBS）， as a novel neuromodulation technique， shows potential therapeutic promise. However， the evidence for its efficacy in treating negative symptoms of schizophrenia and its relationship with associated immuno-inflammatory changes remain to be further elucidated. ObjectiveTo investigate the efficacy of iTBS targeting the left dorsolateral prefrontal cortex （L-DLPFC） on persistent negative symptoms of schizophrenia， and to analyze its relationship with changes in peripheral blood inflammatory markers， so as to provide references for the clinical application of iTBS in treating persistent negative symptoms and to offer clues for further research into its potential biological mechanisms. MethodsA randomized， double-blind， sham-controlled clinical trial was conducted. A total of 60 patients with schizophrenia who were hospitalized at Xuzhou Oriental Peopple's Hospital from February 20， 2024 to May 10， 2025 were consecutively enrolled. All patients met the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） and fulfilled the criteria for persistent negative symptoms. Participants were randomly assigned into the study group and the control group， with 30 patients in each group. The two groups respectively received 20 sessions of either active iTBS or sham stimulation over a 4-week period. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale （PANSS） at the baseline， the end of treatment， and 3 months after treatment. Peripheral blood inflammatory markers were measured at the baseline and at the end of treatment， including white blood cell count， platelet count， neutrophil count， lymphocyte count， and monocyte count， the neutrophil-to-lymphocyte ratio （NLR）， monocyte-to-lymphocyte ratio （MLR）， and platelet-to-lymphocyte ratio （PLR） were also calculated. A linear mixed model was used to compare PANSS scores between the two groups. Spearman correlation analysis was performed to examine the association between reductions in inflammatory markers at the end of treatment and reductions in PANSS negative symptom subscale scores， with body mass index （BMI） and chlorpromazine-equivalent dose as covariates. Results①The time-group interaction effect for the PANSS negative symptom subscale score was statistically significant （F=5.410， P<0.01）. At the end of treatment and 3 months after treatment， the study group had significantly lower scores on the PANSS negative symptom subscale than the control group （P<0.01）. ② At the end of treatment， group differences in reduction scores for neutrophil count， NLR， and PLR were significant （Z=-2.262， -2.048， -2.070， P<0.05）. However， after FDR correction， the between-group differences in reductions in peripheral blood inflammatory markers were no longer statistically significant （P>0.05）. ③ After adjusting for BMI and chlorpromazine equivalents， the reduction in PANSS negative symptom subscale scores was positively correlated with the reduction in neutrophil count in the study group （r_s=0.382， P=0.045）. ConclusioniTBS targeting the L-DLPFC may be beneficial in improving persistent negative symptoms of schizophrenia， and its clinical efficacy may be associated with changes in neutrophil count. ［Funded by National Natural Science Foundation of China （number， 82371510）； Social Development Project of Jiangsu Province （number， BE2023668）. www.chictr.org.cn number， ChiCTR2500101060］

Objective:To investigate the impact of evaluating the alcohol intake on all-cause mortality in patients with metabolic-associated fatty liver disease（MAFLD）and metabolic dysfunction and alcohol-related liver disease（MetALD）.Method:The retrospective study included patients aged 20 to 74 years with hepatic steatosis diagnosed by ultrasound，with data from the Third National Health and Nutrition Examination Survey（NHANES III）between 1988 and 1994. Participants were categorized into light，moderate，and heavy drinking groups according to daily alcohol intake. Multivariable-adjusted hazard ratios（aHR）and their 95% confidence intervals（ CI）were calculated by Cox proportional risk regression modeling to assess the effect of alcohol intake on all-cause mortality. Results:A total of 2 322 patients were included in the study. Males accounted for 50.2%（1 166/2 322），with a age of 42.0（31.3，57.0）years，a median follow-up of 316.0（270.0，337.0）months，and an all-cause mortality rate of 1.48% per person-year. There were 1，763 cases in the light drinking group，333 in the moderate drinking group，and 226 in the heavy drinking group.The all-cause mortality rates for patients in the three drinking groups were 1.38%，1.67%，and 2.10% per person-year，respectively. The moderate（a HR=1.37，95% CI：1.12 to 1.67， P=0.002）and heavy（a HR=1.45，95% CI：1.17 to 1.80， P=0.001）drinking groups were independently associated with increased all-cause mortality following covariate adjustment. There was a difference in all-cause mortality for alcohol intake in non-type 2 diabetes mellitus（T2DM）patients under 60 years of age（ P<0.05），but the difference was not statistically significant between non-T2DM patients over 60 years of age and T2DM patients of all ages（ P>0.05）according to the analysis of diabetes status and age subgroups. Conclusion:Alcohol intake has a dose-dependent negative effect on patients with MAFLD and MetALD. The risk of all-cause mortality increased significantly with increasing alcohol intake.

Objective:To investigate the efficacy of fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet count ratio (APRI), liver stiffness value (LSM), and Agile 3+ score and their combined model in predicting advanced-stage liver fibrosis in patients with chronic hepatitis B (CHB) combined with metabolic-associated fatty liver disease (MAFLD).Methods:A multicenter retrospective cohort study was conducted on the BMOVE population.Nine hundred twenty CHB cases combined with MAFLD who underwent liver biopsy at seven medical centers in China from April 2006 to December 2023 were included. The patients were divided into advanced-stage liver fibrosis (159 cases) and non-advanced-stage liver fibrosis (761 cases) according to the Scheuer's scoring system.The area under the receiver operating characteristic curve (AUROC), decision curve, and calibration curve analysis were used to evaluate the efficacy of the firbrosis-4 index (FIB-4) score, NFS score, APRI index, LSM, and Agile 3+ score and their combined model in predicting advanced-stage fibrosis. The liver fibrosis grade of all patients was diagnosed by liver biopsy. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each scoring model and combined model, as well as the proportion of correctly classified patients, were calculated based on different cutoff values.Results:AUROC analysis showed that Agile 3+ (0.814, 95% CI: 0.787-0.838) and LSM (0.805, 95% CI: 0.778-0.829) had similar accuracy and were superior to FIB-4 (0.721, 95% CI: 0.691-0.749), NFS (0.687, 95% CI: 0.656-0.716) and APRI ( 0.689, 95% CI: 0.658-0.718); however, HBV DNA level and HBV e antigen status had no effect on this outcome. Decision curve analysis showed that interventions based on LSM and Agile 3+ had provided higher net benefits compared with serological scores. Calibration curves showed that Agile 3+ had better predicitive accuracy than all other models. Agile 3+ had the highest PPV (0.54), minimal uncertainty interval (11.6%), and the highest proportion of correctly classified patients (76%); followed by LSM (PPV: 0.43, uncertainty interval: 15.5%, correct classification rate: 66%), and FIB-4 (PPV: 0.42, uncertainty interval: 26.1%, correct classification rate: 62.6%) in terms of identifying advanced-stage liver fibrosis. Combined model analysis demonstrated that FIB-4 combined with Agile 3+ had improved the correct classification rate and reduced the proportion of missed patients compared with FIB-4 combined with LSM. Conclusion:The Agile 3+ score is superior than LSM, FIB-4, NFS, and APRI index at identifying advanced-stage fibrosis in patients with CHB combined with MAFLD. This study supports the use of FIB-4 index combined with Agile 3+ for risk stratification in patients with CHB combined with MAFLD.

Objective:To investigate the impact of evaluating the alcohol intake on all-cause mortality in patients with metabolic-associated fatty liver disease（MAFLD）and metabolic dysfunction and alcohol-related liver disease（MetALD）.Method:The retrospective study included patients aged 20 to 74 years with hepatic steatosis diagnosed by ultrasound，with data from the Third National Health and Nutrition Examination Survey（NHANES III）between 1988 and 1994. Participants were categorized into light，moderate，and heavy drinking groups according to daily alcohol intake. Multivariable-adjusted hazard ratios（aHR）and their 95% confidence intervals（ CI）were calculated by Cox proportional risk regression modeling to assess the effect of alcohol intake on all-cause mortality. Results:A total of 2 322 patients were included in the study. Males accounted for 50.2%（1 166/2 322），with a age of 42.0（31.3，57.0）years，a median follow-up of 316.0（270.0，337.0）months，and an all-cause mortality rate of 1.48% per person-year. There were 1，763 cases in the light drinking group，333 in the moderate drinking group，and 226 in the heavy drinking group.The all-cause mortality rates for patients in the three drinking groups were 1.38%，1.67%，and 2.10% per person-year，respectively. The moderate（a HR=1.37，95% CI：1.12 to 1.67， P=0.002）and heavy（a HR=1.45，95% CI：1.17 to 1.80， P=0.001）drinking groups were independently associated with increased all-cause mortality following covariate adjustment. There was a difference in all-cause mortality for alcohol intake in non-type 2 diabetes mellitus（T2DM）patients under 60 years of age（ P<0.05），but the difference was not statistically significant between non-T2DM patients over 60 years of age and T2DM patients of all ages（ P>0.05）according to the analysis of diabetes status and age subgroups. Conclusion:Alcohol intake has a dose-dependent negative effect on patients with MAFLD and MetALD. The risk of all-cause mortality increased significantly with increasing alcohol intake.

Objective:To investigate the efficacy of fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet count ratio (APRI), liver stiffness value (LSM), and Agile 3+ score and their combined model in predicting advanced-stage liver fibrosis in patients with chronic hepatitis B (CHB) combined with metabolic-associated fatty liver disease (MAFLD).Methods:A multicenter retrospective cohort study was conducted on the BMOVE population.Nine hundred twenty CHB cases combined with MAFLD who underwent liver biopsy at seven medical centers in China from April 2006 to December 2023 were included. The patients were divided into advanced-stage liver fibrosis (159 cases) and non-advanced-stage liver fibrosis (761 cases) according to the Scheuer's scoring system.The area under the receiver operating characteristic curve (AUROC), decision curve, and calibration curve analysis were used to evaluate the efficacy of the firbrosis-4 index (FIB-4) score, NFS score, APRI index, LSM, and Agile 3+ score and their combined model in predicting advanced-stage fibrosis. The liver fibrosis grade of all patients was diagnosed by liver biopsy. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each scoring model and combined model, as well as the proportion of correctly classified patients, were calculated based on different cutoff values.Results:AUROC analysis showed that Agile 3+ (0.814, 95% CI: 0.787-0.838) and LSM (0.805, 95% CI: 0.778-0.829) had similar accuracy and were superior to FIB-4 (0.721, 95% CI: 0.691-0.749), NFS (0.687, 95% CI: 0.656-0.716) and APRI ( 0.689, 95% CI: 0.658-0.718); however, HBV DNA level and HBV e antigen status had no effect on this outcome. Decision curve analysis showed that interventions based on LSM and Agile 3+ had provided higher net benefits compared with serological scores. Calibration curves showed that Agile 3+ had better predicitive accuracy than all other models. Agile 3+ had the highest PPV (0.54), minimal uncertainty interval (11.6%), and the highest proportion of correctly classified patients (76%); followed by LSM (PPV: 0.43, uncertainty interval: 15.5%, correct classification rate: 66%), and FIB-4 (PPV: 0.42, uncertainty interval: 26.1%, correct classification rate: 62.6%) in terms of identifying advanced-stage liver fibrosis. Combined model analysis demonstrated that FIB-4 combined with Agile 3+ had improved the correct classification rate and reduced the proportion of missed patients compared with FIB-4 combined with LSM. Conclusion:The Agile 3+ score is superior than LSM, FIB-4, NFS, and APRI index at identifying advanced-stage fibrosis in patients with CHB combined with MAFLD. This study supports the use of FIB-4 index combined with Agile 3+ for risk stratification in patients with CHB combined with MAFLD.

Tumor microenvironment(TME)is a complex cellular environment where tumor cells reside,along with various types of cells and extracellular components surrounding the tumor cells.Immune cells are key components of TME,including tumor-associated macrophages(TAMs),myeloid-derived suppressor cells(MDSCs),lymphocytes,regulatory T cells(Tregs),natural killer cells(NK cells),dendritic cells(DCs),and many others.It is worth noting that drug resistance is currently a major factor limiting the efficacy of cancer treatment methods such as chemotherapy,radiotherapy,targeted therapy,and immunotherapy,and a leading cause of treatment failure.Research has found that the development of drug resistance in tumor cells is the result of interactions between tumor cells and TME.Consequently,overcoming drug resistance in tumors caused by TME is considered a significant challenge in cancer treatment.In recent years,with in-depth research into immune cells within TME,significant progress has been made in understanding the specific mechanisms by which immune cells regulate drug resistance in tumor cells.Furthermore,therapeutic strategies that target these immune cells,signaling pathways,or cytokines have been shown to effectively combat tumor drug resistance and enhance the therapeutic outcomes of cancer treatment.This article reviews the research advancements regarding the roles of TAMs,MDSCs,Tregs,and NK cells in tumor drug resistance within TME and discusses the development of targeting strategies to overcome this resistance.Additionally,we explore the relationship of tumor-associated neutrophils(TANs)and B regulatory cells(Bregs)with tumor drug resistance.It is hoped that this review will offer insights and serve as reference for reducing tumor drug resistance and improving the efficacy of anti-tumor therapies.

OBJECTIVES: To determine the potential molecular mechanisms underlying the therapeutic effect of curcumin on hepatocellular carcinoma (HCC) by network pharmacology and experimental in vitro validation. METHODS: The predictive targets of curcumin or HCC were collected from several databases. the identified overlapping targets were crossed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. Two of the candidate pathways were selected to conduct an experimental verification. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) assay was used to determine the effect of curcumin on the viability of HepG2 and LO2 cells. The apoptosis and autophagy of HepG2 cells were respectively detected by flow cytometry and transmission electron microscopy. Besides, western blot and real-time polymerase chain reaction (PCR) were employed to verify the p53 apoptotic pathway and adenosine 5'-monophosphate (AMP)‍-activated protein kinase (AMPK) autophagy pathway. HepG2 cells were pretreated with pifithrin-‍α (PFT-‍α) and GSK690693 for further investigation. RESULTS: The 167 pathways analyzed by KEGG included apoptosis, autophagy, p53, and AMPK pathways. The GO enrichment analysis demonstrated that curcumin was involved in cellular response to drug, regulation of apoptotic pathway, and so on. The in vitro experiments also confirmed that curcumin can inhibit the growth of HepG2 cells by promoting the apoptosis of p53 pathway and autophagy through the AMPK pathway. Furthermore, the protein and messenger RNA (mRNA) of the two pathways were downregulated in the inhibitor-pretreated group compared with the experimental group. The damage-regulated autophagy modulator (DRAM) in the PFT-‍α-pretreated group was downregulated, and p62 in the GSK690693-pretreated group was upregulated. CONCLUSIONS Curcumin can treat HCC through the p53 apoptotic pathway and the AMPK/Unc-51-like kinase 1 (ULK1) autophagy pathway, in which the mutual transformation of autophagy and apoptosis may occur through DRAM and p62.
AMP-Activated Protein Kinases/pharmacology* ; Apoptosis ; Carcinoma, Hepatocellular/pathology* ; Curcumin/pharmacology* ; Humans ; Liver Neoplasms/pathology* ; Network Pharmacology ; Tumor Suppressor Protein p53/metabolism*

Objective The objective of this study was to utilize proton magnetic resonance spectroscopy (1H-MRS) to assess metabolites in cerebellar nuclei in unmedicated patients with insomnia disorder. Methods 1H-MRS was performed on cerebellar nuclei in 23 unmedicated patients with insomnia disorder (insomnia group) and 18 normal sleepers (control group). N-acetylaspartate (NAA), choline-containing compound (Cho) and creatine (Cr) were measured and the ratios of NAA/Cr and Cho/Cr were determined.Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) were used to assess the subjective sleep quality and insomnia severity of all subjects, while State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory (BDI) were used to assess the levels of anxiety and depression of all subjects. Sleep parameters of all subjects were measured by polysomnography (PSG). Results Mean NAA/Cr ratio of right cerebellar nuclei in insomnia group was significantly lower than that in control group (1.72±0.37 vs. 2.03±0.50, t=2.280, P=0.028). Mean NAA/Cr ratio of right cerebellar nuclei was significantly higher than that of left cerebellar nuclei within control group (2.03±0.50 vs. 1.68±0.21, t=3.386, P=0.004). There was no significant difference with regard to NAA/Cr ratio between bilateral cerebellar nuclei within insomnia group (t=1.416, P=0.171). Across all subjects, PSQI global scores (r=-0.369, P=0.018), and sleep latency (r=-0.437, P=0.004) and number of awakenings after sleep onset (r=-0.432, P=0.005) measured by PSG were negatively correlated with NAA/Cr ratios of right cerebellar nuclei, while percentages of stage 3 sleep (r=0.377,P=0.015) measured by PSG were positively correlated with NAA/Cr ratios of right cerebellar nuclei,respectively. Conclusion Patients with insomnia disorder have a hemispherically lateralized metabolic disturbance of NAA/Cr in right cerebellar nuclei,indicating that patients with insomnia disorder have neuronal damage in right cerebellar nuclei.

Objective To evaluate the preventive effects of Haishe capsules on the conversion of amnestic mild cognitive impairment (aMCI) to Alzheimer's disease(AD).Methods Patients (n=120) with aMCI from our department were recruited and randomly divided into the treatment group and the control group (n=60 in each group).The treatment group was given 0.9 gram of Haishe capsules three times a day while the control group received no drug treatment.Data on the conversion ratio,memory and cognitive function were comparedbetween the groups in a 24-months follow-up.Results By the end of the study,12 patients in the treatment group and 15 in the control group dropped out.Valid data for 93 patients were available for statistical analysis (48 in the treatment group and 45 in the control group).The number of aMCI patients who converted to AD was 6,with a conversion ratio of 12.5％ (6/48);and the number of patients who went through conversion in the control group was 13,with a conversion ratio of 28.8％ (13/45).The difference in conversion between the two groups was statistically significant (x2 =3.83,P＜0.05).After 24 months,MMSE scores for the treatment group (25.52± 1.07) had no significant change compared with baseline levels,while MMSE scores for the control group decreased significantly(24.75--1.49) and were markedly lower than thosefor the treatment group (t=2.85,P＜0.05).MoCA scores for the treatment group (19.39 ±2.01) did not show decline until the end of the study,while those for the control group started to decrease about half way through the study and were lower than scores for the treatment group (t =2.41,P＜0.05).Compared with baseline levels,ADAS-Cogscores for the treatment group (7.62± 1.06) did not increase significantly during the course of the study.ADAS-Cogscores forthe control group were higher at both half way (7.70±0.75) and the end of the study (8.18±0.80)than base line levels,and there was a statistically significant difference in end-of-study ADAS-Cog scores between the two groups(t =-2.6,P＜ 0.05).Conclusions Haishe capsules not only effectively maintain memory and cognitive function,but also delay the conversion from aMCI to AD.