ObjectiveTo identify protein biomarkers and potential therapeutic targets associated with metabolic dysfunction-associated fatty liver disease （MAFLD） through an integrative multi-omics analysis. MethodsLarge-scale plasma protein quantitative trait locus data were integrated with MAFLD genome-wide association study data， and a proteome-wide Mendelian randomization analysis was performed. Summary data-based Mendelian Randomization （SMR）/heterogeneity in dependent instruments （HEIDI） test and colocalization analysis were used to assess significant proteins. The independent samples t-test was used for comparison of continuous data with homogeneity of variance between two groups， and the Welch-corrected t-test was used for comparison of continuous data with heterogeneity of variance. The transcriptomic validation results were compared with the Mendelian randomization results to evaluate the changing trends of gene expression， and boxplots were used to display the expression distribution of candidate genes between groups. ResultsAmong 7 130 proteins analyzed， 40 showed a causal relationship with MAFLD， among which 26 increased the risk of MAFLD and 14 exerted a protective effect against MAFLD （FDR<0.05）. Nine proteins were supported by SMR/HEIDI （P_SMR<0.05， P_HEIDI>0.05）， and 14 showed a strong colocalization signal （PPH₄>0.9）. The transcriptomic analysis identified 5 differentially expressed proteins （all P<0.05）， i.e.， adenosine diphosphate-ribosylation factor-like GTPase 2， insulin-like growth factor binding protein 2， casein kinase 1 delta （CSNK1D）， leucine-rich repeat neuronal 1， and moesin （MSN）. In vitro validation showed upregulated expression levels of MSN （1.612±0.346 vs 0.569±0.077， P<0.05）， 14-3-3 protein theta （YWHAQ） （1.267±0.126 vs 0.313±0.029， P<0.05）， and CSNK1D （0.871±0.025 vs 0.431±0.080， P<0.05） and a downregulated expression level of histone deacetylase 8 （0.637±0.059 vs 1.097±0.260， P<0.05） in the MAFLD cell model. Functional annotation showed that CSNK1D participated in circadian and metabolic regulation， YWHAQ modulated the Hippo pathway and lipid signal transduction， and MSN was associated with cytoskeletal remodeling and fibrogenic responses. ConclusionThe integrative proteogenomic analysis in this study shows that CSNK1D， YWHAQ， and MSN may be key mediators in the pathogenesis of MAFLD. These proteins have the potential to serve as novel biomarkers and therapeutic targets， providing new directions for research on disease mechanisms and the development of intervention strategies.

Tumor-infiltrating lymphocytes（TILs）are the main anti-tumor immune cells in the tumor microenvironment and play a crucial role in the immunotherapy of solid tumors. However，the presence of an immunosuppressive microenvironment limits their clinical efficacy. As one of the most abundant immunosuppressive cells in the tumor microenvironment，tumor-associated macrophages（TAMs）have a close connection with TILs and play an important role in the immunosuppression on TILs. This review discusses the application of TILs in the field of tumor therapy and their immunosuppressive bottlenecks，elaborates on the role of TAMs in tumor immunosuppression，and summarizes the effects of TAMs on the immune function of TILs through mechanisms such as cytokine secretion，exosome release，metabolic reprogramming，and epigenetic remodeling. In addition，this article also explores the possibility of targeting TAMs as a strategy to improve the anti-tumor efficacy of TILs，aiming to provide new ideas for addressing the immunosuppressive challenges faced by TILs.

Myeloid-derived cells (MDCs) are crucial in immune response and tissue homeostasis. They have high functional plasticity and can be polarized according to microenvironment signals. These cells, including macrophages, neutrophils, and dendritic cells (DCs), exhibit different functional polarization states in different pathological environments and are involved in the occurrence and development of diseases such as inflammation and tumors. Studies have shown that metabolic reprogramming plays a key role in the functional polarization of MDCs, affecting the cellular energy supply and regulating immune function. This paper reviews classification, function and polarization mechanism of MDCs and discusses metabolic reprogramming. In addition, the therapeutic strategies targeting MDC are summarized, which is expected to provide new targets for tumor immunotherapy.
Humans ; Tumor Microenvironment/immunology* ; Myeloid Cells/metabolism* ; Neoplasms/pathology* ; Animals ; Immunotherapy/methods* ; Dendritic Cells/immunology* ; Macrophages/immunology*

Tumor-infiltrating lymphocytes（TILs）are the main anti-tumor immune cells in the tumor microenvironment and play a crucial role in the immunotherapy of solid tumors. However，the presence of an immunosuppressive microenvironment limits their clinical efficacy. As one of the most abundant immunosuppressive cells in the tumor microenvironment，tumor-associated macrophages（TAMs）have a close connection with TILs and play an important role in the immunosuppression on TILs. This review discusses the application of TILs in the field of tumor therapy and their immunosuppressive bottlenecks，elaborates on the role of TAMs in tumor immunosuppression，and summarizes the effects of TAMs on the immune function of TILs through mechanisms such as cytokine secretion，exosome release，metabolic reprogramming，and epigenetic remodeling. In addition，this article also explores the possibility of targeting TAMs as a strategy to improve the anti-tumor efficacy of TILs，aiming to provide new ideas for addressing the immunosuppressive challenges faced by TILs.

Inflammatory bowel disease(IBD)is an immune-mediated inflammatory disorder with high heterogeneity.The safety of its treatment,particularly adverse reactions,is a crucial area that physicians need to focus on.Currently,the biologic agents and small molecule drugs for treating IBD,such as anti-tumor necrosis factor-α agents,anti-integrin agents,interleukin(IL)-12/IL-23-targeting biologic agents,Janus kinase(JAK)inhibitors,and sphingosine-1-phosphate(S1P)receptor modulators,can induce both acute and chronic adverse reactions.Chronic adverse reactions mainly manifest as opportunistic infections,malignancies in different organs,especially lymphomas,as well as adverse reactions in the cardiovascular and nervous systems.The adverse reactions caused by the above-mentioned drugs exhibit both homogeneity and heterogeneity.Employing artificial intelligence(AI)techniques to summarize the patterns of biologic agents and small molecule drugs in the treatment of IBD and constructing models to predict the adverse reactions in heterogeneous individuals might be an important technological approach to enhance the safety of biologic treatments for IBD.This article reviews the research progress on the adverse reactions of biologic agents and small molecule drugs in the treatment of IBD.

Inflammatory bowel disease(IBD)is an immune-mediated inflammatory disorder with high heterogeneity.The safety of its treatment,particularly adverse reactions,is a crucial area that physicians need to focus on.Currently,the biologic agents and small molecule drugs for treating IBD,such as anti-tumor necrosis factor-α agents,anti-integrin agents,interleukin(IL)-12/IL-23-targeting biologic agents,Janus kinase(JAK)inhibitors,and sphingosine-1-phosphate(S1P)receptor modulators,can induce both acute and chronic adverse reactions.Chronic adverse reactions mainly manifest as opportunistic infections,malignancies in different organs,especially lymphomas,as well as adverse reactions in the cardiovascular and nervous systems.The adverse reactions caused by the above-mentioned drugs exhibit both homogeneity and heterogeneity.Employing artificial intelligence(AI)techniques to summarize the patterns of biologic agents and small molecule drugs in the treatment of IBD and constructing models to predict the adverse reactions in heterogeneous individuals might be an important technological approach to enhance the safety of biologic treatments for IBD.This article reviews the research progress on the adverse reactions of biologic agents and small molecule drugs in the treatment of IBD.

Objective:To evaluate modified Lanza score (MLS) of gastric mucosa for predicting the prognosis of geriatric patients with sepsis.Methods:Data of 50 patients with sepsis, who were over 60 years old and underwent gastroscopy for suspected gastrointestinal bleeding in the Department of Geriatric Critical Care Medicine of Guangdong Provincial People's Hospital from January 2019 to April 2022, were retrospectively analyzed. Patients were divided into the death group ( n=32) and the survival group ( n=18) according to their regression within 28 days after gastroscopy. Their gastric mucosa was scored by using MLS system, and the mortality of patients with MLS≥1 was calculated, then the patients were further divided into 2 groups, MLS=0-2 ( n=23, less than 2 regions of lesions ) and MLS=3-5 ( n=27, two or more regions of lesions). The relationship between MLS and acute physiology and chronic health status evaluation (APACHE) Ⅱ score, risk factor of death and mortality in each group were compared. The correlation between MLS and mortality was analyzed. The influence of geriatric sepsis risk factors affecting the prognosis of patients within 28 days were analyzed by using logistic regression. Results:Among the 50 geriatric patients with sepsis, those with gastric mucosal lesions, i.e., MLS ≥1, accounted for 68.00% (34/50), including 84.38% (27/32) patients with MLS≥1 in the death group, which was significantly higher than the 38.89% (7/18) patients with MLS≥1 in the survival group ( χ 2=10.593, P<0.001). Patients with MLS=3-5 had significantly higher APACHE Ⅱ scores (26.09±6.47 VS 18.57±7.66, t=3.527, P=0.001) and higher mortality [85.19% (23/27) VS 39.13% (9/23), χ 2=11.434, P=0.001] compared with MLS=0-2. Correlation analysis showed a significant correlation between MLS and mortality ( r=0.886, P=0.019). Multivariate logistic regression analysis showed that MLS=4-5 was an independent risk factor for death in geriatric patients with sepsis ( OR=17.055, 95% CI: 1.387-209.744, P=0.027). Conclusion:MLS presents high sensitivity in predicting 28-day outcomes for geriatric patients with sepsis. Two or more than 2 regions of gastric mucosal lesions can significantly increase the risk of death in geriatric patients with sepsis.

The purpose of this study was to investigate the injury of aspirin and clopidogrel on small intestinal mucosa in rats and the protective effect of teprenone.The study found that aspirin and clopidogrel could cause intestinal mucosal injury in rats,which was even worse with dual drugs.The mechanism of mucosal injury included free radical injury induced by aspirin and decreased synthesis of vascular endothelial growth factor (VEGF) by clopidogrel.Teprenone may repair intestinal mucosa via boosting VEGF level.

BACKGROUND: Our previous findings indicate that inflammation-activated bone marrow mesenchymal stem cell conditioned medium (MSC-CM) contribute to repairing the structure and function of the small intestine after radiation-induced acute intestinal injury. However, it is unclear whether the repair effect can be achieved by regulating small intestinal stem cells. OBJECTIVE: To investigate the effects of inflammation-activated bone marrow MSC-CM on the small intestinal epithelial stem cells after acute radiation-induced intestinal injury and to further discuss the repairing mechanism. METHODS: Bone marrow mesenchymal stem cells of Sprague-Dawley rats were separated, cultured and identified. Then, the bone marrow mesenchymal stem cells were co-cultured with normal or radiation-induced IEC-6 cell lines in the Transwell system for 24 hours. Inflammation-activated bone marrow mesenchymal stem cells were cultured alone for 48 hours. Non-activated MSC-CM (MSC-CMNOR) and MSC-CM under radiation-induced inflammatory condition (MSC-CMIR) were collected. Adult Sprague-Dawley rats (provided by the Experimental Center of Sun Yat-Sen University North Campus) were randomly divided into four groups with 20 rats in each group: control group, radiation group, radiation+MSC-CMNOR group and radiation+MSC-CMIR group. The rats in the latter three groups were exposed to one-off 14 Gy whole abdominal radiation to make a rat model of acute radiation-induced small intestinal injury. Three-day continuous administration beginning within 4 hours after successful modeling was given via the tail vein and intraperitoneal implantation of Alzet micro-osmotic pumps: EMEM-F12 (200 μL/d) for the radiation group, MSC-CMNOR for radiation+MSC-CMNOR group and MSC-CMIR for radiation+MSC-CMIR group. There was 2 mL of concentrated conditioned medium in the pump which was released at a constant rate of 10 μL/h into the abdominal cavity after implantation. Intestinal samples were collected at 1, 3, 5, 7 days after radiation for immunochemistry staining, western blot and qRT-PCR detection. RESULTS AND CONCLUSION: (1) On the 3rd day after radiation, Lgr5 positive cells, which were actively proliferating on the base of crypts, became significantly reduced compared with the normal control group, and there was nearly no existing Lgr5 positive cells. However, after infusion of MSC-CMIR, Lgr5 positive intestinal stem cells were significantly increased compared with the radiation group, while in the radiation+MSCNOR group, there was no significant increase in Lgr5 positive intestinal stem cells. (2) On the 3rd day after radiation injury, Bmi1 positive intestinal stem cells were almost invisible. After infusion of MSC-CMIR, Bmi1 positive intestinal stem cells increased significantly, and it was observed not only in the +4 cell position but also in the common position used to be Lgr5 stem cells, indicating that Bmi1 stem cells could differentiate into Lgr5 positive cells to act its repairing effect. (3) Western blot and qRT-PCR further confirmed that the radiation+MSC-CMIR group was significantly higher on the Lgr5 expression level than the radiation group and the radiation+MSC-CMNOR group, and it returned to the normal level on the 7th day after the continuous high expression level. The repair effect of radiation+MSC-CMNOR group was weaker, and only on the 7th day, the expression level of Lgr5 was statistically different from the radiation group. To conclude, inflammation-activated bone marrow MSC-CM exert a protective effect on the small intestinal epithelial stem cells after acute radiation-induced intestinal injury

Objective To investigate the efficacy of different adding times,treatment courses and doses of bifidobacterium and lactobacillus triple live bacteria in Helicobacter pylori (Hp) eradication.Methods A total of 280 patients Hp-infected were enrolled and randomly assigned to five groups.Group A received lansoprazole 30 mg,clarithromycin 500 mg and amoxicillin 1,000 mg bid for 14 days;group B received bifidobacterium and lactobacillus triple live bacteria 2,000 mg tid for 14 days followed by regimen of group A for another 14 days;group C1 received regimen of group A with addition of bifidobacterium and lactobacillus triple live bacteria 2,000 mg bid for 14 days;group C2:regimen of group A with addition of bifidobacterium and lactobacillus triple livc bacteria 2,000 mg tid for 14 days;and group D received regimen of group C2 followed by bifidobacterium and lactobacillus triple live bacteria 2,000 mg tid for another 14 days.4 weeks after end of treatment,Hp eradication was assessed by 13C-urea breath test.Adverse effects during the courses of treatment were recorded.Results A total of 252 (90.0％) patients completed the treatment.The completion rate in group A,B,C1,C2,and D were 78.6％ (44/56),92.9％ (52/56),87.5％ (49/56),96.4％ (54/56),and 94.6％ (53/56) respectively;the completion rate was significantly higher in group B,C2 and D than in group A (P ＜ 0.05),but there were no differences among groups B,C2 and D (P ＞ 0.05).According to intention-to-trcat (ITT) analysis,the eradication rate was 62.5％,80.4％,69.6％,85.7％,and 87.5％ in groups A,B,C1,C2,and D respectively.The eradication rate in groups B,C2 and D was significantly higher than that in group A (x2 =4.375,P =0.036;x2 =7.864,P =0.005;x2 =9.333,P =0.002),and the eradication rate was higher in group C2 than in group C1 (x2 =4.171,P =0.041),but there were no differences among groups B,C2 and D (P ＞0.05).As for per-protocol (PP) analysis,the eradication rate was 79.5％,86.5％,79.6％,88.9％ and 92.5％ in groups A,B,C1,C2,and D respectively,but no significant statistical differences were found among the five groups (P ＞ 0.05).Adverse effects included nausea,bloating,taste distortion,anorexia and constipation.The rate of adverse effects in groups A,B,C1,C2 and D was 67.9％ (38/56),26.8％ (15/56),35.7％ (20/56),21.4％ (12/56),and 17.9％ (10/56) respectively.The incidence rate was significantly lower in groups B,C2 and D than in group A (P ＜ 0.05),but no significant statistical differences were found among groups B,C2,and D (P ＞ 0.05).Conclusions The triple therapy combined with bifidobacterium and lactobacillus triple live bacteria can obviously decrease the adverse effects and improve patient compliance,thereby increasing the rate of Hp eradication.14-day therapy with probiotics is the best regimen.