Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8⁺ T-cell-mediated antitumor immunity both in vivo and in vitro. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8⁺ T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.

BACKGROUND: The STAR (Scientific, Transparent, and Applicable Rankings) working group conducts regular evaluations of Chinese guidelines and consensus statements. This study gathered insights from STAR working group members using qualitative interviews. METHODS: From March to August 2023, members of the STAR specialist committees were interviewed using semi-structured interview outline. The interviewees were selected through purpose-based sampling. Subject analysis was employed to summarize the findings. RESULTS: We conducted interviews with 37 members from 36 committees and summarized the contents into four main themes and 16 specific topics. The value of STAR in enhancing the development and selection of high-quality guidelines in China was commonly mentioned. Challenges identified included the lack of resources and suboptimal organizational structures, collaboration, and evaluation efficiency. Suggestions for the STAR tool included developing extensions for different guideline types, adjusting certain items, and better covering guideline applicability. The promotion of STAR and the consideration of an international committee for global outreach were also highlighted. CONCLUSION STAR has exerted a substantial influence on the evaluation of Chinese guidelines, and the insights gained from interviews offer valuable directions for its further enhancement.
Humans ; China ; Qualitative Research ; Practice Guidelines as Topic ; Interviews as Topic

Esophageal cancer is one of the malignant tumors that poses a threat to human health, with both high incidence and malignancy. Currently, surgery following neoadjuvant chemoradiotherapy is the standard treatment for locally advanced esophageal cancer; however, the long-term prognosis remains unsatisfactory. In recent years, inhibitors of programmed death protein-1 (PD-1) and its ligand (programmed death ligand-1, PD-L1) have achieved breakthrough progress in other solid tumors, and research on esophageal cancer is gradually being conducted. With the demonstration of good efficacy of PD-1/PD-L1 inhibitors in the first-line and second-line treatment of advanced unresectable esophageal cancer, their incorporation into neoadjuvant treatment regimens has become a hot topic. Therefore, this article reviews the mechanism of action of PD-1/PD-L1 inhibitors and their application in the neoadjuvant treatment of esophageal cancer.

Objective:To investigate the prevalence status and the clinical characteristics of hepatitis D virus (HDV) among patients chronically infected with hepatitis B virus (HBV) in the Xinjiang region.Methods:A cross-sectional study was conducted. Serum samples from 1 830 patients with chronic HBV infection who visited the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region from December 2022 to October 2023 were collected. All sera were tested for anti-HDV IgG and IgM. Sera positive for anti-HDV IgG or IgM were selected for HDV RNA detection. HDV RNA-positive sera were sequenced to determine the HDV genotype. Age, gender, HBV course, and anti-HBV treatment status were used as scoring items based on the propensity score matching (PSM) method. Chronic HBV patients with negative anti-HDV were matched in a ratio of 1∶1. The clinical characteristics of anti-HDV -positive-patients were analyzed. The t-test was used for comparison between groups of normally distributed continuous data. The Wilcoxon signed-rank test was used for comparison between groups of skewness distribution. The χ2 test was used for comparison between groups of enumeration data. Results:The positive detection rates of anti-HDV IgG, anti-HDV IgM, and HDV RNA in 1 830 cases with chronic HBV infection were 2.24% (41/1 830), 1.09% (20/1 830), and 1.69% (31/1 830), respectively. All HDV RNA-positive patients had HDV genotype 1. Two anti-HDV-positive patients had negative hepatitis B surface antigen (HBsAg). Gender, age, HBV course, and anti-HBV treatment status had no significant difference. The quantification of HBsAg, liver biochemical indexes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bile acids), the proportion of patients with liver cirrhosis, and alpha-fetoprotein were significantly higher in the anti-HDV-positive group than in those in the anti-HDV-negative group ( P<0.05). Conclusion:The prevalence rate of HDV in chronic HBV-infected patients at a single center in the Xinjiang region was 2.24%, with the primary genotype being 1. Furthermore, overlap infection should be paid attention to because it might aggravate liver damage.

Acute kidney injury (AKI) has high morbidity and mortality, but effective clinical drugs and management are lacking. Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets. Emerging evidence has highlighted the importance of forkhead box protein O1 (FoxO1) in mediating macrophage activation and polarization in various diseases, but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear. The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI. We observed a significant upregulation of FoxO1 in kidney macrophages following ischemia-reperfusion (I/R) injury. Additionally, our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome (AS-Lipo), mainly acting on macrophages, effectively mitigated renal injury induced by I/R injury in mice. By generating myeloid-specific FoxO1-knockout mice, we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI. Furthermore, our study provided evidence of FoxO1's pivotal role in macrophage chemotaxis, inflammation, and migration. Moreover, the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1 (ARHGEF1), indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway. Consequently, our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI. Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.

Metabolic reprogramming plays a central role in tumors. However, the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood. Here, we try to identify the mechanism by which histone acetyltransferase 1 (HAT1) confers reprogramming of gluconeogenesis/lipogenesis in liver cancer. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl₄)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice. Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver. Protein phosphatase 2 scaffold subunit alpha (PPP2R1A) promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1 (PCK1) serine 90 dephosphorylation to suppress the tumor growth. HAT1 succinylated PPP2R1A at lysine 541 (K541) to block the assembly of protein phosphatase 2A (PP2A) holoenzyme and interaction with PCK1, resulting in the depression of dephosphorylation of PCK1. HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation, leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1 (SREBP1) nuclear accumulation-induced lipogenesis gene expression, which enhanced the tumor growth. In conclusion, succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer. Our finding provides new insights into the mechanism by which post-translational modifications (PTMs) confer the conversion of tumor suppressor function to oncogene.

Objective To study the therapeutic effect of Baihuang Ganning mixture on mice with cholestatic hepatitis model induced by α-naphthalene isothiocyanate(ANIT),and to explore the mechanism by which Baihuang Ganning mixture improves cholestatic hepatitis.Methods A cholestatic hepatitis model was established in mice by intragastric administration of ANIT(60 mg·kg-1).Sixty mice were randomly divided into six groups(n=10):normal control group,model control group,the ursodeoxycholic acid group,and the high,medium,and low-dose of Baihuang Ganning mixture groups.Parameters including bile flow rate,serum biochemical indices(ALT,AST,T-BiL,D-BiL,ALP and TBA),histopathological changes in liver tissue,hepatic biochemical markers(MDA,NO,Na+-K+-ATPase and SOD),and expression levels of TGF-β1,P-Smad2,and P-Smad3 were evaluated.Results Serum biochemical analysis revealed that,compared to the model control group,the high and medium-dose Baihuang Ganning mixture groups exhibited significant reductions in ALT,AST,T-BiL,D-BiL,ALP,and TBA levels(P<0.01),along with increased bile flow rate(P<0.01).No significant changes were observed in the low-dose group.Histopathological examination demonstrated that high and medium-dose Baihuang Ganning mixture markedly alleviated ANIT-induced bile duct injury,cholestasis,and hepatocyte injury.Compared to the ursodeoxycholic acid group,high and medium-dose Baihuang Ganning mixture significantly reduced hepatic MDA and NO levels,enhanced Na+-K+-ATPase and SOD activities(P<0.01),and downregulated the expression of TGF-β1,P-Smad2,and P-Smad3.Conclusions Baihuang Ganning mixture significantly improved ANIT-induced cholestatic hepatitis in mice.Baihuang Ganning mixture can regulate the metabolism of bile acids,inhibit the proliferation and activation of hepatic stellate cells(HSC)and the synthesis of collagen,and delay the occurrence of cholestatic hepatitis by inhibiting the expression levels of TGF-β1,P-Smad2 and P-Smad3 proteins.

Objective To study the therapeutic effect of Baihuang Ganning mixture on mice with cholestatic hepatitis model induced by α-naphthalene isothiocyanate(ANIT),and to explore the mechanism by which Baihuang Ganning mixture improves cholestatic hepatitis.Methods A cholestatic hepatitis model was established in mice by intragastric administration of ANIT(60 mg·kg-1).Sixty mice were randomly divided into six groups(n=10):normal control group,model control group,the ursodeoxycholic acid group,and the high,medium,and low-dose of Baihuang Ganning mixture groups.Parameters including bile flow rate,serum biochemical indices(ALT,AST,T-BiL,D-BiL,ALP and TBA),histopathological changes in liver tissue,hepatic biochemical markers(MDA,NO,Na+-K+-ATPase and SOD),and expression levels of TGF-β1,P-Smad2,and P-Smad3 were evaluated.Results Serum biochemical analysis revealed that,compared to the model control group,the high and medium-dose Baihuang Ganning mixture groups exhibited significant reductions in ALT,AST,T-BiL,D-BiL,ALP,and TBA levels(P<0.01),along with increased bile flow rate(P<0.01).No significant changes were observed in the low-dose group.Histopathological examination demonstrated that high and medium-dose Baihuang Ganning mixture markedly alleviated ANIT-induced bile duct injury,cholestasis,and hepatocyte injury.Compared to the ursodeoxycholic acid group,high and medium-dose Baihuang Ganning mixture significantly reduced hepatic MDA and NO levels,enhanced Na+-K+-ATPase and SOD activities(P<0.01),and downregulated the expression of TGF-β1,P-Smad2,and P-Smad3.Conclusions Baihuang Ganning mixture significantly improved ANIT-induced cholestatic hepatitis in mice.Baihuang Ganning mixture can regulate the metabolism of bile acids,inhibit the proliferation and activation of hepatic stellate cells(HSC)and the synthesis of collagen,and delay the occurrence of cholestatic hepatitis by inhibiting the expression levels of TGF-β1,P-Smad2 and P-Smad3 proteins.

Objective:To investigate the prevalence status and the clinical characteristics of hepatitis D virus (HDV) among patients chronically infected with hepatitis B virus (HBV) in the Xinjiang region.Methods:A cross-sectional study was conducted. Serum samples from 1 830 patients with chronic HBV infection who visited the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region from December 2022 to October 2023 were collected. All sera were tested for anti-HDV IgG and IgM. Sera positive for anti-HDV IgG or IgM were selected for HDV RNA detection. HDV RNA-positive sera were sequenced to determine the HDV genotype. Age, gender, HBV course, and anti-HBV treatment status were used as scoring items based on the propensity score matching (PSM) method. Chronic HBV patients with negative anti-HDV were matched in a ratio of 1∶1. The clinical characteristics of anti-HDV -positive-patients were analyzed. The t-test was used for comparison between groups of normally distributed continuous data. The Wilcoxon signed-rank test was used for comparison between groups of skewness distribution. The χ2 test was used for comparison between groups of enumeration data. Results:The positive detection rates of anti-HDV IgG, anti-HDV IgM, and HDV RNA in 1 830 cases with chronic HBV infection were 2.24% (41/1 830), 1.09% (20/1 830), and 1.69% (31/1 830), respectively. All HDV RNA-positive patients had HDV genotype 1. Two anti-HDV-positive patients had negative hepatitis B surface antigen (HBsAg). Gender, age, HBV course, and anti-HBV treatment status had no significant difference. The quantification of HBsAg, liver biochemical indexes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bile acids), the proportion of patients with liver cirrhosis, and alpha-fetoprotein were significantly higher in the anti-HDV-positive group than in those in the anti-HDV-negative group ( P<0.05). Conclusion:The prevalence rate of HDV in chronic HBV-infected patients at a single center in the Xinjiang region was 2.24%, with the primary genotype being 1. Furthermore, overlap infection should be paid attention to because it might aggravate liver damage.

Diagnostic criteria, as a critical component of clinical practice guidelines, play a direct role in guiding clinicians' diagnostic and treatment decisions. Although China has increasingly emphasized the development and updating of clinical guidelines in recent years, research focusing on the diagnostic criteria within these guidelines remains limited. This paper aims to explore the types of diagnostic criteria, the issues they present, and the processes involved in their formulation. Based on this analysis, suggestions are proposed to improve the recommendation and application of diagnostic criteria in Chinese guidelines.