Objective:To evaluate the predictive value of whole blood cell derived inflammatory marker (including systemic immunoinflammatory index (SII), systemic inflammatory response index (SIRI), neutrophil count/lymphocyte count (NLR), platelet count/lymphocyte count (PLR), and monocyte count/lymphocyte count (MLR)) and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP) on the prognosis of patients with chronic heart failure.Methods:This study was a retrospective cohort study. Patients with chronic heart failure hospitalized in the Department of Cardiovascular Medicine, Nanfang Hospital, Southern Medical University from January 2019 to August 2022 were enrolled. Patients were followed up and were divided into survival group and death group according to the follow-up results. Clinical characteristics of the two groups were compared. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value of each whole blood cell derived inflammatory marker for predicting all-cause death in patients with chronic heart failure. Kaplan-Meier survival curve was drawn, and log-rank test was used to compare the difference in survival of chronic heart failure patients with different levels of whole blood cell derived inflammatory markers. Univariate and multivariate Cox proportional hazards models were used to analyze the effects of whole blood cell derived inflammatory markers and NT-proBNP on the all-cause death of patients with chronic heart failure. ROC curve was used to analyze the predictive value of whole blood cell derived inflammatory markers combined with NT-proBNP on the prognosis of patients with chronic heart failure.Results:A total of 324 patients with heart failure aged (64.76±13.78) years were enrolled, with 212 males (65.43%). 297 patients (91.67%) completed follow-up, 27 patients (8.33%) were lost to follow-up. The follow-up time was 24.0 (18.0, 41.8) months. There were 258 patients in the survival group and 66 patients in the death group. The optimal cut-off values of SII, SIRI, NLR, PLR and MLR determined by ROC curve were 739.83, 1.65, 3.14, 151.95 and 0.37, respectively. Kaplan-Meier survival curve analysis showed that patients with chronic heart failure with high levels of SII (≥739.83), SIRI (≥1.65), NLR (≥3.14), PLR (≥151.95) and MLR (≥0.37) had higher incidence of all-cause death than patients with low levels of inflammatory markers (all P<0.001). Multivariate Cox proportional hazard regression analysis showed that age ( HR=1.04, 95% CI 1.01-1.06, P=0.002), NT-proBNP ( HR=2.93, 95% CI 1.64-5.23, P<0.001), SII≥739.83 ( HR=3.27, 95% CI 1.18-9.02, P=0.022) and PLR≥151.95 ( HR=2.67, 95% CI 1.02-6.96, P=0.045) were independent predictors of all-cause death in patients with chronic heart failure. ROC curve analysis showed that the predictive value of SII and PLR combined with NT-proBNP ( AUC=0.850) for the prognosis of patients with chronic heart failure was better than that of SII ( AUC=0.779)、PLR ( AUC=0.782)、NT-proBNP ( AUC=0.727) and CRP ( AUC=0.668) alone (all P<0.001). Conclusions:Whole blood cell derived inflammatory markers——SII, PLR, and NT-pro BNP were independently associated with all-cause death in patients with chronic heart failure. SII and PLR can independently predict the prognosis of patients with chronic heart failure, combination of SII and PLR with NT-pro BNP has better predictive value for the prognosis of patients with chronic heart failure.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Objective:This study aimed to systematically evaluate the efficacy of glucagon-like peptide-1(GLP-1) receptor agonists and multi-target analogs on weight reduction and cardiometabolic outcomes in non-diabetic individuals with obesity, and to compare the efficacy and safety across different GLP-1 receptor agonists.Methods:Randomized controlled trials(RCTs) published between January 2000 and March 2025 were identified through a systematic search of CNKI, Wanfang, Web of Science, PubMed, and Cochrane databases. Two reviewers independently screened the studies, extracted data, and assessed methodological quality. Meta-analysis was performed using RevMan 5.4.1 software. Results:A total of 16 RCTs involving 11 032 non-diabetic individuals with obesity were included. Meta-analysis showed that GLP-1 receptor agonists significantly reduced body weight(ΔWeight=-8.71 kg, 95% CI -10.68 to -6.74, P<0.001) and BMI(ΔBMI=-3.01 kg/m 2, 95% CI -3.77 to -2.25, P<0.001), as well as improved systolic blood pressure(ΔSBP=-4.13 mmHg, 1 mmHg=0.133 kPa, 95% CI -4.87 to -3.39, I2=60%) and diastolic blood pressure(ΔDBP=-1.39 mmHg, 95% CI -2.32 to -0.46, I2=95%). Tirzepatide showed the most pronounced effects on both weight and blood pressure reduction. In addition, GLP-1 receptor agonists significantly lowered LDL-C, TC, and TG, while moderately increasing HDL-C levels. In terms of safety, GLP-1 receptor agonists were associated with an increased risk of gastrointestinal adverse events, but did not significantly increase the risk of hypoglycemia. Conclusion:GLP-1 receptor agonists are effective in reducing weight, BMI, and blood pressure, and in improving lipid profiles in non-diabetic individuals with obesity. However, gastrointestinal side effects should be closely monitored. Given the variability in efficacy and safety among various GLP-1 receptor agonists, personalized treatment approaches are recommended.

Objective To investigate the mechanism of autophagy induced by House dust mites(HDM)on airway epithelial tight junction through β-catenin-Snail signaling pathway.Methods Human bronchial epithelial cells(16HBE)were stimulated with HDM at different time points(0,3,6,12,24,48 h)and different concen-trations(0,40,100,200 μg/mL)to screen the appropriate stimulation concentration and stimulation time.16HBE cells were treated with oxidative stress inhibitor N-acetylcysteine(NAC),autophagy inhibitor 3-methylad-enine(3-MA),HDM,and their combinations.Cells were transfected with mCherry-EGFP-LC3B,Beclin-1-siRNA,and ATG14-siRNA lentivirus and then stimulated with NAC and HDM.Immunofluorescence was used to detect the expression levels of autophagy-related protein LC3B,tight junction-related proteins Occludin,and ZO-1 in airway epithelial cells.The level of reactive oxygen species(ROS)was detected by using DCFH-DA in each group.The protein expression levels of Occludin,ZO-1,LC3B,Beclin-1,ATG5,ATG14,P62,Snail,β-catenin and p-β-catenin were detected by Western blot method.Results Immunofluorescence results showed that compared with the control group,200 μg/mL HDM stimulation induced cellular autophagy,increased the expression level of LC3B protein,and promoted the level of ROS,all with statistical significances(all P<0.05).Compared with the HDM group,the HDM+3-MA,HDM+ATG14-si,and HDM+Beclin-1-si groupsall showed significantincreases in the expression levels of tight junction-related proteins Occludin and ZO-1(P<0.05).The HDM+NAC group demonstrated significant decreases both in the level of ROS andin the expression level of LC3B protein.Western blot results revealed that compared with HDM,3-MA and autophagy protein low-expression beads(Beclin-1-si,ATG14-si)attenuated HDM-induced cellular autophagy(P<0.05),inhibited HDM-induced upregulation of Snail and p-β-catenin expression,and improved HDM-induced decreases in Occludin and ZO-1(P<0.05).Moreover,compared with the HDM group,the NAC+HDM group exhibited significant decreases both in the conversion of LC3BⅠ to LC3BⅡ(P<0.001)in the protein levels of Snail,p-β-catenin,Beclin-1 and ATG14(P<0.01),but significant increases in the protein levels of Occludin and ZO-1(P<0.05).Conclusion HDM affects the tight connections between airway epithelial cells by inducing autophagy,which may be attributed to the β-catenin-Snail signaling pathway.

Objective To investigate the mechanism of autophagy induced by House dust mites(HDM)on airway epithelial tight junction through β-catenin-Snail signaling pathway.Methods Human bronchial epithelial cells(16HBE)were stimulated with HDM at different time points(0,3,6,12,24,48 h)and different concen-trations(0,40,100,200 μg/mL)to screen the appropriate stimulation concentration and stimulation time.16HBE cells were treated with oxidative stress inhibitor N-acetylcysteine(NAC),autophagy inhibitor 3-methylad-enine(3-MA),HDM,and their combinations.Cells were transfected with mCherry-EGFP-LC3B,Beclin-1-siRNA,and ATG14-siRNA lentivirus and then stimulated with NAC and HDM.Immunofluorescence was used to detect the expression levels of autophagy-related protein LC3B,tight junction-related proteins Occludin,and ZO-1 in airway epithelial cells.The level of reactive oxygen species(ROS)was detected by using DCFH-DA in each group.The protein expression levels of Occludin,ZO-1,LC3B,Beclin-1,ATG5,ATG14,P62,Snail,β-catenin and p-β-catenin were detected by Western blot method.Results Immunofluorescence results showed that compared with the control group,200 μg/mL HDM stimulation induced cellular autophagy,increased the expression level of LC3B protein,and promoted the level of ROS,all with statistical significances(all P<0.05).Compared with the HDM group,the HDM+3-MA,HDM+ATG14-si,and HDM+Beclin-1-si groupsall showed significantincreases in the expression levels of tight junction-related proteins Occludin and ZO-1(P<0.05).The HDM+NAC group demonstrated significant decreases both in the level of ROS andin the expression level of LC3B protein.Western blot results revealed that compared with HDM,3-MA and autophagy protein low-expression beads(Beclin-1-si,ATG14-si)attenuated HDM-induced cellular autophagy(P<0.05),inhibited HDM-induced upregulation of Snail and p-β-catenin expression,and improved HDM-induced decreases in Occludin and ZO-1(P<0.05).Moreover,compared with the HDM group,the NAC+HDM group exhibited significant decreases both in the conversion of LC3BⅠ to LC3BⅡ(P<0.001)in the protein levels of Snail,p-β-catenin,Beclin-1 and ATG14(P<0.01),but significant increases in the protein levels of Occludin and ZO-1(P<0.05).Conclusion HDM affects the tight connections between airway epithelial cells by inducing autophagy,which may be attributed to the β-catenin-Snail signaling pathway.

Objective:This study aimed to systematically evaluate the efficacy of glucagon-like peptide-1(GLP-1) receptor agonists and multi-target analogs on weight reduction and cardiometabolic outcomes in non-diabetic individuals with obesity, and to compare the efficacy and safety across different GLP-1 receptor agonists.Methods:Randomized controlled trials(RCTs) published between January 2000 and March 2025 were identified through a systematic search of CNKI, Wanfang, Web of Science, PubMed, and Cochrane databases. Two reviewers independently screened the studies, extracted data, and assessed methodological quality. Meta-analysis was performed using RevMan 5.4.1 software. Results:A total of 16 RCTs involving 11 032 non-diabetic individuals with obesity were included. Meta-analysis showed that GLP-1 receptor agonists significantly reduced body weight(ΔWeight=-8.71 kg, 95% CI -10.68 to -6.74, P<0.001) and BMI(ΔBMI=-3.01 kg/m 2, 95% CI -3.77 to -2.25, P<0.001), as well as improved systolic blood pressure(ΔSBP=-4.13 mmHg, 1 mmHg=0.133 kPa, 95% CI -4.87 to -3.39, I2=60%) and diastolic blood pressure(ΔDBP=-1.39 mmHg, 95% CI -2.32 to -0.46, I2=95%). Tirzepatide showed the most pronounced effects on both weight and blood pressure reduction. In addition, GLP-1 receptor agonists significantly lowered LDL-C, TC, and TG, while moderately increasing HDL-C levels. In terms of safety, GLP-1 receptor agonists were associated with an increased risk of gastrointestinal adverse events, but did not significantly increase the risk of hypoglycemia. Conclusion:GLP-1 receptor agonists are effective in reducing weight, BMI, and blood pressure, and in improving lipid profiles in non-diabetic individuals with obesity. However, gastrointestinal side effects should be closely monitored. Given the variability in efficacy and safety among various GLP-1 receptor agonists, personalized treatment approaches are recommended.

Objective:To evaluate the predictive value of whole blood cell derived inflammatory marker (including systemic immunoinflammatory index (SII), systemic inflammatory response index (SIRI), neutrophil count/lymphocyte count (NLR), platelet count/lymphocyte count (PLR), and monocyte count/lymphocyte count (MLR)) and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP) on the prognosis of patients with chronic heart failure.Methods:This study was a retrospective cohort study. Patients with chronic heart failure hospitalized in the Department of Cardiovascular Medicine, Nanfang Hospital, Southern Medical University from January 2019 to August 2022 were enrolled. Patients were followed up and were divided into survival group and death group according to the follow-up results. Clinical characteristics of the two groups were compared. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value of each whole blood cell derived inflammatory marker for predicting all-cause death in patients with chronic heart failure. Kaplan-Meier survival curve was drawn, and log-rank test was used to compare the difference in survival of chronic heart failure patients with different levels of whole blood cell derived inflammatory markers. Univariate and multivariate Cox proportional hazards models were used to analyze the effects of whole blood cell derived inflammatory markers and NT-proBNP on the all-cause death of patients with chronic heart failure. ROC curve was used to analyze the predictive value of whole blood cell derived inflammatory markers combined with NT-proBNP on the prognosis of patients with chronic heart failure.Results:A total of 324 patients with heart failure aged (64.76±13.78) years were enrolled, with 212 males (65.43%). 297 patients (91.67%) completed follow-up, 27 patients (8.33%) were lost to follow-up. The follow-up time was 24.0 (18.0, 41.8) months. There were 258 patients in the survival group and 66 patients in the death group. The optimal cut-off values of SII, SIRI, NLR, PLR and MLR determined by ROC curve were 739.83, 1.65, 3.14, 151.95 and 0.37, respectively. Kaplan-Meier survival curve analysis showed that patients with chronic heart failure with high levels of SII (≥739.83), SIRI (≥1.65), NLR (≥3.14), PLR (≥151.95) and MLR (≥0.37) had higher incidence of all-cause death than patients with low levels of inflammatory markers (all P<0.001). Multivariate Cox proportional hazard regression analysis showed that age ( HR=1.04, 95% CI 1.01-1.06, P=0.002), NT-proBNP ( HR=2.93, 95% CI 1.64-5.23, P<0.001), SII≥739.83 ( HR=3.27, 95% CI 1.18-9.02, P=0.022) and PLR≥151.95 ( HR=2.67, 95% CI 1.02-6.96, P=0.045) were independent predictors of all-cause death in patients with chronic heart failure. ROC curve analysis showed that the predictive value of SII and PLR combined with NT-proBNP ( AUC=0.850) for the prognosis of patients with chronic heart failure was better than that of SII ( AUC=0.779)、PLR ( AUC=0.782)、NT-proBNP ( AUC=0.727) and CRP ( AUC=0.668) alone (all P<0.001). Conclusions:Whole blood cell derived inflammatory markers——SII, PLR, and NT-pro BNP were independently associated with all-cause death in patients with chronic heart failure. SII and PLR can independently predict the prognosis of patients with chronic heart failure, combination of SII and PLR with NT-pro BNP has better predictive value for the prognosis of patients with chronic heart failure.

Objective:To evaluate the efficacy and safety of oliceridine for treatment of moderate to severe pain after surgery with general anesthesia in patients.Methods:The patients with moderate to severe pain (numeric pain rating scale ≥4) after abdominal surgery with general anesthesia from 14 hospitals between July 6, 2021 and November 9, 2021 were included in this study. The patients were assigned to either experiment group or control group using a random number table method. Experiment group received oliceridine, while control group received morphine, and both groups were treated with a loading dose plus patient-controlled analgesia and supplemental doses for 24 h. The primary efficacy endpoint was the drug response rate within 24 h after giving the loading dose. Secondary efficacy endpoints included early (within 1 h after giving the loading dose) drug response rates and use of rescue medication. Safety endpoints encompassed the development of respiratory depression and other adverse reactions during treatment.Results:After randomization, both the full analysis set and safety analysis set comprised 180 cases, with 92 in experiment group and 88 in control group. The per-protocol set included 170 cases, with 86 in experiment group and 84 in control group. There were no statistically significant differences between the two groups in 24-h drug response rates, rescue analgesia rates, respiratory depression, and incidence of other adverse reactions ( P>0.05). The analysis of full analysis set showed that the experiment group had a higher drug response rate at 5-30 min after giving the loading dose compared to control group ( P<0.05). The per-protocol set analysis indicated that experiment group had a higher drug response rate at 5-15 min after giving the loading dose than control group ( P<0.05). Conclusions:When used for treatment of moderate to severe pain after surgery with general anesthesia in patients, oliceridine provides comparable analgesic efficacy to morphine, with a faster onset.