Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

This paper discussed the nature of ulcerative colitis， that is deficiency of the root and excess of the branch， from the theory of sweat pore， and to explore the theoretical basis and experience of treating this disease with retention enema of traditional Chinese medicine （TCM）. The main location of this disease is in the intestine. As a part of sweat pore， the intestinal sweat pore serves as the gateway for the ascending， descending， exiting and entering of qi movement in the zang fu （脏腑） organs， meridians and collaterals， as well as the channel for the transportation of qi， blood and body fluids. The constraint and closure of the intestinal sweat pore are the main pathological basis of ulcerative colitis. According to the manifestations of colonoscopy， and the different etiological factors and pathogenesis that lead to the constraint and closure of sweat pore， there should be different treatment focuses such as expelling wind to open sweat pore， clearing fire to open sweat pore， promoting blood circulation to open sweat pore， for which wind-dispersing herbs， heat-clearing herbs， and blood-activating herbs are used accordingly. The method of retention enema can directly induce Chinese medicinal herbs to the affected part， so as to diffuse and unblock the sweat pore， regulate qi and blood， and thus restore the normal function of the intestinal sweat pore.

ObjectiveTo investigate the serotype distribution and antimicrobial resistance characteristics of foodborne Salmonella in infectious diarrhea cases in Minhang District, Shanghai, and to provide evidence for clinical diagnosis, treatment, prevention, and control of salmonellosis. MethodsFecal or anal swab samples were collected from foodborne diarrhea cases at sentinel hospitals between 2019 and 2023 in Minhang District of Shanghai. Salmonella was isolated, biochemically identified, and serotyped. Antimicrobial susceptibility testing was performed via the microbroth dilution method. ResultsA total of 4 294 samples were collected, from which 224 Salmonella strains were isolated, with an isolation rate of 5.22%. There was no gender difference in the positive rate of Salmonella. The positive rate showed seasonal fluctuations (χ²=160.475, P<0.001), with a higher positive rate in summer and autumn than in spring and autumn. Among different occupational groups, the positive rate was the highest among retired people (7.30%) (χ²=20.023, P=0.001). Among different age groups, the positive rate was the highest among those aged 80 years and above (7.33%) (χ²=13.491, P=0.009). A total of 28 serotypes were identified, with Salmonella Enteritidis being the most predominant, followed by Salmonella Typhimurium. Among them, 154 strains were multi-drug resistant to three or more types of antibiotics (68.75%). The most common drug resistance patterns among multi-drug resistant strains were ampicillin (AMP)-ampicillin/sulbactam (AMS)-sulfamethoxazole/trimethoprim (SXT)-chloramphenicol (CHL)-tetracycline (TET)-streptomycin (STR), AMP-TET-STR and AMP-AMS-TET-STR, with 9 strains being detected in each isolates. ConclusionThe positive rate of foodborne Salmonella in Minhang District, Shanghai, is high in summer and autumn, with a higher infection rate among retired people and those aged 60 years and above being the high-risk group. It is recommended to strengthen the protection for high-risk groups, implement targeted prevention and control measures in summer and autumn to reduce the risk of infection, and pay attention to guiding clinical medication and infection control.

AIM:To investigate the modulatory role of E3 ubiquitin-protein ligase ITCH in Alzheimer disease(AD)-like pathology through the thioredoxin-interacting protein(TXNIP)-nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)signaling pathway using both in vivo and in vitro experimental models.METHODS:(1)Ten 5×FAD(AD model)mice and 10 wild-type(WT)mice at 2-,4-and 6-month-old were randomly allocated into AD and WT groups.Amyloid β-protein(Aβ)plaque burden in the brain was detected by thioflavin-S and immunofluorescence staining,with the latter method additionally applied to assess TXNIP protein expression.The protein levels of ITCH and TXNIP were determined by Western blot,while their interaction was verified by co-immunoprecipitation.(2)Mouse mi-croglia BV2 cells stimulated by lipopolysaccharide(LPS)were used to construct neuroinflammation model,and were di-vided into control(CON)group and LPS+ATP treatment group.The BV2 cells stimulated by Aβ were used to construct AD inflammation model.According to the different treatment time,they were divided into CON,and 12,24 and 48 h treatment groups.Western blot was used to evaluate the expression of ITCH,TXNIP,and NLRP3 inflammasome compo-nents(NLRP3 and caspase-1)as well as the downstream IL-1β.Adenovirus-mediated ITCH overexpression(OE-ITCH)in Aβ-stimulated BV2 cells comprised three experimental groups:negative control group,Aβ oligomer stimulation group,and OE-ITCH group,with subsequent immunoblotting of inflammatory mediators.RESULTS:The deposition of Aβ plaques in the cortex and hippocampus of 5×FAD transgenic mice exhibited an age-dependent progression(P<0.01).Compared with WT mice,the levels of TXNIP protein increased synchronously,and the levels of ubiquitin ligase ITCH was significantly down-regulated(P<0.05).Co-immunoprecipitation confirmed the interaction between ITCH and TXNIP proteins in the brain of 2-and 4-month-old 5×FAD mice,which exhibited marked attenuation by 4 months of age.In BV2 microglial models,Aβ/LPS stimulation provoked significant ITCH suppression,concurrently up-regulating TXNIP,core NLRP3 inflammasome components(NLRP3 and caspase-1),and downstream IL-1β(P<0.05).Overexpression of ITCH significantly inhibited Aβ-induced activation of TXNIP and NLRP3 and therelated inflammatory factors in BV2 cells.CONCLUSION:The results of in vitro and in vivo experiments showed that ITCH protein exerts effects against AD-like pathology by inhibiting the expression of TXNIP-NLRP3 signaling pathway.

Acute myocardial infarction is caused by continuous ischemia and hypoxia of myocardial cells,leading to myocardial cell necrosis.Reperfusion therapy is the standard strategy for reducing infarct size and improving the prognosis of myocardial infarction.However,myocardial injury caused by reperfusion therapy is accompanied by various pathophys-iological processes,such as oxidative stress,inflammatory response,myocardial fibrosis,extracellular matrix remodeling,etc.Transcription factor EB(TFEB)is a central regulatory factor in the autophagy-lysosome signaling pathway,involved in signaling pathways such as stress response,myocardial energy metabolism,autophagy,and lysosomal biogenesis.It is closely related to the repair of myocardial injury after myocardial infarction.This review aims to elucidate the mechanism of TFEB in myocardial ischemic injury.

Acute myocardial infarction is caused by continuous ischemia and hypoxia of myocardial cells,leading to myocardial cell necrosis.Reperfusion therapy is the standard strategy for reducing infarct size and improving the prognosis of myocardial infarction.However,myocardial injury caused by reperfusion therapy is accompanied by various pathophys-iological processes,such as oxidative stress,inflammatory response,myocardial fibrosis,extracellular matrix remodeling,etc.Transcription factor EB(TFEB)is a central regulatory factor in the autophagy-lysosome signaling pathway,involved in signaling pathways such as stress response,myocardial energy metabolism,autophagy,and lysosomal biogenesis.It is closely related to the repair of myocardial injury after myocardial infarction.This review aims to elucidate the mechanism of TFEB in myocardial ischemic injury.

AIM:To investigate the modulatory role of E3 ubiquitin-protein ligase ITCH in Alzheimer disease(AD)-like pathology through the thioredoxin-interacting protein(TXNIP)-nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)signaling pathway using both in vivo and in vitro experimental models.METHODS:(1)Ten 5×FAD(AD model)mice and 10 wild-type(WT)mice at 2-,4-and 6-month-old were randomly allocated into AD and WT groups.Amyloid β-protein(Aβ)plaque burden in the brain was detected by thioflavin-S and immunofluorescence staining,with the latter method additionally applied to assess TXNIP protein expression.The protein levels of ITCH and TXNIP were determined by Western blot,while their interaction was verified by co-immunoprecipitation.(2)Mouse mi-croglia BV2 cells stimulated by lipopolysaccharide(LPS)were used to construct neuroinflammation model,and were di-vided into control(CON)group and LPS+ATP treatment group.The BV2 cells stimulated by Aβ were used to construct AD inflammation model.According to the different treatment time,they were divided into CON,and 12,24 and 48 h treatment groups.Western blot was used to evaluate the expression of ITCH,TXNIP,and NLRP3 inflammasome compo-nents(NLRP3 and caspase-1)as well as the downstream IL-1β.Adenovirus-mediated ITCH overexpression(OE-ITCH)in Aβ-stimulated BV2 cells comprised three experimental groups:negative control group,Aβ oligomer stimulation group,and OE-ITCH group,with subsequent immunoblotting of inflammatory mediators.RESULTS:The deposition of Aβ plaques in the cortex and hippocampus of 5×FAD transgenic mice exhibited an age-dependent progression(P<0.01).Compared with WT mice,the levels of TXNIP protein increased synchronously,and the levels of ubiquitin ligase ITCH was significantly down-regulated(P<0.05).Co-immunoprecipitation confirmed the interaction between ITCH and TXNIP proteins in the brain of 2-and 4-month-old 5×FAD mice,which exhibited marked attenuation by 4 months of age.In BV2 microglial models,Aβ/LPS stimulation provoked significant ITCH suppression,concurrently up-regulating TXNIP,core NLRP3 inflammasome components(NLRP3 and caspase-1),and downstream IL-1β(P<0.05).Overexpression of ITCH significantly inhibited Aβ-induced activation of TXNIP and NLRP3 and therelated inflammatory factors in BV2 cells.CONCLUSION:The results of in vitro and in vivo experiments showed that ITCH protein exerts effects against AD-like pathology by inhibiting the expression of TXNIP-NLRP3 signaling pathway.

Objective:To observe any effect of family rehabilitation interventions based on digital health management on elderly type 2 diabetes mellitus (T2DM) patients with sarcopenia.Methods:One hundred elderly T2DM patients with sarcopenia who had been discharged from hospital after treatment were divided into an observation group and a control group, each of 50. Both groups continued the diet control and training begun during their hospitalization, but the observation group was additionally provided with family rehabilitation based on digital health management. Before and after 3 months, the glucose and lipid metabolism and sarcopenia of both groups were evaluated with related symptom indexes, and their levels of diabetes self-management were compared.Results:Significant improvement was observed in both groups, but the average glucose and lipid metabolism indexes and sarcopenia-related symptom indexes of the observation group were significantly better than the control group′s averages. Their diabetes self-management was also significantly superior.Conclusion:Family rehabilitation based on digital health management can significantly improve glucose and lipid metabolism and muscle mass in elderly T2DM patients with sarcopenia. Such intervention is worthy of promotion and application in clinical practice.

Objective:To explore the predictive value of systemic immune-inflammation index (SII) and small and dense low-density lipoprotein-cholesterol (sdLDL-C) on contrast-induced acute kidney injury (CI-AKI) in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing emergency percutaneous coronary intervention (PCI).Methods:This retrospective analysis included 674 STEMI patients who underwent emergency PCI in Affiliated Hospital of Xuzhou Medical University from November 2019 to October 2021, all patients were divided into a training cohort ( n=450) and validation cohort ( n=224) at a ratio of 2∶1 according to the chronological sequence. The patients in the training cohort were further divided into CI-AKI group ( n=92) and non-CI-AKI group ( n=358). Information at admission and emergency blood biochemical indexes were collected, and the SII was calculated. Multifactorial logistic regression analysis was used to explore the independent factors influencing the occurrence of CI-AKI in STEMI patients undergoing emergency PCI in the training cohort and a predictive model was established. Receiver operating characteristic (ROC) curve and Hosmer-Lemeshow test were used to evaluate the model discrimination and calibration. Results:The prevalence of CI-AKI was 20.4% (92/450). Age, proportion of women, sdLDL-C, urea, baseline creatinine, uric acid, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and SII were significantly higher in the CI-AKI group than in the non-CI-AKI group (all P<0.05), and left ventricular ejection fraction (LVEF), high-density lipoprotein cholesterol, estimated glomerular filtration rate (eGFR) and lymphocyte count were significantly lower in the CI-AKI group than in the non-CI-AKI group (all P<0.05). The results of multifactorial logistic regression analysis showed that age ( OR=1.046, P=0.001), LVEF ( OR=0.916, P<0.001), sdLDL-C ( OR=4.754, P<0.001), uric acid ( OR=1.012, P=0.007), eGFR ( OR=0.994, P=0.002), and lnSII ( OR=2.471, P<0.001) were independent determinants of CI-AKI after emergency PCI in STEMI patients. ROC curve analysis showed that area under the curve (AUC) for the diagnosis of CI-AKI was 0.688 with a sensitivity of 73.9% and specificity of 61.5% for the SII cut-off point of 1 179.07×10 9/L. The AUC for the diagnosis of CI-AKI was 0.709 with a sensitivity of 65.2% and specificity of 77.4% for the sdLDL-C cut-off point of 1.147 mmol/L. The AUC for the diagnosis of CI-AKI was 0.847 with a sensitivity of 88.0% and a specificity of 70.6% for the combination of SII and sdLDL-C with age, LVEF, uric acid and eGFR. The Hosmer-Lemeshow test (χ2=6.913, P=0.546) proved the goodness of fit of the model. Conclusions:SII and sdLDL-C have significant clinical value in the prediction of CI-AKI. SII and sdLDL-C combined with age, LVEF, uric acid and eGFR could further improve the predictive efficacy of CI-AKI.

Objective:To investigate the relationship between mild cognitive impairment (MCI) and time in target range (TIR) and time below target glucose range (TBR) in elderly patients with type 2 diabetes.Methods:Ninety-five elderly patients with type 2 diabetes who were admitted to the Henan Provincial People′s Hospital from November 2017 to November 2018 were selected. Patients were assessed for cognitive function using the Montreal cognitive assessment (MoCA), and were classified into mild cognitive impairment group (MCI group) and non-mild cognitive impairment group (non-MCI group) according to the scores; all enrolled patients were scanned with a glucose monitoring system to record TIR and TBR within the first 24 hours of admission.Results:The MoCA score of the patients in the MCI group was (21.3±3.7)point, which was significantly lower than that in the non-MCI group (28.2±1.2)point, P<0.01); the TIR of the patients in the MCI group was significantly lower than that in non-MCI group [(50.6±24.5)% vs (65.8±28.7)%, P<0.01], the TBR of patients in the MCI group was significantly higher than that in the non-MCI group [(6.6±3.2)% vs (1.2±1.9)%, P<0.01]. Correlation analysis showed that MoCA score was negatively correlated with TBR ( r=-0.892, P<0.01) and positively correlated with TIR ( r=0.816, P=0.001). Multivariate linear regression analysis showed that when adjusted for diabetic duration and HbA 1C, TIR and TBR were independent risk factors for MoCA scores. Conclusion:The cognitive level of elderly patients with type 2 diabetes is closely related to TIR and TBR. At the same time, we must pay attention to TBR while increasing TIR.