Hepatocellular carcinoma (HCC) is one of the fastest growing cancers in the world, ranking fourth among the causes of cancer-induced death in the world. At present, the field of HCC treatment is developing rapidly, and immunotherapy has been recognized as a promising treatment method, in which T cells play a key role in HCC immunotherapy. However, in the case of virus infection or in tumor microenvironment (TME), T cells will be continuously stimulated by antigens and then fall into the state of T cell exhaustion (Tex). This state will not only reduce the immunity of patients but also lead to poor efficacy of immunotherapy. Therefore, to deeply analyze the mechanism of Tex and to explore effective strategies to reverse Tex is the key point in the immunotherapy for HCC. This review aims to summarize the mechanism of Tex in HCC patients, and the current situation and shortcomings of drug research and development to reverse Tex at this stage, in order to provide theoretical basis for the optimization of immunotherapy regimen for HCC patients.
Humans ; Carcinoma, Hepatocellular/therapy* ; Liver Neoplasms/therapy* ; Immunotherapy/methods* ; T-Lymphocytes/immunology* ; Tumor Microenvironment/immunology* ; Animals ; T-Cell Exhaustion

Objective:To explore the diagnostic value of the macrophage activation syndrome/systemic juvenile idiopathic arthritis（MS）score in macrophage activation syndrome（MAS）associated with systemic juvenile idiopathic arthritis（sJIA），and to provide a reference for clinical work.Methods:This study was a retrospective case-control analysis，conducted on the patients initially diagnosed as sJIA-associated with MAS and admitted into the Department of Rheumatology and Immunology of Children's Hospital Affiliated to Xi 'an Jiaotong University from July 1st，2016 to June 30th，2023. All of the patients met the diagnostic criteria for patients with MAS associated with sJIA according to the 2016 European Alliance of Associations for Rheumatology（EULAR）/American College of Rheumatology（ACR）/Pediatric Rheumatology International Trials Organization（PRINTO）standards. The basic information at baseline，clinical manifestations，and auxiliary examination results were collected. The MS score was applied to re-evaluate the children diagnosed as sJIA-associated with MAS. When the MS score ≥-2.1，the possibility of sJIA with MAS was high. Thirty cases of sJIA without MAS were randomly selected as the control group.Results:There were 28 cases in the MAS group，including 13 males（46.43%）and 15 females（53.57%），with an average age of（7.51±4.01）years. Compared with the control group，the MAS group were significantly more likely to have high fever（ χ2=8.539， P=0.003），hepatomegaly（ χ2=11.621， P<0.001），splenomegaly（ χ2=11.710， P<0.001）and neurological involvement（ χ2=27.619， P<0.001），with the differences being statistically significant. Meanwhile，there were statistically significant differences between the two groups in terms of white blood cell count（ Z=-4.001， P<0.001），neutrophil count（ Z=-3.659， P<0.001），platelet count（ Z=-4.687， P<0.001），albumin level（ Z=-4.018， P<0.001），alanine aminotransferase（ Z=-3.846， P<0.001），aspartate aminotransferase（ Z=-5.932， P<0.001），lactate dehydrogenase（ Z=-6.150， P<0.001），triglycerides（ Z=-5.874， P<0.001），fibrinogen（ Z=-5.808， P<0.001），ferritin（ Z=-5.280， P<0.001），erythrocyte sedimentation rate（ Z=-3.971， P<0.001），ferritin/erythrocyte sedimentation rate（ Z=-5.433， P<0.001），reduction of two-line cells in blood（ χ2=11.408， P<0.001）and the presence of hemophagocytosis in bone marrow smears（ χ2=28.260， P<0.001）. Moreover，there was a statistically significant difference in MS scores between the two groups（ Z=-6.148， P<0.001），with higher MS scores in the MAS group. Nevertheless，this study showed the median MS scores of both groups ≥-2.1. Conclusion:The MS score was significant to a certain degree as reference for the diagnosis of MAS，and this study showed that the MS score in the MAS group was significantly higher than the control group. However，the median MS scores in both groups were no less than -2.1. This might be related to the influence of factors during the assessment，which made it necessary to optimize the cutoff values of the MS score. Therefore，prospective studies should be carried out on the role of MS score in early identification of MAS.

Objective To investigate the relationship between the levels of type Ⅲ procollagen(PCⅢ)and heme-binding protein(HPX)in peripheral blood,blood lipid and liver fibrosis in patients with nonalcoholic steatohepatitis(NASH).Methods Totally 126 patients with NASH admitted to the hospital from January 2021 to December 2023 were selected as NASH group,and they were divided into 3 subgroups according to the degree of liver fibrosis:no liver fibrosis group(22 cases),mild group(63 cases),moderate and severe group(41 cases).In addition,150 healthy subjects in the same period were selected as the control group.Enzyme-linked immunosorbent assay(ELISA)was used to detect and compare the levels of PC Ⅲ and HPX in periph-eral blood of all groups,and Pearson correlation analysis was used to explore the correlation between peripher-al blood PC Ⅲ and HPX levels and related indexes of blood lipids in NASH patients.The predictive value of peripheral blood PC Ⅲ and HPX for liver fibrosis in NASH patients was evaluated by receiver operating char-acteristic(ROC)curve.Results The levels of PC Ⅲ and HPX,as well as total cholesterol(TC),triglyceride(TG)and low density lipoprotein cholesterol(LDL-C)in NASH group were higher than those in control group,and the levels of high density lipoprotein cholesterol(HDL-C)were lower than those in control group,and the differences were statistically significant(P＜0.05).Pearson correlation analysis showed that the lev-els of PCⅢ and HPX in peripheral blood of NASH patients were positively correlated with TC,TG and LDL-C(P＜0.05),while negatively correlated with HDL-C(P＜0.05).The levels of PC Ⅲ and HPX in peripheral blood of the non-fibrosis group were lower than those of the mild and moderate severe groups,and the mild group was lower than that of the moderate and severe group,and the differences were statistically significant(P＜0.05).The area under the curve(AUC)of peripheral blood PC Ⅲ and HPX in predicting liver fibrosis in NASH patients were 0.757 and 0.861,respectively,and the cut-off values were 135.51 ng/mL and 804.86 mg/L,respectively.The AUC of the combined prediction for liver fibrosis was 0.905,which was higher than that predicted by the two alone.Conclusion The level of PC Ⅲ and HPX in peripheral blood is closely related to the level of blood lipids and the degree of liver fibrosis in NASH patients,which can be used as potential bi-omarkers to predict liver fibrosis in NASH patients.

Objective: To evaluate the therapeutic potential and underlying mechanisms of action of propolis in db/db mice. Methods: The chemical composition of propolis was analyzed using UHPLC-MS/MS. Thirty mice, including six wt/wt and 24 db/db mice, were randomly assigned to four groups (n = 6 per group): control, model, metformin (250 mg/kg), low dose propolis (100 mg/kg), and high dose propolis (HDP; 400 mg/kg). Treatments were administered orally for four weeks. Body weight and FBG levels were recorded weekly, and an oral glucose tolerance test was conducted on the 25th day. Serum levels of FIN, GSP, connecting peptide, AST, ALT, HDL, LDL, TG, and TC were quantified using ELISA. Liver histopathology was assessed using H&E and PAS staining. Western blotting was performed to examine the expression levels of NF-κB, phosphorylated NF-κB, IκBα, pIκBα, and AKT in liver tissues. Results: The top 10 metabolites of propolis were identified in positive and negative ion modes. The HDP group exhibited a significant reduction in FBG levels, body weight, connecting peptide levels, homeostatic model assessment of β-cell function scores, and homeostasis model assessment of insulin resistance scores (all P < .05). GSP levels were significantly reduced in both treatment groups (all P < .001). The HDP group also exhibited a reduction in TC and LDL levels (both P < .05), whereas HDL levels increased in both treatment groups (all P < .05). Liver weight, AST levels, and ALT levels were reduced in both treatment groups (all P < .05). Histological analysis revealed improved liver morphology. Protein analysis demonstrated downregulation of phosphorylated NF-κB and phosphorylated IκB, alongside upregulation of AKT. Conclusion Propolis exhibited significant antihyperglycemic effects in db/db mice, potentially by modulating the AKT and NF-κB signaling pathways, highlighting its potential as a therapeutic agent for diabetes management.

Objective:To investigate the effects of moxibustion,filiform needle acupuncture,and electroacupuncture on synovial hypoxia and expression of synovial fibrosis markers[transforming growth factor(TGF)-β and collagen alpha-1(Ⅰ)chain(COL1A1)]in knee osteoarthritis(KOA)rats.Methods:Fifty Sprague-Dawley rats were randomly divided into a normal group,a model group,a moxibustion group,an acupuncture group,and an electroacupuncture group,with 10 rats in each group.Except for the normal group,rats in the other four groups were injected with sodium iodoacetate into the right knee joint cavity to establish KOA models.The right Futu(ST32)and Zusanli(ST36)were selected in the moxibustion,acupuncture,and electroacupuncture groups to perform the mild moxibustion with moxa sticks,filiform needle acupuncture,or electroacupuncture,respectively.Each intervention lasted 15 min,once every other day,and continued for 4 weeks,with a total of 14 interventions.The Lequesne score was used to evaluate the degree of knee dysfunction before and after intervention,and the rat's right knee joint diameter was measured to evaluate the degree of knee swelling.Morphological changes of the right knee joint synovial tissue were observed using hematoxylin-eosin staining.Hypoxia probe immunofluorescence staining was used to observe the degree of synovial hypoxia in rats.Western blotting was used to detect the protein expression levels of hypoxia-inducible factor(HIF)-1α,TGF-β,and COL1A1 in the synovial tissue of the right knee joints.Results:Before intervention,the Lequesne score and the right knee joint diameter in the other four groups increased significantly compared to the normal group(P<0.01).After intervention,the Lequesne score and the right knee joint diameter increased significantly in the model group compared to the normal group(P<0.01)together with worsened cartilage deformation and osteophytes,inflammatory cell infiltration and fibrosis in synovial tissue,and hypoxia degree,and the expression levels of HIF-1α,TGF-β,and COL1A1 proteins in the knee joint synovial tissue of rats increased(P<0.01).The Lequesne score and the right knee joint diameter decreased significantly(P<0.01 or P<0.05),the cartilage morphology was normal without obvious osteophytes,and the hypoxia degree reduced in the three intervention groups compared to the model group.Among them,the moxibustion group had the most notable improvement in hypoxia,synovial tissue fibrosis,angiogenesis,and inflammatory cell infiltration.The expression levels of HIF-1α,TGF-β,and COL1A1 proteins decreased in the moxibustion and electroacupuncture groups(P<0.01),and the expression levels of HIF-1α and TGF-β proteins were decreased in the acupuncture group(P<0.01).Conclusion:Moxibustion,filiform needle acupuncture,and electroacupuncture improve knee joint function and reduce knee joint swelling in KOA rats.The mechanism may be to improve synovial fibrosis of the knee joint by regulating HIF-1α;moxibustion has the best effect on improving hypoxia among the three interventions,but the effect of filiform needle acupuncture on COL1A1 is not significant.

OBJECTIVE To explore the effect of the comprehensive unit-based safety program(CUSP)collaborative action strategy on reducing the incidence of catheter-associated urinary tract infection(CAUTI)in elderly patients.METHODS From Jun.to Nov.2024,the Seventh Medical Center of the PLA General Hospital implemented the CUSP collaborative action strategy for intervention.Comparisons were made between pre-intervention(from Dec.2023 to May 2024)and post-intervention(from Jun.to Nov.2024)regarding nurses' know ledge-attitude-practice(KAP)scores on CAUTI prevention,implementation rates of key nursing measures for elderly CAUTI prevention and CAUTI incidence rates among elderly patients.RESULTS The pre-intervention KAP score of nurses from geriatric de-partment on CAUTI prevention was(83.44±6.67),significantly lower than the post-intervention score(108.19±16.27)(P＜0.001).The implementation rates of 10 key nursing measures for elderly CAUTI prevention improved(P＜0.05).The incidence rate of CAUTI was 2.88‰(16/5 546)among 5 546 catheter days before the intervention,and the incidence rate of CAUTI was 0.73‰(4/5 496)among 5 496 catheter days after the intervention(P=0.008).CONCLUSIONS The CUSP collaborative action strategy effectively enhances the KAP levels of nurses from geriatric department on CAUTI prevention,improves the implementation rates of key nursing measures,and reduces CAUTI incidence rates among elderly patients.

Oral squamous cell carcinoma (OSCC) is a malignant tumor that seriously threatens human health. Its typical biological characteristics include strong local invasiveness, high lymph node metastasis rate, and high recurrence rate after treatment. Hepatocyte growth factor (HGF), cellular-mesenchymal to epithelial transition factor (c-Met), and the HGF/c-Met signaling pathway are involved in the regulation of the occurrence and development of OSCC. HGF and c-Met proteins are overexpressed in OSCC, and multiple studies have suggested that they are significantly associated with the malignant characteristics of tumors and poor prognosis. Furthermore, the abnormal activation of the HGF/c-Met signaling pathway (driven by HGF-dependent autocrine/paracrine or non-dependent mechanisms such as MET gene mutations, amplification, fusion, and protein overexpression) can synergistically promote tumor cell invasion, metastasis, and angiogenesis by activating downstream signaling pathways. However, HGF/c-Met can also mediate immune escape by promoting lactate secretion increase, inducing programmed death ligand 1 (PD-L1) expression upregulation, activating and expanding myeloid-derived suppressor cells, and promoting the proliferation of regulatory T cells (Tregs). In addition, the crosstalk between the HGF/c-Met signaling pathway and key pathways such as phosphatidylinositide 3-kinases (PI3K)/protein kinase B (AKT), epidermal growth factor receptor (EGFR), Janus kinase (JAK)/signal transducer and activator of transcription (STAT3), and non-coding RNAs can also promote tumor progression. Currently, three types of targeted drugs have been developed targeting the HGF/c-Met pathway: HGF monoclonal antibody, c-Met monoclonal antibody, and tyrosine kinase inhibitors. Some of these drugs have entered clinical trials. However, the emergence of drug resistance during treatment, especially the bidirectional compensatory activation of alternative signaling pathways such as EGFR, has become a major challenge in clinical practice. This article aims to provide an in-depth analysis of the mechanism of action of the HGF/c-Met pathway in OSCC and its interaction with other pathways, and to review the current research status of existing therapeutic drugs. The aim is to provide an important theoretical basis for developing more effective combined treatment strategies and achieving individualized precise treatment, ultimately improving the clinical prognosis and quality of life of patients.

Objective: To compare and analyze the antibacterial effects of platelets against five common clinical pathogenic bacteria including MRSA, SE, SA, E. coli, and CRKP, and to preliminarily explore the role of DCD sensitivity in the observed variations of antibacterial effects. Methods: The same number of platelets were used to establish co-culture systems of platelets and platelet lysates with the five pathogenic bacteria. The antibacterial effects of platelets and platelet lysates on the five pathogenic bacteria were evaluated by observing the turbidity of the bacterial solution, measuring the OD value of the bacterial solution and counting the colonies. The supernatant protein of platelets co-cultured with MRSA was collected for quantitative proteomics analysis to explore the important antibacterial proteins of platelets. The content of DCD in the supernatant after co-culture of platelets and platelet lysates with the five pathogenic bacteria was detected by ELISA to preliminarily analyze the reasons for the different antibacterial effects of platelets on the five pathogenic bacteria. Results: Compared with the control group of MRSA, SA, and SE, the turbidity of the bacterial solution decreased after co-culture of platelets and platelet lysates with MRSA, SA, and SE for 12 h, and the OD value and colony count were significantly reduced (P<0.05). The turbidity of the bacterial solution did not change significantly after co-culture of platelets and platelet lysates with E. coli for 24 h, but the OD value decreased (P<0.05), and the colony count decreased to 10 CFU/mL but the difference was not statistically significant (P>0.05). Compared with the control group of CRKP, the turbidity, OD value, and colony count of the bacterial solution did not change significantly after co-culture of platelets and platelet lysates with CRKP (P>0.05). Proteomics results showed that after co-culture with MRSA, important proteins related to platelet activation, including collagen, fibrinogen, von Willebrand factor, integrin αIIbβ3, platelet glycoprotein V and IV were significantly up-regulated. ELISA results showed that after co-culture with the five pathogenic bacteria, platelets could secrete a large amount of DCD, with the content around 3 μg/mL. Conclusion: The antibacterial effect of platelets on Gram-positive bacteria MRSA, SA, and SE is better than that on Gram-negative bacteria E. coli and CRKP, and platelets have the best antibacterial effect on MRSA. The differences in antibacterial effects of platelets on the five pathogenic bacteria may be related to the sensitivity of DCD antibacterial peptides to the five pathogenic bacteria.

ObjectiveTo investigate the expression of serum Aldo-keto reductase family 1 member B10 （AKR1B10） in patients with hepatocellular carcinoma （HCC） in northern China， and to provide a new and valuable biomarker for the clinical diagnosis of HCC. MethodsThis study was conducted among 102 patients with HCC， 119 patients with benign liver disease， and 132 patients with other malignant tumors who attended The Affiliated Hospital of Chengde Medical University and 148 healthy individuals who underwent physical examination from May 2020 to May 2024. ELISA and chemiluminescence were used to measure the serum levels of AKR1B10 and alpha-fetoprotein （AFP）. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups， and the Kruskal-Wallis H test was used for comparison between three groups and further comparison between two groups； the chi-square test was used for comparison of categorical data between groups. The area under the ROC curve （AUC） was used to assess diagnostic efficiency. ResultsThe expression level of AKR1B10 was 3 053.79 （1 475.67‍ ‍—‍ ‍4 605.86） pg/mL in the HCC group， 1 324.42 （659.68‍ ‍—‍ ‍2 023.88） pg/mL in the benign liver disease group， 660.68 （377.56‍ ‍—‍ ‍2 087.77） pg/mL in the other malignant tumor group， and 318.30 （82.73‍ ‍—‍ ‍478.82） pg/mL in the healthy group， with a significant difference between the four groups （H=240.86， P<0.001）， and further comparison between two groups showed that the HCC group had a significantly higher level than the other three groups （all P<0.001）. The ROC curve analysis of the HCC group and the other three groups showed that serum AKR1B10 had an optimal cut-off value of 1 584.97 pg/mL in the diagnosis of HCC， with an AUC of 0.86 （95% confidence interval ［CI］： 0.82‍ ‍—‍ ‍0.90）， a sensitivity of 74.3%， and a specificity of 85.2%. Compared with each indicator alone， a combination of AKR1B10 and AFP could improve the sensitivity （81.8%） and specificity （91.4%） of HCC diagnosis. AKR1B10 had an AUC of 0.84 （95%CI： 0.78‍ ‍—‍ ‍0.90） in the diagnosis of patients with early- or middle-stage HCC， with a sensitivity of 76.2% and a specificity of 81.2%. AKR1B10 had an AUC of 0.85 （95%CI： 0.77‍ ‍—‍ ‍0.92） in the diagnosis of patients with AFP-negative HCC， with a sensitivity of 81.6% and a specificity of 79.9%. ConclusionAKR1B10 is a promising serological marker for the diagnosis of HCC， and a combination of AKR1B10 and AFP can improve the detection rate of HCC patients in northern China， especially those with early- or middle-stage HCC and AFP-negative HCC.

Objective To evaluate the feasibility of multi spiral computed tomography(MSCT)for etiological analysis of patients with pelvic venous congestion syndrome(PVCS).Methods The clinical and imaging data of 134 patients diagnosed with PVCS were analyzed retrospectively.The anatomical etiology of PVCS was analyzed,and the clinical and imaging differences between the two groups with and without vascular variation were compared.Results Among the 134 patients,69 had vascular variation,which included 37 distal hypoplasia of left renal vein(LRV),22 nutcracker phenomenon,6 ovarian vein(OV)variation,2 LRV variation,2 portal hyper-tension,2 pelvic arteriovenous fistula,1 left iliac vein compression syndrome,1 left renal malrotation and 1 left renal arteriovenous fistula.The remaining 65 cases showed no vascular variation.There were statistically significant differences in the left ovarian vein(LOV)diameter and reflux degree between the two groups(t=2.544,P=0.012;χ2=21.797,P<0.001).Patients with vascular varia-tion had wider diameter of LOV and higher degree of reflux.There were no statistically significant differences between the two groups regarding age,symptom,times of pregnancy and delivery and body mass index(BMI)values(P>0.05).Conclusion MSCT can provide important reference value for etiological analysis of PVCS,which is helpful for precise treatment.