Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

AIM: To evaluate the effect of remimazolam on early postoperative cognitive function in elderly patients with hip fracture based on a randomized controlled trial. METHODS: A total of 106 elderly patients, aged 65-90 years, ASA grade Ⅱ or III, who underwent hip fracture surgery under combined spinal-epidural anesthesia in the Sixth Affiliated Hospital of Wenzhou Medical University from December 2022 to June 2023 and met the inclusion criteria, were selected and randomized into remimazolam group (group R) and propofol group (group P) according to the random number table, with 53 cases in each group. Patients in group P received a slow intravenous injection of propofol at a dose of 0.3-0.5 mg / kg (injection time of 1min), followed by a pump infusion at 0.5-3 mg · kg

OBJECTIVE To explore the mechanism of action of epigallocatechin-3-gallate(EGCG) in inhibiting laryngeal cancer cells. METHODS The expression of epidermal growth factor receptor(EGFR) in laryngeal cancer cell lines AMC-HN-8, TU686 and TU212 was detected by Western blotting, and the inhibitory effects of cetuximab and EGCG on three laryngeal cancer cells were detected by CCK-8 assay. A lentiviral vector containing EGFR promoter and Luc reporter gene was constructed to generate a TU686-EGFR-Luc cell line that could steadily express Luc activity. Luciferase assay was performed to evaluate the effect of EGCG on the transcription activity of EGFR promoter. Cell cycle and apoptosis of EGCG-treated laryngeal carcinoma cells were analyzed by flow cytometry, and changes of the levels of EGFR and downstream ERK1/2, cell cycle-associated proteins P53 and P27, apoptosis-associated proteins BCL2 and PART, and autophagy marker LC3A/B were further examined. RESULTS The laryngeal carcinoma cell lines were insensitive to cetuximab but could be effectively suppressed by EGCG. EGCG effectively inhibited the transcription activity of EGFR promoter. Treatment of TU686 cells at sub-IC50 dose EGCG resulted in significant cell cycle arrest at S phase with partial apoptosis. Significant inhibition of expression and activation of EGFR and downstream signaling pathway were observed. CONCLUSION EGCG can effectively downregulate EGFR and suppress laryngeal carcinoma cells, further investigation on in vivo effect and mechanisms are anticipated.

Objective:To investigate the value of systemic inflammatory response syndrome (SIRS), pediatric sequential organ failure assessment (pSOFA) and pediatric critical illness score (PCIS) in predicting mortality of pediatric sepsis in pediatric intensive care units (PICU) from Southwest China.Methods:This was a prospective multicenter observational study. A total of 447 children with sepsis admitted to 12 PICU in Southwest China from April 2022 to March 2023 were enrolled. Based on the prognosis, the patients were divided into survival group and non-survival group. The physiological parameters of SIRS, pSOFA and PCIS were recorded and scored within 24 h after PICU admission. The general clinical data and some laboratory results were recorded. The area under the curve (AUC) of the receiver operating characteristic curve was used to compare the predictive value of SIRS, pSOFA and PCIS in mortality of pediatric sepsis.Results:Amongst 447 children with sepsis, 260 patients were male and 187 patients were female, aged 2.5 (0.8, 7.0) years, 405 patients were in the survival group and 42 patients were in the non-survival group. 418 patients (93.5%) met the criteria of SIRS, and 440 patients (98.4%) met the criteria of pSOFA≥2. There was no significant difference in the number of items meeting the SIRS criteria between the survival group and the non-survival group (3(2, 4) vs. 3(3, 4) points, Z=1.30, P=0.192). The pSOFA score of the non-survival group was significantly higher than that of the survival group (9(6, 12) vs. 4(3, 7) points, Z=6.56, P<0.001), and the PCIS score was significantly lower than that of the survival group (72(68, 81) vs. 82(76, 88) points, Z=5.90, P<0.001). The predictive value of pSOFA (AUC=0.82) and PCIS (AUC=0.78) for sepsis mortality was significantly higher than that of SIRS (AUC=0.56) ( Z=6.59, 4.23, both P<0.001). There was no significant difference between pSOFA and PCIS ( Z=1.35, P=0.176). Platelet count, procalcitonin, lactic acid, albumin, creatinine, total bilirubin, activated partial thromboplastin time, prothrombin time and international normalized ratio were all able to predict mortality of sepsis to a certain degree (AUC=0.64, 0.68, 0.80, 0.64, 0.68, 0.60, 0.77, 0.75, 0.76, all P<0.05). Conclusion:Compared with SIRS, both pSOFA and PCIS had better predictive value in the mortality of pediatric sepsis in PICU.

The stability of marginal bone level is an important factor in ensuring long-term good clinical efficacy of implantation.The design of implant-abutment interface(IAI)is of considerable importance,including whether undergoing multiple abutment disconnection,whether platform switching is used,connection type,connection torque,and connection material differences.These fac-tors can affect the micro gap and micro movement of the connection interface,which change the size of micro leakage and mechanical stability,thereby affecting the long-term clinical efficacy of implants.This article presents a detailed review of the progress of research on different designs in implant-abutment interface,in order to provide a theoretical basis for the selection and operation of abutments in clinical diagnosis and treatment.

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death worldwide. It is urgent to develop new drugs to improve the prognosis of ESCC patients. Here, we found benzydamine, a locally acting non-steroidal anti-inflammatory drug, had potent cytotoxic effect on ESCC cells. Benzydamine could suppress ESCC proliferation in vivo and in vitro. In terms of mechanism, CDK2 was identified as a target of benzydamine by molecular docking, pull-down assay and in vitro kinase assay. Specifically, benzydamine inhibited the growth of ESCC cells by inhibiting CDK2 activity and affecting downstream phosphorylation of MCM2, c-Myc and Rb, resulting in cell cycle arrest. Our study illustrates that benzydamine inhibits the growth of ESCC cells by downregulating the CDK2 pathway.
Humans ; Benzydamine ; Esophageal Neoplasms/drug therapy* ; Esophageal Squamous Cell Carcinoma/drug therapy* ; Molecular Docking Simulation ; Phosphorylation ; Cell Proliferation ; Cell Line, Tumor ; Apoptosis ; Cyclin-Dependent Kinase 2

Objective To investigate the risk factors for spontaneous bacterial peritonitis (SBP) in patients with cirrhotic ascites, and to establish a new model for predicting the development of SBP. Methods A total of 215 patients who were diagnosed with cirrhotic ascites in Hebei General Hospital from September 2016 to September 2020 were enrolled, and according to the presence or absence of SBP, they were divided into SBP group with 55 patients and non-SBP group with 160 patients. Related clinical data were collected and albumin-bilirubin (ALBI) score, Model for End-Stage Liver Disease (MELD) score, MELD combined with serum sodium concentration (MELD-Na) score, and Child-Pugh score were calculated. The t -test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups; a multivariate logistic regression analysis was used to screen out independent risk factors, and the receiver operating characteristic (ROC) curve was plotted to evaluate the performance of ALBI score, procalcitonin (PCT), polymorphonuclear neutrophil (PMN) count in ascites, and the ALBI-PMN-PCT combined model in the diagnosis of SBP. Results Compared with the SBP group, the non-SBP group had a significantly higher concentration of Na + ( Z =-3.414, P =0.001) and significantly lower total bilirubin ( Z =-2.720, P =0.007), creatinine ( Z =-1.994, P =0.046), urea nitrogen ( Z =-2.440, P =0.015), C-reactive protein ( Z =-9.137, P < 0.001), PCT ( Z =-8.096, P < 0.001), prothrombin time ( Z =-1.969, P =0.049), international normalized ratio ( Z =-2.073, P =0.038), PMN ( Z =-8.292, P < 0.001), MELD score ( Z =-2.736, P =0.006), MELD-Na score ( Z =-3.188, P =0.001), Child-Pugh score ( Z =-3.419, P =0.001), and ALBI score ( t =-5.010, P < 0.001), and there were also significant differences between the two groups in the presence or absence of gastrointestinal bleeding or hepatic encephalopathy ( χ 2 =16.551 and 8.142, P < 0.001 and P =0.004). The multivariate logistic regression analysis showed that ALBI score (odds ratio [ OR ]=3.460, 95% confidence interval [ CI ]: 1.296-9.240, P =0.013), PMN ( OR =1.012, 95% CI : 1.007-1.017, P < 0.001), and PCT ( OR =6.019, 95% CI : 2.821-12.843, P < 0.001) were independent risk factors for SBP in patients with cirrhotic ascites. The ROC curve showed that ALBI, PCT, PMN, and ALBI-PMN-PCT had areas under the ROC curve of 0.711, 0.866, 0.875, and 0.934, respectively, in the diagnosis of SBP, with sensitivities of 50.91%, 73.36%, 72.73%, and 89.09%, respectively, and specificities of 86.87%, 81.25%, 100.00%, and 91.87%, respectively. The patients with ALBI-PMN-PCT > 0.272 had an increased risk of developing SBP. Conclusion The ALBI-PMN-PCT combined model has a high value in predicting the onset of SBP in patients with cirrhotic ascites.

Drugs targeting immune checkpoint are used for cancer treatment, but resistance to single drug may occur. Combination therapy blocking multiple checkpoints simultaneously can improve clinical outcome. Therefore, we designed a recombinant protein rPC to block multiple targets, which consists of extracellular domains of programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The coding sequence was inserted into expression vector and stably transfected into HEK293 cells. The culture supernatant was collected and rPC was affinity-purified. Real-time quantitative PCR was used to evaluate the expression levels of ligands for PD-1 and CTLA-4 in several human cancer cell lines. The binding of rPC with cancer cells was examined by immunofluorescence cell staining, the influence of rPC on cancer cell growth was assayed by CCK-8. The results showed that rPC could be expressed and secreted by stably transfected HEK293 cells, the purified rPC could bind to lung cancer NCI-H226 cells which have high levels of ligands for PD-1 and CTLA-4, no direct impact on cancer cell growth could be observed by rPC treatment. The recombinant protein rPC can be functionally assayed further for developing novel immunotherapeutic drugs for cancer.
Animals ; CTLA-4 Antigen ; genetics ; Cell Proliferation ; HEK293 Cells ; Humans ; Lung Neoplasms ; metabolism ; Programmed Cell Death 1 Receptor ; genetics ; Protein Binding ; Protein Domains ; genetics ; Recombinant Fusion Proteins ; genetics ; isolation & purification ; metabolism

Objective: To study the effect of WT1 expression on the prognosis of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute leukemia (AL) and its significance as molecular marker to dynamically monitor minimal residual disease (MRD) . Methods: Retrospectively analyzed those AL patients who underwent allo-HSCT in the First Hospital Affiliated to Zhejiang University School of Medicine during Jan 2016 to Dec 2017, a total number of 314 cases, 163 males and 151 females, median age was 30 (9-64) years old. Comparing the difference of WT1 expression at diagnosed, pre-HSCT and after HSCT. Using the receiver operating characteristic (ROC) curve to determine the WT1 threshold at different time so as to predict relapse. The threshold of WT1 expression before transplantation was 1.010%, within 3 months after HSCT was 0.079% and 6 months after HSCT was 0.375%. According to these thresholds, WT1 positive patients were divided into low expression groups and high expression groups. Analyzed the relationship between overall survival (OS) , disease-free survival (DFS) , cumulative incidence of relapse (CIR) and WT1 expression. Results: The OS and DFS of high expression group pre-HSCT were lower than low expression group [69.2% (9/13) vs 89.1% (57/64) , χ²=4.086, P=0.043; 53.8% (7/13) vs 87.5% (56/64) , χ²=9.766, P=0.002], CIR was higher than low expression group [30.8% (4/13) vs 7.8% (5/64) , P=0.017]. There was no significant difference of OS and DFS between high expression and low expression group of 3 months after HSCT (P=0.558, P=0.269) . The OS and DFS of high expression group of 6 months after transplantation were both lower than low expression group (P=0.049, P=0.035) . Multivariate analysis showed that WT1>0.375% when 6 months after transplantation was the only independent prognostic factor for shorter DFS (P=0.022) . There was no statistically significant difference in CIR between the high-expression group and the low-expression group 3 months after transplantation and 6 months after transplantation (P=0.114, P=0.306) . Conclusion High expression of WT1 before and after HSCT was an adverse prognosis factor. It is of clinical practical value to use WT1 as a transplant recommendation index for patients with acute leukemia and as a marker to monitor MRD dynamically.

Objective: To investigate the fatigue status of military personnel stationed in plateau and high cold region, and to analyze the mediator effect of trait coping style on job stress and fatigue. Methods: In October 2010, with the method of cluster random sampling survey, 531 military personnel stationed in plateau and high cold region were chosen as subject. The fatigue status were evaluated by the Chinese version multidimensional fatigue inventory (MFI-20) , job stress were evaluated by the Job Stress Survey (JSS) , and trait coping style were evaluated by the Trait Coping Style Questionnaire (TCSQ) . Results: According to the information of different population characteristics, mean rank of physical fatigue about the urban (town) group were higher than that of rural group (Z=-2.200, P<0.05) ; mean rank of reduced motivation about the urban (town) group were higher than that of rural group (Z=-2.781, P<0.05) ; mean rank of general fatigue scores about the urban (town) group were higher than that of rural group (Z=-3.026, P<0.05) ; mean rank of physical fatigue about the up or equal 20-years old age group were higher than that of below 20-years old age group (Z=-4.045, P<0.05) ; mean rank of reduced motivation about the up or equal 20-years old age group were higher than that of below 20-years old age group (Z=-2.182, P<0.05) ; mean rank of mental fatigue about the up or equal 20-years old age group were higher than that of below 20-years old age group (Z=-2.879, P<0.05) ; mean rank of general fatigue scores about the up or equal 20-years old age group were higher than that of below 20-years old age group (Z=-3.647, P<0.05) ; mean rank of reduced motivation were significant statistical difference among the military officers, sergeancy and soldier group (F=18.965, P<0.05) ; mean rank of general fatigue scores were significant statistical difference among the military officers, sergeancy and soldier group (F=14.711, P<0.05) . The score of negative coping style were positively correlated with the score of physical fatigue (r_s=0.129) , reduced activity (r_s=0.123) , reduced motivation (r_s=0.149) and general fatigue (r_s=0.174) respectively, the score of organizational support lack strength were positively correlated with the score of physical fatigue (r_s=0.090) , reduced activity (r_s=0.098) , reduced motivation (r_s=0.099) and general fatigue (r_s=0.130) respectively. The mediator effect of negative coping style on the job stress and fatigue was 0.013 (P<0.01) . Conclusion The fatigue statuses of the urban (town) group and the up or equal 20-years old age group are poor, and the negative coping style plays mediator effect on the job stress and fatigue.