Bacterial outer membrane vesicles (OMVs) are diminutive vesicles naturally released by Gram-negative bacteria. These vesicles possess distinctive characteristics that attract attention for their potential use in drug administration and immunotherapy in cancer treatment. Therapeutic medicines may be delivered via OMVs directly to the tumor sites, thereby minimizing exposure to healthy cells and lowering the risk of systemic toxicity. Furthermore, the activation of the immune system by OMVs has been demonstrated to facilitate the recognition and elimination of cancer cells, which makes them a desirable tool for immunotherapy. They can also be genetically modified to carry specific antigens, immunomodulatory compounds, and small interfering RNAs, enhancing the immune response to cancerous cells and silencing genes associated with disease progression. Combining OMVs with other cancer treatments like chemotherapy and radiation has shown promising synergistic effects. This review highlights the crucial role of bacterial OMVs in cancer, emphasizing their potential as vectors for novel cancer targeted therapies. As researchers delve deeper into the complexities of these vesicles and their interactions with tumors, there is a growing sense of optimism that this avenue of study will bring positive outcomes and renewed hope to cancer patients in the foreseeable future.

OBJECTIVES: Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM). METHODS: A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups. RESULTS: The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T_1/2), area under the curve (AUC), time to reach maximum concentration (T_max). Compared with the control group, AUC was increased by 23.5%, T_max and T_1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population. CONCLUSIONS Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.
Humans ; Diabetes Mellitus, Type 2/drug therapy* ; Metformin/therapeutic use* ; Acidosis, Lactic ; Tandem Mass Spectrometry ; Hypoxia ; Glucose

Objective:To investigate the effects of melatonin(MLT)on hypothalamic-pituitary-adrenal(HPA)axis in posttraumatic stress disorder(PTSD)rats induced by foot shocks.Methods:The rat model of PTSD was prepared by plantar electroshock,and MLT was given by intraperitoneal injection.The behavioral changes of rats were detected by rejection reaction test,the mRNA expression of corticotropin-releasing hormone(CRH)in hypothalamus was detected by real time RT-PCR,and the contents of adrenocorticotropin hormone(ACTH),epinephrine(EPI)and glucocorticoid(GC)in serum were detected by enzyme-linked immunosorbent assay(ELISA).Results:In the PTSD group,the rejection reaction was obvious,the expression of CRH mRNA in hypothalamus was increased(P＜0.05),the serum ACTH and EPI were increased(P＜0.05),but the GC level was decreased(P＜0.05).After MLT treatment,the rejection reaction of PTSD rats was significantly alleviated,CRH mRNA expression in hypothalamus was decreased(P＜0.05),serum ACTH and EPI levels were decreased(P＜0.05),and GC levels were increased(P＜0.05).Conclusion:MLT treatment can relieve the symptoms of PTSD and restore the neuroendocrine balance of HPA axis in rats.

Objective:To study the expression of peripheral blood NKT-like cells in patients with systemic sclerosis (SSc), to explore the correlation between NKT-like cells and laboratory and clinical indicators of systemic sclerosis, and investigate the role of NKT-like cells in the occurrence and development of Systemic sclerosis.Methods:Forty-six SSc patients (SSc group) were enrolled from Department of Rheumatology and Immunology of Peking University People 's Hospital during December 2018 to December 2019. Thirty healthy subjects with matched age and sex were selected as healthy control group (HC group). The cell count and percentage of NKT-like cells and other lymphocyte subsets in peripheral blood were detected by flow cytometry. At the same time, other laboratory indexes were determined by different methods. Spearman's correlation analysis, Pearson's correlation analysis, Man-Whitney U test and Fisher's exact test were used to analyze the difference and correlation between NKT-like cells and other clinical and laboratory indicators. Results:Compared with HC group [165(72, 226)cells/μl], the cell count of NKT-like cells in peripheral blood of SSc group[30(19, 58)cells/μl] was significantly decreased ( Z=-5.69, P<0.001). Correlation analysis showed that the cell count of NKT-like cells was positively correlated with total T lymphocytes ( r=0.56, P<0.001), CD4 +T cells ( r=0.42, P=0.004), CD8 +T cells ( r=0.60, P<0.001), B cells ( r=0.50, P<0.001) and NK cells ( r=0.33, P=0.024), respectively. The percentage of NKT-like cells in lymphocytes was also positively correlated with the percentage of CD8 +T cells ( r=0.34, P=0.020), but not significantly correlated with other subset of lymphocytes. The ESR of the NKT-like cell decreased group was significantly higher than that of the NKT-like normal group[15(9, 28) mm/1 h vs 8 (4, 16) mm/1 h, Z=-2.04, P=0.042]. Moreover, the cell count of NKT-like cells was negatively correlated with ESR ( r=-0.34, P=0.019). Conclusion:The cell count and percentage of NKT-like cells in peripheral blood of SSc patients decreased significantly. NKT-like cells were not only positively correlated with a variety of lymphocyte subpopulations, but also negatively correlated with ESR. NKT-like cells may be used as an indicator to monitor the disease activity in patients with SSc.

Atorvastatin is a blood lipid-lowering drug widely used clinically. Long-term use can prevent and reduce the occurrence of atherosclerotic cardiovascular disease (ASCVD). However, the efficacy of atorvastatin has significant inter-individual differences. Some individuals failed to achieve the expected lipid-lowering target value or had serious adverse reactions, which were related to the genetic diversity between individuals. Genetic variation can lead to differences in drug configuration, clinical efficacy and adverse reactions. The drug metabolism enzymes, drug transporters, drug targets and genetic polymorphisms related to lipid metabolism were reviewed in this paper that affect the drug response of atorvastatin, and from the gene level to explore the reasons for the differences in the pharmacokinetics, pharmacodynamics and susceptibility to adverse reactions of different individuals using atorvastatin.

Metformin is the most common first-line oral hypoglycemic drug ，but there are large individual differences in pharmacokinetic parameters and pharmacodynamics during clinical use. The dosage of some patients should be adjusted to achieve satisfactory therapeutic effect. Pharmacokinetic parameters of metformin are affected by many factors ，including respects of transporter gene polymorphism ，drug interaction ，intestinal flora ，plateau hypoxia and physiological function and so on. In order to guide the clinical individualized use of metformin ，this study reviews the research progress on the influencing factors of metformin pharmacokinetics.

OBJECTIVE To study the pharm acokinetics of venlafaxine（VEN）combined with vinpocetine （VIN）in rats ，and to investigate the interaction between them. METHODS Healthy male SD rats were randomly divided into VEN group （13.5 mg/kg）， VIN group （1.8 mg/kg） and VEN + VIN group （13.5 mg/kg VEN + 1.8 mg/kg VIN ），with 6 rats in each group. Before administration，rats in each group fasted but didn ’t deprived of water for 12 hours，and were given corresponding drugs intragastrically at one time. Blood was collected from rats in each group through orbital venous plexus at different time points after administration. After plasma sample was pretreated （domperidone as internal standard ），LC-MS/MS method was adopted to determine the concentration of VEN ，active metabolite O-desmethylvenlafaxine of VEN （ODV）and active metabolite apovinblastic acid of VIN （AVA）in plasma. DAS 2.0 software was used to calculate and compare the pharmacokinetic parameters of VEN ，ODV and AVA. RESULTS Compared with VEN group ，the pharmacokinetic parameters cmax，AUC0－t，AUC0－∞，MRT0－t（except for VEN），MRT0－∞（except for VEN ）of VEN and ODV in VEN+VIN group were increased significantly ，while CL/ F and Vz/F were decreased significantly （P＜0.05 or P＜0.01）. Compared with VIN group ，there was no statistical difference in the pharmacokinetic parameters of AVA in rat plasma of VEN+VIN group （P＞0.05）. CONCLUSIONS After the combination of VEN and VIN ，VIN can affect the metabolism of VEN by increasing the absorption of VEN and ODV and slowing down their elimination.

Objective:To explore the diagnostic value of hand tenosynovitis in rheumatoid arthritis (RA).Methods:Seventy-six RA patients were enrolled for hands ultrasound examination. Forty-five RA patients with synovitis and tenosynovitis were selected as the study group, clinical characteristics, laboratory test results, disease activity score for 28 joint counts (DAS28), were evaluated and assessed, and the health assessment questionnaire (HAQ) was filled out, and semi-quantitative classification the ultrasonic indicators (synovial hyperplasia, synovitis, tenosynovitis, bone erosion) were also assessed. Forty-two non-RA patients with hand tenosynovitis were selected as the control group. Mann-whitney U test, Spearman correlation and paired U test were used for statistical analysis. Results:① In the RA group, synovial hyperplasia [7.50(3.00, 17.50)], synovitis [6.00(2.00, 14.00)], tenosynovitis [6.00(2.00, 12.00)], bone erosion [0.50(0.00, 4.00)] were statisticantly different when compared with in non-RA group in hyperplasia [5.00(3.00, 6.00)], synovitis [3.00(2.00, 4.30)], tenosynovitis [2.00(1.00, 3.00)], bone erosion [0.00(0.00, 1.00)] ( Z=2.143, P=0.032; Z=2.756, P=0.006; Z=5.560, P<0.01; Z=2.550, P=0.011). ② In the RA group, synovial hyperplasia and synovitis were positively correlated with swollen joint counts (SJC), tender joint counts (TJC), platelet (PLT), C-reactive pro-tein (CRP) and DAS28 [synovial hyperplasia ( r=0.806, P<0.01; r=0.486, P<0.01; r=0.326, P<0.05; r=0.450, P<0.01; r=0.413, P<0.01); and synovitis ( r=0.819, P<0.01; r=0.446, P<0.01; r=0.351, P<0.05; r=0.481, P<0.01; r=0.412, P<0.01)]. Tenosynovitis was positively correlated with SJC, CRP and DAS28 ( r=0.436, P<0.01; r=0.496, P<0.05; r=0.359, P<0.05) , bone erosion was positively correlated with disease course and anti-cyclic citrullinated peptide (CCP) antibody ( r=0.418, P<0.01; r=0.338, P<0.05) . ③ The sensitivity of synovial hyperplasia, synovitis, tenosynovitis, bone erosion and synovitis combined with tenosynovitis for the diagnosis of RA was 0.41, 0.61, 0.57, 0.48, 0.61 and the specificity was 0.95, 0.76, 1, 0.83, 0.93, respectively. ④ The largest area under the ROC curve was tenosynovitis [area under the curve (AUC)=0.841], the area under the curve of tenosynovitis and synovitis combined with tenosynovitis was significantly different from synovitis hyperplasia, synovitis and bone erosion [tenosynovitis( Z=3.291, P=0.001; Z=2.651, P=0.008; Z=3.032, P=0.002); synovitis combined with tenosynovitis( Z=4.346, P=0.001; Z=3.753, P=0.001; Z=2.547, P=0.012)]. Conclusion:Synovitis has a high sensitivity for the diagnosis of RA, and tenosynovitis has a high specificity for the diagnosis of RA, synovitis combined with tenosynovitis can improve the specificity for the diagnosis of RA.

Objective:To explore and evaluate a three-dimensional (3D) digital simulated design and implementation technique in esthetic rehabilitation.Methods:Thirty patients with esthetic deficiency, who came to the Department of Prosthodontics, Peking University School and Hospital of Stomatology from December 2017 to July 2019, were recruited and randomly assigned into 2 groups. Four males and 11 females which were (36.0±10.5) years old in the experimental group, 6 males and 9 females which were (32.0±6.7) years old in the control group, were enrolled. In the experimental group, 3D digital simulated design was used to predict the post-treatment effect; and the final restorations were designed duplicating from the pre-treatment digital design confirmed by the patient and milled. In the control group, the final restorations were manufactured by the dental technician according to the design of two-dimensional (2D) digital smile design. The simulation degree of digital design and the similarity between preoperative design and postoperative rehabilitation were scored by the patients with visual analogue scales (VAS) in both groups; and the satisfaction rate to the restorations was evaluated by the patients. The quality of the restorations was accessed by a prosthodontist who did not know the grouping of patients according to the modified criteria of United States Public Health Service (USPHS).Results:Three-dimensional digital simulated design and implementation technique was successfully established. The VAS score on the simulation degree of digital design in the experimental group (8.5±0.5) was higher than that in the control group (7.2±0.7) ( P<0.01); the VAS score on the similarity between preoperative design and postoperative rehabilitation in the experimental group (9.6±0.3) was higher than that in the control group (7.0±0.9) ( P<0.01). The satisfaction rate of the patients to the restorations was significantly higher in the experimental group than in the control group ( P<0.05). There was no significant difference of the quality of the restorations between the two groups on the anatomic form, the marginal adaption and the surface quality ( P>0.05). Conclusions:Three-dimensional digital simulated design and implementation technique can help achieving 3D digital simulated design before treatment and duplication to the final restorations, and can improve the patients′ satisfaction in esthetic rehabilitation.

Objective To develop a clinical intelligent management system of dressing consumables to realize precision consumables management without increased manpower consumption.Methods The system was composed of four parts of storage box,display screen,detection unit and control processor.The storage box consisted of storage units,identification unit and an input panel.The storage unit included a box body,a lid and an electronic lock for locking the body and lid,and the lock was connected with the control processor.Results The system recognized the medical prescription automatically,and then corresponding dressing consumables were packed and ejected accordingly.Conclusion The system decreases the costs for time,manpower and medical service,and thus is worthy promoting practically for precision hospital consumables management.