Objective:Chimeric antigen receptor T-cell(CAR-T)immunotherapy has made major breakthroughs in the treatment of blood tu-mors.However,current CAR-T therapies face several limitations:they require autologous cells,involve a lengthy and costly production pro-cess,and use lentiviral transduction that carry risk of insertional carcinogenesis due to random integration.Therefore,there is an urgent need to develop a universal cost-effective cancer immunotherapy method generating CAR-T cells for in vivo cancer immunotherapy.Meth-ods:This study successfully established an exosome-mediated,T-cell targeted delivery system,demonstrating both precise design and func-tional efficacy for biomedical applications.To optimize CAR-T cell generation the transfection dose was adjusted,and the kinetics of CAR-T cell percentage were recorded.The cytotoxicity of the resulting CAR-T cells was evaluated in vitro by calcein-AM release.To test the tumor-killing in vivo of engineered exosomes,human PBMCs were injected into NPG mice via the tail vein to establish humanized mice,followed by intravenous injection of tumor cells to induce cancer.Results:To overcome the limitations of conditional autologous CAR-T cells,we de-veloped a T cell-targeted exosome system capable of specifically targeting human CD3+,CD4+,and CD8+T cells.CAR-T production was dose-dependent,with transfection efficiency reaching upto 97.8%at 106 particles/cell.Both in vitro cytotoxicity assays and in vivo animal experi-ments demonstrated that exosome-incubated CAR-T cells effectively eliminated CD19-positive Raji cells,highlighting their specificity and therapeutic potential in antigen-directed applications.Conclusions:We successfully established a CD8-targeting exosome delivery system for CAR-T cell production capable of transforming CD8+T cells into functional CAR-T cells,which showed significant tumor-killing ability in vitro and in mice.Compared with the traditional lentiviral vector for the preparation of CAR-T cells in vitro,in vivo-reprogrammed CAR-T cells us-ing our CD8-targeted exosome delivery system,with higher transfection efficiency,shorter production period,lower cost,and eliminated the risk of insertion carcinogenesis.This strategy promises to bring a new era of universal CAR-T medicine,which can improve cancer immuno-therapy and may hold promise as a therapeutic platform to treat various diseases.

Objective:Chimeric antigen receptor T-cell(CAR-T)immunotherapy has made major breakthroughs in the treatment of blood tu-mors.However,current CAR-T therapies face several limitations:they require autologous cells,involve a lengthy and costly production pro-cess,and use lentiviral transduction that carry risk of insertional carcinogenesis due to random integration.Therefore,there is an urgent need to develop a universal cost-effective cancer immunotherapy method generating CAR-T cells for in vivo cancer immunotherapy.Meth-ods:This study successfully established an exosome-mediated,T-cell targeted delivery system,demonstrating both precise design and func-tional efficacy for biomedical applications.To optimize CAR-T cell generation the transfection dose was adjusted,and the kinetics of CAR-T cell percentage were recorded.The cytotoxicity of the resulting CAR-T cells was evaluated in vitro by calcein-AM release.To test the tumor-killing in vivo of engineered exosomes,human PBMCs were injected into NPG mice via the tail vein to establish humanized mice,followed by intravenous injection of tumor cells to induce cancer.Results:To overcome the limitations of conditional autologous CAR-T cells,we de-veloped a T cell-targeted exosome system capable of specifically targeting human CD3+,CD4+,and CD8+T cells.CAR-T production was dose-dependent,with transfection efficiency reaching upto 97.8%at 106 particles/cell.Both in vitro cytotoxicity assays and in vivo animal experi-ments demonstrated that exosome-incubated CAR-T cells effectively eliminated CD19-positive Raji cells,highlighting their specificity and therapeutic potential in antigen-directed applications.Conclusions:We successfully established a CD8-targeting exosome delivery system for CAR-T cell production capable of transforming CD8+T cells into functional CAR-T cells,which showed significant tumor-killing ability in vitro and in mice.Compared with the traditional lentiviral vector for the preparation of CAR-T cells in vitro,in vivo-reprogrammed CAR-T cells us-ing our CD8-targeted exosome delivery system,with higher transfection efficiency,shorter production period,lower cost,and eliminated the risk of insertion carcinogenesis.This strategy promises to bring a new era of universal CAR-T medicine,which can improve cancer immuno-therapy and may hold promise as a therapeutic platform to treat various diseases.

Objective To investigate the relationships of nutritional status and length of stay (LOS) with phase angle (PA) in patients with severe craniocerebral injury. Methods A total of 100 patients [Glasgow Coma Scale (GCS) score ≤8 points] admitted outside the department of neurology were selected as study objects. Body composition analysis and blood samples were used to determine the intracellular and extracellular water content, skeletal muscle, PA, prognostic nutritional index (PNI) and LOS. Patients were divided into low PA group (n=42) and normal PA group (n=58) based on PA values. Body composition related indexes, PNI and LOS were compared between the two groups. The correlation between PA and each index was analyzed. The influencing factors of malnutrition were analyzed. The influencing factors of malnutrition were analyzed. Results Intracellular water, total body water, body cell content and PNI in the low PA group were significantly lower, and LOS was significantly longer than that in the normal PA group (P < 0.05). PA was positively correlated with intracellular water, extracellular water, total body water, skeletal muscle, body cell content, bone mineral content, basal metabolic rate and PNI (P < 0.05), while PA was negatively correlated with LOS (P < 0.05). PA (OR=5.441, P=0.001, 95%CI, 2.011 to 14.719) and LOS (OR=8.373, P < 0.001, 95%CI, 3.079 to 22.765) were the influential factors in the occurrence of malnutrition. Conclusion PA is significantly correlated with nutritional status and LOS in patients with severe craniocerebral injury.

AIM: To explore the pharmacokinetic interactions between sorafenib and dapagliflozin in rats and to provide some theoretical basis for the rational clinical use of the two drugs. METHODS: An ultra -performance liquid chromatography-tandem mass spectrometry (UPLC / MS / MS) method was developed for the simultaneous determination of sorafenib and dapagliflozin. Male SD rats were randomly divided into 5 groups (6 rats in each group), including 100 mg / kg sorafenib group, 0.5 mg / kg dapagliflozin group, 1 mg / kg dapagliflozin group, and 100 mg/kg sorafenib combined with 0.5 mg/kg dapagliflozin group and 100 mg/kg sorafenib combined with 1 mg / kg dapagliflozin group, for sorafenib and dapagliflozin drug interaction study. All samples were analyzed using a validated UPLC/ MS/MS method, and the main pharmacokinetic parameters were calculated by compartment model. RESULTS: 1 mg/kg dapagliflozin increased the C

Palbocicril, the first cyclin-dependent kinases 4 and 6 inhibitors, is a crucial milestone in the development history of antineoplastic drugs. It combined with aromatase inhibitor or fulvestrant as first-line, second-line or post-line therapy has good efficacy and safety for hormone receptor-positive, human epidermal growth factor receptor-2 negative locally advanced or metastatic breast cancer, which has a good application prospect. This article summarizes the clinical trials and safety studies related to palbociclib.

Liver fibrosis is a key step in the progression of chronic liver diseases to liver cirrhosis and even liver cancer. In recent years， a large number of studies have shown the necessity of intervening in the process of liver fibrosis， and various anti-liver fibrosis drugs and active ingredients have been discovered. Non-coding RNAs also play an important role in the process of liver fibrosis， and searching for upstream non-coding RNAs that can regulate signaling pathways can provide new insights for anti-liver fibrosis treatment. This article introduces the process of liver fibrosis mediated by the TGF-β， Wnt/β-catenin， PI3K/Akt/mTOR， NF-κβ， Hippo， and MAPK signaling pathways， lists the latest anti-liver fibrosis drugs or active components in each signaling pathway， and summarizes the research advances in anti-liver fibrosis targets and drugs mediated by related non-coding RNAs， so as to provide new research ideas and treatment methods for anti-liver fibrosis treatment.

Objective: To establish the norm of the Physical Activity afterschool Questionnaire for Preschooler(P-PAQ) in urban areas of China, so as to provide a basis for graded guidance from the family perspective and to improve children s physical activity levels. Methods: From October 2020 to January 2021, 6 267 children aged 3-6 years old were recruited from 40 kindergartens in eight cities across six major administrative regions by stratified cluster sampling, and the P-PAQ initially developed by the researchers of this study were completed by the primary caregivers. The questionnaire was administered to collect data relating to the amount of physical activity undertaken by the preschoolers, and the norm was determined by quartiles. Data relating to parental concepts of sports and parental behavior were assessed by calculating mean scores in order to establish the norm. Results: Among preschoolers in urban areas, the M(P 25 ，P 75 ) of total physical activity time (min/day), moderate-to-vigorous physical activity time (min/day), outdoor time (min/day) and screen time (min/day) on school days outside kindergarten and on weekends were 84 (54,120), 22 (8,40), 12 (0,24) and 18 (6,30), and 170 (115,240), 60 (30,95), 90 (35,120) and 30 (20,60), respectively. When the score of parents sports concept and behavior (total score of 40) were≥34, 29-<34, 24-<29, <24, it was defined as four levels about above medium, medium, lower medium and lower, respectively. And for two dimensions，when the score of parental sports concept were ≥19, 17-<19, 15-<17, <15，and the score of parental behaviors were ≥16, 12-<16, 8-<12, <8, it was defined as four levels about upper medium, medium, lower medium and lower, respectively. Conclusion The norm of extracurricular activities among preschool children in Chinese cities has good representativeness and appropriate threshold values, which could provide a valuable reference for early assessment, as well as guidance in relation to out-of-school physical activity behaviors among children aged 3-6 years old.

Drug-drug interactions (DDI) of tyrosine kinase inhibitors (TKIs) mediated by metabolic enzymes and transporters have become an important issue in clinical practice recently. In addition to CYP450 enzymes, uridine diphosphate glucuronidases (UGTs) are another class of metabolic enzymes involved in the metabolism of TKIs, and most TKIs can inhibit the UGTs in vitro. Potential clinically meaningful DDIs may occur with the co-administration of TKIs and substrates or inhibitors of UGTs. This paper will mainly focus on the UGTs-mediated drug-drug and the effect of UGT1A genotype on the drug interactions of TKIs and explores strategies to address, aiming to provide clinicians and pharmacists with references for the safe and rational application of TKIs.

Objective:To explore the correlation between enlarged perivascular spaces and other imaging markers of cerebrovascular disease in patients with ischemic stroke.Methods:Totally 287 patients with ischemic stroke hospitalized in neurology department from January 2018 to January 2019 were selected. According to the severity of EPVS in different parts of the brain, the correlations between the severity of EPVS in different parts of the brain and cerebral microbleeds (CMBs), white matter hyperintensity (WMH), lacunar infarcts (LIs) were analyzed. SPSS 22.0 software was used for analysis. Chi-square test, independent sample t-test, rank-sum test and non parametric Mann-Whitney U test were used for group comparison, and Logistic regression analysis was used for multivariate analysis. Results:EPVS was common and severe in patients with ischemic stroke. Periventricular white matter hyperintensity(PWMH)( β=1.604, P<0.001, OR=4.971, 95% CI=2.015-12.263), CMBs ( β=1.224, P=0.018, OR=3.339, 95% CI=1.232-9.383) and LIs ( β=0.626, P=0.047, OR=1.871, 95% CI=1.009-3.470) were independent risk factors for BG-EPVS. PWMH ( r=0.614), DWMH ( r=0.622), LIs ( r=0.532) were positively correlated with the severity of BG-EPVS (all P<0.01). Conclusion:The imaging makers of CSVD are related to BG-EPVS, which can affect the severity of brain BG-EPVS in patients with ischemic stroke.

The perivascular space is formed by the pia mater around the blood vessels and participates in the fluid exchange and waste clearance in the brain. The enlarged perivascular space (EPVS) indicates the disorder of brain clearance mechanism, which is closely related to the occurrence and development of a variety of clinical diseases. In recent years, there are a lot of studies on the pathogenesis and influencing factors of EPVS. This article reviews its anatomy, neuroimaging, pathogenesis, and risk factors.