[摘 要] 目的：探讨异位表达血红蛋白亚基（HBA/HBB）对缺氧条件下嵌合抗原受体T细胞（CAR-T细胞）功能障碍的改善作用及其对肿瘤细胞的杀伤效应。方法：全基因合成技术合成靶向HER2的CAR序列，构建共表达HBA或HBB的CAR慢病毒载体，包装慢病毒后感染人原代T淋巴细胞，制备异位表达HBA/HBB的CAR-T细胞，命名为HBA CAR-T和HBB CAR-T。采用缺氧探针检测小鼠实体瘤缺氧状态。通过流式细胞术检测瘤内CAR-T细胞占比、异位表达血红蛋白亚基的CAR-T细胞阳性率及CAR-T细胞的活性氧、凋亡水平。WB法检测HBA CAR-T和HBB CAR-T内相关血红蛋白亚基表达情况，采用细胞计数板计数检测细胞增殖水平，通过萤光素酶报告基因法检测CAR-T细胞对肿瘤细胞的杀伤能力，qPCR检测CAR-T细胞中缺氧诱导因子-1α（HIF-1α）表达水平，利用MitoXpress Intra试剂盒检测CAR-T细胞内氧气含量。结果：不同细胞构建的实体瘤模型均存在明显缺氧情况，且CAR-T细胞浸润水平与缺氧程度呈显著负相关（P < 0.000 1）。HBA CAR-T与HBB CAR-T构建成功（阳性率 > 60%），相应血红蛋白亚基可稳定表达。缺氧环境下HBA CAR-T和HBB CAR-T的ROS水平、凋亡水平显著下降，增殖、对肿瘤细胞的体外杀伤能力显著强于传统CAR-T细胞（均P < 0.05）。HBA CAR-T与HBB CAR-T内HIF-1α表达降低（均P < 0.001），且缺氧程度显著降低（均P < 0.001）。结论：异位表达血红蛋白亚基可改善缺氧条件下CAR-T细胞功能障碍并增强其对肿瘤细胞的体外杀伤作用。

OBJECTIVE: To investigate the efficacy and safety of diagnostic-driven therapy for invasive fungal disease(IFD) in patients with myeloid hematologic malignancies. METHODS: A retrospective analysis was conducted on the clinical data of 91 patients with myeloid hematologic malignancies who received diagnostic-driven therapy for IFD at the Second Hospital of Anhui Medical University from January 1, 2020 to December 31, 2023. The patients were divided into two groups based on medication: 44 patients in the caspofungin group and 47 patients in the voriconazole group. The clinical efficacy and adverse reactions of the two groups were compared and analyzed. RESULTS: The overall response rates in the caspofungin and voriconazole groups were 67.4% and 60.0%, respectively. Among patients who transitioned to diagnostic-driven therapy following prophylactic or empirical treatment with triazole antifungal agents, the response rate of the caspofungin group was significantly higher than that of the voriconazole group (76.9% vs 35.3%, P <0.05). A total of 9 patients in both groups experienced adverse reactions, and no grade III or higher adverse reactions occurred. The incidence of grade I-II adverse reactions in the caspofungin group was lower than in the voriconazole group (2.3% vs 17.0%, P <0.05). CONCLUSION In patients with myeloid hematologic malignancies, caspofungin and voriconazole demonstrate comparable clinical efficacy in diagnostic-driven therapy for IFD, but caspofungin is associated with a lower incidence of adverse reactions. Caspofungin exhibits significant effectiveness when initiating diagnostic-driven therapy after prophylactic or empirical treatment with broad-spectrum triazole antifungal agents.
Humans ; Retrospective Studies ; Hematologic Neoplasms/complications* ; Antifungal Agents/therapeutic use* ; Voriconazole/therapeutic use* ; Caspofungin/therapeutic use* ; Invasive Fungal Infections/diagnosis* ; Male ; Female ; Mycoses/drug therapy* ; Middle Aged ; Treatment Outcome ; Aged ; Adult

In recent decades, the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes. The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their clinical use. In this study, we report that berberine (BBR) is an effective drug candidate for the treatment of hyperuricemia, with its mechanism potentially involving the modulation of gut microbiota and its metabolite, succinic acid. BBR has demonstrated good therapeutic effects in both acute and chronic animal models of hyperuricemia. In a clinical trial, oral administration of BBR for 6 months reduced blood uric acid levels in 22 participants by modulating the gut microbiota, which led to an increase in the abundance of Bacteroides and a decrease in Clostridium sensu stricto_1. Furthermore, Bacteroides fragilis was transplanted into ICR mice, and the results showed that Bacteroides fragilis exerted a therapeutic effect on uric acid similar to that of BBR. Notably, succinic acid, a metabolite of Bacteroides, significantly reduced uric acid levels. Subsequent cell and animal experiments revealed that the intestinal metabolite, succinic acid, regulated the upstream uric acid synthesis pathway in the liver by inhibiting adenosine monophosphate deaminase 2 (AMPD2), an enzyme responsible for converting adenosine monophosphate (AMP) to inosine monophosphate (IMP). This inhibition resulted in a decrease in IMP levels and an increase in phosphate levels. The reduction in IMP led to a decreased downstream production of hypoxanthine, xanthine, and uric acid. BBR also demonstrated excellent renoprotective effects, improving nephropathy associated with hyperuricemia. In summary, BBR has the potential to be an effective treatment for hyperuricemia through the gut-liver axis.

OBJECTIVES: To investigate the expression levels of marginal zone B and B1-cell-specific protein (MZB1) in pan-cancer and its association with patient prognosis and tumor microenvironment (TME). METHODS: MZB1 expression data, clinicopathological parameters, and survival data from 33 cancer types were extracted from the UCSC database for analyzing the correlations of MZB1 with clinical stage, patient prognosis, immunomodulatory genes, immune checkpoint genes, tumor stemness, immune cell infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI). MZB1 gene mutations in pan-cancer were assessed using cBioPortal online database, and the value of MZB1 for cancer diagnosis was evaluated using ROC curve analysis. MZB1 expression levels in myeloid leukemia and renal carcinoma cells were detected using RT-qPCR and Western blotting, and the effect of MZB1 knockdown on cell proliferation was examined using EdU assay. RESULTS: MZB1 was significantly overexpressed in 20 cancer types, including kidney renal clear cell carcinoma (KIRC), breast invasive carcinoma, and acute myeloid leukemia. Its expression was associated with TNM stage, clinical stage, overall survival, and progression-free survival in multiple cancers. In most tumors, MZB1 expression was correlated significantly with immunomodulatory genes, immune checkpoint genes, tumor stemness, immune cell infiltration, TMB, and microsatellite instability. Gene amplification was the predominant mutation type of MZB1 in pan-cancer, and MZB1 showed high diagnostic value for skin cutaneous melanoma, KIRC, and head and neck squamous cell carcinoma. MZB1 was highly expressed in different myeloid leukemia cell lines and renal carcinoma cell lines, and MZB1 knockdown significantly suppressed the proliferation of HL60 and 769-P cells. CONCLUSIONS MZB1 is highly expressed in a variety of tumors, and its aberrant expression affects the occurrence and prognosis of many tumors, suggesting its potential as a novel tumor biomarker and immunomodulatory target.
Humans ; Prognosis ; Tumor Microenvironment ; Neoplasms/pathology* ; Cell Line, Tumor ; Mutation ; Kidney Neoplasms ; Microsatellite Instability ; Cell Proliferation ; Carcinoma, Renal Cell

Fusarium head blight (FHB), caused by Fusarium graminearum, not only leads to severe yield losses but also poses a threat to food safety due to the mycotoxins produced by the pathogen. Since this disease is preventable but not curable, the current control mainly relies on chemical fungicides, the long-term use of which may lead to pathogen resistance and environmental pollution. To develop green control methods, we screened 13 biocontrol strains from the rhizosphere soil of wheat, among which strain No. 12 (identified as Pythium aphanidermatum) showed significant antifungal effects. In the plate confrontation test, this strain reduced the colony diameter of the pathogen by 69.2% (1.47 mm vs. 4.78 mm in the control group), with an inhibition rate of 77% (P < 0.01). Microscopic observation revealed obvious deformations in the pathogen hyphae, suggesting a lysing effect. The coleoptile experiment further confirmed that the pre-treatment with this strain reduced the incidence rate to 0. These findings provide new candidate strains for the biocontrol of FHB and offer a scientific basis for reducing the use of chemical fungicides and promoting sustainable agricultural development.
Triticum/growth & development* ; Fusarium/growth & development* ; Plant Diseases/prevention & control* ; Soil Microbiology ; Pest Control, Biological/methods* ; Pythium/physiology* ; Biological Control Agents ; Rhizosphere ; Fungicides, Industrial

Objective To establish a method for the determination of lorlatinib in human plasma by two-dimensional high performance liquid chromatography.Methods In the two-dimensional high performance liquid chromatography method,one-dimensional column SX1E-1A(50 mm × 3.5 mm,5 μm)and two-dimensional column SCB-C18(125 mm × 4.6 mm,5 μm)were used with flow rates of 0.8 mL·min-1 and 1.0 mL·min-1,respectively.The column temperature was 40 ℃,The UV detection wavelength was 317 nm,and the sample size was 500 μL.This study investigated the specificity,standard curve and minimum quantification limit,precision and recovery rate,as well as stability of the method.Results The concentration of lolatinib in human plasma showed a good linear relationship in the range of 11.72-1 018.98 ng·mL-1,and the regression equation was y=944.50x-588.90(R2=0.999 7).The minimum limit of quantification was 11.72 ng·mL-1.The extraction recovery rates of the three quality control samples were 97.61％-99.86％,and the intra-day and inter-day precisions were less than 5.29％,indicating that the detection performance of the method was good.Conclusion The method has the characteristics of good stability,high sensitivity and strong anti-interference ability,and is suitable for the determination of loratinib in human plasma.

Oral health is closely related to systemic health. Common chronic oral diseases, periodontitis and periapical inflammation for example, not only affect the health of oral soft and hard tissues including the alveolar bone and gums, but may also cause changes in systemic conditions such as chronic low-grade inflammation, elevated oxidative stress levels, and dysbiosis of the microbiota. These changes in systemic health can exacerbate the progression of obesity. Therefore, through proactive oral health interventions such as maintaining good oral hygiene habits, modifying dietary structures, and undergoing oral examinations, it is possible to effectively prevent and alleviate inflammatory oral diseases, and actively intervene in obesity. This article delves into the impact of inflammatory oral diseases on obesity and their underlying mechanisms, defines the concept of "oral proactive healthcare", and systematically summarizes their preventive and therapeutic effects on inflammatory oral diseases, thereby demonstrating the potential of improving obesity through proactive oral health strategies.

To analyze the effects of tooth brushing frequency on blood indicators among adolescents and to preliminarily explore the effects of tooth brushing frequency on general health.

G protein-coupled receptor (GPR) 40, as one of GPRs family, plays a potential role in regulating glucose and lipid metabolism. To study the effect of GPR40 novel agonist SZZ15-11 on hyperglycemia and hyperlipidemia and its potential mechanism, spontaneous type 2 diabetic KKA^y mice, human hepatocellular carcinoma HepG2 cells and murine mature adipocyte 3T3-L1 cells were used. KKA^y mice were divided into four groups, vehicle group, TAK group, SZZ (50 mg·kg^-1) group and SZZ (100 mg·kg^-1) group, with oral gavage of 0.5% sodium carboxymethylcellulose (CMC), 50 mg·kg^-1 TAK875, 50 and 100 mg·kg^-1 SZZ15-11 respectively for 45 days. Fasting blood glucose, blood triglyceride (TG) and total cholesterol (TC), non-fasting blood glucose were tested. Oral glucose tolerance test and insulin tolerance test were executed. Blood insulin and glucagon were measured via enzyme-linked immunosorbent assay (ELISA). After mice′s execution, liver tissue was harvested to test TG and TC content. Then pathological morphology of liver was observed through hematoxylin-eosin (HE) staining, and the lipid metabolism relative signal pathway was analyzed by Western blot and RT-PCR. The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. At the same time, Akt phosphorylation level in HepG2 cells and adiponectin in 3T3-L1 cells treated with TNFα were measured with Western blot. The results show that SZZ15-11 not only decreased blood glucose and lipid, improved insulin sensitivity, but also increased fasting blood glucagon and promoted insulin secretion after glucose loading in KKA^y mice. Additionally, SZZ15-11 alleviated hepatic steatosis and liver dysfunction in KKA^y mice. In liver tissue, SZZ15-11 increased AMPKα phosphorylation level and cholesterol metabolism relative gene Abcg8 transcription. In HepG2 cells, SZZ15-11 increased Akt phosphorylation level. In adipocyte 3T3-L1, SZZ15-11 recovered the decreased adiponectin expression by TNFα. This study proved that GPR40 agonist SZZ15-11 could be a candidate compound for regulating glucolipid metabolic disorder.

Objective To explore the construction of comprehensive evaluation model of hospital mobile portal from the perspective of user maintenance.Methods The index system was constructed based on CRM-BSC(customer relationship management-the balanced score card)theory.A comprehensive evaluation model of hospital mobile portal was constructed by introducing cloud model.Finally,three hospital official Apps were selected for empirical research to verify the validity of the model.Results Although the construction status of the hospital's official App is good,it varies greatly in different evaluation dimensions.In the"user value"and"user perceived value"dimension performs well,but in the"user knowledge"and"user interaction"dimension performs poorly,need to be further optimized and improved.Conclusion The comprehensive evaluation model can provide comprehensive evaluation standards and tools for mobile portals,and the research results can provide decision support for medical institutions to improve the services of mobile portals.