The remarkable efficacy of chimeric antigen receptor (CAR) T cell therapy in hematological malignancies has provided a solid basis for the therapeutic concept, wherein specific pathogenic cell populations can be eradicated by means of targeted recognition. During the past few years, CAR-based cell therapies have been extensively investigated in preclinical and clinical research across various non-tumor diseases, with particular emphasis in the treatment of autoimmune diseases (ADs), yielding significant advancements. The recent deployment of CD19-directed CAR T cells has induced long-lasting, drug-free remission in patients with systemic lupus erythematosus (SLE) and other systemic ADs, alongside a more profound immune reconstruction of B cell repertoire compared with conventional immunosuppressive agents and B cell-targeting biologics. Despite the initial success achieved by CAR T cell therapy, it is critical to acknowledge the divergences in its application between cancer and ADs. Through examining recent clinical studies and ongoing research, we highlight the transformative potential of this therapeutic approach in the treatment of SLE, while also addressing the challenges and future directions necessary to enhance the long-term efficacy and safety of CAR-based cell therapies in clinical practice.
Humans ; Lupus Erythematosus, Systemic/immunology* ; Receptors, Chimeric Antigen/metabolism* ; Immunotherapy, Adoptive/methods* ; Cell- and Tissue-Based Therapy/methods* ; Animals ; T-Lymphocytes/immunology*

Objective To investigate the changes and clinical significance of plasminogen activator inhibi-tor-1(PAI-1),transforming growth factor-β(TGF-β),vascular endothelial growth factor(VEGF),and inter-leukin-6(IL-6)in patients with tuberculous pleurisy and pleural fibrosis.Methods A total of 103 patients with tuberculous pleurisy and pleural fibrosis who were treated in a hospital from July 2020 to July 2023 were selected as the research subjects.After 2 weeks of treatment,they were divided into a significant effect group and a non-significant effect group based on the therapeutic efficacy of glucocorticoid treatment.The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion were compared before treatment,after 1 and 2 weeks of treatment.The correlation between the levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion and the therapeutic efficacy was analyzed by Spearman correlation analysis.Pearson correlation analy-sis was used to analyze the correlation between the levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleu-ral effusion and the levels of these indicators in pleural effusion after 2 weeks of treatment.A receiver operat-ing characteristic curve was drawn to analyze the predictive value of the levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion for the efficacy of tuberculous pleurisy and pleural fibrosis patients after 1 and 2 weeks of treatment.Results The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion after 1 and 2 weeks of treatment in both groups were lower than those before treatment,and the levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion after 1 and 2 weeks of treatment in the significant effect group were lower than those in the non-significant effect group,with statistically significant differences(P＜0.05).The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion after 1 and 2 weeks of treatment were negatively correlated with the efficacy(P＜0.05).The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion after 2 weeks of treatment were positively correlated(r=0.761,0.783,0.812,0.741,all P＜0.05).The area under the curve(AUC)of combined detection of serum and pleural effusion in-dicators after 1 and 2 weeks of treatment was greater than the AUC of individual indicators(P＜0.05).Con-clusion The levels of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion of patients with tubercu-lous pleurisy and pleural fibrosis are related to the efficacy of treatment.The combined detection of PAI-1,TGF-β,VEGF,and IL-6 in serum and pleural effusion has good predictive value and can provide reference for clinical intervention.

Objective:To evaluate the role of hippocampal β4-Subunit-Containing Nicotinic Acetylcholine Receptors (Chrnb4) in postoperative delirium in aged mice.Methods:Forty-eight SPF male C57BL/6J mice, aged 18 months, weighing 29-35 g, were assigned into 6 groups using a random number table method: tibial fracture group (TF group, n=6), sham operation group (Sham group, n=6), tibial fracture + adipenine group (TA group, n=9), tibial fracture + control vehicle group (TV group, n=9), sham operation + adipenine group (SA group, n=9), and sham operation + control vehicle group (SV group, n=9). The postoperative delirium model was prepared by tibial fracture under sevoflurane anesthesia. Tibial fracture was simulated by implanting a steel pin into the tibia and then clamping it, while sham group only received a longitudinal incision and suture after anesthesia. A microinjection cannula was implanted into the mouse skull at 5 days before developing the model in TA group, TV group, SA group and SV group. Three mice from each group were randomly selected for microelectrode implantation in the hippocampal CA1 area. Starting from 30 min after surgery, adipenine (62.5 nmol/μl) 2 μl was infused into the cerebral ventricle for 7 consecutive days in TA and SA groups, and vehicle (2 μl) was administered instead at a 24-h interval for 7 consecutive days in TV and SV groups. The expression of Chrnb4 mRNA in the hippocampal tissues was detected by real-time quantitative polymerase chain reaction at 24 h after surgery. On the 7th and 8th days after surgery, the open-field test and O-maze experiment were conducted to assess the impulsive-like behavior in TA, TV, SA and SV groups. After the behavioral test, the expression of glial fibrillary acidic protein (GFAP) and vesicular glutamate transporter 1 (Vglut1) in the hippocampal CA1 region was detected by immunofluorescence staining. The local field potentials in the hippocampal CA1 region were recorded during the open field test. Results:The expression of Chrnb4 mRNA in the hippocampal tissues was significantly up-regulated in TF group compared to Sham group ( P<0.05). Compared with TV group, the percentage of central path distance in the open field test and percentage of time spent in the open arms of the O-maze were significantly decreased, the power of β-waves in the CA1 field potentials was decreased, the expression of GFAP and Vglut1 in the hippocampal CA1 region was down-regulated, and the co-staining area of GFAP + and Vglut1 + was decreased in TA group and SV group ( P<0.05). There was no significant difference in each parameter between SA group and SV group ( P>0.05). Conclusions:Hippocampal Chrnb4 may be involved in the mechanism of postoperative delirium in aged mice, and this process may be related to inhibition of neuron excitotoxicity.

Objective:To analyze the influencing factors of thyroid volume in children aged 8 - 10 in Yunnan Province, and provide scientific basis for improving iodine deficiency disorders monitoring.Methods:From March to July 2020, in 129 counties (cities, districts) under the jurisdiction of Yunnan Province, each county (city, district) was divided into 5 sampling areas based on east, west, south, north, and middle. One township was selected from each area, and 40 non-boarding children aged 8 - 10 from one primary school were selected from each township (age balanced, half male and half female) as survey subjects. One random urine sample and household edible salt samples were collected for urine iodine and salt iodine testing, and physical examination and thyroid volume measurement were conducted for children. The influencing factors of thyroid volume were analyzed using Pearson correlation.Results:A total of 24 934 urine samples were collected from children, with a median urine iodine of 233.2 μg/L. A total of 24 933 household edible salt samples were collected from children, the median salt iodine was 24.17 mg/kg, and the qualified rate of iodized salt was 96.63% (24 003/24 839); A total of 24 937 children were examined of their thyroid gland, with a median thyroid volume of 2.62 ml and a goiter rate of 1.12% (280/24 937). Among them, there were 12 410 boys and 12 527 girls, with thyroid volumes of 2.61 and 2.64 ml, respectively. The thyroid volume of boys was positively correlated with age, height, weight, body mass index, body surface area, and salt iodine ( r = 0.15, 0.21, 0.26, 0.18, 0.25, 0.03, P < 0.001). The thyroid volume of girls was positively correlated with age, height, weight, body mass index, and body surface area ( r = 0.17, 0.26, 0.28, 0.17, 0.27, P < 0.001). Conclusion:Children aged 8 - 10 in Yunnan Province are at an iodine excess level; the age, weight, height, body mass index, and body surface area are influencing factors of thyroid volume.

Objective:To understand the contents of edible salt iodine and urinary iodine of children and pregnant women in Yunnan Province, and to evaluate the iodine nutrition status, so as to provide a basis for scientific prevention and treatment of iodine deficiency disorders (IDD).Methods:From November to December 2020, one county (city) was selected from each prefecture (city), two townships (towns and streets) were selected from each county (city) and two villages (neighborhood committees) were selected from each township (town and street) from each of the 16 prefectures (cities) in Yunnan Province as the investigation sites. A total of 20 non-boarding children (male and female balanced) aged 8 - 10 years old were selected from each primary school in each village (neighborhood committee) to collect salt and urine samples. A total of 80 children were investigated in each county (city). A total of 20 pregnant women were selected from each township (town and street) to collect salt and urine samples. A total of 40 pregnant women were investigated in each county (city). All salt samples and urine samples were tested for iodine contents.Results:A total of 2 009 salt samples and 2 041 urine samples (1 375 for children, 666 for pregnant women) were collected from children aged 8 - 10 years old and pregnant women in 16 counties (cities) of Yunnan Province. Among them, the median salt iodine was 26.0 mg/kg, the coverage rate of iodized salt was 100.0% (2 009/2 009), the qualified rate of iodized salt was 98.7% (1 982/2 009), and the consumption rate of qualified iodized salt was 98.7% (1 982/2 009). The difference of salt iodine content in key populations in different counties (cities) was statistically significant ( H = 258.98, P < 0.01). The median urinary iodine of children aged 8 - 10 years old was 188.5 μg/L. There was statistically significant difference in urinary iodine content among children of different ages ( H = 29.45, P < 0.01), but there was no statistically significant difference in urinary iodine content among children of different genders ( H = 1.43, P > 0.05). In addition, the median urinary iodine of pregnant women was 141.9 μg/L, 52.1% (347/666) was < 150 μg/L. There was statistically significant difference in urinary iodine content of pregnant women in different counties (cities, H = 88.32, P < 0.01). Conclusions:The qualified rate of iodized salt, the coverage rate of iodized salt and the consumption rate of qualified iodized salt in key populations of Yunnan Province are more than 90%, and the iodized salt supply is good. Iodine nutrition of children aged 8 - 10 years old is at an appropriate level (100 - 199 μg/L); iodine nutrition of pregnant women is in an state of iodine deficiency ( < 150 μg/L). It is suggested to strengthen IDD monitoring and health education among key populations, improve residents' awareness of disease prevention, and make scientific iodine supplementation.

Objective:To systematically evaluate the role of air pollutants in the development and exacerbation of autoimmune rheumatic diseases.Methods:We followed PRISMA guidelines and searched EMBASE, Scopus, PubMed, and Cochrane Library databases using keywords and MeSH terms from inception to July 2019. Observational studies reporting the relationship between autoimmune rheumatic diseases and exposure to certain air pollutants were included. Screening of literature according to established inclusion and exclusion criteria. No meta-analysis but the qualitative analysis was conducted due to the high methodological heterogeneity.Results:A total of 24 studies were included. Rheumatoid arthritis (RA) ( n=6), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) ( n=1), ankylosing spondylitis (AS) ( n=1), systemic lupus erythematosus (SLE) ( n=3), childhood-onset systemic lupus erythematosus (cSLE) ( n=3), juvenile idiopathic arthritis (JIA) ( n=2), Kawasaki disease (KD) ( n=4), systemic autoimmune rheumatic diseases (SARD) ( n=4). The results of the study suggested that short-term elevation in particulate matter (PM)2.5 concentration was possibly associated with an increased risk of SLE and cSLE flare-ups, disease activity of AS, JIA and SARDs exacerbation. Studies demonstrated an increased risk of RA with cumulative exposure to carbon monoxide (CO), nitrogen dioxide (NO 2), ozone (O 3), and sulfur dioxide (SO 2). Only one study demonstrated an increased risk of KD admission with elevated O 3 levels. No association was found between AAV and ambient air pollution. Conclusion:Air pollution is likely to be involved in the development and exacerbation of certain autoimmune diseases. At the same time, the mechanism of autoimmune diseases of ambient air pollutants should be actively studied, so as to promote the early prevention of cardiovascular diseases.

Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate (4-OI) is a cell-permeable itaconate derivative and has been recognized as a promising therapeutic target for the treatment of inflammatory diseases. Here, we explored, for the first time, the protective effect of 4-OI on inhibiting periodontal destruction, ameliorating local inflammation, and the underlying mechanism in periodontitis. Here we showed that 4-OI treatment ameliorates inflammation induced by lipopolysaccharide in the periodontal microenvironment. 4-OI can also significantly alleviate inflammation and alveolar bone loss via Nrf2 activation as observed on samples from experimental periodontitis in the C57BL/6 mice. This was further confirmed as silencing Nrf2 blocked the antioxidant effect of 4-OI by downregulating the expression of downstream antioxidant enzymes. Additionally, molecular docking simulation indicated the possible mechanism under Nrf2 activation. Also, in Nrf2^-/- mice, 4-OI treatment did not protect against alveolar bone dysfunction due to induced periodontitis, which underlined the importance of the Nrf2 in 4-OI mediated periodontitis treatment. Our results indicated that 4-OI attenuates inflammation and oxidative stress via disassociation of KEAP1-Nrf2 and activation of Nrf2 signaling cascade. Taken together, local administration of 4-OI offers clinical potential to inhibit periodontal destruction, ameliorate local inflammation for more predictable periodontitis.
Alveolar Bone Loss/prevention & control* ; Animals ; Antioxidants/pharmacology* ; Inflammation ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Mice ; Mice, Inbred C57BL ; Molecular Docking Simulation ; NF-E2-Related Factor 2/metabolism* ; Periodontitis/prevention & control* ; Succinates

Objective:To systematically evaluate the effectiveness and safety of intra-articular in-jection of mesenchymal stem cells (MSCs) and hyaluronic acid (HA) in the treatment of knee osteoarthritis.Methods:The relevant literatures published in both English and Chinese were systematically searched in PubMed, Embase, Wanfang database, China Knowledge Network (CNKI), SinoMed database and other data-bases from inception to May 2020. Two researchers independently extracted data and evaluated the included literature. Risk assessment of literature bias was carried out. RevMan 5.3 software was used for Meta analysis, and the combined sensitivity were calculated.Results:Finally, 13 references were included, including a total of 726 patients with knee osteoarthritis. Meta-analysis results showed that compared with the HA group, the Western Ontario and McMaster University Osteopathic Index Total Score (WOMAC) [ MD=-10.92, 95% CI (-16.87, -4.96), P<0.01], the visual analogue scale (VAS) score [ MD=-1.70, 95% CI(-2.44, -0.95), P<0.01], and the knee joint Lequesne index score of MSCs group all decreased significantly [ MD=-13.78, 95% CI (-15.03,-12.52), P<0.01]. Furthermore, there was no significant difference in the incidence of adverse events (AEs) between the two groups [ RR=1.11, 95% CI(0.90, 1.37), P=0.33]. However, American Knee Association Score (AKS score) [ MD=-10.15, 95% CI(-22.33, 2.03), P=0.10] and whole-organ magnetic resonance imaging score (WORMS) [ MD=-3.93, 95% CI(-11.60, 3.75), P=0.32] were not statistically significant ( P>0.05). Conclusion:Compared with intra-articular injection of HA, intra-articular injection of MSCs can significantly improve the symptoms and dysfunction, and has favorable clinical tolerability and safety, suggesting that MSCs is expected to bea new treatment for knee osteoarthritis.

Objective:To accurately grasp the current status of water iodine distribution in environmental of Yunnan Province, and provide a basis for scientific iodine supplementation.Methods:In 2017, according to the "National Drinking Water Iodine Content Survey Program", a survey of water iodine content was conducted in townships. In 2018, a search survey was carried out for administrative villages with water samples of iodine content > 40 μg/L in drinking water found in previous surveys. In centralized water supply villages, 2 samples of end water were collected. In decentralized or partially decentralized water supply villages, each village was divided into 5 parts: east, south, west, north and center. In villages with more than 50 water sources, 10% of the water sources were selected from each part; villages with less than 50 water sources, one water source was selected from each part; villages with less than 5 water sources, all the water sources were selected to determine the water iodine content. At the same time, the mode of water supply and demographic data were investigated.Results:At the township level water iodine survey, a total of 24 589 water samples were collected from 1 389 townships in 129 counties of 16 prefectures (cities). The median water iodine content of township was 1.3 μg/L, ranging 0.0 - 9.3 μg/L. The population covered by the survey accounted for 53.94% (25 013 804/46 371 207) of the total population of the province. According to the survey results of high iodine villages, 93 administrative villages in 68 townships of 37 counties in 12 prefectures (cities) were surveyed, covering 40 940 households and 208 880 people. A total of 761 samples of drinking water were tested, and the median water iodine content of administrative villages was 1.3 μg/L (ranging 0.0 - 196.8 μg/L). There were 2 administrative villages with iodine higher than 100 μg/L, which were Xiaobona Administrative Village (145.8 μg/L) in Liuchang Township, Xiangyun County, and Dasongshu Administrative Village (196.8 μg/L) in Yangchang Township, Xuanwei City.Conclusions:The iodine content of water in Yunnan Province is generally low, which belongs to the area of environmental iodine deficiency. For the high iodine villages, further investigation should be carried out to clarify the prevention and control measures.

Objective:To evaluate the association between the efficacy and safety of metformin and the influence of variants in SLC47A1 rs2289669 G>A polymorphism in the treatment of systemic lupus erythematosus (SLE).Methods:A multicenter, randomized, double-blind, placebo-controlled trial was conducted. Patients were consented at enrollment for blood donation for genotyping, and their peripheral blood were used to detect the distribution frequency of SLC47A1 mutations. The major or mild/moderate flares defined by modified safety lupus erythematosus national assessment (SELENA)-systemic lupus erythematosus disease activity index (SLEDAI) Flare Index (SFI) and adverse events were recorded at 12 months of follow-up. The correlation between efficacy/safety and genotype was analyzed. Student's t test and χ2 test was used to assess the continuous variables and categorical variables. Results:Between May 24, 2016, and Dec 13, 2017, a total of 31 patients in the metformin group and 35 in the placebo group were detected. There were no statistical significant differences in the clinical manifestations, SELENA-SLEDAI scores, and therapy of the participants at baseline. There was no significant difference in the frequency of AA genotype, GA genotype, and GG genotype of SLC47A1 rs2289669 distribution between the metformin group and the placebo group. In the metformin group, patients who flared had a lower frequency of A alleles than those non-flared [25%(4/16) vs 61%(28/46), χ2=6.116, P=0.019 8]; the flare rate was significantly lower in patients with AA genotype than in GG genotype [0%(0/8) vs 57%(4/7), χ2=6.234, P=0.012 5]. The infection rate was lower in the metformin group than that in the placebo group [38%(12/31) vs 69%(24/35), χ2=5.913, P=0.015 0], but there was no significant difference among different genotypes in the metformin group. Compared to GG geno-type, AA genotype showed a trend of decrease in infection rate[38%(3/8) vs 72%(5/7), χ2=1.727, P=0.188 8]. Conclusion:Metformin has a favorable safety profile and may reduce the frequency of flares in SLE patients with low-grade lupus disease activity. The metformin therapeutic efficacy in SLE is relevant to the SLC47A1 gene polymorphism. Patients of the AA genotype may benefit most from metformin than those of the GG and GA genotypes.