BACKGROUND:Macrophage migration inhibitory factor(MIF)is a pleiotropic cytokine,which is secreted in different types of stem cells and can regulate the proliferation,differentiation and migration of various types of stem cells.Our previous research has confirmed that human embryonic stem cells secrete MIF and that its concentration in the culture medium is relatively stable.However,whether MIF is involved in the survival,proliferation and differentiation of human embryonic stem cells remains unclear. OBJECTIVE:To investigate the effects of MIF on survival,proliferation,and differentiation of human embryonic stem cells. METHODS:(1)Human embryonic stem cells H9 were cultured.The growth curve of cells was detected and plotted by CCK-8 assay.Enzyme-linked immunosorbent assay was used to determine the level of MIF in the medium.(2)To determine the effects of exogenous MIF on the survival and proliferation of human embryonic stem cells,different groups were established:the control group,which was cultured in stem cell medium without any modifications;the exogenous MIF group,which was treated with different concentrations(30,100,300 ng/mL)of MIF in the stem cell medium;the MIF inhibitor ISO-1 group,which was treated with different concentrations(2,7,21 μmol/L)of ISO-1 in the stem cell medium;and the MIF+ISO-1 group,which was treated with different concentrations of ISO-1 along with 100 ng/mL of MIF.Cell viability was assessed using the CCK-8 assay.(3)To further elucidate the effect of MIF gene on survival and proliferation of human embryonic stem cell,the MIF knockout H9 cell line was constructed by CRISPR-Cas 9 technology to observe the lineage establishment.(4)To determine the effect of high concentrations of MIF on human embryonic stem cell differentiation,100 ng/mL MIF and 100 ng/mL of CXCR4 neutralizing antibody were separately added to the normal stem cell culture medium.The expression levels of self-renewal factors(KLF4,c-MYC,NANOG,OCT4,and SOX2)and differentiation transcription factors(FOXA2,OTX2)were measured using real-time quantitative polymerase chain reaction,immunofluorescence staining,and western blot analysis. RESULTS AND CONCLUSION:(1)The logarithmic growth phase of H9 cells was between 3-6 days.Under normal growth conditions,human embryonic stem cells secreted MIF at a concentration of approximately 20 ng/mL,independent of cell quantity.(2)Compared to the control group,the addition of different concentrations of MIF had no effect on the proliferation of human embryonic stem cells(P>0.05).ISO-1 significantly inhibited the proliferation of human embryonic stem cells,with a stronger inhibition observed at higher concentrations of ISO-1(P<0.05).The addition of MIF in the presence of ISO-1 reduced the inhibitory effect of ISO-1(P<0.05).(3)Real-time quantitative polymerase chain reaction showed that knocking out 50%of the MIF gene resulted in a significant decrease in the growth vitality of human embryonic stem cells and failure to establish cell lines.(4)Adding 100 ng/mL exogenous MIF to the culture medium resulted in a decrease in the mRNA,protein,and fluorescence expression levels of the self-renewal transcription factor KLF4,while the mRNA,protein,and fluorescence expression levels of the differentiation factor FOXA2 increased.(5)When 100 ng/mL CXCR4 neutralizing antibody was added to the culture medium,the mRNA and protein expression levels of KLF4 increased,while the mRNA and protein expression levels of FOXA2 decreased,contrary to the expression trend observed in the MIF group.In conclusion,the endogenous secretion of MIF by human embryonic stem cells is essential for their survival.The addition of MIF to the culture medium does not promote the proliferation of human embryonic stem cells.However,it can lead to a decrease in the expression of the self-renewal factor KLF4 and an increase in the expression of the transcription factor FOXA2.This provides a clue for further investigation into the effects and mechanisms of MIF on the differentiation of human embryonic stem cells.The MIF-CXCR4 axis plays a regulatory role in this process.

ObjectiveTo observe the clinical efficacy of modified Jinwei Guben Decoction （金卫固本汤， MJGD） combined with Bailing Capsule （百令胶囊， BC） in the treatment of chronic obstructive pulmonary disease （COPD） patients in the stable stage with qi deficiency， blood stasis and phlegm obstruction syndrome， in addition to conventional western medicine treatment. MethodsA total of 102 patients with stable COPD and qi deficiency， blood stasis， and phlegm obstruction syndrome were included in the study. According to the patients'preferences， they were divided into treatment group （49 cases） and control group （53 cases）. The control group received conventional western medicine treatment， while the treatment group was given MJGD （1 dose daily） combined with BC （2.0 g each time， three times a day） additionally. The treatment period was 3 months， and the patients were followed up for 1 year after the treatment. The acute exacerbation frequency （mild， moderate， severe） before treatment， during treatment， at 6-month follow-up， and at 1-year follow-up was compared between groups. Additionally， the lung function indicators such as FEV₁， FEV₁%pred， FVC， and FEV₁/FVC ratio， traditional Chinese medicine （TCM） syndrome scores， modified British Medical Research Council （mMRC） dyspnea scale， and the COPD Assessment Test （CAT） scores before and after treatment were compared. A logistic regression model was constructed to analyze the impact of MJGD combined with BC on clinical efficacy. ResultsFour patients dropped out from the treatment group and eight from the control group， leaving 45 patients of each group for statistical analysis. The number of mild and moderate acute exacerbations in the treatment group was lower than that in the control group during the treatment period， at 6-month follow-up and within 1 year of follow-up （P＜0.05） .The number of severe acute exacerbations was only lower in the treatment group than in the control group at 6-month follow-up （P＜0.05）. Compared with that before treatment， the number of acute exacerbations of all degrees in the treatment group was significantly reduced within 1 year of follow-up （P＜0.05），while only the number of mild acute exacerbations in the control group was significantly reduced within 1 year of follow-up （P＜0.05）. The treatment group showed significant improvement in FEV₁ and FEV₁%pred and FEV₁/FEV， while the control group showed a significant decline in FEV₁ and FVC （P＜0.05）. After treatment， both groups showed significant reductions in TCM syndrome scores， including coughing， sputum， wheezing， chest tightness， shortness of breath， and fatigue， as well as mMRC and CAT scores （P＜0.05）， with the treatment group having significantly lower scores than the control group （P＜0.05）. The overall clinical effective rate of in the treatment group was 93.33% （42/45）， significantly higher than that of the control group， 75.56% （34/45， P＜0.05）. Multivariate logistic regression analysis showed that the use of MJGD combined with BC （OR = 4.68， 95%CI： 1.15 - 19.09， P = 0.03） was positively correlated with clinical efficacy. ConclusionsIn addition to conventional western medicine treatment， the combination of MJGD and BC can reduce the frequency of acute exacerbations， delay the decline of lung function， improve clinical symptoms， and significantly enhance the clinical efficacy in patients with stable COPD and qi deficiency， blood stasis， and phlegm obstruction syndrome.

ObjectiveTo study the effect of Jinwei Pingchuan decoction combined with conventional Western medicine on the number of acute exacerbations， lung function， and clinical symptoms in patients with acute exacerbation of chronic obstructive pulmonary disease （COPD） with phlegm-heat obstruction in lung syndrome. MethodsA non-randomized controlled trial was conducted to include 60 patients with acute exacerbation of COPD with phlegm-heat obstruction in lung syndrome. Patients were divided into a treatment group and a control group based on whether they received Jinwei Pingchuan decoction， with 30 patients in each group. The treatment group received Jinwei Pingchuan decoction combined with conventional Western medicine therapy， while the control group received conventional Western medicine therapy alone. Both groups received treatment for 7 days. The number of acute exacerbations and lung function indices were followed up and recorded before treatment and three months after treatment. The following outcomes were observed before and after treatment： the number of acute exacerbations， lung function indices （forced expiratory volume in one second ［FEV₁］， percentage of predicted value ［FEV₁%pred］， forced vital capacity ［FVC］， and FEV₁/FVC ratio）， the degree of acute exacerbation， TCM syndrome score， COPD assessment test （CAT） score， modified British Medical Research Council Dyspnea Questionnaire （mMRC） score， C-reactive protein （CRP）， and white blood cell （WBC） count. ResultsAfter 3 months of follow-up， the treatment group showed a significant reduction in the number of acute exacerbations compared with the pre-treatment values （P<0.05）. After treatment， the treatment group had fewer acute exacerbations than the control group （P<0.05）. The degree of acute exacerbation in the treatment group improved significantly compared with the pre-treatment values （P<0.05）. After treatment， the degree of acute exacerbation in the treatment group was improved compared to the control group （P<0.05）. Regarding lung function， FEV₁， FEV₁%pred， FVC， and FEV₁/FVC ratio increased significantly in the treatment group compared with the pre-treatment values （P<0.05）， and similar improvements were observed in the control group （P<0.05）. After treatment， FEV₁ and FVC were higher in the treatment group than the control group （P<0.05）. Regarding TCM syndrome scores， the scores for individual symptoms such as wheezing， cough， expectoration， chest tightness， shortness of breath， and fatigue， as well as the total score， decreased significantly in the treatment group compared with the pre-treatment values （P<0.05）. In the control group， the scores for cough， expectoration， chest tightness， fatigue， and palpitation， as well as the total score， also decreased （P<0.05）. After treatment， the treatment group showed significantly lower scores for wheezing， cough， chest tightness， shortness of breath， and the total score than the control group （P<0.05）. Regarding the CAT score， the scores for cough， expectoration， chest tightness， climbing stairs， going out， activity， and energy， as well as the total score， decreased significantly in the treatment group compared with the pre-treatment values （P<0.05）. In the control group， the scores for cough， expectoration， chest tightness， sleep， energy， and the total score decreased （P<0.05）. After treatment， the treatment group showed significantly lower scores for cough， expectoration， chest tightness， activity， and going out than the control group （P<0.05）. Regarding the mMRC score， CRP level， and WBC count， all these parameters decreased significantly in the treatment group compared with the pre-treatment values （P<0.05）， and similar reductions were observed in the control group （P<0.05）. ConclusionJinwei Pingchuan decoction can reduce the number of acute exacerbations and the degree of acute exacerbation in patients with acute exacerbation of COPD with phlegm-heat obstruction in lung syndrome. It also improves lung function and symptoms such as cough and chest tightness， thereby enhancing the quality of life of patients.

ObjectiveTo study the effect of Jinwei Pingchuan decoction combined with conventional Western medicine on the number of acute exacerbations， lung function， and clinical symptoms in patients with acute exacerbation of chronic obstructive pulmonary disease （COPD） with phlegm-heat obstruction in lung syndrome. MethodsA non-randomized controlled trial was conducted to include 60 patients with acute exacerbation of COPD with phlegm-heat obstruction in lung syndrome. Patients were divided into a treatment group and a control group based on whether they received Jinwei Pingchuan decoction， with 30 patients in each group. The treatment group received Jinwei Pingchuan decoction combined with conventional Western medicine therapy， while the control group received conventional Western medicine therapy alone. Both groups received treatment for 7 days. The number of acute exacerbations and lung function indices were followed up and recorded before treatment and three months after treatment. The following outcomes were observed before and after treatment： the number of acute exacerbations， lung function indices （forced expiratory volume in one second ［FEV₁］， percentage of predicted value ［FEV₁%pred］， forced vital capacity ［FVC］， and FEV₁/FVC ratio）， the degree of acute exacerbation， TCM syndrome score， COPD assessment test （CAT） score， modified British Medical Research Council Dyspnea Questionnaire （mMRC） score， C-reactive protein （CRP）， and white blood cell （WBC） count. ResultsAfter 3 months of follow-up， the treatment group showed a significant reduction in the number of acute exacerbations compared with the pre-treatment values （P<0.05）. After treatment， the treatment group had fewer acute exacerbations than the control group （P<0.05）. The degree of acute exacerbation in the treatment group improved significantly compared with the pre-treatment values （P<0.05）. After treatment， the degree of acute exacerbation in the treatment group was improved compared to the control group （P<0.05）. Regarding lung function， FEV₁， FEV₁%pred， FVC， and FEV₁/FVC ratio increased significantly in the treatment group compared with the pre-treatment values （P<0.05）， and similar improvements were observed in the control group （P<0.05）. After treatment， FEV₁ and FVC were higher in the treatment group than the control group （P<0.05）. Regarding TCM syndrome scores， the scores for individual symptoms such as wheezing， cough， expectoration， chest tightness， shortness of breath， and fatigue， as well as the total score， decreased significantly in the treatment group compared with the pre-treatment values （P<0.05）. In the control group， the scores for cough， expectoration， chest tightness， fatigue， and palpitation， as well as the total score， also decreased （P<0.05）. After treatment， the treatment group showed significantly lower scores for wheezing， cough， chest tightness， shortness of breath， and the total score than the control group （P<0.05）. Regarding the CAT score， the scores for cough， expectoration， chest tightness， climbing stairs， going out， activity， and energy， as well as the total score， decreased significantly in the treatment group compared with the pre-treatment values （P<0.05）. In the control group， the scores for cough， expectoration， chest tightness， sleep， energy， and the total score decreased （P<0.05）. After treatment， the treatment group showed significantly lower scores for cough， expectoration， chest tightness， activity， and going out than the control group （P<0.05）. Regarding the mMRC score， CRP level， and WBC count， all these parameters decreased significantly in the treatment group compared with the pre-treatment values （P<0.05）， and similar reductions were observed in the control group （P<0.05）. ConclusionJinwei Pingchuan decoction can reduce the number of acute exacerbations and the degree of acute exacerbation in patients with acute exacerbation of COPD with phlegm-heat obstruction in lung syndrome. It also improves lung function and symptoms such as cough and chest tightness， thereby enhancing the quality of life of patients.

In recent years, the incidence of multiple primary lung cancer (MPLC) has been increasing, and it cannot be ignored in clinical practice. The treatment of MPLC is still controversial, but surgical treatment is recognized as the most important treatment. However, current studies have shown that the treatment of MPLC needs to develop multimodal treatment according to different patients. This review summarizes multiple treatment method for MPLC, including surgery, ablation, chemotherapy, radiotherapy, targeted therapy, and immunotherapy in order to enhance understanding of MPLC treatment.
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Humans ; Lung Neoplasms/surgery* ; Immunotherapy ; Combined Modality Therapy

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice via suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5-NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5-NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5-NEK7 interaction.

Pelvic organ prolapse (POP), whose etiology is influenced by genetic and clinical risk factors, considerably impacts women's quality of life. However, the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored. This study constructed the first polygenic risk score (PRS) for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study. We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls. Results showed that the case group exhibited a significantly higher PRS than the control group. Moreover, the odds ratio of the top 10% risk group was 2.6 times higher than that of the bottom 10%. A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths. As far as we know, the integrated prediction model, which combined PRS and clinical risk factors, demonstrated better predictive accuracy than other existing PRS models. This combined risk assessment model serves as a robust tool for POP risk prediction and stratification, thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.
Humans ; Female ; Pelvic Organ Prolapse/epidemiology* ; Middle Aged ; Risk Assessment/methods* ; China/epidemiology* ; Multifactorial Inheritance ; Aged ; Risk Factors ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Case-Control Studies ; Adult ; Polymorphism, Single Nucleotide ; Genetic Risk Score ; East Asian People

Objective To evaluate the impact of flash glucose monitoring(FGM)system on glycemic control and adverse pregnancy outcome in pregnant women with type 2 diabetes mellitus(T2DM).Methods This prospective,open-label,randomized,controlled clinical trial involved 109 women with T2DM at 16～18 weeks of gestation who visited Liaocheng People's hospital and Liaocheng Women and Children Hospital from June 2018 to June 2022.They were randomly assigned to FGM group(54 cases)and control group(55 cases).The FGM group wore FGM at 20,24,28 and 32 weeks of pregnancy respectively.The Con group underwent self-monitoring of blood glucose(SMBG).Both groups adjusted insulin doses based on blood glucose monitoring results.HbA1c was measured at 18 weeks and 36 weeks of pregnancy.Information related to adverse pregnancy outcomes was compared between the two groups.Results Fasting and postprandial glucose and HbA1c were significantly lower in FGM group compared with con group(P<0.05).Neonatal hypoglycemia was significantly lower in FGM group(P<0.05).There was no difference between the two groups in terms of BMI,insulin dose,gestational week of delivery,Apgar score,neonatal weight and the incidence of preeclampsia,premature delivery,polyhydramnios,cesarean section,SGA,macrosomia and postpartum hemorrhage(P>0.05).Time in range(TIR),time below range(TBR),time above range(TAR),and mean amplitude of glucose excursion(MAGE)were significantly improved at 32 weeks compared to 20 weeks in FGM group(P<0.05).Conclusions Repeated intermittent use of FGM in pregnant women with T2DM could reduce the blood glucose level and the incidence of neonatal hypoglycemia.

Objective:To assess the performance of machine learning(ML),and integrate the clinical parameters with coronary artery calcium(CAC)score of computed tomography(CT)and quantification of automated epicardial adipose tissue(EAT),so as to predict the long-term risk of myocardial infarction(MI)and cardiogenic death in asymptomatic patients.Methods:A total of 1 058 subjects with cardiovascular risk factors and without symptoms of coronary heart disease who underwent physical examination at the Fifth Medical Center of Chinese PLA General Hospital from January 2013 to October 2015 were selected as this study subjects.A long-term follow-up was conducted on them after CAC score.EAT volume and density were quantified using a fully automated deep learning method.ML extreme gradient boosting was trained by using clinical data,risk score of atherosclerotic cardiovascular disease,CAC score and automated EAT measure,and the repeated 10-fold cross validation was used to verify the model.Results:During the 8-year follow-up period,61 cases of 1 058 subjects occurred events of MI and(or)cardiac death.The area under curve(AUC)value of ML was significantly higher than that of the atherosclerotic cardiovascular disease(ASCVD)risk and the predicting events of CAC score(ML:0.82,ASCVD:0.77,CAC:0.77).Compared with ML with only clinical variable,machine learning based on ASCVD,CAC and EAT had more predictive ability for MI and cardiac death[AUC 0.82(95%CI:77-87)vs.0.78(95%CI:0.72-0.84),P=0.02].The survival rate of subjects with high ML scores had a greater decline degree with the increasing of time,therefore,the subjects with higher ML scores were more likely to experience events.Conclusion:ML,which integrated clinical and quantitative imaging variables,can provide long-term risk prediction for patients with cardiovascular risk factors.