Objective To explore the potential causal relationship between childhood obesity and the risk of inflammatory bowel disease(IBD)based on Mendel randomization(MR).Methods The genome-wide association study(GWAS)data for childhood obesity included 5 530 cases and 8 318 controls.The GWAS data for IBD included 5 673 cases and 213 119 controls.The GWAS data for ulcerative colitis included 4 320 cases and 210 300 controls.The GWAS data of Crohn's disease included 2 056 cases and 210 300 controls.The risk association between obesity and the occurrence of IBD was analyzed using the inverse variance weighted meth-od(IVW),general model,weighted model,weighted median,and MR-Egger.Results Fourteen independent single nucleotide polymorphisms(SNP)significantly associated with childhood obesity were screened out as instrumental variables.IVW analysis results showed that no potential causal association was found between childhood obesity and IBD(OR=1.048,95%CI:0.976-1.125),ulcerative colitis(OR=1.026,95%CI:0.946-1.113),and Crohn's disease(OR=1.123,95%CI:0.993-1.269,P>0.05).Conclusion There was no causal relationship between childhood obesity and the risk of IBD.

Objective:To explore the diagnostic value of the macrophage activation syndrome/systemic juvenile idiopathic arthritis（MS）score in macrophage activation syndrome（MAS）associated with systemic juvenile idiopathic arthritis（sJIA），and to provide a reference for clinical work.Methods:This study was a retrospective case-control analysis，conducted on the patients initially diagnosed as sJIA-associated with MAS and admitted into the Department of Rheumatology and Immunology of Children's Hospital Affiliated to Xi 'an Jiaotong University from July 1st，2016 to June 30th，2023. All of the patients met the diagnostic criteria for patients with MAS associated with sJIA according to the 2016 European Alliance of Associations for Rheumatology（EULAR）/American College of Rheumatology（ACR）/Pediatric Rheumatology International Trials Organization（PRINTO）standards. The basic information at baseline，clinical manifestations，and auxiliary examination results were collected. The MS score was applied to re-evaluate the children diagnosed as sJIA-associated with MAS. When the MS score ≥-2.1，the possibility of sJIA with MAS was high. Thirty cases of sJIA without MAS were randomly selected as the control group.Results:There were 28 cases in the MAS group，including 13 males（46.43%）and 15 females（53.57%），with an average age of（7.51±4.01）years. Compared with the control group，the MAS group were significantly more likely to have high fever（ χ2=8.539， P=0.003），hepatomegaly（ χ2=11.621， P<0.001），splenomegaly（ χ2=11.710， P<0.001）and neurological involvement（ χ2=27.619， P<0.001），with the differences being statistically significant. Meanwhile，there were statistically significant differences between the two groups in terms of white blood cell count（ Z=-4.001， P<0.001），neutrophil count（ Z=-3.659， P<0.001），platelet count（ Z=-4.687， P<0.001），albumin level（ Z=-4.018， P<0.001），alanine aminotransferase（ Z=-3.846， P<0.001），aspartate aminotransferase（ Z=-5.932， P<0.001），lactate dehydrogenase（ Z=-6.150， P<0.001），triglycerides（ Z=-5.874， P<0.001），fibrinogen（ Z=-5.808， P<0.001），ferritin（ Z=-5.280， P<0.001），erythrocyte sedimentation rate（ Z=-3.971， P<0.001），ferritin/erythrocyte sedimentation rate（ Z=-5.433， P<0.001），reduction of two-line cells in blood（ χ2=11.408， P<0.001）and the presence of hemophagocytosis in bone marrow smears（ χ2=28.260， P<0.001）. Moreover，there was a statistically significant difference in MS scores between the two groups（ Z=-6.148， P<0.001），with higher MS scores in the MAS group. Nevertheless，this study showed the median MS scores of both groups ≥-2.1. Conclusion:The MS score was significant to a certain degree as reference for the diagnosis of MAS，and this study showed that the MS score in the MAS group was significantly higher than the control group. However，the median MS scores in both groups were no less than -2.1. This might be related to the influence of factors during the assessment，which made it necessary to optimize the cutoff values of the MS score. Therefore，prospective studies should be carried out on the role of MS score in early identification of MAS.

Objective To observe the clinical efficacy of Xiaoyu Sanjie Prescription,which is derived from classical prescriptions Chaihu Guizhi Ganjiang Tang and Huoluo Xiaoling Dan,in treating middle-risk lung nodules of phlegm blended with blood stasis type.Methods A total of 104 cases of patients with middle-risk lung nodules of phlegm blended with blood stasis type who met the inclusion criteria were randomly divided into the trial group and the control group,with 52 cases in each group.Eventually,a total of 97 cases completed the trial for epidemic outbreak,of which 48 cases were in the trial group and 49 cases were in the control group.Both groups received health training,and then the control group was only given regular follow-up,while the trial group was treated with Xiaoyu Sanjie Prescription orally.The course of treatment covered three months.The changes in traditional Chinese medicine(TCM)syndrome scores and the area of maximum lung nodule of patients in the two groups before and after treatment were observed.After treatment,overall TCM syndrome efficacy and overall western medicine efficacy as well as their efficacies for various nodules types in the two groups were assessed.Results(1)After treatment,the distribution of the grade of TCM syndrome scores in the trial group was improved significantly when compared with that before treatment(P<0.01),while that in the control group showed no significant improvement(P>0.05),and the intergroup comparison after treatment showed that the improvement in the trial group was significantly superior to that in the control group(P<0.01).(2)The total effective rate of overall TCM syndrome efficacy in the trial group was 81.25%(39/48),and that in the control group was 20.41%(10/49);the intergroup comparison(tested by rank sum test)showed that the overall TCM syndrome efficacy in the trial group was significantly superior to that in the control group(P<0.01).In terms of the efficacy for various nodule types,the trial group had stronger TCM syndrome efficacy for multiple nodules,mixed solid nodules,pure ground glass nodules and solid nodules than the control group,in particular the efficacy for multiple nodules and mixed solid nodules,and the differences were all statistically significant(P<0.05 or P<0.01).(3)After treatment,the area of the maximum lung nodule in the trial group was significantly reduced(P<0.01),whereas there was no significant reduction in the control group compared with that before treatment(P>0.05).Statistically significant difference was shown in the post-treatment area between the two groups and in the pre-and post-treatment difference of the area between the two groups(P<0.05 or P<0.01),which suggested that the trial group's effect on the reduction of maximum lung nodule area was significantly superior to that of the control group.(4)With regard to the efficacy of western medicine,on the whole,the total effective rate of overall western medicine efficacy in the trial group was 45.83%(22/48),while that in the control group was 6.12%(3/49),and the intergroup comparison(tested by rank sum test)showed that the overall western medicine efficacy in the trial group was significantly superior to that in the control group(P<0.01).The western medicine efficacy for multiple nodules in the trial group was superior to that in the control group(P<0.01),while no statistically significant difference was presented in western medicine efficacy for mixed solid nodules,solid nodules,and pure ground glass nodules between the two groups(P>0.05).Conclusion Xiaoyu Sanjie Prescription is effective on relieving the clinical symptoms of patients with middle-risk lung nodules of phlegm blended with blood stasis type,and is effective on stabilizing,reducing or even eliminating some of the lung nodules.The compatibility principle of the formula deserves further discussion.

Objective To target at the NKG2A-HLA-E inhibitory axis,a pluripotent stem cell(iPSC)-derived geneti-cally engineered natural killer cells(NK cells)with NKG2A knockout(NKG2A KO-iNK)were prepared and then their tumor-killing efficacy was evaluated in vitro.Methods NKG2A was knocked out in iPSCs using gene-editing technology.These cells were then differentiated into NKG2A KO-iNK cells.Surface markers at each differentiation stage were analyzed by flow cytometry.Western blot confirmed NKG2A knockout,and flow cytometry assessed expres-sion of activating receptors(NKG2D)and natural cytotoxicity receptors(NKp30,NKp44,NKp46)in NKG2A KO-iNK cells.Cytotoxic activity against tumor cell lines with varying human leukocyte antigen E(HLA-E)expression level was evaluated via lactate dehydrogenase(LDH)release assay.Results Co-transfection of iPSCs with Cas9 pro-tein and three small-guide RNAs(sgRNAs)targeting at exons 1 and 2 of the KLRC1 gene(encoding NKG2A)suc-cessfully generated monoclonal NKG2A-knockout iPSCs(NKG2A KO-iPSCs)with a single T-base insertion in exon 1.During iPSC differentiation into NK cells,CD34 expression reached 30％-50％at the embryoid body(EB)stage(day 8),while CD56 and CD 16 expression exceeded 80％by day 28.Western blot confirmed complete NKG2A knockout in NKG2A KO-iNK cells.Flow cytometry revealed comparable expression level of activating receptor NKG2D and cytotox-icity receptors(NKp30,NKp44,NKp46)between NKG2A KO-iNK and wild-type iNK(WT-iNK)cells.The LDH assay results indicated that the cytotoxic activity of NKG2A KO-iNK cells against the HLA-E highly-expressed B-cell precursor leukemia cell line Nalm6 cells was significantly higher than that of WT-iNK cells,while there was no signif-icant difference between them and human myeloma cell line H929 cells with low HLA-E expression and human hepa-tocellular carcinoma cell line HepG2 cells with almost no HLA-E expression.Interferon-γ(IFN-γ)pretreatment up regulated HLA-E expression in Nalm6 cells,further amplifying NKG2A KO-iNK-mediated cytotoxicity.Conclusions By disrupting the NKG2A-HLA-E inhibitory axis,NKG2A KO-iNK cells exhibit markedly enhanced in vitro cytotoxic-ity against HLA-E-high tumor cells.This result highlights their potential function as a novel adoptive cell therapy strategy for cancers reliant on HLA-E-mediated immune evasion.

Pancreatic cancer is among the most malignant cancers,and thus early intervention is the key to better survival outcomes.However,no methods have been derived that can reliably identify early precursors of development into malignancy.Therefore,it is urgent to discover early molecular changes during pancreatic tumorigenesis.As aberrant glycosylation is closely associated with cancer progression,numerous efforts have been made to mine glycosylation changes as biomarkers for diagnosis;however,detailed glycoproteomic information,especially site-specific N-glycosylation changes in pancreatic cancer with and without drug treatment,needs to be further explored.Herein,we used comprehensive solid-phase chemoenzymatic glycoproteomics to analyze glycans,glycosites,and intact glycopeptides in pancreatic cancer cells and patient sera.The profiling of N-glycans in cancer cells revealed an increase in the secreted glycoproteins from the primary tumor of MIA PaCa-2 cells,whereas human sera,which contain many secreted glycoproteins,had significant changes of glycans at their specific glycosites.These results indicated the potential role for tumor-specific glycosylation as disease biomarkers.We also found that AMG-510,a small molecule inhibitor against Kirsten rat sarcoma viral oncogene homolog(KRAS)G12C mutation,profoundly reduced the glycosylation level in MIA PaCa-2 cells,suggesting that KRAS plays a role in the cellular glycosylation process,and thus glycosylation inhibition contributes to the anti-tumor effect of AMG-510.

BACKGROUND:Semen cuscutae has the effect of tonifying the liver and kidney system and benefiting the essence.The main pathogenesis of osteoarthritis is deficiency of the liver and kidneys.Therefore,it is hypothesized that there is a link between semen cuscutae and osteoarthritis. OBJECTIVE:To explore the potential relationship between osteoarthritis and semen cuscutae and validate the mechanism of semen cuscutae based on the network pharmacology and molecular docking analysis. METHODS:First,the active ingredients and targets of semen cuscutae were screened in TCMSP,and the genes related to osteoarthritis were collected in the disease databases GeneCard's,OMIM and TTD.The intersected genes were taken and then subjected to a series of analyses and screened for hub genes.Through the enrichment analysis of hub genes,the pathway of semen cuscutae acting on osteoarthritis was selected.The role of hub genes was verified by molecular docking.Therefore,the appropriate active ingredients of semen cuscutae were selected for experimental verification. RESULTS AND CONCLUSION:There were 11 active ingredients of semen cuscutae,66 intersection target genes of semen cuscutae and osteoarthritis,and 12 hub genes,including tumor necrosis factor,interleukin 1B,TP53,RAC-alpha serine/threonine protein kinase(AKT1),vascular endothelial growth factor A,matrix metalloproteinase 9,prostaglandin peroxidase 2,cystatinase 3,epidermal growth factor,peroxisome proliferator-activated receptor gamma,interleukin 10,vascular cell adhesion factor 1.After the enrichment analysis of the hub genes,the classical inflammatory pathway,nuclear factor-κB signaling pathway,was selected for subsequent validation of semen cuscutae to alleviate osteoarthritic inflammation.Through the results obtained after molecular docking of each active ingredient and the hub gene of the pathway prostaglandin peroxidase 2,sesamin with the highest affinity was selected for subsequent cell experiments,and the experimental results confirmed that sesamin,the active ingredient of semen cuscutae,could reduce the expression of cyclooxygenase 2 by inhibiting the nuclear factor-κB signaling pathway induced by interleukin-1β.To conclude,sesamin,the active ingredient of semen cuscutae,reduces the expression of cyclooxygenase 2 by inhibiting the nuclear factor-κB signaling pathway induced by interleukin-1β,thereby improving inflammation in osteoarthritis and expanding the therapeutic effect of semen cuscutae in osteoarthritis.

Objective To investigate the effect of Xuebijing injection on the inflammatory and coagulation response of complicated intra-abdominal infection by sepsis.Methods A retrospective study was conducted.A total of 274 patients with complicated intra-abdominal infection by sepsis admitted to Yidu Central Hospital of Weifang from June 2020 to July 2023 were enrolled.According to whether Xuebijing was used or not,the patients were divided into an observation group(141 cases)and a control group(133 cases).The patients in both groups were treated with conventional western medicine,and those in the observation group were additionally given Xuebijing(Xuebijing injection 100 mL in 0.9%NaCl solution 100 mL via intravenous infusion,twice per day for a continuous application of 5 days).The differences of clinical prognosis and the serum levels of inflammatory indicators[interleukin-6(IL-6),procalcitonin(PCT),C-reactive protein(CRP)and endotoxin]and coagulation indexes[D-dimer,fibrinogen(FIB),prothrombin time(PT)and activated partial thromboplastin time(APTT)before treatment and on the 2nd,3rd,5th day respectively after treatment were compared,and the clinical prognosis was observed.Results There were no significant differences in the indexes of inflammation and coagulation function between the two groups before treatment.With the extension of therapy duration,following treatment in two groups,the serum levels of inflammatory indicators and coagulation indexes(D-dimer,FIB)decreased,as did coagulation indexes(PT,APTT),reaching the lowest levels on the 5th day.The inflammatory markers and coagulation indexes of observation group were significantly lower than those of control group[IL-6(ng/L):18.89±8.22 vs.24.59±10.39,PCT(μg/L):0.30±0.16 vs.0.52±0.20,CRP(mg/L):13.13±6.54 vs.28.87±8.66,endotoxin(kEU/L):0.17±0.06 vs.0.22±0.08,D-dimer(mg/L):1.75±0.61 vs.1.96±0.77,FIB(g/L):2.50±0.78 vs.3.10±0.94,PT(s):14.16±1.90 vs.15.05±1.46,APTT(s):34.52±5.40 vs.36.21±4.72,both P<0.05].The intensive care unit(ICU)stay time and total hospitalization time were shortened in the observation group than those in the control group[ICU stay time(days):5.71±2.22 vs.6.86±2.99,hospitalization time(days):15.50±6.39 vs.17.02±5.70,both P<0.05];the mortality was significantly lower in the observation group than that in the control group[21.27%(30/141)vs.32.33%(43/133),P<0.05].Conclusion The treatment of complicated intra-abdominal infection by sepsis with Xuebijing injection while receiving conventional western medicine treatment can effectively decrease inflammatory and coagulation response,have high efficacy of inflammatory and coagulation co-treatment,and have some important clinical values.

Humans ; Neoplasms, Second Primary/epidemiology* ; Neoplasms/epidemiology* ; Risk Factors ; Prognosis

OBJECTIVE To study the effect and mechanism of N1,N2 bis(2,3-dihydroxy-4,6-disul-fonic acid benzyl)ethylenediamine sodium salt(NBED)on uranium excretion.METHODS ICR mice were divided into the blank control group,uranium exposure group(0.03 mg·mouse-1),uranium expo-sure+diethylenetriamine pentaacetic acid(DTPA-CaNa3)(150 mg·kg-1)group,and the uranium expo-sure+NBED(45,90,180 mg·kg-1)group.After uranyl acetate was injected into the tail vein of mice,appro-priate doses of NBED or DTPA-CaNa3 were injected into the tail vein.After 24 h,the uranium contents in the kidney,bone and liver+spleen+muscle were determined by inductively coupled plasma mass spectrometry(ICP-MS).The dissociation constant of NBED and the complexation constant of NBED with uranyl were determined via potentiometric titration.RESULTS Animal experiments showed that NBED 45,90 and 180 mg·kg-1 could significantly reduce the uranium accumulation in the kidney by 48.2%-66.5%,in the bone by 21.4%-54.8%,and in liver+spleen+muscle by 38.2%(P<0.01),compared to the uranium exposure group,47.8%,21.4%and 22.7%respectively by DTPA-CaNa3(P<0.05),and the effect in the NBED 180 mg·kg-1 group was significantly better than in the DTPA-CaNa3 group(P<0.05).The results of potentiometric titration showed that there was about 22.3%LH5,59.8%LH4 and 17.85%LH3(L means NBED)in NBED at pH 7.4,and the secondary dissociation LH4 was the main form.In the range of pH 3-11,there were four complex compounds of NBED and uranyl,and their step-wise complex cumulative constants were logβ111(12.5),logβ101(9.8),logβ102(15.3),logβ1-12(6.5)respectively.The(UO2)L22-was the main species(75.3%)at physiological pH 7.4,and the-log[UO22+free]value(pUO2)of free uranyl ion in solution was 9.57.CONCLUSION NBED mainly exists in the form of secondary dissociated LH4in vivo,and chelates with uranyl 2:1 to form uranyl complex,which is excreted in vitro.Intravenous administration of NBED can more effectively promote excretion than DTPA-CaNa3.

Objective To investigate the predictive value of peripheral blood LMR and LMR/LDH on the prognosis of primary Waldeyer's Ring DLBCL patients. Methods We collected 71 patients with primary Waldeyer's Ring DLBCL. The ROC curve was used to determine the optimal critical values of LMR and LMR/LDH before treatment. The chi-square test was used to analyze the constituent ratio and rate of high and low LMR groups as well as high and low LMR/LDH groups. Kaplan-Meier method was used to calculate survival rate. Log rank method and Cox risk regression model were used for univariate and multivariate analyses, respectively. Results The optimal critical values of LMR and LMR/LDH were 2.97 and 1.56, respectively. The prognosis of patients in the high LMR group was significantly better than that in the low LMR group (P < 0.001). The prognosis of patients in the high LMR/LDH group was significantly better than that in the low LMR/LDH group (P < 0.001). Univariate analysis showed that age, B symptoms, clinical stage, treatment efficacy, IPI score, LDH level, LMR and LMR/LDH were important factors that influenced the prognosis of early-stage Waldeyer's Ring DLBCL. Multivariate analysis showed that the age, clinical stage and LMR/LDH were independent prognostic factors. Conclusion LMR and LMR/LDH before treatment may have certain value in predicting the prognosis of Waldeyer's Ring DLBCL patients.