Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Objective To explore the value of serum stearoyl sphingosine(C18∶1-Cer)and 1-stearoyl-sn-glycero-3-phospho-choline(LPC 18∶0)levels in pregnant women's serum samples during pregnancy in predicting gestational diabetes mellitus(GDM).Methods The clinical data and laboratory indicators of 126 pregnant women were retrospectively analyzed.The sub-jects were divided into GDM group(n=66)and control group(n=60)according to the GDM diagnosis results.Mass spec-trometry was used to detect the serum C18∶1-Cer and LPC18∶0 levels of the subjects in early and mid pregnancy.Logistic re-gression analysis was used to screen out the risk factors for GDM.Receiver operating characteristic(ROC)curve was used to evaluate the predictive value of C18∶1-Cer,LPC18∶0 and their combination for GDM.Results Compared with the control group,the serum C18∶1-Cer and LPC18∶0 levels of the subjects in the GDM group were significantly increased in early(18.92±2.77ng/ml vs 23.47±4.18ng/ml,41.32±17.55ng/ml vs 88.08±16.02ng/ml)and mid pregnancy(23.14±4.10ng/ml vs 18.76±4.05ng/ml,84.60±14.53ng/ml vs 40.50±17.79ng/ml),and the differences were statistically significant(t=7.127,15.637;-5.984,2.174,all P＜0.05)C18∶1-Cer was positively correlated with fasting plasma glucose(FPG),fasting plasma insulin(FPI),homeostasis model assessment of insulin resistance(HOMA-IR),glycated hemoglobin(HbA1c)and triglyceride(TG)(r=0.458,0.209,0.317,0.223,0.219,all P<0.05).LPC18.0 was positively correlated with FPG,FPI,HOMA-IR,HbA1c,total cholesterol(TC)and TG(r= 0.715,0.426,0.580,0.465,0.232,0.372,all P<0.05).Logistic regression analysis results showed that C18∶1-Cer[OR(95%CI):1.522(1.136～2.039),P<0.05]and LPC18:0[OR(95%CI):1.198(1.102～1.302),P<0.001]were independent risk factors for GDM.ROC curve analysis results showed that the area under the curve(AUC)of serum C18∶1-Cer,LPC18∶0 and the combination of the two indicators were 0.819,0.971 and 0.986,respectively.The predictive performance of the combination of the two indicators was better than that of the single detection.Conclusion Serum C18∶1-Cer and LPC18∶0 in early pregnancy were closely related to the occurrence of GDM.C18∶1-Cer combined with LPC 18∶0 has a certain predictive value for the early diagnosis of GDM.

Objective:To investigate the rates of low disease activity and clinical remission in patients with systemic lupus erythematosus(SLE)in a real-world setting,and to analyze the related factors of low disease activity and clinical remission.Methods:One thousand patients with SLE were enrolled from 11 teaching hospitals.Demographic,clinical and laboratory data,as well as treatment regimes were collec-ted by self-completed questionnaire.The rates of low disease activity and remission were calculated based on the lupus low disease activity state(LLDAS)and definitions of remission in SLE(DORIS).Charac-teristics of patients with LLDAS and DORIS were analyzed.Multivariate Logistic regression analysis was used to evaluate the related factors of LLDAS and DORIS remission.Results:20.7％of patients met the criteria of LLDAS,while 10.4％of patients achieved remission defined by DORIS.Patients who met LLDAS or DORIS remission had significantly higher proportion of patients with high income and longer disease duration,compared with non-remission group.Moreover,the rates of anemia,creatinine eleva-tion,increased erythrocyte sedimentation rate(ESR)and hypoalbuminemia was significantly lower in the LLDAS or DORIS group than in the non-remission group.Patients who received hydroxychloroquine for more than 12 months or immunosuppressant therapy for no less than 6 months earned higher rates of LLDAS and DORIS remission.The results of Logistic regression analysis showed that increased ESR,positive anti-dsDNA antibodies,low level of complement(C3 and C4),proteinuria,low household in-come were negatively related with LLDAS and DORIS remission.However,hydroxychloroquine usage for longer than 12 months were positively related with LLDAS and DORIS remission.Conclusion:LLDAS and DORIS remission of SLE patients remain to be improved.Treatment-to-target strategy and standar-dized application of hydroxychloroquine and immunosuppressants in SLE are recommended.

Objective To investigate the predictive value of inflammatory cells and clinical features in the prognosis of immune checkpoint inhibitors (ICIs) treating non-small cell lung cancer (NSCLC).Methods The data of 163 cases of stage Ⅲ and Ⅳ NSCLC patients treated with the ICIs in this hospital from January 1,2017 to December 31,2022 were collected.The CT examination was conducted after 6-8 weeks treatment.The pa-tients were divided into the objective remission group[complete remission (CR)+partial remission (PR)]and non-objective remission group[stable disease (SD)+progressed disease (PD)],disease control group (CR+PR+SD) and non-disease control group (PD),persistent clinical benefit group (DCB) and non-DCB group.The differences in clinical features and inflammatory cells indicators were compared among the differ-ent groups.The receiver operating characteristic (ROC) curve was adopted to evaluate the predictive efficiency of the inflammatory cells indicators for DCB.The influencing factors analysis of progression free survival (PFS) time and overall survival (OS) time adopted the Cox regression analysis.Results The lymphocyte count (ALC) in the disease control group was higher than that in the non-disease control group.The neutro-phil to lymphocyte ratio (NLR),platelet-lymphocyte ratio (PLR) and mononuclear lymphocyte ratio (MLR) were lower than those in the non-disease control group.The proportions of squamous cell carcinoma,stage Ⅲ,ECOG score 0-1 point,adverse reactions in the DCB group were higher than those in the non-DCB group (P<0.05),the PLT count,NLR,PLR and MLR were lower than those in the non-DCB group (P<0.05). The ROC curve analysis results showed that PLT,NLR,PLR and MLR could serve as the indicators for pre-dicting DCB,the area under of ROC curve (AUC) was 0.633,0.602,0.635 and 0.604 respectively,the opti-mal cut off values were 187×109/L (P=0.004),5.0 (P=0.026),235 (P=0.003) and 0.35 (P=0.024) re-spectively.The multivariate Cox regression analysis showed that non-squamous carcinoma including adenocar-cinoma (HR=1.565,95％CI:1.057-2.316) and other pathologic types (HR=2.285,95％CI:1.326-3.936),ECOG score 2-3 points (HR=2.375,95％CI:1.652-3.415),AMC≥0.65×109/L (HR=1.847,95％CI:1.160-2.938) and PLR≥235 (HR=1.557,95％CI:1.016-2.386) were the independent risk factors for short PFS.The ECOG score 2-3 points (HR=4.615,95％CI:2.882-7.391),AMC≥0.65×109/L (HR=5.161,95％CI:2.984-8.925) and PLR ≥235 (HR=1.732,95％CI:1.059-2.833) were the independent risk fac-tors for short OS (P<0.05),and having adverse reactions (HR=0.472,95％CI:0.294-0.757) was the independ-ent protective factor for short OS (P<0.05).Conclusion Lower PLT,AMC,NLR,MLR and PLR,higher ALC,squamous cell carcinoma,TNM stage Ⅲ,ECOG score 0-1 point and immunotherapy related adverse reactions could prompt that the prognosis is good in ICIs treating advanced NSCLC.PLT,NLR,PLR and MLR could serve as the indicators for predicting DCB.

ObjectiveTo investigate clinical features and outcomes in acute ischemic stroke patients with remote symptomatic intracranial hemorrhage (sICHr) after intravenous thrombolysis.MethodsThe acute ischemic stroke patients with sICHr after intravenous thrombolysis therapy were enrolled retrospectively.The clinical data were collected and the related literature was analyzed and summarized.ResultsA total of 6 acute ischemic stroke patients with sICHr were enrolled, including 4 males.Three patients had a history of using antiplatelet agents, 2 with atrial fibrillation, 4 with hypertension, 3 with previous stroke history, 4 with smoking history, and 4 had sICHr at 2 h after intravenous thrombolysis.Of the 14 hemorrhagic foci (except in the infarct areas), 10 were in the cerebral cortex.Three patients died within 1 week, and 1 was in a persistent vegetative state.Conclusions SICHr after intravenous thrombolysis in patients with acute ischemic stroke is mainly located in the cerebral cortex.The outcomes in acute ischemic stroke patients with SICHr after intravenous thrombolysis are poor, and the mortality is high.

Objective To evaluate the clinical efficacy of intra-articular injection of ozone in collagen-induced arthritis (CIA) rats and to assess its effects on serum receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) levels. Methods Forty weight age malched Wistar rats were randomly divided into normal control group (normal group), the CIA model group (CIA group), ozone (O 3 group), and methotrexate (MTX group). In addition to the normal control group, Freund's complete adjuvant and bovine type Ⅱ collagen were injected to establish the rat model of CIA. After the model was sucessfully developed, double ankle injection concentration ozone group of 40 μg/ml of O3 each 1 ml, 1 times a week, a total of injection for 3 weeks for the experimenal group. MTX group of 0.9 mg/kg was injected 1 times a week for 3 weeks for the MTX group. Degree of foot swelling was measured, and radiographic assessment of arthritis index (AI) score was performed. One week after treatment, angular vein blood was collected for the rats after the intervention, flow multi-factor detection technology was used to test each rat. T test or Wilcoxon rank test was used to compare the difference between groups. Results ① After 3 week administration with O3, dcgree of foot swelling, and AI of the O3 group was reduced significanly than the CIA group during the same period (foot swelling degree: O3 group: (4.21±0.14) ml, CIA group (9.12±0.17) ml, T=64.08, P=0.00; AI O3 group: [(2.97± 0.18) ml, CIA group: 5.76 ±0.13, T=37.24, P=0.00], and X-ray showed joint damage was alleviated. ② The serum level of RANKL in the CIA group was significantly higher than of the normal group [CIA model group 1890.70(797.03, 10571.94)], normal group [74.46(29.21, 95.37), T=43, P=0.005] during the same period; The serum level of RANKL in the O3 group was significantly lower than the CIA group [O3 group 28.09 (14.11, 207.30), CIA group 1890.70 (797.03, 10571.94), T=39, P<0.05]; RANKL level of the Ozone group when compared with MTX group, was not statistically significantly difference (T=52, P>0.05).③Serum RANKL/OPG of the CIA group was significantly higher than that of the normal group during this period, the difference was statistically significant [CIA group 250.68(42.33, 2959.78), normal group 4.32(3.16,5.30), T=36, P<0.01);The serum level of RANKL/OPG in the O3 group was significantly lower than the CIA group [O3 treatment group 5.10 (3.38, 6.64), CIA group 250.68 (42,33, 2959.78), T=36, P<0.01]; There was no statistically significant difference of the serum RANKL/OPG between the O3 group and the MTX group (T=62.5, P>0.05). Conclusion Intra-articular injection of concentration of 40 μg/ml of O3 can reduce RA rat joint swelling degree, which may relate to the mechanism that O3 can lower levels of serum RANKL and RANKL/OPG ratio, reduce osteoclast formation and activation.

Objective To observe the effects of intra-articular ozone injection on the secretion of tumor necrosis factor (TNF)-α,Interleukin (IL)-6,IL-17A,and vascular endothelial growth factor (VEGF) in the serum of rats with collagen-induced arthritis (CIA) and explore the therapeutic mechanism of ozone in RA treatment.Methods Thrity-two Wistar rats were randomized into 4 groups,including the ozone groups that receivedintra-articularinjection of 40 μg/ml ozone (O3 group),a blank control group (normal group),a methotrexate (MTX) group (MTX group) anda collagen-induced arthritismodel (CIA group).All the rats,except for those in the blank control group,were subjected to hypodermic injection of bovine collagen Ⅱ and complete Freund's adjuvant to induce CIA.Ozone treatment was administered once weekly for 3 weeks starting at 14 days after the model were established.MTX group were treated with methotrexate 0.9 mg/kg,once a week,a total of three weeks.The swelling degree of the foot were observed,and the serum contents of TNF-oα,IL-6,IL-17A and VEGF were detected.One-way analysis of variance or Kruskal-Wallis test was used to evaluate the experimental data.Results At the end of treatment,the degree of foot swelling was reduced significantly in rats with O3 group compared with that in the CIA group [(4.21±0.14) ml vs (9.12±0.17) ml,t=8.43,P=0.023].The serum concentration of TNF-α,IL-6 and VEGF showed significant difference between the CIA group and the O3 group[91.55(86.55,98.53) pg/ml vs 14.45 (12.55,16.15) pg/ml,x2=6.216,P=0.002;145.08(37.44± 362.82) pg/ml vs 5.84(5.47,15.93) pg/ml,x2=13.136,P=0.004;51.56(46.09,74.10) pg/ml vs.36.22(32.18,41.69) pg/ml,x2=3.732,P=0.002].There was no statistically significant difference between the O3 group and MTX group [14.45(12.55,16.15) pg/ml vs [12.45(11.80,15.60) pg/ml,x2=0.243,P＞0.05;5.84(5.47,15.93) pg/ml vs 7.86(5.25,15.23) pg/ml,x2=0.058,P＞0.05;36.22(32.18±41.69) pg/ml vs 40.17(35.47,50.73) pg/ml,x2=0.516,P＞0.05].The serum concentration of IL-17A showed no significant difference between the normal group,the CIAgroup,the MTX group and the O3 group (F=1.827,P=0.165).Conclusion Intra-articular injecfion of 40 μg/ml ozone can attenuate synovitis in rats with CIA,the mechanism may relate to the inhibition of TNF-oα,IL-6 and VEGF in the serum.

OBJECTIVE:To investigate the effectiveness and safety of 2 kinds of proton pump inhibitors in the treatment of coronary heart disease (CHD).METHODS:In retrospective study,a total of 92 patients with CHD were selected from our hospital during Jun.2015-May 2016,and then divided into rabeprazole group (30 cases),esomeprazole group (32 cases) and control group (30 cases) according to therapy plan.Control group received basic therapy plan.Rabeprazole group and esomeprazole group were additionally given sodium rabeprazole enteric-coated tablets and Esomeprazole magnesium enteric-coated tablets 20 mg,po,bid,on the basis of control group.A treatment course lasted for 30 d,and both medication groups received 2 courses of treatment.Blood uric acid levels,urine pH values,blood ion levels (Na+,K+,Ca2+,Cl-) were detected before and after treatment.The occurrence of cardiovascular adverse events,coronary adverse events and other adverse events were observed in 2 groups during treatment.RESULTS:Before treatment,there was no statistical significance in above indexes among 3 groups (P＞0.05).After treatment,the levels of blood uric acid,K+ (except for control group),Ca2+ and Cl-were decreased significantly,while urine pH values and blood Na+ levels were increased significantly;the levels of blood uric acid and Ca2+ in rabeprazole group and esomeprazole group were significantly lower than control group,while urine pH value and blood Na+ level were significantly higher than control group,with statistical significance (P＜0.05).After treatment,the level of blood uric acid in rabeprazole group was significantly lower than esomeprazole group,with statistical significance (P＜0.05).But there was no statistical significance in urine pH values or ion levels between 2 groups (P＞0.05).Compared with control group,the incidence of acute thrombosis in rabeprazole group and esomeprazole group were decreased significantly,and the incidence of joint swelling and pain were increased significantly,with statistical significance (P＜0.05).There was no statistical significance in the incidence of coronary adverse events among 3 groups (P＞0.05).CONCLUSIONS:Rabeprazole and esomeprazole can significantly reduce the level of blood uric acid and the incidence of acute thrombosis,increase urine pH value and blood Na+ levels,decrease blood Ca2+ level and increase the risk of fracture or hypocalcemia in patients with CHD.Therefore,the dosage regimen should be adjusted according to the specific situation of patients in clinical practice

Rheumatoid diseases (RD) are a group of diseases affecting bones,joints,and the surrounding soft tissues,such as muscle,synovial membrane,tendons,fascia,nervus.The etiology and pathogenesis are complicated.Since most RD are systemic diseases,traditional imaging techniques have limited value for the diagnosis and treatment monitoring of RD.18F-FDG PET/CT can display morphologic and metabolic information simultaneously,and is considered as a potential tool for the diagnosis of RD.This review summarizes the application of 18F-FDG PET/CT in RD,such as systemic vasculitis,relapsing polychondritis and rheumatoid arthritis.

Objective To assess the improvement of articular symptoms on collagen induced arthritis (CIA) rats after injecting arsenic trioxide (ATO) intraperitoneal and observe its effects on serum RANKL, OPG on CIA rats and discuss the possible mechanism on RANK/RANKL/OPG system.Methods Numberd twentyeight Wistar rats with correspond weight and age consecutively, then using random number table select 8 rats as blank control group A.Another other 20 as model group (16 wistar rats are established as CIA models by immunized twice with bovine type Ⅱ collagen and Freund's complete adjuvant emulsion).Using ranllm numbor table divided CIA rast into the CIA model control group B (n=8) and ATO treatment group C (n=8) randomly.After grouping for 3 days, ATO treatment group were injected with ATO liquid intraperitoneally for 1 week (dose of 4 mg· g-1·d-1, last 1 day raise to 8 mg/kg).Serum were collected after 3 days , while rates in the control group were given same quantity of saline solution with the same method.Arthritis index (AI) and X-ray radiography were assessed for limb joint damage.Flow cytometry (FMC) was used to detect chemokines quantitatively of each rats serum, including Nuclear factor kappa B ligand receptor activation factor/bone protection predominate (RANKL/OPG).According to the data distribution, t test or Wilcoxon test were used to compare the difference between groups.Results ① After administration with ATO for 1 week arthritis index of group C reduced significantly than the CIA model group (2.63±0.92, 6.62±0.91, t=8.73, P＜0.01), and X-ray showed joint damage alleviated.② The serum level of RANKL in the CIA model group was significantly higher than the blank control group [(1 890.70(797.03, 10 571.94) pg/ml, 74.46(29.21, 95.37) pg/ml, T=43, P=0.005];③ The serum level of RANKL in the ATO treatment group was significantly lower than the CIA model group [44.78 (21.41, 79.83), 1 890.70 (797.03, 10 571.94), T=47, P=0.01].④ There was no statistically significant difference of the Serum OPG level between the three groups [16.87(6.91, 17.64), 5.32(3.42, 33.14),14.24(6.96, 21.86) pg/ml, x2=5.078, P=0.166].Conclusion The inflammatory mediators in the process of bone metabolism of CIA rats is disordered , the most significant presentation is the rise of serum RANKL level.Intraperitoneal injection of ATO could improve the arthritis index of CIA rats and its mechanism may be reducing the concentration of serum RANKL/OPG ratio.