Screening of a novel CRM1 targeting inhibitor and its effects on the proliferation and growth of extranodal NK/T cell lymphoma / 中国药科大学学报

@#The purpose of this study was to screen out the novel chromosome maintenance protein 1(CRM1)covalent targeting inhibitors by computer-assisted drug design(CADD), and to study their effects on the proliferation of extranodal nature killer/T cell lymphoma(ENKTL). A novel CRM1 inhibitor LFS-829 was designed based on the molecular structure of LFS-01 by means of ADME/T and covalent docking. The target binding of LFS-829 with CRM1 was analyzed by MALDI-TOF mass spectrometry. The effects of LFS-829 on the proliferation of extranodal NK/T cell lymphoma SNK6 and HANK-1 cells were detected by CCK-8. The cell morphology was observed by live cell workstation. Immunofluorescence experiments were used to analyze the effect of LFS-829 on nuclear export function of CRM1. The changes of NF-κB signaling pathway under different concentrations of LFS-829 were analyzed by Western blot, dual luciferase reporter gene assay and enzyme-linked immunosorbent assay. Apoptosis was detected by flow cytometry, and the expression of proteins related to apoptosis pathway was detected by Western blot. Tests of peripheral blood mononuclear lymphocyte(PBMC)toxicity, platelet toxicity and mouse acute toxicity were done to make sure that it is not harmful to human. LFS-829 could bind covalently to the cysteine residue of the hydrophobic active pocket of CRM1. LFS-829 could selectively kill SNK6 and HANK-1 cells, with IC50 of 366 nmol/L and 158 nmol/L in 72 h, respectively, and cell morphology was significantly changed. LFS-829 at 800 nmol/L significantly inhibited the nuclear export function of CRM1, promoted nuclear assembly of IκB-α, down-regulated the transcriptional activity of NF-κB signaling pathway, significantly up-regulated the expression of apoptotic pathway protein p53, cleaved Caspase 3 and cleaved Caspase 9 and induced apoptosis, with no obvious killing effect on PBMC or platelets. It did not cause substantial tissue damage to mice at the high dose of 300 mg/kg, which shows its great prospect of future application.

Role and mechanism of endoplasmic reticulum stress response induced by wear particles in osteolysis / 中国骨伤

OBJECTIVE@#To analyze the role of endoplasmic reticulum stress response in the development of osteoblast apoptosis and osteolysis in osteolytic bone tissue, and to explore the causes of artificial joint loosening, so as to provide new ideas and theoretical basis for the prevention and treatment of artificial joint loosening.@*METHODS@#The animal model of osteolysis induced by wear particles was established by mouse skull, and randomly divided into 4 groups, 7 rats in each group:group 1, blank control group;group 2, wear particles tial6v4 nano alloy powder (TiNPs) group;group 3, endoplasmic reticulum stress response positive control (TiNPs+Tg) group; group 4, endoplasmic reticulum stress response inhibitor (TiNPs+4-PBA) group. The pathological changes of osteolysis were observed by toluidine blue staining, HE staining and ALP staining;the expression of endoplasmic reticulum stress response marker protein was detected by Western Blotting;the apoptosis of osteoblasts in osteolytic skull tissue was detected by TUNEL and Caspase-3 immunohistochemistry.@*RESULTS@#Wear particles TiNPs can induce osteolysis in vitro, aggravate the infiltration of inflammatory cells and inhibit the differentiation and maturation of osteoblasts. At the same time, wear particles can also up regulate the markers of endoplasmic reticulum stress response and promote the apoptosis of osteoblasts in osteolytic bone tissue. After adding 4-PBA, an inhibitor of endoplasmic reticulum stress (4-PBA), on the basis of wear particles TiNPs, the symptoms of osteolysis were significantly relieved, bone erosion and inflammatory infiltration were significantly reduced, the differentiation and maturation of osteoblasts were improved, the number of apoptotic osteoblasts decreased sharply, and the expression of endoplasmic reticulum stress marker protein gradually decreased.@*CONCLUSION@#Endoplasmic reticulum stress is involved in the formation of osteolysis and plays an important role in the occurrence and development of osteolysis. At the same time, endoplasmic reticulum stress can be used as a new therapeutic target to provide new ideas and methods for clinical reversal or treatment of osteolysis and aseptic loosening.

Psychosocial functioning and risk factors of children with juvenile idiopathic arthritis / 中国医师杂志

Objective To investigate the psychosocial functioning and risk factors of children with juvenile idiopathic arthritis (JIA).Methods A total of 79 children with JIA were selected from the inpatients and outpatients in the department of clinical immunology,a top-grade hospital in Xi'an from February to December,2017.Their demographic and disease data were collected by self-designed questionnaires.Disease remission was confirmed by using the JADAS-27 and pain intensity by visual analogue scale (VAS).The Children's Depression Inventory (CDI) and Multidimensional Anxiety Scale for Children (MASC) were rated by the children themselves.All data were analyzed with SPSS 17.0.Results A total of 316 effective questionnaires were collected,including 79 demographic questionnaires,disease questionnaires,CDI and MASC respectively.(1) The total scores of CDI were 15.22 ± 9.56.The highest scores were found for the subscale of "lack of happiness" (4.57 ± 3.63),while the lowest for the subscale of "low self-esteem" (1.75 ± 1.57).The total scores of MASC were 39.15 ±21.12.The highest scores were found for the subscale of "Injury avoidance" (13.09 ± 5.57) while the lowest for the subscale of "separation anxiety" (7.68 ± 5.66).(2) Multiple stepwise linear regression analysis showed that pain,disease activity,hormonal side effects and fatigue were the main risk factors of the psychosocial functioning of the children with JIA.Conclusions The psychosocial functioning of children with JIA was not satisfied.It suggested that we should not only take the appropriate clinical treatment to control the disease but also take combined therapy such as psychological intervention as early as possible.

A multi-center,double-blind,randomized,placebo-controlled study on the efficacy and safety of etanercept and methotrexate in the treatment of active rheumatoid arthritis / 中华风湿病学杂志

Objective To compare the efficacy and safety ofetanercept injection 50 mg once weeklycombined with methotrexate (MTX) therapy for patients withactive rheumatoid arthritis.Methods This studyconsists of 2 parts：a 12-week double-blind treatmentperiod (part A) followed by a 12-week open-labelsafety study period (part B).The randomization oftreatments in double-blind treatment period was completedthrough the clinical operations randomization environment(CORE) system.During part A,the subjects wererandomly assigned to the etanercept 50 mg or placebo group. The dosage regimen for etanercept was 50 mgadministered subcutaneously once weekly while MTX wasadministered orally.All subjects who completed partA received 50 mg etanercept once weekly and MTX1 during theopen-label treatment.The primary endpointwas ACR 20 response at week 12.Secondary endpoint variablesincluded physician／patient global assessmentsof disease activities,duration of morning stiffness,painvisual analog scale (VAS),health assessment questi onnaire (HAQ),CRP level and tender and swollen joint counts .The results of safety between the two groupswere compared.The primary endpoint and other secondarybinary endpoints were analyzed using the Fisher’sexact test.For continuous endpoints.the change frombaseline was analyzed with analysis of covariance.Results One hundred and fifty six subjects satisfiedmodified intent-to-treat (mITT) population were enrolled during part A,of which 77 subjects were in theetanercept+MTX group,and 79 subjects were in theplacebo+MTX group respectively.A total of 149 subjectscompleted part A.As early as week 4.the ACR 20response achieved 39％ (30,77) in the etanerceptgroup,which was significantly higher than that of theplacebogroup [16％(13／79),P<0.001].At week 12,the ACR 20respouse achieved 62％(48,77)in the etanercept group and 23％(18／79) in the placebo group (P<0.01).Fromweek 4,other study endpoints including physician global assessment,patient globalassessment,duration of morning stiffness,painVAS,HAQ,CRPlevel,tender joint counts,swollen joint counts were alsocompared.The results showed that all above efficacyendpoints in the etanercept+MTX group were better than thoseof the placebo+MTX group(P<0.01).Butthere Was no significant difference in the total adverseeriects between the two groups.ConclusionEtanercept 50 mg once weekly + MTX treatment for 24 weeks iswell tolerated.During the first 12-weektreatment period,the etanercept group has shown a rapidefficacy onset and a significantly better therapeuticeffect compared to that of the placebo group.

The relationship between soluble CD147 and the risk factors of atherosclerosis in rheumatoid arthritis / 中华风湿病学杂志

Objective To study the relationship between soluble CD147 (sCD147) level in peripheral blood and serum lipid level and explore the effect of sCD147 on atherosclerosis in rheumatoid arthritis (RA). Methods The level of sCD147 in 36 patients with RA,36 patients with coronary artery disease (CAHD) and 30 healthy volunteers was detected by enzyme linked immunosorbent assay (ELISA) .The disease activity score (DAS28) in RA patients was evaluated and the correlation between sCD147 level and DAS28 score was analyzed.The serum lipid level of RA patients was detected by an automatic biochemical analyzer and the cor relation between sCD147 level and serum lipid level was analyzed.Results The level of sCD147 in serum of RA patients was significantly higher than that in patients with CAHD and healthy volunteers,sCDI47 level in the RA group with high DAS28 score was significantly higher than that with low or medium DAS28 score.In RA patients,elevated total cholesterol (TC) and triglyceride (TG) level was positively correlated with serum sCDI47 level (r=0.84,P＜0.05;r=0.87,P＜0.05;while slightly elevated,normal TC and normal TG had no correlation with serum sCDI47 level (r=0.41,P=0.21;r=0.14,P=0.57;r=0.49,P=0.87).Elevated or slight ly elevated LDL-C was positively correlated with serum sCD147 level (r=0.86,P＜0.05;r=0.81,P＜0.05), while no correlation could be found in the group with normal LDL-C level (r=0.78,P=0.22).The high density lipoprotein-cholesterol (HDL-C) level decrease in RA patients had no correlation with serum sCD147 level (r--0.04,P=0.96;r=0.13,P--0.87).Conclusion sCD147 may be involved in the pathogenesis of RA and associate with disease activity.Elevated sCD147 level may be associated with abnormal serum lipid in RA.

Prevalence of seronegative spondyloarthritis in the army force of China / 中华流行病学杂志

<p><b>OBJECTIVE</b>To investigate the prevalence and epidemiologic characteristics of seronegative spondyloarthritis (SpAs) in Chinese army force in different areas.</p><p><b>METHODS</b>4-phase survey was conducted in 21 750 Chinese army, including: face-to-face interviews with standardized COPCORD questionnaires (Phase I screening); further examination on the suspected cases; identification of inflammatory joint and spinal diseases (Phase II); identification of SpAs (AS and uSpA) by more than two experienced specialists in rheumatology; further examination with X-rays and laboratory detection of HLA-B27 (Phase III); and data analysis (Phase IV).</p><p><b>RESULTS</b>Among 21 750 army men, 21 cases of RA, 106 cases of SpAs were identified, with prevalence rates of 0.966 per thousand, 4.87 per thousand respectively. In 106 cases of SpAs, there were 46 cases of ankylosing spondylitis (AS), 52 cases of undifferentiated SpAs (uSpAs) with the prevalence rates of 2.11 per thousand and 2.39 per thousand respectively. Few cases of reactive arthritis (ReA) and Reiter's syndrome (RS) were identified (6 and 1 cases respectively). The prevalence of AS, uSpAs were higher in navy than that in the ground force or the air force. Soldiers in cold and damp areas had higher prevalence rates than that in the plain and drought areas.</p><p><b>CONCLUSION</b>The prevalence of SpA (especially AS and uSpA) in Chinese army force was similar to that in the civilians. SpA (AS and uSpA) was more prevalent seen in the Navy. The incidence of SpA (AS and uSpA) was influenced by environmental factors such as coldness and dampness.</p>

Serum level of soluble interleukin-2 receptors in hepatitis B patients / 中国免疫学杂志

The level of serum soluble interleukin-2 receptor(sIL-2R)was measured in 103 patientswith hepatitis B and 26 hepatitis B virus(HBV)carriers by enzyme-linked assay.The sIL-2Rconcentration were elevated significantly in each type of hepatitis B patients and HBV carriers,compared with control group(P