CXCR4/SDF-1 axis is involved in lymph node metastasis of gastric carcinoma

AIM:To investigate the role of CXC chemokine receptor-4 (CXCR4) and stromal cell-derived factor-1 (SDF-1) in lymph node metastasis of gastric carcinoma.METHODS:In 40 cases of gastric cancer,expression of CXCR4 mRNA in cancer and normal mucous membrane and SDF-1 mRNA in lymph nodes around the stomach was detected using quantitative polymerase chain reaction (PCR) (TaqMan) and immunohistochemistric assay.SGC-7901 and MGC80-3 cancer cells were used to investigate the effect of SDF-1 on cell proliferation and m...     

The expression of chemokine receptor CXCR3: relevance to disease activity of rheumatoid arthritis

 CXC chemokine receptor 3 (CXCR3) is selectively expressed on T helper 1 (Th1) type T cells and has been shown to be responsible for Th1-dominant immune responses. In this study, we analyzed the expression of CXCR3 on peripheral blood T lymphocytes of patients with rheumatoid arthritis (RA) by FACS analysis using antihuman CXCR3 monoclonal antibody and determined the clinical relevance in this disease. Significantly higher expression of CXCR3 was found on peripheral blood CD4+ T lymphocytes of RA patients than healthy controls. The CXCR3 expression in RA patients with a high erythrocyte sedimentation rate was significantly higher than in those with a low erythrocyte sedimentation rate. Moreover, we found that the CXCR3 expression in RA patients with long-term disease duration was significantly higher than in those with short-term disease. On the other hand, CC chemokine receptor 4 (CCR4), which was shown to be selectively expressed on Th2-type T cells, was expressed at low levels in RA patients as well as in healthy controls. The serum level of interleukin (IL)-18 in RA patients was higher than that in healthy controls, although there was no statistically significant difference. This study suggests that the Th1 immune response is predominant in RA and that CXCR3 may have relevance in regard to the disease course in RA patients. Received: January 28, 2002 / Accepted: August 14, 2002     

基质细胞衍生因子-1/CXCR4轴与肝脏疾病

基质细胞衍生因子-1(SDF-1)/CXCR4轴及其介导的细胞信号转导通路在肝脏疾病中的作用是国内外研究的热点.研究发现SDF-1/ CXCR4信号转导途径与肝脏再生、炎症、肝硬化以及肿瘤等疾病有关,但其具体机制尚未完全清楚.在细胞微环境中,SDF-1/CXCR4相互作用促进肝癌细胞生长,增强肿瘤的迁移、浸润以及转移能力.本文就SDF-1/CXCR4通路在肝再生、炎症、肿瘤疾病中的病理特征和致病机制的研究进展作一综述.     

Effectiveness of golimumab for rheumatoid arthritis in patients with an inadequate response to tocilizumab

Objectives: Several biological disease–modifying antirheumatic drugs (bDMARDs) are currently available for the treatment of rheumatoid arthritis (RA). Increasing evidence indicates that second-line bDMARDs are effective for inadequate responders to first-line bDMARDs. However, all previous studies investigated the use of tumor necrosis factor inhibitors (TNFi) as a first-line bDMARD, while investigated the efficacy of second-line bDMARDs after the use of tocilizumab (TCZ), a non-TNFi, as a first-line bDMARD. Thus, we investigated the efficacy of golimumab (GLM) as a second-line bDMARD after treatment with TCZ as a first-line bDMARD.

Methods: The final study population consisted of 26 patients (inadequate responders to TCZ; TCZ group) with moderate or high disease activity (DAS28-ESR ≥3.2) at week 24 of treatment with TCZ as a first-line bDMARD or whose DAS28-ESR score worsened after starting TCZ treatment. These patients could be followed for another 52 weeks or more after the subsequent switch to GLM treatment. For comparison, 19 patients treated with TNFi as a first-line bDMARD and inadequate response to TNFi (TNFi group) were included.

Results: The DAS28-ESR score at week 52 after the start of treatment with GLM improved significantly compared with baseline in the TCZ and TNFi groups. However, the TCZ group showed significantly better improvement. Patients in both groups had significantly improved treatment outcomes according to European League Against Rheumatism response criteria, but there was no statistically significant difference among them. The retention rate at week 52 after the start of treatment with GLM was significantly higher in the TCZ group than in the TNFi group (81% vs. 68%, respectively). In addition, no difference was found in the progression of bone destruction determined by the change in van der Heijde modified total Sharp scoring system scores between groups.

Conclusions: GLM was an effective therapeutic option for inadequate responders to TCZ.     

基质细胞衍生因子-1/趋化因子受体CXCR4轴与支气管哮喘

基质细胞衍生因子-1（stromal cell—derived factor-1,SDF-1）是趋化因子亚家族的成员之一,SDF1与趋化因子受体CXCR4（CXCR4）作用,构成SDF-1／CXCR4反应轴,在介导造血干细胞迁移及归巢、恶性肿瘤浸润转移、HIV感染、胚胎发育、免疫与炎症反应等方面发挥着重要作用。SDF1／CXCR4通过调节炎症细胞、血管形成、气道高反应性（AHR）等方面参与支气管哮喘（哮喘）的发生发展。     

Histological analysis of synovium in cases of effect attenuation associated with infliximab therapy in rheumatoid arthritis

To investigate the histological changes of synovium in cases of effect attenuation occurring after the use of infliximab in the treatment of rheumatoid arthritis (RA), we histologically assessed synovial tissue from ten methotrexate-treated RA patients and 12 infliximab-treated RA patients after arthroscopic synovectomy. The synovium was observed using hematoxylin and eosin (H&E) stain and analyzed immunohistochemically for expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), B-cell transmembrane protein, cluster of differentiation 20 (CD20), nuclear factor kappa B (NFkB), bromodeoxyuridine (BrdU), and vascular endothelial growth factor (VEGF). H&E staining showed significant vascular proliferation in the synovium of the RA patients in the infliximab group (p < 0.05). Immunohistochemical examinations showed that TNF-α was completely blocked in patients with effect attenuation who received infliximab (p < 0.05). IL-6 was more strongly expressed in the interstitial cells of synovium of patients who received infliximab than in the cells of patients in the control group (p < 0.05). MMP-3 was expressed on the surface of synovium, and CD20 and BrdU were strongly expressed in the infliximab group compared with the control group (p < 0.05). NFkB was expressed in both groups. VEGF was decreased in the infliximab group compared with control. These findings indicate that the expression pattern of immunohistochemical findings in synovium was changed in effect attenuation cases among RA patients treated with infliximab.     

Comparison of golimumab 100-mg monotherapy to golimumab 50 mg plus methotrexate in patients with rheumatoid arthritis: Results from a multicenter,cohort study

Objective. The aim of this study was to compare the efficacy and safety of golimumab (GLM) 50 mg + methotrexate (MTX) combination therapy and GLM 100 mg monotherapy in patients with rheumatoid arthritis (RA).

Methods. The subjects were 115 RA patients (92 females and 23 males; median (range) age, 64 (17–87) years; median (range) disease duration, 8 (0.6–48) years) started on GLM. Eighty-three patients received GLM 50 mg/4 weeks + MTX (C group; median (range) MTX dosage 8 (2–16) mg/week), and 32 patients received GLM 100 mg/4 weeks (M group).

Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), matrix metalloproteinase-3, disease activity score (DAS) 28-ESR, DAS28-CRP, simplified disease activity index, and clinical disease activity index were evaluated 4, 12, and 24 weeks after starting GLM.

Results. There were no significant differences in disease activity, adverse events, and drug continuation rates at 24 weeks between the groups. The DAS28-ESR remission rate was 34% in the C group and 26% in the M group.

Conclusions. GLM 100 mg monotherapy improved disease activity as well as GLM 50 mg + MTX combination therapy. GLM 100 mg monotherapy appears to have a sufficient therapeutic effect in RA patients who cannot take MTX.     

Assessment of the effectiveness of golimumab 50-mg and 100-mg regimens in patients with rheumatoid arthritis in daily practice

Abstract

Objectives. To assess the effectiveness of the golimumab (GLM) 50-mg and 100-mg regimens in patients with rheumatoid arthritis (RA) in daily practice. Methods. We retrospectively analyzed RA patients who started GLM between September 2011 and July 2012. Patients were divided into three groups: a 50-mg group; a 50/100-mg group (had a dose increase to 100 mg); and a 100-mg group (started GLM at 100 mg). We assessed Disease Activity Score 28 (DAS28) and treatment continuation rate. Risk factors associated with time to discontinuation of the 50-mg regimen were determined with proportional hazards analysis. Results. We analyzed 74 patients: 43 in the 50-mg group, 23 in the 50/100-mg group, and 8 in the 100-mg group. DAS28 improved from 4.0 ± 1.0, 4.8 ± 1.0, and 4.7 ± 1.9, respectively, at baseline to 2.4 ± 1.2, 3.3 ± 1.5, and 2.5 ± 0.7, respectively, at week 52. Treatment continuation rates at week 52 were 73.7%, 60.9%, and 87.5%, respectively. In the 50/100-mg group, the mean DAS28 improved significantly from 4.4 ± 1.2 before to 3.6 ± 1.3 12 weeks after the dose increase. Oral corticosteroid therapy ≥ 5 mg/day, previous use of two biologic agents, and DAS28 > 5.1 at initiation of GLM were significantly associated with discontinuation of the 50-mg regimen. Conclusions. Both GLM 50-mg and 100-mg regimens are effective in patients with RA in daily practice.     

Serum matrix metalloproteinase-3 in rheumatoid arthritis patients: Correlation with disease activity and joint destruction

Aim of the workThis study was designed to measure the serum level of matrix metalloproteinase-3 (MMP-3) in rheumatoid arthritis (RA) patients and its correlation with functional status, disease activity and joint damage.Patients and methodsThe study included 50 RA patients satisfying 2010 ACR/EULAR classification criteria recruited from Bani-Suef University Hospital and 20 controls. Functional disability was assessed according to Modified Health Assessment Questionnaire (MHAQ). Disease activity score in 28-joints (DAS28) and visual analogue scale (VAS) of pain were evaluated. Radiological joint damage was assessed by Van der Heijde-modified Sharp Score (vdHSS). Serum levels of MMP-3 were measured for all subjects.ResultsRA patients (44 females and 6 males) had a mean age of 46.36 ± 13.63 years and disease duration of 5.6 ± 4.75 years. Serum MMP-3 levels were higher in patients than in controls (46.78 ± 46.99 versus 1.98 ± 1.71 ng/ml respectively, p = 0.0001) and significantly correlated with erythrocyte sedimentation rate (p = 0.001) and were significantly higher in patients with positive C-reactive protein, rheumatoid factor and anti-cyclic citrullinated peptide (p = 0.0001, p = 0.009, p = 0.042, respectively). MMP-3 significantly correlated with DAS28 (p = 0.0001) and vdHSS (r = 0.78, p = 0.0001) and a significant difference was shown in those with erosions compared to those without (p = 0.001). Serum MMP-3 levels significantly correlated negatively with cumulative steroid dose (r = −0.2, p = 0.03) and were significantly higher in patients who never received disease-modifying antirheumatic drugs (p = 0.001). There were no significant relations of MMP-3 with age, MHAQ, VAS for pain.ConclusionThese results indicate that serum MMP-3 is a measurable, useful specific marker of disease activity and joint damage in RA patients.     

Clinical efficacy,radiographic progression,and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial

Objective: To evaluate the safety and efficacy of golimumab?+?methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA).

Methods: Japanese patients with active RA despite MTX were randomized to placebo?+?MTX (Group 1, n?=?88), golimumab 50?mg?+?MTX (Group 2, n?=?86), or golimumab 100?mg?+?MTX (Group 3, n?=?87). Patients with?<20% improvement in swollen/tender joint counts entered early escape at week 16. At week 24, all remaining placebo patients crossed over to golimumab 50?mg. Efficacy assessments included ACR20, DAS28-ESR, and HAQ-DI. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score.

Results: ACR20 response rates in Group 1, Group 2, and Group 3 were 67.9, 86.1, and 82.4%, respectively, at week 52 and were maintained through week 104 (87.1, 94.0, and 88.7%) and week 156 (97.1, 94.1, and 89.5%). Proportions of patients with good/moderate DAS28-ESR response or clinically meaningful improvement in HAQ-DI were also maintained through week 156. The majority of patients did not experience radiographic progression through week 156. Among 257 golimumab-treated patients, 251 (97.7%) had?≥1 AE; 54 (21.0%) had?≥1 serious AE through week 156. Infections were the most common type of AE.

Conclusions: Response to golimumab?+?MTX was maintained over 3 years in Japanese patients with active RA despite MTX. Safety results were consistent with the known safety profile of golimumab.     

电针联合脂肪源性干细胞移植对脑缺血/再灌注大鼠SDF-1和CXCR4表达的影响

目的探讨电针联合脂肪源性干细胞(ADSC)移植对大鼠缺血/再灌注损伤后趋化因子SDF-1及其受体CXCR4的影响。方法成年大鼠随机分为模型组、电针组、ADSC移植组、电针+ADSC组。线栓法制作大鼠大脑中动脉缺血(MCAO)2h再灌注模型,电针组取大椎穴和内关穴行电针治疗。ADSC组尾静脉注射PKH26标记的ADSC细胞悬液,电针+ADSC组联合电针和AD-SC移植治疗。缺血7d后行神经功能损害评分(NSS),采用Western bolt法及实时荧光定量PCR检测海马区SDF-1、CXCR4蛋白和mRNA表达。结果电针+ADSC组海马区PKH-26标记的细胞个数高于ADSC组(P<0.05)。与模型组比较,电针组、ADSC组和电针+ADSC组NSS评分均显著降低,海马区SDF-1、CXCR4蛋白和mRNA表达增加(P<0.05)。其中电针+ADSC组较电针组和ADSC组NSS评分显著降低,而SDF-1、CXCR4蛋白和mRNA表达显著增加(P<0.05)。结论电针联合脂肪源性干细胞移植促进脑缺血再灌注大鼠神经功能恢复作用优于单独治疗组,其机制可能与电针上调脑海马区SDF-1和CXCR4表达,促进移植的ADSC迁移和存活有关。     

Infiltrations of plasma cells in synovium are highly associated with synovial fluid levels of APRIL in inflamed peripheral joints of rheumatoid arthritis

Infiltration of plasma cells can be a histopathological hallmark of articular synovium with rheumatoid arthritis (RA). A proliferation-inducing ligand (APRIL) may have key roles in homeostasis and development of B cells, and the differentiation of B cells into plasma cells. This study was designed to explore the relationships between the infiltrations of plasma cells in synovium and the synovial fluid levels of APRIL in inflamed peripheral joints of RA. Synovium and synovial fluid were sampled from 21 RA patients underwent arthroscopic synovectomy for inflamed peripheral joints. The variants of rheumatoid synovium were classified into the follicular and diffuse synovitis by hematoxylin and eosin staining, and the infiltrations of plasma cells in rheumatoid synovium were quantified under the light microscope. The synovial fluid levels of APRIL were measured with the enzyme-linked immunosorbent assay. The mean number of infiltrating plasma cells in synovium and the mean synovial fluid level of APRIL were significantly increased in follicular synovitis compared with those in diffuse synovitis (P = 0.009, and P = 0.018, respectively), and there was a highly positive association between the infiltrations of plasma cells and the synovial fluid levels of APRIL among all of the RA patients (Rs = 0.776, P < 0.001). These findings suggest that the local production of APRIL may be associated with the ectopic lymphoid neogenesis in rheumatoid synovium and may have a role in contributing to the infiltration of plasma cells in synovium within inflamed peripheral joints of RA.     

Knee and/or hip joint destruction in rheumatoid arthritis is associated with HLA-DRB1*0405 in Japanese patients

To determine the prognostic factors for knee and/or hip joint destruction in rheumatoid arthritis (RA) patients, we typed 379 RA patients for HLA-DRB1 alleles and analysed the antigen frequencies. The DRB1^*0405 antigen frequency in RA patients who underwent total knee replacement and/or total hip replacement was significantly higher than in those who did not have replacements, which meant that DRB1^*0405 was associated with knee and/or hip joint destruction. This finding may be of value for predicting knee and/or hip joint destruction in RA.     

Prevention of joint destruction in patients with high disease activity or high C-reactive protein levels: Post hoc analysis of the GO-FORTH study

Objectives: To assess the influence of golimumab dosage and disease activity on joint destruction in patients with active rheumatoid arthritis (RA) in the GO-FORTH study.

Methods: Efficacy was compared among groups given basal methotrexate plus placebo, golimumab (50?mg), or golimumab (100?mg) with stratification by high (HDA) or moderate (MDA) baseline disease activity and by high or low baseline C-reactive protein (CRP).

Results: Among HDA or high CRP patients, the mean change of the total Sharp score was 3.48 and 3.41 in the placebo group, 1.94 and 2.71 in the 50?mg group, and 0.39 and 1.15 in the 100?mg group, respectively. The percentage of progression-free patients with HDA or high CRP was 40.4% and 40.0%, 43.1% and 38.2%, and 69.8% and 61.5%, respectively. Among MDA or low CRP patients, both golimumab doses showed similar prevention of joint destruction. Among HDA or high CRP patients, a shorter disease duration and higher TSS/disease duration ratio were associated with joint destruction.

Conclusion: Both doses of golimumab (50 or 100?mg) prevented joint destruction in MDA or low CRP patients, but 100?mg was better for HDA or high CRP patients with a shorter disease duration or higher TSS/disease duration ratio.     

The relationship between disease activity and depression in Egyptian patients with rheumatoid arthritis

Aim of the workTo estimate the prevalence of depression and its relationship with disease activity parameters in Egyptian patients with RA.Patients and methodsA cross sectional study was conducted on 170 patients with RA. The following values were assessed for each patient: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), swollen and tender joint counts (SJC and TJC), disease activity score 28 (DAS28), health assessment questionnaire score (HAQ), visual analogue scale (VAS) of pain and hospital anxiety and depression scale-depression subscale (HADS-D).ResultsThe prevalence of depression was 15.29% (26 RA patients). In the depressed RA patients, positive significant correlations were found between HADS-D score and age, disease duration, HAQ score, VAS, DAS28 score and CRP. However, no significant correlation was found between HADS-D score and ESR, number of swollen and tender joints. No significant difference (P > 0.05) was found between depressed male and female patients with RA.ConclusionPatients with RA and co-morbid depression have worse health outcomes. RA cases should be monitored for accompanying depression during follow-up. The identification and treatment of depression in RA paramount to the overall management of RA.     

Interleukin 1 activity in the synovial fluid of patients with rheumatoid arthritis

Summary The synovial fluids (SF) of patients with rheumatoid arthritis (RA) were investigated for their effects on thymocytes of C3H/HeJ mice. Of the 20 SF tested, 17 (85%) showed an augmentation of the phytohaemagglutinin (PHA) induced thymocyte stimulation. Out of 16 SF of patients with osteoarthrosis, such an activity was detected in only one (6.25%). Further characterisation of the amplification factor revealed that (1) the SF of RA patients augmented both the PHA and the Concanavalin A response of the thymocytes (2) in the absence of mitogens, SF-treated thymocytes showed an increased uptake of ³H-thymidine, (3) the SF did not propagate the growth of an interleukin 2 dependent ovalbumin specific T cell clone, but (4) the SF were found to be required for optimal interleukin 2 release by spleen cells stimulated with suboptimal doses of lectin. Based on these biological effects the factor in the SF of RA patients is suggested to represent an interleukin 1 (IL-1). IL-1 produced in cultures by activated macrophages has been shown to stimulate T and B cell functions and to induce the production of collagenase and prostaglandins by cultured synovial cells. Both properties of IL-1 could be relevant in the pathogenesis of RA.     

Predictive factors related to shoulder joint destruction in rheumatoid arthritis patients treated with biologics: A prospective study

Objective: The aim of this study was to assess the risk factors for shoulder joint destruction in rheumatoid arthritis (RA) patients treated with biologics.

Methods: Thirty shoulders of 29 patients with RA were assessed using 18F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) before starting biologics and 6 months later. The mean age (range) was 54 (18–72) years, and the mean disease duration was 7 (0.8–30) years. The radiographic findings were assessed at baseline and 3 years later. The inflammation markers and RA disease activity were also assessed. These parameters were compared between the progression of joint destruction group and the no progression group.

Results: The SUVmax on PET, the rate of synovitis, and the rate of rotator cuff tear on MRI before biologic treatment were significantly higher in the progression of joint destruction group. SUVmax and synovitis on MRI after 6 months were also significantly higher in the progression of joint destruction group. On logistic regression analysis, the SUV at baseline of the shoulder joint was the main risk factor for joint destruction.

Conclusion: The detection of synovitis by imaging was more important than disease activity and inflammation markers for assessing the progression of shoulder joint destruction.     

外周血SDF-1/CXCR4轴与急性心肌梗死患者冠状动脉侧支循环形成的关系

目的 检测急性心肌梗死(acute myocardial infarction,AMI)患者外周血基质细胞衍生因子-1(stromalcell derived factor 1,SDF-1)、CXC趋化因子受体-4(C-X-C chemokine receptor 4,CXCR4)的浓度,探讨两者在AMI患者冠状动脉侧...     

Binucleated and multinucleated forms of plasma cells in synovia from patients with rheumatoid arthritis

A morphological examination of synovial tissue from 25 patients with rheumatoid arthritis revealed that binucleated or multinucleated plasma cells were present in all samples and absent in synovia obtained from 16 control patients. Plasma cells containing two, three of four nuclei constitutet a mean 3% of the total plasma cell population. They were aways found amongst plasma cell infiltrates and in close association with small blood vessels. Ultrastructural analysis found no evidence of cellular membranes separating the individual nuclei in binucleated or multinucleated plasma cells, suggesting that the cells did not arise from fusion. Some of these plasma cells had a diameter approaching 100 μm, and many were in intimate contact with macrophages. The demonstration of a few cells with mitotic figures within the infiltrates suggests that the maintenance of plasma cell numbers in rheumatoid synovium may depend, in part, upon their local proliferation. Received: 25 August 1997 / Accepted: 2 October 1997     

Antiperinuclear factor – clinical, serological and genetic correlates in Israeli patients with rheumatoid arthritis

The possible association between the presence of antiperinuclear factor (APF) and clinical and genetic parameters was investigated in 54 Israeli patients with rheumatoid arthritis (RA). Rheumatoid factor (RF) was detected in the sera of 43 patients (80%) and APF was positive in 33 (61%). No significant statistical differences were found in the presence of HLA-DR4 and/or DR1 between APF-positive and -negative patients. Furthermore, neither the Ritchie articular index nor the patient's functional class correlated with the presence of APF. The results of our study suggested that although Israeli patients have a different genetic background, the presence and behaviour of APF is similar to that of other Caucasian populations. Received: 14 April 1997 / Accepted: 25 August 1997