Energy focusability of spatial incoherent beam combining for pulse laser propagation in marine atmosphere.

In this study, we have deduced the generalized scintillation index of the plane wave and plane wave structure function based on the modified non-Kolmogorov power spectrum of atmospheric refractive index with the spectrum power index α. In addition, we have analyzed the fluctuation of atmospheric density due to thermal blooming. Based on the interaction of six beams in thermal blooming, the thermal phase screening and intensity distribution are simulated. Under the influence of atmospheric turbulence and thermal blooming, the six-beam combination is then simulated numerically to obtain the equivalent radius with long exposure (RL), power in the bucket (PIB), Strehl ratio (SR), and peak value of intensity (Ip). Results show that PIB, Ip, and SR of the pulse beam combination decrease with an increase in α; however, RL operates in reverse mode and the short pulse durations reduce the thermal blooming. Moreover, laser of short duration cannot generate high ring energy on the target.

FYCO1 regulates migration, invasion, and invadopodia formation in HeLa cells through CDC42/N-WASP/Arp2/3 signaling pathway.

FYCO1, an autophagy adaptor, plays an essential role in the trafficking toward the plus-end of microtubules and the fusion of autophagosomes. Autophagic dysfunction is involved in numerous disease states, including cancers. Previous studies have implicated FYCO1 as one of the critical genes involved in the adenoma to carcinoma transition, but the biological function and mechanism of FYCO1 in carcinogenesis remain unclear. This study aims to elucidate the role and mechanism of up- and downregulation of FYCO1 in mediating tumor effects in HeLa cells. Functionally, FYCO1 promotes cellular migration, invasion, epithelial-mesenchymal transition, invadopodia formation, and matrix degradation, which are detected through wound healing, transwell, immunofluorescence, and Western blot approaches. Interestingly, the data show that although FYCO1 does not affect HeLa cell proliferation, cell cycle distribution, nor vessels' formation, FYCO1 can block the apoptotic function. FYCO1 inhibits cleavage of PARP, caspase3, and caspase9 and increases Bcl-2/Bax ratio. Then, we used CK666, an Arp2/3 specific inhibitor, to confirm that FYCO1 may promote the migration and invasion of HeLa cells through the CDC42/N-WASP/Arp2/3 signaling pathway. Taken together, these results provide a new insight that FYCO1, an autophagy adaptor, may also be a new regulator of tumor metastasis.

Identification and functional study of FOXC1 variants in Chinese families with glaucoma.

This study aimed to identify the disease-causing gene of three Chinese families with glaucoma. Whole exome sequencing was performed on the probands and detected three different variants (c.405C>A (p.Cys135Ter), c.851G>T (p.Ser284Ile), and c.392C>T (p.Ser131Leu)) in FOXC1 as a causative gene of glaucoma, and Sanger sequencing was performed for verification and cosegregation analysis. Three in silico tools all predicted these two missense variants to be probably disease-causing. Western blot analysis, immunofluorescence, and dual-luciferase assay were further used to evaluate the effect of FOXC1 missense variants, and demonstrated that the two variants resulted in decreased transactivation activity of FOXC1 although the variants had no effect on the protein amount and the nucleus subcellar localization of FOXC1 compared with the wild type, which implies that both of two variants may be probably pathogenic. In this study, we reported two novel FOXC1 variants as well as a reported variant and the phenotypes associated to these variants, which expands the spectrum and relevant phenotypes of FOXC1 variants. Additionally, the functional analysis of FOXC1 variants provides further insight into the possible pathogenesis of anterior segment anomaly related to FOXC1.

Myosin light chain 2 marks differentiating ventricular cardiomyocytes derived from human embryonic stem cells.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have great value for studies of human cardiac development, drug discovery, disease modeling, and cell therapy. However, the mixed cardiomyocyte subtypes (ventricular-, atrial-, and nodal-like myocytes) and the maturation heterogeneity of hPSC-CMs restrain their application in vitro and in vivo. Myosin light chain 2 (MYL2, encoding the ventricular/cardiac muscle isoform MLC2v protein) is regarded as a ventricular-specific marker of cardiac myocardium; however, its restricted localization to ventricles during human heart development has been questioned. Consequently, it is currently unclear whether MYL2 definitively marks ventricular hESC-CMs. Here, by using a MYL2-Venus hESC reporter line, we characterized a time-dependent increase of the MYL2-Venus positive (MLC2v-Venus+) hESC-CMs during differentiation. We also compared the molecular, cellular, and functional properties between the MLC2v-Venus+ and MYL2-Venus negative (MLC2v-Venus-) hESC-CMs. At early differentiation stages of hESC-CMs, we reported that both MLC2v-Venus- and MLC2v-Venus+ CMs displayed ventricular-like traits but the ventricular-like cells from MLC2v-Venus+ hESC-CMs displayed more developed action potential (AP) properties than that from MLC2v-Venus- hESC-CMs. Meanwhile, about a half MLC2v-Venus- hESC-CM population displayed atrial-like AP properties, and a half showed ventricular-like AP properties, whereas only ~ 20% of the MLC2v-Venus- hESC-CMs expressed the atrial marker nuclear receptor subfamily 2 group F member 2 (NR2F2, also named as COUPTFII). At late time points, almost all MLC2v-Venus+ hESC-CMs exhibited ventricular-like AP properties. Further analysis demonstrates that the MLC2v-Venus+ hESC-CMs had enhanced Ca2+ transients upon increase of the MLC2v level during cultivation. Concomitantly, the MLC2v-Venus+ hESC-CMs showed more defined sarcomeric structures and better mitochondrial function than those in the MLC2v-Venus- hESC-CMs. Moreover, the MLC2v-Venus+ hESC-CMs were more sensitive to hypoxic stimulus than the MLC2v-Venus- hESC-CMs. These results provide new insights into the development of human ventricular myocytes and reveal a direct correlation between the expression profile of MLC2v and ventricular hESC-CM development. Our findings that MLC2v is predominantly a ventricular marker in developmentally immature hESC-CMs have implications for human development, drug screening, and disease modeling, and this marker should prove useful in overcoming issues associated with hESC-CM heterogeneity.

Role of CXCL16 in BLM-induced epithelial-mesenchymal transition in human A549 cells.

Alveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial-mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-ß1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-ß1/Smad3 signaling pathway.

Validation of new classification criteria of rheumatoid arthritis in an international multicentre study.

OBJECTIVES: Early identification of patients with rheumatoid arthritis (RA) is essential to allow prompt therapy. In this study, we aimed to evaluate the performance of the newly proposed ERA criteria, compared to the 1987 ACR and 2010 ACR/EULAR criteria in an international multicentre study. METHODS: A total of 606 patients with disease duration ≤2 years and age ≥16 years who were diagnosed as RA or non-RA were enrolled from China, Sweden and India. The clinical and laboratory parameters were recorded. We compared the sensitivity, specificity, predictive value, likelihood ratio (LR), and the area under the ROC curve (AUC) of three criteria in these cohorts. Concordance between the three criteria was calculated with the Kappa coefficient. RESULTS: Three hundred and twelve RA and 294 non-RA patients were included. The Early Rheumatoid Arthritis (ERA) criteria had significantly higher specificity compared to the 2010 ACR/ EULAR criteria (83.7% vs. 78.2%, p=0.02) and sensitivity were similar (79.2% vs. 78.5%, p=0.883). In comparison with the 1987 ACR criteria, the ERA criteria had higher sensitivity (79.2% vs. 54.5%, p<0.001) but lower specificity (83.7% vs. 89.1%, p<0.001), and the AUC of the ERA criteria (0.878) was comparable to the 2010 ACR/EULAR criteria (0.849) and higher than the 1987 ACR criteria (0.791, p<0.0001). Patients from the three countries, seronegative and very early arthritis cohorts yielded consistent results. CONCLUSIONS: The ERA criteria demonstrate a better performance across ethnics in early RA diagnosis, and is more feasible in daily practice.

Interleukin-21 enhances Toll-like receptor 2/4-mediated cytokine production via phosphorylation in the STAT3, Akt and p38 MAPK signalling pathways in human monocytic THP-1 cells.

Interleukin-21 (IL-21) is a type I cytokine produced by activated T cells that promotes cytokine production in monocytes. Monocytes are activated by Toll-like receptors (TLRs) to produce pro-inflammatory mediators. However, little is known about the regulatory effect of IL-21 on TLR-mediated inflammation in human monocytes. This study investigated the potential association between IL-21 and TLR2/4-mediated inflammation in human monocytic THP-1 cells. First, the expression of the IL-21 receptor (IL-21R) in human monocytic THP-1 cells was examined by flow cytometry. Then, THP-1 cells were treated with either the TLR2 ligand peptidoglycan (PGN) or the TLR4 ligand lipopolysaccharide (LPS) with or without IL-21. Then, the production of several cytokines (IL-6, IL-8, TNF-α, IFN-γ and IL-10), expression of TLR2/4, and activation of the downstream signaling pathways of mitogen-activated protein kinase (MAPK), Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and nuclear factor-kappa B (NF-κB) were determined. We found that IL-21R was highly expressed in human monocytic THP-1 cells and that IL-21 induced TLR2 and TLR4 expression and further enhanced PGN/LPS-mediated TLR2/4 expression. In addition, IL-21 also upregulated the expression of IL-6, IL-8, TNF-α, IFN-γ and IL-10 and enhanced TLR2/4-mediated cytokine production in THP-1 cells via phosphorylation of the STAT3, Akt and p38 MAPK signalling pathways. Our study suggests, for the first time that IL-21 enhances TLR2/4-mediated cytokine production in human monocytic THP-1 cells by activating the STAT3, PI3K/Akt and p38 MAPK signalling pathways.

Constant hypoxia inhibits osteoclast differentiation and bone resorption by regulating phosphorylation of JNK and IκBα.

BACKGROUND: Osteoclasts are responsible for the bone loss in rheumatoid arthritis (RA). Hypoxia has been suggested to play key roles in pathological bone loss. However, the current understanding of the effects of hypoxia on osteoclastogenesis is controversial. Effects of hypoxia on both the formation and function of osteoclasts requires examination. In the current study, we aimed to explore the effect of hypoxia on osteoclast differentiation and the underlying mechanisms. METHODS: RAW264.7 cells and murine bone-marrow-derived monocytes were used to induce osteoclastogenesis in the presence of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL). Hypoxic conditions were maintained in a hypoxic chamber at 5% CO2 and 1% O2, balanced with N2. Osteoclasts were detected by tartrate-resistant acid phosphatase (TRAP) staining. A bone resorption assay was carried out in vitro using bone slices. RT-PCR was conducted to detect osteoclast markers and transcription factors. The phosphorylation of nuclear factor-κBα (IκBα), c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase (ERK), and p38 was detected by western blotting. Mann-Whitney U test or Student's t test was used to compare differences between the two groups. RESULTS: TRAP staining and the bone resorption assay revealed that hypoxia-restrained osteoclast differentiation and bone resorption. Expression of osteoclast markers including cathepsin K, RANK, and TRAP decreased during osteoclast differentiation under hypoxic conditions (all P < 0.05). Hypoxia at 1% O2 did not affect cell viability, whereas it dramatically abated RANKL-dependent phosphorylation of the JNK-mitogen-activated protein kinases (MAPK) and IκBα pathways. Moreover, the expression of nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) was inhibited under hypoxic conditions (all P < 0.05). CONCLUSIONS: These results suggest that constant hypoxia at 1% O2 significantly restrains osteoclast formation and resorbing function without affecting cell viability. Constant hypoxia might inhibit RANKL-induced osteoclastogenesis by regulating NFATc1 expression via interfering the phosphorylation of JNK and IκBα.

Efficacy and safety of certolizumab pegol in combination with methotrexate in methotrexate-inadequate responder Chinese patients with active rheumatoid arthritis: 24-week results from a randomised, double-blind, placebo-controlled phase 3 study.

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) in Chinese patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: This 24-week, phase 3, double-blind, placebo-controlled study was conducted in 30 centres across China. A total of 430 patients were randomised 3:1 to receive CZP 200 mg every 2 weeks (loading dose: 400 mg CZP at Weeks 0, 2 and 4) plus MTX or placebo (PBO) plus MTX. The primary endpoint was ACR20 response at Week 24, for which the superiority of CZP+MTX over PBO+MTX was evaluated. Additional parameters for clinical efficacy, health outcomes, immunogenicity and safety were assessed. RESULTS: At Week 24, 54.8% of CZP+MTX patients and 23.9% of PBO+MTX patients achieved ACR20 (odds ratio: 3.9, p<0.001). CZP+MTX patients also achieved greater improvements in HAQ-DI, higher ACR50/70 responses and higher DAS28(ESR) remission rate at Week 24. Rapid onset of response to CZP+MTX was observed as early as Week 1 for most of the clinical, functional and patient-reported outcomes. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment arms. Serious TEAEs were reported by 6.3% of CZP+MTX patients and 2.7% of PBO+MTX patients. No new safety signals were observed. CONCLUSIONS: CZP in combination with MTX showed an acceptable safety profile, a rapid onset of response and sustained effects in reducing the signs and symptoms of RA and improving physical function in Chinese patients with RA and an inadequate response to MTX.

Extracellular Signal-regulated Kinases (ERKs) Phosphorylate Lin28a Protein to Modulate P19 Cell Proliferation and Differentiation.

Lin28a, originally discovered in the nematode Caenorhabditis elegans and highly conserved across species, is a well characterized regulator of let-7 microRNA (miRNA) and is implicated in cell proliferation and pluripotency control. However, little is known about how Lin28a function is modulated at the post-translational level and thereby responds to major signaling pathways. Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200. By editing lin28a gene with the CRISPR/Cas9-based method, we generated P19 mouse embryonic carcinoma stem cells expressing Lin28a-S200A (phospho-deficient) and Lin28a-S200D (phospho-mimetic) mutants, respectively, to study the functional impact of Ser-200 phosphorylation. Lin28a-S200D-expressing cells, but not Lin28a-S200A-expressing or control P19 embryonic carcinoma cells, displayed impaired inhibition of let-7 miRNA and resulted in decreased cyclin D1, whereas Lin28a-S200A knock-in cells expressed less let-7 miRNA, proliferated faster, and exhibited differentiation defect upon retinoic acid induction. Therefore our results support that ERK kinase-mediated Lin28a phosphorylation may be an important mechanism for pluripotent cells to facilitate the escape from the self-renewal cycle and start the differentiation process.

Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis.

Phosphoglycerate kinase 1 (PGK1) is an important enzyme in the metabolic glycolysis pathway. In this study, we observed a significant overexpression of PGK1 in liver cancer tissues and a negative correlation between PGK1 expression and liver cancer patient survival. Furthermore, depletion of PGK1 dramatically reduced cancer cell proliferation and tumorigenesis, indicating an oncogenic role of PGK1 in liver cancer progression. Moreover, we identified acetylation at the K323 site of PGK1 as an important regulatory mechanism for promoting its enzymatic activity and cancer cell metabolism. And we further characterized P300/cyclic adenosine monophosphate response element binding protein-binding protein-associated factor (PCAF) and Sirtuin 7 as the enzymes regulating K323 acetylation from both directions in liver cancer cells. CONCLUSION: These findings demonstrate a novel regulation of PGK1 as well as its important role in liver cancer progression. (Hepatology 2017;65:515-528).

Mimotope mimicking epidermal growth factor receptor alleviates mononuclear cell infiltration in exocrine glands induced by muscarinic acetylcholine 3 receptor.

The muscarinic type 3 receptor (M3R) plays a pivotal role in the pathogenesis of Sjögren's syndrome (SS). Characterization of the crosstalk between M3R and EGFR has been investigated in some human malignancies. In the current study, we sought to investigate whether EGFR mimic immunization could alleviate the abnormal immune responses in an experimental SS-like model triggered by M3R peptides. After immunization with the combination of mimotope and M3R peptide, the active immunization targeting EGFR induced by the mimotope could reduce the marked infiltration of mononuclear cells, the high titer of antibodies against M3R and the accumulation of crucial pro-inflammatory cytokines in mice immunized with M3R peptide. Mechanistic analysis showed that mimotope immunization could alleviate the autoimmune response through inhibiting mitochondrion-mediated anti-apoptosis and up-regulating the FAS apoptosis pathway. These results may help to clarify the role of M3R in the pathogenesis of SS and suggested that transactivation of the EGFR signaling pathway may help M3R activate the autoimmune response in the pathogenesis of SS.

CXCL16 upregulates RANKL expression in rheumatoid arthritis synovial fibroblasts through the JAK2/STAT3 and p38/MAPK signaling pathway.

OBJECTIVE: To explore the influence of chemokine, CXCL16, on the expression of the receptor activator nuclear factor κB ligand (RANKL) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS). METHODS: The expression of CXCL16/CXCR6 and RANKL in RA or osteoarthritis (OA) patient synovia was examined by Western blot and immunohistochemistry. The serum concentration of CXCL16 and RANKL was measured by enzyme-linked immunosorbent assay (ELISA). RA-FLS were treated with recombinant CXCL16, and RANKL mRNA and protein were measured using PCR, Western blot and ELISA. RESULTS: The synovial expression of CXCL16, CXCR6, and RANKL was higher in RA patients than in patients with OA. The serum CXCL16 and RANKL levels were higher in RA patients compared with OA patients and healthy controls. CXCL16 correlated with erythrocyte sedimentation rate, C reactive protein, disease activity, serum rheumatoid factor, and RANKL. RA-FLS treated with CXCL16 showed markedly increased expression of RANKL. When STAT3 or p38 activation was blocked by an inhibitor, CXCL16 failed to upregulate RANKL expression. In contrast, inhibiting the Akt or Erk pathway did not achieve the same effect. CONCLUSIONS: CXCL16 upregulates RANKL expression in RA-FLS and these effects are mainly mediated by the JAK2/STAT3 and p38/MAPK signaling pathways.

Disease association and arthritogenic potential of circulating antibodies against the α1,4-polygalacturonic acid moiety.

Much progress has been made in recent years on the diagnostic value, Ag specificity, and pathogenic roles of autoantibodies correlated to the development of rheumatoid arthritis (RA) in humans. However, carbohydrate Ag-specific autoantibodies that may also play important roles in RA have largely been ignored. In this article, we report that serum levels of Abs capable of recognizing α1,4-polygalacturonic acid [(PGA); major structural component of pectin] strongly correlate with RA in humans. The measurements of PGA-specific Abs (PGA-Abs) in sera are comparable to rheumatoid factors and anti-cyclic citrullinated peptide Abs as serological diagnostic markers for RA in terms of sensitivity and specificity. Immunohistochemical staining results indicate that the PGA-Abs selectively bound synovial membrane cells and chondrocytes in the joints of both humans and rabbits (but not rodents). Induction of PGA-Abs by s.c. immunization of rabbits with carrier protein-conjugated synthetic PGA led to severe inflammatory reactions (synovial hyperplasia, small vessel proliferation, and inflammatory cell infiltration) in the joints. Injection of affinity purified anti-PGA IgG into the synovial cavity of rabbits resulted in accumulation of proinflammatory cytokines such as TNF-α, IL-8, and IL-1ß in synovial fluid, as well as local pathological damage. We conclude that the PGA-cross-reactive moiety represents a major autoantigen in the joints and can be targeted by autoantibodies capable of triggering arthritogenic responses in vivo.

Active immunization with Tocilizumab mimotopes induces specific immune responses.

BACKGROUND: Tocilizumab is a humanized monoclonal antibody showing high-affinity binding to both soluble interleukin-6 receptor (sIL-6R) and membrane bound IL-6R (mIL-6R), thereby preventing pro-inflammatory effects of IL-6. However, therapeutic antibodies still have practical limitations. To overcome these limitations, we generated Tocilizumab specific epitope mimics by using the phage display technology and tested whether the peptide mimics could induce similar humoral responses in mice immunized with the peptides. RESULTS: Seven phage mimics were obtained by using phage display peptide library. Four phage mimics (YHTTDKLFYMMR, YSAYEFEYILSS, KTMSAEEFDNWL and LTSHTYRSQADT) were shown to mimic Tocilizumab epitope using immunoassays. The mimotopes were conjugated to immunogenic carrier proteins and used to intraperitoneally immunize BALB/c mice. Sera from the mimotopes immunized mice not only showed specific binding to recombinant IL-6R, but can also IL-6R expressed in Hela, U-937, Jurkat cell lines and in fibroblast-like synoviocytes from patients with RA (FLS-RA). Furthermore, sera from mice immunized with mimotopes-KLH conjugate could reduce the level of phosphorylated- signal transducers and activator of transcription (STAT3), STAT3, phosphorylated- extracellular signal-regulated kinase (Erk) 1/2 and Erk1/2 in HeLa and Jurkat cells. Antibody-dependent cellular cytotoxicity (ADCC) assay showed that antibodies induced by mimotopes-KLH conjugate could elicit specific lysis in Hela and U-937 cells. CONCLUSIONS: From phage display library, we successfully isolated four Tocilizumab mimotopes which induced specific humoral and cellular reponses in vitro and in vivo.

The impact of rheumatoid arthritis on work capacity in Chinese patients: a cross-sectional study.

OBJECTIVE: To evaluate the impact of RA on work capacity and identify factors related to work capacity impairment in patients with RA. METHODS: A cross-sectional multicentre study was performed in 21 tertiary care hospitals across China. A consecutive sample of 846 patients with RA was recruited, of which 589 patients of working age at disease onset constituted the study population. Information on the socio-demographic, clinical, working and financial conditions of the patients was collected. Logistic regression analyses were used to identify factors associated with work capacity impairment. RESULTS: The rate of work capacity impairment was 48.0% in RA patients with a mean disease duration of 60 months (interquartile range 14-134 months), including 11.7% leaving the labour force early, 33.6% working reduced hours and 2.7% changing job. Multivariable logistic regression analysis showed that reduced working hours was significantly related to current smoking [odds ratio (OR) 2.07 (95% CI 1.08, 3.97)], no insurance [OR 1.94 (95% CI 1.20, 3.12)], in manual labour [OR 2.66 (95% CI 1.68, 4.20)] and higher HAQ score [OR 2.22 (95% CI 1.36, 3.60)]. There was an association of current smoking [OR 3.75 (95% CI 1.54, 9.15)], in manual labour [OR 2.33 (95% CI 1.17, 4.64)], longer disease duration [OR 1.01 (95% CI 1.00, 1.01)] and lower BMI [OR 0.90 (95% CI 0.82, 0.99)] with leaving the labour force early. CONCLUSION: There is a substantial impact of RA on the work capacity of patients in China. Social-demographic, disease- and work-related factors are all associated with work capacity impairment.

Classification criteria of early rheumatoid arthritis and validation of its performance in a multi-centre cohort.

OBJECTIVES: To develop classification criteria for early rheumatoid arthritis (ERA) based on a large cohort of early inflammatory arthritis patients and to evaluate the performance of these criteria. METHODS: The study population comprised a cohort of early inflammatory arthritis patients with symptom duration less than one year. Classification criteria of ERA were developed by incorporating the most sensitive or specific variables. Performance of the ERA criteria, 1987 ACR and 2010 ACR/EULAR criteria were evaluated. RESULTS: A total of 803 patients were enrolled in this study. By the end of the one year follow-up, 514 patients were diagnosed with RA, 251 with other rheumatic diseases, and 38 patients with undifferentiated arthritis. The ERA criteria are as follows: 1) morning stiffness ≥30 minutes; 2) arthritis of 3 or more joint areas; 3) arthritis of hand joints; 4) positive RF; 5) positive anti-CCP antibody. Rheumatoid arthritis is defined by the presence of 3 or more of the criteria. The sensitivity (84.4%) of the ERA classification criteria was much higher than the 1987 ACR criteria (58.0%). In a validation cohort of early inflammatory arthritis patients, the area under the ROC curves (AUC) showed a better performance for the ERA criteria (0.906, 95%CI 0.866 to 0.945) than the 1987 ACR criteria (0.786, 95%CI 0.725 to 0.848) and the 2010 ACR/EULAR criteria (0.745, 95%CI 0.677 to 0.814). CONCLUSIONS: A set of ERA classification criteria has been developed with good performance for early RA. It is applicable in clinical practice and research.

[Pregnancy outcome in 54 patients with antiphospholipid syndrome: a retrospective clinical study].

OBJECTIVE: To summarize the maternal/fetal outcome of pregnancy in antiphospholipid syndrome (APS) patients to evaluate the influence of treatment on the outcomes of pregnancy, and to investigate the possible clinical predictors of unsuccessful pregnancy. METHODS: The clinical characteristics, laboratory profiles and the outcomes of delivery of 54 APS patients from January 2000 to March 2013 were investigated retrospectively. RESULTS: (1) Maternal/fetal outcome: 17 pregnancies (31.4%) resulted in full term delivery, 7 (12.9%) in stillbirth, 16 (29.6%) in spontaneous abortion,10 (18.5%) in premature birth due to eclampsia or severe preeclampsia or signs of placental insufficiency, 4 (7.4%)received therapeutic termination of pregnancy due to eclampsia or severe preeclampsia. In 27 live birth cases, 8 (29.6%) were fetal growth restriction, 4 (14.8%) were low birth weight infants, and 3 (11.1%) were very low birth weight infants. (2) Influence of treatment on the pregnancy outcomes and complications: 24 APS patients were given the treatment of aspirin or aspirin combined with low molecular weight heparin, and 30 patients received no treatment. Compared with the untreated group, the treated group had lower rate of fetal loss, higher rate of full-term delivery, increased gestational age and birth weight, decreased incidence of preeclampsia / eclampsia and thrombocytopenia. There was a significant difference between the two groups (P<0.05). (3)Possible risk factors of unsuccessful pregnancy: there were 17 successful pregnancies and 37 unsuccessful pregnancy. The rate of double APL positive and antibody titers ≥ three times the upper limit of normal were higher in the unsuccessful pregnancy group than the successful pregnancy group. Antibody negative rate before pregnancy proportion of patients received treatment and the level of complement 4 were lower in the unsuccessful pregnancy group. CONCLUSION: Pregnant women with APS are an extremely high risk group for adverse maternal /fetal outcome. Treatments can improve the pregnancy outcome of the APS patients. APL not turning negative before pregnancy double APL positive, antibody titers ≥ three times the upper limit of normal and complement 4 decrease may be the risk factors for pregnancy failure and treatment may be a protective factor for successful pregnancy.

[A multi-center retrospective study of organ involvement in adult patients with polymyositis or dermatomyositis].

OBJECTIVE: To explore the prevalence and characteristics of main organ involvement in adult patients with polymyositis (PM) or dermatomyositis (DM) and determine their specific relative factors. METHODS: Using unified questionnaire, we retrospectively collected the medical records of 1 387 confirmed adult PM/DM patients from 2007 to 2012 at 22 rheumatology centers in China. Statistical analyses were performed with chi-square or Fisher exact test and multivariate analyses with logistic regression. RESULTS: A total of 1 387 patients were collected with 460 (33.2%) PM and 927 (66.8%) DM. The female:male ratio was 2.4: 1. Their onset age was ( 47 ± 14) years. A total of 1 031 (74.3%) patients had organ involvement. The prevalence of pulmonary involvement, arthritis, gastrointestinal and cardiac involvement were 44.6%, 32.3%, 21.9% and 20.3% respectively. The multivariate analysis indicated that older onset age (P < 0.01) was positively associated with pulmonary involvement while myalgia (P < 0.05) was negatively associated. Fever (P < 0.05), weight loss (P < 0.05) and Raynaud's phenomenon (P < 0.01) were positively associated with arthritis while muscle weakness (P < 0.05) negatively associated. Weight loss (P < 0.05), Raynaud's phenomenon (P < 0.01) and muscle weakness (P < 0.05) were positively associated with gastrointestinal involvement. Weight loss (P < 0.05) and swollen limbs (P < 0.05) were positively associated with cardiac involvement. CONCLUSION: The prevalence of organ involvement is high in adult PM/DM patients. Our study may aid the diagnosis of organ damage in PM/DM patients.

AG490 inhibits NFATc1 expression and STAT3 activation during RANKL induced osteoclastogenesis.

Commonly, JAK/STAT relays cytokine signals for cell activation and proliferation, and recent studies have shown that the elevated expression of JAK/STAT is associated with the immune rejection of allografts and the inflammatory processes of autoimmune disease. However, the role which JAK2/STAT3 signaling plays in the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis is unknown. In this study, we investigated the effects of AG490, specific JAK2 inhibitor, on osteoclast differentiation in vitro. AG490 significantly inhibited osteoclastogenesis in murine osteoclast precursor cell line RAW264.7 induced by RANKL. AG490 suppressed cell proliferation and delayed the G1 to S cell cycle transition. Furthermore, AG490 also suppressed the expression of nuclear factor of activated T cells (NFAT) c1 but not c-Fos in RAW264.7. Subsequently, we investigated various intracellular signaling components associated with osteoclastogenesis. AG490 had no effects on RANKL-induced activation of Akt, ERK1/2. Interestingly, AG490 partly inhibited RANKL-induced phosphorylation of Ser(727) in STAT3. Additionally, down-regulation of STAT3 using siRNA resulted in suppression of TRAP, RANK and NFATc1 expression. In conclusion, we demonstrated that AG490 inhibited RANKL-induced osteoclastogenesis by suppressing NFATc1 production and cell proliferation via the STAT3 pathway. These results suggest that inhibition of JAK2 may be useful for the treatment of bone diseases characterized by excessive osteoclastogenesis.