Sub-pm linewidth, high pulse energy, high beam quality microsecond-pulse Ti:sapphire laser at 766.699†nm.

In this letter, a sub-pm linewidth, high pulse energy and high beam quality microsecond-pulse 766.699 nm Ti:sapphire laser pumped by a frequency-doubled Nd:YAG laser is demonstrated. At an incident pump energy of 824 mJ, the maximum output energy of 132.5 mJ at 766.699 nm with linewidth of 0.66 pm and a pulse width of 100 µs is achieved at a repetition rate of 5 Hz. To the best of our knowledge, this is the highest pulse energy at 766.699 nm with pulse width of hundred micro-seconds for a Ti:sapphire laser. The beam quality factor M2 is measured to be 1.21. It could be precisely tuned from 766.623 to 766.755 nm with a tuning resolution of 0.8 pm. The wavelength stability is measured to be less than ±0.7 pm over 30 min. The sub-pm linewidth, high pulse energy and high beam quality Ti:sapphire laser at 766.699 nm can be used to create a polychromatic laser guide star together with a home-made 589 nm laser in the mesospheric sodium and potassium layer for the tip-tilt correction resulting in the near-diffraction limited imagery on a large telescope.

Methylprednisolone pulse therapy promotes the differentiation of regulatory T cells by inducing the apoptosis of CD4+ T cells in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate the differentiation of regulatory T cells (Tregs) induced by methylprednisolone (MP) pulse therapy in patients with Systemic Lupus Erythematosus (SLE). METHODS: We enrolled 30 patients with SLE and analyzed peripheral blood mononuclear cells (PBMCs) before and after MP pulse therapy. Peripheral Tregs, apoptosis of PBMCs subsets, and TGFß production by monocytes was quantified by flow cytometry. Proliferation and IFN-γ production of CD4+ T cells were measured. Furthermore, TGFß1 production by human monocyte-derived macrophages (HMDM) stimulated with MP-treated CD4+ T cells were quantified by ELISA. RESULTS: Peripheral Tregs was significantly increased after MP pulse therapy (6.76 ± 1.46% vs. 3.82 ± 1.02%, p < 0.01), with an expansion of Nrp1- induced Tregs (4.54 ± 0.46% vs. 1.75 ± 0.38%, p < 0.01). Proliferation and IFN-γ production of CD4+ T cells were significantly decreased after MP pulse therapy. MP pulse therapy induced CD4+ T cell apoptosis (early apoptosis, 26.34 ± 3.54% vs. 14.81 ± 2.89%, p < 0.01) and TGFß expression on monocytes (6.02% vs. 2.45%, p < 0.01). Furthermore, MP induced CD4+ T cell apoptosis in vitro, which stimulated HMDM to produce TGFß. Moreover, elevated TGFß level in supernatant from HMDM stimulated with MP-treated CD4+ T cells promoted Tregs differentiation. CONCLUSIONS: MP pulse therapy induces CD4+ T cell apoptosis, which promotes monocytes to produce TGFß and further facilitates Tregs differentiation. Newly-differentiated Tregs suppress proliferation and IFN-γ production of CD4+ T cells and contribute to immunoregulatory milieu after MP pulse therapy.

Characteristics of Acquired Inhibitors to Factor VIII and Von Willebrand Factor Secondary to Systemic Lupus Erythematosus: Experiences From a Chinese Tertiary Medical Center.

OBJECTIVE: Because acquired hemophilia (AH) is a rare entity in systemic lupus erythematosus (SLE), we aimed to investigate the clinical features of SLE-related AH in Chinese patients. METHODS: This is a medical records review study carried out at a large tertiary care hospital in China from years 1986 to 2018. We searched the case database in Peking Union Medical College Hospital using the International Classification of Diseases. The clinical data on SLE-related AH patients were collected. RESULTS: A total of 9282 SLE patients had been hospitalized. Six female SLE-related AH patients were identified. Four patients had acquired hemophilia A (AHA), and 2 patients had acquired von Willebrand syndrome. Their mean age was 33.67 ± 13.77 years. Five patients had active disease. The mean SLE disease activity index measured at the time of diagnosis of AH was 10.50 ± 5.28. The average level of activated partial thromboplastin time was 86.5 seconds. Coexistence of secondary antiphospholipid syndrome and AHA was found in one case, and pulmonary embolism was observed 3 years later. After immunosuppressive therapy and symptomatic treatment, an overall remission rate of 83.3% was achieved. CONCLUSIONS: The frequency of SLE-related AH was low. The development of AH in SLE patients frequently occurs with active disease. The AH could be the first clinical presentation of SLE. Secondary antiphospholipid syndrome and AHA could appear in the same SLE patient. Early and aggressive treatment contributes to a favorable prognosis.

Elevated EPSTI1 promote B cell hyperactivation through NF-κB signalling in patients with primary Sjögren's syndrome.

BACKGROUND: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterised by aberrant B cell hyperactivation, whose mechanism is partially understood. METHODS: We performed whole transcriptome sequencing of B cells from three pSS patients and three matched healthy controls (HC). Differentially expression genes (DEGs) were confirmed with B cells from 40 pSS patients and 40 HC by quantitative PCR and western blot. We measured the proliferation potential and immunoglobulins production of siRNA-transfected or plasmid-transfected B cells stimulated with cytosine-phosphate-guanine (CpG) or anti-IgM. We also explored Toll-like receptor 9 (TLR9) signalling to reveal the potential mechanism of B cell hyperactivation in pSS. RESULTS: We identified 77 upregulated and 32 downregulated DEGs in pSS B cells. We confirmed that epithelial stromal interaction (EPST1) expression in pSS B cells was significantly higher than that from HCs. EPSTI1-silencing B cells stimulated with CpG were less proliferated and produced lower level of IgG and IgM comparing with control B cells. EPSTI1-silencing B cells expressed lower level of p-p65 and higher level of IκBα, and B cells with overexpressed EPSTI1 showed higher level of p-p65 and lower level of IκBα. Finally, IκBα degradation inhibitor Dehydrocostus Lactone treatment attenuated p65 phosphorylation promoted by EPSTI1. CONCLUSION: Elevated EPSTI1 expression in pSS B cells promoted TLR9 signalling activation and contributed to the abnormal B cell activation, which was promoted by facilitating p65 phosphorylation and activation of NF-κB signalling via promoting IκBα degradation. EPSTI1 might be implicated in pSS pathogenesis and was a potential therapeutic target of pSS.

Antagonizing miR-7 suppresses B cell hyperresponsiveness and inhibits lupus development.

OBJECTIVES: The objective of this study was to address the biological function of miR-7 in an animal model of systemic lupus erythematosus. METHODS: MRLlpr/lpr lupus mice were administrated antagomiR-7 or a scramble control by tail vein for 5weeks. Three groups of animals' tissues were assessed for lupus manifestations by immunofluorescence and immunohistochemistry, and serum was examined for levels of autoantibodies and inflammatory cytokines. Splenic B cell subsets were assessed for intracellular expression of PI3K signaling by FACS. Finally, the ability of the miR-7 antagomir to regulate the expansion of T follicular helper (Tfh) cells and B cell hyperresponsiveness was further explored. RESULTS: We found that miR-7 was up-regulated in MRLlpr/lpr lupus mice and directly targeted PTEN mRNA in B cells. Up-regulated miR-7 in MRLlpr/lpr lupus B cells was negatively correlated with PTEN expression. Notably, miR-7 antagomir treatment reduced lupus manifestations in MRLlpr/lpr lupus mice. miR-7-mediated down-regulation of PTEN/AKT signaling promoted B cell differentiation into plasmablasts/plasma cells and spontaneous germinal center (GC) formation, whereas miR-7 antagomir normalized splenic B cell subtypes. Besides suppressing the activation of B cells, miR-7 antagomir intervention also down-regulated STAT3 phosphorylation and production of IL-21 and reduced Tfh expansion. CONCLUSION: The above data have demonstrated the critical roles of miR-7 not only in regulating PTEN expression and also B cell and Tfh cell function in lupus-prone MRLlpr/lpr lupus mice. Furthermore, the disease manifestations in MRLlpr/lpr lupus mice are efficiently improved by miR-7 antagomir, indicating miR-7 as a potential treatment strategy in SLE.

EZH2 deficiency attenuates Treg differentiation in rheumatoid arthritis.

The chromatin modifier enhancer of zeste homolog 2 (EZH2) methylates lysine 27 of histone H3 (H3K27) and regulates T cell differentiation. However, the potential role of EZH2 in the pathogenesis of rheumatoid arthritis (RA) remains elusive. We analyzed EZH2 expression in PBMC, CD4+ T cells, CD19+ B cell, and CD14+ monocytes from active treatment-naïve RA patients and healthy controls (HC). We also suppressed EZH2 expression using EZH2 inhibitor GSK126 and measured CD4+ T cell differentiation, proliferation and apoptosis. We further examined TGFß-SMAD and RUNX1 signaling pathways in EZH2-suppressed CD4+ T cells. Finally, we explored the regulation mechanism of EZH2 by RA synovial fluid and fibroblast-like synoviocyte (FLS) by neutralizing key proinflammatory cytokines. EZH2 expression is lower in PBMC and CD4+ T cells from RA patients than those from HC. EZH2 inhibition suppressed regulatory T cells (Tregs) differentiation and FOXP3 transcription, and downregulated RUNX1 and upregulated SMAD7 expression in CD4+ T cells. RA synovial fluid and fibroblast-like synoviocytes suppressed EZH2 expression in CD4+ T cells, which was partially neutralized by anti-IL17 antibody. Taken together, EZH2 in CD4+ T cells from RA patients was attenuated, which suppressed FOXP3 transcription through downregulating RUNX1 and upregulating SMAD7 in CD4+ T cells, and ultimately suppressed Tregs differentiation. IL17 in RA synovial fluid might promote downregulation of EZH2 in CD4+ T cells. Defective EZH2 in CD4+ T cells might contribute to Treg deficiency in RA.

Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis.

Excessive inflammatory cytokines play crucial roles in the pathogenesis of rheumatoid arthritis (RA), however, the underlying mechanism remains unclear. In this study, we demonstrated that pentaxin 3 (PTX3), an essential component of innate immunity, was elevated in RA and preferentially bound to CD14+ monocytes. C1q promoted the binding and resulted in increased cell proliferation, activation and caspase-1-related late apoptotic cells (7-AAD+annexin V+), as well as enhanced release of inflammatory cytokines including TNF-α, IL-1ß and IL-6. Serum from RA patients, compared with healthy controls, induced gasdermin D (GSDMD)-dependent pyroptosis in monocytes, and this ability was associated with disease activity. Moreover, PTX3 synergized with C1q to promote pyroptosis in RA-serum pre-incubated monocytes by coordinately enhancing NLRP3 inflammasome over-activation and inducing GSDMD cleavage, cell swelling with large bubbles, caspase-1-dependent cell death and inflammatory cytokine release including IL-6. On the other hand, IL-6 promoted PTX3 plus C1q-induced pyroptosis in both normal and RA serum pre-incubated monocytes. These findings collectively implicated an important role of IL-6 in driving PTX3 plus C1q-mediated pyroptosis in RA and shed lights on a potential new treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.

Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis.

OBJECTIVE: Gut dysbiosis has been reported implicated in ankylosing spondylitis (AS), a common chronic inflammatory disease mainly affects sacroiliac joints and spine. Utilizing deep sequencing on the feces of untreated AS patients, our study aimed at providing an in-depth understanding of AS gut microbiota. METHODS: We analyzed the fecal metagenome of 85 untreated AS patients and 62 healthy controls by metagenomic shotgun sequencing, and 23 post-treatment feces of those AS patients were collected for comparison. Comparative analyses among different cohorts including AS, rheumatoid arthritis and Behcet's disease were performed to uncover some common signatures related to inflammatory arthritis. Molecular mimicry of a microbial peptide was also demonstrated by ELISpot assay. RESULTS: We identified AS-enriched species including Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri. Pathway analysis revealed increased oxidative phosphorylation, lipopolysaccharide biosynthesis and glycosaminoglycan degradation in AS gut microbiota. Microbial signatures of AS gut selected by random forest model showed high distinguishing accuracy. Some common signatures related to autoimmunity, such as Bacteroides fragilis and type III secretion system (T3SS), were also found. Finally, in vitro experiments demonstrated an increased amount of IFN-γ producing cells triggered by a bacterial peptide of AS-enriched species, mimicking type II collagen. CONCLUSIONS: These findings collectively indicate that gut microbiota was perturbed in untreated AS patients with diagnostic potential, and some AS-enriched species might be triggers of autoimmunity by molecular mimicry. Additionally, different inflammatory arthritis shared some common microbial signatures.

[Clinical Features of Relapsing Polychondritis Patients Presented with Arthropathy].

Objective To explore the clinical characteristics of relapsing polychondritis(RP)patients presented with arthropathy. Methods We retrospectively analyzed the clinical data of 201 RP patients who were hospitalized in our center between December 2005 and February 2019.After 16 patients with co-existing other autoimmune diseases and malignancies were ruled out,185 RP patients entered the final analysis,among whom 16 RP patients were presented with arthropathy and 169 without arthropathy.The demographic data,clinical manifestations,laboratory findings,and prognosis were compared between these two groups. Results Five of the 16 RP patients with arthropathy at presentation were misdiagnosed as rheumatoid arthritis.Compared with RP patients without arthropathy at presentation,RP patients with arthropathy at presentation had a longer disease course[(37.50±66.50)months vs.(9.00±11.00)months,z=-3.186,P =0.001],longer time of diagnostic delay[(24.00±41.25)months vs.(7.00±9.00)months,z=-2.890,P=0.004],and higher incidence of eye(62.50% vs. 36.09%,χ2=4.309,P=0.038)and nervous system involvements(43.75% vs. 15.38%,χ2=6.205,P=0.013). Conclusions RP patients with arthropathy at presentation are most likely to be misdiagnosed as rheumatoid arthritis.These patients are characterized by longer disease course and diagnostic delay and more frequrent eye and nervous system involvements.

Identification of Novel Biomarkers for Behcet Disease Diagnosis Using Human Proteome Microarray Approach.

Behcet disease (BD) is a chronic systemic vasculitis and considered as an autoimmune disease. Although rare, BD can be fatal due to ruptured vascular aneurysms or severe neurological complications. To date, no known biomarker has been reported for this disease, making it difficult to diagnosis in the clinics. To undertake this challenge, we employed the HuProt arrays, each comprised of ∼20,000 unique human proteins, to identify BD-specific autoantibodies using a Two-Phase strategy established previously. In Phase I, we profiled the autoimmunity on the HuProt arrays with 75 serum samples collected from 40 BD patients, 15 diagnosed autoimmune patients who suffer from Takayasu arteritis (TA; n = 5)), ANCA associated vasculitis (AAV; n = 5), and Sjogren's syndrome (SS; n = 5), and 20 healthy subjects, and identified 20 candidate autoantigens that were significantly associated with BD. To validate these candidates, in Phase II we constructed a focused array with these 20 candidate BD-associated antigens, and use it to profile a much larger cohort, comprised of serum samples collected from 130 BD patients, 103 autoimmune patients (i.e. 40TA, 40 AAV and 23 SS), and 110 healthy controls. This allowed us to validate CTDP1 (RNA polymerase II subunit A C-terminal domain phosphatase)as a BD-specific autoantigen. The association of anti-CTDP1 with BD patients was further validated using the traditional Western blotting analysis. In conclusion, anti-CTDP1 antibody serves a novel autoantibody for Behcet disease and is expected to help more accurate clinical diagnosis.

Good outcome of severe lupus patients with high-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation: a 10-year follow-up study.

OBJECTIVES: This study aimed to examine the long-term efficacy, remission and survival of patients with severe systemic lupus erythematosus (SLE) after the combination treatment with high-dose immunosuppressive therapy (HDIT) and autologous peripheral blood stem cell transplantation (APBSCT). METHODS: Chinese patients with severe SLE receiving combination therapy with HDIT and APBSCT in Peking Union Medical College Hospital were enrolled from July 1999 to October 2005. Disease activity, treatment, and adverse effects of these patients were evaluated. The 10-year overall survival and 10-year remission survival were also analysed. RESULTS: Among the 27 patients, one patient failed to collect enough CD34+ cells and data was missing for two patients. In the end, 24 patients were included in the final analysis. After APBSCT, one patient died, two patients achieved partial remission and 21 (87.5%) achieved remission at 6 months. The median follow-up duration of the 23 patients was 120 months. Fourteen patients had completed a ten-year follow-up. The median proteinuria level of the 14 patients with LN with ten years of follow-up significantly decreased from 4.00 g/24 hours at pre-treatment to 0.00g/24 hours at year 5 and 0.00 g/24 hours at year 10 (both p=0.001). The 10-year overall survival rate and 10-year remission survival rate were both 86.0% (95% CI: 71.1-100.9%). After a median follow-up for 120 months, 16 patients (66.7%) remained in remission, 4 patients were lost to follow-up, 2 patients died and 1 patient remained active. CONCLUSIONS: The combination of HDIT and APBSCT may be an option to improve the survival of severe lupus patients.

Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial.

OBJECTIVES: To compare the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with methotrexate (MTX) in the treatment of active rheumatoid arthritis (RA). METHODS: Design: a multicentre, open-label, randomised controlled trial. All patients were assessed by trained investigators who were unaware of the therapeutic regimen. INTERVENTION: 207 patients with active RA were randomly allocated (1:1:1) to treatment with MTX 12.5 mg once a week, or TwHF 20 mg three times a day, or the two in combination. At week 12, if reduction of the 28-joint count Disease Activity Score (DAS28) was <30% in the monotherapy groups, the patient was switched to MTX+TwHF. The primary efficacy point was the proportion of patients achieving an American College of Rheumatology (ACR) 50 response at week 24. RESULTS: 174/207 (84.1%) patients completed 24 weeks of the trial. In an intention-to-treat analysis, the proportion of patients reaching the ACR50 response criteria was 46.4% (32/69), 55.1% (38/69) and 76.8% (53/69), respectively, in the MTX, TwHF and MTX+TwHF groups (TwHF vs MTX monotherapy, p=0.014; MTX+TwHF vs MTX monotherapy, p<0.001). Similar statistically significant patterns at week 24 were found for ACR20, ACR70, clinical Disease Activity Index good responses, EULAR good response, remission rate and low disease activity rate. Significant improvement in the Health Assessment Questionnaire and 36-item Short-Form Health Survey questionnaire scores from baseline to week 24 was seen in each treatment arm (p<0.05), though no significant difference was found among the treatment arms (p>0.05). The result of per-protocol analysis agreed with that seen in the intention-to-treat analysis. Seven, three and five women in the TwHF, MTX and combination groups, respectively, developed irregular menstruation (TwHF vs MTX monotherapy, p=0.216). CONCLUSIONS: TwHF monotherapy was not inferior to, and MTX+TwHF was better than, MTX monotherapy in controlling disease activity in patients with active RA. TRIAL REGISTRATION NUMBER: NCT01613079.

A single-nucleotide polymorphism of CCL21 rs951005 T>C is associated with susceptibility of polymyositis and such patients with interstitial lung disease in a Chinese Han population.

OBJECTIVES: Our objective was to better understand the roles of single nucleotide polymorphisms (SNPs) in the CCL21, ERBB3, and TERT genes region in the development of idiopathic inflammatory myopathies (IIMs), we explored the associations between SNPs in the mentioned three genes and IIMs susceptibility in a Chinese Han population. METHODS: Chinese polymyositis (PM) patients (n =291), dermatomyositis (DM) patients (n=526) and ethnically-matched healthy controls (n =968) were genotyped for the CCL21 region SNPs (rs951005 and rs2492358), ERBB3 (rs2292239 and rs11171739), and TERT (rs2853676 and rs10069690), by using the Sequenom MassArray system. RESULTS: Our study indicated strong allele and genotype associations between rs951005 (OR: 1.65, 95%CI: 1.18-2.30, Pc=0.015; Pc=0.041, respectively) in CCL21 gene and PM patients. Additionally, rs951005 was associated with interstitial lung disease (ILD) in PM patients (Pc =0.01), and was associated with PM patients in additive model. However, the Chinese Han PM/DM patients and controls had statistically similar frequencies of alleles, genotypes and different genetic models (additive, dominant, and recessive) of ERBB3 and TERT polymorphisms. CONCLUSIONS: This was the first study to demonstrate that the CCL21 gene SNP (rs951005) might confer genetic predisposition to PM patients or such patients with ILD in a Chinese Han population.

Telangiectasia as a potential clinical marker of microvascular lesions in systemic sclerosis patients from EUSTAR data in China.

OBJECTIVES: To investigate the prevalence and clinical relevance of telangiectasia in Chinese patients with systemic sclerosis (SSc). METHODS: Data from 230 SSc EUSTAR patients from Peking Union Medical College Hospital (2009-2011) that fulfilled the 1980 American College of Rheumatology SSc classification criteria were prospectively collected. Demographic, clinical, and laboratory data were calculated between groups with and without telangiectasia, and a six-minute walk test, pulmonary function test (PFT), transthoracic echocardiography (TTE), right heart catheterisation (RHC) and modified Rodnan skin score (mRSS) were performed. RESULTS: 96 patients (41.7%) were diagnosed with telangiectasia. There were no significant differences between patients with and without telangiectasia based on gender, age at onset, Raynaud's phenomenon (RP) duration, or SSc classification. Disease duration both from RP onset of patients and from first non-RP manifestation of patients with telangiectasia was significantly longer than patients without (p<0.05). RP (97.9% vs. 90.3%), finger/toe sclerosis (96.9% vs. 88.1%), facial sclerosis (68.8% vs. 53.7%), digital ulcers (DUs; 40.6% vs. 23.1%), digital pitting (49.0% vs. 33.8%), joint contracture (20.8% vs. 10.4%) and erythrocyte sedimentation rate elevation (26.7% vs. 14.8%) were significantly greater in telangiectasia patients (p<0.05). There were no differences in autoantibody development between patients with and without telangiectasia (p>0.05). PFT showed that forced vital capacity (77.0±17.26 vs. 83.05±16.53, p=0.005) and diffusion capacity for CO of the lung (58.9±19.4 vs. 65.7±19.7, p=0.030) were lower, while forced expiratory volume ratio (87.02±7.8 vs. 84.33±7.1, p=0.029) was higher in SSc with telangiectasia. Pulmonary artery hypertension (PAH) prevalence (25.0% vs. 14.2%) was significantly greater in patients with telangiectasia. CONCLUSIONS: Telangiectasia are common in Chinese SSc patients and usually associated with DUs, RP, and PAH. Telangiectasia could be a clinical marker of microvascular disease in SSc.

Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis: results of a 14-year cohort study.

UNLABELLED: The biochemical response to ursodeoxycholic acid (UDCA) in primary biliary cirrhosis is a strong predictor of long-term outcome and thus facilitates the rapid identification of patients needing new therapeutic approaches. Numerous criteria for predicting outcome of treatment have been studied based on biochemical response to UDCA at 1 year. We sought to determine whether an earlier biochemical response at 3 or 6 months could as efficiently identify patients at risk of poor outcome, as defined by liver-related death, liver transplantation, and complications of cirrhosis. We analyzed the prospectively collected data of 187 patients with a median follow-up of 5.8 years (range, 1.3-14 years). The survival rates without adverse outcome at 5 years and 10 years were 86% and 63%. Under UDCA therapy, laboratory liver parameters experienced the most prominent improvement in the first 3 months (P < 0.0001) and then stayed relatively stable for the following months. The Paris, Barcelona, Toronto, and Ehime definitions, but not the Rotterdam definition, applied at 3, 6, and 12 months significantly discriminated the patients in terms of long-term outcome. Compared with biochemical responses evaluated after 1 year of UDCA therapy, biochemical responses at the third month demonstrated higher positive predictive value (PPV) but lower negative predictive value (NPV) and increased negative likelihood ratio (NLR) by all definitions; biochemical responses at the sixth month showed higher or the same PPV and NPV and lower NLR by all definitions. CONCLUSION: For the previously published criteria, biochemical responses at the sixth month can be used in place of those evaluated after 1 year of UDCA therapy. Our findings justify a more rapid identification of patients who need new therapeutic approaches.

Identification of new autoantigens for primary biliary cirrhosis using human proteome microarrays.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology and is considered to be an autoimmune disease. Autoantibodies are important tools for accurate diagnosis of PBC. Here, we employed serum profiling analysis using a human proteome microarray composed of about 17,000 full-length unique proteins and identified 23 proteins that correlated with PBC. To validate these results, we fabricated a PBC-focused microarray with 21 of these newly identified candidates and nine additional known PBC antigens. By screening the PBC microarrays with additional cohorts of 191 PBC patients and 321 controls (43 autoimmune hepatitis, 55 hepatitis B virus, 31 hepatitis C virus, 48 rheumatoid arthritis, 45 systematic lupus erythematosus, 49 systemic sclerosis, and 50 healthy), six proteins were confirmed as novel PBC autoantigens with high sensitivities and specificities, including hexokinase-1 (isoforms I and II), Kelch-like protein 7, Kelch-like protein 12, zinc finger and BTB domain-containing protein 2, and eukaryotic translation initiation factor 2C, subunit 1. To facilitate clinical diagnosis, we developed ELISA for Kelch-like protein 12 and zinc finger and BTB domain-containing protein 2 and tested large cohorts (297 PBC and 637 control sera) to confirm the sensitivities and specificities observed in the microarray-based assays. In conclusion, our research showed that a strategy using high content protein microarray combined with a smaller but more focused protein microarray can effectively identify and validate novel PBC-specific autoantigens and has the capacity to be translated to clinical diagnosis by means of an ELISA-based method.

Association of TNFSF4 polymorphisms with susceptibility to primary Sjögren's syndrome and primary biliary cirrhosis in a Chinese Han population.

OBJECTIVES: We aimed to evaluate the association between polymorphisms of TNFSF4 and primary Sjögren's syndrome (pSS) and primary biliary cirrhosis (PBC) in a Chinese Han population. METHODS: A total of 250 pSS patients, 221 PBC patients, and 393 healthy controls were enrolled. All individuals were ethnic Chinese Han, and each group was matched for gender ratio and age. We identified single nucleotide polymorphisms (SNPs) via the HapMap Han Chinese Beijing databank for a genetic region containing TNFSF4, and then identified haplotype tagging SNPs with the Tagger programme of Haploview. DNA samples were amplified through polymerase chain reaction (PCR) and extension products were differentiated via mass spectrometry. Association analyses were performed using PLINK software. RESULTS: In TNFSF4, T allele and TT genotype of rs2205960, and G allele of rs1234313, were associated with pSS (p<0.05); T allele of rs2205960 was correlated with PBC (p<0.05) as a risk factor. In the haplotype analysis, TAGG and TGGT were correlated with pSS (p<0.05). In genetic additive, dominant, and recessive models analysis, rs2205960 had a significant association with both pSS and PBC, and rs1234313 presented a significant association with pSS (p<0.05). However, no statistically significant difference was found after Bonferroni corrections. CONCLUSIONS: Overall, no association between the allele, or genotype, or haplotype frequencies of TNFSF4 and the risk of pSS or PBC was found. TNFSF4 may have little significance as a common genetic component of pSS and PBC in the Chinese Han population.

Clinical characteristics of systemic sclerosis patients with digital ulcers in China.

OBJECTIVES: To investigate the clinical characteristics of SSc patients with DUs in China. METHODS: The data of 267 consecutive SSc patients based on the EUSTAR DATABASE from Peking Union Medical College Hospital from February 2009 to March 2012 were prospectively collected. The patients with DUs were compared to those without DUs. RESULTS: Seventy-nine patients (29.6%) had DUs out of 267 SSc patients analysed. There were significant differences between patients with and without DU based on sex (female/male: 65/14 vs. 174/14), age of onset of SSc (32.3±11.7 vs. 40.4±12.6 y), age of onset of Raynaud's phenomenon (31.8±12.3 vs. 38.7±12.2) (p<0.05). In addition, there was a higher rate of diffuse SSc, gastrointestinal involvement, (especially esophageal involvement), and pericardial effusion, higher mRodnan score, and more anti-scl70 antibody positivity in patients with DU (p<0.05). A multivariate analysis identified anti-Scl70 antibody positivity, gastrointestinal involvement and a younger age at disease onset as three risk factors for developing DUs in SSc patients. CONCLUSIONS: The occurrence of DUs in Chinese SSc patients is frequent. It is possible that SSc patients with DUs were influenced by the disease earlier in life, which should be detected early for effective intervention.

A systematic review of vinorelbine for the treatment of breast cancer.

The purpose of this study was to investigate the efficacy and safety profile of vinorelbine-based chemotherapy in different settings for the treatment of breast cancer. We performed a computerized search using combinations of the following keywords: "breast cancer", "breast neoplasms", "trial", "vinorelbine" and "navelbine". A total of 20 trials were included in this analysis, with a total of 5,080 patients accrued. Taxane was associated with enhanced overall survival (OS; p = 0.027) and response rate (RR; p = 0.037) as compared with vinorelbine in monotherapy, but did not show significantly favored progression-free survival (PFS; p = 0.136). Vinorelbine alone was equivalent to fluoropyrimidine treatment in RR (p = 0.79) for the treatment of metastatic breast cancer. For vinorelbine-combined regimens, the analysis showed that the vinorelbine group gave similar results as other regimens for OS (p = 0.849) and PFS (p = 0.143). The RR of vinorelbine-combined regimens was slightly better than that of the other regimens (OR, 1.17), but the difference was not statistically significant. In neoadjuvant setting, vinorelbine treatment was as active as AC (doxorubicin, cyclophosphamide) or DAC (doxorubicin, cyclophosphamide, docetaxel) regimens with respect to RR (p = 0.76) and pathologic complete response (pCR; p = 0.77), but showed lower occurrence of grade 3/4 adverse effects. The analysis also demonstrated that vinorelbine-containing therapy is effective as adjuvant, front-line or salvage therapy of metastatic breast cancer, even for patients who were previously treated with anthracyclines or taxanes.

[The clinical analysis of 14 cases of systemic lupus erythematosus complicated by thrombotic thrombocytopenic purpura].

OBJECTIVE: To analyze the clinical features, diagnosis and treatment of thrombotic thrombocytopenic purpura (TTP) in patients with systemic lupus erythematosus (SLE). METHODS: Clinical manifestations, laboratory findings, diagnosis,treatment and prognosis of 14 SLE patients with TTP were retrospectively analyzed. RESULT: Of the 14 patients diagnosed with SLE and TTP, 4 were men and 10 were women. The median age at diagnosis was 23 (17-69) years old. In five patients, the onset of SLE preceded TTP, and in nine patients SLE and TTP occurred simultaneously. All the 14 patients had thrombocytopenia and hemolytic anemia, 12 had fever, 11 had neurologic abnormalities, and 11 had renal dysfunction. Eight patients presented with the classic pentad of symptoms. Six patients were given steroids (alone or in combination with intravenous immunoglobulin and cyclophosphamide), and eight patients were treated with steroids in combination with plasmapheresis, with response rates of 2/6 and 6/8, respectively. Six patients died, with overall mortality rate of 6/14. No patients relapsed during the follow-up period. CONCLUSIONS: SLE and TTP share some similar clinical symptoms. As a result, repeated examinations of peripheral blood smears are very important for early diagnosis. The renal damage in patients of co-existing diseases is more serious than those with TTP alone or SLE alone. Early diagnosis and prompt treatment with plasma exchange and steroids may improve the prognosis in SLE patients with TTP.