Differences of RUNX2 gene promoter methylation and transcription level in ankylosing spondylitis.

BACKGROUND AND OBJECTIVE: Ankylosing spondylitis is a refractory immune disease that seriously affects the life and work of patients. Epigenetic modifications, especially DNA methylation, have become a research hotspot in complex diseases. We aim to explore the changes in runt-related transcription factor 2 (RUNX2) gene promoter methylation and transcription level in AS. METHOD: We detected the RUNX2 gene promoter methylation in 83 AS patients and 83 healthy controls (HCs), then inspected the mRNA difference of RUNX2 between 30 AS patients and 30 HCs by the quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The RUNX2 gene promoter was hypomethylated in AS patients compared to HCs (p < .001). The research involved 4 CpG regions and 74 CpG sites of RUNX2, of which CpG-2, CpG-4 regions, and 18 CpG sites have been differentially methylated. The CpG-4 island methylation was negatively correlated with C-reactive protein (p < .05) in AS patients. In the qRT-PCR validation phase, the mRNA level of RUNX2 in AS patients was significantly higher than HCs (p < .05), and in AS patients who were treated with biologics, the methylation level of CpG-2 island showed a negative correlation to mRNA (p < .05). ROC results indicated that RUNX2 methylation and its transcription level have good potential to distinguish AS patients from HCs. CONCLUSION: The RUNX2 gene promoter was hypomethylated in AS patients. Meanwhile, the qRT-PCR verified the up-regulated expression on the transcription level, suggesting the abnormal methylation of RUNX2 contributes to the pathogenesis of AS.

RIOK3 potentially regulates osteogenesis-related pathways in ankylosing spondylitis and the differentiation of bone marrow mesenchymal stem cells.

RNA-binding proteins (RBPs), which are key effectors of gene expression, play critical roles in inflammation and immune regulation. However, the potential biological function of RBPs in ankylosing spondylitis (AS) remains unclear. We identified differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of five patients with AS and three healthy persons by RNA-seq, obtained differentially expressed RBPs by overlapping DEGs and RBPs summary table. RIOK3 was selected as a target RBP and knocked down in mouse bone marrow mesenchymal stem cells (mBMSCs), and transcriptomic studies of siRIOK3 mBMSCs were performed again using RNA-seq. Results showed that RIOK3 knockdown inhibited the expression of genes related to osteogenic differentiation, ribosome function, and ß-interferon pathways in mBMSCs. In vitro experiments have shown that RIOK3 knockdown reduced the osteogenic differentiation ability of mBMSCs. Collectively, RIOK3 may affect the differentiation of mBMSCs and participate in the pathogenesis of AS, especially pathological bone formation.

Could endothelial progenitor cells complement the diagnosis of inflammatory arthritis? A systematic review and meta-analysis.

The objective of this meta-analysis was to systematically review existing evidence and evaluate variations in levels of circulating endothelial progenitor cells (EPCs) among individuals with psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), and rheumatoid arthritis (RA). Relevant studies were identified through database searches, and 20 records were enrolled. We used the fixed-effect model or random-effect model to estimate the pooled standardized mean difference (SMD) with 95% confidence intervals (CIs) in circulating EPC levels between inflammatory arthritis patients and controls. The results showed that circulating EPC levels differed among subtypes of inflammatory arthritis, with significantly lower levels in patients with RA (SMD = -0.848, 95% CI = -1.474 to -0.221, p = 0.008) and PsA (SMD = -0.791, 95% CI = -1.136 to -0.446, p < 0.001). However, no statistically significant difference was found in circulating EPC levels between patients with JIA and controls (SMD = -1.160, 95% CI = -2.578 to 0.259, p = 0.109). Subgroup analyses suggested that in patients with RA, circulating EPC levels were influenced by age, disease activity, and duration. Although many studies have investigated circulating EPC levels in patients with inflammatory arthritis, the results have been inconsistent. This meta-analysis offers a comprehensive overview of the existing evidence and emphasizes the association between levels of circulating EPCs and various types of arthritis. However, further research is needed to determine the specific mechanisms underlying the observed differences in EPC levels in different types of arthritis and to establish the clinical utility of this biomarker.

Clinical features and prognostic factors of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with rapidly progressive interstitial lung disease in Chinese patients.

OBJECTIVE: The objective of this study is to investigate clinical features and prognostic factors of antimelanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis with rapidly progressive interstitial lung disease (RP-ILD) in Chinese patients. METHODS: Clinical features and prognostic factors of patients with newly diagnosed or recurrent dermatomyositis patients were retrospectively analyzed. All patients were divided into the anti-MDA5-positive or negative dermatomyositis, and with or without RP-ILD groups. Clinical features and prognostic factors were statistically compared among different groups. RESULTS: The serum ferritin (SF) levels (1500.0 [658.80, 1844.0]) and γ-glutamyl transpeptidase (γ-GT) (125.5 [61.0, 232.0] vs. 28 [16.0, 41.0], Z = 5.528; p < .001) were markedly higher, and phosphocreatine myoenzyme (CK) (73.0 [42.0, 201.0] vs. 1333.0 [79.0, 8000.0], Z = -2.739, p = .006), serum albumin level (32.51 ± 5.23 vs. 35.81 ± 5.88, t = -2.542, p = .013), and lymphocyte count (0.80 ± 0.36 vs. 1.45 ± 0.77, t = -4.717, p < .001) were lower than those in anti-MDA5-negative counterparts. Among patients with anti-MDA5 antibody (Ab) with RP-ILD, the SF level (1531.0 [1163.8, 2016.5] vs. 584.9 [564.8, 1042.5], Z = 2.664, p = .008), γ-GT (134.0 [81.0, 204.5] vs. 123.0 [76.0, 189.0], Z = 3.136, p = .002) and positive rate of anti-RO-52 Ab (90.9% vs. 50.0%, χ2 = 7.222, p = .013) were higher and lymphocyte count (0.79 ± 0.38 vs. 1.32 ± 0.74, t = -3.025, p = .029) was lower than those in their counterparts without RP-ILD. The SF level of anti-MDA5 nonsurvivors (1544 [1447.32, 2089.0] vs. 584.9 [515.7, 1500.0], Z = 2.096, p = .030), anti-RO-52 Ab-positive rate ([16/18, 88.9%] vs. [9/16, 56.2%], χ2 = 4.636, p = .031) were higher than those in survivors. Lymphocytopenia was a risk factor for RP-ILD and death of patients with anti-MDA5-positive dermatomyositis. The area under receiver operating characteristic curve was 0.888 (95% confidence interval: 0.756, 1.000; p < .001), the sensitivity was 85.7%, the specificity was 93.8%, and Youden's index was 0.795. CONCLUSIONS: Anti-MDA5-positive dermatomyositis patients are prone to developing RP-ILD. Declined lymphocyte count is a critical risk factor for RP-ILD, probably acting as a simple and effective predictor for Chinese patients with anti-MDA5-positive dermatomyositis.

Global burden and risk factors of musculoskeletal disorders among adolescents and young adults in 204 countries and territories, 1990-2019.

BACKGROUND: Current studies on musculoskeletal (MSK) disorders mainly focus on the elderly, while adolescents and young adults (AYAs) are often neglected despite their unique epidemiology, healthcare needs and societal implications. To bridge this gap, we evaluated the global burden and temporal trends of MSK disorders among AYAs from 1990 to 2019, as well as their common categories and main risk factors. METHODS: Data on the global burden and risk factors of MSK disorders were obtained from the Global Burden of Diseases study 2019. Age standardized rates for incidence, prevalence and disability-adjusted life-years (DALYs) were calculated using the world population age standard, and their temporal trends were evaluated by estimated annual percentage changes (EAPC). Locally estimated scatterplot smoothing (LOESS) regression was used to explore the association between two variables. RESULTS: Over the past 30 years, MSK disorders have become the third leading cause of global DALYs among AYAs, with 36.2%, 39.3%, and 21.2% of increases in incident cases, prevalent cases and DALYs, respectively. In 2019, age standardized incidence, prevalence and DALY rates for MSK disorders were positivity associated with socio-demographic index (SDI) among AYAs in 204 countries and territories. The global age-standardized prevalence and DALY rates of MSK disorders began to increases among AYAs since 2000. In the last decade, countries with high SDI not only presented the only increase in age-standardized incidence rate across all SDI quintiles (EAPC = 0.40, 0.15 to 0.65), but also displayed the most rapid increases in age-standardized prevalence and DALY rates (EAPC = 0.41, 0.24 to 0.57; 0.39, 0.19 to 0.58, respectively). Low back pain (LBP) and neck pain (NP) were the most common MSK disorders among AYAs, accounting for 47.2% and 15.4% of global DALYs of MSK disorders in this population, respectively. Rheumatoid arthritis (RA), osteoarthritis (OA), and gout exhibited increasing trends in global age-standardized incidence, prevalence, and DALY rates among AYAs over the past 30 years (all EAPC >0), whereas LBP and NP showed declining trends (all EAPC <0). Occupational ergonomic factors, smoking and high BMI accounted for 13.9%, 4.3%, and 2.7% of global DALYs for MSK disorders among AYAs, respectively. The proportion of DALYs attributable to occupational ergonomic factors was negatively associated with SDI, whereas the proportions attributable to smoking and high BMI increased with SDI. Over the last 30 years, both the proportions of DALYs attributable to occupational ergonomic factors and smoking have consistently decreased globally and across all SDI quintiles, while the proportion attributable to high BMI has increased. CONCLUSIONS: MSK disorders have emerged as the third leading cause of global DALYs among AYAs over the past three decades. Countries with high SDI should make more efforts to tackle the dual challenges posed by the high levels and rapid increases in age standardized incidence, prevalence, and DALY rates in the last decade.

Systemic lupus erythematosus associated with multiple myeloma: Two case reports and a literature review.

INTRODUCTION: Systemic lupus erythematosus (SLE) complicated by multiple myeloma (MM) is a relatively rare clinical presentation, and is easily ignored due to their similar or even identical manifestation, which may lead to misdiagnosis and mistreatment. CASE REPORT: We report two cases of SLE with MM. Case 1 was a 59-year-old male who was diagnosed with SLE 11 years ago. Abnormal kidney function was detected 4 months ago and a bone marrow aspirate revealed MM. He then received three cycles of bortezomib, dexamethasone, and chemotherapy with liposomal doxorubicin, and one cycle of lenalidomide plus dexamethasone. He died of infectious shock. Case 2 was a 58-year-old female who was diagnosed with SLE 27 years ago. After the onset of abnormal renal function 4 years ago, the patient was still treated according to SLE disease activity. When renal function rapidly deteriorated, serum and urine immunofixation electrophoresis was positive for IgG γ with free light chains and she was diagnosed with SLE complicated by MM. She did not agree to the treatment for MM as advised and was discharged from the hospital against medical advice. Case 2 died of cardiac failure. Thirteen cases of SLE with MM reported from 2000 to 2022 in PUBMED and Mendeley and our above two cases were reviewed. Among the 15 patients, 13 were females and 2 were males. The median age at the time of SLE with MM diagnosis was 50 years, and the median time to a delayed diagnosis was 7 years. The serum monoclonal immunoglobulin level was elevated and extramedullary manifestations of renal dysfunction were common. CONCLUSIONS: An elevated monoclonal immunoglobulin level or newly unexplained renal dysfunction occurring in a patient with SLE should prompt monitoring and further screening of MM, rather than treatment as a secondary manifestation of SLE.

Laparoscopic versus open liver resection for hepatocellular carcinoma in elderly patients: A systematic review and meta-analysis of propensity score-matched studies.

Purpose: Laparoscopic liver resection (LLR) is a widely practiced therapeutic method and holds several advantages over open liver resection (OLR) including less postoperative pain, lower morbidity, and faster recovery. However, the effect of LLR for the treatment of hepatocellular carcinoma (HCC) in elderly patients remains controversial. Therefore, we aimed to perform the first meta-analysis of propensity score-matched (PSM) studies to compare the short- and long-term outcomes of LLR versus OLR for elderly patients with HCC. Methods: Databases including PubMed, Embase, Scopus, and Cochrane Library were systematically searched until April 2022 for eligible studies that compared LLR and OLR for the treatment of HCC in elderly patients. Short-term outcomes include postoperative complications, blood loss, surgical time, and length of hospital stay. Long-term outcomes include overall survival (OS) rate and disease-free survival (DFS) rate at 1, 3, and 5 years. Results: A total of 12 trials involving 1,861 patients (907 in the LLR group, 954 in the OLR group) were included. Compared with OLR, LLR was associated with lower postoperative complications (OR 0.49, 95% CI 0.39 to 0.62, P < 0.00001, I 2 = 0%), less blood loss (MD -285.69, 95% CI -481.72 to -89.65, P = 0.004, I 2 = 96%), and shorter hospital stay (MD -7.88, 95% CI -11.38 to -4.37, P < 0.0001, I 2 = 96%), whereas operation time (MD 17.33, 95% CI -6.17 to 40.83, P = 0.15, I 2 = 92%) was insignificantly different. Furthermore, there were no significant differences for the OS and DFS rates at 1, 3, and 5 years. Conclusions: For elderly patients with HCC, LLR offers better short-term outcomes including a lower incidence of postoperative complications and shorter hospital stays, with comparable long-term outcomes when compared with the open approach. Our results support the implementation of LLR for the treatment of HCC in elderly patients. Systematic review registration: https://inplasy.com/inplasy-2022-4-0156/, identifier INPLASY202240156.

A Real-World Study on the Effect of Imrecoxib for Patients with Axial Spondyloarthritis.

Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) have generally been viewed as first-line therapy for axial spondyloarthritis (axSpA). Imrecoxib is a selective COX-2 inhibitor developed independently in China. At present, only one single-center RCT trial has shown that imrecoxib is equally effective as celecoxib in treating axSpA. Based on real-world data, our study aims to explore the efficiency of imrecoxib and TNF inhibitor (TNFi) combined with imrecoxib in treating axSpA. Patients and Methods: A total of 163 patients with axSpA who had more than two follow-up records in 6 months and treated with imrecoxib/celecoxib/TNFi combined with imrecoxib/TNFi combined with celecoxib from the First Affiliated Hospital of Anhui Medical University SpA Real World Database (AHSpA) were selected for analysis of our study. The linear mixed model was used to compare efficacy indexes before and after treatment and between different groups, adjust baseline measurement value and follow-up time. The Kaplan-Meier survival analysis was used to identify the differences in cumulative clinical remission rates between groups with different treatment at the follow-up period. Results: Results showed that after treatment ASDAScrp was slightly improved in imrecoxib group and celecoxib group within 6 months (p < 0.05). CRP, ESR, BASDAI, ASDAScrp, BASFI, occiput to wall distance and finger floor distance all significantly improved in TNFi combined with imrecoxib group and TNFi combined with celecoxib group within 6 months (all p < 0.05). According to the Kaplan-Meier survival curve and Log rank test analysis, the clinical remission rate was not significantly different between different treatment during 24-month follow-up (all p > 0.05). Conclusion: ASDAScrp improved slightly within 6 months after treatment with imrecoxib, and TNFi combined with imrecoxib significantly improved multiple effect indexes in axSpA patients. The efficacy of imrecoxib and celecoxib in the treatment of axSpA is equivalent. Also, they have the same efficacy after being combined with TNFi.

FOXO3a Alleviates the Inflammation and Oxidative Stress via Regulating TGF-ß and HO-1 in Ankylosing Spondylitis.

This study aimed to investigate whether Forkhead box O3a (FOXO3a) modulates inflammation and oxidative stress in ankylosing spondylitis (AS). We applied bioinformatics analysis, quantitative real-time polymerase chain reaction, immunoblotting, enzyme linked immunosorbent assay, chromatin immunoprecipitation, and dual-luciferase reporter assay. Gene overexpression and knockdown of FOXO3a were conducted via lentivirus and small interfering RNA, respectively. Downregulated FOXO3a expression was first confirmed in AS patients. Interleukin-8 (IL-8) and IL-17A were highly expressed and negatively related with FOXO3a in AS. Total antioxidant capacity (T-AOC) were markedly decreased and positively associated with FOXO3a in AS. Overexpression of FOXO3a inhibited the secretion of inflammatory cytokines and promoted the production of antioxidant enzymes in Jurkat cells. Transforming growth factor-ß (TGF-ß) and heme oxygenase 1 (HO-1), which had binding sites to FOXO3a based on bioinformatics analysis, were abnormally expressed and positively related with FOXO3a. Accordingly, FOXO3a obviously elevated the protein and transcription levels of TGF-ß and HO-1 in Jurkat cells. The above results were verified by silencing FOXO3a. Moreover, FOXO3a directly interacted with and promoted the transcription of TGF-ß and HO-1. In summary, the modulation of cellular inflammation and oxidative stress via FOXO3a-mediated TGF-ß and HO-1 activation is partly involved in the pathogenesis of AS.

WWP2 overexpression inhibits the antitumor effects of doxorubicin in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common liver cancer that accounts for 90% of cases. Doxorubicin exhibits a broad spectrum of antitumor activity and is one of the most active agents in HCC. WW domain-containing protein 2 (WWP2) is highly expressed in HCC tissues and activates protein kinase B (AKT) signaling pathway to enhance tumor metastasis. However, the role of WWP2 in the glycolysis and antitumor effects of doxorubicin and the epigenetic alterations of WWP2 in HCC remain to be elucidated. The levels of WWP2 and N6-methyladenosine methyltransferase-like 3 (METTL3) in clinical samples and cells were investigated. WWP2 were silenced or overexpressed to study the role of WWP2 in regulating cell proliferation, colony formation, and glycolysis. RNA immunoprecipitation was performed to test m6 A levels. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot were used to measure mRNA and protein, respectively. WWP2 silencing inhibits cell proliferation, colony formation, and glycolysis, while WWP2 overexpression has the inverse effects via the AKT signaling pathway. Silencing WWP2 enhances doxorubicin's antitumor effect, while WWP2 overexpression suppresses doxorubicin's antitumor effect. Data also support that METTL3 mediates WWP2 m6A modification, and m6A reader, IGF2BP2, binds to the methylated WWP2 to promote the stability of WWP2, leading to upregulation of WWP2. METTL3 mediates WWP2 m6A modification, which can be recognized and bound by IGF2BP2 to increase the stability of WWP2, leading to WWP2 overexpression which inhibits the antitumor effects of doxorubicin through METTL3/WWP2/AKT/glycolysis axis.

Presence of subclinical inflammation in axial spondyloarthritis patients with NSAID/anti-TNF-α drug-induced clinical remission.

OBJECTIVE: To investigate the rate of subclinical inflammation in patients with axial spondyloarthritis (axSpA) with nonsteroidal anti-inflammatory drug (NSAID)/anti-tumor necrosis factor (TNF)-α drug-induced clinical remission and to explore factors influencing clinical and imaging remission. METHODS: One hundred twenty-five patients with axSpA followed up for at least 6 months were enrolled in this prospective study and randomly divided into two groups. Ninety patients were treated with anti-tumor necrosis factor (TNF)-α or anti-TNF-α combined with nonsteroidal anti-inflammatory drugs (NSAIDs) (anti-TNF-α treatment group), and thirty-five patients were treated with only NSAIDs (non anti-TNF-α treatment group). The improvements in the clinical remission rate, imaging remission rate, and disease parameters before and after the different treatments were compared. Risk factors for clinical and imaging remission were analyzed by multivariate logistic regression analysis. RESULTS: The clinical and imaging remission rate was increased after treatment especially in the anti-TNF-α group (P < 0.001). The remission rate of imaging in the group with clinical remission was higher than that in the group with clinical non-remission (P < 0.05). After treatment, the remission rates of imaging in the clinical remission and non-remission group were significantly higher than those before treatment (P < 0.0001). The results of multivariate logistic regression analysis showed that higher CRP was a risk factor for failure of clinical remission in axSpA (OR = 2.034, 95% CI:1.595 ~ 2.617, P < 0.001), while higher ASDAScrp was a risk factor for failure of imaging remission (OR = 1.306, 95% CI:1.026 ~ 1.688, P < 0.05). Anti-TNF-α treatment was a protective factor for both clinical (OR = 0.234, 95% CI:0.091 ~ 0.605, P < 0.05) and imaging remission (OR = 0.511, 95% CI:0.286 ~ 0.914, P < 0.05). CONCLUSION: Even after regular treatment, some clinical remission patients continued to have evidence of subclinical inflammation. Higher CRP and ASDAScrp are risk factors for clinical and imaging non-remission in axSpA respectively, Continuous NSAID treatment (more than 1 year) can effectively improve clinical and MRI inflammation in patients, but anti-TNF-α treatment is more beneficial for clinical and imaging remission. Key Points • Some patients achieving ASDAScrp remission status continue to have inflammation when assessed with objective imaging techniques. • MRI can sensitively measure bone marrow inflammation and may provide a more accurate assessment of remission. • Controlling inflammation, especially reducing CRP and ASDAScrp levels, is a key factor for achieving clinical and imaging remission in patients with axSpA.

Association of interleukin-6 promoter polymorphism with rheumatoid arthritis: a meta-analysis with trial sequential analysis.

OBJECTIVES: The association of interleukin-6 (IL-6) -174G/C (rs1800795) and IL-6 -572G/C (rs1800796) single-nucleotide polymorphism (SNP) with the risk of acquiring rheumatoid arthritis (RA) was inconsistent among previous studies. This paper aims to investigate the association between IL-6 promoter polymorphism with RA in different ethnics. METHODS: Relevant studies were searched using Medline and Google Search engines; STATA software was used to perform the meta-analysis. Pooled odds ratios (OR) were calculated to estimate the potential genetic associations. Subgroup analysis and sensitivity analysis were applied to explore the sources of heterogeneity. Lastly, we used TSA (trial sequential analysis) software to verify the reliability of meta-analysis results. RESULTS: A total of 18 studies were included, involving 8116 subjects (3820 RA patients and 4296 controls). We found a tendency to associate RA with the IL-6 -174G/C allele in Asians (C vs G: OR = 4.56, 95% CI = 1.85-11.23; P < 0.001); with IL-6 -572G/C genotype or allele frequencies, there was no statistical differences between RA patients and controls (P > 0.05). TSA results indicate that the current meta-analysis can draw conclusions. CONCLUSIONS: IL-6-174G/C gene polymorphism were associated with increased risk of RA in Asians, but not in Caucasians. There was no association between IL-6 -572G/C gene polymorphism and the risk of RA. Key Points • Although the association between interleukin-6 (IL-6) promoter polymorphism and rheumatic arthritis (RA) has been discussed in the previous meta-analysis, their conclusions are inconsistent. • In this study, trial sequential analysis (TSA) was introduced into the meta-analysis, and the following two important conclusions were confirmed: (1) IL-6-174G/C gene polymorphism was associated with increased risk of RA in Asians, but not in Caucasians. (2) There was no association between IL-6 -572G/C gene polymorphism and the risk of RA.

The Potential Regulatory Mechanism of lncRNA 122K13.12 and lncRNA 326C3.7 in Ankylosing Spondylitis.

This work aims to analyze and construct a novel competing endogenous RNA (ceRNA) network in ankylosing spondylitis (AS) with bone bridge formation, lncRNA. Using RNA sequencing and bioinformatics, we analyzed expression profiles of long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in whole blood cells from 5 AS patients and 3 healthy individuals. Next, we verified the expression levels of candidate lncRNAs in 97 samples using the ΔΔCt value of real-time quantitative polymerase chain reaction (qRT-PCR). We used multivariate logistic regression analysis to screen lncRNAs and clinical indicators for use in the prediction model. Both SPSS 24.0 and R software were used for data analysis and prediction model construction. The results showed that compared with the normal controls, 205 long noncoding RNAs (lncRNAs), 961 microRNAs (miRNAs), and 200 mRNAs (DEmRNAs) were differentially expressed in the AS patients. We identified lncRNA 122K13.12 and lncRNA 326C3.7 among 205 lncRNAs differentially expressed between AS patients and healthy humans. Then, we noted that 30 miRNAs and five mRNAs formed a ceRNA network together with these two lncRNAs. These ceRNA networks might regulate the tumor necrosis factor (TNF) signaling pathway in AS development. In addition, the expression level of lncRNA 122K13.12 and lncRNA 326C3.7 correlated with various structural damage indicators in AS. Specifically, the lncRNA 326C3.7 expression level was an independent risk factor in bone bridge formation [area under the ROC curve (AUC) = 0.739 (0.609-0.870) and p = 0.003], and the best Youden Index was 0.405 (sensitivity = 0.800 and specificity = 0.605). Moreover, we constructed a lncRNA-based nomogram that could effectively predict bone bridge formation [AUC = 0.870 (0.780-0.959) and p < 0.001, and the best Youden Index was 0.637 (sensitivity = 0.900 and specificity = 0.737)]. In conclusion, we uncovered a unique ceRNA signaling network in AS with bone bridge formation and identified novel biomarkers and prediction models with the potential for clinical applications.

Bioinformatics analysis of the role of CXC ligands in the microenvironment of head and neck tumor.

Chemokines play a significant role in cancer. CXC-motif chemokine ligands (CXCLs) are associated with the tumorigenesis and progression of head and neck squamous cell carcinoma (HNSC); however, their specific functions in the tumor microenvironment remain unclear. Here, we analyzed the molecular networks and transcriptional data of HNSC patients from the Oncomine, GEPIA, String, cBioPortal, Metascape, TISCH, and TIMER databases. To verify immune functions of CXCLs, their expression was analyzed in different immune cell types. To our knowledge, this is the first report on the correlation between CXCL9-12 and 14 expression and advanced tumor stage. CXCL2, 3, 8, 10, 13, and 16 were remarkably related to tumor immunity. Kaplan-Meier and TIMER survival analyses revealed that high expression of CXCL1, 2, 4, and 6-8 is correlated with low survival in HNSC patients, whereas high expression of CXCL9, 10, 13, 14, and 17 predicts high survival. Only CXCL13 and 14 were associated with overall survival in human papilloma virus (HPV)-negative patients. Single-cell datasets confirmed that CXCLs are associated with HNSC-related immune cells. Thus, CXCL1-6, 8-10, 12-14, and 17 could be prognostic targets for HNSC, and CXCL13 and 14 could be novel biomarkers of HPV-negative HNSC.

Association of FOXO3a gene polymorphisms and ankylosing spondylitis susceptibility in Eastern Chinese Han population.

OBJECTIVE: To investigate the association of FOXO3a polymorphisms and ankylosing spondylitis (AS) susceptibility in Eastern Chinese Han population. METHODS: FOXO3a polymorphisms rs12206094, rs12212067, rs2253310, rs3800232, and rs4946933 were genotyped in 650 AS patients and 646 controls by the improved Multiple Ligase Detection Reaction. RESULTS: The distribution of genotype in rs12212067 polymorphism was significantly different between AS patients and controls (P = 0.020), especially in male population (P = 0.009). There was significant difference of the genotype frequency distribution at rs3800232 between patients and controls in male population. The results of binary regression analysis showed that the rs12212067 GG genotype and rs3800232 TT genotype were obviously correlated with elevated AS risk, and the associations were still significant after being adjusted by age and gender (all P < 0.05). Interestingly, rs12212067 and rs3800232 genotypes were associated with disease activity of patients. Additionally, haplotype block rs12212067G- rs3800232T (OR = 1.403, 95%CI = 1.011-1.949) was further shown to confer promoting effect on developing AS. CONCLUSION: Among Eastern Chinese Han population, FOXO3a polymorphism rs12212067 and rs3800232 may contribute to increased risk of developing AS, but well-designed multicenter studies are needed to further confirm these preliminary findings in the future.

Single nucleotide polymorphisms of TRAF2 and TRAF5 gene in ankylosing spondylitis: a case-control study.

Objective To investigate the role of eight locus polymorphisms of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF5 gene and their interaction in the susceptibility to ankylosing spondylitis (AS) in Chinese Han population. Methods Eight single nucleotide polymorphisms (SNPs) of TRAF2 (rs3750511, rs10781522, rs17250673, rs59471504) and TRAF5 (rs6540679, rs12569232, rs4951523, rs7514863) gene were genotyped in 673 AS patients and 687 controls. Results The SNPs of TRAF2 and TRAF5 do not indicate a correlation with the susceptibility of AS in Chinese Han population. Genotype frequencies of rs3750511 were statistically significant in females between patients and controls. The allele frequencies of rs10781522 and genotype frequencies of rs3750511 were statistically significant between groups of different diseases activity. One three-locus model, TRAF2 (rs10781522, rs17250673) and TRAF5 (rs12569232), had a maximum testing accuracy of 52.67% and a maximum cross-validation consistency (10/10) that was significant at the level of P = 0.0001, after determined empirically by permutation testing. As to environmental variables, only marginal association was found between sleep quality and AS susceptibility. Conclusion TRAF2 rs3750511 polymorphism may be associated with the susceptibility and severity of AS. Besides, the interaction of TRAF2 and TRAF5 genes may be associated with AS susceptibility, but many open questions remain.

BAFF, involved in B cell activation through the NF-κB pathway, is related to disease activity and bone destruction in rheumatoid arthritis.

B cell activating factor of TNF family (BAFF) is a member of TNF ligand superfamily and plays a key role in B cell homeostasis, proliferation, maturation, and survival. In this study, we detected BAFF level, the expressions of BAFF receptors and important molecules in NF-κB pathway in rheumatoid arthritis (RA) patients and analyzed the correlation between BAFF level and clinical variables, laboratory parameters or X-ray scores in order to elucidate the roles of BAFF in RA. A total of 50 RA patients and 50 healthy controls (HCs) were enrolled. We showed that the serum BAFF level in RA patients was significantly higher than that of HCs, and the percentages of B cell subsets (CD19+ B cells, CD19+CD27+ B cells, CD19+CD20+CD27+ B cells, and CD19+CD20-CD27+ B cells) in the serum of RA patients were significantly increased compared with those of HCs. The percentages of CD19+BAFFR+ B cells, CD19+ BCMA+ B cells, and CD19+ TACI+ B cells in RA patients were significantly increased compared with those in HCs. The expression of important molecules in the NF-κB pathway (MKK3, MKK6, p-P38, p-P65, TRAF2, and p52) was significantly higher in RA patients than in HCs, but p100 level in RA patients was lower than that in HCs. The serum BAFF level was positively correlated with C-reactive protein, rheumatoid factor, disease activity score (in 28 joints), swollen joint counts, tender joint counts, and X-ray scores. When normal B cells were treated with BAFF in vitro, the percentages of the B cell subset and the expression of BAFF receptors were significantly upregulated. BAFF also promoted the expression of MKK3, MKK6, p-P38, p-P65, TRAF2, and p52. In conclusion, this study demonstrates that BAFF level is correlated with the disease activity and bone destruction of RA. BAFF is involved in the differentiation, proliferation, and activation of B cells in RA through NF-κB signaling pathway, suggesting that BAFF might be an ideal therapeutic target for RA.

G protein-coupled receptor 30 activation protects hepatic ischemia-reperfusion injury of liver tissue through inhibiting NLRP3 in the rat model.

One of the most prominent characteristics of hepatic ischemia-reperfusion injury (HI/R) is an intense inflammatory reaction, which plays a key role in inflammatory injury induced by ischemia-reperfusion. Nucleotide-binding oligomerization domain-containing protein (NOD-), leucine-rich repeat (LRR), and pyrin domains-containing protein 3 (NLRP3) are involved in the inflammatory injury of ischemia-reperfusion as an important pattern recognition receptor for innate immunity. G protein-coupled receptor 30 (GPR30) is a newly identified as 7-transmembrane G protein-coupled receptor and can be activated by many stimulations including estrogen. The current study aims to explore whether GPR30 agonist (G1) can alleviate hepatic ischemia-reperfusion injury HI/R by inhibiting NLRP3. An induced HI/R rat model was generated, blood and liver samples were gathered and subjected to histological examination, biochemical assays, Western blot assays, and qRT-PCR. Our results indicated GPR30 agonist (G1) pretreatment or NLRP3 silencing significantly decreased the serum levels of Interleukin 1ß (IL-1ß), alanine aminotransferase (ALT) and aspartate aminotransferase, improved histological alterations and hepatocyte apoptosis. Moreover, G1 pretreatment or NLRP3 silencing downregulated the protein level of Caspase-1 and pro-Interleukin 1ß (pro-IL-1ß) while G1 pretreatment upregulated the expression of GPR30 (p < 0.05). In conclusion, the salutary effects of GPR30 agonists on HI/R are mediated at least in part through downregulating NLRP3 expression. GPR30 may be used as a therapy target of HI/R.

B7-H3: A promising therapeutic target for autoimmune diseases.

B7-H3 as a newly identified costimulatory molecule that belongs to B7 ligand family, is broadly expressed in both lymphoid and non-lymphoid tissues. The overexpression of B7-H3 has been verified to be correlated with the poor prognosis and poor clinical outcome of several human cancers. In recent years, researchers reveal that B7-H3 is involved in the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren's syndrome (SS), ankylosing spondylitis (AS), etc. In this review, we will discuss the biological function of B7-H3 and summarize the progress made over past years regarding its role in the occurrence and development of autoimmune diseases. The insights gained from these findings could serve as the foundation for future therapies of these diseases.

H19 Increases IL-17A/IL-23 Releases via Regulating VDR by Interacting with miR675-5p/miR22-5p in Ankylosing Spondylitis.

Long non-coding RNA (lncRNA) H19 is associated with inflammatory diseases, but the molecular mechanism of H19 in the inflammatory process of ankylosing spondylitis (AS) is unclear. Here, we investigated the role of H19 and its downstream molecules in the inflammation of AS by microarray analysis, qRT-PCR, western blot, and dual-luciferase reporter assay. H19 small interfering RNA (siRNA) (Si-H19) and adenovirus (AD-H19) were used to decrease and increase H19 expression, respectively. 42 annotated lncRNAs were identified, and H19 was overexpressed. H19, vitamin D receptor (VDR), and transforming growth factor ß (TGF-ß) can bind to microRNA22-5p (miR22-5p) and miR675-5p. Si-H19 significantly downregulated miR22-5p and upregulated miR675-5p expression; Si-H19 decreased the protein and mRNA expression of VDR and decreased the cytokine and mRNA levels of interleukin-17A (IL-17A) and IL-23. These results were verified by AD-H19. In addition, miR22-5p and miR675-5p inhibitors increased the protein and mRNA expression of VDR and increased the cytokine and mRNA levels of IL-17A and IL-23. These results were also confirmed by miRNA mimics. Furthermore, H19 directly interfered with miR22-5p and miR675-5p expression, whereas the two miRNAs directly inhibited VDR expression. Overall, the H19-miR22-5p/miR675-5p-VDR-IL-17A/IL-23 signaling pathways have important roles in the pathogenesis of AS.