Profiling the metabolic disorder and detection of colorectal cancer based on targeted amino acids metabolomics.

BACKGROUND: The morbidity of cancer keeps growing worldwide, and among that, the colorectal cancer (CRC) has jumped to third. Existing early screening tests for CRC are limited. The aim of this study was to develop a diagnostic strategy for CRC by plasma metabolomics. METHODS: A targeted amino acids metabolomics method was developed to quantify 32 plasma amino acids in 130 CRC patients and 216 healthy volunteers, to identify potential biomarkers for CRC, and an independent sample cohort comprising 116 CRC subjects, 33 precancerosiss patients and 195 healthy volunteers was further used to validate the diagnostic model. Amino acids-related genes were retrieved from Gene Expression Omnibus and Molecular Signatures Database and analyzed. RESULTS: Three were chosen out of the 32 plasma amino acids examined. The tryptophan / sarcosine / glutamic acid -based receiver operating characteristic (ROC) curve showed the area under the curve (AUC) of 0.955 (specificity 83.3% and sensitivity 96.8%) for all participants, and the logistic regression model were used to distinguish between early stage (I and II) of CRC and precancerosiss patients, which showed superiority to the commonly used carcinoembryonic antigen. The GO and KEGG enrichment analysis proved many alterations in amino acids metabolic pathways in tumorigenesis. CONCLUSION: This altered plasma amino acid profile could effectively distinguish CRC patients from precancerosiss patients and healthy volunteers with high accuracy. Prognostic tests based on the tryptophan/sarcosine/glutamic acid biomarkers in the large population could assess the clinical significance of CRC early detection and intervention.

Simultaneous Determination of 34 Amino Acids in Tumor Tissues from Colorectal Cancer Patients Based on the Targeted UHPLC-MS/MS Method.

A targeted ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was established and validated for the simultaneous determination of 34 amino acids in tissue samples from colorectal cancer (CRC) patients. The chromatographic separation was achieved on an Agilent ZORBAX SB-C18 column (3.0 × 150 mm, 5 µm) with a binary gradient elution system (A, 0.02% heptafluorobutyric acid and 0.2% formic acid in water, v/v; B, methanol). The run time was 10 min. The multiple reaction monitoring mode was chosen with an electrospray ionization source operating in the positive ionization mode for data acquisition. The linear correlation coefficients were >0.99 for all the analytes in their corresponding calibration ranges. The sample was pretreated based on tissue homogenate and protein precipitation with a 100 mg aliquot sample. The average recovery and matrix effect for 34 amino acids and 3 internal standards were 39.00%∼146.95% and 49.45%∼173.63%, respectively. The intra- and interday accuracy for all the analytes ranged from -13.52% to 14.21% (RSD ≤8.57%) and from -14.52% to 12.59% (RSD ≤10.31%), respectively. Deviations of stability under different conditions were within ±15% for all the analytes. This method was applied to simultaneous quantification of 34 amino acids in tissue samples from 94 CRC patients.

Upregulated miR-155 inhibits inflammatory response induced by C. albicans in human monocytes derived dendritic cells via targeting p65 and BCL-10.

BACKGROUND: Candida albicans (C. albicans) is one of the most common fungal pathogens causing superficial and systemic infections. The innate immune system is the first defense line against C. albicans infection. MiR-155, a multifunctional microRNA (miRNA), has been proved to be a crucial regulator in innate immune response against bacterial and virus. However, the biological function of miR-155 in innate immune response against C. albicans infection remains unknown. METHODS: The expression miR-155, as well as inflammatory factors [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)], in monocytes derived dendritic cells (DCs) during heat-killed C. albicans infection was detected by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). The biological functions of miR-155 were investigated with "gain- and loss-of-function" experiments. Potential targets of miR-155 were identified by bioinformatics analysis, luciferase assay and western blot. Small interfering RNA (siRNA) was used to validate the function of miR-155 target. RESULTS: C. albicans increased the expression of miR-155 and pro-inflammatory factors. MiR-155 induced by C. albicans was depended on Dectin-1-spleen tyrosine kinase (Syk)/Raf-1-MAPK signaling pathway. Furthermore, miR-155 suppressed the secretion of pro-inflammatory cytokines induced by C. albicans by targeting NF-κB p65 and B cell leukemia/lymphoma 10 (BCL-10). CONCLUSIONS: In conclusion, up-regulated miR-155 acts as a negative feedback regulator in the innate immune response against C. albicans infection.

MicroRNA-142-3p inhibits IFN-γ production via targeting of RICTOR in Aspergillus fumigatus activated CD4+ T cells.

BACKGROUND: Aspergillus fumigatus (AFE) is a well-adapted, opportunistic fungus that causes a severe and commonly fatal disease, wherein IFN-γ is one of the most important protective cytokines. The aim of this study was to investigate the microRNA expression profile and explore the underlying mechanism during infection with AFE. METHODS: CD4+ T cells were activated by co-culturing with dendritic cells (DCs), which were pre-treated with AFE. Next, we performed microRNA microarray expression profiles of activated and control T cells, following which, miRNA-142-3P was selected. To explore the effect of miR-142-3P on T cell activation, miRNA-142-3P expression was disrupted by transient transfection with miR-142-3P mimic or inhibitor. Then, levels of RICTOR, phosphorylated AKT and IFN-γ were detected via Western blotting and qPCR respectively. We further used siRNA to decrease RICTOR expression and determined the role played by RICTOR in miR-142-3P mediated-IFN-γ expression by qPCR following AFE-mediated T cell activation. RESULTS: The heat-map of miRNA expression profiles showed that 54 microRNAs (miRNAs) were filtered, the levels of which, were significantly different between CD4+ T cells activated by AFE and control T cells, in which microRNA-142-3 was involved. Forced expression of miRNA-142-3P dramatically suppressed RICTOR levels, phosphorylated AKT and IFN-γ in AFE activated T cells. Conversely, loss of miRNA-142-3P elevated RICTOR levels, phosphorylated AKT and IFN-γ. Notably, RICTOR deficiency decreased AKT phosphorylation levels and IFN-γ secretion. CONCLUSIONS: Observations indicated that down-regulation of microRNA-142-3p enhanced IFN-γ expression, and did so by promoting RICTOR expression in CD4+ T cells activated by AFE.

Implication of increased serum stromal cell-derived factor-1 for primary biliary cholangitis.

BACKGROUND: Stromal cell-derived factor-1 (SDF-1), also called chemokine (C-X-C motif) ligand 12 (CXCL12), as a chemokine for premature B cells, T cells and monocytes, is detected in liver, pancreas, spleen and heart. However, its diagnostic value for primary biliary cholangitis (PBC) as well as the association of SDF-1 with inflammatory and fibrotic progression is unclear. The aim of this study was to determine serum stromal cell-derived factor-1 (SDF-1) level and to explore its diagnostic value for primary biliary cholangitis (PBC) as well as the association of SDF-1 with inflammatory and fibrotic progression of PBC. METHODS: A total of 60 PBC patients who received liver biopsy, 32 age- and sex-matched patients with chronic hepatitis B (CHB) and 30 age- and sex-matched healthy controls (HC) were recruited. The sera were measured for SDF-1, interleukin-4 (IL-4), interferon gamma (IFN-γ) and IL-17 using multiplex immunoassay. PBC was divided into four histologic stages according to Scheuer's classification. RESULTS: The results showed significantly higher median level of serum SDF-1 (median, interquartile (IQR), 1186.96, 1002.05-1471.33 pg/mL) in PBC patients than those with CHB (median, IQR, 740.69,600.30-1239.27 pg/mL) and HC (median, IQR, 738.44, 687.65-879.33 pg/mL) (P < 0.001). There was no significant difference between CHB patients and HC (P = 0.526). The receiver operating characteristic curves (ROC) showed good diagnostic performance of serum SDF-1 for PBC, AMA-positive and -negative PBC. In particular for AMA-negative PBC, the area under ROC was 0.817, with optimal cutoff value of 802.64 pg/mL and the sensitivity of 100%. Serum SDF-1 level was not associated with other immune, inflammatory and fibrotic indicators, including AMA, ANA, anti-gp210, sp100 and centromere antibodies, bilirubin, ALT, AST, ALP, GGT, WBC, neutrophil, lymphocyte, platelet, Neutrophil- (NLR) and platelet-lymphocyte (PLR), AST to ALT ratio, AST to platelet ratio index (APRI) and FIB-4 index (P > 0.05). Also, there was no significant difference for serum SDF-1 among histological stages (P = 0.091). However, Serum SDF-1 level was significantly correlated with serum IL-17 (r = 0.373, P = 0.004), but not with IL-4 (r = 0.110, P = 0.407) and IFN-γ (r = 0.215, P = 0.098) in those with PBC. CONCLUSION: Serum SDF-1 is increased in and may be a potential useful marker for PBC. Moreover, it may be associated with Th17 recruitment and differentiation in PBC. However, serum SDF-1 may not be associated with the progression of PBC.

APOC3 induces endothelial dysfunction through TNF-α and JAM-1.

BACKGROUND: The fatality rate for cardiovascular disease (CVD) has increased in recent years and higher levels of triglyceride have been shown to be an independent risk factor for atherosclerotic CVD. Dysfunction of endothelial cells (ECs) is also a key factor of CVD. APOC3 is an important molecule in lipid metabolism that is closely associated with hyperlipidemia and an increased risk of developing CVD. But the direct effects of APOC3 on ECs were still unknown. This study was aimed at determining the effects of APOC3 on inflammation, chemotaxis and exudation in ECs. METHODS: ELISA, qRT-PCR, immunofluorescence, flow cytometry and transwell assays were used to investigate the effects of APOC3 on human umbilical vein endothelial cells (HUVECs). SiRNA-induced TNF-α and JAM-1 silencing were used to observe how APOC3 influenced the inflammatory process in the ECs. RESULTS: Our results showed that APOC3 was closely associated with the inflammatory process in ECs, and that this process was characterized by the increased expression of TNF-α. Inflammatory processes further disrupted the tight junctions (TJs) between HUVECs by causing increased expression of JAM-1. JAM-1 was involved in maintaining the integrity of TJs, and it promoted the assembly of platelets and the exudation of leukocytes. Changes in its expression promoted chemotaxis and the exudation of ECs, which contributed to atherosclerosis. While the integrity of the TJs was disrupted, the adhesion of THP-1 cells to HUVECs was also increased by APOC3. CONCLUSIONS: In this study, we describe the mechanism by which APOC3 causes inflammation, chemotaxis and the exudation of ECs, and we suggest that controlling the inflammatory reactions that are caused by APOC3 may be a new method to treat CVD.

Human Epididymis Protein 4: A Novel Biomarker for Lupus Nephritis and Chronic Kidney Disease in Systemic Lupus Erythematosus.

BACKGROUND: Human epididymis protein 4 (HE4) is an available tumor biomarker for detecting ovarian cancer. However, it is unknown if serum HE4 could be a novel biomarker for diagnosis of lupus nephritis (LN) and chronic kidney disease (CKD) in patients with systemic lupus erythematosus (SLE). METHODS: This study enrolled 209 SLE patients, 75 patients with renal dysfunction without SLE and 32 healthy subjects. HE4 concentrations were analyzed by ELISA (enzyme-linked immunosorbent assay; Fujirebio Diagnostics, Sweden). The receiver operating characteristic (ROC) curves were constructed to assess diagnostic accuracy of HE4 for LN or CKD in SLE. RESULTS: Serum HE4 level was significantly higher in SLE patients than that in healthy controls (P < 0.001), especially for those with LN or CKD. It was also higher in patients with renal dysfunction without SLE than healthy controls (P < 0.001), while there was no significant difference between these patients and those with SLE with CKD (P = 0.73). Multivariate analysis showed significant association between increased HE4 and LN or CKD after controlling for confounders. ROC curves showed the cutoff values were 150.1 pM (sensitivity, 76.8%; specificity, 91.1%) for the diagnosis of LN in SLE and 233.9 pM (sensitivity, 92.9%; specificity, 93.5%) for CKD in SLE. CONCLUSIONS: Increased serum HE4 level is closely associated with the development of LN or CKD in SLE patients. Furthermore, it can be used as a novel and useful biomarker for diagnosis of LN or CKD.

Elevated red blood cell distribution width is associated with liver function tests in patients with primary hepatocellular carcinoma.

BACKGROUND: Red blood cell distribution width (RDW), a routinely tested parameter of the complete blood count (CBC), has been reported to be increased in various cancers and correlated with the patients' clinical characteristics. However, the significance of RDW in primary hepatocellular carcinoma (pHCC) is largely unknown. The aim of this study was to evaluate the associations between RDW and the clinical characteristics of pHCC patients. METHODS: Medical records of 110 treatment-naive pHCC patients were retrospectively reviewed. Their clinical characteristics on admission, including RDW, liver function tests and tumor stage, were extracted, and their relationships were analyzed using Spearman correlation and Kruskal-Wallis test. Sixty-eight healthy individuals were set as controls. RESULTS: RDW was significantly increased in pHCC patients and correlated with the liver function tests. However, no correlation between RDW and tumor stage was found. CONCLUSION: RDW may be used to assess the liver function, but not the tumor stage in pHCC patients.

Decreased expression of TIPE2 contributes to the hyperreactivity of monocyte to Toll-like receptor ligands in primary biliary cirrhosis.

BACKGROUND AND AIM: Previous studies have shown differential TIPE2 expression in several autoimmune diseases. However, the expression levels of TIPE2 in primary biliary cirrhosis (PBC) remained unclear. The purposes of this study were to evaluate TIPE2 expression levels in patients with PBC and further investigate its role in PBC pathogenesis. METHODS: A total of 40 PBC patients and 44 healthy controls were included in the present study. Quantitative reverse-transcription polymerase chain reaction and western blotting were used to determine the differences in mRNA and protein expression levels of TIPE2. The correlations of TIPE2 expression levels and clinical characteristics, inflammatory cytokines, and ursodeoxycholic acid treatment were also assessed. Besides, the influence of TIPE2 on the reactivity of monocyte to Toll-like receptor ligands was further analyzed. RESULTS: The expression levels of TIPE2 were significantly decreased in PBC patients compared with normal controls (P < 0.01). The expression levels of TIPE2 were negatively correlated with alanine aminotransferase (r = -0.40, P = 0.01), alkaline phosphatase (r = -0.36, P = 0.02), gamma glutamyl transpeptidase (r = -0.53, P < 0.01), tumor necrosis factor (TNF)-α (r = -0.332, P = 0.03), interleukin (IL)-1ß (r = -0.386, P = 0.01), and IL-8 (r = -0.366, P = 0.02) levels in sera from PBC patients. TIPE2 expression level could be significantly increased after ursodeoxycholic acid treatment (P < 0.01). The production of TNF-α, IL-1ß, and IL-8 by monocytes from PBC patients after stimulation with lipopolysaccharide and lipoteichoic acid was significantly increased when TIPE2 was knocked down. Furthermore, TIPE2 knockdown could promote activation of nuclear factor-κB pathways through increasing phosphorylation and degradation of IκB in peripheral blood monocytes from PBC patients. CONCLUSION: The present study reported that insufficient expression of TIPE2 might be involved in the hyperreactivity of monocyte to Toll-like receptor ligands in PBC.

Adjuvant therapy in the treatment of gallbladder cancer: a meta-analysis.

BACKGROUND: The benefit of adjuvant therapy (AT) for gallbladder cancer (GBC) is unclear as evidenced by conflicting results from nonrandomized studies. Here we aimed to perform a meta-analysis to determine the impact of AT on overall survival (OS). METHODS: We used data from MEDLINE, EMBASE and the Cochrane Collaboration Library and published between October 1967 and October 2014. Studies that evaluated AT compared with curative-intent surgery alone for resected GBC were included. Subgroup analyses of benefit based on node status, margins status, and American Joint Committee on Cancer (AJCC) staging were prespecified. Data were weighted and pooled using random-effect modeling. RESULTS: Ten retrospective studies involving 3,191 patients were analyzed. There was a nonsignificant improvement in OS with AT compared with surgery alone (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.56-1.03). A significant improvement was observed in OS with chemotherapy (CT) compared with surgery alone (HR, 0.42; 95% CI, 0.22-0.80) by sensitivity analysis. The greatest benefit for AT was also observed in those with R1 disease (HR, 0.33; 95% CI, 0.19-0.59), LN-positive disease (HR, 0.71; 95% CI, 0.63-0.81), and AJCC staging meeting or exceeding tumor Stage II (HR, 0.45; 95% CI, 0.26-0.79), but not in those with LN-negative or R0 disease. CONCLUSION: Our results strongly support the use of CT as an AT in GBC. Moreover, patients with node positivity, margin positivity, or non-stage I disease are more likely to benefit from AT.

Diagnostic value of osteopontin in ovarian cancer: a meta-analysis and systematic review.

AIMS: Osteopontin (OPN) plays an important role in many physiological and pathological processes (wound healing, inflammation, immune response, and tumorigenesis). This meta-analysis assessed the diagnostic value of osteopontin in ovarian cancer. METHODS AND RESULTS: Searches in Embase and PubMed were conducted, in order to identify eligible studies on osteopontin expression and its diagnostic value in ovarian cancer. The revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) tool was applied to examine the quality of these studies and the overall osteopontin diagnostic accuracy in ovarian cancer was pooled using the bivariate model. The publication bias was assessed using funnel plots and Deek's test. This search methodology resulted in 13 studies with a total of 839 ovarian cancer patients and 1439 controls in this meta-analysis. The overall osteopontin diagnostic sensitivity and specificity of ovarian cancer were 0.66 (95% CI, 0.51-0.78) and 0.88 (95% CI, 0.78-0.93), respectively. The area under summary receiver operating characteristic (sROC) curves (AUC) was 0.85 (95%CI, 0.81-0.88). There was no significant publication bias observed across the eligible studies. However, a major design deficiency of the eligible studies is the issue of subject selection bias. CONCLUSIONS: Osteopontin could be a useful biomarker in diagnosis of ovarian cancer. Due to the design deficits of the eligible studies, a future study with a larger sample size and better design is needed to rigorously confirm the diagnostic potential of osteopontin in ovarian cancer.

Prognostic value of neutrophil to lymphocyte ratio for gastric cancer.

BACKGROUND: Although the prognostic value of the neutrophil to lymphocyte ratio (NLR) in gastric cancer (GC) patients has been investigated by many studies, the results are heterogeneous. The objective of this systematic review is to ascertain the prognostic value of NLR in GC patients. METHODS: PubMed and Embase were retrieved to identify potential studies published before 8 June, 2014. Newcastle-Ottawa Scale (NOS) for cohort study was used to assess the quality of all eligible studies. RESULTS: Of the 20 studies included in this systematic review, 17 studies investigated the effect of NLR on overall survival (OS), 11 studies reported that NLR negatively affected OS in their multivariante analysis, and 16 studies reported that NLR negatively affected OS in univariate analysis. Three studies investigated the effect of NLR on progression-free survival (PFS), reporting that increased NLR was associated with worse PFS. Four studies investigated the effect of NLR on disease-free survival (DFS), two of which reported that increased NLR was associated with worse DFS. Two studies investigated the effect of NLR on disease special survival (DSS), but neither observed any significant association between NLR and DSS. The major design deficiencies of the studies available were retrospective data collection, inadequacy of follow-up cohorts, and unavailability of the method used for outcome assessment. CONCLUSIONS: Based on the above findings, we conclude that NLR may be a useful prognostic index (PI) for GC. In addition, future studies with prospective design, long-term follow-up and fully adjusted confounding factors are needed to rigorously assess the prognostic value of NLR for GC.

The association of Tyro3/Axl/Mer signaling with inflammatory response, disease activity in patients with primary Sjögren's syndrome.

OBJECTIVES: Defects in Tyro3/Axl/Mer signaling may lead to impaired phagocytosis of apoptotic cells, eventually contributing to the development of autoimmune disease. The association of TAM signaling with several autoimmune disease has been investigated, but it remains unclear in primary Sjögren's syndrome. Therefore, the aim of this study was to evaluate the level of TAM signaling in primary Sjögren's syndrome with its clinical significance. METHODS: Real-Time Polymerase Chain Reaction was used to determine the mRNA expression of Mer, Tyro-3, Axl, Gas6, and Protein S in Peripheral Blood Mononuclear Cell from 43 pSS and 46 control. The Enzyme-Linked Immunosorbent Assay method was used to test plasma levels of soluble TAM signaling from those individuals, and the relationship of their levels with clinical characteristic was evaluated. RESULTS: The mRNA expression levels of Tyro-3, Axl were decreased in pSS patients. When considering the plasma level, increased levels of soluble Mer was observed with statistically significant difference. Soluble Mer levels were positively correlated with IgG levels (r=0.53, P<0.01), Erythrocyte Sedimentation Rate levels (r=0.44, P<0.01) and Sjögren's Syndrome Disease Activity Index (r=0.48, P<0.01). And the levels of soluble Mer in patients with the presence of SSA/SSB were higher than those without SSA/SSB. CONCLUSIONS: The plasma levels of sMer were increased in pSS patients, which was associated with inflammatory response and disease activity.

Polymyositis/dermatomyositis and malignancy risk: a metaanalysis study.

OBJECTIVE: To investigate the association between polymyositis (PM)/dermatomyositis (DM) and risks of malignancy. METHODS: We searched Pubmed for articles dated before August 16, 2013. Studies were included if they met the following criteria: (1) a cohort or observational study; (2) PM or DM as one of the exposures of interest; (3) cancer as an outcome of interest; and (4) the rate ratio (RR) or standardized incidence ratio (SIR) were available with their 95% CI. We used random-effects or fixed-effects models to calculate the pooled RR according to the heterogeneity test. RESULTS: Twenty publications were included. Compared with the general population, the pooled RR for patients with PM, DM, and PM/DM were 1.62 (95% CI 1.19-2.04), 5.50 (4.31-6.70), and 4.07 (3.02-5.12), respectively. The increased risks were more significant in patients within the first year of myositis diagnosis, male patients, and population-based studies (for DM). A significant association was also found between PM or DM and most site-specific malignancies. However, both PM and DM were not associated with stomach and prostate cancers. Significant heterogeneity was found between studies on association between PM/DM and overall malignancy, but not between PM/DM and the majority of site-specific malignancies, suggesting that that inherent malignancy difference may be a major source of heterogeneity. CONCLUSION: The present metaanalysis indicates that PM and DM are significantly associated with increased risks of overall malignancy and most site-specific malignancies. The number of studies on association between PM or DM and some malignancies is too small to draw a firm conclusion. Accordingly, more research is needed for these malignancies.

The association between Cytotoxic T lymphocyte associated antigen-4, Fas, tumour necrosis factor-α gene polymorphisms and autoimmune hepatitis: a meta-analysis.

BACKGROUND: Several previous studies have assessed the association of Cytotoxic T Lymphocyte Associated Antigen-4, Fas, and Tumour Necrosis Factor-α gene polymorphisms with autoimmune hepatitis risk, but the results were inconsistent and inconclusive. We performed a meta-analysis to better evaluate these associations. METHODS: PubMed, EMBASE and MEDLINE were searched in all languages. Overall odd ratios with 95% confidence intervals were calculated to assess the strength of associations using a fixed-effects or random-effects models. RESULTS: 15 relevant studies were identified. No significant association was found between CTLA-4+49A/G and AH. TNF-α-308A/G was significantly associated with autoimmune hepatitis risk. Individuals with the "A" allele had a 67% increased risk of autoimmune hepatitis (odds ratio=1.67, 95% confidence interval 1.11-2.52). The genotype "AA" was a potential predisposing factor for autoimmune hepatitis, when compared with the genotype "GG" and "AG+GG" (odds ratio=2.71, 95% confidence interval 1.12-6.57; odds ratio=2.14, 95% confidence interval 1.30-3.52). Besides, no significant association was found between the Fas-670G/A and TNF-α-238A/G polymorphisms and autoimmune hepatitis risk using any model. CONCLUSION: The meta-analysis identified the TNF-α-308 "A" allele as a predisposing factor for autoimmune hepatitis, whereas the genotype "GG" was a protective factor. This study did not find a significant association between CTLA-4+49A/G, Fas-670G/A, TNF-α-238A/G and susceptibility to autoimmune hepatitis.

Increased expression of Siglec-1 on peripheral blood monocytes and its role in mononuclear cell reactivity to autoantigen in rheumatoid arthritis.

OBJECTIVES: Elevated expression of Siglec-1 on circulating monocytes has been reported in some inflammatory and autoimmune diseases, but its expression and role in RA has not been elucidated. The aims of this study were to determine the expression of Siglec-1 in peripheral blood and to explore its role in mononuclear cell reactivity to autoantigen in RA. METHODS: Siglec-1 protein and mRNA levels in 42 RA patients, 39 OA patients, 28 SLE patients and 42 normal controls were determined by flow cytometry and quantitative RT-PCR, respectively. In addition, 10 patients with active RA received DMARDs for 12 weeks and the frequencies of Siglec-1-positive cells and the 28-joint DAS (DAS28) were assessed before and after therapy. Furthermore, TNF-α, IFN-γ and type II collagen were used to up-regulate Siglec-1. Peripheral blood mononuclear cells (PBMCs) from different groups were stimulated with mitogens or antigens and cell proliferation and cytokine production were determined. RESULTS: The protein and mRNA levels of Siglec-1 on PBMCs and monocytes in RA patients were significantly higher than those in OA patients and healthy controls. Moreover, the expression of Siglec-1 protein on PBMCs was positively correlated with DAS28, ESR, high-sensitivity CRP and IgM-RF, but not with anti-CCP antibody. Interestingly, Siglec-1 expression was decreased in parallel with the decrease in the DAS28 after 12 weeks of anti-rheumatic treatment. Furthermore, TNF-α, IFN-γ and type II collagen can up-regulate Siglec-1 in PBMCs. Elevated PBMC proliferation and proinflammatory cytokine production to collagen stimulation in RA patients decreased when Siglec-1 was inhibited by anti-Siglec-1 antibodies. CONCLUSION: Elevated Siglec-1 expression in PBMCs and monocytes can potentially serve as a biomarker for monitoring disease activity in RA. Siglec-1 may also play a proinflammatory role in stimulating lymphocyte proliferation and activation in RA.

A meta-analysis of the association of IL-6 -174 G/C and -572 G/C polymorphisms with systemic lupus erythematosus risk.

The results from previous studies on association of IL-6 -174 G/C and -572 G/C polymorphisms with the risk of systemic lupus erythematosus (SLE) remained inconsistent. Therefore, a meta-analysis was performed to assess the association between these two polymorphisms and SLE susceptibility. A literature-based search was conducted to identify all relevant studies. Pooled data were estimated by fixed- and random-effects models when appropriate. Nine publications were included in the meta-analysis, seven for -174 G/C polymorphism and three for -572 G/C polymorphism. The results indicated that IL-6 -174 G/C polymorphism was significantly associated with SLE risk for recessive model and allele analysis in overall populations (OR 1.64, 95 % CI 1.10-2.45, P = 0.016; and 1.34, 1.05-1.72, P = 0.019, respectively, for recessive model and allele analysis) or in Caucasians (OR 1.37, 95 % CI 1.04-1.82, P = 0.027; and 1.27, 1.04-1.54, P = 0.018, respectively, for recessive model and allele analysis). Also, significant association between IL-6 -572 G/C polymorphism and SLE was found under recessive model (OR 1.49, 95 % CI 1.10-2.01, P = 0.009), but not under dominant model and allele analysis (OR 1.05, 95 % CI 0.77-1.43, P = 0.750; and 1.21, 1.00-1.48, P = 0.054, respectively, for dominant model and allele analysis). Additionally, our meta-analysis showed that IL-6 -174 G/C polymorphism was significantly associated with discoid skin lesions (P < 0.05). The present study indicates that IL-6 -174 G/C and -572 G/C polymorphisms could be candidates for susceptibility to SLE. Furthermore, a large number of studies should be performed to explore the association of IL-6 polymorphisms with the risk and clinical characteristics of SLE patients in different ethnics.

Primary Sjogren's syndrome and malignancy risk: a systematic review and meta-analysis.

OBJECTIVE: To investigate the association between primary Sjögren's syndrome (pSS) and the risks of malignancy including overall malignancy and site-specific malignancies through a systematic review and meta-analysis. METHODS: We searched Pubmed before January 2013, with a restriction to English language publications. Studies were included if they met the following criteria: (1) a cohort or observational study; (2) pSS as one of the exposure interests; (3) cancer as an outcome of interest; (4) relative risk (RR) or standardised incidence rate (SIR) with 95% CIs. We used a random or fixed effects model to calculate the pooled RR according to the heterogeneity test. RESULTS: Fourteen studies involving more than 14 523 patients with pSS were included. Compared with the general population, patients with pSS had significantly increased risks of overall cancer (pooled RR 1.53; 95% CI 1.17 to 1.88), non-Hodgkin lymphoma (NHL) (pooled RR 13.76; 95% CI 8.53 to 18.99) and thyroid cancer (pooled RR 2.58; 95% CI 1.14 to 4.03). A significant association was found in various subgroup meta-analyses for NHL but, for overall malignancy, a significant association was only found in some groups. Additionally, the number of studies exploring the association of pSS with the risk of solid malignancies was so small that we could not carry out subgroup meta-analyses. CONCLUSIONS: This meta-analysis indicates that pSS is significantly associated with increased risks of overall malignancy, NHL and thyroid cancer. However, it is not yet known whether the apparent increased risk of overall malignancy in patients with pSS is due to the relatively high prevalence of NHL in that group.

Meta-analysis of the association between the IL-12B +1188 A/C polymorphism and cancer risk.

BACKGROUND: Because of inconsistent results from previous studies on the association of IL-12B +1188 A/C polymorphism with cancer risk, a meta-analysis was performed to assess the association. MATERIALS AND METHODS: A literature search was performed to identify all relevant studies to May 31, 2012, with a restriction to English and Chinese publications. Pooled data were estimated using a random-effects model. RESULTS: 17 publications were included in the meta-analysis. The results indicated that the polymorphism was significantly associated with a decreased risk for overall cancer (odds ratio (OR), 95% confidence interval (CI): 0.86, 0.76-0.97, p = 0.007; 0.80, 0.68-0.95, p = 0.012; and 0.88, 0.78-0.99, p = 0.032, respectively for dominant model, recessive model, and allele analysis) or nasopharyngeal cancer and hepatocellular carcinoma. This association was also found in Asians (OR, 95% CI: 0.89, 0.80-0.99, p = 0.031; 0.82, 0.68-0.98, p = 0.027; and 0.89, 0.80-1.00, p = 0.047, respectively for dominant model, recessive model, and allele analysis), but not in Europeans and Americans. CONCLUSION: The present study indicates that the IL-12B +1188 A/C polymorphism could play a protective role in the development of cancer. More investigations involving various cancer types among various populations are needed.

An abnormal elevation of serum CA72-4 by ganoderma lucidum spore powder.

We reported three patients with an abnormal elevation of serum CA72-4 levels when taking GLSP, which is commonly used as a dietary supplement for cancer patients across the globe. Furthermore, the results were not due to the apparent analytical interference. In case 1 and case 2, excessive examinations were carried out because of a lack of timely communication with patients when the abnormal elevation of CA724 was found. In contrast, the lesson from these two cases made us communicate with the patient in a timely manner in Case 3, avoiding unnecessary examinations when the same situation happened. Therefore, it is necessary to communicate with patients in a timely manner once an abnormal elevation of serum CA72-4 is found.