Circulating heat shock protein 90 (Hsp90) and autoantibodies to Hsp90 are increased in patients with atopic dermatitis

Atopic dermatitis (AD) is one of the most common chronic inflammatory dermatoses characterized by persistent itching and recurrent eczematous lesions. While the primary events and key drivers of AD are topics of ongoing debate, cutaneous inflammation due to inappropriate IgE (auto)antibody–related immune reactions is frequently considered. Highly conserved and immunogenic heat shock protein 90 (Hsp90), a key intra- and extracellular chaperone, can activate the immune response driving the generation of circulating anti-Hsp90 autoantibodies that are found to be elevated in several autoimmune disorders. Here, for the first time, we observed that serum levels of Hsp90 and anti-Hsp90 IgE autoantibodies are significantly elevated (p < 0.0001) in AD patients (n = 29) when compared to age- and gender-matched healthy controls (n = 70). We revealed a positive correlation (0.378, p = 0.042) between serum levels of Hsp90 and the severity of AD assessed by Scoring Atopic Dermatitis (SCORAD). In addition, seropositivity for anti-Hsp90 IgE has been found in 48.27% of AD patients and in 2.85% of healthy controls. Although further studies on a larger group of patients are needed to confirm presented data, our results suggest that extracellular Hsp90 and autoantibodies to Hsp90 deserve attention in the study of the mechanisms that promote the development and/or maintenance of atopic dermatitis.     

Hsp27 (HSPB1): a possible surrogate molecular marker for loss of heterozygosity (LOH) of chromosome 1p in oligodendrogliomas but not in astrocytomas

In oligodendrogliomas, 1p loss of heterozygosity (LOH) is a predictor of good prognosis and treatment response. In contrast, in uveal melanomas, LOH of chromosome 3 has been linked to poor prognosis and downregulation of Hsp27. In the present study, we have analyzed the expression of heat-shock proteins (Hsps) to characterize subtypes of gliomas and their histopathologic features and to correlate with other molecular markers including LOH of 1p. Biopsies from patients with primary gliomas (n = 65) were analyzed by immunohistochemistry, chromogenic in situ hybridization and fluorescent in situ hybridization and methylation-specific PCR (MSP). Elevated Hsp27 and total Hsp70 expression levels were associated with high-grade astrocytomas (p = 0.0001 and p = 0.01, respectively). In grade III oligodendrogliomas, the Hsp27 levels were significantly higher (p = 0.03). Low O6-methylguanine-DNA methyltransferase (MGMT) expression was associated with grade II astrocytomas. Elevated β-catenin expression was associated with grade III/IV astrocytomas (p = 0.003); p53 (+) tumors were more frequently found in grade III/IV astrocytomas (p = 0,001). LOH on 1p was associated with oligodendroglial tumours. In addition, a higher Hsp27 expression correlated with LOH of 1p (p = 0.017); this was also tested in two glioma cell lines. MSP was successful in only six samples. No significant correlations were found for the other markers. In conclusion, in oligodendroglial tumors, Hsp27 appeared as a surrogate marker of LOH of 1p which could also help to predict the disease prognosis. In gliomas, p53, Hsp27, Hsp70, MGMT, and β-catenin correlated with histopathological characteristics, suggesting that these markers could predict the disease outcome and the response to treatments.     

The level of Hsp27 in lymphocytes is negatively associated with a higher risk of lung cancer

Heat shock proteins (Hsps) can protect cells, organs, and whole organisms against damage caused by abnormal environmental hazards. Some studies have reported that lymphocyte Hsps may serve as biomarkers for evaluating disease status and exposure to environmental stresses; however, few epidemiologic studies have examined the associations between lymphocyte Hsps levels and lung cancer risk. We examined lymphocyte levels of Hsp27 and Hsp70 in 263 lung cancer cases and age- and gender-matched cancer-free controls by flow cytometry. Multivariate logistic regression models were used to estimate the association between lymphocyte Hsps levels and lung cancer risk. Our results showed that Hsp27 levels were significantly lower in lung cancer cases than in controls (16.5 vs 17.8 mean fluorescence intensity, P < 0.001). This was not observed for Hsp70 levels. Further stratification analysis revealed that lymphocyte Hsp27 levels were negatively associated with lung cancer risk especially in males and heavy smokers. There was a statistical trend of low odd ratios (95% confidence intervals) and upper tertile levels of Hsp27 [1.000, 0.904 (0.566–1.444) and 0.382 (0.221–0.658, P _trend = 0.001) in males and 1.000, 0.9207 (0.465–1.822) and 0.419 (0.195–0.897, P _trend = 0.036) in heavy smokers] after adjustment for confounding factors. These results suggest that lower lymphocyte Hsp27 levels might be associated with an increased risk of lung cancer. Our findings need to be validated in a large prospective study. Feng Wang and Maohui Feng contributed equally to this work.     

Selenoproteins and heat shock proteins play important roles in immunosuppression in the bursa of Fabricius of chickens with selenium deficiency

Selenium (Se) is necessary for the immune system in chicken and mediates its physiological functions through selenoproteins. Heat shock proteins (Hsps) are indispensable for maintaining normal cell function and for directing the immune response. The aim of the present study was to investigate the effects of Se deficiency on the messenger ribonucleic acid (mRNA) expression levels of selenoproteins and Hsps as well as immune functions in the chicken bursa of Fabricius. Two groups of chickens, namely the control and Se-deficient (L group) groups, were reared for 55 days. The chickens were offered a basal diet, which contained 0.15 mg Se/kg in the diet fed to the control group and 0.033 mg Se/kg in the diet fed to the L group. We performed real-time quantitative polymerase chain reactionto detect the mRNA expression levels of selenoproteins and Hsps on days 15, 25, 35, 45 and 55. Western blotting was used to determine the protein expression levels of Hsps on days 35, 45 and 55, and immune functions were assessed through an enzyme-linked immunosorbent assay on days 15, 35, and 55. The data showed that the mRNA expression levels of selenoproteins, such as Txnrd1, Txnrd2, Txnrd3, Dio1, Dio2, Dio3, GPx1, GPx2, GPx3 GPx4, Sepp1, Selo, Sel-15, Sepx1, Sels, Seli, Selu, Selh, and SPS2, were significantly lower (P < 0.05) in the L group compared with the control group. Additionally, the mRNA and protein expression levels of Hsps (Hsp27, Hsp40, Hsp60, Hsp70, and Hsp90) were also significantly higher (P < 0.05) in the L group. The expression levels of IL-2, IL-6, IL-8, IL-10, IL-17, IL-1β, IFN-α, IFN-β, and IFN-γ were significantly lower (P < 0.05) and TNF-α was significantly higher (P < 0.05) in the L group compared with the control group. Our results show that immunosuppression was accompanied by a downregulation of mRNA expression levels of selenoproteins and an upregulation of the Hsp mRNA expression levels. Thus, Se deficiency causes defects in the chicken bursa of Fabricius, and selenoproteins and Hsps play important roles in immunosuppression in the bursa of Fabricius of chickens with Se deficiency.     

Genetic association study of intron variants in the forkhead box protein P3 gene in Chinese patients diagnosed with cervical cancer

The aim of this study was to investigate the effects of forkhead box protein P3 (FOXP3) intron single nucleotide variants (SNVs) in high‐risk human papilloma virus (HR‐HPV) infection and cervical cancer (CC) malignant lesions. We performed FOXP3 genotyping in 350 patients with CC and 350 healthy controls using the ImLDR multiple single nucleotide polymorphism genotyping technology. The heterozygous mutation TC in rs2294021 decreased the risk of HR‐HPV infection and CC malignant lesions (TC vs. TT: OR = 0.71, 95% CI = 0.51–0.99); the dominant model TC+CC and allele C in rs2294021 decreased the risk of CC malignant lesions (TC+CC vs. TT: OR = 0.69, 95% CI = 0.50–0.95; C vs. T: OR = 0.78, 95% CI = 0.63–0.97). The heterozygous mutation GA, dominant model GA+AA and allele A in rs3761549 also decreased the risk of HR‐HPV infection and CC malignant lesions (GA vs. GG: OR = 0.70, 95% CI = 0.51–0.96; GA+AA vs. GG: OR = 0.69, 95% CI = 0.51–0.94; A vs. G: OR = 0.75, 95% CI = 0.58–0.96). Patients with CC and HR‐HPV infection carrying rs2294021 TC and rs3761549 GA had lower expression of FOXP3 protein. Haplotype analysis revealed that T‐C‐A decreased the risk of HR‐HPV infection. Furthermore, we found a significant association between immune cells infiltration and prognosis in patients with CC. Our findings demonstrated that rs2294021 and rs3761549 variants may protect against HR‐HPV and CC malignant lesions by downregulating FOXP3 and that FOXP3 was associated with immune cells infiltration, which affected the prognosis of CC.     

Association of chemotactic chemokine ligand 5 rs2107538 polymorphism with tuberculosis susceptibility: A meta-analysis

A meta-analysis was carried out in this study by summarizing relevant research to evaluate the relationship between rs2107538 polymorphism in the chemotactic chemokine ligand 5 (CCL5) gene and tuberculosis (TB) susceptibility. Published studies were retrieved from PubMed, Embase, and CNKI databases using the keywords ‘CCL5’, ‘TB’, and ‘polymorphism’. Nine studies involving 2584 patients with TB and 2265 controls were included in the current meta-analysis. The combined results suggested that the CCL5 rs2107538 polymorphism was correlated with TB susceptibility (recessive model: OR = 1.45, 95% CI = 1.02–2.07). Subgroup analysis according to race indicated that such correlation could be detected in Caucasians (CT versus CC: OR = 1.53, 95% CI = 1.20–1.95; dominant model: OR = 1.58, 95% CI = 1.25–1.99), but not in East Asian, South Asian, and South African populations. In conclusion, the results of our meta-analysis suggest that CCL5 rs2107538 polymorphism might contribute to the risk of TB, especially in Caucasians. Well-designed studies with more subjects will be required for further validation of these results.     

Vitamin D deficiency in chronic inflammatory rheumatic diseases: results of the cardiovascular in rheumatology [CARMA] study

IntroductionThe aim was to study the association between 25-hydroxyvitamin D (25(OH)D) levels and the clinical characteristics of patients with chronic inflammatory rheumatic diseases (CIRD).MethodsWe studied a cross-section from the baseline visit of the CARMA project (CARdiovascular in rheuMAtology), a 10-year prospective study evaluating the risk of cardiovascular events in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients, and non-CIRD patients who attended rheumatology outpatient clinics from 67 hospitals in Spain. Non-CIRD group was frequency matched by age with the joint distribution of the three CIRD groups included in the study. 25(OH)D deficiency was defined if 25(OH)D vitamin levels were < 20 ng/ml.Results2.234 patients (775 RA, 738 AS and 721 PsA) and 677 non-CIRD subjects were assessed. The median (p25-p75) 25(OH)D levels were: 20.4 (14.4-29.2) ng/ml in RA, 20.9 (13.1-29.0) in AS, 20.0 (14.0-28.8) in PsA, and 24.8 (18.4-32.6) ng/ml in non-CIRD patients. We detected 25(OH)D deficiency in 40.5 % RA, 39.7 % AS, 40.9 % PsA and 26.7 % non-CIRD controls (p < 0.001). A statistically significant positive association between RA and 25(OH)D deficiency was found (adjusted (adj.) OR = 1.46; 95 % CI = 1.09-1.96); p = 0.012. This positive association did not reach statistical significance for AS (adj. OR 1.23; 95 % CI = 0.85-1.80) and PsA (adj. OR 1.32; 95 % CI = 0.94-1.84). When the parameters of disease activity, severity or functional impairment were assessed, a marginally significant association between 25(OH)D deficiency and ACPA positivity in RA patients (adj. OR = 1.45; 95 % CI = 0.99-2.12; p = 0.056), and between 25(OH)D deficiency and BASFI in AS patients (adj. OR = 1.08; 95 % CI = 0.99-1.17); p = 0.07) was also found.ConclusionsPatients with RA show an increased risk of having 25(OH)D deficiency compared to non-CIRD controls.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0704-4) contains supplementary material, which is available to authorized users.     

Association between the XRCC1 Polymorphisms and Thyroid Cancer Risk: A Meta-Analysis from Case-Control Studies

Background

The previous published data on the association between the X-ray repair cross-conplementation group 1 (XRCC1) polymorphisms and thyroid cancer risk remained controversial. Hence, we performed a meta-analysis on all available studies that provided 1729 cases and 3774 controls (from 11 studies) for XRCC1 Arg399Gln, 1040 cases and 2487 controls for Arg194Trp (from 7 studies), and 1432 cases and 3356 controls for Arg280His (from 8 studies).

Methodology/Principal Findings

PubMed, CNKI, and EMBASE database were searched to identify relevant studies. Overall, no significant association was found between XRCC1 Arg399Gln (recessive model: OR = 0.95, 95% CI = 0.77–1.15; dominant model: OR = 0.89, 95% CI = 0.75–1.05; homozygote model: OR = 0.92, 95% CI = 0.69–1.23; Heterozygote model: OR = 0.91, 95% CI = 0.80–1.03; additive model: OR = 0.93, 95% CI = 0.81–1.07), Arg194Trp (recessive model: OR = 1.41, 95% CI = 0.62–3.23; dominant model: OR = 1.01, 95% CI = 0.77–1.34; homozygote model: OR = 1.42, 95% CI = 0.55–3.67; Heterozygote model: OR = 1.03, 95% CI = 0.85–1.26; additive model: OR = 1.08, 95% CI = 0.81–1.42), and Arg280His (recessive model: OR = 1.08, 95% CI = 0.56–2.10; dominant model: OR = 1.01, 95% CI = 0.84–1.22; homozygote model: OR = 1.00, 95% CI = 0.51–1.96; Heterozygote model: OR = 1.04, 95% CI = 0.75–1.42; additive model: OR = 1.03, 95% CI = 0.86–1.23) and thyroid cancer risk when all the eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significant association was still not found in these three genetic polymorphisms.

Conclusions/Significance

In summary, this meta-analysis indicates that XRCC1 Arg399Gln, Arg280His, and Arg194Trp are not associated with thyroid cancer.     

Polymorphisms in SPARC and Coal Workers' Pneumoconiosis Risk in a Chinese Population

Background

The SPARC is a crucial matricellular protein and may influence the course of various diseases like tumor metastasis and fibrosis. In the present study, we investigated the association between the potential functional polymorphisms in SPARC and coal workers'' pneumoconiosis (CWP) risk in a Chinese population.

Methods

Five potentially functional polymorphisms (rs1059279, rs1059829, rs1053411, rs2304052 and rs4958281) in SPARC were genotyped and analyzed in a case-control study including 697 CWP cases and 694 controls. The genotyping was used by the TaqMan method with the ABI 7900HT Real Time PCR system.

Results

Our results revealed that three SNPs (rs1059279, rs1059829, rs1053411) were significantly associated with increased risk of CWP under an additive model (OR = 1.35, 95%CI = 1.06–1.71, P = 0.015 for rs1059279; OR = 1.20, 95%CI = 1.03–1.39, P = 0.021 for rs1059829; OR = 1.31, 95%CI = 1.03–1.65, P = 0.025 for rs1053411). In the stratification analysis, significant associations were observed between each of these three SNPs and patients with 0–20 pack-years of smoking (OR = 1.73, 95%CI = 1.21–2.45 for rs1059279; OR = 1.48, 95%CI = 1.07–2.05 for rs105982; OR = 1.58, 95%CI = 1.13–2.22 for rs1053411). Furthermore, the association between rs1059279 and CWP risk remained significant among subjects with over 27 years of exposure (OR = 1.27, 95%CI = 1.03–1.56, P = 0.023). In the combined analysis of these five polymorphisms, individuals with multiple risk alleles had a higher risk of CWP (Ptrend = 0.015).

Conclusion

Our results indicate that three functional SPARC SNPs are associated with an increased risk of CWP in a Chinese population. Further functional research and validation studies with diverse populations are warranted to confirm our findings.     

Association between CYP1A1 Ile462Val Variation and Acute Leukemia Risk: Meta-Analyses Including 2164 Cases and 4160 Controls

Background

Previously, CYP1A1 Ile462Val polymorphism has been indicated to be a risk factor for several malignancies. Increasing reports have focused on the association of CYP1A1 Ile462Val polymorphisms with susceptibility to acute leukemia and have generated controversial results. The goal of the present study was to derive a more precise estimation of the relationship.

Methods

Relevant literature has been rigorously searched and screened. Eligible studies were identified for the period up to Apr 2012. Meta-analyses evaluating the association of CYP1A1 Ile462Val variation with acute leukemia were carried out. Subgroup analyses on ethnicity, clinical types and source of controls were further performed.

Results

A total of thirteen publications including fourteen case-control studies with 2164 cases and 4160 controls were selected for analysis. The overall data indicated a significant association of CYP1A1 Ile462Val polymorphism with acute leukemia risk (Val/Val vs Ile/Ile OR = 1.49; 95% CI = 1.11–1.98; dominant model: OR = 1.26; 95% CI = 1.05–1.51; recessive model: OR = 1.38; 95% CI = 1.04–1.83). In subgroup analysis on ethnicity, increased risk was shown among mixed ethnicities (Val/Val vs Ile/Ile: OR = 2.36; 95% CI = 1.46–3.82; dominant model: OR = 1.37; 95% CI = 1.01–1.86; recessive model: OR = 2.20; 95% CI = 1.37–3.53) but not Asians or Caucasians. In subgroup analysis on clinical types, increased risk was observed in the acute lymphocytic leukemia (ALL) subgroup (Val/Val vs Ile/Ile: OR = 2.06; 95% CI = 1.42–3.01; recessive model: OR = 1.91; 95% CI = 1.32–2.76) but not in the acute myeloid leukemia (AML) subgroup.

Conclusion

The results of the present study suggest that CYP1A1 Ile462Val polymorphism might be a low-penetrant risk factor for acute leukemia. Subgroup analyses suggest that homozygous Val/Val alleles might modify the susceptibility to ALL.     

Association between Chronic Obstructive Pulmonary Disease and Lung Cancer: A Case-Control Study in Southern Chinese and a Meta-Analysis

Background

Lung cancer and chronic obstructive pulmonary disease (COPD) share a common risk factor in cigarette smoking and a large portion of patients with lung cancer suffer from COPD synchronously. We therefore hypothesized that COPD is an independent risk factor for lung cancer. Our aim was to investigate the intrinsic linkage of COPD (or emphysema, chronic bronchitis and asthma) and lung cancer.

Methods

The present hospital-based case-control study included 1,069 patients with newly diagnosed lung cancer and 1,132 age frequency matched cancer-free controls. The odds ratios (ORs) for the associations between each previous pulmonary disease and lung cancer were estimated with logistic regression models, adjusting for age, sex, family history of cancer, BMI and pack year smoking. In meta-analysis, the pooled effects of previous pulmonary diseases were analyzed with random effects models; and stratification analyses were conducted on smoking status and ethnicity.

Results

In the case-control study, previous COPD was associated with the odds for increased risk of lung cancer (OR = 1.29, 95% confidence interval [CI] = 1.00∼1.68); so were emphysema (OR = 1.55, 95%CI = 1.03∼2.32) and chronic bronchitis (OR = 1.22, 95%CI = 0.99∼1.67); while asthma was associated with odds for decreased risk of lung cancer (OR = 0.29, 95%CI = 0.16∼0.53). These associations were more pronounced in smokers (P<.05 for all strata), but not in non-smokers. In meta-analysis, 35 studies (22,010 cases and 44,438 controls) were identified. COPD was significantly associated with the odds for increased risk of lung cancer (pooled OR = 2.76; 95% CI = 1.85–4.11), so were emphysema (OR = 3.02; 95% CI = 2.41–3.79) and chronic bronchitis (OR = 1.88; 95% CI = 1.49–2.36); and these associations were more pronounced in smokers than in non-smokers (P<.001 respectively). No significant association was observed for asthma.

Conclusion

Previous COPD could increase the risk of lung cancer, especially in smokers.     

Selective stimulation of Hsp27 and αB-crystallin but not Hsp70 expression by p38 MAP kinase activation

The levels of Hsp27 and αB-crystallin in C6 rat glioma cells, that had been heated at 43°C for 30 min with a subsequent culture for 16 h at 37°C, were markedly increased. The exposure of the cells to a low concentration (0.1–3 µg/ml) of anisomycin for a few hours after heat stress stimulated the accumulation of the small stress proteins Hsp27 and αB-crystallin, but not that of Hsp70. The levels of mRNAs for Hsp27 and αB-crystallin but not that for Hsp70 increased in cells that had been exposed to heat and subsequently for 2 h to 0.1–3 µg/ml anisomycin. The results of a reporter assay, using an αB-crystallin promotor fused to a luciferase reporter gene, suggested that the increase in level of αB-crystallin mRNA was due to the production of new mRNA. The activation of the binding of heat shock factors to heat shock elements induced in cells that had been heat stressed was barely affected by subsequent exposure to anisomycin at 0.3 µg/ml. The stimulatory effects of anisomycin were also observed in cells that had been exposed to NaAsO₂, or CdCl₂. The active form of p38 mitogen activated protein (MAP) kinase was increased in cell that had been subjected to heat shock and subsequent exposure to 0.3 µg/ml of anisomycin. The heat-induced accumulations of Hsp27 and αB-crystallin were also stimulated by cycloheximide, another stimulator of p38 MAP kinase. SB202190, a specific inhibitor of p38 MAP kinase, suppressed the stimulation by anisomycin of the heat stress-induced expressions of Hsp27 and αB-crystallin. These results suggest that the signal transduction pathway of the stress-induced expressions of Hsp27 and αB-crystallin in C6 glioma cells includes a process that is sensitive to p38 MAP kinase.     

Higher Blood 25(OH)D Level May Reduce the Breast Cancer Risk: Evidence from a Chinese Population Based Case-Control Study and Meta-Analysis of the Observational Studies

Experimental data suggest a protective effect of vitamin D on breast cancer; however, epidemiologic results remain inclusive. With a Chinese population-based case-control study and meta-analysis of the observational studies, we here systematically evaluated the association of blood 25(OH)D level and breast cancer risk. With 593 breast cancer cases and 580 cancer-free controls from Shanghai, China, we found that 80% of the normal women had severe vitamin D deficiency (less than 20 ng/mL) and 15.2% had mild deficiency (20 to 30 ng/mL) and only 4.8% of women had sufficient vitamin D level (>30 ng/mL) while the proportion was 96.1%, 3.2% and 0.7% respectively for the breast cancer patients. Compared to those with the lowest quartile of plasma 25(OH)D level, women with highest quartile 25(OH)D level showed a significant decreased breast cancer risk (Q4 vs.Q1: OR = 0.10, 95% CI = 0.06–0.15) and every 1 ng/ml increment of plasma 25(OH)D level led to a 16% lower odds of breast cancer (OR = 0.84, 95% CI = 0.81–0.87; P<0.001). From the meta-analysis of the observational studies, we found that women with highest quantile of blood 25(OH)D level was associated with a significantly reduced breast cancer risk compared to those with lowest quantile of blood 25(OH)D level for the 11 nested case-control and retrospective studies (pooled OR = 0.86, 95% CI = 0.75–1.00) and 10 case-control studies (7 population based, OR = 0.35, 95% CI = 0.24–0.52; 3 hospital based, OR = 0.08, 95% CI = 0.02–0.33). These results suggest that vitamin D may have a chemo-preventive effect against breast cancer.     

Association of plasma sRAGE,but not esRAGE with lung function impairment in COPD

Rationale

Plasma soluble Receptor for Advanced Glycation End Product (sRAGE) is considered as a biomarker in COPD. The contribution of endogenous sRAGE (esRAGE) to the pool of plasma sRAGE and the implication of both markers in COPD pathogenesis is however not clear yet. The aim of the current study was therefore to measure plasma levels of esRAGE comparative to total sRAGE in patients with COPD and a control group. Further, we established the relations of esRAGE and total sRAGE with disease specific characteristics such as lung function and D_LCO, and with different circulating AGEs.

Methods

Plasma levels of esRAGE and sRAGE were measured in an 88 patients with COPD and in 55 healthy controls. FEV₁ (%predicted) and FEV₁/VC (%) were measured in both groups; D_LCO (%predicted) was measured in patients only. In this study population we previously reported that the AGE N^ϵ-(carboxymethyl) lysine (CML) was decreased, N^ϵ-(carboxyethyl) lysine (CEL) increased and pentosidine was not different in plasma of COPD patients compared to controls.

Results

Plasma esRAGE (COPD: 533.9 ± 412.4, Controls: 848.7 ± 690.3 pg/ml; p = 0.000) was decreased in COPD compared to controls. No significant correlations were observed between plasma esRAGE levels and lung function parameters or plasma AGEs. A positive correlation was present between esRAGE and total sRAGE levels in the circulation. Confirming previous findings, total sRAGE (COPD: 512.6 ± 403.8, Controls: 1834 ± 804.2 pg/ml; p < 0.001) was lower in patients compared to controls and was positively correlated FEV₁ (r = 0.235, p = 0.032), FEV₁/VC (r = 0.218, p = 0.047), and D_LCO (r = 0.308, p = 0.006). sRAGE furthermore did show a significant positive association with CML (r = 0.321, p = 0.003).

Conclusion

Although plasma esRAGE is decreased in COPD patients compared to controls, only total sRAGE showed a significant and independent association with FEV₁, FEV₁/VC and D_LCO, indicating that total sRAGE but not esRAGE may serve as marker of COPD disease state and severity.     

Association between XRCC1 and XRCC3 Polymorphisms with Lung Cancer Risk: A Meta-Analysis from Case-Control Studies

Many studies have reported the association of X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln, Arg194Trp, Arg280His, −77T>C, and X-ray repair cross-complementing group 3 (XRCC3) T241M polymorphisms with lung cancer risk, but the results remained controversial. Hence, we performed a meta-analysis to investigate the association between lung cancer risk and XRCC1 Arg399Gln (14,156 cases and 16,667 controls from 41 studies), Arg194Trp (7,426 cases and 9,603 controls from 23 studies), Arg280His (6,211 cases and 6,763 controls from 16 studies), −77T>C (2,487 cases and 2,576 controls from 5 studies), and XRCC3 T241M (8,560 cases and 11,557 controls from 19 studies) in different inheritance models. We found that −77T>C polymorphism was associated with increased lung cancer risk (dominant model: odds ration [OR] = 1.45, 95% confidence interval [CI] = 1.27–1.66, recessive model: OR = 1.73, 95% CI = 1.14–2.62, additive model: OR = 1.91, 95% CI = 1.24–1.94) when all the eligible studies were pooled into the meta-analysis. In the stratified and sensitive analyses, significantly decreased lung cancer risk was observed in overall analysis (dominant model: OR = 0.83, 95% CI = 0.78–0.89; recessive model: OR = 0.90, 95% CI = 0.81–1.00; additive model: OR = 0.82, 95% CI = 0.74–0.92), Caucasians (dominant model: OR = 0.82, 95% CI = 0.76–0.87; recessive model: OR = 0.89, 95% CI = 0.80–0.99; additive model: OR = 0.81, 95% CI = 0.73–0.91), and hospital-based controls (dominant model: OR = 0.81, 95% CI = 0.76–0.88; recessive model: OR = 0.89, 95% CI = 0.79–1.00; additive model: OR = 0.80, 95% CI = 0.71–0.90) for XRCC3 T241M. In conclusion, this meta-analysis indicates that XRCC1 −77T>C shows an increased lung cancer risk and XRCC3 T241M polymorphism is associated with decreased lung cancer risk, especially in Caucasians.     

Pre-miR-27a rs895819A/G Polymorphisms in Cancer: A Meta-Analysis

Background

MicroRNAs (miRNAs) negatively regulate the 3′ untranslated region (3′-UTR) of coding genes by suppressing translation or degrading mRNAs, and they act as oncogenes or tumor suppressors. Recently, several studies investigated the association between pre-miR-27a rs895819 polymorphism and the risks of various cancers, but the results were inconsistent.

Methodology/Principal Findings

We conducted a meta-analysis of 13 studies that included 6501 cancer cases and 7571 controls to address this association. Overall, this meta-analysis showed that the pre-miR-27a rs895819 A/G polymorphism was not statistically associated with cancers risk in all genetic models. In the stratified analysis by cancer types, when compared with the ancestral A allele, individuals with the variant G allele was consistently associated with reduced risks of breast cancer (OR = 0.92, 95% CI = 0.85–0.99), renal cell cancer (OR = 0.81, 95% CI = 0.67–0.97) and nasopharyngeal cancer (OR = 0.84, 95% CI = 0.72–0.97). Inversely, individuals with the heterozygote AG was associated with an increased risk of digestive tract cancers compared with AA genotype (AG vs. AA: OR = 1.16, 95% CI = 1.01–1.32). In the stratified analysis by ethnicity, the pre-miR-27a rs895819 polymorphism showed statistically significant association with decreased risks of cancers in Caucasians (G vs. A allele: OR = 0.90, 95% CI = 0.83–0.97; AG vs. AA: OR = 0.84, 95% CI = 0.75–0.94; AG/GG vs. AA: OR = 0.85, 95% CI = 0.76–0.94) but not in Asians.

Conclusion/Significance

This meta-analysis suggests that the pre-miR-27a rs895819 polymorphism may contribute to the susceptibilities of some specific-type of cancers, including breast cancer, renal cell cancer, nasopharyngeal cancer and digestive tract cancers, as well as the susceptibilities of cancers in Caucasians to some extent.     

Chronic Obstructive Pulmonary Disease and Altered Risk of Lung Cancer in a Population-Based Case-Control Study

Background

Chronic obstructive pulmonary disease (COPD) has been consistently associated with increased risk of lung cancer. However, previous studies have had limited ability to determine whether the association is due to smoking.

Methodology/Principal Findings

The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study recruited 2100 cases and 2120 controls, of whom 1934 cases and 2108 controls reported about diagnosis of chronic bronchitis, emphysema, COPD (chronic bronchitis and/or emphysema), or asthma more than 1 year before enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. After adjustment for smoking, other previous lung diseases, and study design variables, lung cancer risk was elevated among individuals with a history of chronic bronchitis (OR = 2.0, 95% CI = 1.5–2.5), emphysema (OR = 1.9, 95% CI = 1.4–2.8), or COPD (OR = 2.5, 95% CI = 2.0–3.1). Among current smokers, association between chronic bronchitis and lung cancer was strongest among lighter smokers. Asthma was associated with a decreased risk of lung cancer in males (OR = 0.48, 95% CI = 0.30–0.78).

Conclusions/Significance

These results suggest that the associations of personal history of chronic bronchitis, emphysema, and COPD with increased risk of lung cancer are not entirely due to smoking. Inflammatory processes may both contribute to COPD and be important for lung carcinogenesis.     

Genome-wide identification of heat shock proteins (Hsps) and Hsp interactors in rice: Hsp70s as a case study

Background

Heat shock proteins (Hsps) perform a fundamental role in protecting plants against abiotic stresses. Although researchers have made great efforts on the functional analysis of individual family members, Hsps have not been fully characterized in rice (Oryza sativa L.) and little is known about their interactors.

Results

In this study, we combined orthology-based approach with expression association data to screen rice Hsps for the expression patterns of which strongly correlated with that of heat responsive probe-sets. Twenty-seven Hsp candidates were identified, including 12 small Hsps, six Hsp70s, three Hsp60s, three Hsp90s, and three clpB/Hsp100s. Then, using a combination of interolog and expression profile-based methods, we inferred 430 interactors of Hsp70s in rice, and validated the interactions by co-localization and function-based methods. Subsequent analysis showed 13 interacting domains and 28 target motifs were over-represented in Hsp70s interactors. Twenty-four GO terms of biological processes and five GO terms of molecular functions were enriched in the positive interactors, whose expression levels were positively associated with Hsp70s. Hsp70s interaction network implied that Hsp70s were involved in macromolecular translocation, carbohydrate metabolism, innate immunity, photosystem II repair and regulation of kinase activities.

Conclusions

Twenty-seven Hsps in rice were identified and 430 interactors of Hsp70s were inferred and validated, then the interacting network of Hsp70s was induced and the function of Hsp70s was analyzed. Furthermore, two databases named Rice Heat Shock Proteins (RiceHsps) and Rice Gene Expression Profile (RGEP), and one online tool named Protein-Protein Interaction Predictor (PPIP), were constructed and could be accessed at http://bioinformatics.fafu.edu.cn/.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-344) contains supplementary material, which is available to authorized users.     

Association between MLH1 -93G>A Polymorphism and Risk of Colorectal Cancer

Background

The -93G>A (rs1800734) polymorphism located in the promoter of mismatch repair gene, MLH1, has been identified as a low-penetrance variant for cancer risk. Many published studies have evaluated the association between the MLH1 -93G>A polymorphism and colorectal cancer (CRC) risk. However, the results remain conflicting rather than conclusive.

Objective

The aim of this study was to assess the association between the MLH1 -93G>A polymorphism and the risk of CRC.

Methods

To derive a more precise estimation of the association, a meta-analysis of six studies (17,791 cases and 13,782 controls) was performed. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the association. Four of these published studies were performed on subjects of known microsatellite instability (MSI) status. An additional analysis including 742 cases and 10,895 controls was used to assess the association between the MLH1 -93G>A polymorphism and the risk of MSI-CRC.

Results

The overall results indicated that the variant genotypes were associated with a significantly increased risk of CRC (AG versus GG: OR = 1.06, 95% CI = 1.01–1.11; AA/AG versus GG: OR = 1.06, 95% CI = 1.01–1.11). This increased risk was also found during stratified analysis of MSI status (AA versus GG: OR = 2.52, 95% CI = 1.94–3.28; AG versus GG: OR = 1.29, 95% CI = 1.10–1.52; AA/AG versus GG: OR = 1.45, 95% CI = 1.24–1.68; AA versus AG/GG: OR = 2.29, 95% CI = 1.78–2.96). Egger’s test did not show any evidence of publication bias.

Conclusion

Our results suggest that the MLH1 -93G>A polymorphism may contribute to individual susceptibility to CRC and act as a risk factor for MSI-CRC.