Disease Markers - Volume 30, issue 5

Authors: Antczak, Adam | Piotrowski, Wojciech | Marczak, Jerzy | Ciebiada, Maciej | Gorski, Pawel | Barnes, Peter J.

Article Type: Research Article

Abstract: Exhaled breath condensate (EBC) has been increasingly used as a new and non-invasive method to study airway inflammation. In this study we have compared the concentrations of lipid mediators in EBC with concentrations in bronchoalveolar lavage fluid (BALF). We included 37 patients undergoing bronchoscopy (12 sarcoidosis, 12 COPD, 6 lung cancer, 5 chronic cough, 1 Wegener's granulomatosis, 1 sclerodermia). Patients were not allowed to have exacerbation or any change in concomitant medication for at …least 4 weeks prior to the study. In all patients, EBC was collected immediately prior to the bronchoscopy. The levels of cys-LTs, LTB_{4} , 8-isoprostane were significantly higher in BALF compared to EBC (p < 0.0001, p< 0.001, p< 0.0001 for cys-LTs, LTB4, 8-isoprostane respectively). Moreover, there was a strong positive correlation between both leukotriene B_{4} and 8-isoprostane in BALF and EBC (r=0.53 and r=0.79, p< 0.01, respectively) in patients with sarcoidosis and COPD but there was no correlation between eicosanoids BALF and EBC in patients with chronic cough and lung cancer. This is the first study to compare EBC and BALF in different lung diseases which demonstrated significant correlations between the levels of eicosanoids in BALF and EBC in patients with COPD and sarcoidosis. EBC may be useful in measuring inflammation in several inflammatory lung diseases. Show more

Keywords: Cysteinyl-leukotrienes, 8-isoprostane, prostaglandin E_{2}, exhaled breath condensate, bronchoalveolar lavage, bronchoscopy

DOI: 10.3233/DMA-2011-0776

Citation: Disease Markers, vol. 30, no. 5, pp. 213-220, 2011

Authors: Etienne, Gabriel | Dupouy, Maryse | Costaglioli, Patricia | Chollet, Claudine | Lagarde, Valérie | Pasquet, Jean-Max | Reiffers, Josy | Garbay, Bertrand | Mahon, François-Xavier | Turcq, Béatrice

Article Type: Research Article

Abstract: Objective: Imatinib mesylate is a tyrosine kinase inhibitor used as first line treatment in chronic myeloid leukaemia. Despite a remarkable effectiveness, treatment failure cases have been reported in 20 percent of CML patients. The identification of biomarkers which can predict the response to imatinib is our point of interest. Methods: Gene expression profiling microarray was carried out on secondary imatinib resistant patients. Longitudinal studies were performed on imatinib treated responder/resistant …patients. Then, Q-RT/PCR studies were realized on patients prior imatinib initiation. Results: For imatinib responder patients, we observed a strong and lasting decrease of α-defensin 1-3 and α-defensin 4 expression. For relapse patients, we observed a dramatic increase of α-defensin 1-3 and α-defensin 4 expression before BCR-ABL transcript increase. Moreover, before imatinib initiation, α-defensin 1-3 and α-defensin 4 expression was significantly lower in the resistant group than in the responder group. Conclusion: The variation of expression of α-defensin 1-3 and α-defensin 4 in peripheral blood is associated with imatinib resistance and may reflect an adequate immune control of the disease. Monitoring of α-defensin 1-3 and α-defensin 4 could be helpful to predict the patients who are not going to respond to the treatment. Show more

Keywords: Chronic myeloid leukaemia, imatinib resistance, α-defensin, predictive biomarker

DOI: 10.3233/DMA-2011-0777

Citation: Disease Markers, vol. 30, no. 5, pp. 221-227, 2011

Authors: Heiduschka, Gregor | Erovic, Boban M. | Pammer, Johannes | Kotowski, Ulana | Kaider, Alexandra | Ch. Grasl, Matthaeus | Thurnher, Dietmar

Article Type: Research Article

Abstract: The anti-apoptotic protein Mcl-1 is highly expressed in various types of malignant tumors. Overexpression is reported to correlate with poor prognosis and disease progression. We report the expression levels of Mcl-1 in tumor samples of the parotid gland. A retrospective study containing 108 patients was performed. A tissue microarray of six malignancies of the parotid gland and pleomorphic adenoma as control was constructed. Parotid gland tumor samples were immunohistochemically stained for Mcl-1 and expression intensities …were assessed. Statistical analysis included correlation to patients' clinical data and comparison of malignancies to the adenoma. All malignancies had significantly higher expression of Mcl-1 than the pleomorphic adenomas. The intensity, however, had no significant correlation to overall survival. Our immunohistochemical findings indicate that parotid gland malignancies produce high levels of Mcl-1 protein. Therefore, Mcl-1 might serve as a predictive co-marker in tumors of the parotid gland. Show more

Keywords: Mcl-1, cancer, parotid, salivary gland, head and neck

DOI: 10.3233/DMA-2011-0779

Citation: Disease Markers, vol. 30, no. 5, pp. 229-233, 2011

Authors: Ahmad, Jamal | Gupta, Anuj | Alam, Khursheed | Farooqui, Khalid Jamal

Article Type: Research Article

Abstract: Aims: The vascular tissues have a long memory of their previous glycemic control and intervention studies have demonstrated that microvascular complications are highly correlated with mean glycemic control as measured by glycolated hemoglobin A_{1} C (HbA_{1} c). The present study was carried out to evaluate the autoantibodies against glycosylated DNA (DNA-AGEs) in diabetic sera to see if the level of HbA1c has correlation with the activity of DNA-AGEs, another marker of chronic glycemia. …Methods: Glucose-6-phosphate induced glycosylation of native DNA was studied in 150 diabetic sera (T1DM=9, T2DM=141) by spectroscopic techniques (UV and fluorescence) and agarose gel electrophoresis. Direct binding and inhibition enzyme immunoassays were carried out to evaluate binding and specificity of anti-glycated-DNA autoantibodies (anti-DNA-AGE autoantibodies) in sera of diabetes patients. A quantitative estimation of HbA_{1c} was carried out in normal and diabetes sera. Results: Anti-DNA-AGEs autoantibodies in 55% of diabetic sera (85/150) showed more binding with glycated-DNA compared to native DNA which was subjected to inhibition ELISA indicating true interaction of these autoantibodies in diabetes with glycated DNA. Higher binding with glycosylated-DNA against native-DNA was observed in subjects with HbA1c of 9.8 ± 3.3% compared to those with HbA1c of 7.7 ± 1.7% (p< 0.001). Linear correlation analysis showed that mean absorbance difference was significantly related to HbA1c (r=0.486, p< 0.001), nephropathy (r= 0.239, p< 0.003), retinopathy (r=0.165, p< 0.05). Conclusions: Autoantibodies against glycosylated DNA were correlated with HbA_{1} c and microvascular complications and may be useful as another biomarker for assessment of chronic glycemia. Show more

Keywords: Autoantibodies, glycosylated-DNA, diabetes mellitus

DOI: 10.3233/DMA-2011-0780

Citation: Disease Markers, vol. 30, no. 5, pp. 235-243, 2011

Authors: Bergheanu, Sandrin C. | van der Laarse, Arnoud | van der Bom, Johanna G. | van der Hoeven, Bas L. | le Cessie, Saskia | de Jong, Margreet G. | Liem, Su-San | Schalij, Martin J. | Jukema, J. Wouter

Article Type: Research Article

Abstract: High Asymmetric Dimethylarginine (ADMA) levels are associated with increased platelet activity, elevated blood pressure, vasoconstriction and impaired vascular relaxation. We hypothesized that the myocardial infarction morning peak of occurrence is closely related to a morning peak of ADMA levels. We performed a cross-sectional study among patients with documented myocardial infarction who had been enrolled in the prospective MISSION! Intervention Study. In total, serum ADMA levels were measured in their acute setting of …myocardial infarction in 120 patients. The frequency of myocardial infarction onset of symptoms and emergency coronary catheterization and the ADMA levels displayed a similar daily pattern with a morning peak between 06:00–11:59 h. The absolute ADMA levels peak was between 06:00–07:59 h with a median (interquartile range) peak value of 1.01 (0.84–1.21) μmol/L for the n=9 patients vs. 0.75 (0.61–0.89) μmol/L for the remaining 111 patients admitted throughout the rest of the 24-hour interval (p=0.003 for between groups comparison). The amplitude (95% 0.08 μmol/L (0.004–0.16) with p=0.042 for statistic model significance. In conclusion, ADMA levels display a 24-hour variation with a significant morning peak in patients with acute myocardial infarction. These findings may relate ADMA levels to the acute onset of thrombotic cardiovascular events. Show more

Keywords: Asymmetric dimethylarginine, myocardial infarction, circadian rhythm, platelets, thrombosis

DOI: 10.3233/DMA-2011-0781

Citation: Disease Markers, vol. 30, no. 5, pp. 245-252, 2011

Authors: Lakhdar, Ramzi | Denden, Sabri | Knani, Jalel | Leban, Nadia | Daimi, Houria | Hassine, Mohsen | Lefranc, Gérard | Chibani, Jemni Ben | Khelil, Amel Haj

Article Type: Research Article

Abstract: Smoking is considered as the major causal factor of chronic obstructive pulmonary disease (COPD). Nevertheless, a minority of chronic heavy cigarette smokers develops COPD. This suggests important contribution of other factors such as genetic predisposing. Our objective was to investigate combined role of EPHX1, GSTP1, M1 and T1 gene polymorphisms in COPD risk, its phenotypes and lung function impairment. Prevalence of EPHX1, GSTP1, M1 and T1 gene polymorphisms were assessed in 234 COPD patients and 182 …healthy controls from Tunisia. Genotypes of EPHX1 (Tyr113His; His139Arg) and GSTP1 (Ile105Val; Ala114Val) polymorphisms were performed by PCR-RFLP, while the deletion in GSTM1 and GSTT1 genes was determined using multiplex PCR. Analysis of combinations showed a significant association of 113His/His EPHX1/null-GSTM1 (OR=4.07) and null-GSTM1/105Val/Val GSTP1 (OR =3.56) genotypes with increased risk of COPD (respectively P=0.0094 and P=0.0153). The null-GSTM1/ null-GSTT1, 105Val/Val GSTP1/null GSTT1, 113His/His EPHX1/null-GSTM1 and null-GSTM1/105Val/Val GSTP1 genotypes were related to emphysema (respectively P=0.01; P=0.009; P=0.008 and P=0.001). Combination of 113His/His EPHX1/null-GSTM1 genotypes showed a significant association with the decrease of Δ FEV1 in patients (P =0.028). In conclusion, our results suggest combined EPHX1, GSTP1, GSTM1 and GSTT1 genetic polymorphisms may play a significant role in the development of COPD, emphysema and decline of the lung function. Show more

Keywords: Chronic obstructive pulmonary disease, microsomal epoxide hydrolase, glutathione S-transferase, emphysema, genetic polymorphism

DOI: 10.3233/DMA-2011-0782

Citation: Disease Markers, vol. 30, no. 5, pp. 253-263, 2011

Authors: Mitrovič, Mitja | Potočnik, Uroš

Article Type: Research Article

Abstract: Inflammatory bowel diseases (IBD) are usually classified into Crohn's disease (CD) and ulcerative colitis (UC). NOD2/CARD15 was the first identified CD-susceptibility gene and was confirmed as the most potent disease gene in CD pathogenesis. Three NOD2/CARD15 variants, namely two missense polymorphisms R702W (rs2066844) and G908R (rs2066845), and a frame shift polymorphism L1007fs (rs2066847), were associated with CD in Caucasian populations. High resolution melting analysis (HRMA) with saturation LCGreen dyes was previously reported …as a simple, inexpensive, accurate and sensitive method for genotyping and/or scanning of rare variants. For this reasons we used qPCR-HRMA for genotyping NOD2/CARD15 variants in 588 Slovenian IBD patients and 256 healthy controls. PCR-RFLP was used as a reference method for genotyping of clinical samples. The optimization of an HRM experiment required careful design and adjustment of main parameters, such as primer concentration, MgCl_{2} concentration, probe design and template DNA concentration. Different HRMA approaches were tested and used to develop a reliable and low-cost SNP genotyping assays for polymorphisms in NOD2/CARD15 gene. Direct HRMA was the fastest and cheapest HRMA approach for L1007fs and R702W polymorphisms, yet for G908R polymorphism sufficient reliability was achieved after introduction of unlabeled probe. In association analysis, we found statistically significant association of L1007fs (p =0.001, OR=3.011, CI95%=1.494–6.071) and G908R (p=2.62 × 10^{-4} , OR=14.117, CI95%= 1.884–105.799) polymorphisms with CD patients. At least one of NOD2/CARD15 polymorphisms was found in 78/354 (22.03% (12.69%) in UC patients and in 26/256 (10.15%) in healthy controls. We have successfully implemented NOD2/CARD15 HRMA assays, which may contribute to the development of genetic profiles for risk prediction of developing CD and for differential diagnosis of CD vs. UC. Show more

Keywords: High-resolution melting analysis, NOD2/CARD15, inflammatory bowel diseases

DOI: 10.3233/DMA-2011-0783

Citation: Disease Markers, vol. 30, no. 5, pp. 265-274, 2011