Disease Markers - Volume 23, issue 3

Authors: Laine, Antti-Pekka | Holmberg, Hanna | Nilsson, Anita | Örtqvist, Eva | Kiviniemi, Minna | Vaarala, Outi | Åkerblom, Hans K. | Simell, Olli | Knip, Mikael | Ludvigsson, Johnny | Ivarsson, Sten-A | Larsson, Karin | Lernmark, Åke | Ilonen, Jorma

Article Type: Research Article

Abstract: We have developed high-throughput tests for the detection of the insulin gene region SNPs −23HphI and −2221MspI. The potential of these markers to enhance the efficiency of type 1 diabetes risk screening was then evaluated by analyzing them in Finnish and Swedish populations. Blood spots on filter paper were analyzed using PCR followed by sequence-specific hybridization and time-resolved fluorometry reading. Distribution of the genotypes at both positions differed significantly among the affected …children compared to the controls. The risk genotypes (CC, AA) were significantly more common in Finland than in Sweden, both among patients and controls. The VNTR genotype homozygous for the protective class III alleles showed a significantly stronger protective effect than the heterozygote (p=0.02). Analyzing both SNPs enabled the detection of VNTR class III subclasses IIIA and IIIB. The observed significance between effects of the protective genotypes was due to the strong protective effect of the IIIA/IIIA genotype. IIIA/IIIA was the only genotype with significant discrepancy between protective effects compared to the other class III genotypes. These observations suggest that heterogeneity between the protective IDDM2 lineages could exist, and analyzing both −23HphI and −2221MspI would thus potentially enhance the sensitivity and specificity of type 1 diabetes risk estimation. Show more

Keywords: Type 1 diabetes, insulin gene region, Finnish population, screening for genetic risk

Citation: Disease Markers, vol. 23, no. 3, pp. 139-145, 2007

Authors: Hsieh, Tzu-Feng | Yu, Ken-Jen | Lin, Shan-Yang

Article Type: Research Article

Abstract: There is lack of a worldwide standard technique for clinical diagnosis of interstitial cystitis (IC). Raman spectroscopy with higher specificity and sensitivity has been extensively used to act as a non-destructive analytical technique without special sample preparation. In this preliminary study, possible use of Raman microspectroscopy as an IC diagnostic tool was attempted. Twenty-two participants were screened by clinical features, history, urodynamic evaluations and potassium sensitivity test (PST). The freeze-dried water samples …voided from all the participants after PST were directly determined by using a confocal Raman microspectroscopy to search the biomarker. Participants with or without IC symptom were separated into control and clinical groups, according to the above screening. The participants in the clinical group were further divided into mild and severe subgroups by PST. The symptom of urinary pain and urgency was significant difference between the mild and severe subgroups (p<0.05). A significant increase in urinary frequency but a marked reduction in bladder capacity, maximum cystometric capacity and maximum voiding flow rate were obtained for clinical group of IC participants, as compared with the result of control group (p<0.05). By using Raman microspectroscopic determination, the band near 1003 or 1005 cm^{-1} assigned to phenylalanine was respectively detected from the freeze-dried water sample of control group or mild subgroup, but the band at 1010 cm^{-1} due to tryptophan was found in the freeze-dried water sample of severe subgroup. The result of this preliminary study first suggests a possible application of Raman microspectroscopy to strongly certify the results of PST for IC diagnosis. Phenylalanine or tryptophan might be acted as a biomarker to assist the diagnosis of IC after PST. Particularly, the appearance of tryptophan might be used to discriminate the severity of IC symptom. Show more

Keywords: Interstitial cystitis, potassium sensitivity test, Raman microspectroscopy, phenylalanine, tryptophan

Citation: Disease Markers, vol. 23, no. 3, pp. 147-152, 2007

Authors: Tsai, Wen-Chiuan | Chao, You-Chen | Sheu, Lai-Fa | Chang, Junn-Liang | Nieh, Shin | Jin, Jong-Shiaw

Article Type: Research Article

Abstract: Objective: Fascin-1 is an actin-binding protein that promotes cell proliferation, adhesion and motility. We tested the hypothesis that fascin-1 expression correlates with clinicopathological parameters of colorectal adenocarcinomas. Methods: Immunohistochemical analysis of fascin-1 was performed in tissue microarrays of 91 surgical specimens, including 32 well, 33 moderately, and 26 poorly differentiated colorectal adenocarcinomas; and in 22 specimens from colorectal adenomas with dysplasia. Results: Scattered fascin-1 expression was demonstrated in 9 …control specimens of normal colonic glandular epithelia. Higher fascin-1 immunostaining scores were significantly associated with advanced dysplasia in colorectal adenomas (mild 4.2 ± 1.3, moderate 13.5 ± 5.3, and severe 22.5 ± 6.7) and high-grade histopathological differentiation of colorectal adenocarcinomas (grade I 88.6 ± 9, grade II 101 ± 11, and grade III 144 ± 13). Higher immunostaining scores of fascin-1 were also significantly associated with advanced T stage (T1: 42 ± 10, T2: 60 ± 12, T3: 108 ± 12, and T4: 142 ± 15). Higher fascin-1 scores were related with more advanced M and N stages of colorectal carcinomas, but not significant correlation. Conclusions: Higher expression of fascin-1 correlates significantly with tumor grades and TNM stages in colorectal adenocarcinomas and also with levels of dysplastic change in colorectal adenomas. Show more

Keywords: Colorectal cancer, colorectal adenoma, fascin-1, immunostaining scores, tissue microarray

Citation: Disease Markers, vol. 23, no. 3, pp. 153-160, 2007

Authors: Cagatay, Penbe | Susleyici-Duman, Belgin | Ciftci, Cavlan

Article Type: Research Article

Abstract: Our aim was to determine whether lipoprotein lipase gene PvuII polymorphism can be considered as an independent risk factor for coronary artery disease (CAD) by conducting a meta-analysis of all available published trials, including our own study. In 7 seperate studies, 3289 subjects were screened for this substitution; meta-analysis included only some of these individuals. Among the 7 studies, 6 were performed on white subjects, whereas 1 was on patients with Saudi Arabic descent.Subgroup analysis indicated …that individuals with PvuII substitution does not have an increased risk for CAD. The LPL-PvuII genotype and allele frequency distributions did not differ significantly between CAD patients and healthy controls. There was no difference in the distribution of LPL-PvuII genotypes between the healthy subjects and the patients with CAD. However, no significant differences in lipid variables (triglyceride and HDL-cholesterol) were determined for the PvuII polymorphisms in the patients with CAD. No significant differences were found in serum triglyceride and HDL-cholesterol levels for LPL-PvuII genotypes when the control and CAD groups were pooled. In conclusion, LPL-Pvu II polymorphism cannot be used as independent genetic risk factor for CAD. Show more

Keywords: Lipoprotein lipase, coronary artery disease, genetic polymorphism, meta-analysis

Citation: Disease Markers, vol. 23, no. 3, pp. 161-166, 2007

Authors: Neşe, Nalan | Çaǧırgan, Seçkin | Ertan, Yešim | Sönmez, Ayhan | Soydan, Saliha | Hekimgil, Mine

Article Type: Research Article

Abstract: Systemic mastocytosis is a disease characterized by multifocal mast cell proliferation in the bone marrow or other extracutaneous organs. Because of loosely scattered and hypo-/agranular mast cells, the diagnosis is sometimes very difficult. In the bone marrow, mast cell infiltration may be associated with prominent lymphoid infiltration leading to a misdiagnosis of a low grade non-Hodgkin lymphoma. A 49-year-old woman presented with right arm and leg pain, psychiatric symptoms, and diarrhea for four years. …Physical examination and laboratory investigation revealed hepatosplenomegaly, anemia, mild thrombocytosis, mild leucocytosis and lymphocytosis. In the bone marrow biopsy, there was a prominent B lymphocyte proliferation reminiscent of a low grade non-Hodgkin lymphoma/leukemia and there were some spindle cells aggregates in paratrabecular location. The consecutive bone marrow biopsies were similar to the first. The subsequent splenectomy specimen exhibited striking fibrosis. In the lymph node sections, there was marginal zone hyperplasia. Multifocal accumulations of mast cells were strongly positive with mast cell tryptase and CD117 on immunohistochemical staining, though no metachromasia was identified in Giemsa and Toluidine Blue stained aspirates and tissue sections, probably due to hypo-/agranulation of mast cells. The case was presented to emphasize the importance of the antibody to mast cell tryptase in the diagnosis of mastocytosis and to discuss problems of differential diagnosis of systemic mastocytosis. Show more

Keywords: Systemic mastocytosis, fibrosis of spleen, mast cell tryptase, smoldering variant

Citation: Disease Markers, vol. 23, no. 3, pp. 167-171, 2007

Authors: Yeboah, Joseph | Sane, David C. | Crouse, John R. | Herrington, David M. | Bowden, Donald W.

Article Type: Research Article

Abstract: Objective: We tested associations of the growth factors VEGF, FGF-2, HGF and PDGF-BB with coronary artery calcium scores and cardiovascular events (CVD) in type 2 diabetes mellitus (T2DM). Methods: A cross-sectional study selected 40 frequency matched (by age, gender and race) subjects with T2DM from the first (0–111) and the third (> 1400) coronary artery calcium (CAC) score tertiles in the Diabetes Heart Study (DHS), in which 36 were with and 41 were without …history of CVD events. Plasma levels of VEGF, FGF-2, HGF and PDGF-BB were measured in all subjects. Results: None of the growth factors was significantly different between the first and third CAC score tertiles. Mean plasma FGF-2 and PDGF-BB levels were significantly higher in the group without prior CVD events compared with the group with prior CVD events [mean(95%CI): 219.20 (194.42–247.15) vs. 152.93 (135.64–172.43) pg/ml, p=0.03] and [mean(95%CI): 106.70 (89.12–127.74) vs. 61.56 (50.91–74.44) pg/ml, p=0.03], respectively. Subgroup analysis in the first CAC tertile showed a significantly higher PDGF-BB levels in those without compared with those with CVD events [mean (95%CI): 208.36 (190.57–228.15) vs. 102.93 (80.64–125.21) pg/ml, p=0.004]. Conclusion: Plasma growth factor levels were not significantly different between the extremes of CAC scores in T2DM. However, low plasma levels of PDGF-BB and FGF-2 are associated with prior cardiovascular events in T2DM. Studies are needed to confirm our results and also to establish temporality of this association. Show more

Keywords: Diabetes mellitus, macrovascular complications, angiogenic factors, growth factors, cardiovascular events

Citation: Disease Markers, vol. 23, no. 3, pp. 173-178, 2007

Authors: Pedroni, M. | Roncari, B. | Maffei, S. | Losi, L. | Scarselli, A. | Di Gregorio, C. | Marino, M. | Roncucci, L. | Benatti, P. | Ponti, G. | Rossi, G. | Menigatti, M. | Viel, A. | Genuardi, M. | de Leon, M. Ponz

Article Type: Research Article

Abstract: Hereditary NonPolyposis Colorectal Cancer (Lynch syndrome) is an autosomal dominant disease caused by germline mutations in a class of genes deputed to maintain genomic integrity during cell replication, mutations result in a generalized genomic instability, particularly evident at microsatellite loci (Microsatellite Instability, MSI). MSI is present in 85–90% of colorectal cancers that occur in Lynch Syndrome. To standardize the molecular diagnosis of MSI, a panel of 5 microsatellite markers was proposed (known as …the "Bethesda panel"). Aim of our study is to evaluate if MSI testing with two mononucleotide markers, such as BAT25 and BAT26, was sufficient to identify patients with hMLH1/hMSH2 germline mutations. We tested 105 tumours for MSI using both the Bethesda markers and the two mononucleotide markers BAT25 and BAT26. Moreover, immunohistochemical evaluation of MLH1 and MSH2 proteins was executed on the tumours with at least one unstable microsatellite, whereas germline hMLH1/hMSH2 mutations were searched for all cases showing two or more unstable microsatellites. The Bethesda panel detected more MSI(+) tumors than the mononucleotide panel (49.5% and 28.6%, respectively). However, the mononucleotide panel was more efficient to detect MSI(+) tumours with lack of expression of Mismatch Repair proteins (93% vs 54%). Germline mutations were detected in almost all patients whose tumours showed MSI and no expression of MLH1/MSH2 proteins. No germline mutations were found in patients with MSI(+) tumour defined only through dinucleotide markers. In conclusion, the proposed mononucleotide markers panel seems to have a higher predictive value to identify hMLH1 and hMSH2 mutation-positive patients with Lynch syndrome. Moreover, this panel showed increased specificity, thus improving the cost/effectiveness ratio of the biomolecular analyses. Show more

Keywords: MSI, HNPCC, colorectal cancer, MLH1, MSH2

Citation: Disease Markers, vol. 23, no. 3, pp. 179-187, 2007

Authors: Decock, J. | Hendrickx, W. | Drijkoningen, M. | Wildiers, H. | Neven, P. | Smeets, A. | Paridaens, R.

Article Type: Research Article

Abstract: Objective: Aberrant expression of individual matrix metalloproteinases has been associated with poor prognosis in various human carcinomas. The current study aimed at defining an RNA expression profile of various MMPs in breast cancer and correlating their expression with clinicopathological parameters. Methods: The RNA expression patterns of 6 MMPs (MMP2, MMP8, MMP9, MMP10, MMP11, MMP13) were determined in 25 breast carcinomas using quantitative RT-PCR and correlated with clinicopathological parameters, including menopausal …status, tumor size and grade, and lymph node involvement. Results: We observed high MMP2 levels more frequently in premenopausal than in postmenopausal women (p=0.02). Analysis of luminal A type invasive ductal carcinomas (19/25), revealed an even stronger association of MMP2 with menopausal status (p=0.005). Within this subgroup, we also found a correlation between MMP11 and menopausal status (p=0.02). No correlation was found between MMP expressions and other clinicopathological parameters. In co-expression analyses MMP2-MMP10 and MMP8-MMP9 showed a weak correlation of their expression. Conclusions: Although this is a pilot study, our findings indicate that luminal A invasive ductal carcinomas commonly express high MMP2 and MMP11 levels in premenopausal breast cancer patients and suggest a co-regulation of MMP2-MMP10 and MMP8-MMP9. Show more

Keywords: Breast cancer, matrix metalloproteinases, menopausal status, luminal A, clinicopathological parameters

Citation: Disease Markers, vol. 23, no. 3, pp. 189-196, 2007