Isabela J. Wastowski

Percival D. Sampaio-Barros

Gustavo Martelli-Palomino

Jo&#xe3;o Francisco Marques-Neto

Janaina C. O. Crispim

Diane M. Rassi

Eduardo A. Donadi

Association of Interferon-Gamma Gene Polymorphism (&#x2B;874 T/A) with Systemic Sclerosis

Due to the highly glycolytic metabolism of solid tumours, there is an increased acid production, however, cells are able to maintain physiological pH through plasma membrane efflux of the accumulating protons. Acid efflux through MCTs (monocarboxylate transporters) constitutes one of the most important mechanisms involved in tumour intracellular pH maintenance. Still, the molecular mechanisms underlying the regulation of these proteins are not fully understood. We aimed to evaluate the association between CD147 (MCT1 and MCT4 chaperone) and MCT expression in cervical cancer lesions and the clinico-pathological significance of CD147 expression, alone and in combination with MCTs. The series included 83 biopsy samples of precursor lesions and surgical specimens of 126 invasive carcinomas. Analysis of CD147 expression was performed by immunohistochemistry. CD147 expression was higher in squamous and adenocarcinoma tissues than in the non-neoplastic counterparts and, importantly, both MCT1 and MCT4 were more frequently expressed in CD147 positive cases. Additionally, co-expression of CD147 with MCT1 was associated with lymph-node and/or distant metastases in adenocarcinomas. Our results show a close association between CD147 and MCT1 and MCT4 expressions in human cervical cancer and provided evidence for a prognostic value of CD147 and MCT1 co-expression.

C&#xe9;line Pinheiro

Adhemar Longatto-Filho

S&#xf4;nia Maria Miranda Pereira

Daniela Etlinger

Marise A. R. Moreira

Luiz Fernando Jub&#xe9;

Geraldo Silva Queiroz

Fernando Schmitt

F&#xe1;tima Baltazar

Monocarboxylate Transporters 1 and 4 Are Associated with CD147 in Cervical Carcinoma

The presence of HLA-B&#x2a;27 allele with patients suspected with ankylosing spondylitis can be used in the diagnostic process. We have developed an assay for typing for the HLA-B&#x2a;27 in whole blood dried on sample collection cards using pre-dried reagent wells and homogeneous time-resolved fluorescence based PCR approach. Essentially only the sample needs to be added to the dry ready-to-use reaction well in order to start the homogenous amplification assay. The method was validated with 229 samples also typed with an existing DELFIA-based method and results of both assays were 100&#x25; concordant. The dried reagents were shown to be stable at least up to eight weeks at room temperature without any decline in their performance.

Minna Kiviniemi

Jorma Ilonen

Timo L&#xf6;vgren

A Homogeneous HLA-B&#x2a;27 Genotyping Assay Using Dried Reagent Mixtures

Objective: To evaluate the possible relationship between HLA alleles and bony ankylosis of the spine (bamboo spine) in Taiwanese patients with ankylosing spondylitis (AS).Methods: A small cohort of HLA-B27 positive AS patients was conducted to analyze the effects of alleles and haplotypes on the development of bamboo spine. DNA typing of HLA class I and class II genes were performed by SSP method on primary ankylosing spondylitis patients with bamboo spine (n = 84) and spinal enthesopathy controls (n = 228). Odds ratios with 95&#x25; confidence intervals and P value were estimated. Determination of the most probable HLA haplotypes on all patients were constructed by comparison of the alleles carried by each patient with the HLA haplotype database established in Taiwanese population studies using homozygosity approach [1] and by expectation-maximum algorithm [2].Results: Allele frequencies of HLA A33, B58, Cw10, DR4, DR17 and DQ2 were significantly lower in bamboo patients as compared to non-bamboo controls. In contrast, allele frequencies of A24, B54, Cw15, DR11 and DR14 were significantly higher in bamboo patients. Less remarkably, high frequencies of B39, B51, Cw1 and Cw2 alleles were also noted in bamboo patients. Considering linkage disequilibria of alleles in haplotypes, HLA-A11-B27-Cw12 was the most common haplotype in both bamboo and non-bamboo groups (95.23&#x25; vs. 91.22&#x25;, respectively, P = 0.238). Haplotypes A33-B58-Cw10, A33-B58-Cw10-DR13 and A33-B58-Cw10-DR17 were significantly lower in bamboo patients as compared to those in controls (P &#60; 0.001, P = 0.001, P = 0.002, respectively).Conclusion: Haplotypes A33-B58-Cw10, A33-B58-Cw10-DR13 and A33-B58-Cw10-DR17 showed a strong association with bamboo spine in Taiwanese AS patients. Detection of such haplotypes might be a great aid in the management of patients with the disease.

Ming-Chi Lu

Kuo-Liang Yang

Kuang-Yung Huang

Chien-Hsueh Tung

Su-Qin Liu

Ning-Sheng Lai

HLA Haplotype A33-B58-Cw10 May Modulate Radiographic Development of Bamboo Spine in Taiwanese Patients with Primary Ankylosing Spondylitis

Objective: Melanoma associated antigens-A (MAGE-A) expression is highly specific to cancer cells. Thus, they can be the most suitable targets for the diagnosis of malignancy. The aim of this study was to evaluate the sensitivity of multiple MAGE-A expression analysis for the diagnosis of oral squamous cell carcinoma (OSCC).Methods: Total of 70 OSSC and 20 normal oral mucosal (NOM) samples of otherwise healthy volunteers were examined for the expression of 10 different single antigens out of 12 different MAGE-A subtypes by highly sensitive reverse transcriptase polymerase chain reaction (RT-PCR) methods. The results were correlated to clinicopathological parameters of tumor samples.Results: Expression of MAGE-A was restricted to OSCC. The expression frequency of single antigen was between 10&#x25; and 55&#x25;. However, expression rate was increased up to 93&#x25; by the elevated number of genes examined. A significant correlation was found between the expression of MAGE-A and malignancy (p &#x3D; 0.0001). In addition, multiple MAGE-A detection has also correlated to the incidence of lymph node metastasis, grading and advanced clinical stages.Conclusions: Analysis of multiple MAGE-A expression is more sensitive than the analysis of a single MAGE-A for the diagnostic evaluation of OSCC. Multiple MAGE-A expression analysis may be a very sensitive method to be used for the diagnosis even in the early stage of OSCC.

Jutta Ries

Nur Mollaoglu

Takeshi Toyoshima

Eleftherios Vairaktaris

Friedrich W. Neukam

Sabine Ponader

Emeka Nkenke

A novel Multiple-Marker Method for the Early Diagnosis of Oral Squamous Cell Carcinoma

Glutathione S-transferases (GSTs) play an important role in detoxification of various toxic compounds like carcinogens in cigarette smoke and tobacco by conjugating to toxic compounds and inactivating their hazardous effect. Variation in Glutathione S-Transferases (GSTs) genes may alter the catalytic efficiency of GST isoenzymes leading to potential increase in cancer susceptibility due to various carcinogens. We therefore, investigated association of GSTM1, GSTM3 and GSTT1 variants with susceptibility to benign prostate hyperplasia (BPH) and cigarette, tobacco chewing and alcohol consumption as confounding factors in 141 BPH and 184 healthy controls. Results showed increased risk for BPH susceptibility in patients with GSTM1 null genotype (OR-2.03, p = 0.013) and smoking (OR-3.12, p = 0.028), tobacco chewing (OR-2.54, p = 0.039) and alcohol habits (OR-3.39, p = 0.010). Null genotype of GSTM1 with cigarette, tobacco and alcohol habits predisposed increased risk for BPH.

Rama Devi Mittal

Pravin Kesarwani

Ranjana Singh

Dinesh Ahirwar

Anil Mandhani

GSTM1, GSTM3 and GSTT1 Gene Variants and Risk of Benign Prostate Hyperplasia in North India

Variation in the NOS3 gene has been related to the development of restenosis. The Glu298Asp polymorphism has previously been investigated for its effect on NO levels and the development of restenosis. However, the variability of findings gave rise to the hypothesis that the functional significance of this polymorphism may only become manifest under conditions of endothelial dysfunction. Since patients with the metabolic syndrome are known to have endothelial dysfunction, we aimed to investigate if the significance of NOS3 polymorphisms may depend on the presence of the metabolic syndrome.We examined the impact of the -949 A/G, the -716 C/T and the Glu298Asp polymorphisms in the NOS3 gene on the risk of clinical restenosis in a previously described subpopulation of the GENDER-study, a multicenter prospective study design that enrolled consecutive patients after successful PCI. This subpopulation consisted of 901 patients of whom sufficient data were available to establish absence or presence of the metabolic syndrome. Of these patients, 448 had the metabolic syndrome. Clinical restenosis, defined as target vessel revascularization (TVR), was the primary endpoint.We demonstrated that the minor -949G, -716T and 298Asp alleles were associated with a significantly increased risk of TVR in patients with the metabolic syndrome (HR: 1.58 [95&#x25;CI: 1.04&#x2013;2.40], HR: 1.95 [95&#x25;CI: 1.02&#x2013;3.70] and HR: 1.67 [95&#x25;CI: 1.09&#x2013;2.54], respectively). In the group without the metabolic syndrome we observed no association between the three polymorphisms and TVR.

Douwe Pons

Pascalle S. Monraats

Aeilko H. Zwinderman

Moniek P. M. de Maat

Pieter A. F. M. Doevendans

Robbert J. de Winter

Ren&#xe9; A. Tio

Johannes Waltenberger

J. Wouter Jukema

Metabolic Background Determines the Importance of NOS3 Polymorphisms in Restenosis after Percutaneous Coronary Intervention: A Study in Patients with and without the Metabolic Syndrome

Background: Glatiramer acetate (GA, Copaxone&#xae;) has beneficial effects on the clinical course of relapsing-remitting multiple sclerosis (RRMS). However, the exact molecular mechanisms of GA effects are only partially understood.Objective: To characterized GA molecular effects in RRMS patients within 3 months of treatment by microarray profiling of peripheral blood mononuclear cells (PBMC).Methods: Gene-expression profiles were determined in RRMS patients before and at 3 months after initiation of GA treatment using Affimetrix (U133A-2) microarrays containing 14,500 well-characterized human genes. Most informative genes (MIGs) of GA-induced biological convergent pathways operating in RRMS were constructed using gene functional annotation, enrichment analysis and pathway reconstruction bioinformatic softwares. Verification at the mRNA and protein level was performed by qRT-PCR and FACS.Results: GA induced a specific gene expression molecular signature that included altered expression of 480 genes within 3 months of treatment; 262 genes were up-regulated, and 218 genes were down-regulated. The main convergent mechanisms of GA effects were related to antigen-activated apoptosis, inflammation, adhesion, and MHC class-I antigen presentation.Conclusions: Our findings demonstrate that GA treatment induces alternations of immunomodulatory gene expression patterns that are important for suppression of disease activity already at three months of treatment and can be used as molecular markers of GA activity.

Anat Achiron

Anna Feldman

Michael Gurevich

Molecular Profiling of Glatiramer Acetate Early Treatment Effects in Multiple Sclerosis

Uveitis is a clinical feature of the Blau syndrome, a disease linked to CARD15 (also referred to as NOD2) mutations. Three main mutations in this gene (R334W, R334Q and L469F) have been reported as Blau syndrome risk factors, a disease that manifests uveitis as one of its clinical features. However, little is known on the involvement of this gene in idiopathic uveitis. We thus sought to determine the frequency of these Blau-related CARD15 mutations in a cohort of Spanish patients with idiopathic uveitis. To this aim, 110 patients with idiopathic uveitis, followed at the Department of Ophtalmology of a tertiary hospital (Hospital Universitario Alcal&#xe1; de Henares, Madrid. Spain) were enrolled. As a control population, 104 healthy subjects were used. DNA was extracted from blood samples and the Blau-related CARD15 mutations were analysed either by PCR-RFLP or direct DNA sequencing. None of the mutations studied was found in any of the individuals tested, whether diseased or healthy. It seems thus that Blau syndrome-related CARD15 mutations are not involved in idiopathic uveitis, a finding which allows us to suggest that the genetic aetiology of the idiopathic uveitis or the Blau-associated uveitis is different.

Noelia Rodr&#xed;guez-P&#xe9;rez

Ana Aguinaga-Barrilero

Marina B. Gorro&#xf1;o-Echebarr&#xed;a

Mercedes P&#xe9;rez-Blas

Jos&#xe9; M. Mart&#xed;n-Villa

Blau Syndrome-Related CARD15/NOD2 Mutations Are Not Linked to Idiopathic Uveitis in Spanish Patients

Objective: We studied the relationship between the severity of inflammation and IL-1&#x3b2; production and relative expression level of IL-1&#x3b2; mRNA in irrigation fluid and synovial tissue obtained from the knee joint during the acute stage of a murine model of type II collagen antibody-induced arthritis (CAIA). This model is used to identify potential therapeutic markers for treating rheumatoid arthritis.Methods: Irrigation fluid and synovium tissue were harvested from the knee joint of BALB/c mice in acute stage of CAIA induction. The IL-1&#x3b2; protein level was measured by enzyme-linked immunosorbent assay, and the relative expression level of IL-1&#x3b2; mRNA was analyzed by reverse transcription-polymerase chain reaction. Two investigators analyzed expression levels and histopathological changes.Results: IL-1&#x3b2; concentration was higher in irrigation fluid from the knee joint than in the serum in the acute stage of CAIA. The relative expression level of IL-1&#x3b2; mRNA was elevated in synovial tissue. Histopathological changes in the knee joint and foot indicated similar severity.Conclusions: IL-1&#x3b2; concentration in irrigation fluid and relative expression level of IL-1&#x3b2; mRNA in the synovium have potential as therapeutic markers in studying and treating CAIA.

Wei-Tso Chia

Li-Tzu Yeh

Yuan-Wu Chen

Herng-Sheng Lee

Deh-Ming Chang

Huey-Kang Sytwu

IL-1&#x3b2; in Irrigation Fluid and MRNA Expression in Synovial Tissue of the Knee Joint as Therapeutic Markers of Inflammation in Collagen Antibody-Induced Arthritis

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Disease Markers publishes papers related to the identification of disease markers, the elucidation of their role and mechanism, as well as their application in the prognosis, diagnosis and treatment of diseases.

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Chief Editor Paola Gazzaniga is an Associate Professor in the Department of Molecular Medicine at Sapienza University of Rome, Italy. Her core research focuses on liquid biopsies in patients with solid tumors.

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Disease Markers publishes papers related to the identification of disease markers, the elucidation of their role and mechanism, as well as their application in the prognosis, diagnosis and treatment of diseases.

Disease Markers