bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Polymorphisms of Infectious Diseases in Case-Control Studies
Authors: Pacheco Antonio G. , Moraes Milton O.
Published: June 2013

In the past decade, genetic epidemiological analyses in infectious diseases have increased drastically since the publication of human genome and all the subsequent projects analyzing human diversity at molecular level. The great majority of studies use classical epidemiological designs applied to genetic data, and more than 80% of published studies use population-based case-control designs with widely spread genetic markers in human genome, like short tandem repeats (STR) or single nucleotide polymorphisms (SNP), in genes chosen by their physiological association with the disease (candidate genes). Even though genetic data is less prone to several bias issues inherent to case-control studies, some care has to be taken when designing, performing, analyzing and interpreting results from such studies. Here we discuss some basic concepts of genetics and epidemiology as a departure to evaluate and review every step that should be followed to design, conduct, analyze, interpret and present data from those studies, using particularities of infectious diseases, especially leprosy and tuberculosis as models.
Investigating the Impact of the Down Syndrome Related Common MTHFR 677C>T Polymorphism in the Danish Population
Authors: Kokotas Haris , Grigoriadou Maria , Mikkelsen Margareta , Giannoulia-Karantana Aglaia , Petersen Michael B.
Published: June 2013

Chromosomal aneuploidy consists the leading cause of fetal death in our species. Around 50% of spontaneous abortions until 15 weeks of gestational age are chromosomally aneuploid, with trisomies accounting for 50% of the abnormal abortions. Trisomy 21 is the most common chromosome abnormality in liveborns and is usually the result of nondisjunction of chromosome 21 in meiosis in either oogenesis or spermatogenesis. To investigate the relationship between folate metabolism and Down syndrome (DS) in a Danish population, we analyzed the common 677C>T genetic polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. Our cohort consisted of 181 mothers of children with DS versus 1,084 healthy controls. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to examine theMTHFR677C>T polymorphism. No significant association between the polymorphism and the risk for DS was found. We conclude that the commonMTHFR677C>T polymorphism is not likely to be a maternal risk factor for DS in our cohort and that the difference to previous studies can probably be explained by small sample size or geographic variation in gene polymorphisms involving gene-nutritional or gene-gene or gene-nutritional-environmental factors.
Retinol Binding Protein-4 Is Associated with TNF-αand Not Insulin Resistance in Subjects with Type 2 Diabetes Mellitus and Coronary Heart Disease
Authors: Al-Daghri Nasser M. , Al-Attas Omar S. , Alokail Majed , Draz Hossam M. , Bamakhramah Ahmed , Sabico Shaun
Published: June 2013

We studied the association between RBP4 and various markers related to insulin resistance and diabetic complications as well as inflammatory markers in Saudi population suffering from type 2 diabetes and coronary heart disease. Patients with type 2 diabetes were divided into 3 groups according to the type of treatment and involvement of coronary artery disease. Serum RBP4, TNF-α, insulin, CRP, resistin, leptin and adiponectin were analysed in all samples. RBP4 levels increased significantly in the group of diabetic subjects treated with oral hypoglycemic agents and diabetic patients with coronary heart disease (30.2 ± 11.8; 33.4 ± 13.6 respectively), while there was no significant change in the other group for diabetic subjects on low-carbohydrate diet (25.1 ± 10.9) compared to control group (22.6 ± 9.5). RPB4 levels were positively correlated with TNF-α in the group of diabetic subjects on oral hypoglycemic agents and diabetic patients with coronary heart disease (r= 0.52,P< 0.05;r= 0.58,P< 0.05 respectively). No correlations were found between RBP4 levels and insulin resistance in all studied groups. Our findings suggest that serum RBP4 levels is associated with pro-inflammatory cytokine (TNF-α) and is not associated with insulin resistance among patients with type 2 diabetes and coronary heart disease.
IL-1βin Irrigation Fluid and MRNA Expression in Synovial Tissue of the Knee Joint as Therapeutic Markers of Inflammation in Collagen Antibody-Induced Arthritis
Authors: Chia Wei-Tso , Yeh Li-Tzu , Chen Yuan-Wu , Lee Herng-Sheng , Chang Deh-Ming , Sytwu Huey-Kang
Published: June 2013

Objective: We studied the relationship between the severity of inflammation and IL-1βproduction and relative expression level of IL-1βmRNA 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-1βprotein level was measured by enzyme-linked immunosorbent assay, and the relative expression level of IL-1βmRNA was analyzed by reverse transcription-polymerase chain reaction. Two investigators analyzed expression levels and histopathological changes.

Results: IL-1βconcentration 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-1βmRNA was elevated in synovial tissue. Histopathological changes in the knee joint and foot indicated similar severity.

Conclusions: IL-1βconcentration in irrigation fluid and relative expression level of IL-1βmRNA in the synovium have potential as therapeutic markers in studying and treating CAIA.
Use of Obesity Biomarkers in Cardiovascular Epidemiology
Authors: Pischon Tobias
Published: June 2013

Obesity is an established risk factor for cardiovascular disease (CVD), yet, the underlying mechanisms are only poorly understood. The adipose tissue produces a variety of hormones and cytokines and thereby actively participates in a network of biomarkers that may be relevant for the development of CVD. Such obesity biomarkers have a great potential to better characterize the obesity phenotype that may be relevant for the risk of CVD beyond anthropometric parameters. They may be used to support mechanistic studies, to help identify individuals at risk for CVD, and to evaluate the effect of preventive measures. The present article discusses the role of some of the most promising obesity biomarkers in cardiovascular epidemiology, including inflammatory markers, adiponectin, resistin, and fetuin-A. Importantly, some of these markers have been related to cardiovascular risk even after accounting for anthropometric parameters. Further, the potential ability to manipulate blood levels of some of these biomarkers through medication, diet and lifestyle make them attractive markers for cardiovascular risk. However, many open questions remain – especially with regard to the causal role of the factors as well as with regard to the extent of improvement in CVD prediction by these markers – before measurement of these biomarkers may be recommended on a public health level.
Markers of Inflammation and Risk of Coronary Heart Disease
Authors: Sarwar Nadeem , Thompson Alexander J. , Di Angelantonio Emanuele
Published: June 2013

Cardiovascular disease is the leading cause of global mortality, with coronary heart disease (CHD) its major manifestation. Although inflammation, the body’s response to noxious stimuli, is implicated in several stages of CHD development, the relevance of circulating levels of markers of inflammation to CHD risk remains uncertain. This review summarizes available epidemiological evidence for four emerging inflammatory markers implicated in CHD (fibrinogen, C-reactive protein, lipoprotein-associated phospholipase A2and interleukin-6); considers their likely utility in cardiovascular risk prediction; and outlines areas of outstanding uncertainty.
Genetic Variation in Osteopontin Gene Is Associated with Susceptibility to Sarcoidosis in Slovenian Population
Authors: Maver A. , Medica I. , Salobir B. , Tercelj M. , Peterlin B.
Published: June 2013

Sarcoidosis is a systemic inflammatory disease characterised by appearance of granulomas. Precise etiology has not been elucidated. Osteopontin (Opn) is a Th1 cytokine whose levels have been found increased in granulomas and serum samples from patients with sarcoidosis. We investigated whether genetic variation in Osteopontin gene (OPN) gene contributes to susceptibility to sarcoidosis. Haplotype-block structure in the OPN gene region was investigated using data from HapMap project. Three representative SNPs have been selected from each block of SNPs in linkage disequilibrium (rs11730582-C/T, rs11728697-C/T and rs4754-C/T). Genotyping was performed using TaqMan SNP Genotyping Assays on a sample of 165 patients and 284 controls. Statistical analyses of association were performed using Chi-Square test and algorithms implemented in the haplo.stats and PHASE packages. Genotyping analysis revealed a significant difference in genotype frequencies at rs4754 polymorphism in groups of patients and controls under recessive genetic model (p=0.036, OR=1.99, 95%CI=1.04-3.82), CC homozygotes being significantly over-represented in the patients group. However these results failed to reach significance after correction for multiple testing (p=0.25). The frequencies of predicted haplotypes differed between patient and control groups, frequency of TTT haplotype was found to be significantly decreased in the group of patients with sarcoidosis (p=0.014, OR=0.40, 95%CI=0.20-0.79). Our results suggest that variation in the OPN gene might be significantly associated with sarcoidosis and that the TTT haplotype in OPN may act as a protective factor in sarcoidosis.
A Study of GluK1 Kainate Receptor Polymorphisms in Down Syndrome Reveals Allelic Non-Disjunction at 1173(C/T)
Authors: Ghosh Debarati , Sinha Swagata , Chatterjee Anindita , Nandagopal Krishnadas
Published: June 2013

Mechanisms underlying Down syndrome (DS)-related mental retardation (MR) remain poorly understood. In trisomic offspring, non-disjunction may result in the reduction to homozygosity of a susceptibility allele inherited from a heterozygous parent. Accordingly, we sought evidence for allelic non-disjunction in the GluK1 gene that encodes the critical kainite-binding glutamate receptor subunit-5, maps to chromosome 21q22.1 in the DS critical region and is expressed in brain regions responsible for learning and memory. Three polymorphisms of GluK1 [522(A/C) rs363538; 1173(C/T) rs363430 and 2705(T/C) rs363504] were genotyped in 86 DS patient families by means of PCR-coupled RFLP assays and evaluated with respect to allele frequency, heterozygosity, linkage disequilibrium, stage and parental origin of allelic non-disjunction. We report that the distribution of allele frequencies is in Hardy-Weinberg equilibrium. Moderate heterozygosity (0.339) and a major allele frequency of 0.78 render the 1173(C/T) marker informative. Pair-wise comparisons reveal that 522(A/C)-1173(C/T) [χ2= 31.2,df= 1,p= 0.0001;D’ = 0.42] and 1173(C/T)-2705(T/C) [χ2= 18.3,df= 1,p= 0.0001;D’ = 0.34] are in significant linkage disequilibrium of weak magnitude. The estimated ratio of meiosis-I to meiosis-II errors arising from allelic non-disjunction of 1173(C/T) is 4:1 in maternal cases and 2:1 in paternal cases. Studies including additional markers and patient samples are warranted to further substantiate present findings.
Clinicopathological Significance of microRNA-31, -143 and -145 Expression in Colorectal Cancer
Authors: Wang Chao-Jie , Zhou Zong-Guang , Wang Ling , Yang Lie , Zhou Bin , Gu Jun , Chen Hong-Ying , Sun Xiao-Feng
Published: June 2013

We are just beginning to understand how microRNAs (miRNAs) are involved in tumor-related processes in humans. Applying real-time RT-PCR, we investigated the miR-31, miR-143 and miR-145 expression in 98 primary CRC specimens, along with the corresponding normal mucosa specimens, and analyze the relationship of their expression with clinicopathological features. Our results showed the miR-31 expression was up-regulated in CRC compared to normal mucosa (p= 0.001). Furthermore, miR-31 expression was positively related to advanced TNM stage (p= 0.026) and deeper invasion of tumors (p= 0.024). MiR-145 was down-regulated in both colon (p= 0.001) and rectal (p= 0.012) cancer. MiR-143 was only down-regulated in colon cancer (p= 0.023) but not in rectal cancer (p= 0.351). There was no relationship of miR-143 and miR-145 expression with other clinicopathological features (p> 0.05), except that the miR-145 expression was related to cancer site (p= 0.03). In conclusion, the miR-31 overexpression may be involved in the development and progression of CRC. The miR-143 and miR-145 may play a certain role in the development of colon and/or rectal cancers but not in progression of the disease.
Expression of HER2 in Colorectal Cancer Does Not Correlate with Prognosis
Authors: Kruszewski Wiesław Janusz , Rzepko Robert , Ciesielski Maciej , Szefel Jarosław , Zieliński Jacek , Szajewski Mariusz , Jasiński Wojciech , Kawecki Krzysztof , Wojtacki Janusz
Published: June 2013

Estimation of HER2 membranous expression is routinely used in breast and gastric cancers, as both a prognostic and a predictive factor. To date there is no evidence for similar application of HER2 expression in colorectal cancer (CRC) cells. In CRC, HER2 is sometimes overexpressed in the cell membrane and very often in the cytoplasm. This study was conducted to determine possible correlations between both membranous and cytoplasmatic expression of HER2 in CRC cells and the outcome of the disease. The prognostic significance of combined staining intensity in the cell membrane and cytoplasm in the entire CRC cell was also investigated. HER2 expression in resectable colorectal adenocarcinoma cells was evaluated by immunohistochemistry in specimens taken from 202 patients. The percentage of cancer cells with membranous or cytoplasmatic reactions and the staining intensity of the reaction in the whole cell were recorded. A membranous reaction was present in 27% of cases, and cytoplasmatic reaction in 66% of cases. The total staining intensity in the entire cell was evaluated as moderate (2+) in 32% of cases and strong (3+) staining in 15%. There was no correlation found between either membranous or cytoplasmatic HER2 expression and survival. Furthermore combined staining intensity did not provide any prognostic information. We conclude that HER2 expression in CRC does not correlate with prognosis.
HLA-DR Association in Papillary Thyroid Carcinoma
Authors: Amoli Mahsa M. , Yazdani Nasrin , Amiri Parvin , Sayahzadeh Forogh , Haghpanah Vahid , Tavangar Seyed Mohammad , Amirzargar Ali , Ghaffari Hamidollah , Nikbin Behrooz , Larijani Bagher , Mostaan Leila V. , Bazzaz Javad Tavakkoly
Published: June 2013

Objective:Papillary thyroid carcinoma (PTC) is the most frequent types of thyroid malignancies. Several genes may be involved in susceptibility of thyroid cancer including Human Leukocyte Antigens (HLA). The association of thyroid carcinoma with HLA alleles has been previously studied in other populations and certain HLA alleles were shown to be either predisposing or protective. The aim of this study was to determine the association between HLA-DR and papillary thyroid carcinoma in an Iranian population.

Design:HLA-DR antigen frequencies were determined in patients with papillary thyroid carcinoma (N = 70) and non-related healthy controls (N=180) using PCR -SSP.

Main Outcome:We found that HLA-DRB1*04 frequency was significantly higher in our patients compared to the controls [P= 0.02, OR; 1.9, 95% CI (1.04–3.57)].

Conclusions:Our results revealed HLA-DRB1*04 as predisposing factor in papillary thyroid carcinoma in Iranian population. This confirms the previous findings for associations between HLA-DRB1 and differentiated carcinomas in other populations.
Systems Biology and the Discovery of Diagnostic Biomarkers
Authors: Wang Kai , Lee Inyoul , Carlson George , Hood Leroy , Galas David
Published: June 2013

Systems biology is an approach to the science that views biology as an information science, studies biological systems as a whole and their interactions with the environment. This approach, for the reasons described here, has particular power in the search for informative diagnostic biomarkers of diseases because it focuses on the fundamental causes and keys on the identification and understanding of disease- perturbed molecular networks. In this review, we describe some recent developments that have used systems biology to address complex diseases – prion disease and drug induced liver injury- and use these as examples to illustrate the importance of understanding network structure and dynamics. The knowledge of network dynamics through in vitro experimental perturbation and modeling allows us to determine the state of the networks, to identify molecular correlates, and to derive new disease treatment approaches to reverse the pathology or prevent its progress into a more severe state through the manipulation of network states. This general approach, including diagnostics and therapeutics, is becoming known as systems medicine.
Relation between Development of Cardiovascular Disease and the C242T CYBA Polymorphism of the NADPH Oxidase in ESRD Patients
Authors: Tang Feng-Ying , Zhu Ying , Wang Gui Hua , Xie Xiong-Wei
Published: June 2013

Background: The development of cardiovascular disease in ESRD patients is considered to be associated with oxidative stress. NAD(P)H oxidase has attracted attention as mechanisms of generating oxidative stress. We investigated the relation between the genotype of the C242T CYBA polymorphism of the NADPH oxidase and the development of cardiovascular disease in ESRD patients.

Methods: A total of 289 ESRD patients were recruited and allocated to one of the two groups: patients without cardiovascular disease (group N; n=192) and patients developing cardiovascular disease (group D; n=97). The C242T CYBA polymorphism was determined by RFLP-PCR methods.

Results: The frequency of the C242T CT+TT genotype was significantly lower in group D than in group N (9.1 vs. 20.2%). In multiple Logistic regression analysis, systolic blood pressure, smoking history and this gene polymorphism were shown to be independent variables for the development of cardiovascular disease in ESRD patients.

Conclusions: These results suggest that assessment of the C242T CYBA polymorphism of the NADPH oxidase may be useful in identifying the risk for developing cardiovascular disease in ESRD patients.
Systems Biology Approaches to Disease Marker Discovery
Authors: Sharon Donald , Chen Rui , Snyder Michael
Published: June 2013

Our understanding of human disease and potential therapeutics is improving rapidly. In order to take advantage of these developments it is important to be able to identify disease markers. Many new high-throughput genomics and proteomics technologies are being implemented to identify candidate disease markers. These technologies include protein microarrays, next-generation DNA sequencing and mass spectrometry platforms. Such methods are particularly important for elucidating the repertoire of molecular markers in the genome, transcriptome, proteome and metabolome of patients with diseases such as cancer, autoimmune diseases, and viral infections, resulting from the disruption of many biological pathways. These new technologies have identified many potential disease markers. These markers are expected to be valuable to achieve the promise of truly personalized medicine.
Lack of Association betweenPRNPM129V Polymorphism and Multiple Sclerosis, Mild Cognitive Impairment, Alcoholism and Schizophrenia in a Korean Population
Authors: Choi Ihn-Geun , Woo Sung-Il , Kim Ho Jin , Kim Dai-Jin , Park Byung Lae , Cheong Hyun Sub , Pasaje Charisse Flerida A. , Park Tae Joon , Bae Joon Seol , Chai Young Gyu , Shin Hyoung Doo
Published: June 2013

The genetic variant at codon 129 (M129V) of the prion protein gene (PRNP) is considered to be a major genetic risk factor for prion diseases. In this study, we examined the possible genetic association ofPRNP*129Valwith multiple sclerosis (MS,n= 681), mild cognitive impairment (MCI,n= 801), alcoholism (n= 761) and schizophrenia (n= 715) in a Korean population, and compared the data with previous genetic association studies of the variant. The minor allele frequency ofPRNP*129Val(MAF = 0.025) was significantly lower in Korean population (n= 2,479) compared to Caucasian populations (P< 0.0001), suggestive of a weak influence of the variant in the previous population. Statistical analysis revealed no significant association betweenPRNP*129Valand MS (P = 0.76), MCI (P = 0.46), alcoholism (P = 0.84) and schizophrenia (P = 0.69). These findings were discussed in the context of prior inconsistent reports on the role ofPRNP*129Valpolymorphism in several diseases. Results from this study may provide further evidence thatPRNP M129Vis not a genetic susceptibility factor for MS, MCI, alcoholism and schizophrenia in a Korean population.
Coincidence of Moderately Elevated N-Terminal Pro–B-Type Natriuretic Peptide, Endothelial Progenitor Cells Deficiency and Propensity to Exercise-Induced Myocardial Ischemia in Stable Angina
Authors: Surdacki Andrzej , Marewicz Ewa , Rakowski Tomasz , Szumańska Monika , Szastak Grzegorz , Pryjma Juliusz , Dubiel Jacek S.
Published: June 2013

Aim:To assess endothelial progenitor cells (EPC) counts, a novel prognostic marker, in relation to classical adverse outcome predictors–N-terminal pro–B-type natriuretic peptide (NT-proBNP), impaired left ventricular (LV) relaxation and exercise-induced ischemia–in stable coronary artery disease (CAD) with preserved LV systolic function.

Methods:We studied 30 non-diabetic men with one-vessel CAD, LV ejection fraction ≥ 60% and normal LV diastolic function (n= 16) or impaired LV relaxation (by ultrasound including tissue Doppler) (n= 14), and 14 non-CAD controls matched for risk profile and medication. CD34+/kinase-insert domain receptor (KDR)+ cells (CD34+/KDR+ cells), a leukocytes subpopulation enriched for EPC, were enumerated by flow cytometry.

Results:CAD patients with abnormal LV relaxation exhibited significantly elevated NT-proBNP and decreased CD34+/KDR+ cells vs. CAD with regular diastolic function and non-CAD controls. An inverse NT-proBNP–CD34+/KDR+ cells relationship was precipitated by the clustering of high resting NT-proBNP and low CD34+/KDR+ cells in the subjects with a lower Duke treadmill score.

Conclusions:Propensity to symptomatic exertional ischemia may underlie the coincidence of moderately elevated NT-proBNP and EPC deficiency in stable angina. Additionally, chronic subclinical ischemia can also be involved in these associations. These might result from BNP overexpression in the ischemic myocardium and a hypothetical exhaustion of the bone marrow capacity to mobilize EPC at multiple ischemic episodes, thus contributing to NT-proBNP prognostic effect irrespective of hemodynamic factors.
Blood Absolute T Cell Counts may Predict 2-Month Treatment Response in Patients with Pulmonary Tuberculosis
Authors: Chen Yung-Che , Chang Huang-Chih , Chen Chung-Jen , Liu Shih-Feng , Chin Chien-Hung , Wu Chao-Chien , Chao Tung-Ying , Lie Chien-Hao , Wang Chin-Chou , Lin Meng-Chih
Published: June 2013

Background and objective:Little is known about the usefulness of lymphocyte subsets as early predictors of anti-tuberculosis (TB) treatment response in immuno-competent patients.

Methods:Among a total of 64 patients with culture positive pulmonary TB, 29 remained sputum smear/culture positive or had delayed resolution on CXR (slow responders (SR)), and 35 had sputum culture conversion to negative and rapid resolution on CXR (fast responders (FR)) after two months of anti-tuberculosis treatment. Clinical parameters and lymphocyte subsets were investigated.

Results:A larger proportion of patients in the SR group had cavities on CXR, bilateral lung involvement, positive acid-fast bacilli stains, and complaint of cough at diagnosis than those in the FR group. Absolute counts of CD3+T cells (p= 0.016) and CD8+T cells (p= 0.012) at diagnosis were both significantly higher in the SR group. This trend was present throughout the 6-month treatment course. Absolute T cell counts (odds ratio (OR) 1.002, 95% confidence interval (CI) 1.0–1.004), positive sputum acid fast bacilli stain (OR 6.69, 95% CI 1.37–32.77) and bilateral lung involvemment on CXR (OR 13.114, 95% CI 1.87–92.14) at diagnosis were independent predictors for a slow response. Combining these three predictors, a prediction score (PS) could be calculated to display an optimal discrimination for slow response (area under the curve (AUC) = 0.855,p< 0.001) whereas absolute T cell counts yielded the highest discriminative value on an individual level (AUC = 0.676,p= 0.015).

Conclusions:A higher T cell count at diagnosis in patients with TB may predict a slow response to two months of treatment. The calculation of a PS further increased predictive accuracy and performance.
Maternal Gene Polymorphisms Involved in Folate Metabolism as Risk Factors for Down Syndrome Offspring in Southern Brazil
Authors: Brandalize Ana Paula Carneiro , Bandinelli Eliane , Santos Pollyanna Almeida Dos , Schüler-Faccini Lavínia
Published: June 2013

This study aimed to investigate the role of maternal polymorphisms, as well as their risk genotypes combinations ofMTRA2756G,MTRRA66G,CBS844ins68, andRFCA80G, involved in folate/homocysteine metabolism, as possible risk factors for Down syndrome (DS) in Southern Brazil. A case-control study was conducted with 239~mothers of DS children and 197 control mothers. The investigation of polymorphisms was performed by PCR and PCR-RFLP. The distribution of genotypic variants was similar in both groups when they were analyzed separately. An investigation of combined risk genotypes showed that the risk of having a DS child for one, two or three risk genotypes was 6.23, 6.96 and 5.84 (95%CI 1.48–26.26; 1.69–28.66; 1.37–24.86), respectively. The combinedMTRR66G andMTHFR677T alleles were significantly more common among mothers of children with DS than among control mothers (OR 1.55; IC 95% 1.03–2.35). The results show that individual polymorphisms studied in this work are not associated with DS; however, the effects of the combined risk genotypes amongMTR, MTRR, CBSandRFCgenes are considered maternal risk factors for DS offspring in our population.
A Systems Approach to the Proteomic Identification of Novel Cancer Biomarkers
Authors: Pitteri Sharon , Hanash Sam
Published: June 2013

The proteomics field has experienced rapid growth with technologies achieving ever increasing accuracy, sensitivity, and throughput, and with availability of computational tools to address particular applications. Given that the proteome represents the most functional component encoded for in the genome, a systems approach to disease investigations and biomarker identification benefits substantially from integration of proteome level studies. Here we present proteomic approaches that have allowed systematic searches for potential cancer markers by integrating cancer cell profiling with additional sources of data, as illustrated with recent studies of ovarian cancer.
SLC26A4 Variations Among Graves’ Hyper-Functioning Thyroid Gland
Authors: Hadj-Kacem Hassen , Kallel Rihab , Belguith-Maalej Salima , Mnif Mouna , Charfeddine Ilhem , Ghorbel Abdelmounem , Abid Mohamed , Ayadi Hammadi , Masmoudi Saber
Published: June 2013

Deleterious mutations ofSLC26A4cause Pendred syndrome (PS), an autosomal recessive disorder comprising goitre and deafness with enlarged vestibular aqueducts (EVA), and nonsyndromic hearing loss (NSHL). However, theSLC26A4hyperactivity was recently associated with the emergence of autoimmune thyroid diseases (AITD) and asthma among human and mouse model. Here, by direct sequencing, we investigate the sequences of the 20 coding exons (2 to 21) of SLC26A4 and their flanking intron-exon junctions among patients affected with Graves' disease (GD) hyperthyroidism. Ten mono-allelic variants were identified, seven of which are intronic and previously unreported. Two, c.898A>C (p.I300L) and c.1061T>C (p.F354S), of the three exonic variants are non synonymous. The p.F354S variant is already described to be involved in PS or NSHL inheritances. The exploration by PCR-RFLP of p.I300L and p.F354S variants among 132 GD patients, 105 Hashimoto thyroiditis (HT), 206 Healthy subjects and 102 families with NSHL have shown the presence of both variants. The p.F354S variation was identified both among patients (1~HT and 3 GD) and healthy subjects (n=5). Whereas, the p.I300L variant was identified only in GD patients (n=3). Our studies provide evidence of the importance of systematic analysis ofSLC26A4gene sequences on models other than deafness. This approach allows the identification of new variants and the review of the pathogenic effects of certain mono-allelic variants reported responsible for PS and NSHL development.
Genetic Polymorphism of Glutathione S Transferases M1 and T1 in Indian Patients with Hepatocellular Carcinoma
Authors: Asim Mohammad , Khan Luqman A. , Husain S. A. , Husain Sajid , Sarma Manash P. , Ahmad Istaq , Sharma J. K. , Sharma Anita , Sharma Shashi , Thayumanavan L. , Kar P.
Published: June 2013

Objective:Our aim was to evaluate whether the association of GSTM1/T1 gene polymorphisms modifies the risk of Hepatocellular carcinoma (HCC) and what is its correlation with other predisposing risk factors like alcohol intake, cigarette smoking and hepatitis B and C infections.

Study design/setting:It was a case-control study, included 254 HCC cases compared with 525 hospital-based age and sex matched cases of chronic liver disease without HCC as controls from Indian population. The GSTM1 and GSTT1 genotypes were detected using conventional multiplex PCR method.

Results:In this case-control study, we observed a positive correlation between age, HBV and HCV infection, smoking habit of > 20 packs/year, alcohol consumption of > 100 g/day and risk of liver cancer. We found significantly increased risk associated with GSTM1 null genotype (OR = 3.49; 95% CI = 2.52–4.84) as well as GSTT1 null genotype (OR = 3.12; 95% CI = 2.19–4.45), respectively. However, an increased risk of HCC was observed among heavy drinkers with GSTM1 (OR = 2.01; 95% CI = 1.11–3.66). Further, cigarette smoking showed a non-significant association with GSTT1 (OR = 1.49; CI = 0.69–3.25).

Conclusion:Our results suggest that the variants in low penetrance gene such as GSTM1 and GSTT1 are associated with an increased liver cancer risk. Further, an influence of GSTM1/T1 null genotypes may contribute in the etiology of HCC in patients with higher cigarette and alcohol consumption.
The Antioxidant EnzymeGPX1Gene Polymorphisms Are Associated with Low BMD and Increased Bone Turnover Markers
Authors: Mlakar Simona Jurkovic , Osredkar Josko , Prezelj Janez , Marc Janja
Published: June 2013

Recently, oxidative stress has been suggested as participating in the development of osteoporosis. Glutathione peroxidase 1 (GPX1) is one of antioxidant enzymes responsible for the defence of cells against oxidative damage and thus for protection against age related diseases such as osteoporosis.

The aim of present study was to associate genetic variances of GPX1 enzyme with bone mineral density (BMD) and biochemical bone turnover markers and to show the influence of antioxidative defence system in genetics of osteoporosis.

We evaluated 682 Slovenian subjects: 571 elderly women and 111 elderly men. All subjects were genotyped for the presence ofGPX1gene polymorphisms Pro198Leu and polyAla region. BMD and biochemical markers were also measured. General linear model analysis, adjusted to height, and (one-way) analysis of variance were used to assess differences between the genotype.and haplotype subgroups, respectively.

The significant or borderline significant associations were found between the polyAla or the Pro198Leu polymorphisms and total hip BMD (0.018; 0.023, respectively), femoral neck BMD (0.117; 0.026, respectively) and lumbar spine BMD (0.032; 0.086, respectively), and with biochemical bone turnover markers such as plasma osteocalcin (0.027; 0.025, respectively) and serum C-terminal telopeptide of type I collagen concentrations (0.114; 0.012, respectively) in whole group. Haplotype analysis revealed that the 6-T haplotype is associated significantly with low BMD values (p> 0.025) at all measured locations of the skeleton, and with high plasma osteocalcin concentrations (p= 0.008).

This study shows for the first time that the polymorphisms polyAla and Pro198Leu of theGPX1gene, individually and in combination, are associated with BMD and therefore may be useful as genetic markers for bone disease. Moreover, it implies the important contribution of the oxidative stress to pathogenesis of osteoporosis.
Rac GTPases in Human Diseases
Authors: Pai Sung-Yun , Kim Chaekyun , Williams David A.
Published: June 2013

Rho GTPases are members of the Ras superfamily of GTPases that regulate a wide variety of cellular functions. While Rho GTPase pathways have been implicated in various pathological conditions in humans, to date coding mutations in only the hematopoietic specific GTPase,RAC2, have been found to cause a human disease, a severe phagocytic immunodeficiency characterized by life-threatening infections in infancy. Interestingly, the phenotype was predicted by a mouse knock-out ofRAC2and resembles leukocyte adhesion deficiency (LAD). Here we review Rho GTPases with a specific focus on Rac GTPases. In particular, we discuss a new understanding of the unique and overlapping roles of Rac2 in blood cells that has developed since the generation of mice deficient in Rac1, Rac2 and Rac3 proteins. We propose that Rac2 mutations leading to disease be termed LAD type IV.
Multiplex Ligation-Dependent Probe Amplification Analysis ofGATA4Gene Copy Number Variations in Patients with Isolated Congenital Heart Disease
Authors: Guida Valentina , Lepri Francesca , Vijzelaar Raymon , De Zorzi Andrea , Versacci Paolo , Digilio Maria Cristina , Marino Bruno , De Luca Alessandro , Dallapiccola Bruno
Published: June 2013

GATA4mutations are found in patients with different isolated congenital heart defects (CHDs), mostly cardiac septal defects and tetralogy of Fallot. In addition,GATA4is supposed to be the responsible gene for the CHDs in the chromosomal 8p23 deletion syndrome, which is recognized as a malformation syndrome with clinical symptoms of facial anomalies, microcephaly, mental retardation, and congenital heart defects. Thus far, no study has been carried out to investigate the role ofGATA4copy number variations (CNVs) in non-syndromic CHDs. To explore the possible occurrence ofGATA4gene CNVs in isolated CHDs, we analyzed by multiplex ligation-dependent probe amplification (MLPA) a cohort of 161 non-syndromic patients with cardiac anomalies previously associated withGATA4gene mutations. The patients were mutation-negative forGATA4,NKX2.5, andFOG2genes after screening with denaturing high performance liquid chromatography. MLPA analysis revealed that normalized MLPA signals were all found within the normal range values for all exons in all patients, excluding a major contribution ofGATA4gene CNVs in CHD pathogenesis.
PBC Triggers in Water Reservoirs, Coal Mining Areas and Waste Disposal Sites: From Newcastle to New York
Authors: Smyk Daniel , Mytilinaiou Maria G. , Rigopoulou Eirini I. , Bogdanos Dimitrios P.
Published: June 2013

Various environmental factors have been proposed as triggers of primary biliary cirrhosis (PBC), a progressive autoimmune cholestatic liver disease which is characterised by the destruction of the small intrahepatic bile ducts. Support for their pathogenic role in PBC is provided by epidemiological studies reporting familial clustering and clusters of the disease within a given geographical area. The seminal study by Triger reporting that the great majority of PBC cases in the English city of Sheffield drank water from a specific water reservoir, has been followed by studies reporting disease 'hot spots' within a restricted geographic region of the former coal mining area of Newcastle. The New York study reporting an increased risk and significant clustering of PBC cases near toxic federal waste disposal sites has added strength to the notion that environmental factors, possibly in the form of infectious agents or toxic/chemical environmental factors in areas of contaminated land, water or polluted air may play a key role in the development of the disease. This review discusses the findings of reports investigating environmental factors which may contribute to the cause of primary biliary cirrhosis.
Clinical Manifestations of Hyper IgE Syndromes
Authors: Freeman Alexandra F. , Holland Steven M.
Published: June 2013

Over the last 4 years, three genetic etiologies of hyper IgE syndromes have been identified: STAT3, DOCK8, and Tyk2. All of these hyper IgE syndromes are characterized by eczema, sinopulmonary infections, and greatly elevated serum IgE. However, each has distinct clinical manifestations. Mutations in STAT3 cause autosomal dominant HIES (Job’s syndrome), which is unique in its diversity of connective tissue, skeletal, and vascular abnormalities. DOCK8 deficiency is characterized by severe cutaneous viral infections such as warts, and a predisposition to malignancies at a young age. Only one individual has been identified with a hyper IgE phenotype associated with Tyk2 deficiency, which is characterized by nontuberculous mycobacterial infection. The identification of these genetic etiologies is leading to advances in understanding the pathogenesis of these syndromes with the goal of improving treatment.
BRCA1andBRCA2Germline Mutations Screening in Algerian Breast/Ovarian Cancer Families
Authors: Cherbal Farid , Bakour Rabah , Adane Saida , Boualga Kada , Benais-Pont Gaelle , Maillet Philippe
Published: June 2013

Background:Breast cancer is the leading cause of cancer death in women in Algeria. The contribution ofBRCA1andBRCA2mutations to hereditary breast/ovarian cancer in Algerian population is largely unknown. Here, we describe analysis ofBRCA1andBRCA2genes in 86 individuals from 70 families from an Algerian cohort with a personal and family history suggestive of genetic predisposition to breast cancer.

Methods:The approach used is based onBRCA1andBRCA2mutations screening by High-Resolution Melting (HRM) curve analysis followed by direct sequencing. All samples for which no pathogenic mutation was found were analyzed by MLPA for large deletions or duplications.

Results:Three distinct pathogenic mutations c.83_84delTG, c.181T>G, c.798_799delTT and two large rearrangements involving deletion of exon 2 and exon 8 respectively, were detected inBRCA1gene. Moreover 17 unclassified variants and polymorphisms were detected inBRCA1gene (6 described for the first time). Two pathogenic mutations, c.1310_1313delAAGA and c.5722_5723delCT and 40 unclassified variants and polymorphisms (14 never described before) were identified inBRCA2gene.

Conclusions:For the first time, we used HRM and MLPA to identifyBRCA1andBRCA2mutations in Algerian patients with a personal and family history suggestive of genetic predisposition to breast cancer. The implications of these new findings in regard to genetic testing and counseling are substantial for the Algerian population.
Peptides in Low Molecular Weight Fraction of Serum Associated with Hepatocellular Carcinoma
Authors: An Yanming , Bekesova Slavka , Edwards Nathan , Goldman Radoslav
Published: June 2013

The incidence of hepatocellular carcinoma (HCC) in the United States is increasing and the increase is projected to continue for several decades. The overall survival of HCC patients is poor and treatments are not effective in part because most of the diagnoses come at a late stage. The development of new markers for detection of HCC would significantly improve patient prognosis. This paper describes identification of candidate markers previously reported in our serologic study of an Egyptian population by quantitative comparison of matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectra. To identify these marker candidates, we performed LC-MS/MS sequencing that identified nine native peptides associated with HCC, including two reported previously. Four truncations of N terminus of complement C3f and a fibrinopeptide increased in control sera; two complement C4α peptides, a zyxin peptide, and a coagulation factor XIII peptide increased in cancer patient sera. We have also identified increased biliverdin diglucuronide in the sera of cancer patients. These peptides could potentially serve as markers of HCC following additional validation studies; however, association of similar peptides with other diseases and cancers dictates a very cautious approach.
Prognostic Significance ofNOTCH1andFBXW7Mutations in Pediatric T-ALL
Authors: Erbilgin Yucel , Sayitoglu Muge , Hatirnaz Ozden , Dogru Omer , Akcay Arzu , Tuysuz Gulen , Celkan Tiraje , Aydogan Gonul , Salcioglu Zafer , Timur Cetin , Yuksel-Soycan Lebriz , Ure Umit , Anak Sema , Agaoglu Leyla , Devecioglu Omer , Yildiz Inci , Ozbek Ugur
Published: June 2013

The NOTCH signaling pathway plays important role in the development of multicellular organisms, as it regulates cell proliferation, survival, and differentiation. In adults, it is essential for the T- or B-lymphocyte lineage commitment.NOTCH1and FBXW7 mutations both lead the activation of theNOTCH1pathway and are found in the majority of T-ALL patients. In this study, the mutation analysis ofNOTCH1andFBXW7genes was performed in 87 pediatric T-ALLs who were treated on the ALL-BFM protocols. In 19 patients (22%), activatingNOTCH1mutations were observed either in the heterodimerization domain or in the PEST domain and 7 cases (10%) demonstrated FBXW7 mutations (2 cases had bothNOTCH1andFBXW7mutations). We also analyzed the relationship of the mutation data between the clinical and biological data of the patients.NOTCH1andFBXW7,NOTCH1alone were found correlated with lower initial leucocyte counts which was independent from the sex and T- cell immunophenotype. However,NOTCH1andFBXW7mutations were not predictive of outcome in the overall cohort of pediatric T-ALLs.
SOD2 V16A SNP in the Mitochondrial Targeting Sequence is Associated with Noise Induced Hearing Loss in Chinese Workers
Authors: Liu Yi-Min , Li Xu-Dong , Guo Xiao , Liu Bin , Lin Ai-Hua , Ding Yuan-Lin , Rao Shao-Qi
Published: June 2013

Objective:To investigate whether single nucleotide polymorphisms (SNPs) in the Mn-superoxide dismutase gene (SOD2) underlie the susceptibility to noise-induced hearing loss (NIHL).

Methods:Audiometric data from 2400 Chinese Han workers who exposed to occupational noise were analyzed. DNA samples were collected from the 10% most susceptible and the 10% most resistant individuals, and five SNPs (SOD2 rs2842980, rs5746136, rs2758331, rs4880 and rs5746092) were genotyped by Taqman SNP Genotyping Kits. The SNP main effects and interactions between noise exposure and SNP were analyzed using logistic regression. Haplotypes were analyzed by using Haploview software.

Results:The CT genotype of rs4880 (SOD2 V16A SNP) was associated with a higher risk of NIHL (covariates-adjusted OR, 2.18; 95% CI, 1.34–3.54,P= 0.002). Haplotype analysis revealed that the frequency of AGCCG at the five SNP loci was significantly higher in the susceptible group (P= 0.020). With AGCTG as the reference, the OR (95% CI) was 2.63 (1.14, 6.06). The rs4880 polymorphisms imposed larger effects when the carriers were exposed to higher levels of noise, indicating the interaction between SNP and noise exposure.

Conclusions:Our results suggest that SOD2 V16A SNP in the mitochondrial targeting sequence is associated with noise induced hearing loss in Chinese workers, and this effect was enhanced by higher levels of noise exposure.
The Allele Frequencies of Three Polymorphisms in Genes Involved in Homocysteine Metabolism in a Group of Unrelated Healthy Singaporeans
Authors: Chen Chuanfei , Gan Yik-Yuen
Published: June 2013

The cystathionineβ-synthase (CBS) 844ins68 polymorphism, methionine synthase (MS) A2756G SNP, and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T SNP are associated with homocysteine (Hcy) level in humans. Elevated Hcy level is considered a risk factor for atherosclerotic diseases among Asian populations. Therefore, the three polymorphisms may vary the risk for developing such diseases in Singaporeans. In this study, the three polymorphisms were determined in a group of unrelated healthy Singaporeans (273 Chinese, 127 Indians, and 156 Malays). Regarding allele frequencies, Indians had the highest frequencies of the CBS insertion allele (2.0%) and the MS 2756G allele (26.4%), while Chinese had the highestMTHFR677T allele frequency (27.5%). In addition, theMTHFR677T allele was found significantly lower in Chinese males than in their female counterparts. As the CBS insertion allele was suggested to be associated with lower Hcy level, whereas the MS 2756G allele and theMTHFRT/T genotype were related to higher Hcy level, the MS A/G or G/G genotype and theMTHFRT/T genotype were considered double genetic risk factors for elevated Hcy level. The frequency of such double genetic risk was 0.7% (4 subjects) in the total population consisting of 3 Chinese (1.1%) and 1 Malays (0.6%). NoMTHFRT/T genotype was found in Indians. Such results suggested that Chinese could have higher Hcy levels than Malays while the situation for Indians was complicated. Since human Hcy levels are also affected by environmental factors, further studies are required to better evaluate the association between these three polymorphisms and Hcy levels and/or disease susceptibilities in Singaporeans.
Infectious Agents in the Pathogenesis of Primary Biliary Cirrhosis
Authors: Ortega-Hernandez Oscar-Danilo , Levin Nancy-Agmon , Altman Arie , Shoenfeld Yehuda
Published: June 2013

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, specially the pyruvate dehydrogenase E2 complex (PDC-E2). The breakdown of the tolerance to such antigens leads to an autoimmune process characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Epidemiological studies have suggested that infections agents can trigger or even exacerbate the disease. Among other gram negative bacteria,Escherichia Coli, andNosphingobium aromaticivoransare the most associated agents reported hitherto. Epidemiological and molecular evidence points towards molecular mimicry between some components of these microorganisms and specific amino-acid sequences that are present in proteins on normal cells of the biliary tract. In this review, we revisit all reports suggesting that infectious agents might be associated with the autoimmune pathogenesis of PBC. We also retrieve the immune molecular mimicry mechanisms that are likely involved with the autoimmune process in PBC.
Genetic, Clinical, and Laboratory Markers for DOCK8 Immunodeficiency Syndrome
Authors: Davis Jeremiah C. , Dove Christopher G. , Su Helen C.
Published: June 2013

DOCK8 immunodeficiency syndrome (DIDS) is a combined immunodeficiency characterized by recurrent viral infections, severe atopy, and early onset malignancy. Genetic studies revealed large, unique deletions in patients from different families and ethnic backgrounds. Clinical markers of DIDS include atopic dermatitis, allergies, cutaneous viral infections, recurrent respiratory tract infections, and malignancy. Immune assessments showed T cell lymphopenia, hyper-IgE, hypo-IgM, and eosinophilia. The impaired lymphocyte functions in DIDS patients appear central for disease pathogenesis.