BioMed Research International The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease Mon, 03 Aug 2015 13:46:59 +0000 Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs) in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance. Paloma Almeda-Valdes, Nancy E. Aguilar Olivos, Beatriz Barranco-Fragoso, Misael Uribe, and Nahum Méndez-Sánchez Copyright © 2015 Paloma Almeda-Valdes et al. All rights reserved. Interleukin-1β Modulates Melatonin Secretion in Ovine Pineal Gland: Ex Vivo Study Mon, 03 Aug 2015 13:27:38 +0000 The study was designed to determine the effect of proinflammatory cytokine, interleukin- (IL-) 1β, on melatonin release and expression enzymes essential for this hormone synthesis: arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT) in ovine pineal gland, taking into account the immune status of animals before sacrificing. Ewes were injected by lipopolysaccharide (LPS; 400 ng/kg) or saline, two hours after sunset during short day period (December). Animals were euthanized three hours after the injection. Next, the pineal glands were collected and divided into four explants. The explants were incubated with (1) medium 199 (control explants), (2) norepinephrine (NE; 10 µM), (3) IL-1β (75 pg/mL), or (4) NE + IL-1β. It was found that IL-1β abolished () NE-induced increase in melatonin release. Treatment with IL-1β also reduced () expression of AA-NAT enzyme compared to NE-treated explants. There was no effect of NE or IL-1β treatment on gene expression of HIOMT; however, the pineal fragments isolated from LPS-treated animals were characterized by elevated () expression of HIOMT mRNA and protein compared to the explants from saline-treated ewes. Our study proves that IL-1β suppresses melatonin secretion and its action seems to be targeted on the reduction of pineal AA-NAT protein expression. A. P. Herman, J. Bochenek, J. Skipor, K. Król, A. Krawczyńska, H. Antushevich, B. Pawlina, E. Marciniak, and D. Tomaszewska-Zaremba Copyright © 2015 A. P. Herman et al. All rights reserved. Identifying and Assessing Interesting Subgroups in a Heterogeneous Population Mon, 03 Aug 2015 13:21:57 +0000 Biological heterogeneity is common in many diseases and it is often the reason for therapeutic failures. Thus, there is great interest in classifying a disease into subtypes that have clinical significance in terms of prognosis or therapy response. One of the most popular methods to uncover unrecognized subtypes is cluster analysis. However, classical clustering methods such as k-means clustering or hierarchical clustering are not guaranteed to produce clinically interesting subtypes. This could be because the main statistical variability—the basis of cluster generation—is dominated by genes not associated with the clinical phenotype of interest. Furthermore, a strong prognostic factor might be relevant for a certain subgroup but not for the whole population; thus an analysis of the whole sample may not reveal this prognostic factor. To address these problems we investigate methods to identify and assess clinically interesting subgroups in a heterogeneous population. The identification step uses a clustering algorithm and to assess significance we use a false discovery rate- (FDR-) based measure. Under the heterogeneity condition the standard FDR estimate is shown to overestimate the true FDR value, but this is remedied by an improved FDR estimation procedure. As illustrations, two real data examples from gene expression studies of lung cancer are provided. Woojoo Lee, Andrey Alexeyenko, Maria Pernemalm, Justine Guegan, Philippe Dessen, Vladimir Lazar, Janne Lehtiö, and Yudi Pawitan Copyright © 2015 Woojoo Lee et al. All rights reserved. Detecting Genetic Interactions for Quantitative Traits Using -Spacing Entropy Measure Mon, 03 Aug 2015 13:10:36 +0000 A number of statistical methods for detecting gene-gene interactions have been developed in genetic association studies with binary traits. However, many phenotype measures are intrinsically quantitative and categorizing continuous traits may not always be straightforward and meaningful. Association of gene-gene interactions with an observed distribution of such phenotypes needs to be investigated directly without categorization. Information gain based on entropy measure has previously been successful in identifying genetic associations with binary traits. We extend the usefulness of this information gain by proposing a nonparametric evaluation method of conditional entropy of a quantitative phenotype associated with a given genotype. Hence, the information gain can be obtained for any phenotype distribution. Because any functional form, such as Gaussian, is not assumed for the entire distribution of a trait or a given genotype, this method is expected to be robust enough to be applied to any phenotypic association data. Here, we show its use to successfully identify the main effect, as well as the genetic interactions, associated with a quantitative trait. Jaeyong Yee, Min-Seok Kwon, Seohoon Jin, Taesung Park, and Mira Park Copyright © 2015 Jaeyong Yee et al. All rights reserved. A Comparative Study on Multifactor Dimensionality Reduction Methods for Detecting Gene-Gene Interactions with the Survival Phenotype Mon, 03 Aug 2015 13:06:31 +0000 Genome-wide association studies (GWAS) have extensively analyzed single SNP effects on a wide variety of common and complex diseases and found many genetic variants associated with diseases. However, there is still a large portion of the genetic variants left unexplained. This missing heritability problem might be due to the analytical strategy that limits analyses to only single SNPs. One of possible approaches to the missing heritability problem is to consider identifying multi-SNP effects or gene-gene interactions. The multifactor dimensionality reduction method has been widely used to detect gene-gene interactions based on the constructive induction by classifying high-dimensional genotype combinations into one-dimensional variable with two attributes of high risk and low risk for the case-control study. Many modifications of MDR have been proposed and also extended to the survival phenotype. In this study, we propose several extensions of MDR for the survival phenotype and compare the proposed extensions with earlier MDR through comprehensive simulation studies. Seungyeoun Lee, Yongkang Kim, Min-Seok Kwon, and Taesung Park Copyright © 2015 Seungyeoun Lee et al. All rights reserved. Interleukin-27 Protects Cardiomyocyte-Like H9c2 Cells against Metabolic Syndrome: Role of STAT3 Signaling Mon, 03 Aug 2015 13:01:52 +0000 The present results demonstrated that high glucose (G), salt (S), and cholesterol C (either alone or in combination), as mimicking extracellular changes in metabolic syndrome, damage cardiomyocyte-like H9c2 cells and reduce their viability in a time-dependent manner. However, the effects were greatest when cells were exposed to all three agents (GSC). The mRNA of glycoprotein (gp) 130 and WSX-1, both components of the interleukin (IL)-27 receptor, were present in H9c2 cells. Although mRNA expression was not affected by exogenous treatment with IL-27, the expression of gp130 mRNA (but not that of WSX-1 mRNA) was attenuated by GSC. Treatment of IL-27 to H9c2 cells increased activation of signal transducer and activator of transcription 3 (STAT3) and protected cells from GSC-induced cytochrome c release and cell damage. The protective effects of IL-27 were abrogated by the STAT3 inhibitor, stattic. The results of the present study clearly demonstrate that the STAT3 pathway triggered by anti-inflammatory IL-27 plays a role in protecting cardiomyocytes against GSC-mediated damage. Wei-Lian Phan, Yu-Tzu Huang, and Ming-Chieh Ma Copyright © 2015 Wei-Lian Phan et al. All rights reserved. On the Estimation of Heritability with Family-Based and Population-Based Samples Mon, 03 Aug 2015 13:00:35 +0000 For a family-based sample, the phenotypic variance-covariance matrix can be parameterized to include the variance of a polygenic effect that has then been estimated using a variance component analysis. However, with the advent of large-scale genomic data, the genetic relationship matrix (GRM) can be estimated and can be utilized to parameterize the variance of a polygenic effect for population-based samples. Therefore narrow sense heritability, which is both population and trait specific, can be estimated with both population- and family-based samples. In this study we estimate heritability from both family-based and population-based samples, collected in Korea, and the heritability estimates from the pooled samples were, for height, 0.60; body mass index (BMI), 0.32; log-transformed triglycerides (log TG), 0.24; total cholesterol (TCHL), 0.30; high-density lipoprotein (HDL), 0.38; low-density lipoprotein (LDL), 0.29; systolic blood pressure (SBP), 0.23; and diastolic blood pressure (DBP), 0.24. Furthermore, we found differences in how heritability is estimated—in particular the amount of variance attributable to common environment in twins can be substantial—which indicates heritability estimates should be interpreted with caution. Youngdoe Kim, Young Lee, Sungyoung Lee, Nam Hee Kim, Jeongmin Lim, Young Jin Kim, Ji Hee Oh, Haesook Min, Meehee Lee, Hyeon-Jeong Seo, So-Hyun Lee, Joohon Sung, Nam H. Cho, Bong-Jo Kim, Bok-Ghee Han, Robert C. Elston, Sungho Won, and Juyoung Lee Copyright © 2015 Youngdoe Kim et al. All rights reserved. MicroRNAs: Novel Players in the Dialogue between Pancreatic Islets and Immune System in Autoimmune Diabetes Mon, 03 Aug 2015 12:53:25 +0000 MicroRNAs are small noncoding RNA molecules that regulate gene expression in all cell types. Therefore, these tiny noncoding RNA molecules are involved in a wide range of biological processes, exerting functional effects at cellular, tissue, and organ level. In pancreatic islets of Langerhans, including beta-cells, microRNAs are involved in cell differentiation as well as in insulin secretion, while in immune cells they have been shown to play pivotal roles in development, activation, and response to antigens. Indeed, it is not surprising that microRNA alterations can lead to the development of several diseases, including type 1 diabetes (T1D). Type 1 diabetes is the result of a selective autoimmune destruction of insulin-producing beta-cells, characterized by islet inflammation (insulitis), which leads to chronic hyperglycemia. Given the growing importance of microRNA in the pathophysiology of T1D, the aim of this review is to summarize the most recent data on the potential involvement of microRNAs in autoimmune diabetes. Specifically, we will focus on three different aspects: (i) microRNAs as regulators of immune homeostasis in autoimmune diabetes; (ii) microRNA expression in pancreatic islet inflammation; (iii) microRNAs as players in the dialogue between the immune system and pancreatic endocrine cells. Giuliana Ventriglia, Laura Nigi, Guido Sebastiani, and Francesco Dotta Copyright © 2015 Giuliana Ventriglia et al. All rights reserved. Concordance of Hypermethylated DNA and the Tumor Markers CA 15-3, CEA, and TPA in Serum during Monitoring of Patients with Advanced Breast Cancer Mon, 03 Aug 2015 12:18:55 +0000 The serological protein tumor markers CA 15-3, CEA, and TPA are frequently used to monitor tumor burden among metastatic breast cancer patients. Breast cancer is associated with global DNA hypomethylation and hypermethylation of some promoter regions. No monitoring study has yet investigated the interrelationship between protein tumor markers, the global DNA hypomethylation, and hypermethylated genes in serum from patients with advanced disease. Twenty-nine patients with histologically proven advanced breast cancer received first-line chemotherapy with epirubicin. Samples were collected prior to each treatment and prospectively analyzed for CA 15-3, CEA, and TPA. The same samples were retrospectively analyzed for the concentration of hypermethylated RASSF1A and for global DNA hypomethylation using LINE-1. Among patients with elevated concentrations of the protein markers, concordance could be observed between serial changes of the hypermethylated RASSF1A gene and the protein markers. Among patients with lower concentrations, RASSF1A could only be detected periodically. There was discordance between changes of the hypomethylated LINE-1 as compared to the protein markers. Circulating hypermethylated RASSF1A and protein markers may have similar kinetics during monitoring of tumor burden. Further investigations are needed to determine whether any of the hypermethylated DNA genes may provide predictive information during monitoring. Søren Kristiansen, Lars Mønster Jørgensen, Morten Høgh Hansen, Dorte Nielsen, and György Sölétormos Copyright © 2015 Søren Kristiansen et al. All rights reserved. Effect of Environmental Chemical Stress on Nuclear Noncoding RNA Involved in Epigenetic Control Mon, 03 Aug 2015 12:11:08 +0000 In the last decade the role of noncoding RNAs (ncRNAs) emerges not only as key elements of posttranscriptional gene silencing, but also as important players of epigenetic regulation. New kind and new functions of ncRNAs are continuously discovered and one of their most important roles is the mediation of environmental signals, both physical and chemical. The activity of cytoplasmic short ncRNA is extensively studied, in spite of the fact that their function and role in the nuclear compartment are not yet completely unraveled. Cellular nucleus contains a multiplicity of long and short ncRNAs controlling at different levels transcriptional and epigenetic processes. In addition, some ncRNAs are involved in RNA editing and quality control. In this paper we review the existing knowledge dealing with how chemical stressors can influence the functionality of short nuclear ncRNAs. Furthermore, we perform bioinformatics analyses indicating that chemical environmental stressors not only induce DNA damage but also influence the mechanism of ncRNAs production and control. Patrizio Arrigo and Alessandra Pulliero Copyright © 2015 Patrizio Arrigo and Alessandra Pulliero. All rights reserved. Association between Genetic Polymorphisms of DNA Repair Genes and Chromosomal Damage for 1,3-Butadiene-Exposed Workers in a Matched Study in China Mon, 03 Aug 2015 12:09:58 +0000 The aim of the study was to examine the association between polymorphisms of DNA repair genes and chromosomal damage of 1,3-butadiene- (BD-) exposed workers. The study was conducted in 45 pairs of occupationally exposed workers in a BD product workshop and matched control workers in an administrative office and a circulatory water workshop in China. Newly developed biomarkers (micronuclei, MNi; nucleoplasmic bridges, NPBs; nuclear buds, NBUDs) in the cytokinesis-blocked micronucleus (CBMN) cytome assay were adopted to detect chromosomal damage. PCR and PCR-restriction fragment length polymorphism (RFLP) are adopted to analyze polymorphisms of DNA repair genes, such as X-ray repair cross-complementing Group 1 (XRCC1), O6-methylguanine-DNA methyltransferase (MGMT), poly (adenosine diphosphate-ribose) polymerases (ADPRT), and apurinic/apyrimidinic endonucleases (APE1). The BD-exposed workers exhibited increased frequencies of MNi and NPBs when compared to subjects in the control group. The results also show that the BD-exposed workers carrying XRCC1 diplotypes TCGA-CCGG () (, 95% CI: 1.03–4.28) and TCGG-TCGA () (, 95% CI: 0.76–2.65) had statistically higher NBUD frequencies than those who carried diplotype TCGG-TCGG (). Our study suggests that polymorphisms of XRCC1 gene may influence chromosomal damage in BD-exposed workers. Menglong Xiang, Lei Sun, Xiaomei Dong, Huan Yang, Wen-bin Liu, Niya Zhou, Xue Han, Ziyuan Zhou, Zhihong Cui, Jing-yi Liu, Jia Cao, and Lin Ao Copyright © 2015 Menglong Xiang et al. All rights reserved. Improved Production of Sublancin 168 Biosynthesized by Bacillus subtilis 168 Using Chemometric Methodology and Statistical Experimental Designs Mon, 03 Aug 2015 12:05:52 +0000 Sublancin 168, as a distinct S-linked antimicrobial glycopeptide produced by Bacillus subtilis 168, is effective in killing specific microorganisms. However, the reported yield of sublancin 168 is at a low level of no more than 60 mg from 1 L fermentation culture of B. subtilis 168 by using the method in the literature. Thus optimization of fermentation condition for efficiently producing sublancin 168 is required. Here, Box-Behnken design was used to determine the optimal combination of three fermentation parameters, namely, corn powder, soybean meal, and temperature that were identified previously by Plackett-Burman design and the steepest ascent experiment. Subsequently, based on the response surface methodology, the quadratic regression model for optimally producing sublancin 168 was developed, and the optimal combination of culture parameters for maximum sublancin 168 production of 129.72 mg/L was determined as corn powder 28.49 g/L, soybean meal 22.99 g/L, and incubation temperature 30.8°C. The results showed that sublancin 168 production obtained experimentally was coincident with predicted value of 125.88 mg/L, and the developed model was proved to be adequate, and the aim of efficiently producing sublancin 168 was achieved. Shengyue Ji, Weili Li, Haiyun Xin, Shan Wang, and Binyun Cao Copyright © 2015 Shengyue Ji et al. All rights reserved. Bioconcentration and Acute Intoxication of Brazilian Freshwater Fishes by the Methyl Parathion Organophosphate Pesticide Mon, 03 Aug 2015 11:49:36 +0000 Three species of freshwater Brazilian fishes (pacu, Piaractus mesopotamicus; piavussu, Leporinus macrocephalus, and curimbatá, Prochilodus lineatus) were exposed to an acute dose of 5 ppm methyl parathion organophosphate pesticide. Three to five individuals per species were exposed, one at a time, to 40 liters tap water spiked with Folidol 600. Pesticide concentrations and cholinesterase (ChE) activities were evaluated in serum, liver, brain, heart, and muscle. The bioconcentration of methyl parathion was similar for all studied fishes. Brain tissue showed the highest pesticide concentration, reaching 80 ppm after exposure for 30 min to methyl parathion. Three to 5 hours of 5 ppm methyl parathion exposure provoked the death of all P. lineatus at 92% brain AChE inhibition, whereas fish from the other two species survived for up to 78 hours with less than 80% brain AChE inhibition. Our results indicate that acute toxic effects of methyl parathion to fish are correlated with brain AChE sensitivity to methyl paraoxon. João Bosco de Salles, Renato Matos Lopes, Cristiane M. C. de Salles, Vicente P. F. Cassano, Manildo Marcião de Oliveira, Vera L. F. Cunha Bastos, and Jayme Cunha Bastos Copyright © 2015 João Bosco de Salles et al. All rights reserved. Differential Expression Analysis in RNA-Seq by a Naive Bayes Classifier with Local Normalization Mon, 03 Aug 2015 11:48:07 +0000 To improve the applicability of RNA-seq technology, a large number of RNA-seq data analysis methods and correction algorithms have been developed. Although these new methods and algorithms have steadily improved transcriptome analysis, greater prediction accuracy is needed to better guide experimental designs with computational results. In this study, a new tool for the identification of differentially expressed genes with RNA-seq data, named GExposer, was developed. This tool introduces a local normalization algorithm to reduce the bias of nonrandomly positioned read depth. The naive Bayes classifier is employed to integrate fold change, transcript length, and GC content to identify differentially expressed genes. Results on several independent tests show that GExposer has better performance than other methods. The combination of the local normalization algorithm and naive Bayes classifier with three attributes can achieve better results; both false positive rates and false negative rates are reduced. However, only a small portion of genes is affected by the local normalization and GC content correction. Yongchao Dou, Xiaomei Guo, Lingling Yuan, David R. Holding, and Chi Zhang Copyright © 2015 Yongchao Dou et al. All rights reserved. Considerable Variation of Antibacterial Activity of Cu Nanoparticles Suspensions Depending on the Storage Time, Dispersive Medium, and Particle Sizes Mon, 03 Aug 2015 11:46:27 +0000 Suspensions of Cu nanoparticles are promising for creating the new class of alternative antimicrobial products. In this study we examined copper nanoparticles of various sizes obtained by the method of wire electric explosion: nanopowder average size 50 nm (Cu 50) and 100 nm (Cu 100). The paper presents the complex study of the influence of physicochemical properties such as particle size and concentration of the freshly prepared and 24-hour suspensions of Cu nanoparticles in distilled water and physiological solution upon their toxicity to bacteria E. coli M-17. Ionic solution of Cu2+ and sodium dichloroisocyanurate was used for comparison study. It has been shown that decrease in the nanoparticle size leads to changes in the correlation between toxicity and concentration as toxicity peaks are observed at low concentrations (0.0001⋯0.01 mg/L). It has been observed that antibacterial properties of Cu 50 nanoparticle suspensions are ceased after 24-hour storage, while for Cu 100 suspensions no correlation between antibacterial properties and storage time has been noted. Cu 100 nanoparticle suspensions at 10 mg/L concentration display higher toxicity at substituting physiological solution for water than Cu 50 suspensions. Dependence of the toxicity on the mean particle aggregates size in suspension was not revealed. Olga V. Zakharova, Anna Yu. Godymchuk, Alexander A. Gusev, Svyatoslav I. Gulchenko, Inna A. Vasyukova, and Denis V. Kuznetsov Copyright © 2015 Olga V. Zakharova et al. All rights reserved. Heterologous Reconstitution of Omega-3 Polyunsaturated Fatty Acids in Arabidopsis Mon, 03 Aug 2015 11:35:05 +0000 Reconstitution of nonnative, very-long-chain polyunsaturated fatty acid (VLC-PUFA) biosynthetic pathways in Arabidopsis thaliana was undertaken. The introduction of three primary biosynthetic activities to cells requires the stable coexpression of multiple proteins within the same cell. Herein, we report that C22 VLC-PUFAs were synthesized from C18 precursors by reactions catalyzed by -desaturase, an ELOVL5-like enzyme involved in VLC-PUFA elongation, and -desaturase. Coexpression of the corresponding genes (McD6DES, AsELOVL5, and PtD5DES) under the control of the seed-specific vicilin promoter resulted in production of docosapentaenoic acid (22:5 n-3) and docosatetraenoic acid (22:4 n-6) as well as eicosapentaenoic acid (20:5 n-3) and arachidonic acid (20:4 n-6) in Arabidopsis seeds. The contributions of the transgenic enzymes and endogenous fatty acid metabolism were determined. Specifically, the reasonable synthesis of omega-3 stearidonic acid (18:4 n-3) could be a useful tool to obtain a sustainable system for the production of omega-3 fatty acids in seeds of a transgenic T3 line 63-1. The results indicated that coexpression of the three proteins was stable. Therefore, this study suggests that metabolic engineering of oilseed crops to produce VLC-PUFAs is feasible. Sun Hee Kim, Kyung Hee Roh, Jong-Sug Park, Kwang-Soo Kim, Hyun Uk Kim, Kyeong-Ryeol Lee, Han-Chul Kang, and Jong-Bum Kim Copyright © 2015 Sun Hee Kim et al. All rights reserved. Antibacterial Discovery and Development: From Gene to Product and Back Mon, 03 Aug 2015 11:35:01 +0000 Concern over the reports of antibiotic-resistant bacterial infections in hospitals and in the community has been publicized in the media, accompanied by comments on the risk that we may soon run out of antibiotics as a way to control infectious disease. Infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and other Enterobacteriaceae species represent a major public health burden. Despite the pharmaceutical sector’s lack of interest in the topic in the last decade, microbial natural products continue to represent one of the most interesting sources for discovering and developing novel antibacterials. Research in microbial natural product screening and development is currently benefiting from progress that has been made in other related fields (microbial ecology, analytical chemistry, genomics, molecular biology, and synthetic biology). In this paper, we review how novel and classical approaches can be integrated in the current processes for microbial product screening, fermentation, and strain improvement. Victor Fedorenko, Olga Genilloud, Liliya Horbal, Giorgia Letizia Marcone, Flavia Marinelli, Yossi Paitan, and Eliora Z. Ron Copyright © 2015 Victor Fedorenko et al. All rights reserved. Applying a Weight-of-Evidence Approach to Evaluate Relevance of Molecular Landscapes in the Exposure-Disease Paradigm Mon, 03 Aug 2015 11:34:50 +0000 Information on polymorphisms, mutations, and epigenetic events has become increasingly important in our understanding of molecular mechanisms associated with exposures-disease outcomes. Molecular landscapes can be developed to illustrate the molecular characteristics for environmental carcinogens as well as associated disease outcomes, although comparison of these molecular landscapes can often be difficult to navigate. We developed a method to organize these molecular data that uses a weight-of-evidence approach to rank overlapping molecular events by relative importance for susceptibility to an exposure-disease paradigm. To illustrate the usefulness of this approach, we discuss the example of benzene as an environmental carcinogen and myelodysplastic syndrome (MDS) as a causative disease endpoint. Using this weight-of-evidence method, we found overlapping polymorphisms in the genes for the metabolic enzymes GST and NQO1, both of which may infer risk of benzene-induced MDS. Polymorphisms in the tumor suppressor gene, TP53, and the inflammatory cytokine gene, TNF-α, were also noted, albeit inferring opposing outcomes. The alleles identified in the DNA repair gene RAD51 indicated an increased risk for MDS in MDS patients and low blood cell counts in benzene-exposed workers. We propose the weight-of-evidence approach as a tool to assist in organizing the sea of emerging molecular data in exposure-disease paradigms. Sherilyn A. Gross and Kristen M. Fedak Copyright © 2015 Sherilyn A. Gross and Kristen M. Fedak. All rights reserved. Gamma-Glutamylcyclotransferase: A Novel Target Molecule for Cancer Diagnosis and Treatment Mon, 03 Aug 2015 11:33:40 +0000 Gamma-glutamylcyclotransferase (GGCT) is one of the major enzymes involved in glutathione metabolism. However, its gene locus was unknown for many years. Recently, the gene for GGCT was found to be identical to C7orf24, which is registered as a hypothetical protein. Orthologs have been found in bacteria, plants, and nematodes as well as higher organisms, and the GGCT gene is highly preserved among a wide range of species. GGCT (C7orf24) was also reported as an upregulated protein in various cancers. Although the function of GGCT in cancer cells has not been determined, the following important activities have been reported: (1) high expression in various cancer tissues and cancer cell lines, (2) low expression in normal tissues, (3) inhibition of cancer cell proliferation via anti-GGCT RNAi, (4) inhibition of cancer cell invasion and migration via anti-GGCT RNAi, (5) an epigenetic transcriptional regulation in cancer cells, and (6) an antitumor effect in cancer-bearing xenograft mice. Therefore, GGCT is promising as a diagnostic marker and a therapeutic target for various cancers. This review summarizes these interesting findings. Susumu Kageyama, Eiki Hanada, Hiromi Ii, Keiji Tomita, Tatsuhiro Yoshiki, and Akihiro Kawauchi Copyright © 2015 Susumu Kageyama et al. All rights reserved. Reproductive Factors but Not Hormonal Factors Associated with Thyroid Cancer Risk: A Systematic Review and Meta-Analysis Mon, 03 Aug 2015 11:33:38 +0000 Many studies have investigated the association between hormonal and reproductive factors and thyroid cancer risk but provided contradictory and inconclusive findings. This review was aimed at precisely estimating this association by pooling all available epidemiological studies. 25 independent studies were retrieved after a comprehensive literature search in databases of PubMed and Embase. Overall, common hormonal factors including oral contraceptive and hormone replacement therapy did not alter the risk of thyroid cancer. Older age at menopause was associated with weakly increased risk of thyroid cancer in overall analysis (RR = 1.24, 95% CI 1.00–1.53, ); however, longer duration of breast feeding was related to moderately reduced risk of thyroid cancer, suggested by pooled analysis in all cohort studies (RR = 0.7, 95% CI 0.51–0.95, ). The pooled RR in hospital-based case-control studies implicated that parous women were more susceptible to thyroid cancer than nulliparous women (RR = 2.30, 95% CI 1.31–4.04, ). The present meta-analysis suggests that older age at menopause and parity are risk factors for thyroid cancer, while longer duration of breast feeding plays a protective role against this cancer. Nevertheless, more relevant epidemiological studies are warranted to investigate roles of hormonal and reproductive factors in thyroid carcinogenesis. Yijuan Cao, Zengyan Wang, Juan Gu, Fangfang Hu, Yujuan Qi, Qianqian Yin, Qingqing Sun, Guotao Li, and Bin Quan Copyright © 2015 Yijuan Cao et al. All rights reserved. Combination of Antiestrogens and Omega-3 Fatty Acids for Breast Cancer Prevention Mon, 03 Aug 2015 11:30:55 +0000 The molecular and biological heterogeneity of human breast cancer emphasizes the importance of a multitargeted approach for effective chemoprevention. Targeting the estrogen receptor pathway alone with the antiestrogens, Tamoxifen and Raloxifene reduces the incidence of estrogen receptor positive tumors but is ineffective against the development of hormone independent cancers. Our preclinical data indicate that the administration of omega-3 fatty acids potentiates the antitumor effects of Tamoxifen by inhibiting multiple proliferative and antiapoptotic pathways, several of which interact with estrogen receptor signaling. The complementarity in the mechanism of antitumor action of Tamoxifen and omega-3 fatty acids is well supported by our signaling, genomic, and proteomic studies. Furthermore, administration of omega-3 fatty acids allows the use of lower and, hence, likely less toxic doses of Tamoxifen. If these findings are supported in the clinical setting, the combination of omega-3 fatty acids and anteistrogens may emerge as a promising, effective, and safe chemopreventive strategy to be tested in a large multi-institutional trial using breast cancer incidence as the primary endpoint. Andrea Manni, Karam El-Bayoumy, Christine G. Skibinski, Henry J. Thompson, Julia Santucci-Pereira, Lucas Tadeu Bidinotto, and Jose Russo Copyright © 2015 Andrea Manni et al. All rights reserved. Biologically Active Metabolites Synthesized by Microalgae Mon, 03 Aug 2015 11:25:43 +0000 Microalgae are microorganisms that have different morphological, physiological, and genetic traits that confer the ability to produce different biologically active metabolites. Microalgal biotechnology has become a subject of study for various fields, due to the varied bioproducts that can be obtained from these microorganisms. When microalgal cultivation processes are better understood, microalgae can become an environmentally friendly and economically viable source of compounds of interest, because production can be optimized in a controlled culture. The bioactive compounds derived from microalgae have anti-inflammatory, antimicrobial, and antioxidant activities, among others. Furthermore, these microorganisms have the ability to promote health and reduce the risk of the development of degenerative diseases. In this context, the aim of this review is to discuss bioactive metabolites produced by microalgae for possible applications in the life sciences. Michele Greque de Morais, Bruna da Silva Vaz, Etiele Greque de Morais, and Jorge Alberto Vieira Costa Copyright © 2015 Michele Greque de Morais et al. All rights reserved. -Profiles: A Nonlinear Clustering Method for Pattern Detection in High Dimensional Data Mon, 03 Aug 2015 11:22:13 +0000 With modern technologies such as microarray, deep sequencing, and liquid chromatography-mass spectrometry (LC-MS), it is possible to measure the expression levels of thousands of genes/proteins simultaneously to unravel important biological processes. A very first step towards elucidating hidden patterns and understanding the massive data is the application of clustering techniques. Nonlinear relations, which were mostly unutilized in contrast to linear correlations, are prevalent in high-throughput data. In many cases, nonlinear relations can model the biological relationship more precisely and reflect critical patterns in the biological systems. Using the general dependency measure, Distance Based on Conditional Ordered List (DCOL) that we introduced before, we designed the nonlinear -profiles clustering method, which can be seen as the nonlinear counterpart of the -means clustering algorithm. The method has a built-in statistical testing procedure that ensures genes not belonging to any cluster do not impact the estimation of cluster profiles. Results from extensive simulation studies showed that -profiles clustering not only outperformed traditional linear -means algorithm, but also presented significantly better performance over our previous General Dependency Hierarchical Clustering (GDHC) algorithm. We further analyzed a gene expression dataset, on which -profile clustering generated biologically meaningful results. Kai Wang, Qing Zhao, Jianwei Lu, and Tianwei Yu Copyright © 2015 Kai Wang et al. All rights reserved. Violacein: Properties and Production of a Versatile Bacterial Pigment Mon, 03 Aug 2015 11:20:01 +0000 Violacein-producing bacteria, with their striking purple hues, have undoubtedly piqued the curiosity of scientists since their first discovery. The bisindole violacein is formed by the condensation of two tryptophan molecules through the action of five proteins. The genes required for its production, vioABCDE, and the regulatory mechanisms employed have been studied within a small number of violacein-producing strains. As a compound, violacein is known to have diverse biological activities, including being an anticancer agent and being an antibiotic against Staphylococcus aureus and other Gram-positive pathogens. Identifying the biological roles of this pigmented molecule is of particular interest, and understanding violacein’s function and mechanism of action has relevance to those unmasking any of its commercial or therapeutic benefits. Unfortunately, the production of violacein and its related derivatives is not easy and so various groups are also seeking to improve the fermentative yields of violacein through genetic engineering and synthetic biology. This review discusses the recent trends in the research and production of violacein by both natural and genetically modified bacterial strains. Seong Yeol Choi, Kyoung-hye Yoon, Jin Il Lee, and Robert J. Mitchell Copyright © 2015 Seong Yeol Choi et al. All rights reserved. Comparison of Simultaneous Nitrification and Denitrification for Three Different Reactors Mon, 03 Aug 2015 11:18:36 +0000 Discharge of high NH4-N containing wastewater into water bodies has become a critical and serious issue due to its negative impact on water and environmental quality. In this research, the performance of three different reactors was assessed and compared with regard to the removal of NH4-N from wastewater. The highest nitrogen removal efficiency of 98.3% was found when the entrapped sludge reactor (ESR), in which the sludge was entrapped in polyethylene glycol polymer, was used. Under intermittent aeration, nitrification and denitrification occurred simultaneously in the aerobic and anaerobic periods. Moreover, internal carbon was consumed efficiently for denitrification. On the other hand, internal carbon consumption was not found to occur in the suspended sludge reactor (SSR) and the mixed sludge reactor (MSR) and this resulted in nitrogen removal efficiencies of SSR and MSR being 64.7 and 45.1%, respectively. Nitrification and denitrification were the main nitrogen removal processes in the aerobic and anaerobic periods, respectively. However, due to the absence of sufficient organic carbon, denitrification was uncompleted resulting in high NO3-N contents in the effluent. W. Khanitchaidecha, A. Nakaruk, P. Koshy, and K. Futaba Copyright © 2015 W. Khanitchaidecha et al. All rights reserved. Lesser-Known Molecules in Ovarian Carcinogenesis Mon, 03 Aug 2015 11:17:59 +0000 Currently, the deciphering of the signaling pathways brings about new advances in the understanding of the pathogenic mechanism of ovarian carcinogenesis, which is based on the interaction of several molecules with different biochemical structure that, consequently, intervene in cell metabolism, through their role as regulators in proliferation, differentiation, and cell death. Given that the ensemble of biomarkers in OC includes more than 50 molecules the interest of the researchers focuses on the possible validation of each one’s potential as prognosis markers and/or therapeutic targets. Within this framework, this review presents three protein molecules: ALCAM, c-FLIP, and caveolin, motivated by the perspectives provided through the current limited knowledge on their role in ovarian carcinogenesis and on their potential as prognosis factors. Their structural stability, once altered, triggers the initiation of the sequences characteristic for ovarian carcinogenesis, through their role as modulators for several signaling pathways, contributing to the disruption of cellular junctions, disturbance of pro-/antiapoptotic equilibrium, and alteration of transmission of the signals specific for the molecular pathways. For each molecule, the text is built as follows: (i) general remarks, (ii) structural details, and (iii) particularities in expression, from different tumors to landmarks in ovarian carcinoma. Ludmila Lozneanu, Elena Cojocaru, Simona Eliza Giuşcă, Alexandru Cărăuleanu, and Irina-Draga Căruntu Copyright © 2015 Ludmila Lozneanu et al. All rights reserved. Heterogeneity of Genetic Damage in Cervical Nuclei and Lymphocytes in Women with Different Levels of Dysplasia and Cancer-Associated Risk Factors Mon, 03 Aug 2015 11:15:50 +0000 The comet assay can be used to assess genetic damage, but heterogeneity in the length of the tails is frequently observed. The aims of this study were to evaluate genetic damage and heterogeneity in the cervical nuclei and lymphocytes from patients with different levels of dysplasia and to determine the risk factors associated with the development of cervical cancer. The study included 97 females who presented with different levels of dysplasia. A comet assay was performed in peripheral blood lymphocytes and cervical epithelial cells. Significant genetic damage () was observed only in patients diagnosed with nuclei cervical from dysplasia III (NCDIII) and lymphocytes from dysplasia I (LDI). However, the standard deviations of the tail lengths in the cervical nuclei and lymphocytes from patients with dysplasia I were significantly different () from the standard deviations of the tail lengths in the nuclei cervical and lymphocytes from patients with DII and DIII (NCDII, NCDIII and LDII, LDIII), indicating a high heterogeneity in tail length. Results suggest that genetic damage could be widely present but only manifested as increased tail length in certain cell populations. This heterogeneity could obscure the statistical significance of the genetic damage. Carlos Alvarez-Moya, Mónica Reynoso-Silva, Alejandro A. Canales-Aguirre, José O. Chavez-Chavez, Hugo Castañeda-Vázquez, and Alfredo I. Feria-Velasco Copyright © 2015 Carlos Alvarez-Moya et al. All rights reserved. B-Cell Activating Factor as a Cancer Biomarker and Its Implications in Cancer-Related Cachexia Mon, 03 Aug 2015 11:05:51 +0000 B-cell activating factor (BAFF) is a cytokine and adipokine of the TNF ligand superfamily. The main biological function of BAFF in maintaining the maturation of B-cells to plasma cells has recently made it a target of the first FDA-approved selective BAFF antibody, belimumab, for the therapy of systemic lupus erythematosus. Concomitantly, the role of BAFF in cancer has been a subject of research since its discovery. Here we review BAFF as a biomarker of malignant disease activity and prognostic factor in B-cell derived malignancies such as multiple myeloma. Moreover, anti-BAFF therapy seems to be a promising approach in treatment of B-cell derived leukemias/lymphomas. In nonhematologic solid tumors, BAFF may contribute to cancer progression by mechanisms both dependent on and independent of BAFF’s proinflammatory role. We also describe ongoing research into the pathophysiological link between BAFF and cancer-related cachexia. BAFF has been shown to contribute to inflammation and insulin resistance which are known to worsen cancer cachexia syndrome. Taking all the above together, BAFF is emerging as a biomarker of several malignancies and a possible hallmark of cancer cachexia. Michal Rihacek, Julie Bienertova-Vasku, Dalibor Valik, Jaroslav Sterba, Katerina Pilatova, and Lenka Zdrazilova-Dubska Copyright © 2015 Michal Rihacek et al. All rights reserved. Omega-3 Polyunsaturated Fatty Acids Intake to Regulate Helicobacter pylori-Associated Gastric Diseases as Nonantimicrobial Dietary Approach Mon, 03 Aug 2015 11:01:42 +0000 Omega-3 polyunsaturated fatty acids (n-3 PUFAs), commonly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been acknowledged as essential long-chain fatty acids imposing either optimal health promotion or the rescuing from chronic inflammatory diseases such as atherosclerosis, fatty liver, and various inflammatory gastrointestinal diseases. Recent studies dealing with EPA and DHA have sparked highest interests because detailed molecular mechanisms had been documented with the identification of its receptor, G protein coupled receptor, and GPR120. In this review article, we have described clear evidences showing that n-3 PUFAs could reduce various Helicobacter pylori- (H. pylori-) associated gastric diseases and extended to play even cancer preventive outcomes including H. pylori-associated gastric cancer by influencing multiple targets, including proliferation, survival, angiogenesis, inflammation, and metastasis. Since our previous studies strongly concluded that nonantimicrobial dietary approach for reducing inflammation, for instance, application of phytoceuticals, probiotics, natural products including Korean red ginseng, and walnut plentiful of n-3 PUFAs, might be prerequisite step for preventing H. pylori-associated gastric cancer as well as facilitating the rejuvenation of precancerous atrophic gastritis, these beneficial lipids can restore or modify inflammation-associated lipid distortion and correction of altered lipid rafts to send right signaling to maintain healthy stomach even after chronic H. pylori infection. Jong-Min Park, Migyeong Jeong, Eun-Hee Kim, Young-Min Han, Sung Hun Kwon, and Ki-Baik Hahm Copyright © 2015 Jong-Min Park et al. All rights reserved. Isolation and Characterization of Hydrocarbon-Degrading Yeast Strains from Petroleum Contaminated Industrial Wastewater Mon, 03 Aug 2015 10:49:23 +0000 Two yeast strains are enriched and isolated from industrial refinery wastewater. These strains were observed for their ability to utilize several classes of petroleum hydrocarbons substrates, such as n-alkanes and aromatic hydrocarbons as a sole carbon source. Phylogenetic analysis based on the D1/D2 variable domain and the ITS-region sequences indicated that strains HC1 and HC4 were members of the genera Candida and Trichosporon, respectively. The mechanism of hydrocarbon uptaking by yeast, Candida, and Trichosporon has been studied by means of the kinetic analysis of hydrocarbons-degrading yeasts growth and substrate assimilation. Biodegradation capacity and biomass quantity were daily measured during twelve days by gravimetric analysis and gas chromatography coupled with mass spectrometry techniques. Removal of n-alkanes indicated a strong ability of hydrocarbon biodegradation by the isolated yeast strains. These two strains grew on long-chain n-alkane, diesel oil, and crude oil but failed to grow on short-chain n-alkane and aromatic hydrocarbons. Growth measurement attributes of the isolates, using n-hexadecane, diesel oil, and crude oil as substrates, showed that strain HC1 had better degradation for hydrocarbon substrates than strain HC4. In conclusion, these yeast strains can be useful for the bioremediation process and decreasing petroleum pollution in wastewater contaminated with petroleum hydrocarbons. Boutheina Gargouri, Najla Mhiri, Fatma Karray, Fathi Aloui, and Sami Sayadi Copyright © 2015 Boutheina Gargouri et al. All rights reserved.