• Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice.

      Neschen, Susanne; Morino, Katsutaro; Rossbacher, Jörg C.; Pongratz, Rebecca L.; Cline, Gary W.; Sono, Saki; Gillum, Matthew; Shulman, Gerald I. (2006-04)
      Adiponectin has insulin-sensitizing, antiatherogenic, and anti-inflammatory properties, but little is known about factors that regulate its secretion. To examine the effect of fish oil on adiponectin secretion, mice were fed either a control diet or isocaloric diets containing 27% safflower oil or 27, 13.5, and 8% menhaden fish oil. Within 15 days, fish oil feeding raised plasma adiponectin concentrations two- to threefold in a dose-dependent manner, and the concentrations remained approximately twofold higher for 7 days when the fish oil diet was replaced by the safflower oil diet. Within 24 h, fish oil markedly induced transcription of the adiponectin gene in epididymal adipose tissue but not in subcutaneous fat. The increase of plasma adiponectin by fish oil was completely blocked by administration of the peroxisome proliferator-activated receptor (PPAR)gamma inhibitor bisphenol-A-diglycidyl ether. In contrast, there was no effect of fish oil feeding on adiponectin secretion in PPARalpha-null mice. These data suggest that fish oil is a naturally occurring potent regulator of adiponectin secretion in vivo and that it does so through a PPARgamma-dependent and PPARalpha-independent manner in epididymal fat.
    • Five glutathione s-transferase gene variants in 23,452 cases of lung cancer and 30,397 controls: meta-analysis of 130 studies.

      Ye, Zheng; Song, Honglin; Higgins, Julian P. T.; Pharoah, Paul; Danesh, John (2006-04)
      BACKGROUND: Glutathione S-transferases (GSTs) are known to abolish or reduce the activities of intracellular enzymes that help detoxify environmental carcinogens, such as those found in tobacco smoke. It has been suggested that polymorphisms in the GST genes are risk factors for lung cancer, but a large number of studies have reported apparently conflicting results. METHODS AND FINDINGS: Literature-based meta-analysis was supplemented by tabular data from investigators of all relevant studies of five GST polymorphisms (GSTM1 null, GSTT1 null, I105V, and A114V polymorphisms in the GSTP1 genes, and GSTM3 intron 6 polymorphism) available before August, 2005, with investigation of potential sources of heterogeneity. Included in the present meta-analysis were 130 studies, involving a total of 23,452 lung cancer cases and 30,397 controls. In a combined analysis, the relative risks for lung cancer of the GSTM1 null and GSTT1 null polymorphisms were 1.18 (95% confidence interval [CI]: 1.14-1.23) and 1.09 (95% CI: 1.02-1.16), respectively, but in the larger studies they were only 1.04 (95% CI: 0.95-1.14) and 0.99 (95% CI: 0.86-1.11), respectively. In addition to size of study, ethnic background was a significant source of heterogeneity among studies of the GSTM1 null genotype, with possibly weaker associations in studies of individuals of European continental ancestry. Combined analyses of studies of the 105V, 114V, and GSTM3*B variants showed no significant overall associations with lung cancer, yielding per-allele relative risks of 1.04 (95% CI: 0.99-1.09), 1.15 (95% CI: 0.95-1.39), and 1.05 (95% CI: 0.89-1.23), respectively. CONCLUSIONS: The risk of lung cancer is not strongly associated with the I105V and A114V polymorphisms in the GSTP1 gene or with GSTM3 intron 6 polymorphism. Given the non-significant associations in the larger studies, the relevance of the weakly positive overall associations with the GSTM1 null and the GSTT1 null polymorphisms is uncertain. As lung cancer has important environmental causes, understanding any genetic contribution to it in general populations will require the conduct of particularly large and comprehensive studies.
    • Frequency of RAS gene mutation and its cooperative genetic events in Southeast Asian adult acute myeloid leukemia.

      Auewarakul, Chirayu U.; Lauhakirti, Darat; Tocharoentanaphol, Chintana (2006-07)
      RAS gene as one of the most frequently mutated genes in acute myeloid leukemia (AML) has become an attractive target for molecular therapy. The role of oncogenic RAS and its associated genetic events in AML are not yet defined. We examined the frequency of RAS mutation in 239 Thai de novo adult AML patients using polymerase chain reaction-single-strand conformational polymorphism analysis. Thirty-five RAS mutations were found in 32 cases (13%) predominantly classified as M1/M2 (53%) followed by M4/M5 subtype (38%). Ten cases were positive for N-RAS codon 12, 11 cases for N-RAS codon 61, 13 cases for N-RAS codon 13, and one case for K-RAS codon 13. No mutation was found in K-RAS exon 2 or H-RAS. The most common base substitution was the G to A transition at codon 13. Most M1/M2 cases had mutations at codon 12 or 13, whereas M4/M5 cases preferentially affected codon 61. Half of the patients with RAS mutations had abnormal karyotypes with the majority involving chromosomes 21, 11 and 7. Four patients had core-binding factor leukemia and four additional patients had coexisting FLT3 or AML1 mutation. One patient had RAS, FLT3 and t(8;21) and the other had RAS, AML1 point mutation and del(9q). In conclusion, mutation of RAS gene was not as common in the Thais as in the western population. Several additional genetic abnormalities occurred in RAS-mutated patients. Future molecular-targeting approaches should take into account the multiple genetic events that coexist with RAS mutations in AML patients.
    • Functional analysis of a metal response element in the regulatory region of flounder cytochrome P450 1A and implications for environmental monitoring of pollutants.

      Lewis, Nick A.; Williams, Tim D.; Chipman, James K. (2006-08)
      Cytochrome P450 1A (CYP 1A) is a member of a multigene family of xenobiotic metabolizing enzymes. CYP 1A is highly inducible by numerous environmental contaminants including polycyclic aromatic hydrocarbons (PAHs) and is widely used in biomonitoring studies. Therefore, understanding the regulation of this gene is important for accurate interpretation of biomarker data. We describe here the functional role of a metal response element (MRE) in the European flounder CYP 1A promoter region. To help elucidate the potential role of this MRE, reporter gene constructs, with or without site-directed mutagenesis, were used in conjunction with a dual-luciferase assay. The electrophoretic mobility shift assay (EMSA) was also used to investigate potential protein binding at this MRE site. Treatment with the prototypical PAH 3-methylcholanthrene (3MC) (1.0 microM) produced a dose-dependent response at the CYP 1A promoter, whereas treatment with cadmium (0-1.0 microM) produced little transcriptional activity at either the wild-type or mutated promoter. Cotreatment with cadmium (1.0 microM) and 3MC (1.0 microM) reduced induction at this promoter to 1.83-fold compared to 3MC treatment alone (4.0-fold induction). Mutation of the MRE site resulted in abolishment of this cadmium-related loss of 3MC-dependent activity. Furthermore, a retarded band was observed in the EMSA when the MRE was used as a probe and incubated with liver nuclear protein from flounder treated with cadmium. The results not only add to knowledge of the diversity in vertebrate CYP 1A regulation but also raise the complexity of interpretation of CYP 1A induction in monitoring studies that involve mixtures of PAHs and metals.
    • Functional nsSNPs from carcinogenesis-related genes expressed in breast tissue: potential breast cancer risk alleles and their distribution across human populations.

      Savas, Sevtap; Schmidt, Steffen; Jarjanazi, Hamdi; Ozcelik, Hilmi (2006-03)
      Although highly penetrant alleles of BRCA1 and BRCA2 have been shown to predispose to breast cancer, the majority of breast cancer cases are assumed to result from the presence of low-moderate penetrant alleles and environmental carcinogens. Non-synonymous single nucleotide polymorphisms (nsSNPs) are hypothesised to contribute to disease susceptibility and approximately 30 per cent of them are predicted to have a biological significance. In this study, we have applied a bioinformatics-based strategy to identify breast cancer-related nsSNPs from 981 carcinogenesis-related genes expressed in breast tissue. Our results revealed a total of 367 validated nsSNPs, 109 (29.7 per cent) of which are predicted to affect the protein function (functional nsSNPs), suggesting that these nsSNPs are likely to influence the development and homeostasis of breast tissue and hence contribute to breast cancer susceptibility. Sixty-seven of the functional nsSNPs presented as commonly occurring nsSNPs (minor allele frequencies > or =5 per cent), representing excellent candidates for breast cancer susceptibility. Additionally, a non-uniform distribution of the common functional nsSNPs among different human populations was observed: 15 nsSNPs were reported to be present in all populations analysed, whereas another set of 15 nsSNPs was specific to particular population(s). We propose that the nsSNPs analysed in this study constitute a unique resource of potential genetic factors for breast cancer susceptibility. Furthermore, the variations in functional nsSNP allele frequencies across major population backgrounds may point to the potential variability of the molecular basis of breast cancer predisposition and treatment response among different human populations.
    • Gene expression profiles of head and neck carcinomas from Sudanese and Norwegian patients reveal common biological pathways regardless of race and lifestyle.

      Dysvik, Bjarte; Vasstrand, Endre N.; Løvlie, Roger; Elgindi, Osman A-Aziz; Kross, Kenneth W.; Aarstad, Hans J.; Johannessen, Anne Chr; Jonassen, Inge; Ibrahim, Salah O. (2006-02-15)
      PURPOSE: To explore possible range of gene expression profiles in head and neck squamous cell carcinomas (HNSCC) and pairwised normal controls from Sudanese (n = 72) and Norwegian (n = 45) patients using a 15K cDNA microarray and to correlate the findings with clinicopathologic variables. EXPERIMENTAL DESIGN: Samples from Sudan were grouped according to anatomic location/patients' habit of toombak (snuff) use, and 37 pools of 2 to 11 tumors matched to 37 pools of their normal controls from the same patients, respectively, were prepared. For Norway, eight pools of 3 to 11 tumors matched to eight pools of their normal controls from the same patients, respectively, were prepared according to anatomic location. Pools (n = 45) were hybridized to microarrays. For controls, 33 of the pools were hybridized against Human Reference RNA. Scanned array images were recorded, and data analysis was done in groups. For verification, results for selected genes were analyzed using quantitative real-time PCR/immunohistochemistry. RESULTS: We identified 136 genes from Sudan and 154 from Norway as differentially expressed between tumors and controls. Changes of the genes found were confirmed in >70% of the pools by hybridization against Reference RNA. Seventy-three genes and three main pathways (signal transduction, cell communication, and ligand-receptor interaction) were of relevance to the HNSCCs from both countries. Hierarchical clustering of the 73 genes identified subclasses of mixed tumors from the two populations, two independent subgroups for Norwegian tumors by their anatomic sites, and five subgroups for Sudanese tumors by their toombak habits. Quantitative real-time PCR/immunohistochemistry validated the microarray-based data. CONCLUSIONS: Differences in gene expression between tumor and nontumor tissues were identified in HNSCCs. Analysis of the two population groups revealed a common set of 73 genes within three main biological pathways. This indicates that the development of HNSCCs is mediated by similar biological pathways regardless of differences related to race, ethnicity, lifestyle, and/or exposure to environmental carcinogens. Of particular interest, however, was the valuable association of gene expression signature found with toombak use and anatomic site of the tumors.
    • The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms.

      Bavik, Claes; Coleman, Ilsa; Dean, James P.; Knudsen, Beatrice; Plymate, Steven; Nelson, Peter S. (2006-01-15)
      The greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia.
    • Gene-environment interaction involved in oral carcinogenesis: molecular epidemiological study for metabolic and DNA repair gene polymorphisms.

      Sugimura, Tomotaka; Kumimoto, Hiroshi; Tohnai, Iwai; Fukui, Takafumi; Matsuo, Keitaro; Tsurusako, Shinichi; Mitsudo, Kenji; Ueda, Minoru; Tajima, Kazuo; Ishizaki, Kanji (2006-01)
      BACKGROUND: Exposure to environmental carcinogens leads to oral squamous cell carcinoma (OSCC); however, the impact of genetic variations in carcinogen metabolisms and DNA repair on OSCC risk considering environmental exposures has not been clearly elucidated. METHODS: We conducted a case-control study with 122 cases and 241 controls. The risk of OSCC was evaluated in 10 genetic polymorphisms of nine genes, such as CYP1A1, CYP2E1, GSTM1, GSTT1, XPA, XPC, XPC, XPF and ERCC1. Gene-environment interaction was also evaluated. RESULTS: We found that CYP2E1 and XPA polymorphisms significantly affected the OSCC risk. Gene-environment interactions with smoking were significant for CYP2E1 and ERCC1 polymorphisms. Odds ratios for gene-environment interaction were 7.98 (P = 0.036), 9.67 (P = 0.017) and 8.49 (P = 0.031) for CYP2E1RsaI, DraI and ERCC1 polymorphisms, respectively. No interaction was observed with heavy drinking and any polymorphisms. CONCLUSION: CYP2E1, XPA and ERCC1 polymorphisms may affect the risk of OSCC.
    • Genetic predisposition to fiber carcinogenesis causes a mesothelioma epidemic in Turkey.

      Dogan, A. Umran; Baris, Y. Izzettin; Dogan, Meral; Emri, Salih; Steele, Ian; Elmishad, Amira G.; Carbone, Michele (2006-05-15)
      Malignant mesothelioma in the western world is often associated with asbestos exposure. It is a relatively rare cancer that causes approximately 2,500 deaths yearly in the United States and 1,000 deaths yearly in the United Kingdom. In contrast, among people born in the Cappadocian (Turkey) villages of Tuzkoy, Karain, and "Old" Sarihidir, approximately 50% of deaths are caused by malignant mesothelioma. This epidemic has been attributed to erionite exposure, a type of fibrous zeolite mineral commonly found in this area of Turkey. In these three villages, malignant mesothelioma occurs in certain houses but not in others. The hypothesis was that a unique and more carcinogenic erionite was present in certain houses and caused malignant mesothelioma. We determined the X-ray diffraction pattern and the crystal structure of erionite from malignant mesothelioma villages and compared the results with the erionite samples from nearby non-malignant mesothelioma villages and from the United States. We found the same type of erionite in Cappadocian villages, with or without a malignant mesothelioma epidemic, in households with high or no incidence of malignant mesothelioma and in the United States. Pedigree studies of the three malignant mesothelioma villages showed that malignant mesothelioma was prevalent in certain families but not in others. When high-risk malignant mesothelioma family members married into families with no history of it, malignant mesothelioma appeared in the descendants. Genetically predisposed family members born and raised outside the malignant mesothelioma villages did not seem to develop malignant mesothelioma. In summary, pedigree and mineralogical studies indicate that the malignant mesothelioma epidemic is caused by erionite exposure in genetically predisposed individuals. This is the first time that genetics is shown to influence mineral fiber carcinogenesis.
    • Genetic variation of GSTM1, GSTT1 and GSTP1 genes in a South Indian population.

      Vettriselvi, V.; Vijayalakshmi, K.; Solomon Fd, Paul; Venkatachalam, P. (2009-03-11)
      The glutathione S transferase (GST) family of enzymes play a vital role in the phase II biotransformation of environmental carcinogens, pollutants, drugs and other xenobiotics. GSTs are polymorphic and the polymorphisms in GST genes have been associated with cancer susceptibility and prognosis. Moreover, distinct ethnic differences have been observed in the type and frequency of GST gene polymorphisms. Hence, the present study was aimed to determine the frequencies of GSTM1, GSTT1 and GSTP1 polymorphisms in 255 healthy random volunteers from South India. The GSTM1 and GSTT1 genotypes were determined by PCR and GSTP1 by PCR-RFLP using peripheral blood DNA.The GSTM1 and GSTT1 null genotype frequencies were found to be 22.4% and 17.6% respectively. The GSTP1 allelic frequency was 0.78 for the Ile allele and 0.22 for the Val allele and the genotype frequency was 58.4% for Ile/Ile, 38.4% for Ile/Val, and 3.1% for Val/Val. Comparison of the frequencies of GST polymorphisms observed in the present study with other Indian and world populations revealed a distinctive nature of the South Indian population with respect to polymorphims at the GST gene loci. A better understanding of carcinogen metabolizing gene distribution should contribute to risk assessment of humans exposed to environmental carcinogens.
    • Genotoxic effects of myosmine in a human esophageal adenocarcinoma cell line.

      Vogt, Sarah; Fuchs, Katharina; Richter, Elmar (2006-05-01)
      The incidence of esophageal adenocarcinoma is rapidly rising in Western populations. Gastroesophageal reflux disease (GERD) is thought to be one of the most important risk factors. However, the mechanisms by which GERD enhances tumor formation at the gastroesophageal junction are not well understood. Myosmine is a tobacco alkaloid which has also a wide spread occurrence in human diet. It is readily activated by nitrosation and peroxidation giving rise to the same hydroxypyridylbutanone-releasing DNA adducts as the esophageal carcinogen N'-nitrosonornicotine. Therefore, the genotoxicity of myosmine was tested in a human esophageal adenocarcinoma cell line (OE33). DNA damage was assessed by single-cell gel electrophoresis (Comet assay). DNA strand breaks, alkali labile sites and incomplete excision repair were expressed using the Olive tail moment (OTM). The Fapy glycosylase (Fpg) enzyme was incorporated into the assay to reveal additional oxidative DNA damage. DNA migration was determined after incubation of the cells for 1-24h. Under neutral conditions high myosmine concentrations of 25-50mM were necessary to elicit a weak genotoxic effect. At pH 6 genotoxicity was clearly enhanced giving a significant increase of OTM values at 5mM myosmine. Lower pH values could not be tested because of massive cytotoxicity even in the absence of myosmine. Co-incubation of 25 mM myosmine with 1mM H(2)O(2) for 1h significantly enhanced the genotoxicity of H(2)O(2) but not the oxidative lesions additionally detected with the Fpg enzyme. In the presence of the peroxynitrite donor 3-morpholinosydnonimine (SIN-1) a dose-dependent significant genotoxic effect was obtained with 1-10mM myosmine after 4h incubation. NS-398, a selective inhibitor of cyclooxygenase 2, did not affect the SIN-1 stimulated genotoxicity of myosmine. Finally, the 23 h repair of N-methyl-N'-nitro-N-nitrosoguanidine-induced DNA lesions was significantly inhibited in the presence of 10mM myosmine. In conclusion, myosmine exerts significant genotoxic effects in esophageal cells under conditions which may prevail in GERD such as increased oxidative and nitrosative stress resulting from chronic inflammation.
    • Glucoraphanin, the bioprecursor of the widely extolled chemopreventive agent sulforaphane found in broccoli, induces phase-I xenobiotic metabolizing enzymes and increases free radical generation in rat liver.

      Perocco, Paolo; Bronzetti, Giorgio; Canistro, Donatella; Valgimigli, Luca; Sapone, Andrea; Affatato, Alessandra; Pedulli, Gian Franco; Pozzetti, Laura; Broccoli, Massimiliano; Iori, Renato; et al. (2006-03-20)
      Epidemiological and animal studies linking high fruit and vegetable consumption to lower cancer risk have strengthened the belief that long-term administration of isolated naturally occurring dietary constituents could reduce the risk of cancer. In recent years, metabolites derived from phytoalexins, such as glucoraphanin found in broccoli and other cruciferous vegetables (Brassicaceae), have gained much attention as potential cancer chemopreventive agents. The protective effect of these micronutrients is assumed to be due to the inhibition of Phase-I carcinogen-bioactivating enzymes and/or induction of Phase-II detoxifying enzymes, an assumption that still remains uncertain. The protective effect of glucoraphanin is thought to be due to sulforaphane, an isothiocyanate metabolite produced from glucoraphanin by myrosinase. Here we show, in rat liver, that while glucoraphanin slightly induces Phase-II enzymes, it powerfully boosts Phase-I enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), nitrosamines and olefins. Induction of the cytochrome P450 (CYP) isoforms CYP1A1/2, CYP3A1/2 and CYP2E1 was confirmed by Western immunoblotting. CYP induction was paralleled by an increase in the corresponding mRNA levels. Concomitant with this Phase-I induction, we also found that glucoraphanin generated large amount of various reactive radical species, as determined by electron paramagnetic resonance (EPR) spectrometry coupled to a radical-probe technique. This suggests that long-term uncontrolled administration of glucoraphanin could actually pose a potential health hazard.
    • Glutathione S-transferase T1 status and gastric cancer risk: a meta-analysis of the literature.

      Boccia, Stefania; La Torre, Giuseppe; Gianfagna, Francesco; Mannocci, Alice; Ricciardi, Gualtiero (2006-03)
      To clarify the risk of gastric cancer associated with glutathione S-transferase T1 (GSTT1) status, a meta-analysis of published studies was performed. Eligible studies included all reports investigating an association between GSTT1 status and gastric cancer published before October 31, 2005. A qualitative scoring of papers was applied to evaluate the quality of the published data. The principal outcome measure was the odds ratio (OR) for the risk of gastric cancer associated with GSTT1 deletion status using a random effects model. Eighteen case-control studies detailing a possible association between the GSTT1 null genotype and gastric cancer were selected. Combining data from these studies, totalling 2508 cases and 4634 controls, a non-statistically significant OR for gastric cancer risk associated with GSTT1 deficiency emerged [OR = 1.09; 95% confidence interval (CI): 0.97-1.21; I(2) = 0%]. When only high-quality scored studies were considered, a statistically significant increased risk appeared (OR = 1.23; 95% CI: 1.04-1.45; I(2) = 0%), as well as considering only Caucasians (OR = 1.23; 95% CI: 1.03-1.56; I(2) = 0%). By pooling data from seven studies (319 cases and 656 controls) that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for gastric cancer (OR = 1.95, 95% CI: 1.42-2.67; I(2) = 0%) was detected for individuals with deletion mutations in both genes compared with wild-types. In conclusion, this meta-analysis suggests that the GSTT1 null genotype may slightly increase the risk of gastric cancer and that interaction between unfavourable GST genotypes may exist. Greater attention should, therefore, be paid to the design of future studies; the investigation of interactions among multiple genotypes and environmental exposures are justified to clarify GSTT1 null status influence on gastric cancer risk.
    • GSTM1 polymorphism and oral leukoplakia.

      Duarte, Eliza Carla Barroso; da Silva, Marina Sena Lopes; Gomez, Marcus Vinícius; Gomez, Ricardo Santiago (2006-04)
      BACKGROUND: Molecular epidemiological studies have now provided evidence that an individual susceptibility to cancer is mediated by genetic and environmental factors. Genetic polymorphisms have been described for enzymes involved in the metabolism of tobacco carcinogens and cancer risk is determined by the degree of expression and/or activity of enzymes involved in carcinogen activation or deactivation. The objective of this study was to investigate the GSTM1 null polymorphism and the risk for oral leukoplakia in individuals with tobacco-smoking habit in a Brazilian population. METHODS: A total of 52 tobacco-smoking patients with oral leukoplakia and 52 tobacco-smoking controls were recruited in a Brazilian population. The GSTM1 genotypes were studied by polymerase chain reaction-based methods. RESULTS: The frequency of the GSTM1 null genotype in the group with oral leukoplakia (57.7%) was statistically different from the controls (34.6%; OR: 2.57, 95% CI: 1.16-5.69, P < 0.05). The stratification of the samples according to the level of dysplasia showed increased prevalence of GSTM1 null genotype on lesions with moderate/severe histological dysplasia (68.2%) compared with the control group (31.9%). This difference was statistically significant (OR: 4.59, 95% CI: 1.29-16.33, P < 0.05). CONCLUSION: In conclusion, the GSTM1 null genotype may increase the risk for oral leukoplakia development.
    • Helicobacter pylori infection and gastric cancer.

      Matysiak-Budnik, Tamara; Mégraud, Francis (2006-04)
      The pathogenesis of gastric cancer (GC) includes a sequence of events that begins with Helicobacter pylori-induced chronic superficial gastritis, progressing towards atrophic gastritis, intestinal metaplasia, dysplasia and eventually GC. The association between H. pylori and GC is supported by experimental data showing a capacity of H. pylori to induce GC in animals, and the results of interventional studies showing that H. pylori eradication can lower the risk of GC and prevent development of pre-cancerous lesions in humans and in experimental animals. The "driving force" of gastric carcinogenesis is a chronic gastric inflammation, whose intensity and localisation depending on bacterial, host and environmental factors, determines the risk of GC. The mechanisms by which chronic inflammation lead to epithelial and pre-cancerous lesions include induction of oxidative stress, perturbation of the epithelial cells proliferation/apoptosis ratio, and cytokine secretion. Several molecular alterations associated with gastric carcinogenesis have also been described.
    • Higher urine 1-hydroxy pyrene glucuronide (1-OHPG) is associated with tobacco smoke exposure and drinking maté in healthy subjects from Rio Grande do Sul, Brazil.

      Fagundes, Renato B.; Abnet, Christian C.; Strickland, Paul T.; Kamangar, Farin; Roth, Mark J.; Taylor, Philip R.; Dawsey, Sanford M. (2006)
      BACKGROUND: The highest rates of esophageal squamous cell carcinoma (ESCC) in Brazil occur in Rio Grande do Sul, the most southern state, which has incidence rates of 20.4/100,000/year for men and 6.5/100,000/year for women. Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs) through tobacco smoke and other sources may increase the risk of ESCC. The aims of the current study were to investigate the degree and sources of PAH exposure of the inhabitants of this region of southern Brazil. METHODS: Two hundred healthy adults (half smokers, half non smokers, half male and half female) were recruited, given a standardized questionnaire, and asked to provide a urine sample for measurement of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite). Urine 1-OHPG concentrations were measured using immunoaffinity chromatography and synchronous fluorescence spectroscopy and urine cotinine was measured using a dipstick test. We examined factors associated with 1-OHPG concentration using Wilcoxon tests and multiple linear regression. RESULTS: Urine 1-hydroxypyrene glucuronide (1-OHPG) was successfully measured on 199 subjects. The median (interquartile range) of urine 1-OHPG in the 199 participants was 2.09 pmol/mL (0.51, 5.84). Tobacco smoke exposure and maté drinking were statistically significantly associated with higher urine 1-OHPG concentrations in the multivariate linear regression model. CONCLUSION: Tobacco smoke and maté both contribute to high levels of benzo[a]pyrene exposure in the people of southern Brazil. This high PAH exposure may contribute to the high rates of ESCC observed in this population. The increased urine 1-OHPG concentrations associated with maté suggest that contaminants, not just thermal injury, may help explain the increased risk of ESCC previously reported for maté consumption.
    • HLA-B67 may be a male-specific HLA marker of susceptibility to relapsed childhood ALL in Hong Kong Chinese and HLA-A33 or HLA-B17 signifies a higher presentation leukocytosis: A retrospective analysis on 53 transplant candidates (1989-2003).

      Ng, Margaret H.L.; Lau, K.M.; Hawkins, B.R.; Chik, K.W.; Chan, Natalie P.H.; Wong, W.S.; Tsang, K.S.; Shing, Matthew M.K.; Li, C.K. (2006-08)
      We performed a retrospective analysis on the human leukocyte antigen (HLA) data of 53 consecutive Chinese patients with high-risk childhood acute lymphoblastic leukemia (ALL) diagnosed from 1989 to 2003. A significantly higher frequency of HLA-B67 in the male relapse group of patients [OR, 23.08; 95% CI, 5.31-100.36; p = 0.0042; for statistical significance after Bonferroni correction (Bc) p (Bc) < 0.0083] was identified after Bonferroni correction. Although not surviving the Bonferroni correction, gender effects on the association were also observed with HLA-A11, HLA-A32, HLA-A33, and HLA-B22, which were however more prevalent in the female patients and particularly those developing relapse. Two patients with HLA-A29 and HLA-B7 revealed significantly shortened survivals, suggestive of their potential prognostic impacts. Notably, for the first time, we found a significant correlation of leukocyte count with HLA types, where HLA-A33 (p = 0.006) or HLA-B17 (p < 0.001) signifies higher leukocytosis at presentation. Taken together, our findings support the involvement of HLA in Chinese high-risk childhood ALL.
    • HPV-induced carcinogenesis of the uterine cervix is associated with reduced serum ATRA level.

      Berlin Grace, V. M.; Niranjali Devaraj, S.; Radhakrishnan Pillai, M.; Devaraj, Halagowder (2006-10)
      OBJECTIVE: In uterine cervical cancer, certain oncogenic HPV types are considered as key etiologic factor. But the progression of HPV associated cervical precancerous lesions depends on many other factors such as oncogenes, immune system, anti-viral factors etc. This study is therefore focused on the effect of an important dietary anti-viral factor called All Trans Retinoic Acid (ATRA) on the development of HPV associated cervical cancer as it is found higher in poor socioeconomic people. METHOD: We analyzed a total population of 130 including control subjects who have no complaints of uterine cervical lesions and the HPV-6/11, 16/18 infected cases of low grade squamous intraepithelial lesions [SIL], high grade squamous intraepithelial lesions [HSIL], and invasive cancers, for serum ATRA level. This study also focused to find out the association of serum ATRA level with the proliferation status in terms of proliferating cell nuclear antigen (PCNA) expression as it is an anti-proliferation agent and with the grades of cervical lesions, using SPSS statistical package. RESULTS: The results showed a highly significant negative association for serum ATRA level with different stages of cervical lesions (F = 3.305; P = 0.000) by one-way ANOVA and with intensity of PCNA expression (r = -0.825; P < 0.01) by Pearson's correlation test. A highly significant association was observed for the PCNA expression with the grades of cervical lesions too (F = 37.89; P = 0.000). Further, we found from our data that all the invasive cancer cases were infected with HPV-16/18 and none with HPV-6/11. Hence, we analyzed the association of serum ATRA level with HPV-16/18 infected preinvasive cases in developing invasiveness, by Fisher's Exact Test, using Graph Pad Prism as shown in Table 1. The results show an odds ratio (OR) of 36.93 and a relative risk (RR) of 4.99 with an 95% interval being 2.896 to 8.603, which is significant at the level of P = 0.0001 for the reduced [<0.6 mug/ml] serum ATRA level in developing invasive cancer in HPV-16/18 infected preinvasive cases. CONCLUSION: All these results suggest that the serum ATRA level highly influences the progression of cervical lesions to invasive cancer and can be therefore aimed as a marker for progression in combination with HPV-16/18, which helps to enhance the modalities of therapy towards cost effectiveness.
    • Immunohistochemical study of cell proliferation, Bcl-2, p53, and caspase-3 expression on preneoplastic changes induced by cadmium and zinc chloride in the ventral rat prostate.

      Arriazu, Riánsares; Pozuelo, José M.; Henriques-Gil, Nuno; Perucho, Teresa; Martín, Rocío; Rodríguez, Rosario; Santamaría, Luis (2006-09)
      This work was directed to evaluate immunoexpression of markers for apoptosis, resistance to apoptosis, and cell proliferation, as well as estimates of nuclear size in ventral prostate of rats treated with cadmium chloride and cadmium+zinc chloride because a possible protective effect of zinc has been postulated. The following variables were studied: volume fraction (VF) of Bcl-2 immunostaining, percentage of cells immunoreactive to proliferating cell nuclear antigen (LIPCNA) and p53 (LIp53), numerical density of caspase-3 immunoreactive cells (NV caspase-3), and estimates of volume-weighted mean nuclear volume (upsilonV). The LIPCNA and VF of Bcl-2 were significantly increased in the treated animals. The dysplasias (independent of their origin) showed a significant increase of the LIp53, NV caspase-3, and upsilonV in comparison with normal acini from treated and control animals. It can be concluded that cell proliferation is enhanced in long-term cadmium-exposed rats, and exposure to zinc combined with cadmium had no effect on any of the variables studied when comparing with normal acini. The increase of nuclear upsilonV could indicate a more aggressive behavior for pretumoral lesions.
    • Incidence of cancer among female flight attendants: a meta-analysis.

      Tokumaru, Osamu; Haruki, Kosuke; Bacal, Kira; Katagiri, Tomomi; Yamamoto, Taisuke; Sakurai, Yutaka (2009-05-20)
      BACKGROUND: Airline flight personnel work in a unique environment with exposure to known or suspected carcinogens and mutagens including ionizing cosmic radiation. A meta-analysis was conducted to study whether the occupational exposure of female flight attendants (FA) increased their relative risk of cancer incidence. METHODS: A bibliographical computer search from 1966 to 2005 of cancer incidence cohort studies of female FA was performed. Combined relative risks (RRc) in cancer incidence were calculated by means of meta-analysis. RESULTS: RRc and 95% confidence interval (CI) for malignant melanoma and breast cancer in female FA were 2.13 (95% CI: 1.58-2.88) and 1.41 (1.22-1.62) (p < 0.0001). Excess risk was not significant for all-site cancer with RRc of 1.10 (0.99-1.21). CONCLUSIONS: The meta-analysis confirmed the significantly increased risks for malignant melanoma and breast cancer in female FA. Increased exposure to cosmic radiation during flight has been suggested as a potential occupational risk factor. Ultraviolet radiation exposure on board seems an unlikely occupational risk, but nonoccupational leisure time sun exposure is a possible risk factor. The etiology of the observed increase in incidence of some cancers remains controversial because assessment of possible confounders, especially nonoccupational exposure factors, has thus far been limited.