Now showing items 21-40 of 184

    • 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.
    • 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.
    • Dietary effects of soy isoflavones daidzein and genistein on 7,12-dimethylbenz[a]anthracene-induced mammary mutagenesis and carcinogenesis in ovariectomized Big Blue transgenic rats.

      Manjanatha, Mugimane; Shelton, Sharon; Bishop, Michelle; Lyn-Cook, Lascelles; Aidoo, Anane (2006-10)
      The major constituents of isoflavones daidzein (DZ) and genistein (GE) interact with the and estrogen receptors in several tissues including mammary tissues. In this study, we used ovariectomy (OVX) to model menopause and determined the effects of DZ, GE or 17beta-estradiol (E(2)) exposures on chemically induced mutagenesis and carcinogenesis in the mammary glands of female Big Blue transgenic rats. The rats were fed control diet containing the isoflavones and E(2) and treated with a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at PND50. Animals were euthanized at 16 or 20 weeks post-carcinogen treatment to assess mutant frequencies (MFs) and histopathological parameters, respectively. The isoflavones or E(2) supplementation alone resulted in the lac I MFs that were not significantly different from the MFs measured in rats fed the control diet alone. DMBA exposure, however, induced significant increases in the lac I MFs in the mammary tissues of both OVX and INT rats and Hprt MFs in spleen lymphocytes (P < 0.01). In general, feeding the isoflavones or E(2) did not cause any significant changes in DMBA-induced mutagenicity in the mammary tissues. However, feeding the isoflavone mixture (daidzein + genistein; DZG) resulted in a significant reduction in the DMBA-induced lac I MFs (P < 0.05). Cell proliferation as measured by PCNA immunohistochemistry was increased in both OVX and INT rats exposed to DMBA as compared with rats fed control diet (P < 0.05). Mammary histology indicated that hyperplasia was induced in most of the treatment groups including control. Although DMBA did not induce mammary tumors in the OVX rats, adenoma and adenocarcinoma were detected in the mammary glands of INT rats.
    • Vegetable-derived isothiocyanates: anti-proliferative activity and mechanism of action.

      Zhang, Yuesheng; Yao, Song; Li, Jun (2006-02)
      Many isothiocyanates (ITC), which are available to human subjects mainly through consumption of cruciferous vegetables, demonstrate strong cancer-preventive activity in animal models. Human studies also show an inverse association between consumption of ITC and risk of cancer in several organs. Whereas earlier studies primarily focused on the ability of ITC to inhibit carcinogen-activating enzymes and induce carcinogen-detoxifying enzymes, more recent investigations have shown that ITC inhibit the proliferation of tumour cells both in vitro and in vivo by inducing apoptosis and arresting cell cycle progression. ITC cause acute cellular stress, which may be the initiating event for these effects. These findings shed new light on the mechanism of action of ITC and indicate that ITC may be useful both as cancer-preventive and therapeutic agents. ITC activate caspase 9-mediated apoptosis, apparently resulting from mitochondrial damage, and also activate caspase 8, but the mechanism remains to be defined. Cell cycle arrest caused by ITC occurs mainly in the G2/M phase, and both the G2 and M phases are targetted; critical G2-phase regulators, including cyclin B1, cell division cycle (Cdc) 2 and Cdc25C, are down regulated or inhibited, and tubulin polymerization and spindle assembly are disrupted. Moreover, ITC are metabolized in vivo through the mercapturic acid pathway, giving rise to thiol conjugates (dithiocarbamates). Studies show that these dithiocarbamates are similar to their parent ITC in exerting anti-proliferative activity. Taken together, dietary ITC are highly-promising anti-cancer agents, capable of targetting multiple cellular components that are important for tumour cell survival and proliferation.
    • Targeting apoptosis with dietary bioactive agents.

      Martin, Keith R. (2006-02)
      Apoptosis, a form of programmed cell death, is a pivotal defense against the occurrence of cancer and is essential to metazoans in maintaining tissue homeostasis. Apoptosis exhibits a distinctive phenotype and involves elimination of potentially deleterious cells. Many diseases have been associated with aberrantly regulated apoptotic cell death, ultimately leading to inhibition of apoptosis and propagation of diseases such as cancer. Elucidation of the critical events associated with carcinogenesis provides the opportunity for dietary intervention to prevent cancer development through induction of apoptosis, particularly by bioactive agents or functional foods. Diet is a significant environmental factor in the overall cancer process and can exacerbate or interfere with carcinogenesis. Apoptosis occurs primarily through two well-recognized pathways in cells, including the intrinsic, or mitochondrial-mediated, effector mechanism and the extrinsic, or death receptor-mediated, effector mechanism. In addition to diet's effects on protein expression and function, evidence is also accumulating that a large number of dietary food components can exert effects on the human genome, either directly or indirectly, to modulate gene expression. In fact, many diet-related genes are involved in carcinogenesis as well as apoptosis, and thus are ultimately molecular targets for dietary chemoprevention. There are multiple steps within pathways in which dietary components can alter gene expression and phenotypes of cells and thus influence cancer outcomes (nutritional transcriptomic effect). Thus, apoptosis is an emerging therapeutic target of bioactive agents of diet. In this review, the process of apoptosis is discussed and the potential mechanistic interaction of bioactive agents, as components of functional foods, is explored within the context of apoptosis.
    • Cruciferous vegetables and colo-rectal cancer.

      Lynn, Anthony; Collins, Andrew; Fuller, Zoë; Hillman, Kevin; Ratcliffe, Brian (2006-02)
      Cruciferous vegetables have been studied extensively for their chemoprotective effects. Although they contain many bioactive compounds, the anti-carcinogenic actions of cruciferous vegetables are commonly attributed to their content of glucosinolates. Glucosinolates are relatively biologically inert but can be hydrolysed to a range of bioactive compounds such as isothiocyanates (ITC) and indoles by the plant-based enzyme myrosinase, or less efficiently by the colonic microflora. A number of mechanisms whereby ITC and indoles may protect against colo-rectal cancer have been identified. In experimental animals cruciferous vegetables have been shown to inhibit chemically-induced colon cancer. However, the results of recent epidemiological cohort studies have been inconsistent and this disparity may reflect a lack of sensitivity of such studies. Possible explanations for the failure of epidemiological studies to detect an effect include: assessment of cruciferous vegetable intake by methods that are subject to large measurement errors; the interaction between diet and genotype has not been considered: the effect that post-harvest treatments may have on biological effects of cruciferous vegetables has not been taken into account.
    • Revised assessment of cancer risk to dichloromethane: part I Bayesian PBPK and dose-response modeling in mice.

      Marino, Dale J.; Clewell, Harvey J.; Gentry, P. Robinan; Covington, Tammie R.; Hack, C. Eric; David, Raymond M.; Morgott, David A. (2006-06)
      The current USEPA cancer risk assessment for dichloromethane (DCM) is based on deterministic physiologically based pharmacokinetic (PBPK) modeling involving comparative metabolism of DCM by the GST pathway in the lung and liver of humans and mice. Recent advances in PBPK modeling include probabilistic methods and, in particular, Bayesian inference to quantitatively address variability and uncertainty separately. Although Bayesian analysis of human PBPK models has been published, no such efforts have been reported specifically addressing the mouse, apart from results included in the OSHA final rule on DCM. Certain aspects of the OSHA model, however, are not consistent with current approaches or with the USEPA's current DCM cancer risk assessment. Therefore, Bayesian analysis of the mouse PBPK model and dose-response modeling was undertaken to support development of an improved cancer risk assessment for DCM. A hierarchical population model was developed and prior parameter distributions were selected to reflect parameter values that were considered the most appropriate and best available. Bayesian modeling was conducted using MCSim, a publicly available software program for Markov Chain Monte Carlo analysis. Mean posterior values from the calibrated model were used to develop internal dose metrics, i.e., mg DCM metabolized by the GST pathway/L tissue/day in the lung and liver using exposure concentrations and results from the NTP mouse bioassay, consistent with the approach used by the USEPA for its current DCM cancer risk assessment. Internal dose metrics were 3- to 4-fold higher than those that support the current USEPA IRIS assessment. A decrease of similar magnitude was also noted in dose-response modeling results. These results show that the Bayesian PBPK model in the mouse provides an improved basis for a cancer risk assessment of DCM.
    • 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.
    • The vitamin D questions: how much do you need and how should you get it?

      Wolpowitz, Deon; Gilchrest, Barbara A. (2006-02)
      UV radiation is a well-documented human carcinogen, indisputably linked to the current continued increased rate of skin cancer. UV radiation is also responsible for cutaneous synthesis of vitamin (vit) D3, a substance that is then sequentially hydroxylated in the liver and kidney to yield 1,25(OH)2 vit D, a hormone critical for calcium homeostasis and skeletal maintenance. Because the UV action spectra for DNA damage leading to skin cancer and for vit D photosynthesis are virtually identical, the harmful and beneficial effects of UV irradiation are inseparable. This has given rise to the argument that sun avoidance, with a goal of skin cancer prevention, may compromise vit D sufficiency. Public interest in this matter has been heightened in recent years by multiple studies correlating the level of 25-OH vit D, the readily measurable "storage" precursor form of the vit, with a variety of benefits separate from skeletal health. Although the studies are of variable quality and all alleged treatment benefits are based on dietary supplementation with vit D, not on increased sun exposure, they have been interpreted by some as support for advocating increased sun exposure of the public at large. The goal of this review is to provide a detailed, balanced, and referenced discussion of the complex literature underlying the current popular interest in vit D and sun exposure for the purpose of increasing vit D photosynthesis. We review the nomenclature, metabolism, and established functions of vit D; the evidence supporting the less well-established but purported vit D effects; the concept of vit D insufficiency; populations at risk for vit D deficiency; and finally the risk/benefit of obtaining vit D from cutaneous photosynthesis versus diet or supplementation.
    • Tandemly repeated DNA sequence instabilities induced by two promoters of morphological transformation in vitro: a short-term response to non-mutagenic agents in C3H/10T1/2 cells.

      Parfett, Craig L.; Healy, Caroline (2006-04-30)
      The ability of tumour promoters to alter DNA stability within regions that contain tandemly repeated sequences (TRSs), was studied in a cell culture model of multi-stage carcinogenesis. Non-cytotoxic concentrations of TPA (12-O-tetradecanoyl-phorbol-13-acetate) and xanthine oxidase with xanthine substrate, sufficient to promote morphological transformation in C3H/10T1/2 cultures, were tested for their effects on mutation frequencies in TRSs by a DNA fingerprinting approach. Specifically, restriction digests of genomic DNA samples from randomly selected, non-transformed clones, isolated from cultures after several days exposure to promoters, were visualized by Southern hybridizations with the multi-locus pentamer repeat sequence probe, Ms6-Hm (Pc-1). Basal and promoter-induced frequencies of sub-clone TRS fingerprint polymorphisms were estimated in five cell populations: an uncloned stock culture, three populations established from normal-appearing sub-clones, and one clonal population established from a 3-methylcholanthrene (MCA)-transformed focus. Basal variant fingerprint frequencies spanned a range from 0.0 to 0.43% mutants/band among cells from the four untransformed populations. Both TPA and xanthine oxidase treatments significantly increased recorded mutation frequencies, 2.3- and 2.7-fold, respectively, using combined data from the progenitor population and three untransformed clones. The untreated MCA-transformed clonal population appeared to contain a single, pre-existing mutant restriction fragment, but additional mutations were induced thereafter, in response to the promoting treatments. Taken together, the measured increases in mutations were highly significant and suggest that promoters of cell transformation in the C3H/10T1/2 cell line might induce a genome-wide instability targeted to regions containing Ms6-Hm sequence motifs.
    • Does butyrate protect from colorectal cancer?

      Sengupta, Shomik; Muir, Jane G.; Gibson, Peter R. (2006-01)
      Butyrate, the four-carbon fatty acid, is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber), and putatively suppresses colorectal cancer (CRC). Butyrate has diverse and apparently paradoxical effects on cellular proliferation, apoptosis and differentiation that may be either pro-neoplastic or anti-neoplastic, depending upon factors such as the level of exposure, availability of other metabolic substrate and the intracellular milieu. In humans, the relationship between luminal butyrate exposure and CRC has been examined only indirectly in case-control studies, by measuring fecal butyrate concentrations, although this may not accurately reflect effective butyrate exposure during carcinogenesis. Perhaps not surprisingly, results of these investigations have been mutually contradictory. The direct effect of butyrate on tumorigenesis has been assessed in a number of in vivo animal models, which have also yielded conflicting results. In part, this may be explained by methodological differences in the amount and route of butyrate administration, which are likely to significantly influence delivery of butyrate to the distal colon. Nonetheless, there appears to be some evidence that delivery of an adequate amount of butyrate to the appropriate site protects against early tumorigenic events. Future study of the relationship between butyrate and CRC in humans needs to focus on risk stratification and the development of feasible strategies for butyrate delivery.
    • Aflatoxin M1 absorption and cytotoxicity on human intestinal in vitro model.

      Caloni, F.; Stammati, A.; Friggè, G.; De Angelis, I. (2006-03-15)
      Aflatoxin M1 (AFM1) is the principal hydroxylated Aflatoxin B1 (AFB1) metabolite and is detected in milk of mammals, after consumption of feed contaminated with AFB1. As it is classified as probable human carcinogen (group 2B of the IARC), most countries have regulated its maximum allowed levels in milk in order to reduce AFM1 risk (50 ng/kg the EU and 500 ng/kg in the USA). It was demonstrated that if AFB1 must be converted into its reactive epoxide to exert its effects, and the protein binding may play an important role in its cytotoxicity. Conversely, the AFM1 epoxidation in human liver microsomes is very limited and studies with human cell line (MCL5), expressing or not expressing cytochrome P450 enzymes, demonstrated a direct toxic potential of AFM1 in absence of metabolic activation. For this reason, while AFM1 is generally considered a detoxification product of AFB1 relatively to carcinogenicity and mutagenicity property, this is not always true for cytotoxicity activity. Aim of this work is to evaluate the intestinal absorption of AFM1 using a human in vitro model, the Caco-2 cell line. Either the parental Caco-2 cell line or its derived clone TC7, with higher metabolic competence, have been used. They were treated with different concentrations of AFM1, that mirror the milk contamination level (0.3-32 nM corresponding to 10-10,000 ng/kg), either in undifferentiated or in differentiated phase of growth. After 48 h of treatment in serum free medium, a dose dependent absorption of AFM1 has been detected in both cell lines, especially in differentiated cells, while, no appreciable effects on cell viability were observed, except for a general cellular suffering, revealed by LDH release, particularly evident in the undifferentiated cells. As well, no metabolites or AFM1 conjugates have been detected. The present results may be crucial for the evaluation of human risk to AFM1 exposure, in particular for children's population, due to their large use of milk and derivatives.
    • Chemoprevention of photocarcinogenesis by selected dietary botanicals.

      Baliga, Manjeshwar S.; Katiyar, Santosh K. (2006-02)
      Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation as a tumor initiator, tumor promoter and complete carcinogen, and their excessive exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. Sunscreens are useful, but their protection is not adequate to prevent the risk of UV-induced skin cancer. It may be because of inadequate use, incomplete spectral protection and toxicity. Therefore new chemopreventive methods are necessary to protect the skin from photodamaging effects of solar UV radiation. Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of skin carcinogenesis. In recent years, considerable interest has been focused on identifying naturally occurring botanicals, specifically dietary, for the prevention of photocarcinogenesis. A wide variety of botanicals, mostly dietary flavonoids or phenolic substances, have been reported to possess substantial anticarcinogenic and antimutagenic activities because of their antioxidant and antiinflammatory properties. This review summarizes chemopreventive effects of some selected botanicals, such as apigenin, curcumin, grape seed proanthocyanidins, resveratrol, silymarin, and green tea polyphenols, against photocarcinogenesis in in vitro and in vivo systems. Attention has also been focused on highlighting the mechanism of chemopreventive action of these dietary botanicals. We suggest that in addition to the use of these botanicals as dietary supplements for the protection of photocarcinogenesis, these botanicals may favorably supplement sunscreens protection and may provide additional antiphotocarcinogenic protection including the protection against other skin disorders caused by solar UV radiation.
    • Constitutive activation of zebrafish Stat5 expands hematopoietic cell populations in vivo.

      Lewis, Rowena S.; Stephenson, Sarah E. M.; Ward, Alister C. (2006-02)
      OBJECTIVE: Constitutive activation of Stat5 has been observed in a variety of malignancies, particularly myeloid leukemias. To directly investigate the in vivo consequences of Stat5 perturbation, we expressed constitutively active forms in zebrafish. METHODS: We generated mutants of the zebrafish stat5.1 protein (N646H, H298R/N714F, and N714F) based on previously identified constitutively active mutants of murine Stat5a. The in vitro properties of these mutants were determined using phosphorylation-specific antibodies and luciferase reporter assays, and their in vivo effects were analyzed through microinjection of zebrafish embryos. RESULTS: Two of these stat5.1 mutants (N646H and H298R/N714F) showed increased tyrosine phosphorylation and transactivation activity compared to the wild-type protein. Expression of either mutant led to a range of hematological perturbations, which were more pronounced for the H298R/N714F mutant. Interestingly, expression of wild-type also produced generally similar phenotypes. Further analysis showed that expression of the H298R/N714F mutant led to increased numbers of early and late myeloid cells, erythrocytes, and B cells. Some nonhematopoietic developmental perturbations were also observed, but these were equally prominent with wild-type or mutant forms. CONCLUSION: These data implicate Stat5 activity as a direct critical regulator of hematological cell proliferation, suggesting a causal role for constitutively-active Stat5 in the etiology of hematological malignancies.
    • Revisiting the population toxicokinetics of tetrachloroethylene.

      Chiu, Weihsueh A.; Bois, Frédéric Y. (2006-06)
    • Differential expression of molecular markers in arsenic- and non-arsenic-related urothelial cancer.

      Hour, Tzyh-Chyuan; Pu, Yeong-Shiau; Lin, Chia-Chi; Huang, Shi-Wei; Chen, Jun; Chiu, Allen W.; Chen, Chien-Jen; Huang, Chao-Yuan (2009-05-15)
      BACKGROUND: Little is known about the mechanisms of arsenic-related urothelial cancer (AsUC). The aim of this study was to reveal the differential expression of molecular markers between AsUC and non-arsenic-related UC (non-AsUC). MATERIALS AND METHODS: Tissues of AsUC (n=33), non-AsUC (n=20) and normal bladder urothelia from patients with benign diseases (n=4) were examined for multiple selected molecular markers responsible for various cellular functions, includingglutathione, GST-pi, Bcl-2, p53 and c-Fos. RESULTS: The mean cellular glutathione content of normal mucosal samples (33.4 +/- 7.2 microM/mg protein) was significantly higher than either non-AsUC (22.8 +/- 1.8, p = 0.04) or AsUC (16.4 +/- 1.6, p = 0.002). The glutathione content of non-AsUC was higher than that of AsUC (p = 0.012). The expressions of Bcl-2 and c-Fos in AsUC were significantly higher than those in non-AsUC (p = 0.004 and p = 0.02, respectively). CONCLUSION: The carcinogenic pathway for AsUC is different, in part, from that of non-AsUC. Cellular glutathione contents may be down-regulated during urothelial carcinogenesis. Bcl-2 and c-Fos may play important roles in arsenic-mediated carcinogenesis of the urothelium.
    • Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells.

      Buterin, Tonko; Koch, Caroline; Naegeli, Hanspeter (2006-08)
      Estrogen receptors display high levels of promiscuity in accommodating a wide range of ligand structures, but the functional consequence of changing receptor conformations in complex with distinct agonists is highly controversial. To determine variations in the transactivation capacity induced by different estrogenic agonists, we assessed global transcriptional profiles elicited by natural or synthetic xenoestrogens in comparison with the endogenous hormone 17beta-estradiol. Human MCF7 and T47D carcinoma cells, representing the most frequently used model systems for tumorigenic responses in the mammary gland, were synchronized by hormone starvation during 48 h. Subsequently, a 24 h exposure was carried out with equipotent concentrations of the selected xenoestrogens or 17beta-estradiol. Analysis of messenger RNA was performed on high-density oligonucleotide microarrays that display the sequences of 33,000 human transcripts, yielding a total of 181 gene products that are regulated upon estrogenic stimulation. Surprisingly, genistein (a phytoestrogen), bisphenol-A and polychlorinated biphenyl congener 54 (two synthetic xenoestrogens) produced highly congruent genomic fingerprints by regulating the same range of human genes. Also, the monotonous genomic signature observed in response to xenoestrogens is identical to the transcriptional effects induced by physiological concentrations of 17beta-estradiol. This striking functional convergence indicates that the transcription machinery is largely insensitive to the particular structure of estrogen receptor agonists. The occurrence of such converging transcriptional programs reinforces the hypothesis that multiple xenoestrogenic contaminants, of natural or anthropogenic origin, may act in conjunction with the endogenous hormone to induce additive effects in target tissues.
    • Stage matters: choosing relevant model systems to address hypotheses in diet and cancer chemoprevention research.

      Fenton, Jenifer I.; Hord, Norman G. (2006-05)
      Clinical evidence reveals that the efficacy of dietary factors to prevent cancer is probably stage-dependent. The ability to demonstrate stage-specific effects of dietary compounds on normal, preneoplastic and malignant cell models may provide insights into puzzling clinical results from cancer chemoprevention trials. The relevance of these models to the field of cancer prevention is immense and will undoubtedly facilitate the ability to discover which dietary factors are most effective at preventing cancer and which, if any, specific steps in neoplastic transformation render cells refractory to the effects of dietary compounds. There are illustrative examples where exposure of high-risk individuals to dietary chemopreventive agents increases rather than decreases cancer risk. While geneticists and clinical oncologists acknowledge the morphological continuum along which tumors develop in specific tissues, tumor cells, rather than normal and preneoplastic cells, continue to be the primary in vitro reductionist tool employed to elucidate mechanisms underlying disease progression and to investigate the potential utility of dietary as well as other chemopreventive agents. Currently, there are few relevant model systems to study the progression of neoplastic transformation, especially in epithelial cells. We highlight examples of model systems isolated from prostate, breast, endometrial and intestinal tissue, with special emphasis on a specific set of non-tumorigenic, conditionally immortal cell lines derived from C57/BL6 mice [YAMC (Young Adult Mouse Colon cells; Apc+/+) cells and IMCE (Immorto-Min Colonic Epithelium cells; ApcMin/+) cells] that have yielded important information on early events in colorectal neoplasia development. These cell lines are an illustrative example of how researchers can examine stage-dependent effects of specific dietary components on carcinogenesis. The utilization of cell culture systems modeling early, middle and late stages of tumorigenesis will yield important insights into mechanisms by which dietary components impact cancer progression.
    • Cytological value of sputum in workers daily exposed to air pollution.

      Alderisio, Mauro; Cenci, Maria; Mudu, Pierpaolo; Vecchione, Aldo; Giovagnoli, Maria Rosaria (2009-05-15)
      In this study, quantitative modifications of dust cells, siderocytes, Curschmann's spirals and asbestos bodies and qualitative modifications (cellular changes and inflammatory infiltrate) in the sputum of 164 traffic police officers and 218 railway workers, occupationally exposed to environmental pollution, and the sputum of 119 inhabitants of a rural area, were evaluated. The results were correlated with time of exposure and smoking habits. Seventy-three (45%) traffic police officers (TPO), 76 (35%) railway workers (RW) and 29 (24%) of the rural population (RP) were smokers. The sputum, collected over a 3-day period, was smeared on glass slides and stained according to the Papanicolaou, Perl and yellow eosin methods. The results of the qualitative cytological diagnosis revealed a statistically significant difference between the TPO, RW and the RP (p < 0.001). The results of the qualitative and quantitative cytological examinations were not significantly correlated to time of occupational exposure, which was considered to be a continuous variable. The qualitative cytological examination of sputa was not statistically significant for the smoking habits of the TPO and the RP, but was significant for the RW (p < 0.0067). In the TPO, the number of dust cells was higher in smokers, and the relative risk (RR) was 3.95. In the RW, the RR was 2.84. The results of our study revealed that for the RW, the qualitative-quantitative cytological alterations in sputum were due much more to smoking habits than to occupational exposure, while the presence of asbestos bodies correlated with work activity. The qualitative-quantitative cytological examinations of the TPO differed significantly from that of the other two populations.
    • Allyl sulfur compounds from garlic modulate aberrant crypt formation.

      Ross, Sharon A.; Finley, John W.; Milner, John A. (2006-03)
      The health benefits of garlic, including inhibition of carcinogenesis, are supported by several epidemiologic and laboratory findings. Garlic's sulfur components have been reported to suppress experimentally induced tumor incidence in several organs, including the colon. Studies in humans also suggest that dietary garlic constituents reduce the risk of colorectal adenomatous polyps, which are considered precursors to colon cancer. Aberrant crypt foci (ACF) are proposed to be early preneoplastic lesions of adenoma-carcinoma in humans and chemically induced colon cancer in rodents. In preclinical studies, both water- and lipid-soluble allyl sulfur compounds arising from processed garlic inhibited ACF. The response to these allyl sulfur compounds appears to depend on several factors, including the speciation, quantity, and duration provided.