segunda-feira, 1 de março de 2010

Estudos nutrição e cancro da mama

 Cancer systems biology: a network modeling perspective

Pamela K. Kreeger and Douglas A. Lauffenburger1,* Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
1 Department of Biological Engineering, Massachusetts Institute of Technology, Building 16, Room 343, 77 Massachusetts Avenue, Cambridge, MA 02139, USA

* To whom correspondence should be addressed. Tel: ; Fax: +1 617 258 0204; Email:
Cancer is now appreciated as not only a highly heterogenous pathology with respect to cell type and tissue origin but also as a disease involving dysregulation of multiple pathways governing fundamental cell processes such as death, proliferation, differentiation and migration. Thus, the activities of molecular networks that execute metabolic or cytoskeletal processes, or regulate these by signal transduction, are altered in a complex manner by diverse genetic mutations in concert with the environmental context. A major challenge therefore is how to develop actionable understanding of this multivariate dysregulation, with respect both to how it arises from diverse genetic mutations and to how it may be ameliorated by prospective treatments. While high-throughput experimental platform technologies ranging from genomic sequencing to transcriptomic, proteomic and metabolomic profiling are now commonly used for molecular-level characterization of tumor cells and surrounding tissues, the resulting data sets defy straightforward intuitive interpretation with respect to potential therapeutic targets or the effects of perturbation. In this review article, we will discuss how significant advances can be obtained by applying computational modeling approaches to elucidate the pathways most critically involved in tumor formation and progression, impact of particular mutations on pathway operation, consequences of altered cell behavior in tissue environments and effects of molecular therapeutics.

Abbreviations: EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; TNF{alpha}, tumor necrosis factor {alpha}
Received August 19, 2009; revised October 17, 2009; accepted October 18, 2009.

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Telomeres and telomerase in cancer

Steven E. Artandi* and Ronald A. DePinho1,* Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
1 Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

* To whom correspondence should be addressed. Email: or
Myriad genetic and epigenetic alterations are required to drive normal cells toward malignant transformation. These somatic events commandeer many signaling pathways that cooperate to endow aspiring cancer cells with a full range of biological capabilities needed to grow, disseminate and ultimately kill its host. Cancer genomes are highly rearranged and are characterized by complex translocations and regional copy number alterations that target loci harboring cancer-relevant genes. Efforts to uncover the underlying mechanisms driving genome instability in cancer have revealed a prominent role for telomeres. Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and are particularly vulnerable due to progressive shortening during each round of DNA replication and, thus, a lifetime of tissue renewal places the organism at risk for increasing chromosomal instability. Indeed, telomere erosion has been documented in aging tissues and hyperproliferative disease states—conditions strongly associated with increased cancer risk. Telomere dysfunction can produce the opposing pathophysiological states of degenerative aging or cancer with the specific outcome dictated by the integrity of DNA damage checkpoint responses. In most advanced cancers, telomerase is reactivated and serves to maintain telomere length and emerging data have also documented the capacity of telomerase to directly regulate cancer-promoting pathways. This review covers the role of telomeres and telomerase in the biology of normal tissue stem/progenitor cells and in the development of cancer.

Abbreviations: acd, adrenocortical dysplasia; aCGH, array comparative genome hybridization; APC, adenomatous polyposis coli; ATM, ataxia telangiectasia mutated; CNA, copy number alterations; DC, dyskeratosis congenita; min, multiple intestinal neoplasia; POT1, protection of telomeres 1; scaRNA, small Cajal body-specific RNA; snoRNA, small nucleolar RNA; TCAB1, telomerase Cajal body protein 1; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TRF1, telomeric repeat binding factor 1; TRF2, telomeric repeat binding factor 2
Received September 25, 2009; revised October 27, 2009; accepted October 27, 2009.

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Senescence: an antiviral defense that is tumor suppressive?

Roger R. Reddel1,2,* 1 Cancer Research Unit, Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, New South Wales 2145, Australia
2 Sydney Medical School, University of Sydney, New South Wales 2006, Australia

* To whom correspondence should be addressed. Tel: +61 2 8865 2901; Fax: +61 2 8865 2860;Email:
Normal mammalian somatic cells proliferate a finite number of times in vitro before permanently withdrawing from the cell cycle into a cellular state referred to as senescence. Senescence may be triggered by excessive mitogenic stimulation or by various forms of cellular damage including excessive telomere shortening. Over the past decade, there has been continuing accumulation of evidence that senescence occurs in vivo, that it is relevant to aging and that it has a tumor suppressor function. However, the phenotype of senescence has also been found to include a number of puzzling features, including the secretion of proinflammatory factors that may foster tumorigenesis as well as the senescence of neighboring cells. On the basis of these antagonistic pro- and antitumorigenic effects, and of the observation that many viruses have developed proteins that prevent senescence of the cells they infect, it is argued that the primary function of senescence may have been as an antiviral defense mechanism. Recent progress in understanding how tumor cells evade senescence is also reviewed here.

Abbreviations: ALT, alternative lengthening of telomeres; PML, promyelocytic leukemia; Rb, retinoblastoma; RNP, ribonucleoprotein; SA, senescence-associated; SAHF, senescence-associated heterochromatin foci; TERC, telomerase RNA Component; TERT, telomerase reverse transcriptase; TMM, telomere length maintenance mechanism
Received October 30, 2009; revised October 30, 2009; accepted October 30, 2009.

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Epigenetics in cancer

Shikhar Sharma1,2, Theresa K. Kelly1 and Peter A. Jones1,* 1 Department of Urology, Biochemistry and Molecular Biology
2 Department of Genetics, Molecular and Cellular Biology, USC/Norris Comprehensive Cancer Center Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9181, USA

* To whom correspondence should be addressed: Tel: +1 323 865 0816; Fax: +1 323 865 0102; Email:
Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.

Abbreviations: DNMT, DNA methyltransferase; ES, embryonic stem; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDM, histone demethylase; HMT, histone methyltransferase; LOI, loss of imprinting; miRNA, microRNA; NFR, nucleosome-free region; NuRD, nucleosome remodeling and deacetylase
Received August 14, 2009; revised September 1, 2009; accepted September 3, 2009.

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Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways

Aaron J. Schetter1, Niels H. H. Heegaard1,2 and Curtis C. Harris1,* 1 Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
2 Department of Clinical Biochemistry and Immunology, Statens Serum Institute, Copenhagen, DK-2300, Denmark

* To whom correspondence should be addressed. Tel: +1 301 496 2048; Fax: +1 301 496 0497; Email:
Chronic inflammation and infection are major causes of cancer. There are continued improvements to our understanding of the molecular connections between inflammation and cancer. Key mediators of inflammation-induced cancer include nuclear factor kappa B, reactive oxygen and nitrogen species, inflammatory cytokines, prostaglandins and specific microRNAs. The collective activity of these mediators is largely responsible for either a pro-tumorigenic or anti-tumorigenic inflammatory response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. As our understanding grows, inflammatory mediators will provide opportunities to develop novel diagnostic and therapeutic strategies. In this review, we provide a general overview of the connection between inflammation, microRNAs and cancer and highlight how our improved understanding of these connections may provide novel preventive, diagnostic and therapeutic strategies to reduce the health burden of cancer.

Abbreviations: CLL, chronic lymphocytic leukemia; COX-2, cyclooxygenase-2; IFN, interferon; IL, interleukin; KRAS, kirsten rat sarcoma oncogene; LPS, lipopolysaccharide; NF{kappa}B, nuclear factor kappa B; NO, nitric oxide; NOS, nitric oxide synthase; NSAIDs, non-steroidal, anti-inflammatory drugs; p53, protein 53; PGs, prostaglandins; RAS, rat sarcoma oncogene; RISC, RNA-induced silencing complex; RONS, reactive oxygen and nitrogen species; TGFβ, transforming growth factor; TNF, tumor necrosis factor; UTR, untranslated region
Received September 22, 2009; revised October 29, 2009; accepted October 29, 2009.

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Chemical biology of mutagenesis and DNA repair: cellular responses to DNA alkylation

Nidhi Shrivastav1,2, Deyu Li1,2 and John M. Essigmann1,2,* 1 Department of Biological Engineering
2 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

* To whom correspondence should be addressed. Tel: +1 6172536227; Fax: +1 6172535445; Email:
The reaction of DNA-damaging agents with the genome results in a plethora of lesions, commonly referred to as adducts. Adducts may cause DNA to mutate, they may represent the chemical precursors of lethal events and they can disrupt expression of genes. Determination of which adduct is responsible for each of these biological endpoints is difficult, but this task has been accomplished for some carcinogenic DNA-damaging agents. Here, we describe the respective contributions of specific DNA lesions to the biological effects of low molecular weight alkylating agents.

Abbreviations: AAG, human 3-methyladenine-DNA glycosylase; AP site, apurinic site; BER, base excision repair; dAMP, deoxyadenosine monophosphate; dCMP, deoxycytidine monophosphate; dGMP, deoxyguanosine monophosphate; dNMP, deoxynucleoside monophosphate; dTTP, deoxythymidine triphosphate; EA, 1,N6-ethanoadenine; eA, 1,N6-ethenoadenine; eC, 3,N4-ethenocytosine; 1EtA, N1-ethyladenine; 3EtC, N3-ethylcytosine; Fapy, formamidopyrimidine; 1MeA, N1-methyladenine; 3MeA, N3-methyladenine; 7MeA, N7-methyladenine; 3MeC, N3-methylcytosine; 1MeG, N1-methylguanine; 3MeG, N3-methylguanine; 7MeG, N7-methylguanine; 8MeG, 8-methylguanine; MePT, methylphosphotriester; 3MeT, N3-methylthymine; MGMT, O6-methylguanine-DNA methyltransferase; MMR, mismatch repair; MMS, methylmethanesulfonate; MNNG, N-methyl-N'-nitro-N-nitrosoguanidine; MNU, N-methyl-N-nitrosourea; MGP, N-methylpurine-DNA glycosylase; NER, nucleotide excision repair; O6EtG, O6-ethylguanine; O6MeG, O6-methylguanine; O4MeT, O4-methylthymine; SAM, S-adenosylmethionine; TAG, 3-methyladenine-DNA glycosylase I
Received August 19, 2009; revised October 20, 2009; accepted October 21, 2009.

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Mycotoxins and human disease: a largely ignored global health issue

Christopher P. Wild* and Yun Yun Gong1 International Agency for Research on Cancer, 69372 Lyon Cedex 08, France
1 Molecular Epidemiology Unit, LIGHT Laboratories, University of Leeds, Leeds, LS2 9JT, UK

* To whom correspondence should be addressed. Tel: +33 (0) 4 72 73 84 85; Fax: +33 (0) 4 72 73 85 64; Email:
Aflatoxins and fumonisins (FB) are mycotoxins contaminating a large fraction of the world's food, including maize, cereals, groundnuts and tree nuts. The toxins frequently co-occur in maize. Where these commodities are dietary staples, for example, in parts of Africa, Asia and Latin America, the contamination translates to high-level chronic exposure. This is particularly true in subsistence farming communities where regulations to control exposure are either non-existent or practically unenforceable. Aflatoxins are hepatocarcinogenic in humans, particularly in conjunction with chronic hepatitis B virus infection, and cause aflatoxicosis in episodic poisoning outbreaks. In animals, these toxins also impair growth and are immunosuppressive; the latter effects are of increasing interest in human populations. FB have been reported to induce liver and kidney tumours in rodents and are classified as Group 2B ‘possibly carcinogenic to humans’, with ecological studies implying a possible link to increased oesophageal cancer. Recent studies also suggest that the FB may cause neural tube defects in some maize-consuming populations. There is a plausible mechanism for this effect via a disruption of ceramide synthase and sphingolipid biosynthesis. Notwithstanding the need for a better evidence-base on mycotoxins and human health, supported by better biomarkers of exposure and effect in epidemiological studies, the existing data are sufficient to prioritize exposure reduction in vulnerable populations. For both toxins, there are a number of practical primary and secondary prevention strategies which could be beneficial if the political will and financial investment can be applied to what remains a largely and rather shamefully ignored global health issue.

Abbreviations: AFB1-N7-Gua, 8,9-dihydro-8-(N7-guanyl)-9-hydroxy AFB1; CYP, cytochrome P450; FAPY, formamidopyrimidine; FB, fumonisins; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HBx, hepatitis B x; HCC, hepatocellular carcinoma; LC-MS, liquid chromatography-mass spectrometry; NTD, neural tube defect; OC, oesophageal cancer; OR, odds ratio
Received October 13, 2009; revised October 18, 2009; accepted October 22, 2009.

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Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research

Stephen D. Hursting1,2,*, Sarah M. Smith1, Laura M. Lashinger1,2, Alison E. Harvey1 and Susan N. Perkins1 1 Department of Nutritional Sciences, The University of Texas at Austin, 103 West 24th Street, Austin, TX 78712,USA
2 Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Smithville, TX 78957, USA

* To whom correspondence should be addressed. Tel: +1 512 971 2809; Fax: +1 512 471 4661;Email:
Calorie restriction (CR) is arguably the most potent, broadly acting dietary regimen for suppressing the carcinogenesis process, and many of the key studies in this field have been published in Carcinogenesis. Translation of the knowledge gained from CR research in animal models to cancer prevention strategies in humans is urgently needed given the worldwide obesity epidemic and the established link between obesity and increased risk of many cancers. This review synthesizes the evidence on key biological mechanisms underlying many of the beneficial effects of CR, with particular emphasis on the impact of CR on growth factor signaling pathways and inflammatory processes and on the emerging development of pharmacological mimetics of CR. These approaches will facilitate the translation of CR research into effective strategies for cancer prevention in humans.

Abbreviations: AMPK, adenosine monophosphate-activated kinase; ATP, adenosine triphosphate; CR, calorie restriction; IGF, insulin-like growth factor; IL, interleukin; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PPAR, peroxisome proliferators-activated receptor; SIRT1, silent mating type information regulation homolog; TNF-{alpha}, tumor necrosis factor-alpha; TSC, tuberous sclerosis complex
Received September 28, 2009; revised November 3, 2009; accepted November 3, 2009.

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Nrf2: friend or foe for chemoprevention?

Thomas W. Kensler1,2,3,* and Nobunao Wakabayashi1,3 1 Department of Environmental Health Sciences, Bloomberg School of Public Health
2 Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA
3 Present address: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA

* To whom correspondence should be addressed. Tel: +410 955 1292; Fax: +410 955 0119; Email:
Health reflects the ability of an organism to adapt to stress. Stresses—metabolic, proteotoxic, mitotic, oxidative and DNA-damage stresses—not only contribute to the etiology of cancer and other chronic degenerative diseases but are also hallmarks of the cancer phenotype. Activation of the Kelch-like ECH-associated protein 1 (KEAP1)–NF-E2-related factor 2 (NRF2)-signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whilst disruption of the pathway exacerbates these outcomes. This pathway can be induced by thiol-reactive small molecules that demonstrate protective efficacy in preclinical chemoprevention models and in clinical trials. However, mutations and epigenetic modifications affecting the regulation and fate of NRF2 can lead to constitutive dominant hyperactivation of signaling that preserves rather than attenuates cancer phenotypes by providing selective resistance to stresses. This review provides a synopsis of KEAP1–NRF2 signaling, compares the impact of genetic versus pharmacologic activation and considers both the attributes and concerns of targeting the pathway in chemoprevention.

Abbreviations: ARE, antioxidant response element; BHT, butylated hydroxytoluene; CDDO-Im, 1-(2-cyano-3,12-dioxooleana-1,9[11]-dien-28-oyl)imidazole; GST, glutathione S-transferase; KEAP1, Kelch-like ECH-associated protein 1; NQO1, NAD(P)H: quinone oxidoreductase 1; NRF2, NF-E2-related factor 2; oltipraz, 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione; sulforaphane, (-)-1-isothiocyanato-(4R)-methylsulfinyl)butane; ROS, reactive oxygen species
Received September 2, 2009; revised September 16, 2009; accepted September 18, 2009.

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The global burden of cancer: priorities for prevention

Michael J. Thun*, John Oliver DeLancey, Melissa M. Center, Ahmedin Jemal and Elizabeth M. Ward American Cancer Society, Research Department, 250 Williams Street, Northwest, Atlanta, GA 30303-1002, USA
* To whom correspondence should be addressed. Tel: +1 404 329 5747; Fax: +1 404 327 6450; Email:
Despite decreases in the cancer death rates in high-resource countries, such as the USA, the number of cancer cases and deaths is projected to more than double worldwide over the next 20–40 years. Cancer is now the third leading cause of death, with >12 million new cases and 7.6 million cancer deaths estimated to have occurred globally in 2007 (1). By 2030, it is projected that there will be ~26 million new cancer cases and 17 million cancer deaths per year. The projected increase will be driven largely by growth and aging of populations and will be largest in low- and medium-resource countries. Under current trends, increased longevity in developing countries will nearly triple the number of people who survive to age 65 by 2050. This demographic shift is compounded by the entrenchment of modifiable risk factors such as smoking and obesity in many low-and medium-resource countries and by the slower decline in cancers related to chronic infections (especially stomach, liver and uterine cervix) in economically developing than in industrialized countries. This paper identifies several preventive measures that offer the most feasible approach to mitigate the anticipated global increase in cancer in countries that can least afford it. Foremost among these are the need to strengthen efforts in international tobacco control and to increase the availability of vaccines against hepatitis B and human papilloma virus in countries where they are most needed.

Abbreviations: EBV, Epstein Barr virus; FCTC, Framework Convention on Tobacco Control; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HAART, highly active antiretroviral therapy; HHV-8, human herpes virus 8; HIV, human immunodeficiency virus; HPV, human papilloma virus; KS, Kaposi’s sarcoma; NHL, non-Hodgkin’s lymphoma; WHO, World Health Organization
Received September 16, 2009; revised October 20, 2009; accepted October 20, 2009.

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Genome-wide association studies in cancer—current and future directions

Charles C. Chung1, Wagner C. S. Magalhaes1,2, Jesus Gonzalez-Bosquet1 and Stephen J. Chanock1,* 1 Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, 20892-4608, USA
2 Departamento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, CEP 31270-910, Belo Horizonte, MG, Brazil

* To whom correspondence should be addressed. Tel: +1 301 435 7559; Fax: +1 301 402 3134; Email:
Genome-wide association studies (GWAS) have emerged as an important tool for discovering regions of the genome that harbor genetic variants that confer risk for different types of cancers. The success of GWAS in the last 3 years is due to the convergence of new technologies that can genotype hundreds of thousands of single-nucleotide polymorphism markers together with comprehensive annotation of genetic variation. This approach has provided the opportunity to scan across the genome in a sufficiently large set of cases and controls without a set of prior hypotheses in search of susceptibility alleles with low effect sizes. Generally, the susceptibility alleles discovered thus far are common, namely, with a frequency in one or more population of >10% and each allele confers a small contribution to the overall risk for the disease. For nearly all regions conclusively identified by GWAS, the per allele effect sizes estimated are <1.3. Consequently, the findings of GWAS underscore the complex nature of cancer and have focused attention on a subset of the genetic variants that comprise the genomic architecture of each type of cancer, which already can differ substantially by the number of regions associated with specific types of cancer. For instance, in prostate cancer, there could be >30 distinct regions harboring common susceptibility alleles identified by GWAS, whereas in lung cancer, a disease strongly driven by exposure to tobacco products, so far, only three regions have been conclusively established. To date, >85 regions have been conclusively associated in over a dozen different cancers, yet no more than five regions have been associated with more than one distinct cancer type. GWAS are an important discovery tool that require extensive follow-up to map each region, investigate the biological mechanism underpinning the association and eventually test the optimal markers for assessing risk for a disease or its outcome, such as in pharmacogenomics, the study of the effect of genetic variation on pharmacological interventions. The success of GWAS has opened new horizons for exploration and highlighted the complex genomic architecture of disease susceptibility.

Abbreviations: CNV, copy number variation; GWAS, genome-wide association studies; LD, linkage disequilibrium; MAF, minor allele frequency; PSA, prostate serum antigen; SNP, single-nucleotide polymorphism
Received October 30, 2009; revised October 30, 2009; accepted October 30, 2009.

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Biomarkers in cancer epidemiology: an integrative approach

Paolo Boffetta* International Prevention Research Institute, 95 cours Lafayette, 69006 Lyon, France
* To whom correspondence should be addressed. Tel: +33 658386724; Fax: +33 472387126; Email:
There are different reasons for the increase in the use of biomarkers in cancer epidemiology which is as follows: (i) the fact that the identification of new carcinogens, characterized by complex exposure circumstances and weak effects, has become increasingly difficult with traditional epidemiological approaches; (ii) the increasing understanding of mechanisms of carcinogenesis and (iii) technical developments in molecular biology and genetics. While a distinction is made between biomarkers of exposure, intermediate events, disease, outcome and susceptibility, their integration in a unique conceptual model is needed. The use of exposure biomarkers in cancer epidemiology aims at measuring the biologically relevant exposure more validly and precisely. In some instances, there is an obvious improvement in using an exposure biomarker, as in the case of urinary markers of aflatoxin and tobacco-specific nitrosamines. Intermediate (effect) biomarkers measure early—in general non-persistent—biological events that take place in the continuum between exposure and cancer development. These include cellular or tissue toxicity, chromosomal alterations, changes in DNA, RNA and protein expression and alterations in functions relevant to carcinogenesis (e.g. DNA repair, immunological response, etc.). The analysis of acquired TP53 mutations is an example of the potentially important. Biomarkers should be validated and consideration of sources of bias and confounding in molecular epidemiology studies should be no less stringent than in other types of epidemiological studies. The overarching goal is the integration of different types of biomarkers to derive risk and outcome profiles for healthy individuals as well as patients.
Received October 7, 2009; revised October 24, 2009; accepted October 27, 2009.

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The evolving discipline of molecular epidemiology of cancer

Margaret R. Spitz and Melissa L. Bondy Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +1 713 792 3020; Fax: +1 713 745 1165. Email:
Classical epidemiologic studies have made seminal contributions to identifying the etiology of most common cancers. Molecular epidemiology was conceived of as an extension of traditional epidemiology to incorporate biomarkers with questionnaire data to further our understanding of the mechanisms of carcinogenesis. Early molecular epidemiologic studies employed functional assays. These studies were hampered by the need for sequential and/or prediagnostic samples, viable lymphocytes and the uncertainty of how well these functional data (derived from surrogate lymphocytic tissue) reflected events in the target tissue. The completion of the Human Genome Project and Hapmap Project, together with the unparalleled advances in high-throughput genotyping revolutionized the practice of molecular epidemiology. Early studies had been constrained by existing technology to use the hypothesis-driven candidate gene approach, with disappointing results. Pathway analysis addressed some of the concerns, although the study of interacting and overlapping gene networks remained a challenge. Whole-genome scanning approaches were designed as agnostic studies using a dense set of markers to capture much of the common genome variation to study germ-line genetic variation as risk factors for common complex diseases. It should be possible to exploit the wealth of these data for pharmacogenetic studies to realize the promise of personalized therapy. Going forward, the temptation for epidemiologists to be lured by high-tech ‘omics’ will be immense. Systems Epidemiology, the observational prototype of systems biology, is an extension of classical epidemiology to include powerful new platforms such as the transcriptome, proteome and metabolome. However, there will always be the need for impeccably designed and well-powered epidemiologic studies with rigorous quality control of data, specimen acquisition and statistical analysis.

Abbreviations: CBMN, cytokinesis-block micronucleus; DRC, DNA repair capacity; GWA, genome-wide association; IARC, International Agency for Research on Cancer; LD, linkage disequilibrium; miRNA, microRNA; MN, micronuclei; NPB, nucleoplasmic bridge; SNP, single-nucleotide polymorphism
Received August 24, 2009; revised October 2, 2009; accepted October 3, 2009.


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A minha fotografia

Luis Guerreiro
* Integrando a equipe de preparação dos vários Detoxes de Tony Samara - Portugal - 2009
* Consultor de Alimentação Viva do Spa Natural Alma Verde - Foz do Iguaçu-PR - Junho, Julho 2008.
* Apresentação de pratos vivos - 23º Congresso Internacional de Educação Física - FIEP 2008 - Foz do Iguaçu/PR
* Consultor e Árbitro da FDAP - Federação de Desportos Aquáticos do Paraná - Novembro de 2007 a Maio 2008 - Foz do Iguaçu-PR
* Criação do Instituto IDEIAS - Foz do Iguaçu - Outubro de 2007.
* Palestras de educação Nutriconal e Administração dos Serviços de Alimentação. - IPEC. Instituto de Permacultura e Ecovilas do Cerrado. Pirenópolis. Goiás.
Aula introdutória sobre alimentação e Nutrição para participantes do curso de Ecovilas e administração junto a uma equipe, dos serviços de alimentação fornecidos durante os sete dias de curso. Início: Outubro de 2007.
* Curso de Alimentação Viva- Restaurante Girassol - Ros Ellis Moraes (nutricionista) e Jacqueline Stefânia (nutricionista) - Agosto de 2007 - Brasilia-DF
* Palestras de educação Nutriconal e Administração dos Serviços de Alimentação.
IPEC - Instituto de Permacultura e Ecovilas do Cerrado. Pirenópolis. Goiás.
Actuação: Aula introdutória sobre alimentação e Nutrição para participantes do curso do SEBRAE e administração junto a uma equipe, dos serviços de alimentação fornecidos durante os sete dias de curso - Agosto de 2007. Com Jacqueline Stefânia (nutricionista)
* Administração dos Serviços de Alimentação.
IPEC - Instituto de Permacultura e Ecovilas do Cerrado. Pirenópolis. Goiás.
Atuação: Curso Bioconstruindo - administração junto a uma equipe, dos serviços de alimentação fornecidos durante os dias de curso.
BIOCONSTRUINDO - Julho 2007 - Com Jacqueline Stefânia (nutricionista)
* Palestra sobre Alimentação Viva - Maçonaria - Julho 2007 - Belo Horizonte-MG - Com Jacqueline Stefânia (nutricionista)
* Oficina de Alimentação Viva "Nutriviva" com a Nutricionista Jacqueline Stefânia Pereira e a professora de Hatha Yoga, Ana Virgínia de Azevedo e Souza - Junho 2007 - Belo Horizonte -MG
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